Lisa K. Cannada-Orthopaedic Knowledge Update 11-American Academy of Orthopaedic Surgeons (2014) PDF

Orthopaedic
Knowledge
Update
Editor
Lisa K. Cannada, MD
DVD-VIDEO INSIDE
e
Orthopaedic
Knowledge
Update
e
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs k eers
rs
b o ook
o b o ook
o b o oo
o
/
e e
/ e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
. m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eerrss
b o ook
o b ooook b oooo
/
e e
/ e b ee/e/e b e/
e e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
e rrss e rrss
/ e
/ bb
e
ooooOrthopaedic
kk e
e /e/ebbooookk e
e/ e
/ b
e
o
booo
e t . m m e t . m m e
Knowledge hhtttp
s
tps: /
: /
/ / t .
hhtttp
tpss: /
: /
/ / t .
/
e e
/ bb
e
oooUpdate
okkeers
rs
ee/e/e
o
bb o
o
k
o
e
k
r
e s
r s
e/
e e
/ b
e
o
booo
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
EDITOR: t
hht
Lisa K. Cannada, MD
t t
hht t
Associate Professor
Department of Orthopaedic Surgery
rs
rs
Saint Louis University
k ee k eerrss
b o ook
o
St. Louis, Missouri
b ooook b oooo
/
e e
/ e b ee/e/e b e/
e e
/ eb
: / t
///t. m
. m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t
Joshua J. Jacobs, MD m
AAOS Board of Directors, 2013-2014
. .m : / t
///t. m
. m
The material presented in Orthopaedic Knowledge
s
tps : s
tps :
hhtttp hhtttp
President Update 11 has been made available by the American
Academy of Orthopaedic Surgeons for educational
Frederick M. Azar, MD
purposes only. This material is not intended to
First Vice President
present the only, or necessarily best, methods or
David D. Teuscher, MD procedures for the medical situations discussed,
Second Vice President but rather is intended to represent an approach,
k eers
rs John R. Tongue, MD
k eers
r s view, statement, or opinion of the author(s) or
producer(s), which may be helpful to others who
ook ook
Past President
b oo Andrew N. Pollak, MD
b oo
face similar situations.
b o oo
o
/
e e
/ eb Treasurer
e/
e e
/ e b ee/ e
/ e b
Some drugs or medical devices demonstrated in
Academy courses or described in Academy print
Annunziato Amendola, MD
: // t/.tm
. m t . m
. m
or electronic publications have not been cleared by
: / / / t
s
William J. Best
s : / ss /
the Food and Drug Administration (FDA) or have
:
hhtttp hhtttp
been cleared for specific uses only. The FDA has
tp
Joseph A. Bosco III, MD
Matthew B. Dobbs, MD tp
stated that it is the responsibility of the physician to
determine the FDA clearance status of each drug or
device he or she wishes to use in clinical practice.
Wilford K. Gibson, MD
David A. Halsey, MD Furthermore, any statements about commercial
rrss rrss
David Mansfield, MD products are solely the opinion(s) of the author(s)
o ke
ke John J. McGraw, MD
o k e
k e
and do not represent an Academy endorsement
oo
or evaluation of these products. These statements
e bboo o Todd A. Milbrandt, MD

e b o
b o o e b o o
may not be used in advertising or for any com-
b
/
e / e Steven D.K. Ross, MD
m ee/ / e mercial purpose.
m ee/ / e
David C. Templeman, MD
: / /
/ t
/ .
t . m : / /t/.t .m
All rights reserved. No part of this publication
may be reproduced, stored in a retrieval system,
/
s :
Karen L. Hackett, FACHE, CAE
s ss :
hhtttp hhtttp
or transmitted, in any form, or by any means, elec-
(Ex-officio)
tp tp
tronic, mechanical, photocopying, recording, or
otherwise, without prior written permission from
the publisher.
Staff
Ellen C. Moore, Chief Education Officer Published 2014 by the
Hans Koelsch, PhD, Director, Department of American Academy of Orthopaedic Surgeons
k eers
rs Publications
k e r
e s
r s
6300 North River Road
bboooo k Lisa Claxton Moore, Managing Editor
b o o
o o k Rosemont, IL 60018
b o oo
o
/
e e
/ e
Kathleen A. Anderson, Senior Editor
Steven Kellert, Senior Editor
ee/ e
/ e b Copyright 2014
e / e
/ e b
by the American Academy of Orthopaedic
e
: / / t . m
. m
Mary Steermann Bishop, Senior Manager,
/ t
Surgeons
: / / t
/ .
t m
. m
ss : /
Production and Content Management
t p p t p ss
p : /
ISBN 978-0-89203-865-7
t
hht t
Courtney Astle, Editorial Production Manager
Abram Fassler, Publishing Systems Manager t
hht t
Library of Congress Control Number:
2013955807
Suzanne O’Reilly, Graphic Designer Printed in the USA
Susan Morritz Baim, Production Coordinator
Karen Danca, Permissions Coordinator
k eers
rs Michelle Wild, Editorial Coordinator
k eers
r s
b ooook Charlie Baldwin, Production Database
b oook
o b oooo
/
e e
/ eb Associate
ee/ e
/e b
Hollie Muir, Production Database Associate
ee/e/e b
: / t . m
. m
Emily Nickel, Page Production Assistant
///t : / t.
///t m
.m
s
tps : s
tps :
iv
hhtttp
© 2014 American Academy of Orthopaedic Surgeons
hhtttp Orthopaedic Knowledge Update 11
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
sAcknowledgments s
k eerrs keerrs
b ooook b o ook
o b o oo
o
/
ee/e b Editorial Board,
ee/ e
/ e b ee/ e
/ e b
: / ///t . m
.m
Orthopaedic Knowledge Update 11
t : / t
///t. m
. m
s :
LISA K. CANNADA, MD
tps s :
TODD A. MILBRANDT, MD
tps
hhtttp hhtttp
Associate Professor Program Director
Department of Orthopaedic Surgery Department of Orthopaedics
Saint Louis University University of Kentucky
St. Louis, Missouri Lexington, Kentucky
k eers
rs MITCHEL B. HARRIS, MD, FACS
Professor, Orthopaedic Surgery
k eers
r s
SAAM MORSHED, MD, PHD, MPH
Assistant Professor
b ooook Department of Orthopaedic Surgery
b ooook
Department of Orthopedic Surgery
b o oo
o
/
e e
/ eb Brigham and Women’s Hospital
Boston, Massachusetts
e/
e e
/ e b Orthopedic Trauma Institute
e / e
/ e b
University of California, San Francisco
e
: // t/.tm
. m San Francisco, California
: / / t
/ .
t m
. m
WILLIAM N. LEVINE, MD
ss : / ss : /
hhtttp
tp hhtttp
tp
Professor of Orthopaedic Surgery JAVAD PARVIZI, MD, FRCS
Department of Orthopaedics Professor of Orthopaedics
Columbia University Department of Orthopaedic Surgery
New York, New York The Rothman Institute at Thomas Jefferson
University
Philadelphia, Pennsylvania
rrss rrss
FRANK A. LIPORACE, MD
o ke
ke
Associate Professor
Director of Orthopaedic Research
o k e
k e oo
e bboo o New York University Hospital for Joint
e b o
b o
KRISTY L. WEBER, MD
o e b
Professor and Vice Chair of Orthopaedic o
b o
/
e / e Diseases
New York, New York
m ee/ / e Surgery
m ee/ / e
: / /
/ t
/ .
t . m Orthopaedics
: / /t/.t .m
University of Pennsylvania Department of
/
ss : ss :
hhtttp hhtttp
THEODORE MICLAU, MD Philadelphia, Pennsylvania
tp
Professor and Vice Chairman
tp
Director, Orthopaedic Trauma Institute
San Francisco, California
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 v
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
b ooook b ooook b o oo
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
s Contributors s
k eerrs keerr s
b ooook b o ook
o b o oo
o
/
ee/e b e / e
/
WILLIAM A. ABDU, MD, MS
e e b e / e
/ e b
APRIL D. ARMSTRONG, MD
e
: / t
///t . m
Associate Professor of Orthopaedic Surgery
.m
Dartmouth-Hitchcock Medical Center
: / ///t. m
Associate Professor
t . m
Department of Orthopaedics
s
tps : s
tps :
hhtttp hhtttp
Lebanon, New Hampshire Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania
JOHN A. ABRAHAM, MD
Chief of Orthopedic Oncology WILLIAM V. ARNOLD, MD, PHD
Rothman Institute Instructor
Thomas Jefferson University Department of Orthopaedic Surgery
k eers
rs Philadelphia, Pennsylvania
k eers
r s
The Rothman Institute at Thomas Jefferson
b ooook b ooook University

b o oo
o
/
e e
/ eb ANIMESH AGARWAL, MD
Professor
e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m
University of Texas Health Science Center
/ / t
/
Associate Professor
: .
t m
GEORGE S. ATHWAL, MD, FRCSC
. m
s
San Antonio, Texas
s : / ss : /
Hand and Upper Limb Centre
hhtttp
tp
VINAY AGGARWAL, BA
Research Fellow
hhtttp
tp
Western University
London, Ontario, Canada
Department of Adult Joint Reconstruction GEORGE C. BABIS, MD, PHD

Rothman Institute at Thomas Jefferson Professor and Chairman
keerrss University
k e rrss
2nd Department of Orthopaedic Surgery
e
bboooo k Philadelphia, Pennsylvania
b o o
o o k University of Athens, Medical School
Athens, Greece
b o oo
o
/
e e
/ e CHRISTOPHER S. AHMAD, MD
ee/ e
/ e b ee/ e
/ e b
Associate Professor
: / / t
/ .
t m
. m
DONALD BAE, MD
/ /t/.tm.m
Assistant Professor of Orthopaedic Surgery
:
ss : /
Columbia University Medical Center
ss : /
hhtttp
tp hhtttp
tp
New York, New York Harvard Medical School
Boston Children’s Hospital
JAIMO AHN, MD, PHD Boston, Massachusetts
Assistant Professor and Co-Director
Department of Orthopaedic Trauma and TESSA BALACH, MD
k eers
rs Fracture Service
k e r s
r s
Assistant Professor
e
bboooo k University of Pennsylvania
b o o
o o k Department of Orthopaedic Surgery
o
New England Musculoskeletal Institute
b oo
o
/
e e
/ e ee/ e
/ e b Farmington, Connecticut
ee/ e
/ e b
University of Connecticut Health Center
TAMARA ALLISTON, PHD
Associate Professor
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
ss : /
t p p t p ss
JAMIE BARATTA, MD
p : /
t
hht t
San Francisco, California t
hht
Instructor
t
Department of Anesthesiology
Jefferson Medical College
DONALD D. ANDERSON, PHD Philadelphia, Pennsylvania
Associate Professor
k eers
rs Department of Orthopaedics and Rehabilitation
k eers
r s
SARINA BEHERA, MD
ook ook
The University of Iowa Clinical Instructor, Pediatric Cardiology
b oo Iowa City, Iowa

b oo Department of Pediatrics
b oooo
/
e e
/ eb ee/ e
/e b ee
San Francisco, California/e/e b
California Pacific Medical Center
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 vii
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b JOHN-ERIK BELL, MD, MS
ee/ e
/ e b RICHARD E. BOWEN, MD
ee/ e
/ e b
Assistant Professor
: / t
///t. m
.m
: / ///t. m
Associate Clinical Professor
t . m
Geffen School of Medicine at University of
s
tps : s
tps :
hhtttp hhtttp
Dartmouth-Hitchcock Medical Center California Los Angeles
Lebanon, New Hampshire Los Angeles Orthopaedic Hospital
Los Angeles, California
KARL A. BERGMANN, MD
Assistant Professor RONALD C. BURGESS, MD
Division of Orthopaedics Clinical Associate Professor
k eers
rs Creighton University
k eers
r sOrthopaedic Department
b ooook Omaha, Nebraska
b ooook University of Kentucky

Lexington, Kentucky
b o oo
o
/
e e
/ eb GREG BERRY, MDCM, FRCSC
e/
e e
/ e b ee/ e
/ e b
Staff Surgeon
: // t/.tm
. m
EDWIN R. CADET, MD
/ / t
/ .
t
Assistant Professor
: m
. m
ss : /
McGill University Health Centre
ss : /
hhtttp
tp
Montreal, Quebec, Canada
MOHIT BHANDARI, MD, PHD, FRCSC

hhtttp
tp
Columbia University
New York, New York
Professor and Academic Head MICHELLE S. CAIRD, MD

Division of Orthopaedic Surgery Assistant Professor of Orthopaedic Surgery
keerrss McMaster University
k e rrss
e
bboooo k Hamilton, Ontario, Canada
b o o
o o k University of Michigan
Ann Arbor, Michigan
b o oo
o
/
e e
/ e LOUIS U. BIGLIANI, MD
ee/ e
/ e b ee/ e
/ e b
: / / t
/ t m
Frank E. Stinchfield Professor and Chairman
. . m
JOHN T. CAPO, MD
/ /t/.tm.m
Professor, Department of Orthopaedics
:
ss : /
Columbia University Medical Center
ss : /
New York University Hospital for Joint
hhtttp
tp hhtttp
tp
New York, New York Diseases
New York, New York
MICHAEL V. BIRMAN, MD
Hand Surgeon, Private Practice EUGENE J. CARRAGEE, MD
Hand Surgery Associates, S.C. Professor and Vice Chairman
k eers
rs Arlington Heights, Illinois
k e r
e s
r s
bboooo k CHRISTOPHER M. BONO, MD

b o o
o o k Stanford University School of Medicine
Redwood City, California
b o oo
o
/
e e
/ e /
Chief, Orthopaedic Spine Service
ee e
/ e b ee/ e
/ e b
Associate Professor
/ /
Harvard Medical School
: t
/ .
t m
. m
CORDELIA W. CARTER, MD
/ /
Assistant Professor
: t
/ .
t m
. m
t p ss
p : /
Brigham and Women’s Hospital
ss : /
Department of Orthopaedics and Rehabilitation
t p p
t
hht t
t
hht t
Yale University
New Haven, Connecticut
PATRICK BOSCH, MD
Associate Professor ANTONIA CHEN, MD, MBA
Department of Orthopaedic Surgery Junior Faculty
k eers
rs University of Pittsburgh Medical Center
k eers
r s
Rothman Institute
ook ook
Children’s Hospital of Pittsburgh Jefferson University
b oo Pittsburgh, Pennsylvania
b oo Philadelphia, Pennsylvania
b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
viii
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b JOHN S. CLAPP, MD
ee/ e
/ e b e /
CHARLES FISCHER, MD, MHSC, FRCSC
e e
/ e b
Orthopaedic Surgeon
: / t
///t. m
.m
Associate Professor
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
University Hospital University of British Columbia
Augusta, Georgia Vancouver, British Columbia, Canada
RACHEL M. DEERING, MPH CYRIL B. FRANK, MD

Clinical Research Coordinator Professor
Orthopaedic Spine Department Department of Surgery
k eers
rs Brigham and Women’s Hospital
k e rs
r s
University of Calgary
e
b ooook Boston, Massachusetts
b ooook
Calgary, Alberta, Canada
b o oo
o
/
e e
/ eb DANIEL R. DZIADOSZ, MD
e/
e e
/ e b LEESA M. GALATZ, MD
ee/ e
/ e b
Orthopaedic Trauma Surgeon
: // t/
Department of Orthopaedics.tm
. m
Associate Professor
/ / t
/ .
t m
. m
Washington University Orthopedics
:
ss :
Inova Fairfax Hospital / ss : /
Barnes-Jewish Hospital
hhtttp
tp
Falls Church, Virginia
SARA EDWARDS, MD
hhtttp
tp
St. Louis, Missouri
KISHOR GANDHI, MD, MPH

Assistant Professor Assistant Professor
Department of Orthopaedic Surgery Department of Anesthesiology
keerrss Northwestern University Feinberg School
k e rrss
e
bboooo k of Medicine
Chicago, Illinois
b o o
o o k
b o oo
o
/
e e
/ e ee/ e
/ e b ROBIN M. GEHRMANN, MD
ee/ e
/ e b
KENNETH A. EGOL, MD
/ /
Professor and Vice Chair
: t
/ .
t m
. m
Chief of Sports Medicine
/ /t
: /.tm.m
ss : /
ss : /
University of Medicine and Dentistry of
hhtttp
tp hhtttp
tp
New York University Hospital for New Jersey
Joint Diseases New Jersey Medical School
New York, New York Newark, New Jersey
BRIAN T. FEELEY, MD ERIC GIZA, MD
k eers
rs Assistant Professor
r s
r s
Chief, Foot and Ankle Surgery
k e e
bboooo k Department of Orthopaedic Surgery
b o o
o o k
o oo
o
University of California Davis Medical Center
b
/
e e
/ e San Francisco, California
ee/ e
/ e b Sacramento, California
ee/ e
/ e b
MARCO FERRONE, MD
: / / t
/ .
t m
. m JESSICA GOETZ, PHD
: / / t
/ .
t m
. m
t p ss
p : /
ss : /
Research Assistant Professor
t p p
t
hht t
Brigham and Women’s Hospital
Dana Farber Cancer Insitute
t
hht t
Department of Orthopaedics and Rehabilitation
University of Iowa
Iowa City, Iowa
GUILLEM GONZALEZ-LOMAS, MD
k eers
rs ANDRZEJ FERTALA, PHD
rs
r s
Assistant Professor
k ee
ook ook
Professor Department of Orthopaedic Surgery
b oo Department of Orthopaedic Surgery

b ooDivision of Sports Medicine
b oooo
/
e e
/ eb Division of Orthopaedic Research
Thomas Jefferson University
ee/ e
/e b Joint Diseases
ee/
New York University Hospital for
e/e b
t
: / ///t. m
. m New York, New York
: / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 ix
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b MELISSA M. GUANCHE, MD
ee/ e
/ e b JOSHUA J. JACOBS, MD
ee/ e
/ e b
: / t
///t. m
Department of Rehabilitation Medicine
.m
Thomas Jefferson University Hospital
: / ///t. m
Professor and Chairman
t . m
s
tps : s
tps :
hhtttp hhtttp
Philadelphia, Pennsylvania Rush University Medical Center
Chicago, Illinois
GEORGE J. HAIDUKEWYCH, MD
Academic Chairman, Orlando Health CHARLES M. JOBIN, MD
Professor, University of Central Florida Assistant Professor of Clinical Orthopaedic
Orlando, Florida Surgery
k eers
rs k eers
r s
b ooook KURT D. HANKENSON, DVM, MS, PHD
b ooook Columbia University

New York, New York
b o oo
o
/
e e
/ eb Associate Professor
e/ e
/ e b
Department of Clinical Studies-New Bolton
e ee/ e
/ e b
Center
: // t/.tm
.
University of Pennsylvania m
JOSEPH A. KARAM, MD
/ / t
/ .
t m
. m
Post-Doctoral Research Fellow
:
ss : /
ss : /
Department of Orthopaedic Research
hhtttp
tp
CHRISTOPHER CHAMBLISS HARROD, MD
Attending Orthopaedic Spine Surgeon
hhtttp
tp
University
Baton Rouge Bone and Joint Clinic
The Spine Center DAVID B. KARGES, DO
keerrss Baton Rouge, Louisiana
k e rrss
Professor
e
bboooo k EDWARD J. HARVEY, MD, MSC
b o o
o o kDepartment of Orthopaedic Surgery
Saint Louis University
b o oo
o
/
e e
/ e Professor of Surgery
ee/ e
/ e b St. Louis, Missouri
ee/ e
/ e b
McGill University
: / / t
/ .
t m
. m
McGill University Health Center
/
DEREK M. KELLY, MD
: /t/.tm.m
ss : /
ss : /
Pediatric Orthopedic Surgeon
hhtttp
tp hhtttp
tp
Campbell Clinic Orthopedics
THERESA A. HENNESSEY, MD University of Tennessee and Le Bonheur
Assistant Professor Children’s Hospital
Department of Orthopaedics Memphis, Tennessee
University of Utah
k eers
rs Shriner’s Hospital for Children
k e r
e s
r s
bboooo k Salt Lake City, Utah
CHRISTINE ANN HO, MD
b o o
o o kGRAHAM J.W. KING, MD, MSC, FRCSC
Professor
b o oo
o
/
e e
/ e Assistant Professor
ee/ e
/ e b Department of Surgery
University of Western Ontario
ee/ e
/ e b
/ / t
/ t m
. . m
University of Texas Southwestern Medical
: : / / t
/ .
t m
. m
Center
t p ss
p : / t p ss
p : /
t
hht t
Children’s Medical Center
Texas Scottish Rite Hospital for Children
Dallas, Texas
t
hht t
BRIAN A. KLATT, MD
Assistant Professor
University of Pittsburgh
Pittsburgh, Pennsylvania
k eers
rs
XIAOBANG HU, MD, PHD
Clinical Research Assistant
k eers
r s
ook ook
GREGG KLEIN, MD
b oo
Scoliosis and Spine Tumor Center
Texas Back Institute
b oo Vice-Chairman
b oooo
/
e e
/ eb ee/ e
/
Texas Health Presbyterian Hospital
e b ee/e/e b
Hackensack University Medical Center
Plano, Texas
: / t
///t. m
. m t.
Hackensack, New Jersey
: / ///t m
.m
s
tps : s
tps :
x
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b CDR KEVIN M. KUHN, MD, MC, USN
ee/ e
/ e b BRETT R. LEVINE, MD, MS
ee/ e
/ e b
: / t
///t. m
Director of Orthopaedic Trauma
.m
: / ///t. m
Assistant Professor and Residency Director
t . m
s
tps : s
tps :
hhtttp hhtttp
Naval Medical Center San Diego Rush University Medical Center
San Diego, California Chicago, Illinois
STEFANIE PEGGY KUHNEL, MD WILLIAM N. LEVINE, MD

Clinical Fellow Professor of Orthopaedic Surgery
Department of Surgery Department of Orthopaedics
k eers
rs Hand and Upper Limb Centre
k eers
r s
Columbia University
b ooook University of Western Ontario

b ooook New York, New York
b o oo
o
/
e e
/ eb e/
e e
/ e b RICHARD L. LIEBER, PHD
ee/ e
/ e b
ALFRED C. KUO, MD, PHD
Assistant Professor
: // t/.tm
. m / / t
/ .
t m
Professor of Orthopaedics and Bioengineering
. m
:
ss : /
ss : /
UC San Diego School of Medicine
hhtttp
tp
San Francisco, California hhtttp
tp
San Diego, California
ISADOR H. LIEBERMAN, MD, MBA, FRCSC

JOSHUA LANGFORD, MD Medical Director
Director, Limb Deformity Service Scoliosis and Spine Tumor Center
keerrss Orlando Health Orthopedic Residency
k e rrss
Texas Back Institute
e
bboooo k Program
Orlando Health
b o o
o o k
Texas Health Presbyterian Hospital
Plano, Texas
b o oo
o
/
e e
/ e Orlando, Florida
ee/ e
/ e b ee/ e
/ e b
JOSEPH M. LANE, MD
: / / t
/ .
t m
. m
JAY R. LIEBERMAN, MD
/ /t/.tm.m
Director, New England Musculoskeletal
:
ss : /
Chief, Metabolic Bone Disease Service Institute
ss : /
hhtttp
tp hhtttp
tp
Professor Professor and Chairman
Department of Orthopaedic Surgery Department of Orthopaedic Surgery
Hospital for Special Surgery University of Connecticut Health Center
New York, New York Farmington, Connecticut
k eers
rs STEVE K. LEE, MD
k r s
r s
FRANK A. LIPORACE, MD
e e
bboooo k Associate Professor of Orthopaedic Surgery
Hand and Upper Extremity Service
b o o
o o k
Associate Professor
Director of Orthopaedic Research
b o oo
o
/
e e
/ e Hospital for Special Surgery
New York, New York
ee/ e
/ e b / e e
New York University Hospital for Joint
Diseases
ee / b
: / / t
/ .
t m
. m New York, New York
: / / t
/ .
t m
. m
PAUL E. LEVIN, MD
t p ss
p : / t p ss
p : /
t
hht t
Associate Professor
Vice-Chairperson
t
hht
LUKE LOPAS, BS
t
Montefiore Medical Center/Albert Einstein Research Fellow
College of Medicine Department of Orthopaedic Surgery
k eers
rs Bronx, New York
k eers
University of Pennsylvania
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xi
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b JEFFREY LOTZ, PHD
ee/ e
/ e b e
SIMON C. MEARS, MD, PHD
e/ e
/ e b
: / t
///t.
m
.m
: / ///t.
Associate Professor
t m
. m
s
tps : s
tps :
hhtttp hhtttp
University of California, San Francisco Johns Hopkins Bayview Medical Center
San Francisco, California Baltimore, Maryland
ANTHONY C. LUKE, MD, MPH SAMIR MEHTA, MD

Professor of Clinical Orthopedics Chief, Orthopaedic Trauma and Fracture
Director, Primary Care Sports Medicine Service
k eers
rs Department of Orthopedics
k eers
r sDepartment of Orthopaedic Surgery
b ooook San Francisco, California

b ooook
b oo
Hospital of the University of Pennsylvania
o o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
TERRY C.P. LYNCH, MD
: // t/.tm
. m
Professor of Clinical Radiology
JOSHUA MEIER, MD
/ / t
/ .
t m
. m
Pediatric Orthopaedic Surgeon
:
ss : /
ss : /
Children and Orthopedics of Louisville
hhtttp
tp
Department of Radiology
San Francisco General Hospital
hhtttp
tp
Clinical Professor
University of Louisville
Louisville, Kentucky
C. BENJAMIN MA, MD
keerrss Associate Professor
k e rrss
e
ERIC MEINBERG, MD
bboooo k Chief, Sports Medicine and Shoulder Surgery

b o o
o o k Assistant Clinical Professor
b o oo
o
/
e e
/ e / e e b
ee / / e e b
ee /
: / / t
/ .
t m
. m : / /t/.tm.m
ss : /
WILLIAM G. MACKENZIE, MD
ss : /
JUSTIN W. MILLER, MD
hhtttp
tp hhtttp
tp
Chairman, Department of Orthopaedic Surgery Spine Surgeon
Nemours/Alfred I. DuPont Hospital Indiana Spine Group
for Children Indianapolis, Indiana
Wilmington, Delaware
HASSAN R. MIR, MD
k eers
rs PETER J. MANDELL, MD
k e r
e s
r s
Assistant Professor
bboooo k Assistant Clinical Professor

b o o
o o k Department of Orthopaedic Surgery
Vanderbilt University
b o oo
o
/
e e
/ e / e e b
ee /
Nashville, Tennessee
ee/ e
/ e b
: / / t
/ .
t m
. m /
BERTON R. MOED, MD
: / t
/ .
t m
. m
t p ss
p : /
IAIN MCFAYDEN, MBCHB, FRCS (TR&ORTH)
ss : /
Professor and Chairman
t p p
t
hht t
Chief of Trauma
Department of Trauma and Orthopaedics
Brighton and Sussex University Hospitals
t
hht t
Saint Louis University School of Medicine
St. Louis, Missouri
Brighton, Sussex, United Kingdom
SAAM MORSHED, MD, PHD, MPH
k eers
rs AMY L. MCINTOSH, MD
k eers
r s
Assistant Professor
ook ook
Assistant Professor Department of Orthopedic Surgery
b oo Department of Orthopedics
b oo Orthopedic Trauma Institute
b oooo
/
e e
/ eb Mayo Clinic
Rochester, Minnesota
ee/ e
/e b ee/
San Francisco, Californiae/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
xii
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b e /
M. LUCAS MURNAGHAN, MD, MED, FRCSC
e e
/ e b DEBRA POPEJOY, MD
ee/ e
/ e b
Assistant Professor
: /
Department of Surgery
t
///t. m
.m : / ///t. m
Pediatric Orthopedic Surgeon
t . m
University of California, Davis
s
tps : s
tps :
hhtttp hhtttp
University of Toronto Sacramento, California
Toronto, Ontario, Canada
ANISH POTTY, MD
ANAND MURTHI, MD Fellow
Attending Orthopaedic Surgeon Department of Orthopaedics
Chief, Shoulder and Elbow Surgery Hospital for Special Surgery
k eers
rs Department of Orthopaedics
k eers
r s
New York, New York
b ooook MedStar Union Memorial Hospital

Baltimore, Maryland
b ooook b o oo
o
/
e e
/ eb e/
e e
/ e b RAJ D. RAO, MD
e / e
/ e b
Professor of Orthopaedic Surgery and
e
Associate Professor
: // t/.tm
UNNI G. NARAYANAN, MBBS, MSC, FRCSC
. m
Neurosurgery
/ / t
/ .
t m
. m
:
ss : /
ss : /
Medical College of Wisconsin
hhtttp
tp
The Hospital for Sick Children
University of Toronto
Toronto, Ontario, Canada
hhtttp
tp
Milwaukee, Wisconsin
MARK C. REILLY, MD
Associate Professor and Chief Orthopaedic
JAVAD PARVIZI, MD, FRCS Trauma Service
keerrss Professor of Orthopaedics
k e rrss
e
bboooo k Department of Orthopaedic Surgery
o
b o
o o k
New Jersey Medical School
Newark, New Jersey
b o oo
o
/
e e
/ e University
ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m
WILLIAM M. RICCI, MD
/ /t/.tm.m
Professor, Chief Orthopaedic Trauma Service
:
ss
ADAM PEARSON, MD, MS
: / ss : /
hhtttp
tp hhtttp
tp
Assistant Professor Washington University School of Medicine
Department of Orthopaedic Surgery St. Louis, Missouri
Dartmouth-Hitchcock Medical Center
The Geisel School of Medicine at Dartmouth JEFFREY A. RIHN, MD
Lebanon, New Hampshire Associate Professor
k eers
rs k e r
e s
r s
bboooo k BRAD PETRISOR, MSC, MD, FRCSC

Associate Professor
b o o
o o k
University
b o oo
o
/
e e
/ e Division of Orthopaedics
McMaster University
ee/ e
/ e b Philadelphia, Pennsylvania
ee/ e
/ e b
/
Hamilton, Ontario, Canada
: / t
/ .
t m
. m SCOTT A. RILEY, MD
: / / t
/ .
t m
. m
t p ss
p : / ss : /
Chief, Hand Surgery Service
t p p
t
hht t
DAVID A. PODESZWA, MD
Associate Professor
University of Texas Southwestern Medical
t
hht t
Shriners Hospital of Lexington
Lexington, Kentucky
Center VASILEIOS I. SAKELLARIOU, MD, PHD

Attending Surgeon Stavros Niarchos – Thomas Sculco
k eers
rs Texas Scottish Rite Hospital for Children
Dallas, Texas
k eers
r s
International Fellow
ook ook
b oo b oo Hospital for Special Surgery

b oooo
/
e e
/ eb ee/ e
/e b New York, New York
ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xiii
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b JONATHON K. SALAVA, MD
ee/ e
/ e b ERIC SCHWENK, MD
ee/ e
/ e b
: / t
///t.
Charlotte, North Carolinam
OrthoCarolina Hip and Knee Center
.m Instructor
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
RICK C. SASSO, MD Philadelphia, Pennsylvania
Spine Surgeon
Indiana Spine Group JESSE SLADE SHANTZ, MD, MBA
Indianapolis, Indiana Clinical Research Fellow
k eers
rs ADAM SASSOON, MD
k eers
r s University of California, San Francisco
b ooook Orthopedic Fellow
b ooook San Francisco, California
b o oo
o
/
e e
/ eb and Reconstruction
e/
e e
/ e b
Department of Orthopedic Traumatology
JODI SIEGEL, MD
ee/ e
/ e b
Orlando, Florida
: // t/.tm
Orlando Regional Medical Center
. m / / t
/ .
Assistant Professor
t m
. m
:
ss : / ss : /
University of Massachusetts Memorial
hhtttp
tp
JEFFREY R. SAWYER, MD
Orthopaedic Surgeon
Department of Pediatric Orthopaedics and
hhtttp
tp
Medical Center
Worcester, Massachusetts
Spinal Deformity JEREMY SIMON, MD

University of Tennessee, Campbell Clinic Clinical Instructor
keerrss Memphis, Tennessee
k e rrss
e
Physical Medicine and Rehabilitation
bboooo k MARA L. SCHENKER, MD

b o o
o o k Department
o oo
o
Thomas Jefferson University Hospital
b
/
e e
/ e e /
e e
/ e b Philadelphia, Pennsylvania
ee/ e
/ e b
University of Pennsylvania
: / / t
/ .
t
Philadelphia, Pennsylvaniam
. m KERN SINGH, MD
: / /t/.tm.m
ss : / ss : /
Assistant Professor
hhtttp
tp hhtttp
tp
JONATHAN G. SCHOENECKER, MD, PHD Department of Orthopaedic Surgery
Assistant Professor Rush University Medical Center
Department of Orthopaedics Chicago, Illinois
Vanderbilt University
Nashville, Tennessee MICHAEL SIRKIN, MD
k eers
rs k e r
e s
r s
Vice Chairman
bboooo k ANDREW J. SCHOENFELD, MD

Assistant Professor
b o o
o o k Department of Orthopaedics
New Jersey Medical School
b o oo
o
/
e e
/ e /
ee e
/ e b Newark, New Jersey
ee/ e
/ e b
El Paso, Texas
: / / t
/ t m
Texas Tech University Health Sciences Center
. . m /
GILLIAN SOLES, MD
: / t
/ .
t m
. m
t p ss
p : / ss : /
Fellow, Orthopaedic Trauma
t p p
t
hht t
ROWAN SCHOUTEN, MBCHB, FRACS
Orthopaedic Surgeon
t
hht t
Unversity of California Davis Medical Center
Sacramento, California
Orthopaedic Department
Christchurch Hospital
Christchurch, New Zealand BRYAN D. SPRINGER, MD
k eers
rs k eers
r s
OrthoCarolina Hip and Knee Center
ook ook
Charlotte, North Carolina
b oo
JOE SCHWAB, MD, MS
Instructor of Orthopaedic Surgery
b oo b oooo
/
e e
/ eb /
ee e
/e b ee/e/e b
/ t
///t
: m
Massachusetts General Hospital
. . m : / t.
///t m
.m
s
tps : s
tps :
xiv
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b JASON W. STONEBACK, MD
ee/ e
/ e b ROCKY S. TUAN, PHD
ee/ e
/ e b
Assistant Professor
: / t
///t. m
.m
Director of Orthopaedic Trauma
Professor
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
Department of Orthopaedics University of Pittsburgh
University of Colorado Hospital Pittsburgh, Pennsylvania
University of Colorado Health Science Center
Denver, Colorado EJOVI UGHWANOGHO, MD
Spine Surgery Fellow
ROBERT J. STRAUCH, MD Texas Back Institute
k eers
rs Professor of Clinical Orthopaedic Surgery
k eers
r s
Plano, Texas
b ooook Department of Orthopaedic Surgery

Columbia University
b ooook b o oo
o
/
e e
/ eb New York, New York
e/
e e
/ e b ALEXANDER R. VACCARO, MD, PHD
Orthopaedic Surgeon
ee/ e
/ e b
MICHAEL P. STAUFF, MD
: // t/.tm
. m / /
Rothman Institute
: t
/ .
t m
. m
ss : /
Assistant Professor and Spine Surgeon
ss : /
hhtttp
Spine Center
tp
Department of Orthopaedics and Physical
Rehabilitation
hhtttp
tp
BENJAMIN VAGHARI, MD
Instructor
University of Massachusetts Medical Center Department of Anesthesiology
Worcester, Massachusetts Jefferson Medical College
keerrss k e rrss
e
bboooo k MAX TALBOT, MD, FRCSC
1 Canadian Field Hospital
b o o
o o kEUGENE VISCUSI, MD
b o oo
o
/
e e
/ e Canadian Armed Forces
ee/ e
/ e b e /
Director, Acute Pain Management
e e
/ e b
: / / t
/ .
t m
. m / /t/ tm
.
: .m
ss : /
VISHWAS R. TALWALKAR, MD
ss : /
hhtttp
tp hhtttp
tp
Associate Professor
Department of Orthopaedic Surgery and PARTH A. VYAS, MD
Pediatrics Fellow
Shriners Hospital for Children Department of Orthopedic Surgery
Lexington, Kentucky Hospital for Special Surgery
k eers
rs k e r
e s
r s
New York, New York
bboooo k PETER TANG, MD, MPH

Assistant Professor
b o o
o o kJ. TRACY WATSON, MD
b o oo
o
/
e e
/ e Department of Orthopaedic Surgery
New York Presbyterian Hospital
ee/ e
/ e b Professor, Orthopaedic Surgery
ee/ e
/ e b
Columbia Orthopaedics
: / / t
/ .
t m
. m / / t
/ t m
Chief, Orthopaedic Trauma Service
. . m
:
t p ss
New York, New York
p : / ss : /
Saint Louis University School of Medicine
t p p
t
hht t
PAUL TORNETTA III, MD
Director, Orthopaedic Trauma
t
hht t
St. Louis, Missouri
Department of Orthopaedic Surgery JENNIFER WEISS, MD

Boston Medical Center Physician/Orthopedic Surgeon
k eers
rs Boston, Massachusetts
k eers
r s
Department of Pediatric Orthopedics and
ook ook
Sports Medicine
b oo b oo b oooo
Southern California Permanente Medical Group
/
e e
/ eb ee/ e
/e b Los Angeles, California
ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xv
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b NATHAN A. WIGNER, MD, PHD
ee/ e
/ e b KIRKHAM B. WOOD, MD
ee/ e
/ e b
Resident
: / t
///t. m
.m
: / ///t. m
Associate Professor
t . m
Chief, Orthopaedic Spine Service
s
tps : s
tps :
hhtttp hhtttp
University of Pennsylvania Department of Orthopaedic Surgery
Philadelphia, Pennsylvania Massachusetts General Hospital
Harvard Medical School
KLANE K. WHITE, MD Boston, Massachusetts
Orthopedic Surgeon BRAD YOO, MD
Department of Orthopedics and Sports Assistant Professor
k eers
rs Medicine
k eers
r s Department of Orthopaedics
b ooook Seattle Children’s Hospital

Seattle, Washington
b ooook Sacramento, California
b oo
o o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
PHILIP WOLINSKY, MD
: // t/.tm
. m
Chief, Orthopaedic Trauma Surgery
/ / t
/ .
t m
BRUCE H. ZIRAN, MD, FACS
. m
Director, Orthopedic Trauma
:
ss : /
ss : /
Orthopedic Surgery Residency Program
hhtttp
tp
Sacramento, California
hhtttp
tp
Atlanta Medical Center
Atlanta, Georgia
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
xvi
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
s Preface s
k eerrs keerr s
b ooook b o ook
o b o oo
o
/
ee/e b e / e
/ e b
I would like to welcome you to Orthopaedic
e e / e
/ e b
increasing number of older individuals
e
: / ///t . m
Knowledge Update 11 (OKU 11).
t .m : / t
///t. m
and the rising rate of hip fractures that all
. m
orthopaedic surgeons must address, regard-
s
tps : s
tps :
hhtttp hhtttp
It is with great honor that I accepted the less of their specialty. In Section 2, Systemic
duties of editor of this incredible book. I Disorders, we have included a chapter dis-
fondly remember reading earlier editions cussing genomics, proteomics, and metabo-
to help provide an overview for residency lomics. As a result of reader comments and
rotations, prepare for my boards, and as a feedback, the orthopaedic oncology section
constant source of up-to-date knowledge. is now a separate chapter instead of being
k eers
rs Fast-forward to OKU 11. My goal was
to make this edition of OKU 11 the go-to
k eers
r s divided among the subspecialties. Section 3,
Upper Extremity, is enhanced by several vid-
b ooook b ooook
guide for the most current information on
o oo
eos and interesting discussions of topics in-
b o
/
e e
/ eb e e
/ e b
a variety of orthopaedic topics. Almost
/
immediately after OKU 10 was published,
e e e
/ e b
volving the shoulder, elbow, hand, and wrist.
/
Section 4, Lower Extremity, has exciting
e
: // t/.tm m
work on the 11th edition began with the as-
. : / / t
/ .
t m
. m
educational videos and new topics, including
ss /
sembly of an all-star team of section editors,
: ss : /
soft-tissue coverage options and segmental
hhtttp hhtttp
who then enlisted their colleagues to write bone loss. Section 5, Spine, highlights the
tp
chapters. The section editors dedicated an
extensive amount of time to this project, in-
tp
latest and most up-to-date information on
spine trauma and diseases, including verte-
cluding traveling to Chicago, along with an bral compression fractures and osteoporosis.
author from each chapter, to review chapters Section 6, Pediatrics, provides the most up-
published in this edition. In the age of social to-date information on a variety of pediatric
keerrss media and multiple venues for education,
k e rrss
e
subjects.
bboooo k including webinars, lectures, and even You
o o
o
Tube videos, it is with great pride that we
b o k o oo
o
Some may ask why I accepted the challenge
b
/
e e
/ e designed to be used regularly.
ee/ e
/ e b
present this edition as an educational tool
ee/ e
/ e b
of being the editor of OKU 11. It is only
because of the great support that I knew I
: / / t
/ .
t m
. m t . m.m
would receive from the section editors, the
: / / / t
ss : /
OKU 11 is different from previous edi-
: /
authors, and the top-notch AAOS staff. I
ss
hhtttp
tp hhtttp
tp
tions in that several chapters have video would like to acknowledge Lisa Claxton
references, including original videos from Moore for her tireless efforts and continued
the authors. The high-quality surgical im- work, along with Michelle Wild, Kathleen
ages throughout the book will enhance Anderson, and Courtney Astle. The market-
the reader’s understanding of the material ing department, particularly Tricia Arnold,
presented. In addition, each chapter ends has assisted with the promotion of this book.
k eers
rs with a summary and three key points. The
k e r
e s
r s
I would also like to thank the following
bboooo k other goal of this update was to ensure
b o o
o
that at least 30% of the references in each
o k b o oo
individuals who provided editing assistance
o
without expecting acknowledgment: Albert
/
e e
/ e / e e
chapter were published within the past 3
ee / b
years. In this way, we are highlighting what / e e b
J. Aboulafia (Baltimore, MD), who helped
ee /
with the tumor section; David J. Anderson
: / / t
/ .
t m
. m
is new and important since the last edition
: / / t
/ .
t m
. m
(St. Louis, MO), who helped review pediat-
was published.
t p ss
p : / ss : /
rics chapters; and Michael Delcore (St. Louis,
t p p
t
hht t
I would like to mention some of the new
topics included in OKU 11. Discussions of
t
hht t
MO), who helped assemble figures and refer-
ence charts for some of the chapters.
American Academy of Orthopaedic Sur- I appeal to residents and young practitioners

geons (AAOS) clinical practice guidelines to get involved in orthopaedic education—
k eers
rs
and the Appropriate Use Criteria for distal
radius fractures have been added to this
k eers
r
I started with writing chapters, became a
s
section editor, and, ultimately, this honor! I
b ooook b oook
edition. In Section 1, Principles of Ortho-
o
paedics, there are new chapters on profes-
b ooo
encourage young orthopaedic surgeons who
o
are reading this book to use this text and
/
e e
/ eb ee/ e
/e b
sionalism and ethics, and the care of geriat-
/e/e b
subsequent editions throughout their career,
ee
/ t
///t m
ric patients. The chapter on geriatric patient
. . m
care is especially important because of the
: / t.
///t m
but also to remember to give back to the
.m
Academy through future contributions.
:
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xvii
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / ///t. m
I would like to acknowledge my husband
t .m
Jeff and my daughter Annalise; without
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
them, nothing would be accomplished. I
also would like to thank my parents, John
and Theresa Metcalf, and my family for
their continued support and encouragement
of my career. The duties of being editor of
OKU 11 would not have been completed
k eers
rs without the support of my entire depart-
k eers
r
ment at Saint Louis University, particularly s
b ooook o ook
J. Tracy Watson and David Karges, and my
b o b o oo
o
/
e e
/ eb chairman, Berton R. Moed.
e/
e e
/ e b ee/ e
/ e b
: // t/.tm m
I hope that you refer to this edition often
. : / / t
/ .
t m
. m
ss /
and look forward to your feedback.
: ss : /
hhtttp
tp Lisa K. Cannada, MD
Editor
hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
xviii
hhtttp
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
hhtttp tps tps
hhtttp
s Table of Contents s
k eerrs keerr s
b ooook b o ook
o b o oo
o
/
ee/e b Section 1: Principles of
ee/ e
/ e b e / e
/ e
CHAPTER 8
e b
Orthopaedics
: / t
///t. m
.m : / t
///t. m
.
Patient-Centered Care:
m
Communication Skills and Cultural
tpss : s
tps : Competence
hhtttp hhtttp
SECTION EDITORS:
THEODORE MICLAU, MD HASSAN R. MIR, MD
SAAM MORSHED, MD, PHD, MPH RAJ D. RAO, MD . . . . . . . . . . . . . . . . . . . . . . 91
KRISTY L. WEBER, MD
CHAPTER 9
CHAPTER 1 Polytrauma Care
k eers
rs Professionalism and Ethics
k eers
r s MAX TALBOT, MD, FRCSC
ook ook
PAUL E. LEVIN, MD . . . . . . . . . . . . . . . . . . . . . 3 GREG BERRY, MDCM, FRCSC
b oo b oo b o oo
o
EDWARD J. HARVEY, MD, MSC . . . . . . . . . . . 103
/
e e
/ eb CHAPTER 2
e/
e
Fracture Repair and Bone Grafting e
/ e b ee
CHAPTER 10/ e
/ e b
MARA L. SCHENKER, MD
: // t/.tm
. m : / / t . m
. m
Medical Issues for the Athlete
/ t
s : /
NATHAN A. WIGNER, MD, PHD
s ss : /BRIAN T. FEELEY, MD
hhtttp
tp hhtttp
tp
LUKE LOPAS, BS SARINA BEHERA, MD
KURT D. HANKENSON, DVM, MS, PHD ANTHONY C. LUKE, MD, MPH. . . . . . . . . . . 115
JAIMO AHN, MD, PHD . . . . . . . . . . . . . . . . . . 15
CHAPTER 11
CHAPTER 3 Coagulation, Blood Management, and
rrss rrss
Articular Cartilage and Intervertebral Disk Thromboembolism in Orthopaedic Surgery
o ke
ke ALFRED C. KUO, MD, PHD
o k e
k e TESSA BALACH, MD
oo
e bboo o TAMARA ALLISTON, PHD
b o
b o o
JEFFREY LOTZ, PHD. . . . . . . . . . . . . . . . . . . . . 27
e
JAY R. LIEBERMAN, MD. . . . . . . . . . . . . . . . . 129
e b o
b o
/
e / e m ee/ / e CHAPTER 12
m ee/ / e
CHAPTER 4
: / / t
/ .
t
Muscle, Tendon, and Ligament
/ . m : / /t/.
Work-Related Illness, Cumulative Trauma,
t .m
and Workers’ Compensation
/
ss : ss :
hhtttp hhtttp
RICHARD L. LIEBER, PHD PETER J. MANDELL, MD . . . . . . . . . . . . . . . . 139
tp tp
CYRIL B. FRANK, MD . . . . . . . . . . . . . . . . . . . 35
CHAPTER 13
CHAPTER 5 Levels of Evidence and Grades
Musculoskeletal Biomechanics of Recommendation
DONALD D. ANDERSON, PHD BRAD PETRISOR, MSC, MD, FRCSC
k eers
rs r s
r s
JESSICA E. GOETZ, PHD . . . . . . . . . . . . . . . . . . 49
k e e
MOHIT BHANDARI, MD, PHD, FRCSC . . . . . 147
bboooo k CHAPTER 6
b o o
o o k CHAPTER 14
b o oo
o
/
e e
/ e / e
Bearing Surface Materials for Hip and
Knee Replacement
ee / e b ee/ e
/ e b
Orthopaedic Research: Health Research
Methodology, Outcomes, and Biostatistics
BRETT R. LEVINE, MD, MS
: / / t
/ .
t m
. m : / / t . m
. m
JESSE SLADE SHANTZ, MD, MBA
/ t
KERN SINGH, MD
t p ss
p : / t p ss
p : /
SAAM MORSHED, MD, PHD, MPH . . . . . . . . 157
CHAPTER 7
t
hht t t
JOSHUA J. JACOBS, MD . . . . . . . . . . . . . . . . . . 61
hht t CHAPTER 15
Care of the Geriatric Patient
Musculoskeletal Imaging ERIC MEINBERG, MD
C. BENJAMIN, MA MD SIMON C. MEARS, MD, PHD . . . . . . . . . . . . . 169
k eers
rs k eers
TERRY C.P. LYNCH, MD . . . . . . . . . . . . . . . . . 77
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xix
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b Section 2: Systemic Disorders /e
ee / e b e / e
/ e b
CHAPTER 24
e
/ t
///t
SECTION EDITOR:
: . m
.m : / t
///t. m
. m Pain Management
JAIME BARATTA, MD
tpss :
JARAD PARVIZI, MD, FRCS
s
tps :
hhtttp hhtttp
KISHOR GANDHI, MD, MPH
ERIC SCHWENK, MD
CHAPTER 16 BENJAMIN VAGHARI, MD
Disease Footprints: Genomics, Proteomics, EUGENE VISCUSI, MD . . . . . . . . . . . . . . . . . . 307
and Metabolomics
JOSEPH A. KARAM, MD
k eers
rs k eers
r s
JAVAD PARVIZI, MD, FRCS . . . . . . . . . . . . . . 183
Section 3: Upper Extremity
b ooook CHAPTER 17
b ooook SECTION EDITOR:

b o oo
o
/
e e
/ eb Bone and Calcium Metabolism
PARTH A. VYAS, MD
e/
e e
/ e b ee/ e
/ e b
WILLIAM N. LEVINE, MD
ANISH POTTY, MD
: // t/.tm
. m : / t . m
. m
CHAPTER 25
/ / t
VINAY AGGARWAL, BA
ss : / ss : /
Shoulder Trauma: Bone
hhtttp
tp hhtttp
tp
GREGG KLEIN, MD JOHN-ERIK BELL, MD, MS
JOSEPH M. LANE, MD . . . . . . . . . . . . . . . . . . 193 EDWIN R. CADET, MD . . . . . . . . . . . . . . . . . 319
CHAPTER 18 CHAPTER 26
Arthritis and Other Cartilage Disorders Shoulder Reconstruction
BRIAN A. KLATT, MD
rrss rrss
CHARLES M. JOBIN, MD
o ke
ke
ANTONIA CHEN, MD, MBA
o k e
k e
ROCKY S. TUAN, PHD . . . . . . . . . . . . . . . . . . 207
LOUIS U. BIGLIANI, MD. . . . . . . . . . . . . . . . . 339
oo
e bboo o e b o
b o o CHAPTER 27
e b o
b o
/
e / e CHAPTER 19
m ee/
Extracellular Matrix and Collagen / e Disease
m ee/ / e
Shoulder Instability and Rotator Cuff
Disorders
: / /
/ t
/ .
t . m : / /
/t/.t .m
SARA EDWARDS, MD
ss :
WILLIAM V. ARNOLD, MD, PHD
ss :
hhtttp hhtttp
LEESA M. GALATZ, MD. . . . . . . . . . . . . . . . . 357
CHAPTER 20
tp tp
ANDRZEJ FERTALA, PHD. . . . . . . . . . . . . . . . . 223
CHAPTER 28
Shoulder and Elbow Disorders
Muscle Disorders in the Athlete
GEORGE C. BABIS, MD, PHD CHRISTOPHER S. AHMAD, MD
k eers
rs k e r
e s
r s
VASILEIOS I. SAKELLARIOU, MD, PHD . . . . . . . 237 WILLIAM N. LEVINE, MD . . . . . . . . . . . . . . . 373
bboooo k CHAPTER 21
b o o
o o k CHAPTER 29
b o oo
o
/
e e
/ e
Nerve Disorders
JEFFREY A. RIHN, MD
ee/ e
/ e b ee e
/ e b
Elbow and Forearm Trauma
/
STEFANIE PEGGY KUHNEL, MD
JEREMY SIMON, MD
: / / t
/ .
t m
. m t . m
. m
GEORGE S. ATHWAL, MD, FRCSC
: / / / t
t p ss
p : /
MELISSA M. GUANCHE, MD. . . . . . . . . . . . . . 253
t p ss
p : /
GRAHAM J.W. KING, MD, MSC, FRCSC . . . . 387
t
hht
CHAPTER 22 t
Musculoskeletal Oncology
t
hht t CHAPTER 30
Elbow Instability and Reconstruction
JOHN A. ABRAHAM, MD . . . . . . . . . . . . . . . . 265 APRIL D. ARMSTRONG, MD
ANAND MURTHI, MD . . . . . . . . . . . . . . . . . . 407
k eers
rs
CHAPTER 23
Orthopaedic Infections
k eers
r s CHAPTER 31
b ooook JONATHON K. SALAVA, MD
b oook
o
BRYAN D. SPRINGER, MD. . . . . . . . . . . . . . . . 287
b oooo
Hand and Wrist Trauma
PETER TANG, MD, MPH
/
e e
/ eb ee/ e
/e b e /e/e b
STEVE K. LEE, MD . . . . . . . . . . . . . . . . . . . . 419
e
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
xx
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b CHAPTER 32
ee/ e
/ e b CHAPTER 40
ee/ e
/ e b
:
MICHAEL V. BIRMAN, MD
/ t
///t.
Hand and Wrist Reconstruction
m
.m : / ///t. m
Soft-Tissue Coverage Options in the Lower
t .
Extremity m
s
tps : s
tps :
hhtttp hhtttp
ROBERT J. STRAUCH, MD . . . . . . . . . . . . . . . 433 JOHN T. CAPO, MD . . . . . . . . . . . . . . . . . . . 567
CHAPTER 41
Knee Reconstruction and Replacement
Section 4: Lower Extremity BRETT R. LEVINE, MD, MS
SECTION EDITOR: FRANK A. LIPORACE, MD . . . . . . . . . . . . . . . 579
k eers
rs FRANK A. LIPORACE, MD
k eers
r s
ook ook
CHAPTER 42
b oo CHAPTER 33
b oo b o oo
o
Tibial Shaft Fractures
/
e e
/ eb Fractures of the Pelvis and the
Acetabulum
e/
e e
/ e b / e
GILLIAN SOLES, MD
ee / e b
PHILIP WOLINSKY, MD . . . . . . . . . . . . . . . . . 605
BERTON R. MOED, MD
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / s
MARK C. REILLY, MD . . . . . . . . . . . . . . . . . . 449
s : /
CHAPTER 43
hhtttp
tp hhtttp
tp Ankle Fractures
CHAPTER 34 KENNETH A. EGOL, MD
Hip Trauma JODI SIEGEL, MD
JASON W. STONEBACK, MD PAUL TORNETTA III, MD. . . . . . . . . . . . . . . . 615
BRUCE H. ZIRAN, MD, FACS . . . . . . . . . . . . 473
rrss rrss
CHAPTER 44
o ke
ke CHAPTER 35
o k e
k e Foot Trauma
oo
e bboo o Hip and Pelvic Reconstruction and
Arthroplasty
e b o
b o o DAVID B. KARGES, DO. . . . . . . . . . . . . . . . . . 631
e b o
b o
/
e / e ADAM SASSOON, MD
m ee/ / e CHAPTER 45
m ee/ / e
: / /
/ t
/ .
t . m
GEORGE J. HAIDUKEWYCH, MD . . . . . . . . . . . 489
: / /
/ /.t m
Foot and Ankle Reconstruction
t .
ERIC GIZA, MD
ss : ss :
hhtttp hhtttp
CHAPTER 36 MICHAEL SIRKIN, MD
tp
Femoral Fractures
CDR KEVIN M. KUHN, MD, MC, USN tp BRAD YOO, MD . . . . . . . . . . . . . . . . . . . . . . 645
ANIMESH AGARWAL, MD . . . . . . . . . . . . . . . . 509 CHAPTER 46

Lower Extremity Amputations
CHAPTER 37 DANIEL R. DZIADOSZ, MD
k eers
rs Tibial Plateau Fractures and Extensor
k e e rrss KARL A. BERGMANN, MD . . . . . . . . . . . . . . . 659
bboooo k Mechanism Injuries

WILLIAM M. RICCI, MD
b oo oo k b o oo
o
/
e e
/ e / e e bSection 5: Spine
SAMIR MEHTA, MD. . . . . . . . . . . . . . . . . . . . 521
ee / ee/ e
/ e b
CHAPTER 38
: / / t
/ .
t m
. m : / / t
/ .
t
SECTION EDITOR: m
. m
t p ss
p : /
Soft-Tissue Injuries About the Knee
t p ss : /
MITCHEL B. HARRIS, MD
p
t t
ROBIN M. GEHRMANN, MD
hht
GUILLEM GONZALEZ-LOMAS, MD. . . . . . . . . . 537 t
hht t
CHAPTER 47
Cervical Spine Trauma
CHAPTER 39
ROWAN SCHOUTEN, MBCHB, FRACS
Bone Loss
CHARLES G. FISHER, MD, MHSC, FRCSC . . . 675
k eers
rs
J. TRACY WATSON, MD
IAIN MCFADYEN, MBCHB, FRCS (TR&ORTH)
k eers
r s
ook ook
CHAPTER 48
b oo
JOSHUA LANGFORD, MD . . . . . . . . . . . . . . . . 555
b oo b o
Thoracolumbar Trauma
ooo
/
e e
/ eb ee/ e
/e b ee/e/e b
CHRISTOPHER CHAMBLISS HARROD, MD
JEFFREY A. RIHN, MD
: / t
///t. m
. m : t.
///t m
.m
ALEXANDER R. VACCARO, MD, PHD . . . . . . . 685
/
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xxi
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs k e er rss
b ooook b o oook b o oo
o
/
ee/e b CHAPTER 49
ee/ e
/ e b Section 6: Pediatrics
ee/ e
/ e b
Cervical Disk Disease
: / t
///t
JUSTIN W. MILLER, MD . m
.m : / t
///t. m
. m
s
tps : s
tps :
SECTION EDITOR:
hhtttp hhtttp
RICK C. SASSO, MD . . . . . . . . . . . . . . . . . . . 695 TODD A. MILBRANDT, MD
CHAPTER 50 CHAPTER 57
Lumbar Stenosis and Degenerative Shoulder, Upper Arm, and Elbow Trauma:
Spondylolisthesis Pediatrics
ADAM PEARSON, MD, MS DEREK M. KELLY, MD
k eers
rs rs
r s
WILLIAM A. ABDU, MD, MS . . . . . . . . . . . . . 703
k ee
JOSHUA MEIER, MD . . . . . . . . . . . . . . . . . . . 785
b ooook CHAPTER 51
b ooook CHAPTER 58
b o oo
o
/
e e
/ eb JOHN S. CLAPP, MD
e/
e e
/ e b
Lumbar and Thoracic Disk Herniations
ee/ e
/ e b
Forearm, Wrist, and Hand
: / t
RACHEL M. DEERING, MPH
/ /.tm
. m : / / t
/ t m
Trauma: Pediatrics
. . m
CHRISTINE ANN HO, MD
s : /
CHRISTOPHER M. BONO, MD . . . . . . . . . . . . 715
s ss : / DONALD S. BAE, MD . . . . . . . . . . . . . . . . . . 797
hhtttp
CHAPTER 52 tp
Disk Degeneration and Pain in the hhtttp
tp CHAPTER 59
Pediatric Upper Extremity Disorders
Lumbar Spine SCOTT A. RILEY, MD
EUGENE J. CARRAGEE, MD RONALD C. BURGESS, MD . . . . . . . . . . . . . . . 811
rrss rrss
MICHAEL P. STAUFF, MD . . . . . . . . . . . . . . . . 727
o ke
ke o k e
k e CHAPTER 60
oo
e bboo o CHAPTER 53
Spine Infections
e b o
b o o Spine Trauma
e b o
Pediatric Spine Disorders and
b o
/
e / e m e / / e
ANDREW J. SCHOENFELD, MD . . . . . . . . . . . . 737
e ee/ / e
AMY L. MCINTOSH, MD
m
CHAPTER 54
: / /
/ t
/ .
t . m : / /t/.t .m
PATRICK BOSCH, MD. . . . . . . . . . . . . . . . . . . 829
/
ss : ss :
hhtttp hhtttp
Adult Lumbar and Thoracolumbar
tp tp
CHAPTER 61
Deformity Trauma to the Pelvis, Hip, and Femur:
KIRKHAM B. WOOD, MD . . . . . . . . . . . . . . . 749 Pediatrics
JEFFREY R. SAWYER, MD
CHAPTER 55 RICHARD E. BOWEN, MD . . . . . . . . . . . . . . . 847
Spine Tumors
k eers
rs MARCO FERRONE, MD
k e r
e s
r s CHAPTER 62
bboooo k b o o
o o k
JOE SCHWAB, MD, MS . . . . . . . . . . . . . . . . . 763
b o oo
Pediatric Hip Disorders
o
JONATHAN G. SCHOENECKER, MD, PHD
/
e e
/ e CHAPTER 56
ee
Vertebral Compression Fractures/ e
/ e b ee/ e
/ e b
DAVID A. PODESZWA, MD . . . . . . . . . . . . . . . 859
EJOVI UGHWANOGHO, MD
: / / t
/ .
t m
. m : / / t
/ .
t m
.
CHAPTER 63m
t p ss
p :
XIAOBANG HU, MD, PHD
/ t p ss
p : /
Knee, Leg, Ankle, and Foot Trauma:
t
hht t
ISADOR H. LIEBERMAN, MD, MBA, FRCSC. . 775
t
hht t Pediatrics
M. LUCAS MURNAGHAN, MD, MED, FRCSC
DEBRA POPEJOY, MD. . . . . . . . . . . . . . . . . . . 875
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
xxii
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b CHAPTER 64
ee/ e
/ e b ee/ e
/ e b
Pediatrics
: / ///t. m
Lower Extremity and Foot Disorders:
t .m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
VISHWAS R. TALWALKAR, MD
THERESA A. HENNESSEY, MD. . . . . . . . . . . . . 883
CHAPTER 65
Injuries and Conditions of the Pediatric
and Adolescent Athlete
k eers
rs CORDELIA W. CARTER, MD
k eers
r s
ook ook
JENNIFER WEISS, MD . . . . . . . . . . . . . . . . . . . 899
b oo b oo b o oo
o
/
e e
/ eb Chapter 66
e/
e e
/
Skeletal Dysplasias, Connective Tissuee b ee/ e
/ e b
t . m
. m
Diseases, and Other Genetic Disorders:
: // / t : / / t
/ .
t m
. m
Pediatrics
ss : / ss : /
hhtttp
tp hhtttp
tp
KLANE K. WHITE, MD
WILLIAM G. MACKENZIE, MD . . . . . . . . . . . . 913
Chapter 67
Neuromuscular Disorders in Children
rrss rrss
UNNI G. NARAYANAN, MBBS, MSC, FRCSC
o ke
ke o k e
MICHELLE S. CAIRD, MD. . . . . . . . . . . . . . . . 933
k e oo
e bboo o b o
b o o
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
e e b o
b o
/
e / e m ee/ / e m ee/ / e
: / /
/ t
/ .
t . m : / /
/t/.t .m
ss : ss :
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 xxiii
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook Section 1 b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
e rs
rs Principles of errss
o k
ook e oook
ok e o oo
/
e e
/ b
eb o Orthopaedics
m
/t.t.m
e/
e e
/ b
e b
/ t .
t m
. mee/ e
/ b
e b o
ss: /
: / / ss: /
: / /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
b oooo k b o o
o o k b o oo
o
/e b
e/e . m mee/ e
/ e b
. m mee/ e
/ e b
Section Editors:
ss: /
: /
/
Theodore Miclau, MD
t
/ t . ss: /
: /
/ t
/ t .
t
hht t p
t p
Saam Morshed, MD, PhD, MPH t
hhtt p
t p
Kristy L. Weber, MD
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 1
e rs
rs e rrss
oo
kProfessionalism
ook e and o Ethics
k
ook
o
e o oo
o
/e/ebb Paul E. Levin, MD
e / e
/ b
e b e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
physician be altruistic, advocate for patients, be honest
Medical Professionalism with patients, respect patient confidentiality, and main-
k eerss k eer
A profession is an occupation or trade that is defined
r
by a body of information and specific technical skillss
r s
tain appropriate relationships with patients. Beyond re-
sponsibilities to patients, professionalism obligates phy-
1: Principles of Orthopaedics
b ooook b oook
that are unique to each particular profession and its
o b o oo
sicians to strive to improve the quality of care and
o
access to care for all citizens, help create a just distribu-
/
e e
/ eb e/ e
/ e b
members. In an expansion of this definition, a medical
professional must demonstrate additional personal
e ee/ e
/ e b
tion of finite healthcare resources, and further scientific
: // t/.tm
traits and qualities beyond those of a nonmedical pro-
. m
fessional. Medical professionals also have an inherent
knowledge.3
: / / t
/ .
t m
. m
The authors of a classic text describe the cornerstone
ss : / s : /
of medical professionalism as establishing “fidelity to
s
hhtttp hhtttp
ethical obligation to his or her patients and society.1,2
tp
Society recognizes the unique nature of the different
professions and expects every professional organization
to ensure that its members maintain their education
tp
trust.”5 A similar philosophy recommends that physi-
cians develop a fiduciary relationship with their pa-
tients.6 In a fiduciary relationship, the interests of the
and skills to be able to safely and effectively function in patient are paramount. Any recommendations made or
their area of professional expertise. Governmental treatment rendered should solely be for the benefit of
the patient. Potential conflicts of interest need to be
k errss
agencies also acknowledge the importance of individual
e k e rrss
e
professional societies and require these organizations to recognized, acknowledged, and, as much as is humanly
bboooo k b o o
o o k
promote activities to ensure the professional expertise
b o oo
possible, eliminated in the planning of patient care.
o
Several necessary personal characteristics have been
/
e e
/ e e / / e b
of their members. The federal government and state
e
governments have created independent agencies that es-
e ee/ e
/ e b
proposed, including excellence, humanism, account-
ability, and altruism, which are supported by the pro-
/ / t
/ t m
tablish standards for professional licensure, oversee
. . m
professional organizations, and set guidelines for pro-
: t . m.m
fessional skills of clinical competence, communication
: / / / t
ss : /
fessional responsibilities to society.
ss : /
skills, and an ethical and legal understanding. “Profes-
hhtttp
tp hhtttp
tp
sionalism is demonstrated through a foundation of clin-
Medical professionalism is a dynamic and abstract
ical competence, communication skills, and ethical and
concept. The American Academy of Orthopaedic Sur-
legal understanding, upon which is built the aspiration
geons (AAOS), the Accreditation Council for Graduate
to and wise application of the principles of profession-
Medical Education (ACGME), the American Medical
alism—clinical competence, ethical understanding, and
Association (AMA), medical schools, and several spe-
communication.”7
k e s
cialty societies have each defined their vision of profes-
rrs
sionalism. They have identified a variety of personal
e k e r
e s
r s Two intersecting attributes—healer and profession-
al— have been described as exemplifying medical pro-
bboooo k b o o
o
consistent with each organization’s concept of profes-k
characteristics, qualities, and professional activities
o b o oo
fessionalism. Many common individual characteristics
o
/
e e
/ e ee/ e
/ e b
sionalism. The AAOS has adapted the guidelines pro-
e e
/ e b
also are frequently cited by numerous ethicists, sociol-
/
ogists, and professional organizations8 (Figure 1). The
e
/ / t t m
posed by the American Board of Internal Medicine
. . m
(2002) in their position statement “Medical Profession-
: / : / / t
/ .
t m
. m
Association of American Medical Colleges and the Na-
ss : /
alism in the New Millennium: A Physician Charter.”3,4
t p p t p ss : /
tional Board of Medical Examiners convened a confer-
ence in 2002 with the charge of defining medical pro-
p
t t
The charter includes overlying fundamental principles
hht
consistent with modern medical ethics, including the
primacy of patient welfare, patient autonomy, and so-
t
hht t
fessionalism and to develop strategies to teach medical
professionalism in medical school. Their comprehensive
report, “Embedding Professionalism in Medical Educa-
cial justice. In addition to respecting the principles of tion: Assessment as a Tool for Implementation” chal-
medical ethics, medical professionalism requires that a lenges medical schools and professional societies to rec-
k eers
rs k eers
r s ognize professionalism as an integral trait of a
successful physician.9 They specifically identified altru-
b ooook b ook
Dr. Levin or an immediate family member serves as a
oo b oooo
ism, honor and integrity, caring and compassion, re-
spect, responsibility and accountability, excellence and
/
e e
/ eb e / e
/e b
board member, owner, officer, or committee member of
the American Academy of Orthopaedic Surgeons Com-
e ee/e/e b
scholarship, and leadership as necessary behaviors and
/ t
///t m
mittee on Ethics and the American Academy of Ortho-
. . m
paedic Surgeons Trauma Program Subcommittee.
: : /
(Table 1).
t.
///t m
characteristics consistent with medical professionalism
.m
s
tps : s
tps :
hhtttp
hhtttp Orthopaedic Knowledge Update 11 3
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
Section 1: Principles of Orthopaedics tps
hhtttp
The basic concepts of professionalism remain consis-
k eers
rs tent among most ethicists and professional societies.
keerrss
b ooook o ook
Earning a professional degree is not synonymous with
o
demonstrating professionalism. Professionalism re-
b b o oo
o
/
ee/e b ee/ e
/ e b
quires that a physician respect and fulfill the basic prin-
ciples of medical ethics as well as adhere to the afore-
ee/ e
/ e b
t . m
.m
mentioned multifaceted personal characteristics and
: / ///t
responsibilities. In addition, physicians must acknowl-
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
edge the economic stresses faced by health care in the
United States and abide by a commitment to social jus-
tice and a just distribution of finite resources.
Medical schools and residency programs have recog-
nized the importance of teaching professionalism and
are creating programs to teach and evaluate a student’s
k eers
rs professionalism. The ACGME has established six core
k eers
r
competencies as necessary skills for a resident to suc- s
b ooook o ook
cessfully learn during his or her training. The required
b o b o oo
o
/
e e
/ eb e/ / e b
competencies include medical knowledge, patient care
e
skills, professionalism, interpersonal and communica-
e Figure 1
ee/ e
/ e b
Intersecting attributes of professionalism.
: // t/.tm
tion skills, practice-based learning and improvement,
. m
and systems-based practice. These six competencies are
: / / t
/ .
t m
. m
(Adapted with permission from Cruess SR,
Cruess RL: The cognitive base of professionalism,
ss : /
included in most definitions of professionalism.10 These
ss : / in Cruess RL, Cruess SR, Steinert Y, eds: Teaching
hhtttp
tp hhtttp
tp
Medical Professionalism. New York, NY, Cam-
competencies also have been included in the new mile- bridge University Press, 2009, pp 7-27.)
stone project of the ACGME. The milestone project
identifies a core of orthopaedic procedures in which the
orthopaedic resident needs to demonstrate an appropri- professional balance creates excessive stress and prema-
ate level of medical knowledge and clinical competence, ture burnout.17,18 Stress affects physician interactions
rrss rrss
incorporating many of the components of professional- with patients and interpersonal relationships and in-
o ke
ke
ism in the evaluation process. According to a recent
o k e
k
study, it is recommended that orthopaedic training pro- e creases the risk for substance abuse, depression, and
oo
e bboo o e b o
grams develop formal and informal programs in the
b o o e b o
suicide. Stress decreases professional satisfaction, in-
b o
creases frustration, and compromises the ability to
/
e / e teaching of medical professionalism.11
m ee/ / e m ee/ / e
demonstrate professionalism and care for patients. Bal-
: / /
/ t
/ .
t . m : / /
/t/.t .m
ance allows physicians to be more successful in their
personal and professional lives.
ss :
Balancing Personal and Professional Life
ss :
hhtttp hhtttp
Professionalism, altruism, and trustworthiness can
tp
Physicians have historically demonstrated professional-
ism by always being available for their patients. This
tp
be maintained through a careful reassessment of how
physicians care for patients in modern society. This will
require a better understanding and a reevaluation of
availability was often associated with significant per-
sonal and family sacrifice and was accompanied by the skills necessary to create an effective doctor-patient
many unintended costs. A national survey of orthopae- relationship. An essential component necessary to
k eers
rs dic residents, resident spouses, attending physicians,
and attending spouses uncovered an alarming rate of
k e r
e s
r s achieve personal/professional balance is effective com-
munication with patients and colleagues.19,20 Patients
bboooo k b o o o
job dissatisfaction, burnout, and personal stress.12 A
o k b o oo
understand that everyone has a personal life separate
o
/
e e
/ e e e
/ e b
high level of burnout, depression, and alcohol abuse is
/
described in a report from the Governors’ Committee
e e / e
/ e b
from one’s professional life. Patients who are active
participants in their health care, achieved through the
e
: / / t
/ .
t m
. m
on Physician Competency and Health of the American
/ / t
/ .
t m
process of shared decision making, gain a full under-
. m
standing of their health-related issues and the strategy
:
t p ss : /
College of Surgeons, recounting the results of national
surveys in 2008 and 2010. Common stressors were the
p ss : /
to address these problems. Patients’ understanding of
t p p
t
hht t
number of hours worked per week, nights on call, hav-
ing children younger than 21 years, and work-home
conflict.13 In a study of orthopaedic leaders, only 15%
t
hht t
their active medical conditions will more successfully
allow the patient to assist a covering physician if a
problem arises (expanded discussion in Orthopaedic
reported satisfaction with their personal/professional Knowledge Update 11, chapter 8, Patient-Centered
balance.14 A secondary analysis of the Physician Care: Communication Skills and Cultural Compe-
k eers
rs Worklife Survey attempted to identify the “difficult
e
doctor.”15 The authors of this study found an associa-
k ers
r s
tence). In addition, physicians who have comprehen-
sively advised their covering physicians of potential is-
b ooook b ook
tion of a higher frustration level in physicians younger
oo
than 40 years and in those working more than 55 hours
b oooo
sues arising with their active patients can safely take
time off and feel comfortable that their patients will be
/
e e
/ eb / e
/e b
per week. Commonly reported symptoms among these
ee ee/e/e
appropriately cared for.b
/ t
///t m
physicians were stress, anxiety, and depression.16
. . m
Unnecessary personal sacrifice and loss of personal/
: : / t.
///t m
Medical students and practicing physicians are rec-
.m
ognizing the importance of personal balance and are
s
tps : s
tps :
4
hhtttp
hhtttp © 2014 American Academy of Orthopaedic Surgeons
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 1: Professionalism and Ethics
k eers
Table 1
rs keerrss
b ooookBehaviors Reflecting Professionalism
b o ook
o b o oo
o
/
ee/e b Altruism
• Offers to help team members who are busy.
ee/ e
/ e b ee/ e
/ e b
: / ///t. m
.m
Colleges and the Organization of Student Representatives.
: / ///t. m
. m
• Contributes to the profession; is active in local and national organizations, such as the Association of American Medical
t t
s
tps : s
tps :
• Does not use altruism as an excuse to misprioritize or rationalize certain behaviors. (“I can’t be with my family because my
hhtttp hhtttp
patients need me.”)
Honor and Integrity
• Is forthcoming with information; does not withhold and/or use information for power.
• Admits errors.
• Deals with confidential information discreetly and appropriately.
• Does not misuse resources (for example, school computers and patients’ food).
k e rs
rs
Caring and Compassion
e k eers
r s
b ooook oook
• Communicates bad news with sincerity and compassion.
b b oo
• Treats the patient as an individual, taking into account lifestyle, beliefs, personal idiosyncrasies, and support system.
o o o
/
e e
/ eb e/
e e
/ e b ee/
• Supports a balance in personal and professional activities for peers and subordinates. e
/ e b
• Deals with sickness, death, and dying in a professional manner with patient and family members.
Respect
: // t/.tm
. m : / / t
/ .
t m
. m
: / : /
• Respects institutional staff and representatives; respects faculty during teaching sessions.
ss ss
hhtttp hhtttp
• Respects patient rights/dignity (privacy/confidentiality, consent); knocks on door, introduces self, drapes patients appropriately,
tp
and shows respect for patient privacy needs.
• Demonstrates tolerance to a range of behaviors and beliefs.
• Does not disturb small group sessions.
tp
Responsibility and Accountability
• Demonstrates awareness of own limitations, and identifies developmental needs and approaches for improvements.
rrss rrss
• Cares for self appropriately and presents self in a professional manner (demeanor, dress, hygiene).
o ke
• Recognizes and reports errors/poor behavior in peers.
ke o k e
k e
• Informs others when not available to fulfill responsibilities and secures replacement.
oo
e bboo o e b o o
• Takes responsibility for appropriate share of teamwork.
b o e b o
b o
/
e / e • Arrives on time.
ee/ / e
• Accountable for deadlines; completes assignments and responsibilities on time.
m m ee/ / e
: / / t
/ .
t m
• Answers letters, pages, e-mail, and phone calls in a timely manner.
/ . : / /
/t/.t .m
Excellence and Scholarship
ss : ss :
hhtttp
tp hhtttp
tp
• Masters techniques and technologies of learning.
• Is self-critical and able to identify own areas for learning/practice improvement.
• Has internal focus and direction; setting own goals.
• Takes initiative in organizing, participating, and collaborating in peer study groups.
Leadership
• Teaches others.
k eers k e r
e s
• Helps build and maintain a culture that facilitates professionalism.
rs r s
• Does not provide disruptive leadership (organizing pranks, inappropriately confronting authority).
bboooo k b o o
o o k b o oo
(Adapted from an Invitational Conference Cosponsored by the Association of American Medical Colleges and the National Board of Medical Examiners: Embedding
o
b b
Professionalism in Medical Education: Assessment as a Tool for Implementation. National Board of Medical Examiners, Philadelphia, PA, 2002.)
/
e e
/ e ee/ e
/ e ee/ e
/ e
: / / / .
t m m
choosing specialties and practice settings by giving
t . : / / t
/ .
t m
. m
feres with the ability to engage safely in professional
t p ss : /
strong consideration to personal lifestyle and quality of
life. Working hour restrictions for medical students and
p t p ss
p : / activities.”22 Physician impairment deleteriously affects
an individual’s cognitive abilities, motor skills, and the
t
hht t
residents, originally implemented to improve patient
safety and physician education, have also put a focus
on personal and professional balance. Physicians are
t
hht t ability to uphold his or her commitment to profession-
alism. Although impairment frequently infers chemical
dependence/substance abuse (prescription and illicit
choosing positions that allow for guaranteed free time, drugs), many physicians are impaired by common psy-
and more physicians are electing to become salaried chological conditions such as anxiety and depression.
k eers
employees with specific guarantees of free time.21
rs k eers
r s Impairment is considered to be a disease and, if left un-
treated, will likely not resolve. Depression is estimated
b ooook b oook
o b ooo
to affect 16% of the general population, and it is
o
widely believed that a greater number of practicing
/
e e
/ eb The Impaired Physician
ee/ e
/e b /e/e b
physicians are affected. The rates of suicide among
ee
/ t
///t m
An impaired physician, as defined by the AMA, “has
. . m
any physical, mental or behavioral disorder that inter-
: : / t.
///t m
.
physicians are higher than in the general population
m
and are often related to depression. Female physicians
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
are affected at greater numbers than male physicians.23 range of 27% to 92%, with abstinence rates of 70% to
k eers
rs Substance abuse among physicians is believed to
keerrss 90%.25,32,33 A review of 904 physicians enrolled in 16
b ooook b o ook
have a lifetime incidence of 8% to 12% and includes
o
alcohol, illicit drugs, and prescription drugs. The pre-
different state programs in 2008 described encouraging
o oo
o
results: 78% of physicians had no positive drug tests
b
/
ee/e b ee/ e
/ b
cise statistics are difficult to ascertain because of diffi-
e
culty identifying and reporting physicians affected.24,25 cine.32
ee/ e
/ e b
over 5 years, and 72% continued to practice medi-
t . m
.m
National anonymous, self-reporting surveys among
: / ///t
physicians find a significant incidence of self-treatment
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
with benzodiazepines and narcotics.26 According to the
Disruptive Behavior
results of a 2010 national survey of surgeons in the
United States, 15.4% of the respondents had findings Disruptive behavior is unprofessional personal conduct
consistent with either alcohol abuse or other chemical that compromises patient safety and negatively affects
dependencies. Female surgeons had nearly twice the the work environment. Approximately 5% of physi-
prevalence for drug abuse or chemical dependence cians demonstrate disruptive behavior, and orthopaedic
k eers
rs (25.6% versus 13.9%).27 Anesthesiologists, emergency
k eers
r
physicians, and psychiatrists have the highest incidences surgeons are the fourth most common group of disrup-
tive physicians after general surgeons, neurosurgeons,
b ooook of prescription drug abuse.28

b ooook o oo
and cardiothoracic surgeons.34 Common disruptive be-
b o
/
e e
/ eb e/ / e b
The medical profession has a long history of institu-
e
tional and individual failures to identify and assist phy-
e ee/ e
/ e b
haviors include a disregard for hospital regulations,
such as an operating room “time-out”(a pause before
// t/.tm
sicians who are burdened with the common personal
. m
problems encountered throughout life. Physicians often
: : / / t
/ .
t m
. m
an incision is made to ensure correct patient, correct
ss : /
fail to recognize, acknowledge, or accept their own per-
ss /
procedure, correct site, and verification that all im-
:
hhtttp hhtttp
plants are available); sarcastic comments; offensive
tp
sonal challenges and need a friend or a colleague to
help them identify and acknowledge that assistance is
needed.29 Individual physicians, physician colleagues,
tp
comments of a sexual nature; shouting and throwing
instruments; and belittling or ignoring suggestions from
associates, students, and residents. Surgeons can be par-
and organizations delivering health care need to be pro- ticularly prone to disruptive behavior as a result of a
active in identifying and assisting impaired physicians, long tradition of operating room hierarchy and culture.
rrss rrss
and if problems are suspected they should be addressed Disruptive behavior can have a significant effect on op-
o ke
ke o k e
immediately. Personality changes, mood changes, irrita-
k
bility, lateness, and falling asleep during the daytime e erating room morale and staff satisfaction, leads to
oo
e bboo o e b o o o
are all potential signs of impairment.30 Recognition of
b e b o
high levels of staff turnover, and can have a deleterious
b o
effect on patient safety. In a disruptive environment,
/
e / e ee/ e
impairment is the first step in the treatment process. If
/
a physician is not able to voluntarily accept the advice
m m ee/ / e
operating room personnel, students, and residents are
/ t . . m
of a colleague and recognize that he or she requires
: / / / t : / /
/t/.
discouraged from speaking up when they believe an al-
t .m
ternative clinical management may be indicated or
s :
help, that physician should be reported to the appropri-
s ss :
when they identify a patient safety concern.35 Surgical
hhtttp
tp hhtttp
tp
ate governmental agency to ensure that he or she re- residents report personal conflict and ethical dilemmas
ceives help and that patients are not harmed. All health when they disagree with the management of a patient
professionals have an ethical, professional, and legal re-
by a surgical attending physician. A disruptive surgeon
sponsibility to report an impaired physician.
fails to create a working environment of mutual re-
The medical profession, as with so many other pro-
spect, and, as a result, the residents are not given an op-
fessions, has been guilty of underreporting and failure
k eers
rs to appropriately assist impaired physicians. In an at-
k e
tempt to protect colleagues and help them avoid profes- r
e s
r s
portunity to address their concerns, so patient safety is
compromised.35
bboooo k b o o o k
sional sanctions, physicians place these colleagues and
o b o oo
A variety of programs have been developed to ad-
o
dress the issue of disruptive behavior, including educa-
/
e e
/ e e e
/ b
their patients at risk. Because some physicians are often
/ e
fearful of the legal implications associated with their
e ee/ e
/ e b
tional forums; strategies for prevention, support, and
: / / t
/ .
t m
. m
impairment, admitting and confronting these problems
: / / t
/ t m
counseling; and, when necessary, the removal of physi-
. . m
cians from the medical staff. Maimonides Medical Cen-
t p ss : /
is often avoided. Surveys demonstrate that physician
colleagues are more likely to report a physician dealing
p ss : /
ter has developed a highly successful program “Code of
t p p
t
hht t
with chemical dependence as opposed to a psychologi-
cal disorder.31
All 50 states have agencies and programs to address
t
hht t
Mutual Respect” that can be accessed online.36,37 The
comprehensive program at Vanderbilt University ad-
dresses disruptive and unprofessional behaviors and
the issues of impaired physicians and substance abuse, teaches professionalism.38
and all recognize impairment as an illness. The goals of
k eers
rs these programs are successful treatment of the underly-
ee
ing medical condition and safely allowing the physician
k rs
r s Medical Ethics
b ooook b ook
to return to practice in a setting that best suits the need
oo
of the individual practitioner. These programs protect Morality
b oooo
/
e e
/ eb / e
/e b
patients, physician colleagues, and the medical profes-
ee ee/e/e b
Morality is an individual’s deep-seated beliefs and inter-
/ t
///t m
sion. The success of these programs has been difficult
. . m
to gauge. Success rates have been reported to be in the
: : / t.
///t m
nal compass of right and wrong. Individuals develop
.m
their own personal morality as a result of upbringing,
s
tps : s
tps :
6
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
education, religion, culture, society, and personal expe- Basic Principles of Bioethics
k eers
rs ke r
riences. A common morality is described as universally
e rss The modern study of bioethics is based on four basic
b ooook b o ook
accepted “standards of action and moral character
o
traits,” and it has been proposed that all moral individ-
b oo
principles: respect for autonomy, beneficence, nonma-
o o
leficence, and distributive justice. These four principles
/
ee/e b / e e b
uals would follow these standards39 (exemplified by the
ee /
following directives: do not kill, do not cause pain or / e e b
integrate to form the foundation of the ethical practice
ee /
of health care in the United States and many other
t . m
.m
suffering to others, prevent evil or harm from occur-
: / ///t t
///t. m
. m
countries throughout the world and are used to analyze
: /
tps :
ring, rescue persons in danger, tell the truth, nurture the
s s :
individual actions, organizational decisions, and public
tps
hhtttp hhtttp
young and dependent, keep promises, do not steal, do health policies. Frequently conflicts will arise in balanc-
not punish the innocent, and obey the law). Character ing these principles in the implementation of sound eth-
traits that reflect a strong moral code include “nonical care of patients.39,40,42
malevolence, honesty, integrity, conscientiousness, fidel-
ity, gratitude, truthfulness, lovingness and kindness.”39 Respect of Autonomy
These character traits are commonly identified as build-
k rs
rs
ing blocks of professionalism.
ee k eers
r s
Among the most cherished principles in a free society is
an individual’s right to live his or her life consistent
ook ook
Beyond the concept of a common morality, individ-
b oo b o
uals in a multicultural society each develop their own
o b o oo
with personal needs, desires, and morality. Respect of a
o
patient’s autonomy and individuality protects this free-
/
e e
/ eb ee e
/ e b
personal moralities and will interpret some clinical pre-
/
sentations with very different moral “authority.” Indi-
ee/ e
/ e b
dom, is a core principle in the current practice of med-
t . m
. m
viduals view personal morality as clear, unwavering prin-
: // / t : / / t t m
icine, and should be the underlying principle in all
. . m
healthcare decisions. This philosophy is diametrically
/
ss /
ciples that are so obvious that explanations or
: s : /
opposed to older practices of paternalism, in which the
s
hhtttp hhtttp
justifications are not needed. However, in a multicultural
tp
society, and certainly when physicians act as profession-
als, they may be called on and should be able to explain tp
physician identified the “best” treatment of his or her
patient and simply advised patients on what needed to
be done. The successful implementation of respecting
the moral reasoning that underlies their specific recom-
patient autonomy requires that the patient have a full
mendations and actions. Undoubtedly, an individual’s
understanding of his or her medical condition and its
morality will affect his or her personal ethical behavior.
rrss rrss
implications, the various options for treatment, and the
o kee
Clinical Ethics and Bioethics
k o k e
k e expected outcomes of each treatment option. Having
oo
all of this information available allows patients to de-
e bboo o e b o
b o
Ethics is a branch of philosophy that evaluates and ex-
o
amines people’s moral actions in an attempt to under-
e b o o
termine which treatment is consistent with their own
b
/
e / e ee/ / e
stand the underlying moral reasoning behind those ac-
m / / e
personal needs and morality. The principle of auton-
m ee
omy does not imply that patients should receive any
: / / t
/ .
t . m
tions. Clinical ethics examines the justifications for a
/
particular behavior in a specific clinical situation by
: / /
/t/.t .m
care that they believe is indicated (see discussion on be-
ss : s :
neficence and nonmaleficence). Respecting autonomy
s
hhtttp hhtttp
evaluating common morality, sociologic norms, and so-
tp
cietal needs; the psychological understanding of human
actions; and a careful analysis of the facts associated tp
does require the physician to acknowledge and address
his or her differing opinion with the patient and, if nec-
essary, refer the patient for an additional evaluation.
with a particular presentation and action. Ultimately,
these deliberations are designed to determine what is This concept should be included in all medical evalua-
right and what is wrong, what is acceptable and what is tions, not just in situations in which an intervention is
k eerss
not acceptable, and what is morally acceptable in the
r k e
context of society.40 Bioethics considers ethical dilem-r
e s
r s
indicated (see chapter 8, Patient-Centered Care: Com-
munication Skills and Culteral Competence, in Ortho-
bboooo k b o o o
mas that encompass more global issues in health care,
o k paedic Knowledge Update 11).
b o oo
o
/
e e
/ e e / / e b
including research with human subjects, utilization of
e
new technologies (such as stem cell research), animal
e
Beneficence
ee/ e
/ e b
: / / / .
t m
research, and public health decisions.
t . m
The study of bioethical principles allows the develop-
/ / t .
t m
The bioethical principle of beneficence obligates the phy-
. m
sician to help his or her patient do well, that is, benefit
: /
ss : /
ment of a structure and a framework to resolve ethical
t p p t p ss
p : /
his or her patient. Beneficence requires that the physi-
t
hht t
conflicts. Bioethical deliberations can also guide the chal-
lenging economic and public health decisions currently
at hand. Ethics consultation services can help give phy-
t
hht t
cian be much more than a neutral source of information
that is respecting a patient’s autonomy by simply ex-
plaining the problem and listing the treatments. To ful-
sicians guidance when addressing ethical dilemmas in the fill the principle of beneficence, the physician needs to
care of their patients. Ultimately, no physician is obli- develop an understanding of the patient’s individuality
k eers
gated to violate his or her own morality. However, when
rs e rs
r
an institution’s or a physician’s moral views are irrecon-
k e s
(such as lifestyle or economic/moral factors) and help pa-
tients achieve the best individual outcome. A beneficent
b ooook b ook
cilably different from those of the patient, the physician
oo
may need to honor the patient’s autonomy and respect
b oooo
physician will be a strong advocate for his or her patient
(see discussion on professionalism). Advocating for or-
/
e e
/ eb / e
/e b
the patient’s morality by referring him or her to another
ee ee/e/e b
thopaedic patients may include assisting the patient in
/ t
///t m
institution or to a physician whose personal morality is
. .
better suited to that patient’s care.41
: m / t.
///t m
obtaining necessary healthcare services to help treat both
.m
musculoskeletal and non-musculoskeletal conditions.
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Nonmaleficence a society and not just the needs of each individual
k eers
rs Nonmaleficence simply states that physicians should
keerrss member of a society. Healthcare resources are limited,
b ooook o
the commonly quoted Latin phrase primum non noc-
b ook
not harm their patients. This concept is consistent with
o
and the amount of money in which an economically
o oo
o
successful society can spend for health care is also lim-
b
/
ee/e b / e e b
ere, which means first do no harm. This principle im-
ee /
plies that any treatment undertaken by the physician is / e e b
ited. Ethical utilization of these resources requires that
ee /
guidelines be established to distribute these resources to
t . m
.m
expected to help not harm the patient. It is a principle
: / ///t : / t
///t. m
. m
most effectively care for all members of society. Ortho-
s
tps :
with a very delicate balance. At times, nonmaleficence
s
tps :
paedic surgeons should be actively involved in policy-
hhtttp hhtttp
may seem to conflict with the principles of patient au- making decisions to ensure appropriate, cost-effective
tonomy and beneficence. A physician may decline a pa- musculoskeletal care for their patients. Value-based
tient’s request for a diagnostic test or intervention, the- medicine has been discussed as a standard that poten-
oretically violating the patient’s autonomy, because the tially will improve outcomes and save healthcare re-
physician does not believe that the request is necessary sources.44
or beneficial and could be potentially harmful. This
k eers
rs k eers
r s
conflict is illustrated in the case of a scholarship-level
ook ook
high school athlete who requested a menisectomy
b oo b o
rather than a meniscal repair to allow him to more rap-
o b o oo
Current Ethical Challenges and Dilemmas
o
/
e e
/ eb ee e
/ b
idly return to the field and be evaluated by college
/ e
scouts.43 Nonmaleficence may conflict with the princi-
ee/ e
/ e
Decision-Making Capacity
b
Patients need to have the ability to understand their
: // t/.tm
. m
ple of beneficence because physicians may initially
: / / t
/ .
t m
. m
personal medical situation to be able to participate in
ss /
“harm” their patients when treating musculoskeletal
: s : /
discussions related to their healthcare needs. The pa-
s
hhtttp hhtttp
pathology. In this instance, although a meniscal repair
tp
is thought to achieve the best long-term prognosis, the
athlete is potentially harmed as an individual by not be- tp
tient’s ability to understand his or her medical condi-
tion and assist in determining the best treatment is
called decision-making capacity. The term decision-
ing allowed to play football and gain a college scholar- making capacity is normally used in medical settings
ship. and the term competence is used in legal forums. In
Nonmaleficence also may conflict with an individual practice, they are often used interchangeably. Capacity
keerrss physician’s personal morality. This conflict may poten-
k e
tially interfere with an individual’s autonomy. For ex- rrss
e
is not an all-or-none phenomenon. Patients may be able
bboooo k b o o
ample, an orthopaedic surgeon may feel morally obli-
o o k to demonstrate complete capacity in some aspects of
b o oo
their lives but have a complete inability to develop an
o
/
e e
/ e e e
gated to save a patient’s life by performing an
/ / e b
emergency amputation to resolve hemodynamic insta-
e ee e
/ e b
objective understanding in other aspects of their lives.45
/
A refusal to consent to a procedure with obvious indi-
: / / / .
t m m
bility secondary to an uncontrollable foot infection.
t . t . m.m
cations does not indicate a lack of capacity. In addition,
: / / / t
ss /
Performing the amputation to preserve life, against the
: ss : /
the presence of psychiatric illness does not automati-
hhtttp hhtttp
patient’s wishes, has potentially “harmed” the patient. cally negate a person’s autonomy and his or her ability
tp
The physician may view the failure to perform an am-
putation as a direct violation of his or her own morality
and the principle of nonmaleficence. Other physicians,
tp
to make decisions related to their health care.45
All physicians are ethically and legally permitted to
make determinations of a patient’s decision-making ca-
although not necessarily comfortable with the patient’s pacity. A basic guideline in this determination is the
choice, would be able to accept the patient’s choice and ability of a patient to demonstrate an understanding of
k eers
rs attempt to care for the patient in a manner acceptable
k
to the patient. (See discussion on informed consent.)
e r
e s
r s his or her condition as well as an understanding of the
different treatments and why a specific treatment is rec-
bboooo k b o o
o o k b o oo
ommended. Having a patient explain what he or she
o
/
e e
/ e
Distributive Justice
e / e
/ e b
Living in a just society implies that all members are en-
e e / e
/ e b
has learned in discussions with the physician and being
able to explain the choice of treatment that he or she
e
: / / / .
t m m
titled to a basic set of rights and freedoms. Clearly,
t .
these rights and freedoms are vigorously debated. The
: / / / .
t m m
has selected is an accepted minimal standard for deter-
t .
mining capacity.46 Whenever a question arises about a
ss : /
principle of distributive justice requires the equitable
t p p t p ss
p : /
patient’s capacity, a consultation with a psychiatry liai-
t
hht t
delivery of healthcare services. Modern bioethicists
contend that basic health care should be a guaranteed
right of all members of society. The American Board of
t
hht t
son service is recommended. In addition, it is recom-
mended that the orthopaedic surgeon discuss the indi-
cations for the surgical procedure and describe his or
Internal Medicine and the AAOS in their policy state- her specific concerns about a patient’s capacity with the
ment on professionalism include social justice as one of liaison psychiatrist before the psychiatrist’s evalua-
k eers
rs k e
This principle obligates the physician to treat all pa-
ers
the primary responsibilities of a medical professional.3,4
r s
tion.47 Some institutions and legal jurisdictions require
a psychiatry consultation for a patient with a history of
b ooook b oook
tients who present for care irrespective of a patient’s
o
sex, sexual orientation, religion, ethnicity, race, or abil-
psychiatric illness.
b oooo
Failure to determine if a patient has decision-making
/
e e
/ eb ity to pay for care.
ee/ e
/e b /e/e b
capacity violates the principles of autonomy, benefi-
ee
/ t
///t m
This is the only one of the four basic principles of
. . m
bioethics that examines the needs of all the members of
: / t.
///t m
cence, and nonmaleficence. Obtaining consent for a
.m
procedure from a patient who lacks capacity will rob
:
s
tps : s
tps :
8
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
that individual of his or her ethical and legal right to that could significantly improve his or her quality of
k e rs
rs
have a designated guardian or healthcare proxy make
e keerrss life. Purposefully withholding information with the
b ooook b o ook
his or her autonomous decisions. Obtaining consent for
o
a procedure from a family member without determin-
goal of ensuring that a patient consents to a recom-
o oo
o
mended procedure is paternalist and not ethically ac-
b
/
ee/e b / e e b
ing a patient’s decision-making capacity also violates
ee /
the principle of respecting a patient’s autonomy. Using
ceptable.
ee/ e
/ e b
Two common standards of the informed consent
t . m
.m
a family member to sign a consent because of language
: / ///t : / t
///t. m
. m
process are frequently used in both the medical and le-
s
tps :
barriers or other medical comorbidities (such as paral-
s
tps :
gal communities. The community standard obligates
hhtttp hhtttp
ysis or hearing loss) are common errors made in deter- the physician to perform the consent process in a fash-
mining decision-making capacity and obtaining in- ion similar to that of other members of the medical
formed consent. community. The reasonable person standard requires
The AAOS has created a web-based ethics syllabus that information be discussed and an understanding es-
based on common patient presentations to assist ortho- tablished for any information of which a “reasonable
paedic residents and practicing physicians in learning person” would want to be aware. Obviously, determin-
k rs
rs
about and understanding these challenging issues.48
ee k eers
r s ing what information a reasonable person would re-
ook ook
quire is an area of significant debate.
b oo Informed Consent
b oo b o oo
A third approach, the subjective standard, believed
o
/
e e
/ eb / e e b
The practice of obtaining informed consent for any
ee /
medical intervention is both an ethical imperative and a
ee e
/ e b
to be more ethically sound,39 recognizes that different
/
individuals require/request different levels of informa-
t . m
. m
legal requirement. Of paramount importance is ensur-
: // / t : / / t
/ .
t m
. m
tion. Care must be taken in using the subjective stan-
: /
ing that the patient understands all pertinent issues in-
ss ss /
dard. Clearly, different individuals are interested in dif-
:
hhtttp hhtttp
ferent degrees of comprehension of their medical
tp tp
volved in making a decision. Developing appropriate
communication skills is critical for the physician to be condition. Most patients are interested in gaining a rea-
able to successfully engage in a comprehensive discus- sonable level of understanding of their condition and
sion related to a recommended intervention. Obtaining treatment options. Some individuals require a far
informed consent fulfills the three basic tenets of bio- greater level of information and understanding prior to
medical ethics: respecting patient autonomy, benefi- consenting to a surgical intervention. Some patients
k errss
cence, and nonmaleficence. Failure to successfully com-
e k e rrss
e
prefer not to be involved in comprehensive discussions.
Patient preferences will usually become evident as the
bboooo k
municate with patients and obtain appropriate
b o o o
informed consent has been found to be associated with
o k b o oo
informed consent discussion evolves.39 Insisting that an
o
/
e e
/ e
some malpractice claims.49-52
ee/ e
/ e b
The consent process requires the orthopaedic sur-
e e
/ e b
individual who is not interested in a comprehensive dis-
/
cussion participate in an overly comprehensive and
e
t . m
. m
geon to discuss all available information and options of
: / / / t : / /t/.tm.m
technical discussion can violate the basic biomedical
ss /
management of the presenting musculoskeletal pathol-
: ss : /
principle of autonomy.
hhtttp hhtttp
ogy that he or she is evaluating and treating. All medi- Caution must be used in applying the subjective stan-
tp
cal interventions have alternatives, although at times
the alternative treatment is an extremely poor option. tp
dard. A physician may assume that a patient does not
need to be informed of an unusual but significant com-
plication because of the belief that a person should not
Alternative treatments include an option of no inter-
vention, even if this could result in the loss of a limb or be burdened with too much information. Unfortunately,
death. Individuals with decision-making capacity have this approach would be paternalistic and not even meet
k eerss
the moral and legal right to decline treatment.
r k e
Beneficence requires the physician to develop an un- r
e s
r s the needs of a subjective standard. Six critical compo-
nents need to be achieved to obtain a successful informed
bboooo k b o o o
derstanding of his or her patient’s individual desires
o k b o oo
consent:54,55 clinical issues, alternatives and options, pros
o
/
e e
/ e e / e
/ e b
and goals, along with an understanding of a patient’s
medical comorbidities, activity level, lifestyle, and per-
e e / e
/ e b
and cons, uncertainties of the decision, assessment of un-
derstanding, and patient preference.
e
: / / / .
t m m
sonal morality to help the patient identify the most ap-
t .
propriate method of treatment. Nonmaleficence obli-
: / / t
/ .
t m
The patient’s full understanding of the proposed in-
. m
tervention is paramount. Studies demonstrate that, in
ss : /
gates the orthopaedic surgeon to arrive at a treatment
t p p t p ss
p : /
general, physicians believe that a full disclosure of a
t
hht t
that does not violate the patient’s personal choices or
his or her moral or religious beliefs. For example, ad-
ministering a blood transfusion and violating an indi-
t
hht t
planned intervention meets the needs of informed con-
sent. A common failure is not establishing that the pa-
tient understands the implications of the complications
vidual’s religious beliefs may save a person’s life but disclosed.54 A reasonable guideline for the informed
leave him or her permanently harmed. consent process is to discuss all common complications
k e rs
Ethicists debate how much information is appropri-
rs
ate to communicate to a patient.53 The goal of in-
e k eers
r s
associated with the planned procedure, as well as less
common complications, which may have significant
b ooook b ook
formed consent is to ensure that an individual under-
oo
stands the proposed intervention. Ideally, the process
b oooo
long-term or permanent consequences.
/
e e
/ eb ee/ e
/e b
will inform the patient, provide assurance that the pro-
/e/e b
Example of Informed Consent, Incomplete
ee
/ t
///t m
cedure will help resolve/improve his or her condition,
. . m
and not deter a person from undergoing a procedure
:
Discussion
/ t.
///t m
.m
Dr. Clarke is having an informed consent discussion
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
with Ms. Swanson regarding her upcoming total hip ar-
k eers
rs throplasty. He has listed all of the commonly encoun-
keerrss Key Study Points
b ooook o ook
tered problems, including injury to the sciatic nerve.
o
The patient develops a complete peroneal nerve palsy
b
•
o oo
Medical professionalism requires a physician to
b o
/
ee/e b ee/ e
/ e b
after surgery and ultimately requires an ankle-foot or-
thosis for ambulation. She is angry and complains to
e e
/ e b
develop a trusting (fiduciary) relationship with a
/
patient. Professionalism obligates the physician
e
t . m
.m
Dr. Clarke that she was never told this injury could
happen.
: / ///t : / t
///t. m
. m
to be altruistic, caring, compassionate, and hu-
manistic and to maintain a current level of excel-
s
tps : s
tps :
hhtttp hhtttp
lence in his or her medical practice.
Example of Informed Consent, Complete Discus- • The four basic biomedical principles of respecting
sion a patient’s autonomy, beneficence, non-
Dr. Clarke has advised Ms. Swanson that if her sciatic maleficence, and justice are the foundation of suc-
nerve is injured, recovery may or not occur. He ex- cessful patient care. Adhering to these principles
plains that if the nerve problem does not improve, a will allow physicians to embrace medical profes-
k eers
rs k eer
plastic leg brace may be required to prevent Ms. Swan-
s
r s sionalism and be successful medical professionals.
son from tripping. Dr. Clarke pauses for a moment,
b ooook o ook
and Ms. Swanson then inquires about the brace and the
b o
•
b oo
The practice of orthopaedic surgery is often
o o
stressful and time consuming. These stresses can
/
e e
/ eb likelihood of that problem occurring.
e/ e
/ e b
These two discussions demonstrate the difference be-
e ee/ e
/ e b
lead to chemical dependence, psychological im-
pairment, and early professional burnout. Estab-
: // /.tm m
tween a disclosure and helping the patient develop a
t .
full understanding of the complication. This explana-
: / / t . m
. m
lishing an appropriate professional and personal
/ t
ss : /
tion would meet the requirements of a reasonable per-
ss : /
balance in life is consistent with modern medical
hhtttp
tp hhtttp
tp
professionalism and helps physicians be profes-
son standard in that one could assume that an individ- sionally and personally successful.
ual consenting to an elective surgical procedure would
want to know how a possible complication could have
a permanent functional implication.
Annotated References
keerrss Summary
k e rrss
e
1. Cruess SR, Johnston S, Cruess RL: “Profession”: A
bboooo k b o o
o o
The four basic principles of modern medical ethics arek Med 2004;16(1):74-76.
b o oo
working definition for medical educators. Teach Learn
o
/
e e
/ e / e e b
integral components of medical professionalism. Pa-
ee /
tients are all unique individuals, with their own moral- ee/ e
/ e b
2. Oxford English Dictionary, ed 2. Oxford, United King-
: / / t
/ .
t m
. m
ity and personal needs who require an appropriate un-
: / /t . m.m
dom, Clarendon Press, 1989.
/ t
s : /
derstanding of pathology and treatment options. A
s ss : /
hhtttp
tp hhtttp
tp
successful medical professional will strive to meet the 3. ABIM Foundation, American Board of Internal Medi-
individual needs of each patient, develop a fiduciary re- cine, ACP-ASIM Foundation, American College of
lationship with his or her patients, and, as a result, Physicians-American Society of Internal Medicine, Eu-
ropean Federation of Internal Medicine: Medical profes-
practice and exemplify professionalism in the care of
sionalism in the new millennium: A physician charter.
his or her patients.
Ann Intern Med 2002;136(3):243-246.
k eers
rs k e r
e s
r s
4. American Academy of Orthopaedic Surgeons: Principles
bboooo k b o o
o o k b o oo
of medical ethics and professionalism in orthopaedic
o
surgery. Guide to Professionalism and Ethics in the
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
Practice of Orthopaedic Surgery. Rosemont, IL, Ameri-
can Academy of Orthopaedic Surgeons January 2012.
: / / t
/ .
t m
. m : / / t . m
. m
http://www.aaos.org/about/papers/ethics/
/ t
t p ss
p : / t p ss
p : /
ethicalpractguide.pdf. Accessed September 12, 2013.
t
hht t t
hht
Regularly updated AAOS guidelines of professionalism
t
and current topics are presented.
5. Pellegrino ED, Thomasma DC: The Virtues in Medical

Practice. New York, NY, Oxford University Press,
1993.
k eers
rs k eers
r s 6. Lo B: Resolving Ethical Dilemmas: A Guide for Clini-
b ooook b oook
o o oo
cians, ed 4. Philadelphia, PA, Lippincott Williams &
b o
/
e e
/ eb ee/ e
/e b ee/e/e b
Wilkins, 2009, pp 32-33.
: / t
///t. m
. m
7.
/ t.
///t m
Stern DT: Measuring Medical Professionalism. New
.m
York, NY, Oxford University Press, 2006, pp 11-20.
:
s
tps : s
tps :
10
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
8. Cruess RL, Cruess SR: Teaching Medical Professional- 19. Tongue JR, Epps HR, Forese LL: Communication skills.
k eers
rs rrs
ism. New York, NY, Cambridge University Press, 2009.
kee s Instr Course Lect 2005;54:3-9.
b ooook9.
b o ook
Embedding professionalism in medical education: As-
o 20.
o oo
o
American Academy of Orthopaedic Surgeons: Commu-
b
/
ee/e b e / e
/ e b
sessment as a tool for implementation. Report from an
Invitational Conference Cosponsored by the Association
e
nication
ee/ e
/ e b
skills mentoring program.
www3.aaos.org/education/csmp/index.cfm.
http://
Accessed
/ ///t. m
.m
of American Medical Colleges and the National Board
t
of Medical Examiners. Baltimore, MD, May 2002.
: : / t
///t. m
. m
September 18, 2013.
s
tps : s
tps :
hhtttp hhtttp
21. Bozic KJ, Roche M, Agnew SG: Hospital-based employ-
10. Accreditation Council for Graduate Medical Education ment of orthopaedic surgeons—passing trend or new
Outcome Project: Common program requirements: paradigm? AOA critical issues. J Bone Joint Surg Am
General competencies. 2007. http://www.acgme.org. 2012;94(9):e59.
Accessed March 24, 2011.
A higher percentage of orthopaedic physicians are opt-
ing for salaried positions. This trend is multifactorial.
11. Zuckerman JD, Holder JP, Mercuri JJ, Phillips DP, Egol
k eers
rs k eers
r
KA: Teaching professionalism in orthopaedic surgery
s
Healthcare institutions are striving to maintain market
share, control costs, and remain profitable, and this
ook ook
residency programs. J Bone Joint Surg Am 2012;
b oo 94(8):e51.
b oo o oo
strategy includes employee physicians. Physicians are
o
examining the economic changes and challenges in
b
/
e e
/ eb / e e b
The authors describe a variety of forums for teaching
ee /
professionalism to orthopaedic residents. / e e b
maintaining a private practice and reassessing profes-
ee /
sional and personal balance.
: // t/.tm
. m : / / t
/ .
t m
. m
12.
: /
Sargent MC, Sotile W, Sotile MO, et al: Managing
ss
22.
ss : /
American Medical Association: Policies related to physi-
hhtttp hhtttp
stress in the orthopaedic family: Avoiding burnout, cian health: H-95.955 Substance abuse among physi-
tp
achieving resilience. J Bone Joint Surg Am 2011;93(8):
e40. tp cians. Chicago, IL, Department of Physician Health &
Health Care Disparities, February 2011. http://
www.ama-assn.org/resources/doc/physician-health/
A sobering survey of the personal health and satisfac- policies-physicain-health.pdf. Accessed September 18,
tion of orthoapedic residents, faculty, and spouses is 2013.
presented.
rrss rrss
This AMA policy statement recognizes that physician
o kee
13.
k k
Kaups KL: Governors’ Committee on Physician Compe-
o e
k e
impairment secondary to substance abuse and psycho-
oo
logical disorders affects a physician to safely practice
e bboo o 96(10):22-25.
e b o
b o o
tency and Health: An update. Bull Am Coll Surg 2011;
o o
medicine. They encourage research to be able to identify
e b b
/
e / e m e / / e
The author presents comprehensive results of a national
e
causes and possibly address practice issues that lead to
ee/ / e
impairment. State programs are encouraged to establish
m
chemical dependence.
: / /
/ t
/ .
t . m
survey of general surgeon’s job satisfaction, stress, and
: / /t/.t .m
programs to successfully treat physicians with impair-
ment issues.
/
ss : ss :
hhtttp
tp hhtttp
tp
14. Saleh KJ, Quick JC, Conaway M, et al: The prevalence 23. Schernhammer ES, Colditz GA: Suicide rates among
and severity of burnout among academic orthopaedic physicians: A quantitative and gender assessment (meta-
departmental leaders. J Bone Joint Surg Am 2007;89(4): analysis). Am J Psychiatry 2004;161(12):2295-2302.
896-903.
24. Peterson RN: Background paper on physicians with
15. Williams ES, Konrad TR, Linzer M, et al: Refining the
k eers
rs k e r
e s
r
measurement of physician job satisfaction: Results from
s
substance abuse issues. Report to AAOS Ethics Com-
mittee. Rosemont, IL, American Academy of Orthopae-
bboooo k 1140-1154.
b o o
o o k
the Physician Worklife Survey. Med Care 1999;37(11): dic Surgeons, June 15, 2012.
b o oo
o
A comprehensive review of substance abuse among phy-
/
e e
/ e 16.
ee/ e
/ e b
Krebs EE, Garrett JM, Konrad TR: The difficult doctor? / e e b
sicians, elaboration of physician responsibilities for re-
ee /
porting colleagues, discussions of programs available for
: / / t
/ .
t m m
Characteristics of physicians who report frustration
. t . m
. m
treatment, and review of current AAOS positions is pre-
: / / / t
t p
Serv Res 2006;6:128.
ss
p : /
with patients: An analysis of survey data. BMC Health
t p ss
p /
sented.
:
17. t
hht t
Dunbar RP Jr: The realities of relationship failure. J Or-
thop Trauma 2012;26(suppl 1):S32-S33.
t
hht t
25. Baldisseri MR: Impaired healthcare professional. Crit
Care Med 2007;35(2, suppl):S106-S116.
A review of the professional stresses that threaten per- 26. Hughes PH, Brandenburg N, Baldwin DC Jr, et al: Prev-
sonal and family relationships is presented. alence of substance use among US physicians. JAMA
k ee
18.rs
rs k ee
Marsh JL: Avoiding burnout in an orthopaedic traumars
r s
1992;267(17):2333-2339.
b ooook b ook
practice. J Orthop Trauma 2012;26(suppl 1):S34-S36.
oo
27.
b oooo
Oreskovich MR, Kaups KL, Balch CM, et al: Prevalence
of alcohol use disorders among American surgeons.
/
e e
/ eb e e
/e b
Orthopaedic trauma practices can be extremely time
/
consuming, threaten personal relationships, and lead to
e ee/e/e b
Arch Surg 2012;147(2):168-174.
/ t
///t m
early burnout. This article reviews the prevalence of
. . m
burnout and describes strategies to achieve balance.
: : / t.
///t m
The authors report the result of a survey with 7197 re-
.m
spondents (28.7% of survey population) revealing a
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
prevalence of alcohol abuse/dependence among male 37. Maimonides Medical Center: Code of Mutual Respect.
k eers
rs rrss
surgeons of 13.9% and female surgeons of 25.6%. Sur-
kee
Adopted November 2008, revised July 2009. http://
www.maimonidesmed.org/
ook ook
geons reporting depression and being burned out were
b oo
more at risk for alcohol problems.
b o o b o oo
Resource.ashx?sn=codeofmutualrespectrev709.
o
/
ee/e b 28.
e / e
/ e b
Garcia-Guasch R, Roigé J, Padrós J: Substance abuse in
e
38.
e / e
/ e b
Hickson GB, Pichert JW, Webb LE, Gabbe SG: A com-
e
204-209.
: / ///t. m
.m
anaesthetists. Curr Opin Anaesthesiol 2012;25(2):
t : / t
///t. m
. m
plementary approach to promoting professionalism:
Identifying, measuring, and addressing unprofessional
s
tps : s
tps : behaviors. Acad Med 2007;82(11):1040-1048.
hhtttp hhtttp
Anesthesiologists have an approximately 2.7 times like-
lihood of substance abuse compared with other medical
specialties. Among the commonly abused medications 39. Beauchamp TL, Childress JF: Moral status, in Principles
were opioids, induction agents, and benzodiazapines. of Biomedical Ethics, ed 6. New York, NY, Oxford Uni-
versity Press, 2009, pp 122-124.
29. Center C, Davis M, Detre T, et al: Confronting depres-
40. English DC: Bioethics: A Clinical Guide for Medical
k eers
rs JAMA 2003;289(23):3161-3166.
k eers
sion and suicide in physicians: A consensus statement.
r s Students. New York, NY, Norton & Company, 2009,

ook ook
pp 16-28.
b oo 30.
b oo
Boisaubin EV, Levine RE: Identifying and assisting the
b o oo
o
/
e e
/ eb e/
e e
/ e b
impaired physician. Am J Med Sci 2001;322(1):31-36.
41.
ee/ e
/ e b
Curlin FA, Lawrence RE, Chin MH, Lantos JD: Reli-
gion, conscience, and controversial clinical practices.
31.
// t .tm
. m
Farber NJ, Gilibert SG, Aboff BM, Collier VU, Weiner
: / : / / t
/ .
t m m
N Engl J Med 2007;356(6):593-600.
.
s : /
J, Boyer EG: Physicians’ willingness to report impaired
s ss : /
hhtttp hhtttp
42. Lo B: Resolving Ethical Dilemmas: A Guide for Clini-
32.
tp
colleagues. Soc Sci Med 2005;61(8):1772-1775.
Carinci AJ, Christo PJ: Physician impairment: Is recov-

tp cians, ed 4. Philadelphia, PA, Lippincott Williams &
Wilkins, 2009.
ery feasible? Pain Physician 2009;12(3):487-491. 43. Ross JR, Capozzi JD, Matava MJ: Discussing treatment
options with a minor: The conflicts related to auton-
33. Brewster JM, Kaufmann IM, Hutchison S, MacWilliam
rrss rrss
omy, beneficence, and paternalism. J Bone Joint Surg
C: Characteristics and outcomes of doctors in a sub-
o ke
ke k
stance dependence monitoring programme in Canada:
o e
k e
Am 2012;94(1):e3, 1-4.
oo
“Ethics in Orthopaedics” discussion in JBJS describing
e bboo o e b o
b o
Prospective descriptive study. BMJ 2008;337:a2098.
o e b o o
the conflict of menisectomy versus meniscal repair in a
b
/
e / e 34.
ee/ / e
Patel P, Robinson BS, Novicoff WM, Dunnington GL,
m ee/ / e
17-year-old scholarship-level high school football player.
The patient is a minor, and consent needs to be obtained
m
: / / t
/ .
t m
Brenner MJ, Saleh KJ: The disruptive orthopaedic sur-
/ .
geon: Implications for patient safety and malpractice li-
: / /t/
tient..t .m
from his mother or father with participation of the pa-
/
ss : ss :
hhtttp hhtttp
ability. J Bone Joint Surg Am 2011;93(21):e1261-
e1266.
tp
Disruptive behavior in the operating room affects pa-
tient safety. Orthopaedic surgeons are the fourth most
tp
44. Bozic KJ, Chiu V: Emerging ideas: Shared decision mak-
ing in patients with osteoarthritis of the hip and knee.
Clin Orthop Relat Res 2011;469(7):2081-2085.
frequently reported physicians to demonstrate disruptive Large regional, racial, and socioeconomic disparities ex-
behavior. ist in the utilization of total joint replacement for the
k eers
rs 35.
k e r s
r
Knifed E, Goyal A, Bernstein M: Moral angst for surgi-
e s management of osteoarthritis. The authors propose a
framework for an investigation to assess the benefit of
bboooo k 199(4):571-576.
b o o
o k
cal residents: A qualitative study. Am J Surg 2010;
o b o oo
shared decision making in resolving these differences in
o
the management of patients with osteoarthritis of the
/
e e
/ e e / e
/ e b
The authors describe interviewing 28 surgical residents
e
hip and knee.
ee/ e
/ e b
: / / t
/ .
t m
to discuss the ethical challenges of surgical training.
. m
Among the issues reported were the belief that patients 45.
: / / t
/ .
t m
. m
Ganzini L, Volicer L, Nelson WA, Fox E, Derse AR: Ten
t p ss
p : /
were not well informed of the resident’s role, the desire
to report intraoperative errors to patients, and concern
t p ss
p : /
myths about decision-making capacity. J Am Med Dir
Assoc 2005;6(3, suppl):S100-S104.
t
hht t
that they were placed in ethically challenging situations
during their training because of the existing models of
t
hht t
46. Appelbaum PS: Clinical practice: Assessment of pa-
training or in disagreeing with the attending surgeon’s tients’ competence to consent to treatment. N Engl J
management plan. Med 2007;357(18):1834-1840.
k eers
rs 36.
mutual respect. AORN J 2010;91(4):495-510.
k eers
Kaplan K, Mestel P, Feldman DL: Creating a culture of
r s 47. Capozzi JD, Rhodes R: Assessing a patient’s capacity to
refuse treatment. J Bone Joint Surg Am 2002;84-A(4):
b ooook oook
The authors report on an initiative to create a “Code of
b o
691-693.
b oooo
/
e e
/ eb e e
/ b
Mutual Respect.” This was designed to address the is-
/ e
sues of disruptive and inappropriate behavior by physi-
e
48.
e /e/e b
American Academy of Orthopaedic Surgeons Ethics
e
/ t
///t m
cians and establish a framework for successfully ad-
. . m
dressing this behavior in the author’s institution.
: : / t.
///t m
Committee: Resident ethics series: Issues and scenarios
.m
for discussion and guidance. Rosemont, IL, American
s
tps : s
tps :
12
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Academy of Orthopaedic Surgeons. http://www. 53. Schwartz PH: Questioning the quantitative imperative:
k eers
rsaaos.org/ethics. Accessed September 12, 2013.
keerrss Decision aids, prevention, and the ethics of disclosure.
ook ook
Hastings Cent Rep 2011;41(2):30-39.
b oo
49.
b o
Bhattacharyya T, Yeon H, Harris MB: The medical-
o b o oo
o
A discussion on how much information to share with a
/
ee/e b e e
/ b
legal aspects of informed consent in orthopaedic sur-
/ e
gery. J Bone Joint Surg Am 2005;87(11):2395-2400.
e sented.
ee/ e
/ e b
patient, including debate over outcome statistics, is pre-
50.
: / t
///t. m
.m
Ambady N, Laplante D, Nguyen T, Rosenthal R, Cha-
: / t
///t. m
. m
s
tps : s
54.
tps :
Braddock CH III, Fihn SD, Levinson W, Jonsen AR,
hhtttp hhtttp
umeton N, Levinson W: Surgeons’ tone of voice: A clue Pearlman RA: How doctors and patients discuss routine
to malpractice history. Surgery 2002;132(1):5-9. clinical decisions: Informed decision making in the out-
patient setting. J Gen Intern Med 1997;12(6):339-345.
51. Beckman HB, Markakis KM, Suchman AL, Frankel
RM: The doctor-patient relationship and malpractice:
Lessons from plaintiff depositions. Arch Intern Med 55. Braddock CH III, Edwards KA, Hasenberg NM, Laidley
1994;154(12):1365-1370. TL, Levinson W: Informed decision making in outpa-
k eers
rs k eers
r s tient practice: Time to get back to basics. JAMA 1999;
282(24):2313-2320.
b ooook
52.
oook
Levinson W, Roter DL, Mullooly JP, Dull VT, Frankel
o
RM: Physician-patient communication: The relationship
b b o oo
o
/
e e
/ eb e/
e e
/ e
and surgeons. JAMA 1997;277(7):553-559. b
with malpractice claims among primary care physicians
ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 2
e rs
rs e r s
rs
ooookFracture
k e Repair ando o
o
k
oBone
k e Grafting o oo
o
/e/ebb e / e
/ b
e b
Mara L. Schenker, MD Nathan A. Wigner, MD, PhD Luke Lopas, BS
e / e
/ b
e b
e t
///t. m
.m e
Kurt D. Hankenson, DVM, MS, PhD Jaimo Ahn, MD, PhD
t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
differentiate directly into bone-forming osteoblasts.
Introduction
k eers
rs k eer
Approximately 7.9 million fractures occur each year ins
r s
Other bones of the vertebrate skeleton form by endo-
chondral ossification, a biphasic process of chondro-
b ooook o ook
the United States, and 5% to 20% of patients experi-
b o b oo
genesis followed by osteogenesis. Endochondral ossifi-
o o
cation occurs via the replacement of cartilaginous
/
e e
/ eb e/ e
/ e b
ence some degree of impaired healing.1 Consequently,
physicians need to understand the complex mechanisms
e ee/ e
/ e b
anlage with bone. Endochondral bones derive from
: // t/.tm
. m
of bone repair, with the ultimate goal to promote and
: / / t
/ t m
mesenchymal progenitors often termed mesenchymal
. . m
stem cells (MSCs) that differentiate into chondrocytes.
ss /
accelerate proper fracture healing in patients. This
: s : /
During endochondral ossification, chondroprogenitor
s
hhtttp hhtttp
chapter reviews the biology of bone repair and the pos-
tp
sible failure of bone healing (that is, nonunion and de-
layed union), as well as recent technologic advances in
the augmentation of fracture repair using grafts, bio-
tp
MSCs condense and differentiate into chondrocytes
that deposit cartilage matrix, principally collagen
type II and aggrecan, a large chondroitin sulfate pro-
teoglycan. In the growth plate, chondrocytes continu-
logic, and mechanobiologic materials. ally secrete extracellular matrix (ECM) proteins and
undergo unidirectional proliferation, forming parallel
keerrss k e rrss
e
columns of dividing cells that result in longitudinal
bboooo kBiology of Bone Repair
b o o
o o k b o oo
bone growth. Chondrocyte differentiation culminates
o
with terminal hypertrophy, apoptosis, and mineraliza-
/
e e
/ e e e
/ b
The vertebrate skeleton forms as a result of two pro-
/ e
cesses: intramembranous ossification and endochondral
e ee/ e
/ e b
tion of the ECM. As the chondrocytes undergo apopto-
sis, blood vessels, osteoblasts, and osteoclasts penetrate
: / / / .
t m m
ossification. Intramembranous ossification is the pro-
t . t . m.m
this zone of hypertrophic chondrocytes. Although os-
: / / / t
ss /
cess by which flat bones, such as the cranium, the scap-
: : /
teoclasts are responsible for resorbing ECM, osteo-
ss
hhtttp hhtttp
ula, innominate pelvic bones, and the clavicle, develop.
tp tp
blasts use the devitalized cartilaginous anlage as a func-
During intramembranous ossification, progenitor cells tional scaffolding to lay down new osteoid. Thus, the
pathways of chondrogenic and osteogenic lineage pro-
gression are fundamentally linked during endochondral
Dr. Hankenson serves as a paid consultant to or is an bone formation.
employee of Venenum; has received research or institu- Fracture healing represents a unique postnatal pro-
k rs
rs
tional support from Synthes; and serves as a board
ee k e r
e s
r s
cess that recapitulates many of the developmental pro-
cesses seen during embryogenesis and during periods of
bboooo k
member, owner, officer, or committee member of the
b o o o
Orthopaedic Research Society, American College of Lab-
o k b o oo
postnatal skeletal growth. Therefore, the same pro-
o
/
e e
/ e ee e
/ e b
oratory Animal Medicine, and American Association for
/
Laboratory Animal Science. Dr. Ahn or an immediate
e e
/ e b
cesses that occur during endochondral ossification also
/
occur during fracture healing. During the initial phases
e
: / / t
/ .
t m m
family member serves as a paid consultant to or is an
. : / / t
/ .
t m
. m
of fracture repair, the skeletal defect is stabilized via the
t p ss : /
employee of Merck and serves as a board member,
owner, officer, or committee member of the American
p t p ss : /
formation of a cartilaginous callus; the callus size often
is inversely related to the mechanical competency
p
t
hht t
Academy of Orthopaedic Surgeons Basic Science Evalua-
tion Subcommittee, the Foundation for Orthopaedic
Trauma Research Committee, the American Physician Sci-
t
hht t
across the bony defect. Thus, the callus not only pro-
vides immediate mechanical stability at the fracture site
but also functions as a template on which new bone is
entists Association Board of Directors, and the National formed.
Board of Medical Examiners Committee for United Fracture healing may be characterized by its progres-
k eers
States Medical Licensing Examination surgery test mate-
rs
rial development. None of the following authors nor
k eers
r ssion through a series of different biologic processes that
comprise four temporally defined but overlapping
b ooook b ook
any immediate family member has received anything of
oo b oooo
phases of repair: the inflammatory phase, characterized
by an inflammatory and marrow response; the early
/
e e
/ eb e / e
/e b
value from or has stock or stock options held in a com-
mercial company or institution related directly or indi-
e ee/e/e b
callus phase, predominated by mesenchymal and vascu-
Dr. Wigner, and Mr. Lopas.

: / t
///t m
rectly to the subject of this chapter: Dr. Schenker,
. . m : / t.
///t m
lar infiltration and chondrogenesis; the mature callus
.m
phase, marked by endochondral ossification and
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e Figure 1
ee/ e
/ e b e / e
/ e b
Images of a tibial shaft fracture in a mouse as it heals. Top row images (×2 magnification) are a series of histologic
e
: / / t
/ t m
. m
callus phase is dominated by chondrogenesis.
: / /t/ tm
sections stained with Fast Green FCF and Safranin-O that have been combined to show the entire tibia. The early
. . .m
ss : / ss : /
hhtttp
tp
primary bone (also called immature or woven bone)
formation; and the remodeling phase, defined by sec-
ondary bone (also called mature or lamellar bone) for-
hhtttp
tp
cavity and the periosteal surface followed by prolifera-
tion.3
mation2 (Figure 1). The Early Callus Phase
k eers
rs The Inflammatory Phase
k e r
e s
r s
The second stage, which may begin within a few days
postfracture and last up to several weeks, is character-
bboooo k b o o
o k
The initial inflammatory stage of fracture healing in pa-
o
tients begins immediately following the fracture to typ-
b o oo
ized by vascularization, the proliferation of chondro-
o
progenitor MSCs and differentiation into chondrocytes,
/
e e
/ e ee/ e
/ e b
ically 3 to 4 days postfracture. A hematoma forms that
/ e
/ e b
and the expression of cartilage-specific matrix proteins.
ee
: / / t
/ .
t m
encompasses the fracture site and a systemic proinflam-
. m
matory response is initiated.3 Similar to other wound
: / / t t m
Chondrogenesis is a multistage process that function-
. . m
ally can be divided into six phases: MSC proliferation,
/
t p ss
p : /
healing processes, this stage is characterized by the re-
t ss : /
MSC condensation, chondrocyte formation, chondro-
p p
t
hht t
lease of proinflammatory mediators, such as interleu-
kin 1 (IL-1), IL-6, and tumor necrosis factor alpha
(TNF-α) produced by T cells, macrophages, neutro-
t
hht t
cyte maturation, hypertrophic differentiation, and
apoptosis. The formation of a cartilage callus not only
provides immediate mechanical stability to the fracture
phils, platelets, and injured bone cells. These inflamma- site but also establishes the spatial geometry on which
tory mediators play a critical role in initiating the re- new bone forms.5 The cartilage callus is composed of
k eers
rs
pair process.4 Proinflammatory molecules reach peak
expression 24 hours following injury and subsequently
k eers
r s
many different ECM proteins, such as collagens and
hyaluronic acid, and sulfated proteoglycans, such as ag-
b ooook b oook
decline to baseline levels by 72 hours following frac-
o
ture. In addition to inflammatory mediators, numerous
b ooo
grecan. During endochondral fracture healing, discrete
o
phases of chondrogenic differentiation can be identified
/
e e
/ eb ee/ e
/e b
growth factors and critical signaling molecules are ex-
/e/e b
by monitoring the differential expression of stage-
ee
/ t
///t m
pressed in the immediate local environment, resulting
. . m
in an influx of MSCs from the surrounding marrow
: / t.
///t m
specific genes, which parallel associated phenotypic
.m
changes. For example, proliferating and mature chon-
:
s
tps : s
tps :
16
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 2: Fracture Repair and Bone Grafting
drocytes predominantly synthesize collagen type II and
k e rs
rs
aggrecan, whereas hypertrophic chondrocytes express
e keerrss
b ooook o
most terminally differentiated chondrocytes ex-
b ook
collagen type X and alkaline phosphatase. Only the
o b o oo
o
/
ee/e b ee/ e
/ e
(MMP13), which degrade the cartilaginous ECM.6b
press proteases, such as matrix metallopeptidase 13
ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
The Mature Callus Phase
s
tps : s
tps :
hhtttp hhtttp
The final two stages of primary and secondary bone
formation occur as the cartilaginous matrix is mineral-
ized and primary bone is laid down on these surfaces.
Prior to the onset of ossification, chondrocytes in these
regions undergo apoptosis, the matrix becomes vascu-
larized, and osteoblasts infiltrate the callus.7
k eers
rs k eers
r s
b ooook
The Remodeling Phase
ooook
Subsequently, the formation of more organized second-
b b o oo
o
/
e e
/ eb / e e b
ary bone begins. During this stage, the original long
ee /
bone structure begins to reestablish as the newly
ee/ e
/ e b
m m
Figure 2 A, Image of a coapteur plate (first used in 1949),
: ///t/.t. m
formed woven bone remodels to reform the mature la-
: / /
/ t . . m
which was used to suppress interfragmentary
/ t
motion and increase the stability of fixation
ss :
mellar bone, restoring the original cortical structure.2
ss :
hhtttp hhtttp
through interfragmentary compression achieved
tp tp
In the clinical setting, fractures are typically considered by tightening the side screw. B, Direct osteonal
healed during the late mature callus phase and early re- proliferation in primary bone healing. (Repro-
modeling phase (several months postfracture). It is im- duced with permission from Uhthoff HK, Poitras
portant to keep in mind, however, that late remodeling P, Backman DS: Internal plate fixation of frac-
tures: Short history and recent developments.
can continue beyond 1 year and can extend into many J Orthop Sci 2006;11[2]:118-126.)
years.
keerrss k e rrss
e
bboooo k
Fracture Healing in Stable Mechanical
Environments
b o o
o o k b o oo
and are characterized by abundant callus formation
o
with a lack of bony bridging. Oligotrophic nonunions
/
e e
/ e / e e b
The spontaneous healing of fractures typically occurs
ee /
as mentioned previously, via secondary bone healing, in / e e b
have the biologic capacity for healing, have no ability
ee /
t . m
. m
the presence of unstable fragment ends. However, in
: / / / t : / /t/ tm
to initiate healing, and are characterized by little to no
. .m
callus formation. Atrophic nonunions have little to no
ss : /
stable mechanical environments, bone has the potential
s : /
capacity for healing and are characterized by sclerotic
s
hhtttp
tp hhtttp
tp
to heal without significant callus formation. In 1949, bone ends with no callus formation and pseudarthrosis.
rigid fixation without callus formation was first de- The risk factors for impaired bone healing in frac-
scribed as “primary bone healing.”8 A later study tures can be classified as modifiable or nonmodifiable.
showed that healing occurs under these conditions via Intervention in modifiable risk factors offers an oppor-
direct osteonal proliferation9 (Figure 2). Stable abut- tunity to enhance bone healing in compromised pa-
ment of the fracture ends is achieved by the application
k eers
rs
of rigid implants, such as compression plates and lag
k e r
e
screws, and is used to precisely align the fracture ends, s
r s
tients.
bboooo k b o
as routinely performed for stabilization of intra-
o
o o k Bone Healing
b o oo
Modifiable Risk Factors for Impaired
o
/
e e
/ e ee e
/ e b
articular fractures and simple fracture patterns.
/ e / e
/ e b
The potential risk factors for impaired bone healing
e
: / / t
/ .
t m
. m / / t
/ t m
that can be modified to improve bone healing are out-
. . m
lined in Table 1. Basic science studies have shown that
:
Failure of Bone Repair:
t p ss
p
Delayed Unions and Nonunions: / ss : /
smoking reduces local blood flow and decreases osteo-
t p p
t
hht t
In the United States, the delayed healing of fractures
has been reported in approximately 600,000 patients
t
hht t
blast formation and bone metabolism, thus impairing
fracture healing.11 Prospective and retrospective cohort
studies have corroborated this basic science evidence
per year, with 100,000 progressing to nonunion.10 Cur- and show trends toward higher rates of nonunion and
rently, no standard criteria exist to define nonunion, al- longer mean healing times for fractures in patients who
k eers
though the FDA defines nonunion as a fractured bone
rs
that has not completely healed within 9 months and
k eers
r s
smoke.12,13
Diabetes mellitus, in addition to its associated risk of
b ooook b ook
shows no progression toward healing on serial radio-
oo
graphs over 3 consecutive months. The three types of
b oooo
peripheral neuropathy and peripheral vascular disease,
directly affects fracture healing. In a study of diabetic
/
e e
/ eb / e
/e b
nonunion are hypertrophic, oligotrophic, and atro-
ee ee/e/e b
rats, fracture calluses were shown to have 29% less
/ t
///t m
phic.10 Hypertrophic nonunions have a biologic capac-
. . m
ity for healing, have inadequate mechanical stability,
: : / t.
///t m
tensile strength and 50% less stiffness compared with
.m
those in the control group.14 This disadvantage can be
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Risk Factors for Fracture Nonunion
b o ook
o b o oo
o
/
ee/e b Modifiable Risk Factors
ee/ e
/ e b Nonmodifiable Risk Factors
ee/ e
/ e b
Substance abuse (alcohol, smoking)
: / t
///t. m
.m / t
///t. m
Injury characteristics (pattern of bone injury, location of fracture,
. m
status of the soft tissues, severe bone loss)
:
s
tps : s
tps :
hhtttp hhtttp
Medication use (NSAIDs, steroids) Patient disease (peripheral vascular disease, genetic disorders)
Infection Advanced age
Diabetes mellitus Sex
Metabolic deficiencies (vitamin D, calcium, parathyroid
hormone, testosterone, thyroid, nutritional)
k eers
rs
Inadequate surgical fixation (for example, insufficient
mechanical stability or high strain)
k eers
r s
o
/
e e
/ eb e/
e e
/ e b
normalized with improved glycemic control.15 Clinical
ee/ e
/ e b
animal models have shown increased callus volume,
: // t/.tm m
studies have shown a higher incidence of delayed
. : / / t
/ .
t m
. m
trabecular bone volume, and bone mineral content with
ss /
union, nonunion, and prolonged healing times in pa-
: ss : /
bisphosphonate treatment but also have shown delayed
hhtttp hhtttp
tients with diabetes when compared with healthy pa- maturation and remodeling of the callus.23 Similarly,
tients.16
tp
Nutritional deficiencies, particularly in dietary cal- tp
clinical studies have shown varied and uncertain effects
on bone repair, making their role in fracture healing
unclear.24
cium and vitamin D, have long been associated with
impaired fracture healing. One study noted that 84%
of patients referred for treatment of a fracture non- Nonmodifiable Risk Factors
keerrss union were found to have a metabolic or an endocrine

abnormality, and 68% were found to have a vitamin D
k e rrss
e
for Impaired Bone Healing
Nonmodifiable risk factors for impaired bone healing10
bboooo k deficiency.17 Additionally, hyperparathyroidism and

b o o
o o k b o oo
are presented in Table 1. Fractures in several anatomic
o
/
e e
/ e e e
low growth hormone levels have been associated with
/ / e b
higher rates of nonunion.18 Based on the high rate of
e e e
/ e b
areas, including the fifth metatarsal metaphysis25 and
/
the proximal pole of the scaphoid,26 are more prone to
e
: / / / .
t m m
association between metabolic and endocrine abnor-
t .
malities and nonunion, some authors have recom-
: / /t/.tm.m
nonunion given the tenuous blood supply. Severe bone
ss : / loss is also a risk factor for nonunion. Although the ab-

ss : /
hhtttp hhtttp
mended referral to an endocrinologist for a complete solute critical size for a bone defect beyond which heal-
tp
workup in cases of nonunion.17
Certain medications have also been shown to limit
the capacity for fracture healing. NSAIDs effectively re-
tp
ing cannot occur in patients is not known, it represents
a deficiency that is not expected to heal without sec-
ondary intervention.10 Other proposed nonmodifiable
duce acute pain and swelling and decrease the require- risk factors for impaired healing may become modifi-
ment for concurrent narcotic therapy in the manage- able in the future via improved mechanistic under-
k eers
rs ment of musculoskeletal injuries, including fractures.
However, basic science evidence has raised concerns
k e r
e s
r
standing of these factors.
s
bboooo k about the use of NSAIDs in routine management fol-
b o o
o o k Modulation of Fracture Healing
b o oo
o
/
e e
/ e e / e
/ e b
lowing a fracture, with the potential of slowing the in-
trinsic fracture healing process and increasing the risk
e e / e
/ e b
Several approaches to enhance fracture healing are
widely used clinically, including optimization of patient
e
/ / t
/ .
t m
of nonunion or delayed union.19 A recent systematic re-
. m
view of the literature did not show a substantial detri-
: : / / t
/ .
t m
risk factors for poor healing, direct augmentation of
. m
the fracture site with biologic materials (for example,
ss : /
mental role of clinical NSAID use in fracture healing;
t p p t p ss
p : /
bone morphogenetic proteins [BMPs]) and grafts (for
t
hht t
the authors concluded that clinical evidence is insuffi-
cient to deny patients with simple fracture patterns the
benefits of these drugs.20 Systemic administration of
t
hht t
example, autografts and allografts) and indirect aug-
mentation of the fracture site with external stimulation
(for example, electric stimulation, ultrasound, shock,
corticosteroids also has been shown to inhibit fracture and vibration). Much research has been dedicated to
healing and reduce callus strength in animal models21 the enhancement of fracture healing, although most
k eers
rs
and increase the rate of nonunion in patients with inter-
trochanteric hip fractures.22 Bisphosphonates are
k eers
r s
data have a low level of evidence.
b ooook b ook
widely used for the treatment of osteoporosis and the
oo
prevention of fragility fractures. Systemically adminis- for Poor Healing Capacity
b oooo
Optimization of Patient Risk Factors
/
e e
/ eb ee/ e
/e b
tered bisphosphonates bind to the hydroxyapatite in
/e/e b
Numerous modifiable risk factors predispose patients
ee
/ t
///t m
bone and inhibit bony resorption by osteoclasts,
. . m
thereby decreasing the rate of bone remodeling. Several
: / t.
///t m
to a poor capacity for healing. Although cessation of
.m
substance abuse, discontinuation of specific medica-
:
s
tps : s
tps :
18
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
tions, and optimization of symptoms for a patient’s dis- ductive (provides scaffolding and an environment for
k eers
rs ke rr
ease are presumed to enhance bone healing, little high-
e ss new bone formation by supporting vascular ingrowth,
b ooook b o ook
level clinical evidence exists to support this claim in
o
patients who have sustained a fracture. Two random-
perivascular tissue, and osteoprogenitor cells). Au-
o oo
o
tograft is also histocompatible and nonimmunogenic.
b
/
ee/e b / e e b
ized controlled trials have evaluated the effects of opti-
ee /
mizing patient metabolic deficiencies during acute frac- / e e b
The potential drawbacks of using autograft include do-
ee /
nor site morbidity (deep infection, pain, and nerve in-
ture healing.1,27
: / t
///t. m
.m : / t
///t. m
. m
jury), increased surgical time and blood loss, and lim-
s
tps :
Parathyroid hormone (PTH) is released by the para-
s
tps :
ited quantity availability. Because of the potential
hhtttp hhtttp
thyroid glands and increases the blood levels of calcium drawbacks, significant research efforts have been dedi-
by indirectly stimulating bone resorption, increasing re- cated to the development of bone graft substitutes.31
nal reabsorption of calcium, and increasing intestinal
calcium absorption. Low-dose intermittent administra- Allografts
tion of PTH has anabolic effects on bone metabolism, Allografts are harvested from cadaver tissue, thereby
although high-dose continuous administration has cat- avoiding all of the donor site morbidities associated
k rs
rs
abolic effects. PTH 1-34 is the active form of PTH; a
ee k eers
r s with autografts. Allograft types include nonstructural
ook ook
commercially available form is FDA approved for the grafts (cancellous or corticocancellous chips), structural
b oo b o
treatment of osteoporosis in postmenopausal women
o b o oo
o
grafts (cortical struts), and demineralized bone matrix
/
e e
/ eb ee e
/ e b
who are at high risk of fracture or who have a history
/
of osteoporotic fracture. Animal models have shown
ee/ e
/ e b
(DBM). DBM is a highly processed allograft subtype
prepared by demineralization of the allograft using an
: // t/.tm
. m
enhanced callus formation and mechanical strength of
t . m
. m
organic solvent, allowing the retention of both collage-
: / / / t
ss /
fractures with the administration of PTH.28 In 2010, a
: : /
nous and noncollagenous proteins (for example,
ss
hhtttp hhtttp
prospective, randomized, double-blind study was con- BMPs). More than 25 DBM products are commercially
tp
ducted on 102 postmenopausal women with nonsurgi-
cally treated distal radius fractures who received tp
available in multiple forms (powder, putty, chips,
crushed granules, or gel-filled syringes).32 Although al-
8 weeks of daily systemic administration of low-dose lograft has both osteoconductive and osteoinductive ca-
recombinant PTH (20 µg), high-dose recombinant PTH pacities, its osteoinductive capacity is less than that of
(40 µg), or a placebo. The time to cortical bridging was autograft. It has been suggested that the process of de-
keerrss
accelerated in the patients treated with low-dose re-
combinant PTH, but no difference was noted between
k e rrss
e
mineralization for DBM may result in improved os-
teoinductive properties compared with traditional al-
bboooo k o o
patients treated with high-dose recombinant PTH and
b o o k b o oo
lograft.32 DMB also has comparable capacity for bone
o
/
e e
/ e
those treated with placebo.1
e / e
/ e b
Dietary supplementation with calcium and vita-
e e e
/ e b
formation compared with autograft, as reported in a
/
subset of patients with humeral nonunions.33 Allografts
e
: / / / .
t m m
min D, long recommended for improving bone health,
t . : / /t/.tm.m
are not inherently osteogenic because they do not have
ss /
is thought to help reduce fracture risk in patients with
: ss : /
viable cells. Allografts are typically processed via me-
hhtttp hhtttp
osteoporosis and enhance fracture healing. Animal chanical débridement of all soft tissues, washing with
tp
models have shown the benefit of systemic administra-
tion of calcium and vitamin D on bone healing after
fracture.29 In 2004, a double-blind prospective trial
tp
ethanol to remove blood and live cells, and gamma ir-
radiation to sterilize the tissues. Although high-dose ir-
radiation kills bacteria and viruses, it may also decrease
evaluated the effects of the daily administration of vita- the biomechanical properties of the allografts and af-
min D (800 IU) and calcium (1 g) on patients with non- fect the osteoconductive and osteoinductive properties
eers
surgically treated proximal humeral fractures compared
rs e
with placebo. The results of the study showed increased
k k r
e s
r sin a dose-dependent fashion.34 A potential drawback of
allograft is the risk of disease transmission. A strict do-
bboooo k b o o
callus formation (as measured by enhanced bone den-
o o k b o oo
nor screening protocol, such as that implemented by
o
/
e e
/ e e / e
/ e b
sity) at 6 weeks in the treatment group when compared
with the control group.27 In 2012, the US Preventive
e e / e
/ e b
the American Association of Tissue Banks, is critical to
ensure the safety of bone allografts. According to do-
e
: / / t
/ .
t m
Services Task Force published a recommendation
. m
against vitamin D supplementation for the prevention
/ / t
/ .
t m
nor screening recommendations, it has been reported
. m
that the chance of obtaining a bone graft from an HIV-
:
t p ss
p : /
of osteoporotic fractures, citing insufficient current ev-
ss : /
infected donor is 1 in 1.67 million,35 and the risk of ob-
t p p
Bone Grafting
t
hht t
idence to assess the benefits.30
t
hht t
taining DBM that contains HIV is 1 in 2.8 billion.36
Other drawbacks of allograft include a risk of immuno-
genic response, longer healing times, and decreased os-
Autogenous Bone Grafts teoinductive capacity when compared with autograft.
Autogenous bone grafting is the gold standard for the
k e rs
treatment of bone defects and the stimulation of new
rs
bone formation. Autograft can be harvested from the
e k eers
r s
Synthetic Bone Substitutes
Synthetic bone substitutes are an alternative to allograft
b ooook b oook
iliac crest or from local metaphyseal areas. Autograft is
o
osteogenic (contains viable donor osteoblasts and their
b ooo
and autograft and include calcium sulfate, calcium
o
phosphate, tricalcium phosphate, and bioglass. Syn-
/
e e
/ eb ee/ e
/e b
precursors in the tissue that promote bone formation),
/e/e b
thetic bone substitutes are available in multiple forms,
ee
/ t
///t m
osteoinductive (recruits pluripotent MSCs that differen-
. . m
tiate into osteoblasts and chondroblasts), and osteocon-
: / t.
///t m
including powder, pellets, and putty. They are osteo-
.m
conductive but not osteoinductive or osteogenic.
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Several clinical studies have evaluated the use of syn- enhance the differentiation of local stem cells and/or
k eers
rs ke rrs
thetic bone substitutes for bone defect filling in frac-
e s lead to enhanced vascular ingrowth. Several stem cell–
b ooook b o ook
tures of the tibial plateau, hip, distal radius, proximal
o
humerus, and calcaneus.37 One randomized controlled
based approaches have shown improved bone regener-
o oo
o
ation in animal models44,45; however, one study pro-
b
/
ee/e b / e e b
study evaluated the treatment of femoral neck fractures
ee /
with closed reduction and percutaneous pinning.38 No / e e b
posed that skeletal repair requires the structural and
ee /
mechanical support provided by a scaffold to be suc-
t . m
.m
difference was found between the reoperation rates of
: / ///t : / t
///t. m
. m
cessful.46 Several products of bone marrow aspirate/
s
tps :
patients whose treatment did include augmentation
s
tps :
allograft scaffold are currently clinically available.47,48
hhtttp hhtttp
with calcium phosphate cement and those whose treat- A reamer-irrigator-aspirator system49 is also available
ment did not. Another randomized controlled study that provides continuous irrigation and suction during
evaluated the use of calcium phosphate for the treat- long bone reaming. The bone is collected in a suction
ment of depressed tibial plateau fractures.39 Fewer com- bag and can be used as graft material. Despite the in-
plications and decreased articular subsidence were tense research interest in this field, considerable over-
found in patients whose treatment was augmented with sight by regulatory committees exists for regenerative
k eers
rs calcium phosphate cement compared with autograft,39
k eers
r s sciences in general, which may slow the approval for
although the effect on clinical outcomes remains un-

ook ook
stem cell–based therapy in fracture healing in the near
b oo
clear.
b oo future.50
b o oo
o
/
e e
/ eb Platelet-Rich Plasma
e/
e e
/ e b ee/ e
/ e b
Bone Morphogenetic Proteins
: // t/.tm
. m
Platelets are a key component of the inflammatory
t . m
. m
BMPs are part of the TGF-β superfamily and are potent
: / / / t
ss /
phase of bone healing, and activated platelets release
: : /
inducers of bone formation. BMPs are synthesized by
ss
hhtttp hhtttp
many growth factors, including platelet-derived growth skeletal cells and are critical for embryogenesis, skeleto-
tp
factor, transforming growth factor-beta (TGF-β), and
vascular endothelial growth factor. These growth fac- tp
genesis, and maintaining bone mass in the mature skel-
eton.51 More than 30 BMPs have been identified, and
tors influence the proliferation and the differentiation murine studies of tibial fracture healing have shown
of cells, including bone cells, and promote healing. The temporal expression of BMP-2, -3, -4, -5, -6, and -7 at
goal of platelet-rich plasma (PRP) therapy is to de- different stages of the fracture healing process, which
keerrss liver supraphysiologic concentrations of platelets and
k
growth factors to sites of injury to enhance healing;
e rrss
e
suggests these proteins play a role in bone healing.52
The biologic importance of BMPs in bone formation is
bboooo k o o o
however, good-quality data that support the use of PRP
b o k b o oo
exemplified in bone overgrowth disorders that result
o
/
e e
/ e e e
/ e b
for clinical applications in general are sparse. Studies of
/
animal models using PRP therapy for the treatment of
e e e
/
tivation of a receptor.54
e e b
from genetic inactivation of an antagonist53 or overac-
/
: / / / .
t m m
fractures have demonstrated enhanced early cellular
t .
proliferation and chondrogenesis as well as subsequent
: / /t/.tm.m
BMPs promote bone formation using several mecha-
ss : / ss : /
nisms.55 The BMPs recruit MSCs from the surrounding
hhtttp hhtttp
improved callus formation and mechanical strength.40 muscle, bone marrow, and vessels and induce these cells
tp
A recent review identified 61 studies on PRP therapies
for long bone healing in adults, but only 1 study fully
met the inclusion criteria.41 That study evaluated pa-
tp
to become osteoblasts to generate bone directly. In ad-
dition, BMPs induce chondrocytes to initiate the pro-
cess of endochondral ossification and can promote vas-
tients who had undergone corrective tibial osteotomies cularization.55
who were prospectively randomized to allograft alone Two clinically available BMPs are FDA approved:
k eers
rs
or allograft and PRP therapy. No differences were
e
found in functional scores at 1 year; however, enhanced
k r
e s
r s recombinant human BMP-2 (rhBMP-2) and rhBMP-7.
rhBMP-2 is currently approved for the treatment of
bboooo k b o
osteotomy site in the PRP group compared with the o
radiographic integration of the graft was noted at the
o o k b o oo
acute open tibial fractures and for use in spine fusion
o
/
e e
/ e ee/ e
/ e b
allograft-only group.42 One additional study, which
e / e
/ e b
surgery. rhBMP-7 is approved for the treatment of re-
calcitrant long bone nonunions for which autograft is
e
/ / t .
t m
was excluded, was a randomized clinical trial that com-
. m
pared two different treatment types (BMP-7 versus
: / : / / t
/ .
t m
. m
unfeasible and alternative treatment options have
failed, as well as in patients at high risk for fusion fail-
t p ss
p : /
PRP) without including a true-negative control group.
ss : /
ure who require revision posterolateral lumbar spinal
t p p
t t
This group included patients with long bone nonunions
hht
and showed enhanced healing in the BMP-7 group
compared with the PRP group.43
t
hht t
fusion. Several randomized prospective controlled stud-
ies have evaluated fracture healing augmented with
rhBMP-2 and rhBMP-7.55 Three studies evaluated the
use of rhBMP-2 (1.5 mg/mL) in open tibial fractures
Bone Marrow Aspirate and delivered directly to the fracture site in an absorbable
k eers
rs
Stem Cell Therapies
ee
Bone marrow aspirate and stem cell therapies are topics
k rs
r s
collagen sponge. Two of the studies showed accelerated
fracture and wound healing times in severe open frac-
b ooook b ook
of considerable current research for the enhancement of
oo
fracture healing. Bone marrow is a source of circulating
b oooo
ture injuries, a decreased need for secondary proce-
dures (bone grafting, invasive procedures, procedures
/
e e
/ eb / e
/e b
endothelial progenitors that can participate in bone
ee ee/e/e b
for delayed union), and lower rates of infection in se-
/ t
///t m
healing either directly by differentiating into osteoblasts
. . m
or indirectly by secreting various growth factors that
: : / t.
///t m
vere open fractures.56,57 The third study did not identify
.m
any differences in healing rate, infection rate, or the
s
tps : s
tps :
20
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
need for secondary surgeries in open tibial fractures trolled trial that evaluated extracorporeal shock wave
k eers
rs ke r
treated by reaming with intramedullary nails.58 A 2006
e rss therapy for acute tibial and femoral fractures was iden-
b ooook b o ook
study evaluated the effects of treating patients who sus-
o
tained tibial fractures with severe bone loss using
tified and found no improvement in achieving union at
o oo
o
12 months, but small differences in the visual analog
b
/
ee/e b / e e b
rhBMP-2 and allograft versus autograft. The study
ee /
noted decreased blood loss in the group treated with / e e b
scale for pain at 3, 6, and 12 months in favor of extra-
ee /
corporeal shock wave therapy.66
t . m
.m
rhBMP-2 and allograft but no difference in healing
: / ///t : / t
///t. m
. m
Vibration therapy is based on Wolff’s law, which
s
tps :
rates or functional outcome scores.59 Four studies eval-
s
tps :
states that bone adapts to its mechanical environment.
hhtttp hhtttp
uated the clinical use of rhBMP-7 for nonunions,43,60 The osteogenic effect of vibration therapy on intact bone
malunions,61 and large fibular defects following high and the stimulating effect on limb blood flow have been
tibial osteotomies62 in randomized controlled trials. documented in animal and human studies67 and is typ-
rhBMP-7 (3.5 mg/mL) was shown to be equivalent to ically administered in a low-magnitude, high-frequency
autograft for the treatment of tibial nonunion60 and su- mode. Whole-body vibration therapy has been proposed
perior to PRP therapy for long bone nonunion.43 The for the treatment of osteoporosis.68 Some animal models
k rs
rs
results of a 1999 study showed increased formation of
ee k eers
r s have demonstrated a marginal or beneficial effect of vi-
ook ook
bone and bridging of the segmental defect in fibular de- bration therapy on fracture healing.69 Well-designed clin-
b oo b o
fects using rhBMP-7 compared with a control group.62
o b o oo
ical studies are needed to better assess the effects of bio-
o
/
e e
/ eb ee e
/ e b
However, a 2008 study found slower healing time in
/
patients with distal radius fracture malunion treated
ee/ e
/ e b
physical stimulation on bone healing.
t . m
. m
with corrective osteotomies and augmented with
: // / t : / / t
/ .
t m
. m
ss /
rhBMP-7 compared with patients treated using au-
: s
Summary
s : /
hhtttp hhtttp
tograft.61
tp
External Stimulation: Electrical Stimulation,
tp
There is considerable interest in unraveling the complex
regulation of bone repair to devise new strategies for
Ultrasound, and Vibration Therapy the enhancement of fracture healing, both in acute frac-
Biophysical treatments, such as electrical stimulation, tures and in delayed unions and nonunions. Recent ad-
ultrasound, shock, and vibration therapy have the po- vances in augmented fracture repair through bone
k errss
tential to improve fracture healing. In 1953, the first
e k e rrss
e
grafting, biologics, and biophysical stimulation have
made significant progress toward enhancing bone re-
bboooo k
work on the effects of electric forces on bone healing
b o o
was published.63 In 1970, early evidence showed that
o o k b o oo
pair, but substantial research is needed to further en-
o
/
e e
/ e ee e
/ e b
electrical stimulation can lead to bone formation.64
/
Since then, there has been considerable interest in the
e e
/ e b
hance the processes of fracture healing, particularly in
/
the compromised patient. Given the high societal bur-
e
t . m
. m
manipulation of electric forces in bone healing; how-
: / / / t : / /t/.tm.m
den of delayed unions, nonunions, and routine fracture
healing, additional strategies, including cell-based and
ss /
ever, clinical data in support of electrical stimulation,
: ss : /
hhtttp hhtttp
ultrasound, shock, and vibration for enhanced fracture scaffold-based therapies, are needed to enhance the
tp
healing are relatively sparse.
In a 2011 review, four randomized placebo- tp
fracture healing process.
controlled studies were identified that evaluated the ef-

fects of electrical stimulation for treating delayed union Key Study Points
or nonunion of long bone fractures in adults.65 The
k eerss
data demonstrated that electrical stimulation was safe,
r k e
with only two minor skin irritations reported. Further, r
e s
r s • The two ways in which fracture healing occurs
bboooo k b o o o k
the results favored electrical stimulation compared with
o
mirrors endochondral (indirect bone formation
b o oo
o
through cartilage phase) and intramembranous
/
e e
/ e e / / e b
placebo, but the overall pooled estimate was not signif-
e
icant (relative risk, 1.96; 95% confidence interval,
e ee/ e
/ e b
(direct bone formation from progenitor cells)
bone formation during development.
0.86-4.48).65
: / / t
/ .
t m
. m
Ultrasound is high-frequency sound waves and is a •
: / / t
/ .
t m
. m
Absolute stability with direct apposition of bone
ss : /
form of mechanical stimulation. For the augmentation
t p p t p ss
p : /
favors direct bone healing, and relative stability
t
hht t
of fracture healing, the ultrasound probe is typically
placed directly over the fracture site for 20 minutes per
day. Three types of ultrasound therapy have been de-
t
hht t
favors indirect healing through a fracture callus.
Various treatments rendered by physicians and
surgeons can alter the degree of stability and af-
scribed: low-intensity pulsed ultrasound, high-intensity fect the mode of healing.
focused ultrasound, and extracorporeal shock wave • The enhancement of problematic fracture heal-
k eers
therapy. Another recent review evaluated the effects of
rs
ultrasound and shock wave therapy for acute fractures
k eers
r s
ing (nonunion, delayed union, gap defect) can be
treated by improving the mechanical environ-
b ooook b ook
in adults.66 The authors identified 11 randomized con-
oo
trolled trials that evaluated low-intensity pulsed ultra-
b oooo
ment; altering modifiable biologic factors sys-
temically; or applying local therapies such as
/
e e
/ eb / e
/e b
sound and found that ultrasound therapy was favored
ee ee/e/e b
bone grafts, biologic factors, or cell-based en-
/ t
///t. m
in acute fractures, but no difference was found in de-
. m
layed unions and nonunions. One randomized con-
:
hancements.
: / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
to nicotine. Gene ontologic analysis showed that many
k eers
rs Annotated References
keerrss of the identified genes play key roles in cellular prolifer-

ation and/or apoptosis.
b ooook 1.
o ook
Aspenberg P, Genant HK, Johansson T, et al: Teri-
b o b o oo
o
/
ee/e b e / / e b
paratide for acceleration of fracture repair in humans: A
e
prospective, randomized, double-blind study of 102
e
12.
e / e
/ e b
Castillo RC, Bosse MJ, MacKenzie EJ, Patterson BM;
LEAP Study Group: Impact of smoking on fracture
e
: / t
///t m
postmenopausal women with distal radial fractures.
. .m
J Bone Miner Res 2010;25(2):404-414.
: / ///t. m
. m
healing and risk of complications in limb-threatening
t
open tibia fractures. J Orthop Trauma 2005;19(3):
s
tps :
Although the clinically approved dose of recombinant
s
tps : 151-157.
hhtttp hhtttp
PTH (teriparatide [20 µg]) reduced the time to cortical
bridging in distal radius fractures when compared with 13. Schmitz MA, Finnegan M, Natarajan R, Champine J:
placebo, the authors were unable show that recombi- Effect of smoking on tibial shaft fracture healing. Clin
nant PTH enhances healing in a dose-dependent man- Orthop Relat Res 1999;365:184-200.
ner. Level of evidence: I.
k eers
rs 2.
rs
Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT,
k ee r s
14. Macey LR, Kana SM, Jingushi S, Terek RM, Borretos J,
Bolander ME: Defects of early fracture-healing in exper-
Einhorn TA: Fracture healing as a post-natal develop-
ook ook
imental diabetes. J Bone Joint Surg Am 1989;71(5):
b oo b o
mental process: Molecular, spatial, and temporal aspects
o 722-733.
b o oo
o
/
e e
/ eb e/
e e
/ e b
of its regulation. J Cell Biochem 2003;88(5):873-884.
15.
ee/ e
/ e b
Kayal RA, Alblowi J, McKenzie E, et al: Diabetes causes
3.
// t/.tm
Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA:
. m
Growth factor regulation of fracture repair. J Bone
: : / / t
/ .
t m
. m
the accelerated loss of cartilage during fracture repair
ss : /
Miner Res 1999;14(11):1805-1815.
ss : /
which is reversed by insulin treatment. Bone 2009;
hhtttp hhtttp
44(2):357-363.
4. tp
Kon T, Cho TJ, Aizawa T, et al: Expression of osteo-
protegerin, receptor activator of NF-kappaB ligand (os-
tp16. Loder RT: The influence of diabetes mellitus on the
healing of closed fractures. Clin Orthop Relat Res
teoprotegerin ligand) and related proinflammatory cyto- 1988;232:210-216.
kines during fracture healing. J Bone Miner Res 2001;
16(6):1004-1014.
rrss rrss
17. Brinker MR, O’Connor DP, Monla YT, Earthman TP:
o ke
ke 5.
o k e
k e
Hankemeier S, Grässel S, Plenz G, Spiegel HU, Bruck-
Metabolic and endocrine abnormalities in patients with
oo
nonunions. J Orthop Trauma 2007;21(8):557-570.
e bboo o e b o
b o
ner P, Probst A: Alteration of fracture stability influ-
o
ences chondrogenesis, osteogenesis and immigration of
e b o
b o
/
e / e m e / / e
macrophages. J Orthop Res 2001;19(4):531-538.
e
18.
/ / e
Lancourt JE, Hochberg F: Delayed fracture healing in
ee
primary hyperparathyroidism. Clin Orthop Relat Res
m
6.
: / /
/ t
/ .
t . m
Gerstenfeld LC, Alkhiary YM, Krall EA, et al: Three-
: / /
/t/.t .m
1977;124:214-218.
ss : ss :
hhtttp hhtttp
dimensional reconstruction of fracture callus morpho-
tp tp
genesis. J Histochem Cytochem 2006;54(11):1215- 19. Brown KM, Saunders MM, Kirsch T, Donahue HJ,
Reid JS: Effect of COX-2-specific inhibition on fracture-
1228.
healing in the rat femur. J Bone Joint Surg Am 2004;
86(1):116-123.
7. Goldring MB, Tsuchimochi K, Ijiri K: The control of
chondrogenesis. J Cell Biochem 2006;97(1):33-44.
20. Kurmis AP, Kurmis TP, O’Brien JX, Dalén T: The effect
k eers
rs 8.
k e r s
r
Danis R: Théorie et pratique de l’ostéosynthèse. Paris,
e s of nonsteroidal anti-inflammatory drug administration
on acute phase fracture-healing: A review. J Bone Joint
bboooo k France, Masson, 1949.
b o o
o o k b o oo
Surg Am 2012;94(9):815-823.
o
/
e e
/ e 9.
/ e e b
Schenk R, Willenegger H: [On the histological picture of
ee /
so-called primary healing of pressure osteosynthesis in
e / e
/ e b
The authors present a review on the controversial topic
of NSAID use during the acute postfracture period. De-
e
t . m
. m
experimental osteotomies in the dog]. Experientia 1963;
: / / / t : / / t t m
spite preclinical animal models suggesting COX-2 inhi-
. . m
bition impairs early fracture healing, there was insuffi-
/
19:593-595.
t p ss
p : / t p ss
p : /
cient evidence to withhold NSAID use clinically. Level
of evidence: IV.
10.
t
hht t
Bishop JA, Palanca AA, Bellino MJ, Lowenberg DW:
Assessment of compromised fracture healing. J Am
Acad Orthop Surg 2012;20(5):273-282.
t
hht t
21. Waters RV, Gamradt SC, Asnis P, et al: Systemic corti-
costeroids inhibit bone healing in a rabbit ulnar osteot-
The authors present a comprehensive review on fracture omy model. Acta Orthop Scand 2000;71(3):316-321.
nonunions, including epidemiology, risk factors, clinical
k eers
rs k eers
evaluation, and classification. Level of evidence: IV.
r s 22. Bogoch ER, Ouellette G, Hastings DE: Intertrochanteric

fractures of the femur in rheumatoid arthritis patients.
b ooook 11.
b ook
Rothem DE, Rothem L, Dahan A, Eliakim R, Soudry
oo
M: Nicotinic modulation of gene expression in osteo-
o oo
Clin Orthop Relat Res 1993;294:181-186.
b o
/
e e
/ eb e/ e
/e b
blast cells, MG-63. Bone 2011;48(4):903-909.
e 23.
e /e/e b
McDonald MM, Dulai S, Godfrey C, Amanat N, Sz-
e
/ t
///t m
Using MG-63 osteoblast-like cells, this study identified
. . m
842 genes whose expression was altered after exposure
: : / t.
///t m
tynda T, Little DG: Bolus or weekly zoledronic acid ad-
.m
ministration does not delay endochondral fracture re-
s
tps : s
tps :
22
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
pair but weekly dosing enhances delays in hard callus 33. Hierholzer C, Sama D, Toro JB, Peterson M, Helfet DL:
k eers
rsremodeling. Bone 2008;43(4):653-662.
keerrss Plate fixation of ununited humeral shaft fractures: Ef-

fect of type of bone graft on healing. J Bone Joint Surg
b ooook
24.
o ook
o
Goldhahn J, Féron JM, Kanis J, et al: Implications for
b b o oo
Am 2006;88(7):1442-1447.
o
/
ee/e b ee e
/ b
fracture healing of current and new osteoporosis treat-
/ e
ments: An ESCEO consensus paper. Calcif Tissue Int 34.
ee/ e
/ e b
Nguyen H, Morgan DA, Forwood MR: Sterilization of
2012;90(5):343-353.
: / t
///t. m
.m : / t
///t. m
. m
allograft bone: Effects of gamma irradiation on allograft
biology and biomechanics. Cell Tissue Bank 2007;8(2):
s
tps :
The authors present a review on current treatment op-
s
tps :
hhtttp hhtttp
tions for osteoporosis, and they conclude that there is 93-105.
no evidence that osteoporosis treatments are detrimental
to bone healing, and they may have some positive ef- 35. Buck BE, Malinin TI: Human bone and tissue allografts:
fects on bone healing. Level of evidence: IV. Preparation and safety. Clin Orthop Relat Res 1994;
303:8-17.
25. Rosenberg GA, Sferra JJ: Treatment strategies for acute
k eers
rssal. J Am Acad Orthop Surg 2000;8(5):332-338.
k eers
fractures and nonunions of the proximal fifth metatar-
r s
36. Russo R, Scarborough N: Inactivation of viruses in de-
mineralized bone matrix. FDA Workshop on Tissue
b ooook
26.
b ooook
Kozin SH: Incidence, mechanism, and natural history of MD, 1995.
b o oo
Transplantation and Reproductive Tissue. Bethesda,
o
/
e e
/ eb / e e b
scaphoid fractures. Hand Clin 2001;17(4):515-524.
ee / 37.
ee/ e
/ e b
Larsson S, Hannink G: Injectable bone-graft substitutes:
27.
: // t/.tm
. m
Doetsch AM, Faber J, Lynnerup N, Wätjen I, Bliddal H,
: / / t
/ .
t m
. m
Current products, their characteristics and indica-
s : /
Danneskiold-Samsøe B: The effect of calcium and vita-
s ss : /
tions, and new developments. Injury 2011;42(suppl 2):
hhtttp hhtttp
S30-S34.
tp tp
min D3 supplementation on the healing of the proximal
humerus fracture: A randomized placebo-controlled This article describes the biomechanical properties of
study. Calcif Tissue Int 2004;75(3):183-188. the most common injectable bone graft substitutes cur-
rently commercially available and their use in specific
28. Andreassen TT, Fledelius C, Ejersted C, Oxlund H: In- clinical situations. Level of evidence: IV.
creases in callus formation and mechanical strength of
keerrss
hormone. Acta Orthop Scand 2001;72(3):304-307.
k e rrss
healing fractures in old rats treated with parathyroid
e
38. Mattsson P, Larsson S: Calcium phosphate cement for
augmentation did not improve results after internal fix-
bboooo k b o o
o o k b o oo
ation of displaced femoral neck fractures: A randomized
o
study of 118 patients. Acta Orthop 2006;77(2):
/
e e
/ e
29.
/ e
/ e b
Delgado-Martínez AD, Martínez ME, Carrascal MT,
Rodríguez-Avial M, Munuera L: Effect of 25-OH-
ee
251-256.
ee/ e
/ e b
Res 1998;16(6):650-653.
: / / t
/ .
t m
vitamin D on fracture healing in elderly rats. J Orthop
. m 39.
: / /t/.tm.m
Russell TA, Leighton RK; Alpha-BSM Tibial Plateau
ss : / ss : /
Fracture Study Group: Comparison of autogenous bone
hhtttp hhtttp
graft and endothermic calcium phosphate cement for
30.
tp
US Preventive Services Task Force: Vitamin D and cal-
cium supplementation to prevent cancer and osteoporo-
tic fractures in adults: US Preventive Services Task Force
tp defect augmentation in tibial plateau fractures: A multi-
center, prospective, randomized study. J Bone Joint Surg
Am 2008;90(10):2057-2061.
recommendation statement. DRAFT. June 12, 2012.
http://www.uspreventiveservicestaskforce.org/uspstf12/
vitamind/draftrecvitd.htm. Accessed February 14, 2012. 40. Kasten P, Vogel J, Geiger F, Niemeyer P, Luginbühl R,
k eers
rs k e r
Sixteen randomized controlled trials with considerable
e s
r
heterogeneity in populations and interventions were ex- s
Szalay K: The effect of platelet-rich plasma on healing in
critical-size long-bone defects. Biomaterials 2008;
bboooo k b o o o k
amined by the US Preventive Services Task Force. They
o
29(29):3983-3992.
b o oo
o
/
e e
/ e ee/ e
/ e b
concluded that the current evidence was insufficient to
determine if vitamin D and calcium supplementation 41.
ee/ e
/ e b
Griffin XL, Wallace D, Parsons N, Costa ML: Platelet
rich therapies for long bone healing in adults. Cochrane
: / / t
/ t m
prevents fractures in premenopausal and postmeno-
. . m
pausal women. Level of evidence: II.
: / / t
/ .
t m
. m
Database Syst Rev 2012;7:CD009496.
t p ss
p : / t p ss
p : /
One randomized controlled trial of 21 participants was
31.
t
Myeroff C, Archdeacon M: Autogenous bone graft: Do-
hht t
nor sites and techniques. J Bone Joint Surg Am 2011;
93(23):2227-2236.
t
hht t included in this systematic literature review. Given the
paucity of eligible studies, the authors determined that
insufficient evidence exists to assess the efficacy of PRP
This review provides a comprehensive overview of au- therapies in long bone healing. Level of evidence: I.
togenous bone grafts, primarily focusing on autogenous
cancellous bone grafting, donor site techniques, associ- 42. Dallari D, Savarino L, Stagni C, et al: Enhanced tibial
k eers
rs k
clinical decision making. Level of evidence: IV.
eers
r s
ated complications, and relevant clinical data to inform osteotomy healing with use of bone grafts supplemented
with platelet gel or platelet gel and bone marrow
b ooook b oook
o b oooo
stromal cells. J Bone Joint Surg Am 2007;89(11):2413-
/
e e
/ eb 32.
e e
/e b
Drosos GI, Kazakos KI, Kouzoumpasis P, Verettas DA:
/
Safety and efficacy of commercially available deminer-
e
2420.
ee/e/e b
: / t
///t. m
alised bone matrix preparations: A critical review of
. m
clinical studies. Injury 2007;38(suppl 4):S13-S21.
43.
: / t.
///t m
Calori GM, Tagliabue L, Gala L, d’Imporzano M, Per-
.m
etti G, Albisetti W: Application of rhBMP-7 and
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
platelet-rich plasma in the treatment of long bone non- This comprehensive paper reviews the role of bone mor-
k eers
rs r
unions: A prospective randomised clinical study on
kee rss phogenic proteins in skeletal disease and therapy. Level

of evidence: IV.
ook ook
120 patients. Injury 2008;39(12):1391-1402.
b oo b o o b o oo
o
/
ee/e b 44.
ee e
/ e b
Bruder SP, Kurth AA, Shea M, Hayes WC, Jaiswal N,
/
Kadiyala S: Bone regeneration by implantation of puri-
52.
e e
/ e b
Kidd LJ, Stephens AS, Kuliwaba JS, Fazzalari NL, Wu
/
AC, Forwood MR: Temporal pattern of gene expression
e
: / ///t.
J Orthop Res 1998;16(2):155-162.m
.m
fied, culture-expanded human mesenchymal stem cells.
t : / t
///t. m
. m
and histology of stress fracture healing. Bone 2010;
46(2):369-378.
s
tps : s
tps :
hhtttp hhtttp
In a rat model of primary bone healing for ulnar stress
45. Kadiyala S, Jaiswal AI, Bruder SP: Culture-expanded, fracture, the authors quantitatively evaluated the tempo-
bone marrow-derived mesenchymal stem cells can re- ral and spatial pattern of gene expression and tissue for-
generate a critical-sized segmental bone defect. Tissue mation for 14 days postfracture. Level of evidence: V.
Eng 1997;3:173-185.
53. Gong Y, Krakow D, Marcelino J, et al: Heterozygous
k eers
rs
46.
k ee s
Khosla S, Westendorf JJ, Mödder UI: Concise review:
rr
Insights from normal bone remodeling and stem cell-
s
mutations in the gene encoding noggin affect human
joint morphogenesis. Nat Genet 1999;21(3):302-304.
b ooook 2124-2128.
b ooook
based therapies for bone repair. Stem Cells 2010;28(12):
54.
b o oo
o
Shore EM, Xu M, Feldman GJ, et al: A recurrent muta-
/
e e
/ eb / e e b
This article presents an evolving view of the role of stem
ee /
cells in normal bone remodeling and in the use of stem / e e b
tion in the BMP type I receptor ACVR1 causes inherited
ee /
and sporadic fibrodysplasia ossificans progressiva. Nat
t . m
. m
cell-based therapies to enhance fracture repair. Level of
: // / t : / / t
/ .
t m
. m
Genet 2006;38(5):525-527.
evidence: IV.
ss : / ss : /
hhtttp hhtttp
55. Garrison KR, Shemilt I, Donell S, et al: Bone morpho-
47.
tp
Guyton GP, Miller SD: Stem cells in bone grafting: Trin-
ity allograft with stem cells and collagen/beta-tricalcium
phosphate with concentrated bone marrow aspirate.
tp genetic protein (BMP) for fracture healing in adults.
Cochrane Database Syst Rev 2010;6:CD006950.
Eleven randomized controlled trials and four economic
Foot Ankle Clin 2010;15(4):611-619. evaluations were included in this systematic review.
This article describes a proprietary bone graft substitute Limited evidence suggests that bone morphogenetic pro-
keerrss combined with concentrated bone marrow aspirates to

promote fracture healing. Level of evidence: V.
k e rrss
e
teins may enhance acute tibial fracture healing; however,
the efficacy of bone morphogenetic proteins for treating
bboooo k 48.
b o o
o o k
Hollawell SM: Allograft cellular bone matrix as an al-
b o oo
nonunions was comparable to that of standard bone
o
grafts. Level of evidence: I.
/
e e
/ e / e e b
ternative to autograft in hindfoot and ankle fusion pro-
ee /
cedures. J Foot Ankle Surg 2012;51(2):222-225. 56.
ee/ e
/ e b
Govender S, Csimma C, Genant HK, et al: Recombi-
/ / t .
t m
. m
The authors treated 20 hindfoot and ankle fusions with
: / : / /t/.tm.m
nant human bone morphogenetic protein-2 for treat-
s : /
a proprietary allogenic cellular bone matrix. Fusion was
s ss : /
ment of open tibial fractures: A prospective, controlled,
hhtttp hhtttp
randomized study of four hundred and fifty patients. J
tp tp
assessed radiographically at 1, 3, 6, and 12 months. The
average time to fusion was 13.5 weeks (range, 8 to 24 Bone Joint Surg Am 2002;84-A(12):2123-2134.
weeks). Level of evidence: IV. The authors randomized 277 open tibial fractures
treated with reamed intramedullary nail fixation versus
49. Cox G, Jones E, McGonagle D, Giannoudis PV: intramedullary nail plus an absorbable collagen sponge
Reamer-irrigator-aspirator indications and clinical re- containing rhBMP-2. The addition of the collagen
k eers
rs sults: A systematic review. Int Orthop 2011;35(7):
951-956.
k e r
e s
r s sponge containing rhBMP-2 did not significantly accel-
erate healing. Level of evidence: I.
bboooo k o o o k
This systematic literature review of the reamer-irrigator-
b o 57.
b o oo
o
Swiontkowski MF, Aro HT, Donell S, et al: Recombi-
/
e e
/ e e / / e b
aspirator reaming systems suggests that it is a reliable
e
method of achieving high volumes of bone graft mate-
e ee/ e
/ e b
nant human bone morphogenetic protein-2 in open tib-
ial fractures: A subgroup analysis of data combined
: / / t
/ t m
rial and mesenchymal stem cells similar to those ob-
. . m
tained using a standard iliac crest bone graft. Level of
: / / t . m
. m
from two prospective randomized studies. J Bone Joint
/ t
evidence: IV.
t p ss
p : / t p ss
p : /
Surg Am 2006;88(6):1258-1265.
50. t
hht t
Cyranoski D: FDA’s claims over stem cells upheld. Na-
ture 2012;488(7409):14.
t
hht t
58. Aro HT, Govender S, Patel AD, et al: Recombinant hu-
man bone morphogenetic protein-2: A randomized trial
This editorial discusses a recent US District Court ruling in open tibial fractures treated with reamed nail fixa-
that affirmed the right of the FDA to regulate therapies tion. J Bone Joint Surg Am 2011;93(9):801-808.
made from a patient’s own processed stem cells. Level of This is a randomized control trial evaluating the effects
k eers
rs evidence: V.
k eers
r s of rhBMP-2 in open tibial fractures treated with reamed
intramedullary nails. The authors concluded that
b ooook 51.
oook
Biver E, Hardouin P, Caverzasio J: The “bone morpho-
b o b oooo
rhBMP-2 did not accelerate fracture healing. Level of
/
e e
/ eb e / e
/e b
genic proteins” pathways in bone and joint diseases:
Translational perspectives from physiopathology to
e
evidence: I.
ee/e/e b
24(1):69-81.
: / t
///t. m
therapeutic targets. Cytokine Growth Factor Rev 2013;
. m
59.
: / t.
///t m
Jones AL, Bucholz RW, Bosse MJ, et al: Recombinant
.m
human BMP-2 and allograft compared with autogenous
s
tps : s
tps :
24
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
bone graft for reconstruction of diaphyseal tibial frac- Four randomized controlled trials involving 125 partic-
k eers
rs rrss
tures with cortical defects: A randomized, controlled
kee
ipants were included in this systematic literature review.
Although electromagnetic field stimulation appears to
ook ook
trial. J Bone Joint Surg Am 2006;88(7):1431-1441.
b oo b o o b o oo
be safe and may provide some benefit, the evidence was
o
/
ee/e b 60.
ee/ e
/ e b
Friedlaender GE, Perry CR, Cole JD, et al: Osteogenic
protein-1 (bone morphogenetic protein-7) in the treat-
e
dence: II.
e/ e
/ e b
insufficient to inform current practice. Level of evi-
: / t
///t
83(pt 2, suppl 1):S151-S158. . mm
ment of tibial nonunions. J Bone Joint Surg Am 2001;
. 66.
: / t
///t. m
. m
Griffin XL, Smith N, Parsons N, Costa ML: Ultrasound
s
tps : s
tps : and shockwave therapy for acute fractures in adults.
hhtttp hhtttp
Cochrane Database Syst Rev 2012;2:CD008579.
61. Ekrol I, Hajducka C, Court-Brown C, McQueen MM:
A comparison of rhBMP-7 (OP-1) and autogenous graft Twelve clinically heterogeneous randomized controlled
for metaphyseal defects after osteotomy of the distal ra- trials involving 648 fractures in 662 participants were
dius. Injury 2008;39(suppl 2):S73-S82. included in this systematic review. The authors found in-
sufficient evidence to support the routine use of ultra-
sound in the treatment of acute fractures. Level of evi-
k
62.
eers
rs
Geesink RG, Hoefnagels NH, Bulstra SK: Osteogenic
eers
r
activity of OP-1 bone morphogenetic protein (BMP-7)
k s dence: II.
b ooook 81(4):710-718.
b ooook
in a human fibular defect. J Bone Joint Surg Br 1999;
67.
o oo
Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod
b o
/
e e
/ eb e/
e e
/ e b e / e
/ e b
K: Anabolism: Low mechanical signals strengthen long
bones. Nature 2001;412(6847):603-604.
e
63.
: / t/ t
J Kyoto Med Soc 1953;4:395-406.
/ m
Yasuda I: Fundamental aspects of fracture treatment.
. . m :
68.
/ / t
/ .
t m
. m
Rubin C, Recker R, Cullen D, Ryaby J, McCabe J,
ss : / ss : /
McLeod K: Prevention of postmenopausal bone loss by
hhtttp
tp hhtttp
tp
64. Friedenberg ZB, Andrews ET, Smolenski BI, Pearl BW, a low-magnitude, high-frequency mechanical stimuli: a
Brighton CT: Bone reaction to varying amounts of clinical trial assessing compliance, efficacy, and safety.
direct current. Surg Gynecol Obstet 1970;131(5): J Bone Miner Res 2004;19(3):343-351.
894-899.
69. Leung KS, Shi HF, Cheung WH, et al: Low-magnitude
65. Griffin XL, Costa ML, Parsons N, Smith N: Electro- high-frequency vibration accelerates callus formation,
keerrss k rrss
magnetic field stimulation for treating delayed union or
e e
non-union of long bone fractures in adults. Cochrane
mineralization, and fracture healing in rats. J Orthop
Res 2009;27(4):458-465.
bboooo k Database Syst Rev 2011;4:CD008471.
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 3
e rs
rs e rrss
oo
kArticular
ook e Cartilage o and
k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Intervertebral t
///t. m
.mDisk
ee t
///t. m
. mee
s: /
: s : /
:
tps
hhtttp tps
hhtttp
Alfred C. Kuo, MD, PhD Tamara Alliston, PhD Jeffrey Lotz, PhD
k eers
rs k eers
r s
b ooook Introduction
b ooook Articular Cartilage
b o oo
o
/
e e
/ eb e/ / e b
Articular cartilage and the intervertebral disk are con-
e
nective tissues that function in load transmission and
e ee/ e
/ e b
Structure/Composition/Function
Articular cartilage has a highly structured organization,
: // /.tm m
motion. Extracellular matrix (ECM) accounts for most
t . t . m
. m
with cellular characteristics and matrix composi-
: / / / t
ss /
of the volume in both of these tissues and allows for
: ss : /
tion varying throughout the depth of the tissue (Fig-
hhtttp hhtttp
their specialized functions. Proteoglycans and collagens ure 1, A). From the joint surface to subchondral bone,
tp
are the major macromolecules in both cartilage and
disk ECM. The glycosaminoglycan (GAG) side chains
of proteoglycans carry a high negative charge density,
tp
cartilage is subdivided into the superficial zone, the in-
termediate (transitional) zone, the deep (radial) zone,
and the calcified zone. The lamina splendens is a cell-
which attracts cations and water and leads to hydro- free layer of matrix at the surface of the superficial
static tissue pressurization. These actions, in turn, sup- zone. The superficial zone has the highest content of
keerrss
port the compressive properties of cartilage and disk.
Collagens form a fibrous network that encases the
k e rrss
e
collagen and the lowest content of proteoglycan. Chon-
drocytes (cartilage cells) in this zone produce lubricin
bboooo k o o o
charged proteoglycans and contributes to tensile prop-
b o k b o oo
and have a flat shape, in contrast to round chondro-
o
/
e e
/ e ee e
/ e b
erties. In adults, cartilage and the nucleus pulposus of
/
the disk lack a blood supply. Diffusion and convection
e e
/ e b
cytes in the deeper zones. The superficial zone contains
/
a population of cells with characteristics of progenitor
e
: / / t
/ .
t m m
(bulk fluid flow) account for the transport of nutrients
. : / /t/.tm.m
cells; however, their role is unclear.1 Collagen fibers in
ss /
and wastes. Because of these factors, as well as low cell
: ss : /
the superficial zone are aligned parallel to the joint sur-
hhtttp hhtttp
density, both tissues have an extremely limited intrinsic face and resist shear. Collagen content decreases and
tp
healing response. Current and developing treatments of
cartilage and disk disorders attempt to overcome these
tp
proteoglycan content increases from the superficial
zone to the deep zone. Collagen fibers transition to an
orientation perpendicular to the joint surface in the
limitations.
deep zone. The tidemark represents the junction be-
tween the deep zone and the zone of calcified cartilage.
k eers
rs k e r
e s
r sThe zone of calcified cartilage contains high levels of
type X collagen as well as a mineralized extracellular
bboooo k
Dr. Kuo or an immediate family member has received re-
b o o o k
search or institutional support from the Musculoskeletal
o b o oo
matrix. Calcified cartilage is permeable to small mole-
o
/
e e
/ e ee e
/ e b
Transplant Foundation and StemRD. Dr. Alliston or an
/
immediate family member serves as a board member,
e / e
/ e b
cules; however, diffusion is diminished relative to un-
calcified cartilage. Analysis of the three-dimensional
e
: / / t
/ .
t m m
owner, officer, or committee member of the American
. : / / t
/ .
t m
structure of cartilage with electron microscopy shows
. m
that collagen is arranged not only as fibers but as lay-
t p ss : /
Academy of Orthopaedic Surgeons and the Orthopaedic
Research Society. Dr. Lotz or an immediate family mem-
p t p ss : /
ered, leaf-like structures that account for the fiber ori-
p
t
hht t
ber serves as a paid consultant to or is an employee of
ISTO Technologies and Nocimed; serves as an unpaid
consultant to Spinal Motion, Simperica Spinal Restora-
t
hht t
entations discussed previously2 (Figure 1, B).
Articular cartilage lines the ends of bones at synovial
joints, functioning in load distribution and allowing al-
tion, Relievant, and SMC Biotech; has stock or stock op- most frictionless movement. Chondrocytes comprise
tions held in ISTO Technologies, Spinal Motion, Reliev- 10% or less of the volume of cartilage. Water makes up
k eers
ant, Nocimed, Simperica Spinal Restoration, Orthofix,
rs k
and Relievant; has received research or institutional
eers
r s
60% to 80% of the wet weight of cartilage, with colla-
gens comprising 10% to 30%, and proteoglycans com-
b ooook b ook
support from Orthofix and Relievant; and has received
oo b oooo
prising 5% to 15%. Type II collagen is the most abun-
dant collagen in cartilage, which also contains smaller
/
e e
/ eb e / e
/e b
nonincome support (such as equipment or services),
commercially derived honoraria, or other non–research-
e ee/e/e b
amounts of types VI, IX, X, and XI collagen. Aggrecan
Technologies.
: / t
///t m
related funding (such as paid travel) from ISTO
. . m : / t.
///t m
is the predominant proteoglycan in cartilage and con-
.m
tains large numbers of the negatively charged GAGs
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs Figure 1
k eers
r s
A, Articular cartilage cross-sectional architecture. The chondrocytes in the superficial zone are small and flattened; in
b ooook b oook b oo
the transitional and deep zones, they are rounded and reside in larger lacunae. B, Scanning electron microscopy
o o o
image of bovine articular cartilage showing the arrangement of collagen leaflets. These leaflets are in a horizontal
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
orientation at the articular surface (AS). (Panel A reproduced from Kim HT, Yoon ST, Jarrett C: Articular cartilage
and intervertebral disk, in Fischgrund JS, ed: Orthopaedic Knowledge Update, ed 9. Rosemont, IL, American Acad-
// /.tm
. m / / t
/ .
t m
. m
emy of Orthopaedic Surgeons, 2008, pp 23-33. Panel B reproduced with permission from Jeffery AK, Blunn GW,
t
Archer CW, Bentley G: Three-dimensional collagen architecture in bovine articular cartilage. J Bone Joint Surg Br
: :
s :
1991;73[5]:795-801.)
s / ss : /
hhtttp
tp
chondroitin and keratan sulfate. Most of the aggrecan
is found in high-molecular-weight aggregates that also
hhtttp
tp biochemical stimuli. Chondrocytes sense and respond
to a diversity of cues: mechanical forces such as ten-
include hyaluronic acid and link protein. Additional sion, compression, fluid flow, hydrostatic pressure, and
proteoglycans include biglycan, decorin, fibromodulin, shear stress; intrinsic physical cues such as ECM stiff-
keerrss lumican, perlecan, and versican.
k e rrss
e
ness and topography; chemical cues such as oxygen
bboooo k Although water, proteoglycans, and collagen con-
o o
o o k
tribute to cartilage’s weight-bearing properties, several
b
tension and pH; and biochemical cues such as growth
b o oo
factors and inflammatory cytokines.5 For example,
o
/
e e
/ e ee/ e
/ e b
molecules contribute to cartilage lubrication. Lubricin/
PRG4/superficial zone protein is a glycoprotein se-
ee e
/ e b
compressive loads that mimic the frequency and the in-
/
tensity of walking stimulate new cartilage matrix syn-
t . m
. m
creted by surface chondrocytes and synovial cells. Mu-
: / / / t : / /t/.tm m
thesis.6 Cyclic compressive loads also contribute to
.
ss /
tations in PRG4 lead to camptodactyly-arthropathy-
: ss : /
fluid flow and therefore the transport of nutrients and
hhtttp hhtttp
coxa vara-pericarditis syndrome, an autosomal waste through cartilage. Deformation of cartilage by
tp
recessive condition that leads to early progressive ar-
thropathy as well as perturbations of other organ sys- tp
compression leads to the migration of water from the
tissue—akin to squeezing a sponge—whereas the re-
lease of load allows restoration of shape and return of
tems. Hyaluronic acid and surface active phospholipids
also reduce joint friction. water. Dynamic shear forces on articular cartilage, as
might be encountered during joint movement and syno-
k eers
rs Metabolism/Nutrition/Homeostasis
k e r
e
In adults, cartilage has low metabolic activity. Cartilage s
r s vial fluid flow, increase the synthesis of lubricin.7 In this
way, the physical demands on cartilage are accommo-
bboooo k b o o o k
matrix turnover is extremely slow: the half-life of col-
o b o oo
dated by a corresponding change in cellular activity.
o
/
e e
/ e e e
/ b
lagen in normal cartilage is estimated to be more than
/ e
100 years,3 whereas the half-life of aggrecan is esti-
e e / e
/ e b
Chondrocyte Integration of Physical
e
: / / / .
t m m
mated to be approximately 20 years.4 Adult chondro-
t . : / / t
/ .
t m
. m
and Biochemical Cues
t p ss : /
cytes are sparsely distributed and undergo little or no
cell division. Because cartilage lacks blood vessels, the
p t p ss : /
Chondrocytes integrate cues from multiple sources to
exert the appropriate response. This integration is crit-
p
t
hht t
transport of nutrients and wastes depends on diffusion
and fluid flow through the tissue. Cartilage is hypoxic,
and thus adenosine triphosphate (ATP) production oc-
t
hht t
ical in cartilage development as stem cells differentiate
into chondrocytes, in mature cartilage as cells synthe-
size ECM, and in tissue engineering techniques to turn
curs through glycolysis. Synovial fluid at the joint sur- stem cells into cartilage. In cartilage development, mes-
face provides much of the nutrition for cartilage; how- enchymal cells condense into high-density aggregates
k eers
rs ever, transport can also occur across subchondral bone
and calcified cartilage.
k eers
r s that subsequently form cartilage in response to bio-
chemical factors. Similarly, chondrogenesis (differentia-
b ooook b oook
Given the low metabolic activity of cartilage, altera-
o
tions in either matrix synthesis or degradation by chon-
b ooo
tion into cartilage) of mesenchymal stem cells (MSCs)
o
is performed in high-density pellet cultures that mimic
/
e e
/ eb ee/ e
/e b
drocytes can disrupt tissue function. Cartilage homeo-
/e/e b
the mesenchymal condensations in cartilage develop-
ee
/ t
///t m
stasis—the maintenance of steady state—requires the
. . m
careful calibration of cellular activity to physical and
: / t.
///t m
ment. The physical cues provided by pellet culture
.m
prime MSCs to more potently respond to differentia-
:
s
tps : s
tps :
28
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 3: Articular Cartilage and Intervertebral Disk
tion factors, such as transforming growth factor-β fects are filled with native tissue with appropriate struc-
k eers
rs ke
(TGF-β). Furthermore, the TGF-β-mediated stimulation
errss ture and mechanical properties. However, donor tissue
b ooook b o ook
of chondrocyte differentiation is enhanced when cells
o
are grown on materials that mimic the physical proper-
availability is limited, and mismatches can exist in car-
o oo
o
tilage depth and contour between donor and recipient
b
/
ee/e b / e e b
ties of articular cartilage.8 This critical ability to inte-
ee /
grate these diverse signals helps chondrocytes maintain / e e b
sites. These three categories of treatments all can lead
ee /
to short-term clinical improvement, with defect and
t . m
.m
homeostasis even within the challenging avascular, me-
: / ///t : / t
///t. m
. m
patient-specific factors affecting outcomes.12
s
tps :
chanically loaded tissue. Consequently, small changes
s
tps :
Exciting new data suggest that the mobilization of
hhtttp hhtttp
in either the physical or the biochemical environment, endogenous stem cell populations may be a promising
as a result of the injury or genetic variation, can signif- strategy for repairing articular cartilage defects. The
icantly affect chondrocyte homeostasis and cartilage in- administration of TGF-β3 to cartilage defects in rabbits
tegrity. was sufficient to fill critical-size lesions with repair tis-
Although the mechanisms by which chondrocytes in- sue.13 TGF-β3 is thought to act as a stem cell homing
tegrate these cues remain unclear, integrin signaling and signal, inducing migration of this cell population to an
k rs
rs
primary cilia have been identified as critical compo-
ee k eers
r s injured site. Although the anabolic activity of the en-
ook ook
nents of this process. Integrins are cell surface proteins dogenous stem cell population declines with age, this
b oo b o
that bind ECM molecules such as type II and VI colla-
o b o oo
discovery may be particularly valuable for younger in-
o
/
e e
/ eb ee e
/ e b
gen.9 This binding of ECM molecules can lead to intra-
/
cellular signaling that can activate SOX9,10 a transcrip-
ee e
/ e b
dividuals with sports injuries if the metabolically active
/
stem cells can localize to the site and initiate repair of
: // t/.tm
. m
tion factor that is a key regulator of cartilage
t . m
. m
the cartilage injury. The source of the mobilizing stem
: / / / t
ss /
differentiation. Because SOX9 is regulated by many
: ss : /
cells is an area of intense investigation. Soft-tissue inju-
hhtttp hhtttp
stimuli, it helps chondrocytes integrate cues from mul- ries about the knee, including chondral injuries, are dis-
tp
tiple sources. Chondrocytes also possess primary cilia,
an organelle that acts as a cellular antenna. Cilia move- tp
cussed in detail in chapter 38, Soft-Tissue Injuries
About the Knee, Orthopaedic Knowledge Update 11.
ment, in response to fluid flow, for example, couples
physical stimuli to biochemical signaling cascades. Pri- Osteoarthritis
mary cilia are important for signaling that is induced Osteoarthritis (OA) is a degenerative process that af-
k errss
by hedgehog, which is a molecule that plays key roles
e k
in cartilage development and has emerging roles in os-
e rrss
e
fects all tissues of a joint. OA can be triggered by either
bboooo k b o o o k
teoarthritis.11 Therefore, understanding the ability of
o
genetic mutations or traumatic injury and mechanical
b o oo
factors. Whether the initiating events are the result of
o
/
e e
/ e e e
/ e b
primary cilia to couple physical and biochemical signal-
/
ing in chondrocytes is clearly important for cartilage bi-
e ee e
/ e b
physical or biochemical factors, the progression of the
/
disease is remarkably similar, ultimately leading to the
ology and disease.
: / / t
/ .
t m
. m t . m.m
loss of chondrocyte homeostasis and progressive artic-
: / / / t
ss : / ss : /
ular cartilage degradation. Initially, osteoarthritic chon-
hhtttp hhtttp
Focal Chondral Injuries drocytes secrete high levels of key cartilage ECM con-
tp
Because of the lack of blood supply, cartilage has a lim-
ited capacity for self-repair. Despite the presence of tp
stituents, including type II collagen and aggrecan, to
compensate for the diminished ability of articular carti-
progenitor-like cells, focal injuries that are confined to lage to withstand mechanical forces.5 However, after
cartilage do not heal. In contrast, deeper injuries that this anabolic burst, matrix synthesis declines and os-
extend into the subchondral plate allow reparative cells teoarthritic chondrocytes and synovial cells often se-
k eerss
from the marrow cavity to migrate into damaged re-
r k e r
e
gions and generate fibrocartilaginous repair tissue. Sur- s
r s crete inflammatory cytokines, such as tumor necrosis
factor-α (TNF-α) and interleukin-1β (IL-1β). This leads
bboooo k o o o k
gical treatments of chondral injuries either directly in-
b o b o oo
to the production of collagenases such as matrix
o
/
e e
/ e e / e
/ e b
troduce cells into injured areas or allow the migration
of local reparative cells. Like full-thickness injuries,
e e / e
/ e b
metalloproteinase-13 (MMP-13) and aggrecanases such
as a disintegrin and metalloproteinase thrombospondin
e
: / / / .
t m m
marrow stimulation techniques such as microfracture
t .
provide paths from the marrow cavity to chondral in-
: / / / .
t m m
motifs 4 (ADAMTS4) and ADAMTS5 that degrade
t .
ECM.14 Between the reduced synthesis and the in-
t p ss
p : /
juries. The advantages of marrow stimulation include
ss : /
creased proteolysis of cartilage ECM, changes in the
t p p
t
hht t
low cost and ease, whereas a disadvantage is the forma-
tion of fibrocartilage, which may not match the longev-
ity and the mechanical properties of native tissue. Au-
t
hht t
physical properties of cartilage ECM are among the
earliest detectable signs of OA, which are apparent
even in grade 1 lesions.15 This matrix catabolism there-
tologous chondrocyte implantation (ACI) involves the fore impairs the ability of the tissue to support mechan-
direct surgical implantation of cartilage cells grown in ical loads while corrupting key physical cues that help
k eers
rs k e
by cost, the need for two procedures (harvest and sub-
ers
tissue culture to sites of cartilage injury. ACI is limited
r s
to maintain chondrocyte homeostasis. Collectively,
these factors help explain the progressive nature of OA
b ooook b oook
sequent implantation), technical difficulty, and frequent
o
formation of fibrocartilage rather than hyaline carti- trix degradation.
b ooo
with the ongoing loss of cellular homeostasis and ma-
o
/
e e
/ eb ee/ e
/e b
lage. Osteochondral grafting fills osteochondral defects
/e/e b
Some human mutations implicated in OA directly
ee
/ t
///t m
with cartilage and bone from an autologous or an allo-
. . m
geneic donor site. In contrast to other techniques, de-
: / t.
///t m
compromise the quality or the quantity of cartilage ma-
.m
trix synthesis. Others interfere with the ability of chon-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
rupted cartilage homeostasis with increased catabolism
k eers
rs keerrss and decreased anabolism. Bone morphogenetic
b ooook b o ook
o
protein-7 (BMP-7) is an anabolic growth factor that
o oo
o
stimulates chondrocytes to synthesize aggrecan, colla-
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
gen, and hyaluronic acid. BMP-7 has been well toler-
ated with a trend toward superior efficacy to placebo in
: / t
///t. m
.m : / t
///t. m
. m
patients with knee OA in a phase I trial.21 Inhibition of
s
tps : s
tps :
catabolic cytokines is also being evaluated. For exam-
hhtttp hhtttp
ple, diacerein, recombinant IL-1 receptor antagonist
(IL-1Ra), and autologous blood products are intended
to decrease the activity of IL-1. However, clinical trials
of these agents have not yet conclusively demonstrated
clinical efficacy.22-24
Arthritis, including the use of platelet-rich plasma as
k eers
rs k eers
r s a therapy, is further discussed in chapter 18, Arthritis
ook ook
and Other Cartilage Disorders, Orthopaedic Knowl-
b oo b oo edge Update 11.

b o oo
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
Intervertebral Disk
ss : / ss : /
hhtttp hhtttp
Figure 2 The healthy intervertebral disk consists of a
tp tp
Structure/Composition/Function
hydrophilic nucleus pulposus, lamellar anulus
fibrosus, and semipermeable cartilage end Loads on the spine are shared between the interverte-
plate. The cartilage end plate is supported by bral disk anteriorly and the two facet joints posteriorly.
adjacent vertebral bone and separates disk cells The intervertebral disk is a pliant, heterogeneous struc-
from blood vessels and nerves in the adjacent ture that separates spinal vertebrae. The disk functions
vertebrae.
to work synergistically with the facets and the interspi-
keerrss k e rrss
e
nous ligaments to support spinal loads and constrain
bboooo k b o o
o o k multiaxial flexibility. Disk/facet interactions vary be-
b o oo
tween different spinal regions as a result of changes in
o
/
e e
/ e e e
/ e b
drocytes to integrate their response to diverse physical
/
and biochemical stimuli to maintain cartilage homeo-
e ee e
/ e b
facet orientation and biomechanical forces: from high
/
rotation and low compression in the cervical spine to
: / / / .
t m m
stasis, such as mutations in SMAD3—a key effector of
t . t . m.m
low rotation and high compression in the lumbar spine.
: / / / t
ss /
TGF-β signaling.16 Although several mutations that
: ss : /
The healthy disk is composed of three distinct tis-
hhtttp hhtttp
predispose individuals to OA have been identified, sues: the nucleus pulposus, the anulus fibrosus, and the
tp
these do not account for most OA cases. Most likely, a
predisposition for OA results from multiple factors that
are not yet defined.
tp
vertebral end plate (Figure 2). The nucleus pulposus
consists largely of aggrecan, other proteoglycans, and
small amounts of type II collagen. GAG side chains are
Factors such as traumatic injury or the increased me- negatively charged, bind mobile ions (mostly sodium),
chanical loading of joints caused by obesity also reflect and thereby generate an osmotic pressure that attracts
k eers
rs the complex interplay between physical and biochemi-
cal factors. Even in obesity, the increased mechanical
k e r
e s
r s water, which makes up approximately 80% of the disk
nucleus by volume. The nucleus is supported laterally
bboooo k b o o
o o
risk of developing OA. Chondrocytes are also affected k
loading on joints is unable to account for the increased
b o oo
by the anulus fibrosus, which is composed of approxi-
o
/
e e
/ e e / e
/ e b
by changes in energy metabolism associated with obe-
e e / e
/ e b
mately 50 layered, type I collagen sheets. The outer an-
ulus layers have collagen fibers that are anchored via
e
: / / t
/ .
t m
sity and by the increased levels of adipose-derived cyto-
. m
kines (adipokines), which are contributors to inflam-
: / / t
/ .
t m
. m
Sharpey fibers to the adjacent vertebral rims. Toward
the inner portions of the anulus fibrosus, the fibers co-
mation.17
t p ss
p : / ss : /
alesce with the hyaline cartilage end plate.
t p p
t
hht t
Therapies Under Development
With more than 21 million Americans having OA, the
t
hht t
The disk end plate is a sandwich composite of carti-
lage and bone. The cartilage end plate separates the nu-
cleus pulposus from the adjacent vertebral bodies and
demand for therapies to prevent or reverse cartilage de- is composed mostly of type II and type IX collagen. It
generation is increasing.18 Although many agents show has a low permeability and serves three principal func-
k eers
rs
promise in animal models, no therapy currently in clin-
ical use modifies the natural history of the disease.
k eers
r s
tions: (1) to work with the inner anulus fibrosus to con-
strain nuclear swelling; (2) to act as a semipermeable
b ooook b oook
Strategies that target individual aspects of the complex
o
pathophysiology of OA are under development.19 For
b ooo
membrane to control transport across the disk/vertebra
o
boundary; and (3) to shield the subchondral bone from
/
e e
/ eb ee/ e
/e b
example, intra-articular injection of recombinant lubri-
/e/e b
tensile loading that can cause end plate cracks.
ee
/ t
///t m
cin may decrease friction and disease progression in os-
. . m
teoarthritic joints.20 As indicated, OA involves dis-
: / t.
///t m
The disk’s overall biomechanical properties are de-
.m
termined by the combined actions of nuclear swelling
:
s
tps : s
tps :
30
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
and, in reaction, annular fiber tension. Together, these pacting matrix, which decreases tissue permeability,
k eers
rs ke
actions support axial compression and provide resis-
errss water content, oxygen tension, and pH. These changes
b ooook b o ook
tance to spine bending, torsion, and shear. Because the
o
end plate is semipermeable, water moves out of the disk
alter proteoglycan and collagen synthesis via changes in
o oo
o
cell volume and the cytoskeleton. Time-dependent disk
b
/
ee/e b / e e b
when spinal stress exceeds its swelling pressure, and
ee /
vice versa. This time-dependent behavior leads to diur- / e e b
biomechanics and frequency-dependent cell responsive-
ee /
ness may underlie the U-shaped relationship between
t . m
.m
nal variations in disk water content, disk height, and
: / ///t : / t
///t. m
. m
physical exposure and back pain, where both low and
spinal flexibility.
s
tps : s
tps :
high exposures are observed to be detrimental.27
Development
hhtttp
During development, the intervertebral disks are
formed at repeated, perinotochordal condensations of
hhtttp
Degeneration
Disk degeneration is a normal, age-related process that
begins in the second decade of life coincident with the
mesenchyme that are separated by the early cartilage of disappearance of nucleus pulposus notochordal cells.
developing vertebrae. At birth, the nucleus pulposus Degeneration typically progresses at 3% to 4% per
k eers
rs k e rs
r s
contains notochordal cells that are remnants of this spi-
e
year, being fastest at the lowest level, L5/S1, where bio-
b ooook b ooook
nal development. In humans, notochordal cells are
gradually replaced over the first two decades of life by oo
mechanical demands are the greatest. Degeneration of
o o
at least one level is apparent in approximately 35% of
b
/
e e
/ eb / e e b
chondrocyte-like cells. This loss of notochordal cells
ee /
may be the result of a combination of increased pres- / e e b
individuals younger than 40 years and in almost all in-
ee /
dividuals older than 60 years.
: // t/.tm
. m
sure from gravity loading, plus decreases in nutrition
t . m
. m
Several factors may accelerate the rate or the severity
: / / / t
ss : /
secondary to changes in adjacent vertebral perfusion.
: /
of degeneration and include excessive mechanical load,
ss
hhtttp
tp hhtttp
tp
Adult nucleus pulposus chondrocytes arise from either smoking, and high body mass index. Studies of identi-
the cartilage end plate or the inner anulus fibrosus. Nu- cal twins show that heritable factors explain most indi-
cleus pulposus cells are considered analogous to articu- vidual variability in disk degeneration (45% to 70%)
lar chondrocytes because they express typical chondro- versus more traditional risk factors such as occupa-
cyte markers such as SOX9 (a master transcription tional loading (2% to 7%).28 Clarification of the mech-
factor for cartilage), aggrecan, and type II collagen. anistic basis for genetic factors that implicate irregular-
k errss
However, there are clear morphologic differences, and
e k e
recently several genes unique to nucleus pulposus cells rrss
e
ities in ECM, inflammation, and pain signaling is in the
bboooo k
have been identified.25
b o o
o o k early stages.29
b o oo
The earliest and most conspicuous feature of disk
o
/
e e
/ e e e
/ e b
Anulus fibrosus cells secrete several matrix proteins,
/
including types I, II, III, and VI collagen. Outer anulus
e ee e
/ e b
degeneration is the loss of nuclear water as a result of
/
reductions in the osmotic pressure of the nucleus pul-
: / / / .
t m m
fibrosus cells do not express chondrogenic markers,
t . t . m.m
posus. Because the disk is part of an integrated biome-
: / / / t
ss /
whereas those in the transition zone express SOX9. Un-
: ss : /
chanical system, the inability of the nucleus pulposus to
hhtttp hhtttp
der certain circumstances, these inner anulus fibrosus attract sufficient water triggers a cascade of effects both
tp
cells can take on a chondrocyte phenotype and revers-
ibly express aggrecan and type II collagen. tp
intrinsic and extrinsic to the disk. Nuclear dehydration
causes reductions of disk height, stress shielding of the
inner anulus fibrosus, redistribution of vertebral end
Metabolism/Nutrition/Homeostasis plate stress, motion segment hypermobility, and facet
Disk cells rely on diffusion from vertebral capillaries overloading. Over time, the nucleus pulposus and the
k eerss
for the transport of nutrients and wastes. Competition
r
for nutrients limits cell density to approximately
k e r
e s
r sinner anulus fibrosus become indistinct as the nucleus
pulposus becomes fibrotic while the annular lamellae
bboooo k o o o
1,600 cells/mm3. Because the disk tissue oxygen levels
b o k b o oo
denature. Annular weakening leads to internal disk dis-
o
/
e e
/ e e / e
/ e b
are low (0.5% to 5%), disk cells create energy via gly-
colysis, which uses glucose and generates lactic acid.
e e / e
/ e b
ruption that includes radial and circumferential fissures
plus end plate cartilage disruptions. As the disk contin-
e
: / / / .
t m m
Accumulation of lactic acid decreases disk pH to al-
t .
most 6.3 and is detrimental to matrix because it de-
: / / / .
t m m
ues to deteriorate, progressive height loss and hypermo-
t .
bility can cause facet arthritis and spinal ligament hy-
t p ss
p : /
creases GAG production and cell viability. The depen-
ss : /
pertrophy. Ultimately, dehydration, tissue crosslinking,
t p p
t
hht t
dence on anaerobic glycolysis for cell production of
ATP makes glucose a critical nutrient. Other factors in
serum are also important because serum deprivation re-
t
hht t
and disk height loss lead to stiffening and restabiliza-
tion.
Fundamentally, degeneration happens because the
sults in decreased cell proliferation and increased cell rate of matrix damage exceeds the disk cell’s ability to
senescence.26 repair. Disk mechanical loading can damage the matrix
k eers
In addition to nutrient availability and the accumu-
rs k eers
r
lation of metabolic waste products, disk cell function is s
and trigger a wound-healing response analogous to that
reported for other tissues. Trauma can activate the re-
b ooook b oook
influenced by spinal load and consequent matrix defor-
o
mations. Nucleus pulposus cells can rapidly detect and
b ooo
lease and the formation of prostaglandins, leukotrienes,
o
and chemokines (for example, monocyte chemoattrac-
/
e e
/ eb ee/ e
/e b
respond to fluctuations in hydrostatic pressure. Simi-
/e/e b
tant protein-1) that regulate early events. These che-
ee
/ t
///t m
larly, annular cells are exquisitely sensitive to stretch.
. . m
Matrix loading also indirectly stimulates cells by com-
: / t.
///t m
moattractants recruit polymorphonuclear cells that mi-
.m
grate from postcapillary venules. Upregulation of
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
proinflammatory cytokines, such as IL-1, IL-6, IL-8, 3. Verzijl N, DeGroot J, Thorpe SR, et al: Effect of colla-
k eers
rs and TNF-α, influence subsequent cell proliferation,
keerrss gen turnover on the accumulation of advanced glycation
ook ook
chemotaxis, and connective tissue formation. These cy- end products. J Biol Chem 2000;275(50):39027-39031.
b oo b o o
tokines also induce matrix remodeling (or degeneration
b o oo
o
/
ee/e b ee
enzymes such as MMP-2, MMP-9, and MMP-13./ e
/ e b
in the case of the disk) by triggering the production of 4.
ee/ e
/ e b
Verzijl N, DeGroot J, Bank RA, et al: Age-related accu-
mulation of the advanced glycation endproduct pentosi-
t . m
.m
Nuclear cells progressively lose their capacity to se-
: / ///t
crete aggrecan and collagen and begin to produce
: / t
///t. m
. m
dine in human articular cartilage aggrecan: The use of
pentosidine levels as a quantitative measure of protein
s
tps : s
tps :
hhtttp hhtttp
matrix-degrading enzymes and cytokines, ultimately turnover. Matrix Biol 2001;20(7):409-417.
becoming senescent and apoptotic. The root of these
problems may be poor disk perfusion as the vertebral 5. Goldring MB, Marcu KB: Cartilage homeostasis in
capillary network deteriorates with age. Deficient end health and rheumatic diseases. Arthritis Res Ther 2009;
plate perfusion not only limits disk cell nutrition but 11(3):224.
also causes the accumulation of degraded matrix frag-
k eers
rs k eer
ments that interact with cells to trigger further cata-
bolic behaviors. Paradoxically, there is no decrease ins
r s
6. Guilak F, Fermor B, Keefe FJ, et al: The role of biome-
chanics and inflammation in cartilage injury and repair.
b ooook o ook
disk cell density with degeneration, which may be the
b o b oo
o o
/
e e
/ eb losses in disk height.30
e/
e / e b
result of shortened diffusion distances accompanying
e 7.
ee/ e
/ e b
Nugent GE, Aneloski NM, Schmidt TA, Schumacher
BL, Voegtline MS, Sah RL: Dynamic shear stimulation
// t/.tm
The diagnosis and treatment of disk herniations are
. m
further discussed in chapter 51, Lumbar and Thoracic
: : / / t . m
. m
of bovine cartilage biosynthesis of proteoglycan 4. Ar-
/ t
ss : /
Disk Herniations, Orthopaedic Knowledge Update, 11.
ss : /
thritis Rheum 2006;54(6):1888-1896.
Summary
hhtttp
tp hhtttp
tp8. Allen JL, Cooke ME, Alliston T: ECM stiffness primes
the TGFβ pathway to promote chondrocyte differentia-
tion. Mol Biol Cell 2012;23(18):3731-3742.
Articular cartilage and intervertebral disk play crucial Chondrocytes grown on a substrate with the stiffness of
articular cartilage produce more proteoglycan and ex-
rrss rrss
structural and functional roles in the musculoskeletal
hibit more cartilage-specific gene expression than cells
o ke
ke
system. These tissues are composed chiefly of ECM,
o k e
k
have a very low cell content, and have little or no bloode grown on other substrates. The combination of optimal
oo
e bboo o e b o o o
supply. Because of these factors, cartilage and disk in-
b pression.
e b o
stiffness and TGF-β further enhances cartilage gene ex-
b o
/
e / e ee/ e
juries and degeneration have limited ability to heal.
/
Many approaches to improve healing are under devel-
m m ee/ / e
/ t . . m
opment, including the use of cell-based therapies and
: / / / t
9.
: / /
/t/.
Loeser RF: Chondrocyte integrin expression and func-
t .m
tion. Biorheology 2000;37(1-2):109-116.
s
anti-inflammatory treatments.
s : ss :
hhtttp
tp hhtttp
tp
10. Haudenschild DR, Chen J, Pang N, Lotz MK, D’Lima
DD: Rho kinase-dependent activation of SOX9 in chon-
drocytes. Arthritis Rheum 2010;62(1):191-200.
Key Study Points The authors studied Rho kinase activity and interactions
related to increased cartilage matrix production via ac-
k eers
rs • Articular cartilage and intervertebral disk have
low rates of metabolism and low healing rates.
k e r
e s
r s
tivation of SOX9.
bboooo k •
b o o
Tissue degeneration occurs when the rate of ma-
o o k 11.
b o oo
Chang CF, Ramaswamy G, Serra R: Depletion of pri-
o
mary cilia in articular chondrocytes results in reduced
/
e e
/ e •
ee/ e
/ e b
trix damage exceeds the rate of tissue repair.
No current therapies reliably slow or prevent
ee/ e
/ e b
Gli3 repressor to activator ratio, increased Hedgehog
signaling, and symptoms of early osteoarthritis. Osteo-
: / / t .
cartilage and disk degeneration.
/ t m
. m : / / t
/ .
t m m
arthritis Cartilage 2012;20(2):152-161.
.
t p ss
p : / t p ss
p : /
The effects of the loss of primary cilia on articular car-
tilage are discussed.
t
hht t t
hht
12.t Harris JD, Siston RA, Pan X, Flanigan DC: Autologous
chondrocyte implantation: A systematic review. J Bone
Joint Surg Am 2010;92(12):2220-2233.
1. Hattori S, Oxford C, Reddi AH: Identification of super- The authors evaluated level I and II studies comparing
k eers
rs k eers
r s
ficial zone articular chondrocyte stem/progenitor cells. ACI with cartilage repair or restoration methods. Level
of evidence: I.
b ooook b ook
Biochem Biophys Res Commun 2007;358(1):99-103.
oo b oooo
/
e e
/ eb 2.
/ ee b
Jeffery AK, Blunn GW, Archer CW, Bentley G: Three-
ee /
dimensional collagen architecture in bovine articular
13.
e /e/e b
Lee CH, Cook JL, Mendelson A, Moioli EK, Yao H,
Mao JJ: Regeneration of the articular surface of the rab-
e
: / t
///t. m
. m
cartilage. J Bone Joint Surg Br 1991;73(5):795-801.
: / t.
///t m
bit synovial joint by cell homing: A proof of concept
.m
study. Lancet 2010;376(9739):440-448.
s
tps : s
tps :
32
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Replacement of the articular surface of rabbit humeral articular BMP-7 for knee OA, which showed no dose-
k eers
rs rrs
heads with bioscaffolds that contained TGF-β3 but no
kee s
cells led to coverage with hyaline cartilage. These results
limiting toxicity and a trend toward more symptom
ook ook
relief than placebo. Level of evidence: I.
b oo b o
suggest that targeted homing of endogenous cells can
o b o oo
o
/
ee/e b stimulate tissue regeneration.
ee/ e
/ e b 22.
ee/ e
/ e b
Bartels EM, Bliddal H, Schøndorff PK, Altman RD,
Zhang W, Christensen R: Symptomatic efficacy and
14.
: / ///t. m
Goldring MB, Otero M: Inflammation in osteoarthritis.
t .m
Curr Opin Rheumatol 2011;23(5):471-478.
: / t
///t. m
. m
safety of diacerein in the treatment of osteoarthritis: A
meta-analysis of randomized placebo-controlled trials.
s
tps : s
tps :
hhtttp hhtttp
This review article discusses novel stress-induced and Osteoarthritis Cartilage 2010;18(3):289-296.
proinflammatory mechanisms underlying the pathogen- The authors studied diacerein as an alternative treat-
esis of OA. ment for OA; its symptomatic benefit after 6 months is
unknown. Level of evidence: I.
15. Kleemann RU, Krocker D, Cedraro A, Tuischer J, Duda
GN: Altered cartilage mechanics and histology in knee 23. Chevalier X, Goupille P, Beaulieu AD, et al: Intraartic-
osteoarthritis: Relation to clinical assessment (ICRS
k eers
rs k eers
r s
Grade). Osteoarthritis Cartilage 2005;13(11):958-963.
ular injection of anakinra in osteoarthritis of the knee:
A multicenter, randomized, double-blind, placebo-
b ooook
16.
ooook
van de Laar IM, Oldenburg RA, Pals G, et al: Muta-
b b oo
controlled study. Arthritis Rheum 2009;61(3):344-352.
o o
/
e e
/ eb e/
e e
/ b
tions in SMAD3 cause a syndromic form of aortic aneu-
e
rysms and dissections with early-onset osteoarthritis.
24.
ee/ e
/ e b
Yang KG, Raijmakers NJ, van Arkel ER, et al: Autolo-
: // t
Nat Genet 2011;43(2):121-126.
/.tm
. m : / / t
/ t m
gous interleukin-1 receptor antagonist improves func-
. . m
tion and symptoms in osteoarthritis when compared to
ss : /
Mutations in SMAD3, a key molecule in TGF-β signal-
ss : /placebo in a prospective randomized controlled trial.
hhtttp hhtttp
ing, are responsible for a connective tissue syndrome as-
tp tp
Osteoarthritis Cartilage 2008;16(4):498-505.
sociated with early-onset OA as well as aortic aneu-
rysms and dissections.
25. Minogue BM, Richardson SM, Zeef LA, Freemont AJ,
Hoyland JA: Characterization of the human nucleus
17. McNulty AL, Miller MR, O’Connor SK, Guilak F: The pulposus cell phenotype and evaluation of novel marker
effects of adipokines on cartilage and meniscus catabo- gene expression to define adult stem cell differentiation.
rrss rrss
lism. Connect Tissue Res 2011;52(6):523-533.
Arthritis Rheum 2010;62(12):3695-3705.
o ke
ke o k e
k
catabolism and the production of proinflammatory me-e
The authors discuss the role of adipokines in increasing
The authors discuss gene expression profiling to identify
oo
e bboo o diators in cartilage and meniscus.
e b o
b o o e b o
the human nucleus pulposus cell phenotype.
b o
/
e / e 18.
ee/ / e
Lawrence RC, Felson DT, Helmick CG, et al: Estimates
m
26.
ee/ / e
Johnson WE, Stephan S, Roberts S: The influence of se-
m
/ t . . m
of the prevalence of arthritis and other rheumatic con-
: / / / t : / /
/t/.t .m
rum, glucose and oxygen on intervertebral disc cell
growth in vitro: Implications for degenerative disc dis-
ss :
ditions in the United States: Part II. Arthritis Rheum
ss :
hhtttp hhtttp
ease. Arthritis Res Ther 2008;10(2):R46.
tp tp
2008;58(1):26-35.
19. Singh JA: Stem cells and other innovative intra-articular 27. Heneweer H, Vanhees L, Picavet HS: Physical activity
therapies for osteoarthritis: What does the future hold? and low back pain: A U-shaped relation? Pain 2009;
BMC Med 2012;10:44. 143(1-2):21-25.
A review of promising but unproven therapies for osteo-
k eers
rs k e
tor antagonists, BMP-7, and botulinum toxin, is pre-r
e s
arthritis, including bone marrow stem cells, IL-1 recep-
r s
28. Battié MC, Videman T, Gibbons LE, Fisher LD, Man-
ninen H, Gill K: 1995 Volvo Award in clinical sciences:
bboooo k sented.
b o o
o o k b o oo
Determinants of lumbar disc degeneration. A study re-
o
lating lifetime exposures and magnetic resonance imag-
/
e e
/ e 20.
e / e
/ e b
Bao JP, Chen WP, Wu LD: Lubricin: A novel potential
e / e e b
ing findings in identical twins. Spine (Phila Pa 1976)
ee /
1995;20(24):2601-2612.
/ / t t m
biotherapeutic approaches for the treatment of osteoar-
. . m
thritis. Mol Biol Rep 2011;38(5):2879-2885.
: / : / / t
/ .
t m
. m
ss : /
A review describing the function of lubricin, animal
t p p t
29.
p ss
p : /
Tegeder I, Lötsch J: Current evidence for a modulation
of low back pain by human genetic variants. J Cell Mol
t
hht t
studies of lubricin as a treatment of OA, and the possi-
ble role of lubricin as a therapy for human OA is pre-
sented.
t
hht t Med 2009;13(8B):1605-1619.
30. Liebscher T, Haefeli M, Wuertz K, Nerlich AG, Boos N:

21. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, Mc- Age-related variation in cell density of human lumbar
Alindon T: Phase 1 safety and tolerability study of intervertebral disc. Spine (Phila Pa 1976) 2011;36(2):
k eers
rsBMP-7 in symptomatic knee osteoarthritis. BMC Mus-
culoskelet Disord 2010;11:232.
k eers
r s 153-159.
ook ook
The authors studied changes in cell density in defined
b oo b oo
The authors describe a phase I, double-blind, random-
b oooo
regions of interest in complete human motion segments.
/
e e
/ eb ee e
/e b
ized, multicenter, placebo-controlled trial of intra-
/ ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 4
e rs
rs e rrss
oo
kMuscle,
ook e Tendon, and
o k
ook
o Ligament
e o oo
o
/e/ebb Richard L. Lieber, PhD
e / e
/ b
e b
Cyril B. Frank, MD
e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
is one of the most important variables for understand-
Skeletal Muscle ing muscle force generation. A device has been devel-
k eers
rs
Functional Anatomy
k eers
r s
oped to measure sarcomere length in human muscles
during orthopaedic surgery procedures.1
ook ook
Surgeons should be cognizant of the fact that a funda-
b oo b o
mental property of skeletal muscle is that the amount
o b o oo
Muscle force generated is highly dependent on sar-
o
comere length. The rigorous demonstration of this fact
/
e e
/ eb ee e
/ e b
of force it generates depends on its length. This is be-
/
cause muscles are composed of sarcomeres, so-called
ee/ e
/ e b
was provided at the level of the single muscle cell in a
: // t/.tm m
molecular machines that are themselves length sensi-
. : / / t t m
classic study.2 In this relationship, skeletal muscle fiber
. . m
force production is defined in terms of myofilament
/
ss /
tive. Sarcomeres are composed of contractile filaments
: s : /
overlap, that is, in terms of sarcomere length (Figure 2).
s
hhtttp hhtttp
termed myofilaments. Two major sets of contractile fil-
tp
aments (one relatively thick, the other relatively thin)
exist in the sarcomere. These thick and thin filaments
represent large polymers of the proteins myosin and ac-
tp
At optimal length, where actin-myosin interactions are
maximal, muscle generates maximum force (region 2 in
Figure 2). As sarcomere length increases (region 3 in
Figure 2), force decreases because of the decreasing
tin, respectively. The myosin-containing filaments and
number of interactions between actin and myosin myo-
the actin-containing filaments interdigitate to form the
filaments. At lengths shorter than the optimum length
k errss k rrss
muscle contractile machine. It is also this interdigitated
e e e
pattern that gives muscle its familiar striated or striped
(region 1 in Figure 2), force decreases because of dou-
bboooo k b o o o
appearance and is observable under a light microscope
o k b o oo
ble interdigitation of actin filaments with both myosin
o
and actin filaments from opposite sides of the sar-
/
e e
/ e
(Figure 1).
ee/ e
/ e b ee/ e
/ e b
comere. Additional information about sarcomere
length changes in wrist muscles and back muscles and
Sarcomere Properties
: / / t
/ .
t m
. m : / /t/.tm.m
ss /
Various sarcomere regions are named based on their
: ss : /
hhtttp hhtttp
appearance so that they can be easily referenced (Fig-
tp
ure 1). For example, the sarcomere region containing
the myosin filaments is known as the A-band (for
anisotropic, an optical term describing what this band
tp
does to incoming light). The region containing the actin
filament is known as the I-band (for isotropic). The re-
k eers
gion of the A-band in which there is no actin-myosin
rs e
overlap is called the H-zone (for heller, which is Ger-
k r
e s
r s
bboooo k b o o
o o k
man for “light”). The dark narrow line that bisects the
b o oo
o
/
e e
/ e e / / e b
I-band is the Z-band (for zwischen, which is German
e
for “between”). Most investigators who quantify sar-
e ee/ e
/ e b
/ / t
/ t m
comere dimensions use the distance from one Z-band
. . m
to the next as the definition of sarcomere length, which
: : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t
Dr. Lieber or an immediate family member serves as a
paid consultant to or is an employee of Allergan, Ha-
t
hht t
lozyme, and Mainstay Medical; has received research or
institutional support from Allergan; and has received Figure 1 Longitudinal electron micrograph of a human
vastus lateralis muscle that was fixed in glutaral-
k eerss
nonincome support (such as equipment or services),
r k e
commercially derived honoraria, or other non–research-
ers
r s dehyde, embedded in plastic, sectioned at ap-
proximately 60-nm thickness, and stained with
b ooook b ook
related funding (such as paid travel) from Allergan.
oo b oooo
heavy metal. This severe processing is necessary
to view the tissue with an electron microscope.
/
e e
/ eb e / /e b
Dr. Frank or an immediate family member has received
e
research or institutional support from Pfizer and serves
e ee/e/e b
The calibration bar corresponds to a distance of
1 µm. m = mitochondrion, Z = Z-band, and
/ t
///t m
as a board member, owner, officer, or committee mem-
. . m
ber of the Canadian Orthopaedic Association.
: : / t.
///t m
.m
t = transverse tubular system.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
cle,9,10 and thus the only way to accurately define mus-
k eers
rs keerrss cle architecture is through direct anatomic microdissec-
b ooook b o ook
o
tion.11
o oo
o
Although variability in muscle architecture exists
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
among muscles within an individual, there is extremely
consistent architectural design within muscles among
: / t
///t. m
.m : / t
///t. m
. m
individuals. Muscle architecture types are referred to by
s
tps : s
tps :
their arrangement of muscle fibers relative to the axis
hhtttp hhtttp
of force generation. Muscles with fibers that extend
parallel to the muscle force-generating axis and extend
most of the muscle length are termed parallel or longi-
tudinally arranged muscles. Muscles with fibers that
are oriented at a single angle relative to the force-
generating axis are termed pennate muscles. (The angle
k eers
rs k eers
r s between the fiber and the force-generating axis gener-
ook ook
ally varies from 0° to 30°.) It is obvious when viewing
b oo b oo b o oo
actual human muscles that most muscles fall into the fi-
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
nal and most general category, multipennate muscles—
muscles composed of fibers that are oriented at several
: // t/.tm
. m t . m
. m
angles relative to the axis of force generation.
: / / / t
ss : / ss : /
In terms of function, the sarcomere length-tension
hhtttp hhtttp
curve described previously can simply be scaled to the
tp tp
Figure 2 The sarcomere length-tension curve for frog
skeletal muscle obtained using sequential iso- whole muscle once muscle fiber length and overall mus-
metric contractions in single muscle fibers is cle architecture are known.10 For example, the length-
shown. Insets show the schematic arrangement
of myofilaments in different regions of the tension curve gets wider with increasing fiber length.
length-tension curve. The numbers shown above The explanation for the relationship between muscle fi-
the curve represent different regions of the ber length and excursion is based on the concept that a
keerrss length-tension curve discussed in the text.
k e rrss
e
greater serial sarcomere number (greater fiber length)
leads directly to a greater muscle excursion because the
bboooo k b o o
o o k b o oo
excursions of the individual sarcomeres in series are ad-
o
/
e e
/ e e / / e b
their functional significance is available.3,4 The length-
e
tension relationships of muscles are beginning to be mea-
e
ditive.
e / e
/ e b
In terms of force production, a muscle’s maximum
e
/ / t
/ t m
sured intraoperatively5 based on classic experiments.6
. . m
The total number of sarcomeres within a fiber de-
: : / /t/.tm.m
force generated is based on the total number of muscle
ss : /
pends on the muscle fiber length and diameter and is
ss /
fibers within the muscle. Unfortunately, it is very diffi-
:
hhtttp hhtttp
cult to quantify either muscle fiber number or the pre-
tp
the most important determinant of muscle fiber func-
tion. Because of the series arrangement of sarcomeres
within a myofibril, the total distance of myofibrillar
tp
cise fiber arrangement within a muscle and therefore
predict peak force. As a result, the total cross-sectional
area of the muscle fibers is approximated mathemati-
shortening is equal to the sum of the shortening dis- cally, by physiologic cross-sectional area (PCSA). One
tances of individual sarcomeres. This is why an entire excellent study performed in guinea pig hindlimb mus-
k eers
rs
muscle may shorten several centimeters even though
each sarcomere can shorten only about 1 µm. It should
k e r
e s
r scles9 showed that PCSA is proportional to isometric
force capacity, with a conversion factor of 22.5 N/cm2
bboooo k b o o
also be stated that the number of sarcomeres in a ma-
o o
ture muscle can change given the appropriate stimulus.k b o oo
(approximately 250 kPa). Thus, it is possible to esti-
o
/
e e
/ e ee/ e
/ e b
This means that muscle fibers have a great capacity to
e / e
/ e b
mate the maximum isometric force a muscle can gener-
ate by multiplying its PCSA by 22.5 N/cm2. This value
e
/ / t .
t m
adapt after surgery, a finding that has been demon-
. m
strated in human muscle undergoing lengthening.7
: / / / t
/ .
t m
can be used to predict force generation by a muscle af-
. m
ter orthopaedic surgery.
:
t p ss
p : / t p ss
p : /
Architecture
t
hht t
Skeletal muscle function is based on what is known as
its fiber architecture. Architecture, or the orientation
t
hht t
Examples of Human Arm Architecture
The architectural properties of 25 upper extremity
muscles have been defined and their fiber length and
and the number of muscle fibers within a muscle, deter- PCSA are plotted12 in Figure 3. Upper extremity mus-
mines that muscle’s force and excursion—not its mass cles possess a wide range of strengths and excursions
k eers
rs
or volume.8 This is critical because most surgeons’ im-
pressions of muscles are based on intraoperative ap-
k eers
r s
that can be exploited to restore function. For example,
in the forearm, the longest and largest muscles are the
b ooook b oook
pearance, anatomic dissection, or view on MRI, all of
o
which are dominated by size or volume. Rigorous ex-
b ooo
flexor digitorum profundus to the middle finger, (FDP
o
M mass = 16.3 g, length = 200 mm) and the brachiora-
/
e e
/ eb / e
/e b
perimental studies have since demonstrated that muscle
ee ee/e/e b
dialis (BR mass = 16.6 g, length = 175 mm). The BR
/ t
///t m
function depends on the number and the orientation of
. . m
muscle fibers, not on the size or the shape of the mus-
: : / t.
///t m
also contains the longest fibers (121 mm) and the high-
.m
est relative fiber length (as quantified by the fiber
s
tps : s
tps :
36
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 4: Muscle, Tendon, and Ligament
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss
Figure 3
e rrss
e
Scattergraph of the fiber length and physiologic cross-sectional areas of muscles in the human arm. Fiber length is
k
bboooo k b o o
o o k b o oo
proportional to muscle excursion, whereas physiologic cross-sectional area is proportional to maximum muscle
o
force. Thus, this graph can be used to compare the relative forces and excursions of arm and forearm muscles.
/
e e
/ e ee e
/ e b e e
/ e b
Muscles placed at extremes of the graph (FDS, FDP, TRI, BRACH, BR, and Bic Br) would be plotted off this scale at
/ /
the position shown. BIC Br L = biceps brachii, long head; Bic Br S = biceps brachii, short head; BR = brachioradialis;
e
: / / t
/ t m
. m : / /t/ tm
ECRB = extensor carpi radialis brevis; ECRL = extensor carpi radialis longus; ECU = extensor carpi ulnaris; EDC = ex-
. . .m
tensor digitorum communis; EDQ = extensor digiti quinti; FCU = flexor carpi ulnaris; FDP = flexor digitorum pollicis;
s : / s : /
FDS = flexor digitorum superficialis; I = index; L = long; PL = pronator longus; PQ = pronator quadratus; PT = pro-
s s
hhtttp hhtttp
nator teres; R = ring; S = short. (Data from Lieber RL, Fazeli BM, Botte MJ: Architecture of selected wrist flexor and
tp tp
extensor muscles. J Hand Surg Am 1990;15A:244-250; and Lieber RL, Jacobson MD, Fazeli BM, Abrams RA, Botte
MJ: Architecture of selected muscles of the arm and forearm: Anatomy and implications for tendon transfer. J
Hand Surg Am 1992;17A:787-798.)
length/muscle length ratio—0.69). Even though the BR (FCU), the flexor digitorum superficialis (FDS) to the
k eers
rs k e r
has the greatest mass in the forearm, it is not the stron-
e s
r s middle finger, and the FDS to the ring finger. From the
bboooo k o o
gest; the pronator teres (PT) has the greatest PCSA,
o o
which is more than three times that of the BR (4.1 ver-
b k o oo
standpoint of architecture alone, the FDS M most
o
closely resembles the EDC in terms of force generation
b
/
e e
/ e / e e b
sus 1.3 cm2, Figure 3) and thus would generate more
ee /
force. These types of comparisons highlight the domi- / e e b
(cross sectional area) and excursion (fiber length) and
ee /
would be the preferred donor.
: / / t
/ .
t m
. m
nance of architecture over raw muscle mass. If force
: / / t
/ .
t m
. m
t p ss
p : /
generation were based on mass alone, the BR would be
t ss : /
Examples of Human Leg Architecture
p p
t
much stronger than the PT. An understanding of mus-
hht t
cle architecture can be useful when selecting skeletal
muscles for surgical tendon transfer. The idea here is
t
hht t
Leg muscles also demonstrate unique architectural
properties. For example, in the entire lower extremity,
the three strongest muscles (based on PCSA) are the so-
that muscles of similar architecture will have similar leus, the vastus lateralis, and the gluteus medius. This is
functions. Thus, when choosing a particular donor not surprising because they are all antigravity muscles,
k e rs
muscle to substitute function, architectural properties
rs
should be matched.13 A specific example is shown
e k eers
r s
but it may be surprising that the single strongest muscle
is observed distally in the leg where muscle volumes
b ooook b oook
graphically in Figure 3, in the surgical restoration of
o
digital extension following high radial nerve palsy,
b ooo
tend to be smallest. The muscles with the longest fiber
o
lengths (implying the greatest excursion) are the sarto-
/
e e
/ eb ee/ e
/e b
where potential donor muscles (which are transferred
/e/e b
rius, the gracilis, and the semitendinosus. Although
ee
/ t
///t m
to the extensor digitorum communis [EDC]) include
. . m
the flexor carpi radialis (FCR), the flexor carpi ulnaris
: / t.
///t m
they all cross the hip and the knee, the feature they
.m
share in common is knee flexion. The semitendinosus
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
ranks high in fiber length only when the proximal and speed. The muscle’s maximum contraction velocity is
k eers
rs ke rrs
distal heads of the muscle are added in series, which is
e s termed Vmax and can be compared among muscles that
b ooook b o ook
likely to reflect the actual function of the muscle based
o
on its dual innervation.14 In terms of fundamental de-
have large differences in fiber type distribution. This
o oo
o
provides a fiber type-specific value for Vmax. It is possi-
b
/
ee/e b / e e b
sign features, large mass and short fiber length both
ee /
contribute to large PCSA when the lower extremity is / e e b
ble to perform contractile experiments on pieces of rat
ee /
muscle fibers. Using this approach, one study has
t . m
.m
considered as a whole. For example, the soleus has
: / ///t : / t
///t. m
. m
shown that Vmax was found to be in the order type 2B >
s
tps :
modest mass but very short fibers, which result in its
s
tps :
type 2X > type 2A > type 1.17 The situation was actu-
hhtttp hhtttp
exceptionally large PCSA. This is in contrast to the vas- ally even more interesting because the study demon-
tus lateralis, which has a much larger mass but modest strated that even in a single cell, multiple MyHC iso-
fiber length. These types of comparisons are critical for forms can be expressed along the fiber’s length.
surgeons to be able to make because the proper choice In a manner similar to that used for measuring Vmax,
of muscles to be used in transfers, the length of muscles maximum tetanic tension (Po) can be measured in mus-
set during surgical procedures, and the prediction of cles of different fiber type distributions. This value is
k eers
rs rs
r s
muscle function after the insertion of prostheses all rely
k ee
then normalized to the PCSA of the muscle studied to
ook ook
heavily on an understanding of architectural properties. yield the value known as specific tension, or the force
b oo b oo b o oo
of contraction per unit of cross-sectional area of mus-
o
/
e e
/ eb Fiber Types
e/
e e
/ e b
The current view of muscle fiber types is that skeletal
ee e
/ e b
cle. In measuring the specific tension of whole skeletal
/
muscle, most investigators find that muscles composed
t . m
. m
muscle fibers possess a wide and nearly continuous
: // / t : / / t
/ .
t m
. m
mainly of fast fibers have a greater specific tension than
: /
spectrum of morphologic, contractile, and metabolic
ss ss /
muscles composed mainly of slow fibers. The typical
:
hhtttp hhtttp
value for specific tension of fast muscle is approxi-
tp tp
properties. The appropriate view of any classification
scheme, therefore, is that it is an artificial system super- mately 22 N/cm2 (250 kPa), whereas that for slow mus-
imposed on a continuum for convenience. Most mod- cle is 10-15 N/cm2 (125 kPa). The common interpreta-
ern muscle fiber classification schemes are based on tion of these whole-muscle experiments has been that
some type of measurement of the myosin molecule. It is fast muscle fibers have a greater specific tension than
important to note that, in terms of functional impor- slow muscle fibers.
keerrss tance, an understanding of muscle architecture, espe-

cially for the orthopaedic surgeon, is much more im-
k e rrss
e
The endurance (or its opposite, fatigue) of muscle fi-
bers is even more difficult to precisely define than speed
bboooo k o
portant than knowledge of the muscle fiber types.
b o
o o k b o oo
or strength. This is because endurance depends on the
o
/
e e
/ e Mammalian Fiber Types Are Based on
ee/ e
/ e b e e
/ e b
type of work the muscle is required to perform. Be-
/
cause force generation involves a chain of events, it is
e
Myosin Heavy Chain Isoforms
: / / t
/ .
t m
. m : / /t/.tm.m
possible to produce fatigue by interrupting any point in
ss /
Using modern immunohistochemical methodology, a
: ss : /
the chain. Thus, a danger exists in simply ascribing a
hhtttp hhtttp
collection of antibodies was created that demonstrated drop in force to muscle fiber fatigue without under-
tp
selective reactivity between fiber types, and the pattern
of reactivity was correlated with the traditional fiber
typing scheme.15,16 The result of these studies was to
tp
standing the basis for the drop.23 Generally, type 1 fi-
bers have the greatest endurance, followed by type 2A
and type 2X fibers, and then type 2B fibers. This is not
generate a set of monoclonal antibodies that could surprising because type 2B fibers have a very low oxi-
identify four major fiber types in adult rat skeletal mus- dative capacity.
k eers
rs cle tissue. Of these four fiber types, one was clearly a
k
slow fiber type, and three fiber types corresponded to
e r
e s
r s Passive Biomechanical Properties
bboooo k b o o
o o k
fast isoforms. The slow fiber type is termed type 1, and
b o oo
The previous functional discussion refers to a muscle’s
o
/
e e
/ e e / e
/ e b
the three fast fiber types are types 2A, 2X, and 2B. It is
now known that these fast fibers vary slightly in speed
e e / e
/ e b
active mechanical properties, but because muscles are
soft tissues as are tendons and ligaments, they also have
e
: / / t
/ .
t m
and power in the order 2A < 2X < 2B.17
. m
Like all mammals, humans have four myosin heavy
: / / t
/ .
t m
. m
a passive stress-strain relationship—that is, a relation-
ship obtained when the muscle is relaxed but passively
t p ss
p : /
chain (MyHC) genes in their genome: type 1, type 2A,
ss : /
stretched. This passive relationship is probably the sin-
t p p
t
hht t
type 2X, and type 2B.18,19 However, despite the pres-
ence of these four MyHC genes, humans do not express
the type 2B MyHC gene.20 This appears to be an issue
t
hht t
gle most common mechanical property that surgeons
experience in the operating room.
In contrast to the active contractile properties of
of scaling with size. For example, very small mammals muscle that were described previously as being pre-
have a relatively fast stride frequency, and analysis of dicted accurately by sarcomere length, passive muscle
k eers
rs
their muscles reveals a high percentage of type 2B mus-
k e
cle fibers, even in what would be considered slow mus-
ers
r s
tension is poorly understood. Increasing muscle length
increases its passive tension (passive in Figure 2), but
b ooook cles such as the soleus.21,22
b oook
o b oooo
there is not a clear relationship between passive tension
and active muscle force produced.10 This idea has been
/
e e
/ eb Functional Differences Among Fiber Types
ee/ e
/e b ee/e/e b
discussed extensively with respect to hand surgery.24,25
/ t
///t m
The force-velocity relationship provides a convenient
. . m
tool for muscle fiber type-specific characterization of
: : / t.
///t m
Experimental studies demonstrate that intracellular cy-
.m
toskeletal proteins26 in combination with extracellular
s
tps : s
tps :
38
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
matrix (ECM) material27,28 combine to create a muscle’s
k e rs
rs
passive properties. Near optimal muscle length (the
e keerrss
b ooook o
tension is almost zero. However, as a muscle is
b ook
length at which active tension is maximum), passive
o b o oo
o
/
ee/e b / e e b
stretched to longer lengths, passive tension increases
dramatically (Figure 2).
ee / ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
Regeneration
s
tps : s
tps :
hhtttp hhtttp
Unlike tendons and ligaments, skeletal muscle as a tis-
sue has a tremendous ability to regenerate. This is
mostly because skeletal muscles have resident stem cells
within the tissue known as satellite cells, so named be-
cause they were first identified at the fiber periphery
more than 50 years ago—the only stem cell to be iden-
k eers
rs k eers
r
tified based on anatomic location.29 Although satellite
s
b ooook oook
cells are normally quiescent, when the muscle cell is in-
o
jured and the natural inhibitory influence of the basal
b b o oo
o
/
e e
/ eb / e e b
lamina released, they enter the cell cycle, proliferate,
ee /
and can repair injured muscle or create new muscle. It
ee/ e
/ e b
t . m
. m
is thus no wonder that muscle satellite cells are widely
: // / t : / / t
/ .
t m
. m
ss : /
used therapeutically in attempts to replace defective Figure 4
ss : /Transmission electron micrographic image of
hhtttp hhtttp
collagen fibrils in a patellar tendon. Note the
tp tp
muscle30 or even deliver specific factors to sick mus-
nearly parallel arrangement at this high magni-
cle.31 This is a fantastic area of study, which promises fication and the 64-nm banded pattern of colla-
both therapeutic and scientific insights. gen fibrils as a result of quarter-stagger overlap
of collagen molecules.
rrss rrss
Tendons
elongation that is conferred in part by whatever is
o kee
In simple terms, tendons form the anatomic connec-
k o k e
k e maintaining the crimp pattern.
oo
e bboo otions between muscles and bones. All tendons are
e b o
b
connected to muscles at one end, and these fusion o o e b o
Tendons also display interesting biologic variations
b o
and are categorized as intrasynovial if they are covered
/
e / e m e / / e
points are referred to as myotendinous junctions. The
e m e / / e
by a synovial sheath or extrasynovial if they are not en-
e
: / /
/ t
/ .
t . m
connection point between the other end of the tendon
and the bone is called an osteotendinous junction or
: / /
/t/.t .m
capsulated by synovium. Some of these anatomic differ-
ences lead to relatively high gliding resistance for the
ss : ss :
hhtttp hhtttp
what is better known clinically as the tendon insertion extrasynovial tendon compared with an intrasynovial
tp
site. Tendons vary in breadth and length from very
small diameters and very long to very large diameters
and very short. Their shapes are also surprisingly
tp
tendon.33
In contrast, intrasynovial tendons have only a single
cell layer of epitenon with a relatively smooth surface;
diverse and range from flat to cylindrical, fan shaped, it is a fine connective sheath covering the tendon a level
or ribbon shaped. Tendons’ lack of vasculature and below the paratenon. As a sandwich layer, epitenon is
eers
ation.
k k e r
their composition creates a relatively dense white color-
rs e s
r scontiguous with the paratenon on the outer surface and
with the endotenon on its inner surface. The endotenon
bboooo k b o o
o o k b o oo
is a thin, loose, connective tissue layer that envelops the
o
/
e e
/ e
Functional Anatomy
e / e
/ e b
Tendons belong to a family of dense connective tissues,
e e / e
/ e b
collagen fiber bundles or fascicles and is the tissue that
carries neurovascular elements along the tendon.34
e
: / / / .
t m m
composed of mostly parallel collagen fiber bundles
t .
(Figure 4). They are primarily composed of type I col-
: / / t
/ .
t m
Tendon grafts can be used to replace an injured seg-
. m
ment of tendon. The outcome is suboptimal when an
ss : /
lagen, with a smaller percentage of minor collagens,
t p p t p ss
p : /
extrasynovial tendon is used as a graft to replace a
t
hht t
proteoglycans, elastin, and water.32 At the finest level,
collagen molecules assemble into fibrils that intertwine
into fibril bundles, fascicles, and fiber bundles, forming
t
hht t
damaged intrasynovial tendon as a result of intrinsic bi-
ologic and biomechanical differences between the two
tendon types. Although extrasynovial tendons generally
a highly organized multihierarchical structure. At a have superior tensile properties, they exhibit elevated
more gross level, longitudinal fibers also do not run adhesion formation and inferior compressive properties
k eers
rs
other to some extent, actually forming spirals. At a
k eers
perfectly parallel to one another, but they do cross each
r s
when compared with intrasynovial tendons.34
b ooook b ook
slightly more macroscopic level (light microscopy), the
oo
collagen fibers in tendons exhibit regular undulations
Biomechanical Properties
b oooo
Tendons primarily function by transmitting tensile
/
e e
/ eb ee/ e
/e b
called crimp. During tendon elongation, this crimp dis-
/e/e b
loads from muscle to bone, thereby permitting locomo-
ee
/ t
///t m
appears but returns after tensile forces are removed.
. . m
This finding suggests some intrinsic resistance to tensile
: / t.
///t m
tion along with supplementing the stability of the joints
.m
that they cross. The hierarchical structural unit for ten-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
dons described previously makes a tendon ideal for power productions (where stiff tendons transmit force
k eers
rs carrying and transmitting large tensile mechanical
keerrss directly to bones with little deformation).
b ooook b o ook
loads.35 As demonstrated with increasing sophistication
o
for the past 3 decades, tendons and tendon cells exhibit oo
Based on their functions, tendons are categorized as
o o
either energy-storing or positional tendons40-43 (Ta-
b
/
ee/e b / e e b
mechanosensitive properties, and, in response to me-
ee /
chanical loads, undergo adaptation by altering their / e e b
ble 1). Examples of energy-storing tendons include the
ee /
Achilles tendon and the equine superficial digital flexor
t . m
.m
structure, composition, and mechanical properties.
: / ///t t
///t. m
. m
tendon, both of which sustain high strain during nor-
: /
tps :
The stiffness and cross-sectional area of tendons in-
s s :
mal physiologic loads and are designed to stretch and
tps
hhtttp hhtttp
creases in response to loading during development36,37 recoil to ensure the efficient return of stored energy.40
and is attributed partly to increasing body and muscle Positional tendons such as equine common digital ex-
mass and increasing muscular forces. Adult tendons extensor tendon or human anterior tibialis tendon are rel-
hibit greater stiffness compared with tendons from chil- atively inextensible. Because of the low strain, posi-
dren, but there are apparently no major sex differences tional tendons are rarely injured.32
in their intrinsic material properties.37 Although aging
k eers
rs rs
r s
generally leads to a decrease in tensile strength, the me-
k ee
Biomechanical Alterations of Tendons With
ook ook
chanical properties of tendons also deteriorate because
b oo b o
of low levels of resistive functional loading, especially
o b o oo
Aging and After Tendon Injury
o
Tendons can be damaged either because of acute injury
/
e e
/ eb in elderly patients.35
e/
e e
/ e b
Different tendons in the body are subjected to differ-
ee/ e
/ e b
or as a result of overuse and degeneration. Repeated
t . m
. m
ent mechanical loads, which is roughly proportional to
: // / t / / t
/ t m
occasional loading with abnormal load cycles can lead
. . m
to overuse damage of tendons by progressively break-
:
ss /
the PCSA (see previous discussion) of the associated
: ss : /
ing individual collagen fibrils. Broken fibrils likely de-
hhtttp hhtttp
muscle. In general, the greater the muscle or muscle
tp
group PCSA, the higher the force that it will produce,
leading to a greater force on its tendon (for example, tp
crease loads on individual cells, causing them to initiate
catabolic responses and degrade local matrix (a normal
response to unloading that can eventually lead to gross
the quadriceps muscles loading the quadriceps and pa-
tellar tendons). Moreover, because of a combination of tendon rupture.44 Different animal models investigating
extrinsic forces and intrinsic muscle loads, different ac- the overuse of tendon (such as rotator cuff and Achil-
rrss rrss
tivities clearly induce quite different levels of forces on les) have demonstrated that increased repetitive activity
o ke
ke the same tendon.38 Although tendon is regarded as a
o k e
k e can lead to local tendon matrix damage, with a cata-
oo
bolic cascade of degradative cellular events that can
e bboo o e b
determined whether forces are transmitted evenlyo
b o
distinct force-transmitting structure, it remains to be
o e b o o
lead to decreased material properties in tendon. During
b
/
e / e m e / / e
throughout each structure and whether stresses experi-
e / / e
these events, tendons can undergo gross thickening ei-
m ee
ther in their midsubstance, at their insertions into bone,
or not.31
: / /
/ t
/ .
t . m
enced by collagen subunits within a tendon are uniform
/ /t/.t .m
or near their muscle-tendon junctions.
: /
ss : ss :
Aging also increases the risk of tendon injury in both
hhtttp hhtttp
Viscoelasticity is a biomechanical behavior of all
tp
connective tissues, meaning, as the word implies, that
tissue properties are a combination of viscosity (veloc-
ity dependent) and elasticity (time independent). Ten-
tp
humans and animals.45 Human tendon collagen content
decreases with age, suggesting either a reduction in the
synthesis of collagen, increased degradation, or a com-
dons are viscoelastic because of complex interactions bination of the two. Furthermore, this decline in colla-
within and among collagen fibers, proteoglycans, and gen synthesis may be caused by either a decrease in the
k eers
rs
water. Recent studies have examined the molecular or-
e r
e
igin of viscoelastic behavior and concluded that the vis-
k s
r s
number of tendon fibroblasts or a decline in their in-
trinsic ability to produce collagen.45
bboooo k b o o
o k
cosity of individual collagen molecules is several orders
o
of magnitude lower than the viscosity of single collagen
b o oo
In general, injured tendons heal by the typical
o
wound-healing processes of inflammation, prolifera-
/
e e
/ e / e
/ e b
fibrils, suggesting that additional molecular mecha-
ee ee/ e
/ e b
tion, and remodeling, but there are functional differ-
/ / t .
t m
nisms, such as the movement of collagen molecules
. m
within collagen fibrils, must be contributing to gross
: / / / t t m
ences in the way different tendons heal, which is an im-
. . m
portant factor to be considered during postoperative
: /
t p ss
p : /
tissue viscoelastic behavior in tendons.39
ss : /
treatment.44 For example, because flexor tendons of the
t p p
Interactions
t
hht t
Functional Significance of Muscle-Tendon t
hht t
hand are encased in synovial sheaths and their func-
tional repair requires both tissue strength and intrasyn-
ovial gliding properties, the prevention of adhesion tis-
As noted previously, muscles often shorten as they exert sue formation between the tendon surface and its
tensile loads on tendons. The affected tendon stretches sheath is critical. The possibility of optimal periods of
k eers
rs
and can subsequently recoil as the muscle relaxes,
e r
which essentially makes the tendon an elastic strain en-
k e s
r s
immobilization and subsequent loading regimens for
different injured tendons are controversial topics.
b ooook b ook
ergy storage material. The capacity of tendons to store
oo
and recover energy is one mechanism that enables indi-
b oooo
Immobilization leads to the development of fibrous
adhesions between the tendon and its synovial sheath
/
e e
/ eb / e
/e b
vidual muscle-tendon units to customize their function
ee ee/e/e b
during the repair of an injured flexor tendon, which can
/ t
///t m
to a particular need, such as high-efficiency (where
. . m
compliant tendons store a great deal of energy) or high-
: / t.
///t m
severely limit range of motion. Long-term removal of
.m
load from a healing tendon also weakens the repair tis-
:
s
tps : s
tps :
40
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 1
rs keerrss
b ooookEnergy-Storing Tendons
b ook
Summary of Functional, Material, and Biomechanical Differences Between the Positional and
o o b o oo
o
/
ee/e b ee/ e
/ e b Tendons
ee/ e
/ e b
Energy Storing
: / t
///t. m
.m Positional
: / t
///t. m
. m References
s
tps : s
tps :
hhtttp hhtttp
Function
Store and release of elastic strain energy Transmit forces generated in muscles to bones Birch41
Material Properties
Bimodal with smaller fibril diameter Unimodal with larger fibril diameter Birch41
Greater glycosaminoglycan and water content: less stiff Lower glycosaminoglycan and water content Batson et al42
k eers
rs
matrix
k eers
r srigid matrix
ook ook
Increased interfascicular gliding because of lower Tightly packed fascicles lead to less Thorpe et al43
b oo
intrafascicular stiffness
b oo b o oo
interfascicular sliding at low loads
o
/
e e
/ eb Biomechanical Properties
e/
e e
/ e b ee/ e
/ e b
Extensible under physiologic loads
Higher failure strain
: // t/.tm
. m : / /
Lower failure strain
t
/ .
t m
Inextensible under physiologic loads
. m
Thorpe et al43
Thorpe et al43
ss : / ss : /
hhtttp hhtttp
Lower modulus and failure strain Higher modulus and failure strain Thorpe et al43
Rate of Injury
More
tp Less
tp Thorpe et al43
Examples
Human Achilles tendon Human anterior tibialis tendon Thorpe et al43
k errss
Equine superficial digital flexor tendon
e k e rrss
Equine common digital extensor tendon
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e / e e b
sue because of decreased production of extracellular ma-
trix.
ee / / e e b
strating NO responses to mechanical stress. Extraneous
ee /
addition of NO can apparently improve some tendon
: / / t
/ .
t m
. m : / /t . m.m
healing by increasing collagen synthesis, whereas com-
/ t
s : /
Biologic Alterations Following Tendon Injury
s s : /
petitive inhibition of NOS activity inhibits tendon heal-
s
hhtttp
tp hhtttp
tp
Degeneration in tendons is apparently not routinely ac- ing.47
companied by evidence of inflammation. Tendinosis
has been reported to occur in the patellar, Achilles, pos- Current Concepts in Tendon Repair
terior tibialis, rotator cuff, long head of the biceps The common goal of the various reparative strategies
brachii, and wrist extensor tendons. Histologically, ten- used after tendon injury is to facilitate early return to
k e rs
dinosis is characterized by the lack of inflammatory
rs
cells with disordered patterns of collagen fibrils, in-
e k e r
e s
r s
preinjury activity levels by promoting early and strong
repair. Improved suture repair techniques are the gold
bboooo k b
sis or programmed cell death (later), and abnormal
o o
creased cellularity and vascularization (early), apopto-
o o k b o oo
standard for repairing completely torn tendons, with
o
minimal durations of immobilization and early (low
/
e e
/ e /
ECM resulting from degradative cell processes.
ee e
/ e b / e
/ e b
load) loading being used to restore tendon function. In
ee
/ / t .
t m
As noted in previous paragraphs, tendon healing af-
. m
ter a rupture where there is local bleeding is similar to
: / / / t t m
addition, several tendon augmentation techniques are
. . m
still being evaluated.
: /
t p ss
p : /
wound healing, including its cellular events. The infil-
t ss : /
Although tissue-engineered application of matrices
p p
t
hht t
tration of mast cells and macrophages in the injury site
leads to the secretion of transforming growth factor-β
(TGF-β), which in turn stimulates excessive production
t
hht t
loaded with growth factors, cells, and other regulators
has been tested in an attempt to augment normal ten-
don repair, only transitory improvement has been noted
of ECM, resulting in the formation of scar. It has been without significant biomechanical improvements thus
shown that a neutralizing antibody of TGF-β can di- far.48 Platelet-rich plasma (PRP) harvested from whole
k e rs
minish excessive production of ECM and improve the
rs
postoperative range of motion in a rabbit model of
e k eers
r s
blood has an array of growth factors that are found in
normal tissue repair. As of 2012, however, convincing
b ooook
flexor tendon transection.46
b oook
o
Nitric oxide (NO) is a small free radical that is gen-
b oooo
clinical evidence for the success of PRP based on ran-
domized trials remains limited.
/
e e
/ eb ee/ e
/e b
erated by nitric oxide synthase (NOS). Normal, unin-
/e/e b
Adult mesenchymal stem cells retain their ability to
ee
/ t
///t m
jured tendons have very little NOS activity, but chronic
. . m
tendon overloading upregulates NOS isoforms, demon-
: / t.
///t m
differentiate into various tissue types and thus are a po-
.m
tentially useful tool for repairing injured tendons,
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
which do not heal intrinsically. The mesenchymal stem In terms of histologic architecture and matrix com-
k eers
rs ke
cells from tendon tissue, referred to as tendon stem/
errss position, the exterior surfaces of extra-articular liga-
b ooook b o ook
progenitor cells, possess multipotent differentiation ca-
o
pacity along with inducing cellular proliferation and
ments are enveloped by a very thin cellular and vascu-
o oo
o
lar layer known as the epiligament. The epiligament
b
/
ee/e b / e e b
angiogenesis as well as reducing apoptosis of endoge-
ee /
nous cells.49 As of 2012, tendon stem/progenitor cells / e e b
merges into the perisoteum and shares the rich cellular-
ee /
ity, vascularity, and sheet-like architecture of the perios-
t . m
.m
are not yet in use clinically because they require further
: / ///t : / t
///t. m
. m
teum. It likely contributes to healing in a way that is
s
tps :
investigation for both safety and efficacy.
s
tps :
analogous to periosteal healing of bone. The cruciate
hhtttp hhtttp
ligaments are unique among all ligaments in having a
synovial sheath that covers them, and they have some
Ligaments healing issues in common with synovial tendons.
Collagen fibers and fiber bundles in the main body
Ligaments are dense, fibrous, connective tissues that of ligaments are configured grossly in a parallel ar-
form the connecting link between two articulating rangement along the long axis of the ligament with a
k eers
rs bones.50 Ligaments come in various shapes and sizes
k eers
r s crimp pattern similar to that seen in tendons (but with
and are named based on their shapes (for example, del-

ook ook
unique periodicity). This crimp has been shown to al-
b oo b o
toid), their relationships to a joint (for example, collat-
o b o oo
low a ligament to elongate (slightly) under tensile loads
o
/
e e
/ eb ee e
/ e b
eral) or to each other (for example, cruciate), or to the
/
bones that they connect (for example, coracoacromial).
ee e
/ e b
without sustaining matrix damage.52 Also similar to
/
tendons, collagen bundles in a ligament exhibit a hier-
: // t/.tm
. m t . m
. m
archical structure, with intertwined collagen fibrils
: / / / t
Functional Anatomy
ss : / ss : /
forming fibers, and fibers forming fiber bundles. Type I
hhtttp hhtttp
collagen is the primary structural constituent of a liga-
tp tp
Ligaments have many subcomponents that are known
as major functional bands that tighten or loosen in dif- ment, but ligaments also contain collagen types III, V,
ferent positions of the joint that they are guiding. The VI, XI, and XIV; proteoglycans; elastin; and other gly-
anterior cruciate ligament (ACL) is described as having coproteins.51
two main functional bundles or bands—the anterome-
dial band (that tightens in knee joint flexion) and the Biomechanical Properties
keerrss posteromedial band (that tightens more in knee joint

extension). Each functional band contains a much
k e rrss
e
The mechanical properties of ligaments are dictated
bboooo k b o
larger number of fibrous subcomponents that carry
o
o o k mainly by the hierarchical organization of their colla-
b o oo
gen fibers. Ligaments are likely not loaded homoge-
o
/
e e
/ e ee e
/ e b
loads in slightly different three-dimensional positions of
/
the bones and thus help guide the bones through these
ee e
/ e b
neously and function normally at less than 20% of
/
their tensile loading capacity, suggesting that they are
: / / t
/ .
t m m
normal motions. This has significance to how ligaments
. t . m.m
somewhat overdesigned biomechanically.
: / / / t
ss /
are injured (for example, the tight parts fail first, and
: ss : /
Collagen content, which dictates the mechanical
hhtttp hhtttp
the parts that are tight are a function of joint position), properties, varies among ligaments. For example, the
tp
why joints need to be examined in the position in
which they were injured (which is why a Lachman test tp
concentration of collagen is higher in the MCL than in
the ACL, making the MCL materially stronger.53 The
is effective in detecting unstable knee joints from ACL magnitudes of these differences can be quite large: the
tears; most ACLs are likely injured by sudden tibial ro- tangent modulus and the tensile strength of a human
tation at 15-30° of knee flexion), and how joints need MCL are approximately 300 MPa and 40 MPa, respec-
k eers
rs to be positioned to minimize pulling torn ligament ends
k e
farther apart (the joint position will determine whetherr
e s
r s tively, whereas comparable modulus values for gleno-
humeral ligaments range from 5 to 42 MPa with tensile
bboooo k or not there is load on the healing part).

b o o
o o k strengths of only 1-6 MPa.
b o oo
o
/
e e
/ e e / e
/ e b
Adult ligaments typically attach to bones through
specialized insertions.51 Each direct insertion has a spe-
e e / e
/ e b
The mechanical properties of ligaments change with
age. An asynchronous maturation process has been
e
: / / / .
t m m
cialized gradation of cells and tissue matrix that merges
t .
from ligament matrix through fibrocartilage into min-
: / / / .
t m m
noted between the bone-ligament-bone complex and
t .
the ligament midsubstance.54 Both stress and motion
t p ss
p : /
eralized fibrocartilage and then into bone. These inser-
ss : /
are necessary for remodeling of normal ligament tissue,
t p p
t
hht t
tions anchor ligaments firmly into bone because the
ends of the collagen fibers that make up the body of the
ligament are literally embedded in bone. Those embed-
t
hht t
and even a few weeks of immobilization can affect joint
stiffness and its structural properties. Load deprivation
leads to increased osteoclastic activity, resorption of
ded fibers are known as Sharpey fibers and are analo- bone, and disruption of the normal attachment of the
gous to similar fibers seen at tendon insertions. A sec- ligament to bone.
k eers
rs
ond type of ligament insertion is more typically seen in
k e
an immature ligament (for example, the tibial insertion
ers
r s
Like all connective tissues, ligaments exhibit interest-
ing viscoelastic behaviors. Type III collagen and elastin
b ooook b oook
of the medial collateral ligament [MCL] during growth)
o
in which a ligament attaches into periosteum and is not
b ooo
contribute to the elastic behavior of ligaments,55
o
whereas many factors appear to contribute to their vis-
/
e e
/ eb ee/ e
/e b
yet embedded into bone. Those periosteal attachments
/e/e b
coelastic properties, including the collagen fibers them-
ee
/
bedded into bone) at maturity.
: t
///t m
are much weaker but do convert to the adult form (em-
. . m / t.
///t m
selves,56 the interaction of collagen fibers with other ex-
.m
tracellular constituents,57 water movement through the
:
s
tps : s
tps :
42
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
Figure 5
ss : / ss : /
A and B, The diameter of collagen fibrils in a rabbit medial collateral ligament increased during 3 to 14 weeks of
hhtttp
tp hhtttp
tp
development. The collagen fibers changed from a relatively unimodal distribution of small diameter fibrils at
3 weeks to a bimodal distribution of small and large diameter fibrils at 14 weeks. C and D, The maturation of scar
tissue from 3 to 14 weeks after injury displayed only small unimodal collagen fibrils, indicating that MCL remodel-
ing may never reach the original levels following injury. (Adapted with permission from Achari Y, Chin JW, Heard
BJ, et al: Molecular events surrounding collagen fibril assembly in the early healing rabbit medial collateral liga-
ment—failure to recapitulate normal ligament development. Connect Tissue Res 2011;52:301-312)
k eers
rs k e r
e s
r s
bboooo k o
by sulfated glycosaminoglycans.58 Ligaments appar-
b o
matrix, and molecular bridges among collagen fibrils
o o k o oo
disrupted, likely exposes the torn ACL to a relatively
o
unfavorable synovial environment for healing.
b
/
e e
/ e / e e b
ently can accumulate damage with repetitive loading
ee /
and fail at stresses below their normal ultimate tensile
ee/ e
/ e b
Biologic Alterations Following
strength.59
: / / t
/ .
t m
. m : / / t
/ .
t
Ligament Injurym
. m
t p ss
p : / t ss : /
A recent report evaluated cytokine levels over time in
p p
Ligament Injury t
Biomechanical Alterations Following
hht t
The MCL of the knee has the capability of relatively
t
hht t
an ACL-deficient knee and found high levels of select
interleukins—namely IL-1β, IL-6 and IL-8 immediately
after injury.60 The levels of tumor necrosis factor-alpha
good functional healing by scar formation and remod- and interleukin 1 receptor agonist (IL-1Ra) were signif-
eling.51 However, this remodeling process takes years, icantly lower following ACL injury and did not return
k eers
and the original levels of material strength are never
rs k eers
r s
fully restored (Figure 5). In contrast, because of the rel-
to normal reported levels.60 In a recent clinical trial, in-
flammation was blocked with a single intra-articular
b ooook b oook
ative lack of a robust or functionally effective response
o
within a joint, ACLs do not enjoy the same functional
b ooo
injection of IL-1Ra (anakinra 150 mg) in patients with
o
an acute ACL tear. No decrease was noted in levels of
/
e e
/ eb ee/ e
/e b
recovery. ACL fibroblasts have limited capacity for cel-
/e/e b
IL-1β, although these patients experienced a reduction
ee
/ t
///t m
lular proliferation and ECM production. Further, the
. . m
ACL is ensheathed by a synovial membrane that, when
: / t.
///t
interval.60
: m
in knee pain and improved joint function over a 2-week
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Current Concepts in Ligament Repair
k eers
rs keerrs
Injury to the ACL is a major area of study to test liga-
s Annotated References
b ooook b ook
ment repairs. Several strategies for ACL repair or re-
o o
placement have evolved. Anatomic placement of grafts
b o oo
o
/
ee/e b ee/ e
/ e b
within tibial and femoral footprints is now considered
to be essential for optimal anatomic reconstruction.
1.
/ e
/ e b
Lieber RL, Loren GJ, Fridén J: In vivo measurement of
human wrist extensor muscle sarcomere length changes.
ee
t
///t. m
.m
Engineered ACL replacements or augmentations
: / : / t
///t. m
J Neurophysiol 1994;71(3):874-881.
. m
s :
have been evaluated extensively. Such replacements
tps s
2.
tps :
Gordon AM, Huxley AF, Julian FJ: The variation in iso-
hhtttp hhtttp
have included sources of reparative cells with a capac- metric tension with sarcomere length in vertebrate mus-
ity for proliferation and matrix synthesis; structural cle fibres. J Physiol 1966;184(1):170-192.
scaffold that facilitates growth of these cells; and an en-
vironment that provides sufficient nutrients. Recently, 3. Loren GJ, Shoemaker SD, Burkholder TJ, Jacobson
in an attempt to rejoin the torn ends of a ruptured MD, Fridén J, Lieber RL: Human wrist motors: Biome-
ACL, a novel suture technique using a scaffold with a chanical design and application to tendon transfers.
k eers
rs combination of collagen with PRP was applied.61 Add-
k eers
r s J Biomech 1996;29(3):331-342.
b ooook ooook
ing PRP may improve graft maturation and remodeling
but not consistently. This composite scaffold also ap-
b
4.
o oo
Ward SR, Kim CW, Eng CM, et al: Architectural analy-
b o
/
e e
/ eb e/
e e
/ e b
parently improved the biomechanical properties of an
ACL reconstruction.61 Thus, as of 2012, there is no re-
e e
/ e b
sis and intraoperative measurements demonstrate the
/
unique design of the multifidus muscle for lumbar spine
e
t . m
. m
liable augmentation for either ACL healing after suture
: // / t : / / t
/ .
t m
. m
stability. J Bone Joint Surg Am 2009;91(1):176-185.
: /
repair and no reliable augment of tendon grafts for
ss ss : /
hhtttp hhtttp
5. Smeulders MJ, Kreulen M, Hage JJ, Huijing PA, van der
tp tp
ACL reconstruction.
Horst CM: Overstretching of sarcomeres may not cause
cerebral palsy muscle contracture. J Orthop Res 2004;
22(6):1331-1335.
Summary
6. Freehafer AA, Peckham PH, Keith MW: Determination
Skeletal muscles, tendons, and ligaments are all mecha- of muscle-tendon unit properties during tendon transfer.
keerrss k
function, and biology to alterations in loading and use rrss
nosensitive connective tissues that alter their structure,
e e
J Hand Surg Am 1979;4(4):331-339.
bboooo k o o o k
conditions. Recent advances in muscle stem cell biology
b o 7.
b o oo
o
Boakes JL, Foran J, Ward SR, Lieber RL: Muscle adap-
/
e e
/ e e e
/ b
promise increased biologic understanding and thera-
/ e
peutic applications. Tissue engineering of ligaments and
e ee/ e
/ e b
tation by serial sarcomere addition 1 year after femoral
lengthening. Clin Orthop Relat Res 2007;456: 250-253.
: / / / .
t m m
tendons promises similar advances and application.
t . : / /t/.tm.m
ss : / 8.
: /
Brand PW, Hollister A: Clinical Mechanics of the Hand,
ss
hhtttp hhtttp
ed 2. St. Louis, MO, Mosby, 1993.
Key Study Points
tp 9. tpPowell PL, Roy RR, Kanim P, Bello MA, Edgerton VR:
Predictability of skeletal muscle tension from architec-
• Understanding muscle structural hierarchy is key tural determinations in guinea pig hindlimbs. J Appl
to understanding its function, and can help with Physiol 1984;57(6):1715-1721.
surgical decision making regarding changes in
k eers
rs muscle length that occur during surgical tendon
k e r
e s
r s 10. Winters TM, Takahashi M, Lieber RL, Ward SR: Whole
bboooo k •
transfers and total joint replacement.
b o
Skeletal muscle performance depends on meta- o
o o k b o oo
muscle length-tension relationships are accurately mod-
o
eled as scaled sarcomeres in rabbit hindlimb muscles.
/
e e
/ e / e
/ e b
bolic factors as well as structural factors. An un-
ee ee/ e
/ e b
J Biomech 2011;44(1):109-115.
: / / t
/ .
t m
derstanding of muscle fiber types will help sur-
. m
geons prescribe rational therapeutic regimens to
: / / t
/ t m
The important contribution of this article is that it dem-
. . m
onstrates experimentally that the three-dimensional
ss : /
increase muscle strength and endurance after in-
t p p t p ss
p : /
model of a whole muscle as numerous sarcomeres in se-
ries and in parallel works for large rabbit muscles.
•
jury.
t
hht t
Ligament and tendon biomechanical properties
serve as the prototype for almost all soft-tissue
t
hht
11.
tLieber RL, Ward SR: Skeletal muscle design to meet
functional demands. Philos Trans R Soc Lond B Biol Sci
mechanics. Understanding this nonlinearity is 2011;366(1570):1466-1476.
key for making decisions that involve surgical
This is an excellent review of the architectural design of
k eers
rs
tendon repair or joint replacement where liga-
ments must be transposed or displaced.
k eers
r s skeletal muscle as well as the skeletal system to which it
attaches.
b ooook •
oook
Novel new treatments involving tissue engineer-
b o b oooo
/
e e
/ eb e e
/e b
ing of artificial ligaments and tendons may pro-
/
vide a new source of tissue and offer new ap-
e
12.
e e/e b
Lieber RL, Jacobson MD, Fazeli BM, Abrams RA, Botte
/
MJ: Architecture of selected muscles of the arm and
e
proaches to treatment.
: / t
///t. m
. m / t.
///t m
forearm: Anatomy and implications for tendon transfer.
.m
J Hand Surg Am 1992;17(5):787-798.
:
s
tps : s
tps :
44
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
13. Zajac FE: How musculotendon architecture and joint 27. Ward SR, Tomiya A, Regev GJ, et al: Passive mechanical
k eers
rs rrss
geometry affect the capacity of muscles to move and ex-
kee
ert force on objects: A review with application to arm
properties of the lumbar multifidus muscle support its
ook ook
role as a stabilizer. J Biomech 2009;42(10):1384-1389.
b oo b o
and forearm tendon transfer design. J Hand Surg Am
o b o oo
o
/
ee/e b 1992;17(5):799-804.
ee/ e
/ e b 28.
ee/ e
/ e b
Prado LG, Makarenko I, Andresen C, Krüger M, Opitz
CA, Linke WA: Isoform diversity of giant proteins in re-
14.
: / ///t. m
Bodine SC, Roy RR, Meadows DA, et al: Architectural,
t .m
histochemical, and contractile characteristics of a
: / t
///t. m
. m
lation to passive and active contractile properties of
rabbit skeletal muscles. J Gen Physiol 2005;126(5):
s :
unique biarticular muscle: The cat semitendinosus.
tps s
tps :
hhtttp hhtttp
461-480.
J Neurophysiol 1982;48(1):192-201.
29. Brack AS, Rando TA: Tissue-specific stem cells: Lessons
15. Schiaffino S, Reggiani C: Molecular diversity of myofi- from the skeletal muscle satellite cell. Cell Stem Cell
brillar proteins: Gene regulation and functional signifi-
2012;10(5):504-514.
cance. Physiol Rev 1996;76(2):371-423.
These authors provide an authoritative and thoughtful
k
16.
eers
rs k eers
r s
Schiaffino S, Gorza L, Sartore S, et al: Three myosin review of the various stem cells present in muscle and
the control of their development and differentiation.
heavy chain isoforms in type 2 skeletal muscle fibres.
b ooook b o
J Muscle Res Cell Motil 1989;10(3):197-205.
oook 30.
b o oo
o
Sampaolesi M, Blot S, D’Antona G, et al: Mesoangio-
/
e e
/ eb 17.
e/ e
/ e b
Bottinelli R, Canepari M, Pellegrino MA, Reggiani C:
e ee/ e
/ e b
blast stem cells ameliorate muscle function in dystrophic
// t tm
Force-velocity properties of human skeletal muscle fi-
. . m
bres: Myosin heavy chain isoform and temperature de-
: / : / / t
/ .
t m
dogs. Nature 2006;444(7119):574-579.
. m
s : /
pendence. J Physiol 1996;495(pt 2):573-586.
s s
31.
s : /
Huard J, Fu FH: Gene Therapy and Tissue Engineering
hhtttp
tp hhtttp
tp
in Orthopaedic and Sports Medicine (Methods in Bioen-
18. Yoon S-J, Seiler SH, Kucherlapati R, Leinwand L: Orga- gineering). Boston, MA, Birkhäuser, 2000, pp xvi, 286.
nization of the human skeletal myosin heavy chain gene
cluster. Proc Natl Acad Sci USA 1992;89(24):12078- 32. Franchi M, Ottani V, Stagni R, Ruggeri A: Tendon and
12082. ligament fibrillar crimps give rise to left-handed helices
of collagen fibrils in both planar and helical crimps.
19.
keerrss
Weiss A, Schiaffino S, Leinwand LA: Comparative se-
k e rrss
e
quence analysis of the complete human sarcomeric my-
J Anat 2010;216(3):301-309.
bboooo k versity. J Mol Biol 1999;290(1):61-75.

b o o
o o k
osin heavy chain family: Implications for functional di-
This study examines the three-dimensional morphology
b o oo
of fibrillar crimp in tendons and ligaments and demon-
o
/
e e
/ e ee/ e
/ e b e e
/ e b
strates that each fibril in the fibrillar region always
/
twists leftward, changing the plane of running, and
e
20.
: / / t
/ t m
Smerdu V, Karsch-Mizrachi I, Campione M, Leinwand
. . m
L, Schiaffino S: Type IIx myosin heavy chain transcripts
: / / /.tm
sharply bends, modifying the course on a new plane.
t .m
Level of evidence: III.
s : /
are expressed in type IIb fibers of human skeletal mus-
s ss : /
hhtttp
tp hhtttp
tp
cle. Am J Physiol 1994;267(6, pt 1):C1723-C1728. 33. Gott M, Ast M, Lane LB, et al: Tendon phenotype
should dictate tissue engineering modality in tendon re-
21. Burkholder TJ, Fingado B, Baron S, Lieber RL: Rela- pair: A review. Discov Med 2011;12(62):75-84.
tionship between muscle fiber types and sizes and mus-
cle architectural properties in the mouse hindlimb. The authors present a detailed discussion on intrasyn-
J Morphol 1994;221(2):177-190. ovial and extrasynovial tendon morphology. Level of ev-
e
22.
k ers
rs
Eng CM, Smallwood LH, Rainiero MP, Lahey M, Ward
k e r
e s
r s
idence: III.
bboooo k b o o
o k
SR, Lieber RL: Scaling of muscle architecture and fiber
o
types in the rat hindlimb. J Exp Biol 2008;211(pt 14):
o oo
34. Wang JH, Guo Q, Li B: Tendon biomechanics and
o
mechanobiology—a minireview of basic concepts and
b
/
e e
/ e 2336-2345.
ee/ e
/ e b quiz 141.
ee/ e
/ e b
recent advancements. J Hand Ther 2012;25(2):133-140,
23.
: / / t
/ .
t m
. m
Fitts RH: Cellular mechanisms of muscle fatigue.
: / / t
/ .
t m
. m
The biomechanical characteristics of tendons are dis-
ss : /
Physiol Rev 1994;74(1):49-94.
t p p t p ss : /
cussed in relation to their unique hierarchical structure
and composition, which enable them to carry and trans-
p
24. t
hht t
Fridén J, Lieber RL: Evidence for muscle attachment at
relatively long lengths in tendon transfer surgery.
t
hht t mit muscular forces effectively. Level of evidence: III.
J Hand Surg Am 1998;23(1):105-110. 35. Arnoczky SP, Lavagnino M, Egerbacher M: The mecha-
nobiological aetiopathogenesis of tendinopathy: Is it the
25. Lieber RL, Murray WM, Clark DL, Hentz VR, Fridén J: over-stimulation or the under-stimulation of tendon
k eers
rs k eers
r s
Biomechanical properties of the brachioradialis muscle:
Implications for surgical tendon transfer. J Hand Surg
cells? Int J Exp Pathol 2007;88(4):217-226.
b ooook Am 2005;30(2):273-282.
b oook
o
36.
b oooo
O’Brien TD, Reeves ND, Baltzopoulos V, Jones DA,
Maganaris CN: Muscle-tendon structure and dimensions
/
e e
/ eb 26.
e / e
/e b
Labeit S, Kolmerer B: Titins: Giant proteins in charge of
e ee/e/e b
in adults and children. J Anat 2010;216(5):631-642.
270(5234):293-296.
: / t
///t m
muscle ultrastructure and elasticity. Science 1995;
. . m : / t.
///t m
In this article, the changes associated with fascicles,
.m
muscles, and tendons with maturation are discussed.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
The study concludes that adult muscles are better de- 46. Chang J, Thunder R, Most D, Longaker MT, Lin-
k eers
rs rrs
signed for force production than children’s muscles.
Level of evidence: II-1.
kee s eaweaver WC: Studies in flexor tendon wound healing:
ook ook
Neutralizing antibody to TGF-beta1 increases postoper-
b oo b o o b o oo
ative range of motion. Plast Reconstr Surg 2000;105(1):
o
/
ee/e b 37.
39(9):1563-1582.
ee e
/ e b
Wang JH: Mechanobiology of tendon. J Biomech 2006;
/
148-155.
ee/ e
/ e b
38.
: / t
///t. m
.m
Magnusson SP, Langberg H, Kjaer M: The pathogenesis
47.
: / t
///t. m
. m
Bokhari AR, Murrell GA: The role of nitric oxide in
tendon healing. J Shoulder Elbow Surg 2012;21(2):
s
tps :
of tendinopathy: Balancing the response to loading. Nat
s
tps :
hhtttp hhtttp
238-244.
Rev Rheumatol 2010;6(5):262-268. A detailed review that addresses the role of NO in rela-
This article discusses the microstructure of tendons and tion to tendon injury and healing is presented. Level of
suggests that one or more weak links are present in the evidence: III.
structure. A deeper understanding of how tendon tissue
adapts to mechanical loading will help in understanding 48. Visser LC, Arnoczky SP, Caballero O, Kern A, Ratcliffe
tendinopathy. Level of evidence: III.
k eers
rs k eers
r s
A, Gardner KL: Growth factor-rich plasma increases
tendon cell proliferation and matrix synthesis on a syn-
b ooook 39.
ooook
Duenwald SE, Vanderby R Jr, Lakes RS: Stress relax-
ation and recovery in tendon and ligament: Experiment
b b o oo
thetic scaffold: An in vitro study. Tissue Eng Part A
o
2010;16(3):1021-1029.
/
e e
/ eb ee e
and modeling. Biorheology 2010;47(1):1-14.
/ / e b
As tendons and ligaments are considered interchange-
e / e
/ e b
This article discusses the use of a bioactive scaffold cre-
e
t . m
. m
able in surgical applications, this study evaluates the
: // / t : / / t
/ t m
ated by a combination of growth factor-rich plasma and
. . m
a synthetic scaffold that enhanced the deposition of a
ss /
ability to predict the nonlinear and viscoelastic behavior
: ss : /collagen-rich extracellular matrix. Level of evidence: III.
hhtttp hhtttp
of tendon and ligament during stress relaxation testing
40.
tp
in a porcine model. Level of evidence: III.
Killian ML, Cavinatto L, Galatz LM, Thomopoulos S:

tp 49. Cao Y, Liu Y, Liu W, Shan Q, Buonocore SD, Cui L:
Bridging tendon defects using autologous tenocyte engi-
neered tendon in a hen model. Plast Reconstr Surg
The role of mechanobiology in tendon healing. J Shoul-
2002;110(5):1280-1289.
der Elbow Surg 2012;21(2):228-237.
keerrss e rrss
This article discusses how adhesion formation impairs
e
the healing of tendons and the effect of loading and mo-
k
50. Frank CB: Ligament structure, physiology and function.
J Musculoskelet Neuronal Interact 2004;4(2):199-201.
bboooo k tion to improve tendon healing.
b o o
o o k b o oo
o
/
e e
/ e 41.
/ e e b
Birch HL: Tendon matrix composition and turnover in
ee /
relation to functional requirements. Int J Exp Pathol
51.
e e
/ e b
Frank CB, Hart DA, Shrive NG: Molecular biology and
/
biomechanics of normal and healing ligaments—a re-
e
2007;88(4):241-248.
: / / t
/ .
t m
. m : / /t/.tm.m
view. Osteoarthritis Cartilage 1999;7(1):130-140.
ss : / ss : /
hhtttp hhtttp
42. Batson EL, Paramour RJ, Smith TJ, Birch HL, 52. Woo SL, Newton PO, MacKenna DA, Lyon RM: A
tp
Patterson-Kane JC, Goodship AE: Are the material
properties and matrix composition of equine flexor and
extensor tendons determined by their functions? Equine
tp comparative evaluation of the mechanical properties of
the rabbit medial collateral and anterior cruciate liga-
ments. J Biomech 1992;25(4):377-386.
Vet J 2003;35(3):314-318.
53. Quapp KM, Weiss JA: Material characterization of hu-
k eers
rs
43. Thorpe CT, Udeze CP, Birch HL, Clegg PD, Screen HR:
e r
Specialization of tendon mechanical properties results
k e s
r s
man medial collateral ligament. J Biomech Eng 1998;
120(6):757-763.
bboooo k 9(76):3108-3117.
b o
o k
from interfascicular differences. J R Soc Interface 2012;
o o 54.
b o oo
o
Jung HJ, Fisher MB, Woo SL: Role of biomechanics in
/
e e
/ e e/ e
/ e b
This article discusses the differences in the movement of
e
fascicles in the energy storing and positional tendons. / e e b
the understanding of normal, injured, and healing liga-
ee /
ments and tendons. Sports Med Arthrosc Rehabil Ther
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
Technol 2009;1(1):9.
44.
t p ss
p : /
Galatz LM, Charlton N, Das R, Kim HM, Havlioglu N,
t p
55.ss
p : /
Puxkandl R, Zizak I, Paris O, et al: Viscoelastic proper-
t
hht t
Thomopoulos S: Complete removal of load is detrimen-
tal to rotator cuff healing. J Shoulder Elbow Surg 2009;
t
hht t ties of collagen: Synchrotron radiation investigations
and structural model. Philos Trans R Soc Lond B Biol
18(5):669-675. Sci 2002;357(1418):191-197.
45. Thornton GM, Hart DA: The interface of mechanical 56. Scott JE: Elasticity in extracellular matrix “shape mod-
k eers
rs k ee
development of tendinosis. J Musculoskelet Neuronalrs
r s
loading and biological variables as they pertain to the ules” of tendon, cartilage, etc.: A sliding proteoglycan-
filament model. J Physiol 2003;553(pt 2):335-343.
b ooook Interact 2011;11(2):94-105.
b oook
o b oooo
/
e e
/ eb e / e
/e b
This article evaluates how tendon overuse injury is related
to abnormal mechanical loading that deviates from nor-
e
57.
e /e/e b
Chimich D, Shrive N, Frank C, Marchuk L, Bray R:
Water content alters viscoelastic behaviour of the nor-
e
/ t
///t m
mal mechanical loading in magnitude, frequency, dura-
. . m
tion, and/or direction. Level of evidence: III.
: : / t.
///t m
mal adolescent rabbit medial collateral ligament. J Bio-
.m
mech 1992;25(8):831-837.
s
tps : s
tps :
46
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
58. Ciarletta P, Micera S, Accoto D, Dario P: A novel mi- 61. Vavken P, Fleming BC, Mastrangelo AN, Machan JT,
k eers
rs rrss
crostructural approach in tendon viscoelastic modelling
kee
Murray MM: Biomechanical outcomes after bioen-
ook ook
at the fibrillar level. J Biomech 2006;39(11):2034-2042. hanced anterior cruciate ligament repair and anterior
b oo b o o b o oo
cruciate ligament reconstruction are equal in a porcine
o
/
ee/e b 59.
e e
/ e b
Georgoulis AD, Papadonikolakis A, Papageorgiou CD,
/
Mitsou A, Stergiou N: Three-dimensional tibiofemoral
e ee e
/ e b
model. Arthroscopy 2012;28(5):672-680.
/
This article has evaluated that bioenhanced ACL repair
/ ///t. m
.m
kinematics of the anterior cruciate ligament-deficient
t
and reconstructed knee during walking. Am J Sports
: : / t . m
. m
produced biomechanical results that were not different
///t
s
tps
Med 2003;31(1):75-79.
: s
tps : from ACL reconstruction in a skeletally immature, large
hhtttp hhtttp
animal model, although both procedures produced sig-
nificantly improved results over ACL transection. Level
60. Kraus VB, Birmingham J, Stabler TV, et al: Effects of in- of evidence: III.
traarticular IL1-Ra for acute anterior cruciate ligament
knee injury: A randomized controlled pilot trial
(NCT00332254). Osteoarthritis Cartilage 2012;20(4):
271-278.
k eers
rs k eers
r s
This study evaluates the clinical effectiveness of IL-1Ra
b ooook for ACL tears. Level of evidence: I
b ooook b o oo
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 5
e rs
rs e rrss
oo
kMusculoskeletal
ook e Biomechanics
o k
ook
o
e o oo
o
/e/ebb Donald D. Anderson, PhD
e / e
/ b
e b
Jessica E. Goetz, PhD
e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
such as in instances when fractures occur or as physical
Introduction activity levels increase or decrease. The associated fluc-
k eerss
matured considerably over the past three decades.
k eers
The scientific field of musculoskeletal biomechanics has
r r s
tuations in bone constitution involve changes in density
and architecture, which can impart considerable change
b ooook b oook
Many educational resources are available to aid in un-
o b o oo
in the mechanical properties of the tissue.
o
Recent research in the area of bone mechanics has
/
e e
/ eb e/ e
/ e b
derstanding this engineering science in the context of
orthopaedics.1,2 A summary of the basic terminology of
e ee/ e
/ e b
focused on methods for noninvasively assessing bone
// t/.tm
biomechanics is provided in Table 1. This chapter fo-
. m
cuses on the evolving role that biomechanics is playing
: : / / t
/ .
t m
properties in live individuals, better understanding how
. m
pathologies (for example, osteoporosis) negatively in-
ss : /
in orthopaedic practice, with background information
s : /
fluence the mechanical integrity of bone, and the devel-
s
hhtttp
tp hhtttp
tp
presented as needed to support this focus. The chapter opment of new (often pharmacologic) approaches to
begins with a brief review of musculoskeletal tissue me- maintaining or restoring more favorable mechanical
chanics (bone, cartilage, tendon, and ligament), de- properties. In this latter respect, bisphosphonates have
scribes evolving biomechanical focus areas, and con- played a primary pharmacologic role in treating osteo-
cludes with a discussion of specific areas in which porosis. Physical interventions (such as certain types of
exercise) also have been studied for this purpose, with
rrss rrss
biomechanical principles are being translated into clin-
o ke
ke
ical application.
o k e
k e
targeted development of protocols to optimize the os-
teogenic signal provided by exercise.6
oo
e bboo o e b o
b o o e b o
b o
/
e / e Musculoskeletal Tissue Mechanics
m ee/ / e Cartilage Mechanics
ee/ / e
Articular cartilage is generally well suited to the de-
m
Bone Mechanics
: / /
/ t
/ .
t . m : / /
/t/.t .m
mands of joint motion. The tissue supports predomi-
ss : s :
nantly compressive loading and affords low-friction
s
hhtttp hhtttp
The macroscopic mechanical properties of bone have
tp tp
motion between opposing joint surfaces. Articular car-
been extensively studied, and much is known in this tilage tissue has a unique biphasic (mixed solid/fluid)
area.3 Bone is a highly mineralized tissue whose prop- character, with corresponding mechanical implications.
erties are largely dictated by its density (mass) and When loaded slowly, the fluid phase of cartilage (water)
structure (global and local architecture). Because of the is able to flow through the porous solid matrix, and the
primary weight-bearing role of the skeleton, bone is apparent cartilage modulus is relatively low. The per-
k ee s
subjected to a highly complex loading environment
rrs e
during the normal activities of daily living. The nature
k r
e s
r s meability of cartilage dictates how slowly the load must
be applied to allow this fluid flow. When loaded more
bboooo k b o o
o
the risk of failure. At a macroscopic level, bone iso
of these dynamic (time-varying) loads subjects bone to
k b o oo
abruptly, there is inadequate time for the fluid to flow
o
/
e e
/ e ee/ e
/ e b
weakest in shear, next weakest in tension, and strongest
e e
/ e b
through the matrix, and the apparent modulus is on the
/
order of 10 to 20 times higher than that associated with
e
/ / t
/ t m
in compression. It is anisotropic, with a preferred direc-
. . m
tionality well suited to resisting routinely encountered
: : / / t
/ .
t m
. m
slow loading. Although there has been much debate in
loads.
t p ss
p : / t p ss : /
this area over the years, it is now widely accepted that
for most functional activities, cartilage is loaded suffi-
p
t t
Bone usually exists in a neutral homeostatic biologic
hht
state, with an even balance between mineral deposition
and resorption. However, bone is commonly subjected
t
hht t
ciently fast to limit fluid flow.
Defects in cartilage can be focal or global, with focal
defects tending to be more traumatic in origin and
to a more net-osteogenic or net-osteoresorptive state,4,5 global defects reflecting a chronic pathologic state.
Both types of defects influence tissue material proper-
k eers
rs k
Dr. Anderson or an immediate family member has stock
eers
r s ties and joint mechanics and are the focus of continuing
research.7 The repair of focal defects is associated with
b ooook b ook
or stock options held in FxRedux Solutions LLC. Neither
oo b oooo
a need to restore local congruity and mechanical integ-
rity in a stable, long-lasting manner. The challenges im-
/
e e
/ eb e / e
/e b
Dr. Goetz nor any immediate family member has re-
ceived anything of value from or has stock or stock op-
e ee/e/e b
posed by these twin necessities have made progress in
/ t
///t m
tions held in a commercial company or institution re-
. . m
lated directly or indirectly to the subject of this chapter.
: : / t.
///t m
this area difficult, but most efforts have focused on
.m
physical replacement with some type of graft. More
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Basic Terminology of Biomechanics
b o ook
o b o oo
o
/
ee/e b Term Definition
ee/ e
/ e b ee/ e
/ e b
Stiffness
: / ///t. m
.
commonly N/mm or N/m.
: / t
///t. m
The ratio of force to displacement (stiffness = force ÷ displacement). Units of measure are most
t m . m
s
tps : s
tps :
hhtttp hhtttp
Load to failure The force that is measured at the time that a specimen breaks in a test involving a continuous
application of force.
Fatigue failure Cyclical subfailure loading may result in failure caused by fatigue. Load-to-failure testing data
are most often reported in the orthopaedic literature; however, clinical failure of fracture
fixation constructs or implants is often caused by fatigue failure.
Strain The amount of deformation per given length of an object. The units for strain are dimensionless,
k eers
rs k eers
r s
but they are often referenced as mm/mm or % strain.
ook ook
Stress The amount of internal forces acting over a given area of an object. The units of measure for
b oo b oo b o oo
stress are thus N/m2 (Pascal [Pa]), but for most orthopaedic applications are more on the order
o
/
e e
/ eb Elastic modulus
e/
e e
/ e b
of MPa (N/mm2).
ee/ e
/ e b
The ratio of the stress to strain over a region for which the deformation is elastic, which is
: // t/.tm m : / / t
/ .
t m
. m
analogous to stiffness for force displacement. The units are the same as for stress.
.
Yield point
ss : / s : /
The point on the stress-strain curve where deformation goes from elastic (fully recoverable on
s
hhtttp
tp hhtttp
tp
unloading) to plastic (unrecoverable).
Strength The highest stress on a stress-strain curve to failure. Strength and stiffness are not the same
thing, and the difference is important.
Anisotropy The concept that properties vary along different directions. Isotropy (in contrast) implies that the
properties are invariant with direction.
rrss rrss
Brittle A material that experiences little plastic deformation (strain) before it fails is said to be brittle
o ke
ke o k e
(for example, glass or cortical bone).
k e oo
e bboo o Ductile
e b o
example, copper).
b o o
If a material has a large plastic deformation region before it fails, it is said to be ductile (for
e b o
b o
/
e / e Toughness
m ee/ / e m e / / e
A material that can absorb more energy before failure (large area under the stress-strain curve)
e
is said to be tougher. Units for toughness are (N/m2)(m/m) or joules/m3.
: / /
/ t
/ .
t . m : / /
/t/.t .m
ss : ss :
hhtttp
tp
global defects in cartilage properties continue to be the
purview of total joint arthroplasty, but mechanical
joint-sparing procedures are also under development.
hhtttp
tp
remaining disorganized matrix material, causing the tis-
sue to appear more compliant. The more highly aligned
the fibers are in the primary direction (that is, the lower
the dispersion), the more dramatic is the anisotropic
Soft-Tissue Mechanics: Tendon and Ligament behavior of the tissue.
k eers
rs Tendons and ligaments are highly specialized to bear
k e r
e s
r s Tendons and ligaments are substantially more com-
pliant than bone or cartilage and exhibit highly nonlin-
bboooo k b o o
the predominantly tensile loads that occur from joining
o o
bones together into a joint and joining active contrac-k b o oo
ear stress-strain behavior, with relatively rapid exten-
o
/
e e
/ e / e e b
tile muscle tissue to bony insertions to facilitate skeletal
ee /
movement. At a microscopic level, this function is ac-
e e
/ e b
sion under low loads and progressively stiffer behavior
/
under higher loads. In the low-load, high-extension
e
: / / t
/ .
t m
. m
commodated by long, thin, collagen fibers, which exist
: / / t
/ .
t m
. m
part of the stress-strain curve (frequently referred to as
ss : /
in a partially crimped state. These crimped bundles are
t p p t p ss : /
the toe region), the applied load is acting to align and
straighten the crimps in the collagen fibers. The less
p
t t
generally aligned along a single primary direction be-
hht
tween bony (or muscular and bony) insertions, with
some variability in the degree of alignment of the colla-
t
hht t
crimped fibers will straighten sooner and begin taking
up load, while other neighboring fibers continue to
straighten. This tissue behavior causes an upward in-
gen fibers along that primary direction. This variability flection in the shape of the stress-strain curve. After all
is frequently called the fiber dispersion and is expressed of the collagen fibers have been pulled straight, they
k eers
rs
as a percentage of fibers aligned along the primary di-
rection. This microstructure causes tendons and liga-
k eers
r s will take up load in a more uniform manner, and the
stress-strain curve will become more linear and much
b ooook b oook
ments to be highly anisotropic. When tension is applied
o
along the main fiber direction, the tissue demonstrates
b ooo
steeper than in the toe region. Although a single elastic
o
modulus can be calculated in this region of the stress-
/
e e
/ eb ee/ e
/e b
its stiffest behavior; however, when tension is applied
/e/e b
strain curve, it is only descriptive of the behavior of
ee
/ t
///t m
perpendicular to the main fiber direction, the load is
. . m
carried by the cross-links between fiber bundles and the
: / t.
///t
loaded.
: m
that tendon or ligament after it has been moderately
.m
s
tps : s
tps :
50
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 5: Musculoskeletal Biomechanics
depending on the activity being performed (for exam-
k eers
rs keerrss ple, jumping versus standing).
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b / e
/ e b
New and Developing Focus Areas in
ee
: / t
///t. m
.m : / t
///t. m
Musculoskeletal Biomechanics
. m
The study of biomechanics has progressed substantially
s
tps : s
tps :
hhtttp hhtttp
beyond macroscopic measurements of bulk tissue be-
havior. Advances in experimental testing equipment,
imaging technology, and computing power have
spurred new developments in musculoskeletal biome-
chanics. Such advances have driven the application of
patient-specific (personalized) medicine, which has
k eers
rs k eers
r s changed the way in which clinical treatment decisions
are made. For example, rapid or real-time analysis of
b ooook b ooook o oo
the mechanics of a given patient’s joint, fracture, or gait
b o
/
e e
/ eb e/
e e
/ e b e / e
/ e b
pattern can be used to provide specific rehabilitation or
surgical care. Continuing advancements in and experi-
e
Figure 1
// /.tm m
Illustrative plot of three different material behav-
t .
iors that can be used to characterize tendon
: : / / / .
t m
. m
ence with benchtop imaging tools (microscopy) and
t
s : /
and ligament behavior. Linear elastic and hyper-
s ss /
noninvasive clinical imaging modalities (such as ultra-
:
hhtttp hhtttp
sound and MRI) have presented new ways to assess the
tp tp
elastic stress-strain behavior are loaded and un-
loaded in the same manner. Viscoelastic mate- mechanical properties of musculoskeletal tissues.
rial unloads in a different manner than it was
loaded because of the time-dependent behavior
of the material. Patient-Specific Treatment Considerations
Macroscopic: Kinematic Modeling
Musculoskeletal modeling provides a comprehensive
keerrss
To fully describe the range of mechanical behavior
k e rrss
e
approach to joint and tissue mechanics. This type of
modeling uses kinematic (relative positions and joint
bboooo k
of tendons or ligaments, more complex material prop-
o
erty models must be used. Two common models appro-
b o
o o k b o oo
angles) and kinetic (forces and moments) data in con-
o
/
e e
/ e ee/ e
/ e b
priate for describing tendon and ligament behavior are
hyperelastic or viscoelastic models (Figure 1). Rather
e e
/ e b
junction with an engineering approach known as in-
/
verse dynamics to calculate forces acting in a series of
e
t . m
. m
than a direct stress versus strain relationship, hyperelas-
: / / / t : / /t/.tm.m
joints, most frequently the arm (shoulder-elbow-wrist-
: /
tic models rely instead on equations describing the re-
ss ss /
finger) or the leg (hip-knee-ankle; Figure 2). Kinematic
:
hhtttp hhtttp
lationship between the strain energy density and tissue data are usually collected using an optoelectronic mo-
tp
stretch ratios. The coefficients in the hyperelastic model
equation are optimized to fit experimentally measured
tp
tion capture system, in which a series of cameras track
markers placed directly on an individual while he or
she performs a physical activity. Kinetic data are col-
tissue behavior. Hyperelastic coefficients typically do
not have any direct physical meaning, which is in con- lected using a force platform or pressure sensors.8,9
trast to Young’s modulus. Hyperelastic material models These two types of data can be used to calculate the ef-
k eerss
used to describe tendon and ligament behavior range in
r
complexity from the single coefficient neo-Hookean
k e r
e s
r s fects of a load applied at the hand or the foot on the
forces that develop in more proximal joints.
bboooo k b o o o k
model, which results in a relatively linear stress-strain
o b o oo
Because this type of modeling uses an individual’s
o
/
e e
/ e e e
curve, to the more complex Ogden model, which can
/ / e b
be of a first, second, or third order (with two, four, or
e e / e
/ e b
movement and loading patterns, it is inherently patient
specific. If a pathologic condition is associated with a
e
: / / t
/ .
t m
. m
six coefficients, respectively). Generally, hyperelastic
/ / t
/ .
t m
particular movement abnormality, movement retraining
. m
can be prescribed.10,11 A key advantage to this type of
:
t p ss : /
models with more coefficients can more accurately de-
scribe highly nonlinear stress-strain behavior, although
p t ss : /
intervention is that it is a conservative treatment specif-
p p
t
hht t
fitting large numbers of model coefficients requires ex-
tensive experimental testing.
Similarly, viscoelastic material models use equations
t
hht t
ically tailored to the needs of an individual patient. Al-
though commonly used after neurologic problems such
as trauma or stroke, gait retraining or modification in
describing changes in material behavior associated with patients without neurologic damage is slowly becoming
time. When tendons or ligaments are loaded for ex- more popular. Typically, a patient is given detailed in-
k eers
tended periods of time, the solid tissue microstructure
rs
can deform and slightly rearrange under a constant
k eers
r s
structions on how to change one or more aspects of his
or her normal walking motion to achieve a specific
b ooook b ook
strain or a constant load. Typically, viscoelastic models
oo
are fit to experimental data captured over an extended
b oooo
change in a movement pattern. The new motion is
practiced while the individual receives biofeedback
/
e e
/ eb / e
/e b
period of time, and these models are especially useful
ee ee/e/e b
ranging in sophistication from verbal feedback to audio
/ t
///t m
for modeling tendon and ligament behavior because
. . m
these tissues are loaded over very different time scales
: : / t.
///t m
feedback to visual feedback based on motion capture
.m
systems.12,13
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
Figure 2
: // t/.tm
. m : / / t
/ .
t m
. m
An example of a two-dimensional free-body diagram that provides the basis for musculoskeletal modeling. A, This
ss : / ss : /
basic model incorporates the joint angles and the applied forces (floor). B, The decomposed model allows for
hhtttp
tp hhtttp
tp
equation development. In each segment, the forces and the moments at the proximal (p) and distal (d) locations
must balance. In addition to joint angles and externally applied forces, the equations also incorporate the weight
of the limb segment (mg), the acceleration of the segment at the instant of the time being modeled (m*ax and
m*ay), and the rotational acceleration (α) of the segment center of mass (I).
rrss rrss
It has been suggested that an individual who has range of patient sizes and requirements. In the simplest
o ke
ke o k
pain or injured soft tissues may benefit from gait re-e
modified his or her gait to compensate for chronic joint
k e of cases, this could involve decision making regarding
oo
the placement and the diameter of a hole in a given
e bboo o e b o o o
training. It is believed that such treatment would pre-
b e b o o
plate so that it does not prematurely fail from stress
b
/
e / e m ee/ / e
vent any abnormal kinematics from stretching a surgi-
cal repair or increasing the load on implant hardware / / e
concentration near the hole. In a more complex sce-
m ee
nario, analyses might involve determining the sizes of
: / / t .
t . m
that could cause premature arthroplasty failure.14,15 An
/ / : / /
/t/.t .m
polyethylene acetabular cups that are generally more
s :
example of a specific gait modification is intentionally
s ss :
prone to wear.
hhtttp
tp hhtttp
tp
increasing lateral trunk lean to decrease the adduction Recently, increased computational capabilities and
moment in the knee.16 Because a decreased knee adduc- the ubiquity of digital medical imaging have made
tion moment would theoretically decrease medial com- patient-specific stress analysis tractable. As a result,
partment stress, such a modification may be useful in treatment considerations are beginning to be analyzed
patients with arthritis. Similarly, a patient who reduces on a patient- and case-specific basis. These methods be-
k eers
rs
his or her hip adduction angle by 5° (23%) while run-
k e
ning reduces the pressure on the lateral side of the pa-r
e s
r s
gin with the ability of an analyst to proceed fairly di-
rectly from CT or MRI information to computational
bboooo k b
capture and computer modeling become more widely
o o
tella and decreases patellofemoral pain.17 As motion
o o k b o oo
models of a patient’s anatomy. In one example, incor-
o
porating bone density information can allow the assess-
/
e e
/ e ee/ e
/ e b
available and patient-specific treatment becomes the
/ e
/ e b
ment of the risks of vertebral fracture in one patient
ee
/ / t .
t m
norm, it will become more common for the required
. m
modifications to be optimized to a patient’s particular
: / / / t t m
versus another.19 Patient-specific analysis also could be
. . m
applicable to planning a complex pelvic osteotomy
: /
t p ss
p : /
movement rather than the patient receiving generic in-
ss : /
aimed at improving femoral head coverage and thereby
t p p
t
hht t
structions about a movement modification needed to
achieve a particular mechanical goal.18 t
hht t
decreasing contact stress to reduce the risk of osteoar-
thritis. The degree of surface incongruity remaining af-
ter surgical repair of a fractured joint can be directly re-
Localized: Numerical Modeling lated to the expected levels of chronic contact stress
Patient-specific analysis on a joint and tissue level is be- exposure that the joint will experience20 (Figure 3).
k eers
rs
coming much more common. Numerical modeling ap-
e
proaches, primarily computational stress analysis meth-
k ers
r s
This information could be helpful in guiding later treat-
ment decisions.
b ooook b ook
ods such as finite element analysis, have played a
oo
critical role in the engineering design of implants and
b oooo
Apart from finite element analysis, CT data obtained
after an articular fracture can provide information to
/
e e
/ eb / e
/e b
devices used throughout orthopaedics. In that context,
ee ee/e/e b
objectively assess the severity of a fracture, stratify the
/ t
///t m
much of the focus has been on establishing a general in-
. . m
ventory of products engineered to accommodate a
: : / t.
///t m
risk associated with the initial trauma, and guide treat-
.m
ment decision making.21 Such methodology is based on
s
tps : s
tps :
52
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
Figure 4 Differential callus formation associated with con-
hhtttp hhtttp
ventional locking plate (LP) and far cortical lock-
tp tp ing (FCL) techniques are shown in a volumetric

rendering of callus from quantitative CT data
obtained at 9 weeks after surgical treatment in
an osteotomy gap fracture model. A 36%
greater callus volume was observed in the FCL
group compared with the LP group (P = 0.03).
rrss rrss
The bone mineral content (BMC) was 44%
o ke
ke o k e
k e
greater in the FCL constructs than in the LP con-
structs (P = 0.01). The box to the left (plate side)
oo
e bboo o e b o
b o o e b o
of the fracture highlights an area in which cal-
b o
lus formation was retarded by preferential con-
/
e / e m ee/ / e / / e
struct stiffness in the LP group. In FCL con-
ee
structs, the medial half of the callus, termed
m
Figure 3
: / /
/ t
/ .
t . m
These contact stress exposures on the distal tibial
: / /
/t/.t .m
near callus, had the same bone mineral content
as the far callus (P = 0.91). In other words,
ss :
articular surface (as seen from an inferior view-
ss : callus formation was symmetric. (Reproduced
hhtttp
tp hhtttp
tp
point) were computed using finite element with permission from Bottlang M, Lesser M,
analysis based on postoperative CT scans. The Koerber J, et al: Far cortical locking can improve
exposures show differential loading for each healing of fractures stabilized with locking
fracture case. (Reproduced with permission from plates. J Bone Joint Surg Am
Masrouha KZ, Anderson DD, Thomas TP, Kuhl 2010;92[7]:1652-1660.)
LL, Brown TD, Marsh JL: Acute articular fracture
severity and chronic cartilage stress challenge as
k eers
rs k e r
e
teoarthritis: Illustrative cases. Iowa Orthop Js
quantitative risk factors for post-traumatic os-
r s dense bone and less allowance of screw toggling within
bboooo k 2010;30:47-54.)
b o o
o o k b o oo
the plate holes, which limits the risk of screw pullout.
o
Important mechanical considerations arise, however,
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
because the stiffness that can be obtained with locking
: / t
/ .
t m
theories of fracture mechanics that allow the calcula-
. m
tion of the amount of physical energy involved in frac-
/ : / / t t m
plates far exceeds that attainable with conventional
. . m
plate and screw combinations. This potential has led to
/
t p ss
p : /
turing a bone by calculating the amount of surface area
ss : /
several loading experiments using cadaver and bone
t p p
t
hht t
liberated in the fracture.
Locked Plating and Related Concepts

t
hht t
surrogate specimens to better understand the mechani-
cal influence of locking screw placement within a given
plate. Plate designs that allow hybrid fixation in which
Locked plating describes fixation systems that couple a certain holes may be locked and others left free further
plate possessing threaded holes and screws with corre- complicate the mechanics of the fixation construct. Re-
k e rs
sponding terminal threads that allow the screw to lock
rs
into the plate when fully advanced. This construct has
e k eers
r s
searchers are attempting to fill this gap in knowl-
edge.22,23
b ooook b ook
been mechanically likened to an “internal” external fix-
oo
ator when taken to the extreme of having the fixator it-
b oooo
Recent research in locking plate fixation has begun
to question whether such constructs can be made so
/
e e
/ eb / e
/e b
self in exceedingly close proximity to the periosteal sur-
ee ee/e/e b
stiff that they actually impede bone healing22 (Figure 4).
/ t
///t m
face of the bone. Some of the mechanical benefits
. . m
imparted by locked plating are better stability in less
: / t.
///t m
Novel designs and techniques, such as overdrilling the
.m
near cortex and using partially threaded screws to pro-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
duce a far cortical locking construct, have arisen to fur- cation within the body, attaching it to external instru-
k eers
rs ke
ther manipulate the mechanics of a locking plate con-
errss mentation, or by exposing it to the outside environ-
b ooook b o ook
struct.23 Under axial loading, the initial stiffness of far
o
cortical locking constructs has been shown to induce
ment for direct visualization). The goal of noninvasive
o oo
o
mechanical testing has prompted the search for meth-
b
/
ee/e b / e e b
comparable amounts of interfragmentary motion at the
ee /
near and the far cortex. This fracture-site motion was / e e b
ods of measuring the mechanical behavior of tissues
ee /
that do not disrupt the native system. One such tech-
t . m
.m
one order of magnitude greater than that of standard
: / ///t : / t
///t. m
. m
nique, which is rapidly gaining in popularity, is elastog-
locking plate constructs.
s
tps : s
tps :
raphy. This technique has been called “an imaging-
hhtttp hhtttp
The relative mechanical merits of one locking plate based counterpart to palpation.”24
construct over another have not been determined, but In elastography, a mechanical stimulus is applied to
there are an exceedingly large number of permutations the tissue of interest. The method of force application
associated with variations in plate design and surgical can vary in sophistication from a clinician manually
technique. This is another area in which biomechanical pressing on the tissue to ultrasonically applied force or
modeling, including patient-specific modeling, may other external loading stimuli. While the tissue is me-
k eers
rs r
provide a sensible method to select the best construct
k ee s
r s chanically loaded, images are collected using a nonin-
ook ook
to stabilize a fracture and optimize the potential for vasive imaging modality, such as ultrasound, MRI, or
b oo healing.
b oo b o oo
optical coherence tomography. The mechanical proper-
o
/
e e
/ eb Noninvasive Assessment
e/
e e
/ e b ee/ e
/ e b
ties are then calculated using the measured displace-
ments from the imaging and the applied force data.
of Mechanical Properties
: // t/.tm
. m : / / t
/ .
t m
. m
s : /
It is reasonably well known that the mechanical prop-
s ss /
Micromechanics
:
hhtttp
tp hhtttp
tp
erties of biologic tissues in different disease states often It is well recognized that the musculoskeletal system
deviate from normal, which frequently leads to screen- adapts and responds to mechanical stimuli. These
ing tests based on physical palpation of the tissue. adaptive responses take place not at the whole-patient
When performed by a clinician, the tissue of interest is or the tissue levels but at a cellular level by prompting
subjected to a manually applied force, and the differ- cell differentiation, changing membrane potentials, or
ence in tissue stiffness is evaluated by subjective touch. activating signaling molecules. In situ, cells are attached
keerrss Although this practice is reasonably effective, objec-
k e rrss
e
to their surrounding matrix material by complex mi-
bboooo k b o o o k
tively quantifying differences in tissue stiffness (for ex-
ample, tissue modulus) is highly desirable. In most bio-
o
crostructures that alter load transmission from the tis-
b o oo
sue as a whole and can constrain the possible mechan-
o
/
e e
/ e ee e
/ e b
mechanical studies, quantitative measurement requires
/
isolating (either excising or surgically exposing) the tis-
ee e
/ e b
ical response of the cell itself. For example, in cartilage,
/
chondrocytes are attached to cartilage via a complex of
: / / t
/ .
t m
. m
sue of interest and physically deforming it in a con-
t . m.m
pericellular collagen fibrils that are oriented differently
: / / / t
ss /
trolled manner while measuring the applied loads and
: ss : /
from the normal zonal distribution of collagen fibrils in
hhtttp hhtttp
the actual tissue displacement. In some instances, tis- the different layers of cartilage.25 Macroscopic tissue
tp
sues can be tested in situ using techniques such as
mounting strain gauges onto the tissue of interest and tp
mechanical behavior is not necessarily indicative of the
mechanical environment that develops inside or imme-
directly measuring strain when the tissue is physiologi- diately adjacent to cells.
cally loaded. Tissue strain also can be measured with- Mechanical study at the microscopic level requires
out direct contact by using videos or photographs of alternative tools and methodologies. Whereas the me-
k eers
rs the deformation of a pattern applied to the surface of
k
the tissue in conjunction with image analysis routines
e r
e s
r s chanical stiffness of a tendon or a piece of cartilage can
be directly measured in simple benchtop studies using
bboooo k o o o k
to calculate strain. All of these methods require direct
b o b o oo
the assumption that the tissue acts as a continuum (it is
o
/
e e
/ e
access to and visualization of the tissue.
e / e
/ e b
The main advantage of direct physical testing is that
e e / e
/ e b
continuously distributed and fills the region of space it
occupies), accurate microscopic mechanical analysis re-
e
: / / / .
t m m
measurements are made on the specific tissue of interest
t .
in a well-controlled environment and, therefore, pro-
: / / / .
t m m
quires incorporating information about the detailed mi-
t .
croscopic structure of the tissue. A continuum assump-
ss : /
vide more repeatable and reliable results. All of these
t p p t p ss
p : /
tion is no longer valid, and characteristics such as cell
t
hht t
direct physical measurement techniques are highly inva-
sive, meaning that they cannot be routinely made on
living patients. The main drawback of these direct mea-
t
hht t
density, collagen fiber orientation, fluid permeability,
and electrical charge density must be included in the
mechanical evaluation. Advances in imaging methods
surement techniques is that the tissue is removed from and computer and materials science technology have
its normal physiologic environment. Because the exper- made it possible to study the specific mechanical
k eers
rs
imentally applied loads may not perfectly replicate
ee
those that occur in vivo, the mechanical data collected
k rs
r s
changes that cause adaptive tissue response at the mi-
croscopic and/or single-cell level.
b ooook physiologic conditions.

b ook
are less useful than measurements made under normal
oo b oooo
Like any other material, cell membranes, cytoskele-
tal filaments, mitochondria, nuclei, and collagen fibers
/
e e
/ eb / e
/e b
Ideally, physical measurements of the mechanical be-
ee ee/e/e b
will mechanically deform under load. The mechanical
/ t
///t m
havior of a tissue would be conducted without altering
. . m
it in any way (such as removing it from its normal lo-
: : / t.
///t m
study of these tissue and cellular components requires
.m
substantially different techniques than those tradition-
s
tps : s
tps :
54
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
ally applied to whole bones and tissues. The three main well, this approach provides understanding about new
k e rs
rs
methods for evaluating microscopic mechanics are
e keerrss fixation devices and application scenarios in relation to
b ooook b o ook
(1) analysis of microscope images, (2) computational
o
modeling and submodeling, and (3) direct physical test-
familiar clinical situations and promotes the adoption
o oo
o
of new technologies with minimal risk to the patient.
b
/
ee/e b / e e b
ing at or below the microscale. In imaging-based meth-
ee /
ods, displacements and deformations of cells or tissue / e e b
Laboratory mechanical assessment uses tight experi-
ee /
mental control to answer specific mechanical questions,
t . m
.m
components under load are recorded using a micro-
: / ///t : / t
///t. m
. m
whereas there is little control in clinical assessments.
s
tps :
scope. Strain behavior is calculated from microscopic
s
tps :
For example, using laboratory testing, a given screw-
hhtttp hhtttp
measurements of deformation.26,27 Microscopic compu- plate construct can be definitively shown to be more or
tational modeling uses traditional mechanical evalua- less stiff than another construct. However, mechanical
tion techniques, such as finite element analysis; how- testing is limited by its inability to predict the ideal me-
ever, the mechanical history of output from a chanical environment for a given fracture and patient.
macroscopic finite element tissue model serves only as By more tightly connecting mechanical testing with
input for a submodel of one or more cells or tissue re- animal testing and noninvasive imaging, researchers
k rs
rs rs
r
gions, with highly detailed mechanical property defini-
ee k ee s have achieved greater success in providing clinical un-
ook ook
tions and features such as aligned collagen fiber rein- derstanding and mechanical insights. These advances
b oo forcement. Direct measurement methods use

b oo b o oo
often rely on the creation of new, objective measure-
o
/
e e
/ eb ee e
/ e b
microscopic testing methods such as nanoindentation,
/
micropipetting plus mathematical modeling, or atomic
ee e
/ e b
ment strategies, which can replace former subjective
/
and categorical scoring methods. In a study involving
force microscopy.28,29
: // t/.tm
. m t . m
. m
locking plate fixation, the use of new methods to char-
: / / / t
ss /
These types of methods have made it possible to
: ss : /
acterize callus formation over time after an experimen-
hhtttp hhtttp
measure mechanical behavior at the level of a single tal fracture in a sheep model clearly showed that far
tp
cell. For example, chondrocyte deformation appears to
be time dependent, with an initial rapid deformation tp
cortical locking enhanced symmetric callus formation.23
under applied loading followed by a prolonged recov- Optimal Implant Positioning to

ery period to the initial state after removal of the Reduce Complications
load.26,28 Static load application causes a decrease in Proper positioning of total joint arthroplasty hardware
k errss
proteoglycan production, whereas dynamic compres-
e k
sion causes increased proteoglycan production.30 Chon-
e rrss
e
is crucial for long-term implant survival. Accurate posi-
bboooo k b o
drocytes appear to be more tolerant of compressive
o
o o k tioning ensures that loading occurs only on the por-
b o oo
tions of the implant designed to articulate with the op-
o
/
e e
/ e e e
/ e b
strain and are likely to be damaged by high tangential
/
strains.31 With the confluence of mechanics and biology
e ee e
/ e b
posing hardware components and guarantees a load
/
distribution that is uniform and as low as possible. Im-
: / / / .
t m m
that is so critical to orthopaedics, it is likely that these
t . t . m.m
plants loaded in configurations other than those in-
: / / / t
ss /
types of micromechanical studies will become more
: ss : /
tended for the specific implant design tend to develop
hhtttp hhtttp
common and begin to explain tissue response to load high stresses and/or point loading conditions. This can
tp
on a more mechanistic level.
tp
cause implant loosening because of increased underly-
ing bony stresses or implant damage from stresses that
exceed the yield stress of the implant material. Typi-
Translating Biomechanics Into Clinical cally, more constrained implant designs (for example,
Applications highly constrained fixed rotational axis total ankle im-
eers
rs
Developments in biomechanics are being translated
k k e r
e s
r s plants versus the lightly constrained ball-and-socket hip
implants) are more susceptible to damage when im-
bboooo k b o
various methods. A direct example of incorporatingo
into new clinical applications in orthopaedics through
o o k b o oo
planted in an improper position.
o
/
e e
/ e ee/ e
/ e b
these new developments occurs when mechanical mod-
e / e
/ e b
Surgical implantation of arthroplasty hardware is
becoming progressively more challenging as patients
e
/ / t .
t m
eling and knowledge gained from physical testing pro-
. m
vide insights into the likelihood of clinical success. In
: / : / / t
/ .
t m
. m
opt for surgeries that minimize surgical exposure and
as implant companies develop more specialized hard-
t p ss
p : /
other instances, the risks for surgical complications are
ss : /
ware designs. Advances in implant hardware have fo-
t p p
t t
reduced based on biomechanical studies of optimal im-
hht
plant positioning, or mechanical unloading from joint
distraction is proposed for the treatment of end-stage
t
hht t
cused on restoring physiologic motion using more com-
plex geometries and patient- or gender-specific designs.
More complex implant geometry requires the axes of
osteoarthritis. Patient-specific treatment and planning the implant to be aligned at specific angles relative to
is beginning to reshape the way in which orthopaedics the native anatomy of the joint; however, the mini-
is practiced.
k eers
rs k eers
r s
mized surgical exposure makes it difficult (if not impos-
sible) for the surgeon to directly visualize the anatomic
b ooook
Mechanical Testing to Gain Insight
in Fracture Treatment
b oook
o b ooo
landmarks required to accurately implant arthroplasty
o
hardware. Although advances in computer-aided sur-
/
e e
/ eb ee/ e
/e b
Over the years, physical testing has provided a valuable
/e/e b
gery have improved implantation accuracy, these sys-
ee
/ t
///t m
tool to help surgeons differentiate between the perfor-
. . m
mances of fracture fixation constructs. When done
: / t.
///t m
tems are expensive and are not available in every loca-
.m
tion where joint arthroplasty is performed. It is
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
hhtttp tps
hhtttp
k eers
rs 120
keerrss 120
ook ook
For cup tilt of 40˚ For cup anteversion of 10˚
b oo
110
b o o b o oo
o
110
Range of Motion (deg)
b b b
Range of Motion (deg)

/
ee/e 100
ee/ e
/ e ee/ e
/ e 100
90
: / t
///t. m
.m : / t
///t. m
. m 90
80
s
tps : s
tps :
hhtttp hhtttp
80
70 70
60 60
50 50
s s
-15 -10 -5 0 5 10 15 20 25 30 35 40
k eerrs k eerr s
15 20 25 30 35 40 45 50 55 60 65
Cup Anteversion (deg) Cup Tilt (deg)
b ooook STS
b ooook STOOP
b o oo
o STS STOOP
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
Figure 5
: // t/ tm
. m : / / t
/ .
t m
Range of motion at incipient impingement for both sit-to-stand (STS) and stooping (STOOP) dislocation challenges
. . m
for (A) 40° of cup tilt as function of cup anteversion and (B) for 10° of cup anteversion as a function of cup tilt.
: / : /
(Reproduced with permission from Elkins JM: Biomechanics of Failure Modalities in Total Hip Arthroplasty. PhD
ss ss
hhtttp hhtttp
Dissertation, The University of Iowa, 2013, p. 74.)
tp
recommended that a surgeon try to position the im-
tp layer and cause implant stresses above the yield stress
plant in a safe zone and assume that the implantation of the metal. Two recent studies used finite element
error around that location is small enough to achieve analysis of metal-on-metal hip bearing surfaces during
keerrss implant safety.

Safe zones can be physically tested by parametrically
k e rrss
e
a variety of kinematic challenges and with a variety of
acetabular cup designs.35,36 When the implant design or
bboooo k varying the position of implant hardware in a cadaver

b o o
o o k b o oo
the kinematics changed, the safe zone also changed
o
/
e e
/ e
joint and determining the effects of the positions on im-
plant stress. Finite element studies have made it possi-
ee/ e
/ e b ee/ e
/ e b
(Figure 5). This finding illustrates the challenges in-
volved in defining an optimal implant location.
ble to investigate a much wider parameter space, and
: /
increasing computational speed has allowed for large-
/ t
/ .
t m
. m : / /t/.tm.m Patient-Specific Treatment and Planning
ss : / ss : /
hhtttp hhtttp
scale, statistically based computer simulations (for ex- It might be reasonably argued that orthopaedic sur-
tp
ample, Monte Carlo simulations) of the effects of im-
plant positioning. Both cadaver and model-based
studies have shown that relatively small deviations in
tp geons have been classifying bodies, joints, bones, and
other factors into contrived groupings for many years
in an attempt to cope with the complex variation in
implant version or rotation increases contact stress suf- anatomy and biomechanical scenarios presented in or-
ficiently to exceed the yield stress of polyethylene.32-34 thopaedics. The advent of patient-specific analysis has
k eers
rs Within the same joint, the safe zone for arthroplasty
hardware is a function of hardware design, joint load-
k e r
e s
r s presented innovative opportunities for analyzing and
planning treatment. With advances in rapid prototyp-
bboooo k ing activity, and patient factors such as obesity or me-
b o o
o o k oo
ing capabilities, custom implants and patient-specific
b o o
/
e e
/ e
chanical alignment.34-37 Therefore, what is safe for one
implant design during a specific kinematic challenge
ee/ e
/ e b ee/ e
/ e b
cutting guides for joint arthroplasty are now being of-
fered by several major orthopaedic implant manufac-
(for example, walking) is not necessarily safe for other
/
implant hardware designs or kinematic challenges (for
: / t
/ .
t m
. m : / / t
/ .
t m
. m turers.
Patient-specific analysis methods are also being used
example, standing from a sitting position).
t p ss
p : / t p ss
p : / in preoperative surgical planning. The mechanical
t t
Advanced bearing surface implants, specifically
hht
metal-on-metal implants and ceramic implants, rely on
highly precise matching between the different compo-
t
hht t implications of nonsurgical and surgical treatment deci-
sions can be analyzed within the context of an individ-
ual patient and a contemplated procedure. For exam-
nents to preserve a microscopic lubricating fluid layer ple, in the prescription of orthotics, the widespread
between the components. Clearance between femoral availability of thin, pressure-sensitive sheets has led
k eers
rs
and acetabular components is ideally 100 to 200 µm in
metal-on-metal implants, which is much tighter than
k eers
r s
some orthotic manufacturing companies to offer in-
store evaluations of foot-floor pressure. Customized
b ooook the clearance between metal and polyethylene compo-

nents. Implant malalignment that causes gapping be-
b oook
o b oooo
prescriptions for shoe orthotics are then made based on
the sensor readings, with the objective of reducing foot-
/
e e
/ eb tween the components or causes the femoral neck to
ee/ e
/e b ee/e/e b floor pressure. Techniques dating back to Ilizarov’s use
impinge on the edge of the cup and lever the head out
/ t
///t
of the acetabular cup will destroy the thin lubricating
: . m
. m : / t.
///t m
.m
of external fixation frames to lengthen bone and cor-
rect malalignment are being changed by new technol-
s
tps : s
tps :
56 Orthopaedic Knowledge Update 11
hhtttp hhtttp © 2014 American Academy of Orthopaedic Surgeons
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
ogy. Surgeons are now aided by computerized systems This chapter provides excellent information on muscu-
k rs
rs
that guide adjustments to a frame to achieve proper
ee keerrss loskeletal biomechanics along with additional back-
ground information on the topic.
b ooook
limb length and correct malalignment.38
b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b 3.
e / e
/ e b
Cole JH, van der Meulen MC: Whole bone mechanics
and bone quality. Clin Orthop Relat Res 2011;469(8):
e
Summary
: / t
///t. m
.m
As the scientific field of musculoskeletal biomechanics
: / ///t. m
. m
2139-2149.
t
This review article, based on a thorough search of the
s
tps : s
tps :
hhtttp hhtttp
continues to evolve, its role in orthopaedic practice also current literature, describes the current understanding of
continues to grow and change. Advances in computa- the relationships between bone quality and mechanical
tional power and medical imaging are making patient- competence.
specific consideration of biomechanics a reality, with
implications in orthopaedic treatment, implant design, 4. Chen JH, Liu C, You L, Simmons CA: Boning up on
and patient rehabilitation. Wolff’s law: Mechanical regulation of the cells that
k eers
rs k eers
r s
make and maintain bone. J Biomech 2010;43(1):
108-118.
b ooookKey Study Points
b ooook b oo
This article describes the latest understanding of mecha-
o o
nobiology and the ways in which bone likely senses and
/
e e
/ eb e/
e e
/ e b ment.
ee/ e
/ e b
responds to its day-to-day mechanical loading environ-
// t/ tm
As assessment and modeling capabilities advance,
. . m
patient-specific treatment and planning concepts
: : / / t
/ .
t m
. m
s : /
are beginning to reshape the way in which ortho-
s s5.
s : /
Mulvihill BM, Prendergast PJ: Mechanobiological regu-
hhtttp
tp hhtttp
tp
paedics is practiced. lation of the remodelling cycle in trabecular bone and
possible biomechanical pathways for osteoporosis. Clin
• Using motion capture and computer modeling, Biomech (Bristol, Avon) 2010;25(5):491-498.
prescribed gait modifications can be optimized to The authors discuss the mechanoregulation of bone at
a specific patient rather than giving the patient the trabecular level, with an emphasis on the formula-
generic instructions about a movement modification of computational theories to explain phenomena.
keerrss
tion to achieve a particular mechanical goal.
• Other treatment considerations can be analyzed
k e rrss
e 6. Srinivasan S, Weimer DA, Agans SC, Bain SD, Gross
bboooo k o o o
on a patient- and case-specific basis. Examples in-
b o k b o oo
TS: Low-magnitude mechanical loading becomes osteo-
o
/
e e
/ e e e
/ e b
clude assessing fracture risk based on a patient’s
/
specific bone density and architecture, planning a
e e e
/ e b
genic when rest is inserted between each load cycle.
/
J Bone Miner Res 2002;17(9):1613-1620.
e
: / / / .
t m m
complex pelvic osteotomy aimed at improving
t . 7.
: / /t/.tm.m
Wong BL, Sah RL: Effect of a focal articular defect on
ss /
femoral head coverage, and making joint replace-
: ss : /
cartilage deformation during patello-femoral articula-
hhtttp hhtttp
ment implant (and implantation) choices based
tp
on specific mechanical considerations.
• In the case of fixation planning, patient-specific
tp tion. J Orthop Res 2010;28(12):1554-1561.
Experiments aimed at exploring the local mechanical
environment near focal articular defects of the patello-
biomechanical modeling offers opportunities to femoral joint are described.
assess the relative structural merits of one fixation
construct over another, including decisions about
k eers
rs
which holes in a plate need to be filled with which
screws for a given fracture. This can then provide
k e r
e s
r s
8. Ledet EH, D’Lima D, Westerhoff P, Szivek JA, Wachs
RA, Bergmann G: Implantable sensor technology: From
bboooo k b o o
guidance in selecting the best construct to stabi-
o o k 2012;20(6):383-392.
b o oo
research to clinical practice. J Am Acad Orthop Surg
o
/
e e
/ e healing.
ee e
lize a fracture and optimize the potential for
/ / e b ee/ e
/ e b
This review article describes ways in which implantable
: / / t
/ .
t m
. m : / / t
/ t m
sensor technologies have evolved and can be used to
. . m
provide exquisitely accurate in vivo data unique to a
t p ss
p : / t p ss
p : /
given patient.
t
hht t t
hht t
9. Kinney AL, Besier TF, Silder A, Delp SL, D’Lima DD,
Fregly BJ: Changes in in vivo knee contact forces
Annotated References through gait modification. J Orthop Res 2013;31(3):
434-440.
1. O’Keefe RJ, Jacobs JJ, Chu CR, Einhorn TA: Orthopae- The authors describe experiments using gait analysis to
k eers
rs k e
Rosemont, IL, American Academy of Orthopaedic Sur-
ers
r s
dic Basic Science: Foundations of Clinical Practice, ed 4. identify and modify mechanically unfavorable walking
patterns in patients with knee osteoarthritis.
b ooook geons, 2007.
b oook
o b oooo
/
e e
/ eb 2.
e / e
/e b
Bottlang M, Fitzpatrick DC, Augat P: Orthopaedic
e
10.
e /e/e b
Chang A, Hayes K, Dunlop D, et al: Hip abduction mo-
ment and protection against medial tibiofemoral osteo-
e
/ t
///t m
Knowledge Update, ed 10. Rosemont, IL, American
. . m
Academy of Orthopaedic Surgeons, 2011, pp 59-72.
: : / t.
///t m
arthritis progression. Arthritis Rheum 2005;52(11):
.m
3515-3519.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
11. Vincent KR, Conrad BP, Fregly BJ, Vincent HK: The 20. Anderson DD, Van Hofwegen C, Marsh JL, Brown TD:
k eers
rs rrss
pathophysiology of osteoarthritis: A mechanical perspec-
kee
Is elevated contact stress predictive of post-traumatic
osteoarthritis for imprecisely reduced tibial plafond
ook ook
tive on the knee joint. PM R 2012;4(5, suppl):S3-S9.
b oo b o o
The authors explore the premise that unfavorable knee
b o oo
fractures? J Orthop Res 2011;29(1):33-39.
o
/
ee/e b ee/ e
/ e b
kinematics may contribute to the onset and/or progres-
sion of knee osteoarthritis. Changing pathologic joint
ee/ e
/ e b
This study showed the value of a patient-specific ap-
proach to relating postoperative contact stress exposure
: / t
///t. m
.m
mechanics with gait modification may have disease-
modifying potential for medial compartment knee os-
: / t
///t. m
. m
(associated with residual fracture incongruity) with the
development of posttraumatic arthritis.
s
tps : s
tps :
hhtttp hhtttp
teoarthritis by slowing disease progression.
21. Thomas TP, Anderson DD, Mosqueda TV, et al: Objec-
12. Maulucci RA, Eckhouse RH: A real-time auditory feed- tive CT-based metrics of articular fracture severity to as-
back system for retraining gait. Conf Proc IEEE Eng sess risk for posttraumatic osteoarthritis. J Orthop
Med Biol Soc 2011;2011:5199-5202. Trauma 2010;24(12):764-769.
A new audio feedback system used with stroke patients The authors describe a CT-based methodology for objec-
k eers
rs k eers
to provide real-time feedback about gait characteristics
r s
is described. The device was tested in a small series of
tively quantifying fracture severity. A 100% success rate
in predicting posttraumatic arthritis after tibial plafond
b ooook b oook
stroke patients and was found to be well tolerated.
o b o oo
intra-articular fractures based on severity was reported.
o
/
e e
/ eb 13.
/ e e b
Hunt MA, Simic M, Hinman RS, Bennell KL, Wrigley
ee /
TV: Feasibility of a gait retraining strategy for reducing
22.
/ e e b
Bottlang M, Doornink J, Lujan TJ, et al: Effects of con-
ee /
struct stiffness on healing of fractures stabilized with
: // t/.tm
. m
knee joint loading: Increased trunk lean guided by real-
: / t . m
. m
locking plates. J Bone Joint Surg Am 2010;92(suppl 2):
/ / t
ss /
time biofeedback. J Biomech 2011;44(5):943-947.
: ss : /
12-22.
hhtttp
tp hhtttp
tp
The authors describe a gait retraining strategy in which This provocative study raises the question of whether a
normal individuals were asked to walk with increasing mechanical construct with locking plates may be so stiff
degrees of lateral trunk lean. Increasing lateral trunk that it impedes fracture healing. Methods are introduced
lean was shown to decrease knee adduction moment. to relate callus formation assessed on radiographs with
the mechanical loading environment of the bone.
14. Noyes FR, Dunworth LA, Andriacchi TP, Andrews M,
rrss rrss
Hewett TE: Knee hyperextension gait abnormalities in 23. Bottlang M, Lesser M, Koerber J, et al: Far cortical
o ke
ke training. Am J Sports Med 1996;24(1):35-45.
o k e
unstable knees: Recognition and preoperative gait re-
k e locking can improve healing of fractures stabilized with
oo
locking plates. J Bone Joint Surg Am 2010;92(7):1652-
e bboo o e b o
b o o 1660.
e b o
b o
/
e / e 15.
m ee/ e
Foucher KC, Hurwitz DE, Wimmer MA: Relative im-
/
portance of gait vs. joint positioning on hip contact
m ee/ / e
This article introduces a novel locking plate construct
design that provides greater control over construct stiff-
: / / t
/ .
t . m
forces after total hip replacement. J Orthop Res 2009;
/ : /
/t/.t .m
ness than is afforded by a locking plate alone. The con-
/
27(12):1576-1582.
ss : ss :
cept of optimizing the plate construct stiffness to best
hhtttp
tp hhtttp
tp
promote fracture healing is addressed.
16. Simic M, Hunt MA, Bennell KL, Hinman RS, Wrigley
TV: Trunk lean gait modification and knee joint load in 24. Mariappan YK, Glaser KJ, Ehman RL: Magnetic reso-
people with medial knee osteoarthritis: The effect of nance elastography: A review. Clin Anat 2010;23(5):
varying trunk lean angles. Arthritis Care Res (Hoboken) 497-511.
2012;64(10):1545-1553. The authors review magnetic resonance elastography,
k eers
rs k e
compartment knee loading in 22 participants with me-r
Modifications in trunk lean were used to reduce medial
e s
r s including details about the specific mechanical, imaging,
and analysis steps. Several applications for elastography
bboooo k dial knee osteoarthritis.
b o o
o o k b o oo
and examples of the results are presented.
o
/
e e
/ e 17.
e/ e
/ e b
Noehren B, Scholz J, Davis I: The effect of real-time gait
e 25.
e / e
/ e b
Korhonen RK, Herzog W: Depth-dependent analysis of
e
: / / t
/ .
t m
retraining on hip kinematics, pain and function in sub-
. m
jects with patellofemoral pain syndrome. Br J Sports
: / / t
/ t m
the role of collagen fibrils, fixed charges and fluid in the
. . m
pericellular matrix of articular cartilage on chondrocyte
t p ss
Med 2011;45(9):691-696.
p : / t p ss
p : /
mechanics. J Biomech 2008;41(2):480-485.
t t
The authors describe the effects of a gait retraining pro-
hht
gram designed to reduce hip adduction in runners. The
particular gait modification proved effective in reducing
t
hht t
26. Abusara Z, Seerattan R, Leumann A, Thompson R,
Herzog W: A novel method for determining articular
patellofemoral pain in the runners studied. cartilage chondrocyte mechanics in vivo. J Biomech
2011;44(5):930-934.
18. Fregly BJ, Reinbolt JA, Rooney KL, Mitchell KH, A setup is described for evaluating the deformation of
k eers
rs k eer
cations for knee osteoarthritis rehabilitation. IEEEs s
Chmielewski TL: Design of patient-specific gait modifi-
r individual chondrocytes in situ in a mouse knee when
the knee is physiologically loaded. The system allowed
b ooook Trans Biomed Eng 2007;54(9):1687-1695.
b oook
o o oo
the measurement of time-dependent deformation and re-
b o
/
e e
/ eb 19.
e / e
/e b
Melton LJ III, Riggs BL, Keaveny TM, et al: Structural
e ee/e/e b
covery of chondrocyte shape under loading.
/
Res 2007;22(12):1885-1892.
: t
///t. m
determinants of vertebral fracture risk. J Bone Miner
. m
27.
: / t.
///t m
Upton ML, Gilchrist CL, Guilak F, Setton LA: Transfer
.m
of macroscale tissue strain to microscale cell regions in
s
tps : s
tps :
58
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
the deformed meniscus. Biophys J 2008;95(4):2116- 34. Li YJ, Yang GJ, Zhang LC, Cai CY, Wu LJ: Influences
k eers
rs2124.
keerrss of head/neck ratio and femoral antetorsion on the safe-
ook ook
zone of operative acetabular orientations in total hip ar-
b oo 28.
o o
Zhang QY, Wang XH, Wei XC, Chen WY: Character-
b b o oo
throplasty. Chin J Traumatol 2010;13(4):206-211.
o
/
ee/e b e e
/ b
ization of viscoelastic properties of normal and osteoar-
/ e
thritic chondrocytes in experimental rabbit model. Os-
e ee/ e
/ e b
A kinematic model of total hip arthroplasty hardware
was used to investigate implantation configurations that
: / ///t. m
.m
teoarthritis Cartilage 2008;16(7):837-840.
t : / t
///t. m
. m
allowed for specific ranges of hip motion. The effects of
s
tps : s
tps : head-to-neck ratio were investigated, and a greater
hhtttp hhtttp
29. Luo S, Shi Q, Zha Z, et al: Morphology and mechanics head-to-neck ratio was found to provide larger implan-
of chondroid cells from human adipose-derived stem tation safe zones.
cells detected by atomic force microscopy. Mol Cell Bio-
chem 2012;365(1-2):223-231. 35. Elkins JM, Kruger KM, Pedersen DR, Callaghan JJ,
The authors describe a biochemical and mechanical Brown TD: Edge-loading severity as a function of cup
evaluation of chondrocytes and two chondrocyte pre- lip radius in metal-on-metal total hips—a finite element
k eers
rs e rs
cursors. Atomic force microscopy was used to directly
r s
measure cell stiffness, which proved to be highly depen-
k e
analysis. J Orthop Res 2012;30(2):169-177.
This article describes a large-scale, parametric, finite el-
b ooook dent on cytoskeletal arrangement.
b ooook o oo
ement model-based investigation of several hardware
b o
/
e e
/ eb 30.
/ e
Moo EK, Herzog W, Han SK, Abu Osman NA,
ee / e b
Pingguan-Murphy B, Federico S: Mechanical behaviour
e e
/ e b
design parameters involving range of motion without
/
impingement for metal-on-metal arthroplasty hardware.
e
: // t/.tm m
of in-situ chondrocytes subjected to different loading
. : / / t
/ .
t m
The results indicate the possibility that severe edge
. m
scraping may occur with various hardware geometry
ss /
rates: A finite element study. Biomech Model Mechano-
: ss : /and implant orientations.
hhtttp hhtttp
biol 2012;11(7):983-993.
tp
This article describes a multiscale finite element model
that was used to investigate strain rate effects on chon-
drocyte viability. Based on the correlation between
tp 36. Elkins JM, O’Brien MK, Stroud NJ, Pedersen DR, Cal-
laghan JJ, Brown TD: Hard-on-hard total hip impinge-
strain rates calculated in the model and impact-related ment causes extreme contact stress concentrations. Clin
cell death, the authors speculate that tangential strain is Orthop Relat Res 2011;469(2):454-463.
related to cell death.
rrss rrss
The authors describe a large-scale, parametric, finite el-
o ke
ke
31.
o
Korhonen RK, Julkunen P, Wilson W, Herzog W: Im-
k e
k e
ement model-based investigation of the effect of implant
oo
positioning on impingement and subluxation events in
e bboo o e b o
b o o
portance of collagen orientation and depth-dependent
fixed charge densities of cartilage on mechanical behav-
e b o o
metal-on-metal and ceramic-on-ceramic arthroplasty
b
/
e / e m e / / e
ior of chondrocytes. J Biomech Eng 2008;130(2):
e ee/ / e
hardware. In some implantation configurations, im-
pingement stresses exceeded material failure strengths,
m
021003.
: / /
/ t
/ .
t . m : / /
/t/.t .m
and scraping wear could be expected in these hard-on-
hard bearings in certain implantation configurations.
ss : ss :
hhtttp hhtttp
32. Fukuda T, Haddad SL, Ren Y, Zhang LQ: Impact of ta-
tp
lar component rotation on contact pressure after total
ankle arthroplasty: A cadaveric study. Foot Ankle Int
2010;31(5):404-411.
tp
37. Lombardi AV Jr, Berend KR, Ng VY: Neutral mechani-
cal alignment: A requirement for successful TKA af-
firms. Orthopedics 2011;34(9):e504-e506.
The authors describe a cadaver investigation of the ef-
The authors present a review of several previous studies
fects of implant alignment on contact stresses in total
and discuss the ongoing debate about optimal position-
k eers
r
ankle arthroplasty hardware. Malaligned hardware
s
components caused point contact, increased contact
k e r
e s
r s ing for total knee arthroplasty hardware. They conclude
that there is no compelling reason to deviate from a ge-
bboooo k the potential for increasing implant wear.

b o o
o k
stress, and increased rotational torque, all of which have
o b o oo
neric safe zone because targeting that range minimized
o
/
e e
/ e 33.
ee/ e
/ e b
Espinosa N, Walti M, Favre P, Snedeker JG: Misalign-
gross malalignment.
ee/ e
/ e b
: / / t
/ .
t m m
ment of total ankle components can induce high joint
.
38.
: / / / .
t m
. m
Rogers MJ, McFadyen I, Livingstone JA, Monsell F,
t
Jackson M, Atkins RM: Computer hexapod assisted or-
1179-1187.
t p ss
p : /
contact pressures. J Bone Joint Surg Am 2010;92(5):
t p ss
p : /
thopaedic surgery (CHAOS) in the correction of long
t
hht t
A parametric, finite element model-based investigation of
t
hht
the effects of implant alignment on contact stresses in to-
tal ankle arthroplasty hardware is presented. The mod-
t bone fracture and deformity. J Orthop Trauma 2007;
21(5):337-342.
els, which were physically validated, indicated that con-

tact stress was particularly sensitive to implant version.
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 6
e rs
rs e r s
rs
ooookBearing
k e Surface Materials
o o
o
k
o k e for Hip o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e and Knee Replacement t
///t. m
.mee t
///t. m
. mee
s: /
: s : /
:
tps
hhtttp tps
hhtttp
Brett R. Levine, MD, MS Kern Singh, MD Joshua J. Jacobs, MD
k eers
rs k eers
r s joint arthroplasty is initiated and can be accelerated by
b ooook b o oo
lapses of sufficient lubrication.
o
The process of surface wear involves five well-
/
e e
/ eb e/ e
/ e b
Current joint arthroplasty implants have excellent long-
term survival in hip and knee arthroplasty. As compo-
e ee/ e
/ e b
described mechanisms (adhesion, abrasion, third body,
: // t/.tm
nent designs have evolved, a major emphasis has been
. m
placed on improving articular bearing surface wear. Since
/ / t .
t m
fatigue, and corrosion). The four classic wear modes
. m
describe the condition of the prosthesis at the time that
: /
ss : / s : /
articular wear occurs.1 Mode 1 wear occurs when two
s
hhtttp hhtttp
the development of the first artificial joint arthroplasties,
tp
many materials have been used for bearing surfaces in
hopes of replicating the complex environment and the
biomechanics of the human body. These materials
tp
bearing surfaces that are intended to be in contact un-
dergo wear. Mode 2 wear describes wear generation in
the setting of a primary bearing surface articulating
with an unintended secondary surface (for example,
include polytetrafluoroethylene, ultra-high–molecular
polyethylene wear-through of a modular acetabular
weight polyethylene (UHMWPE), ceramics, cobalt- component). Mode 3 wear refers to the generation of
keerrss
chromium alloys, and highly cross-linked polyethylene
(HXLPE).
k e rrss
e
third-body wear in which scratched surfaces may accel-
erate mode 1 wear rates. Mode 4 wear occurs when
bboooo k b o o
o o k
To understand bearing surfaces and wear properties,
b o oo
two secondary surfaces come in contact, such as back-
o
/
e e
/ e e / / e b
it is necessary to understand the associated terminology
e
(Table 1). A typical human joint will maintain a low
e e / e
/ e b
side wear, fretting, and taper junction mechanically as-
sisted crevice corrosion. The material properties of the
e
: / / t
/ .
t m
coefficient of friction (ranging from 0.002 to 0.04) be-
. m
cause of the favorable lubrication properties of articu-
: / /t/.tm.m
bearing surface have a substantial effect on the wear
properties of a particular articulation.2,3
ss : /
lar cartilage. The goal of joint arthroplasty is to re-
ss : /
The issue of bearing surface wear has dominated
hhtttp
tp hhtttp
tp
create the process of elastohydrodynamic lubrication joint arthroplasty research over the past two decades.
(the lubricant properties determine the coefficient of The mechanisms and patterns of wear, the pathophysi-
friction because a constant film separates the surfaces) ology of osteolysis, and the effect of particulate debris
while minimizing the amount of time that the bearing on local tissues and surface lubrication have been ex-
surfaces come into direct contact with one another. tensively studied. Regardless of the specific joint, some
k eers
Historically, replacement articulations have been lim-
rs
ited to boundary lubrication, in which the forces in-
k e r
e s
r s
level of bearing surface wear occurs in all articular cou-
ples. There are three broad categories of variables that
bboooo k b o o
o o k
volved with joint loading create a local milieu whereby
b o oo
affect articular wear: design (materials, geometry, and
o
manufacture), environmental (bony structure, weight,
/
e e
/ e e / / e b
the synovial fluid does not fully separate the bearing
e
surfaces. The process of articular surface wear in total
e ee/ e
/ e b
and activity level), and combined variables (component
position, surgical technique, and third-body interac-
: / / t
/ .
t m
. m : / / t . m
. m
tions).4 The design goals for a successful articular sur-
/ t
p ss : /
Dr. Levine or an immediate family member serves as a
t p t p ss
p : /
face are minimizing contact stresses, balancing the
amount of contact area and constraint, maintaining an
t
hht t
paid consultant to or is an employee of DePuy, Johnson
& Johnson, and Zimmer; has received research or institu-
tional support from Biomet and Zimmer; and serves as a
t
hht t
acceptable range of motion, and encouraging fluid-film
lubrication. Despite the most well-conceived designs,
arthroplasty wear performance is often compromised
board member, owner, officer, or committee member of by factors such as impingement, third-body damage,
the American Academy of Orthopaedic Surgeons. and the breakdown of lubricating surfaces. Similarly,
k eerss
Dr. Singh or an immediate family member has received
r k e
royalties from Pioneer and Zimmer and serves as a paid
ers
r s the manufacturing process must be precise because mis-
matches in the congruency of articular couples can lead
b ooook b ook
consultant to or is an employee of DePuy, Stryker, and
oo b oooo
to early run-in wear; poor locking mechanisms and
/
e e
/ eb e / e
/e b
Zimmer. Dr. Jacobs or an immediate family member has
stock or stock options held in Implant Protection and
e ee/e/e b
roughened surfaces can cause backside wear. It is im-
portant to minimize wear debris to decrease local dam-
/ t
///t m
has received research or institutional support from
. . m
Medtronic Sofamor Danek, Nuvasive, and Zimmer.
: : / t.
///t m
age from particulate-induced osteolysis and adverse
.m
local tissue reactions.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Tribologic Terminology
b o ook
o b o oo
o
/
ee/e b Term Definition
ee/ e
/ e b ee/ e
/ e b
Hardness
/ ///t. m
. / t
///t. m
The ability to resist plastic deformation at the articular surface. A higher number indicates a harder
t m . m
surface. Surface treatments (ion implantation, polishing, or nitriding) can alter the hardness of a
: :
s
tps : s :
material. Common scales include Mohs, Rockwell, Vickers, and Brinell.
tps
hhtttp hhtttp
Scratch resistance Related to the hardness of a material. For example, the scratch resistance of ceramic > cobalt-chromium
> titanium.
Friction The resistance to movement as two materials are in contact and relative motion. The concept of
lubrication is to lower the frictional resistance to movement.
Surface roughness (Ra) The average of the absolute value of the measured heights of deviation from the center line along the
k eers
rs k eers
r s
material’s surface (the average of peaks and valleys along the surface). The surface roughness of
articular surfaces are 0.03 µm to 0.10 µm under normal conditions but can increase 2 to 3 times
b ooook b oook b o oo
(UHMWPE can increase 10-fold) with scratches and wear-related conditions.
o o
/
e e
/ eb Hydrodynamic
lubrication
e e
/ e b
important to the motion of the surfaces.
e ee e
/ e b
This occurs when articulating surfaces are fully separated by a lubricant. The viscosity of the lubricant is
/ /
Boundary lubrication
: // t/.tm m : / / t
/ .
t m
. m
This occurs when surfaces are not fully separated because there is a very thin and surface-adherent
.
ss / ss : /
layer between the bearings. Higher friction and wear rates are noted.
:
hhtttp
tp hhtttp
tp
Elastohydrodynamic The bearing surface elastically deforms, allowing the relative articulations to deform and stay
lubrication congruous without plastic deformation. Low wear rates and coefficient of frictions are noted, but
subsurface fatigue may be an issue.
Weeping lubrication This occurs when one surface is porous; the elastohydrodynamic lubrication can be augmented by fluid
expressed from a deforming surface. Important in articular cartilage lubrication.
Wettability This is the ability of a surface to be wetted when in contact with a liquid (theta angle is the contact
keerrss k e rrss
angle between the liquid drop and the solid). It is determined by adhesive and cohesive forces.
e
bboooo k Surface tension
o o
o k
ability of a drop of water to form a spheric shape.
b b o oo
A property of liquids that allows the surface to support light objects/external forces. It affords the
o o
/
e e
/ e Viscoelasticity
ee/ e
/ e b ee/ e
/ e b
The simultaneous exhibition of both viscous and elastic behaviors in a material. Such materials (plastics,
not ceramics or metals) display a time-dependent behavior when a load is applied in regard to flow
: / /
or creep.
t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
Bearing Surfaces
hhtttp
tp hhtttp
tp
elasticity of UHMWPE is decreased, thickness is in-
creased, and the articular surface is more conforming.6
Conventional UHMWPE The properties of UHMWPE have become more consis-
tent because of the adoption of standardized steriliza-
k eers
rs Prior to being supplanted by alternative bearing sur-
faces, conventional UHMWPE bearing surfaces domi-
k e r
e s
r s tion techniques.
bboooo k b o
nated the arthroplasty market. Polyethylene is a two-
o
o o k b o oo
Seven classic patterns of wear damage have been de-
o
scribed for UHMWPE surfaces: embedded debris,
/
e e
/ e
phase polymer fashioned from chains of ethylene
e / e
/ e b
(C2H4) molecules organized into areas of crystalline la-
e ee/ e
/ e b
scratching, pitting, burnishing, surface deformation,
abrasion, and delamination7 (Figure 1). Examples of
: / / t
/ .
t m
mella interspersed with amorphous matrix.5 The crys-
. m
talline lamella are connected to one another via tie mol-
: / / t
/ .
t m
. m
embedded debris are cement and/or metal fragments
ss : /
ecules, which provide additional strength and a means
t p p t p ss
p : /
pressed into the UHMWPE, whereas scratching refers
t
hht t
for load transfer. The typical physical properties of
UHMWPE used in orthopaedic applications are molec-
ular weight, 2 to 6 million g/mole; melting temperature,
t
hht t
to indented lines in the direction of principal motion of
the articulating components.7 Pitting describes small, ir-
regular areas of depression on the bearing surface, and
125° to 138°; tensile modulus of elasticity, 0.8 to burnishing refers to areas that visually appear to be
1.6 GPa; ultimate tensile strength, 39 to 48 MPa; and polished. Surface deformation occurs via creep or cold
k eers
rs
degree of crystallinity, 39% to 75%. Most UHMWPE
components are fabricated from sheets or bars of
k eers
r s
flow and leads to permanent deformation of the bear-
ing surface. Wear caused by abrasion has a more shred-
b ooook GUR 1020 or GUR 1050 polyethylene resin treated
b oook
o
with direct compression molding, hot isostatic pressing,
b oooo
ded appearance, as might be seen with third-body wear.
Delamination is the subsurface failure of UHMWPE
/
e e
/ eb or ram extrusion.
ee/ e
/e b ee/e/e b
and is seen as polyethylene flaking.7
/ t
///t m
To summarize an important tribology concept, max-
. . m
imal contact stress is lowered when the modulus of
: : / t.
///t m
Standard UHMWPE was the gold standard for bear-
.m
ing surfaces in the 1970s through the 1990s. Many
s
tps : s
tps :
62
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 6: Bearing Surface Materials for Hip and Knee Replacement
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Figure 1
e/
e e
/ e b e / e
/ e b
A, Demonstrations of clear areas of delamination and fatigue failure as significant portions of the polyethylene in-
sert have been completely destroyed. B, Diffuse pitting of the surface is seen on this retrieved polyethylene liner.
e
: // t/.tm
. m : / / t
/ .
t m
. m
ss : /
long-term follow-up studies reported good results in
ss : /
at the articular surface and backside wear have been re-
hhtttp
tp
terms of wear and osteolysis, which were the primary
concerns for limiting implant longevity8-17 (Table 2). hhtttp
tp ported in machined UHMWPE liners compared with
those manufactured using direct compression mold-
ing.18,19
Applications in Total Knee Arthroplasty Articular surface geometry plays a role in wear be-
In total knee arthroplasties (TKAs) performed in the cause contact stresses vary based on the radii of curva-
k errss
articulation is a derivative of UHMWPE. Polyethylene
k rrss
United States, the only available alternative surface for
e e e
ture match of the surfaces, physiologic load, and
UHMWPE thickness. In TKA liners, the maximal shear
bboooo k b o o
o o k
is used for the tibiofemoral surfaces and in resurfacing
b o oo
stress occurs 1 to 2 mm beneath the articular surface,
o
/
e e
/ e e / e
/ e b
the patella. Tibial and patellar all-polyethylene compo-
nents are available, but the evolution of TKA drove the
e e / e
/ e b
where the component is weakest and susceptible to fa-
tigue, delamination, and accelerated wear rates.6 Addi-
e
: / / t
/ .
t m
development of metal-backed and modular compo-
. m
nents. The major drawback of these advances was that
: / /t/.tm
tional concerns occur with component malalignment
.m
and the use of more constrained liners. Added con-
ss : / ss : /
straint coupled with the motion pattern of directed
hhtttp hhtttp
metal-backed components led to the use of thinner
tp
UHMWPE (which was catastrophic in some patella de-
signs) and the potential for backside wear in modular
tibial components. In addition, mobile-bearing compo-
tp
femoral rollback can lead to tibial post wear and, pos-
sibly, fracture.
Metal-backed components were developed to reduce
nent options exist in which the tibial articular surface is stress at the bone-implant interface and improve load-
highly congruent with the femoral condyles to reduce ing of the proximal tibia. Despite improved proximal
eers
contact stresses and maximize the contact area. The
rs e
forces of increased conformity are offset by the second
k k r
e s
r s
load transfer, there is concern about backside wear be-
cause micromotion is often related to the design of the
bboooo k b o o
o o k
polyethylene articulation, with the tibial component as
b o oo
locking mechanism.20 This motion may lead to burnish-
o
ing, scratching, and fraying of the locking mechanism
/
e e
/ e e / / e b
a rotating platform or meniscal bearing surface option.
e
Several factors may affect the wear characteristics of
e ee/ e
/ e b
and result in wear debris of 0.32 to 0.35 µm.18 This
/ / t
/ t m
polyethylene bearing surfaces in TKA, including the
. . m
method of manufacture, articular surface geometry,
: : / / t
/ .
t m
smaller size particle is associated with a greater volu-
. m
metric load and adjacent osteolysis. Factors contribut-
ss : /
modularity, ligamentous balancing, UHMWPE oxida-
t p p t p ss
p : /
ing to backside wear include the performance of the
t
hht t
tion, limb alignment, and motion pattern. The multi-
factorial nature of polyethylene wear makes it difficult
to model with computers and wear simulators.18 Peri-
t
hht t
locking mechanism, the tibial baseplate surface, im-
plant duration, and the patient’s activity level. Radia-
tion treatments to cross-link polyethylene particles,
implant particulate-induced osteolysis has been re- polyethylene doping with antioxidant materials, and al-
ported to account for 25% of TKA revisions. ternative bearing surfaces are some of the modifications
k e rs
The manufacturing processes for UHMWPE compo-
rs
nents are important because a failure of the UHMWPE
e k eers
r s
that have been developed to improve the wear charac-
teristics of conventional UHMWPE.
b ooook b ook
resin to fuse can introduce defects, which may result in
oo
wear damage, cracking, and delamination. Direct com-
b oooo
Applications in Total Hip Arthroplasty
/
e e
/ eb ee/ e
/e b
pression molding of liners has achieved better clinical
/e/e b
Conventional UHMWPE has been used extensively in
ee
/ t
///t m
results compared with implants machined from ex-
. . m
truded bars. Greater levels of pitting and delamination
: / t.
///t m
total hip arthroplasty (THA) and has achieved excellent
.m
long-term results. The articular couple is often the
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 2
keerrss
b ooook Summary of Conventional UHMWPE Outcomes in THA
b o ook
o b o oo
o
/
ee/e b Number of
ee/ e
/ e b
Average Age
Average
Follow-up
ee/ e
/ e b
Study (Year) Patients
: / t
///t. m
.m (Years) (Years)
: / t
///t. m
. m
Outcomes
Crowther and
s
tps :
56 Co-Cr 37
s
tps
11
: 23% pelvic osteolysis, 0.15 mm/year linear
hhtttp hhtttp
Lachiewicz wear rate, increased wear with younger
(2002)8 age and better hip scores, and average
polyethylene thickness = 7.8 mm
Eggli et al (2002)9 89 Co-Cr 66.5 5.95 Linear wear rate greater in first 2 years
(49, 22-mm heads; (run-in period); average linear wear rate =
40, 32-mm heads) 0.11 mm/year and 0.15 mm/year for 22-mm
k eers
rs k eers
r s and 32-mm heads, respectively
b ooook Kim et al (2003)10 80 Co-Cr (118 hips)
b ooook
47 9.8
b o oo
No aseptic loosening, 12% calcar and 9%
o
acetabular osteolysis, 0.12 mm/year linear
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
wear rate, and average polyethylene
thickness = 10.7 mm
Keener et al
/
43 Co-Cr
: / t/.tm
. m < 50 25
: / / t
/ .
t m
. m
Survivorship of acetabulum at 30 years for
(2003)11
ss : / ss : / aseptic loosening was 72%; no osteolysis
hhtttp
tp hhtttp
tp
data reported
Capello et al 91 Co-Cr 39 11.25 47% with osteolysis around femoral stem and
(2003)12 12 revisions for polyethylene wear/lysis
McAuley et al 488 (561 hips) 40 6.9 Average wear rate for patients younger than
(2004)13 50 years was 0.14 mm/year in nonrevised
and 0.29 mm/year in revised components;
keerrss k e rrss
e
survival for cup for any revision = 97.4%,
87.6%, and 53.8% at 5, 10, and 15 years,
bboooo k b o o
o o k b o
respectively
oo
o
/
e e
/ e
Singh et al (2004)14 36 ceramic; 2 Co-Cr
ee/ e
/ e b42 10
/ e b
No osteolysis, cementless cups performed
ee / e
better, and 1 revision for extensive wear
Kearns et al
/ t .
221 patients;
: / / t m
. m 41.1 8.4
: / /t/. m.m
31 patients (33 hips) revised for polyethylene
t
(2006)15
: /
191 Co-Cr;
ss ss : / wear; 24 cases of substantial osteolysis; cup
hhtttp hhtttp
90 ceramic; survivorship with revision as end point =
Burston et al
tp18 titanium
47 (58 hips) 39
tp
12
98.7%, 84.6%, and 52.5% at 5, 10, and
15 years, respectively
26% of patients with osteolysis in one or
(2010)16 more Gruen zones; average wear rate was
≥ 0.21 mm/year for patients younger than
k eers
rs McLaughlin and 79 Co-Cr 36
k e r
e s
r s 16
50 years
1% of cases with distal osteolysis and no
bboooo k Leeo (2011)17 (94 hips)
b o o
o o k (range, 11-18.5)
oo
aseptic femoral component loosening
b o o
/
e e
/ e
Co-Cr = cobalt-chromium.
ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : /
weak link, requiring revision surgery for wear, osteoly-
ss : /
phasis on using larger diameter femoral heads to lower
t p p
t
sis, and subsequent aseptic loosening15,21,22 (Figure 2).
hht t
THA surfaces are inherently highly conforming, with
typical clearances of approximately 0.1 mm; however,
t
dislocation rates. The minimum allowable thickness of
hht t
the liner is dependent on factors such as wear resis-
tance, locking mechanism design, component orienta-
approximately 100 million microscopic UHMWPE tion (vertical cups exhibit greater edge loading), head
wear particles are generated daily.23 Finite element diameter, and stiffness of the acetabular component.24
k eers
rs
models have shown that with perfect conformity, the
contact stresses are independent of the modulus of elas-
k eers
r s
Traditionally, wear rates of conventional UHMWPE
were reported to be 0.18 mm/year for the first 5 years
b ooook ticity of UHMWPE; increasing the head size in a fixed
b oook
o
shell size reduces the contact stresses; and the stresses
b ooo
and then 0.1 mm/year thereafter.6 Wear rates vary
o
based on the patient’s age and activity level, adjacent
/
e e
/ eb ee/ e
/e b
are independent of the liner thickness if the head size
/e/e b
joint degenerative changes, sterilization techniques, and
ee
/ t
///t m
remains fixed and the inner diameter of the cup is in-
. . m
creased.4 This is important because of the current em-
: / t.
///t m
component positioning and design. Despite wear rates
.m
that may limit the long-term success of conventional
:
s
tps : s
tps :
64
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
4 hours and functions by oxidizing biologic matter.27
k eers
rs keerrss Increased wear rates have been reported in UHMWPE
b ooook b o ook
o
sterilized via gamma irradiation in air (0.19 mm/year)
o oo
o
compared with a gas-plasma technique (0.097 mm/
b
/
ee/e b ee/ e
/ e b year).28
ee/ e
/ e b
: / t
///t. m
.m t
///t. m
. m
Highly Cross-Linked Polyethylene
: /
s
tps : s :
Attempts to improve on the longevity of UHMWPE
tps
hhtttp hhtttp
have led to the evolution of HXLPE options in which
the components are irradiated to induce higher rates of
molecular cross-linking. The amount of radiation and
the method of administration have a direct effect on the
properties of the polyethylene bearing surface. Radia-
tion doses of 5, 7.5, and 10 Mrad result in improved
k e rs
rs
Figure 2
e k e rs
r s
Supine radiograph of the hip showing eccentric
e
wear properties as the dose is increased. Beyond
polyethylene wear with osteolysis and subse-
b ooook at 15 years postoperatively.

b ooook
quent failure of the left acetabular component
10 Mrad, no further improvements have been noted.29
b o oo
o
Similarly, mechanical properties improve from 5 to
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
7.5 Mrad and then decrease with elevated doses of ir-
radiation. Advantages of HXLPE include reduced artic-
: // t/.tm
. m
UHMWPE, a recent meta-analysis showed similar out-
: / / t
/ .
t m
. m
ular and backside wear rates, and greater resistance to
s : /
comes in clinical and radiographic parameters com-
s ss : /
surface pitting and delamination.
hhtttp
tp hhtttp
tp
pared with modern metal-on-metal implants.25 A lower
complication rate was reported in the UHMWPE group Applications in TKA
compared with patients with metal-on-metal implants The longevity of TKA is often limited by the bearing
who had a 3.37 times higher complication rate. A ran- surface. Currently, the reported rates of osteolysis after
domized clinical trial comparing conventional TKAs range from 5% to 20% at approximately 5- to
UHMWPE and HXLPE reported that there were no 15-year follow-up.29 The benefits of decreased wear as-
e rrss
differences in cup migration, radiolucencies, or func-
k e k e rrss
e
sociated with HXLPE have not been as widely em-
braced in TKA. The increased contact stresses in TKA
bboooo k
UHMWPE in THA over the past 10 years are summa-
b o o
tional scores.26 The clinical results for conventional
o o k b o oo
have led to concerns related to reduced mechanical
o
/
e e
/ e rized in Table 2.
ee/ e
/
In reviewing the outcomes of conventional e b ee e
/ e b
properties, including lower resistance to fatigue, frac-
/
ture, and decreased ductility.30 The strength of HXLPE
t . m
. m
UHMWPE implants, it is important to consider the
: / / / t : / /t/.tm m
can be enhanced by (1) preserving the crystalline struc-
.
: /
variability associated with changes in head size, compo-
ss ss /
ture by annealing the UHMWPE at temperatures below
:
hhtttp hhtttp
its melting point, with cycles of irradiation and anneal-
tp tp
nent manufacturing, sterilization techniques, and femo-
ral head material. Femoral head size is important in the ing required to quench free radicals; (2) mechanical de-
calculation of volumetric wear (v = πr2w, where w = the formation of UHMWPE below its melting temperature,
linear wear rate and r = the radius of the femoral head). which mobilizes the crystalline phase and allows
Although dislocation rates are reportedly lower with quenching of free radicals; and (3) adding scavenger
larger diameter heads, in practice it is important to agents for free radicals, with vitamin E being the most
k eerss
consider the effect of wear, particulate debris genera-
r k e
tion, and the need for revision surgery when choosing a r
e s
r s commonly used agent.30
Beneficial wear rates for the HXLPE liners have been
bboooo k b o o
head size. Several studies support lower linear wear
o o k b o oo
reported in wear stimulation studies under optimal and
o
/
e e
/ e liners machined from extruded bar stock.
ee e
/ e b
rates with direct compression molding compared with
/ e / e
/ e b
adverse conditions. In a study using retrieval data from
HXLPE bearing surfaces, the predominant modes of
e
: / / t
/ .
t m
. m
The sterilization and packaging of UHMWPE affects
/ / t
/ .
t m
surface damage were machine mark loss and abra-
. m
sion.31 Patient weight and the conformity of the knee
:
t p ss : /
wear characteristics and survivorship. Early UHMWPE
component designs were irradiated with 2.5 to 4 Mrad
p ss : /
design were important predictors of surface damage.
t p p
t
hht t
in a standard room air environment. The gamma irra-
diation sterilized the implants while creating intrasub-
stance free radicals from cleavage of the UHMWPE co-
t
hht t
Concerns for mechanical failure and fracture have not
been realized at short-term follow-up; however, tibial
post fractures have been reported for conventional
valent bonds. These free radicals undergo oxidation in UHMWPE, and longer follow-up is needed to deter-
air, which leads to truncation of the large polymer mine if this incidence will be greater with the dimin-
k eers
chains and a reduction in fracture strength.27 Gamma
rs
irradiation is now performed in inert environments to
k eers
r s
ished fatigue properties of HXLPE.
b ooook b ook
achieve the benefits of cross-linking without the delete-
oo
rious effects of oxidation. Alternatively, diffusion of
Applications in THA
b oooo
The currently available options for THA liners and
/
e e
/ eb / e
/e b
ethylene oxide gas for sterilization is possible but fol-
ee ee/e/e b
dual mobility femoral heads are fabricated using vari-
/ t
///t m
lows a process that is more than 40 hours in length.
. . m
Gas plasma surface sterilization takes between 1.2 and
: / t.
///t m
ous proprietary methods by individual manufacturers.
.m
Typically, the process starts with ram-extruded bar
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Compared with metal-on-polyethylene bearing sur-
k eers
rs keerrss faces, ceramic surfaces have superior lubrication,
b ooook b o ook
o
smoother surfaces, and are less susceptible to third-
o oo
o
body wear. Early designs used in Europe had poor sur-
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
vivorship, with failure rates of 16% to 25% at 10-year
follow-up.42 Material and design concerns centered on
: / t
///t. m
.m : / t
///t. m
. m
high rates of aseptic loosening and ceramic fracture in
s
tps : s
tps :
3% to 5% of patients.42 Modern advancements, which
hhtttp hhtttp
have reduced grain size, inclusions, and grain boundar-
ies and improved taper tolerances, provide more suc-
cessful alumina materials for ceramic-on-ceramic sur-
face bearing options42-48 (Table 4). Such options are
mainly available for THAs, with limited applications in
TKA and total disk arthroplasty.
k eers
rs k eers
r s
b ooook Figure 3
b oook
The lip at the rim of an HXLPE liner fractured sec-
o
ondary to a fall and traumatic hip dislocation.
Applications in TKA
o oo
o
Articular surfaces that are not highly conforming may
b
/
e e
/ eb / e e b
The thin cross-section of polyethylene and in-
ee /
creased modulus of elasticity of cross-linking
ee/ e
/ e b
provide limited applications for ceramic bearing sur-
faces. The use of ceramic prostheses in the knee has
of injury.
: // /.tm m
may make these liners susceptible to this type
t . t . m
. m
been limited by concerns about component fracture.
: / / / t
ss : / s : /
Laboratory studies have reported some success with re-
s
hhtttp hhtttp
sisting the forces generated by the knee and lower wear
tp
stock exposed to various doses of radiation, which is
then followed by thermal treatment, sterilization, and
tp rates in simulator testing.30 Although not currently in
use in the United States, alumina-on-polyethylene com-
ponents are available in other countries, and a 94%
packaging. It is generally accepted that remelting de-
survivorship has been reported at 6-year follow-up.49
creases component strength and annealing leads to ele-
No component fractures have been reported; however,
rrss rrss
vated oxidation levels.32 Laboratory studies have
these results many not apply to heavier patient popula-
o ke
ke shown reduced wear rates for HXLPE femoral heads
ranging from 22 to 46 mm compared with conven-
o k e
k e tions.
oo
e bboo o e b o o o
tional polyethylene.33 This finding has led to the adop-
b e b o
Other options include alternative ceramicized bear-
b o
ing surfaces, such as oxygen diffusion–hardened
/
e / e / / e
tion of large-diameter femoral heads (> 36 mm) in
m ee
THA and the acceptance of thinner polyethylene liners
m e / / e
zirconium-niobium alloy. This material may be less sus-
e
: / /
/ t .
t . m
to reduce the rates of dislocation and limb-length dis-
/ : / /
/t/.t m
ceptible to catastrophic failure because it combines the
.
potential advantages of the lower wear rate of ceramics
crepancy.
ss : ss :
hhtttp hhtttp
with the strength of a metal core. Wear reduction rates
tp
Further laboratory studies using adverse condition
testing reported favorable results in the wear of
HXLPE compared with conventional UHMWPE. This
tp
of 85% have been reported in laboratory studies.50
Early follow-up has shown good results with oxidized
zirconium alloy femoral components.51 Fatigue-related
testing stressed the need for protecting the femoral pitting and delamination are wear modes that com-
head intraoperatively and minimizing the potential for monly affect TKA implants, and ceramic materials may
k eers
rs
third-body wear. Vertically placed acetabular compo-
nents and malpositioned components leading to im-
k e r
e s
r s not provide an advantage in this regard.
bboooo k b o o
o k
pingement can create increased material stress and sub-
o
sequently fracture thinner HXLPE liners34-36 (Figure 3).
Applications in THA
b o oo
o
/
e e
/ e ee/ e
/ e b
Relevant clinical studies have shown equivalent
e / e
/ e b
Alumina-on-Alumina Ceramics
Currently available THA options include ceramic-on-
e
/ / t .
t m
functional and pain scores for conventional UHMWPE
. m
and HXLPE and substantially lower wear rates for
: / : / / t
/ .
t m
. m
ceramic prostheses made of high-quality alumina mate-
rials with a reduced grain size. Modern components are
t p ss
p : /
HXLPE at midterm follow-up20,36-41 (Table 3). Radi-
t ss : /
extremely hard, are scratch resistant, maintain a low
p p
t t
ostereometric analysis has found wear rates of
hht
0.005 mm/year compared with 0.037mm/year for
HXLPE versus conventional UHMWPE, respectively.
t
hht t
coefficient of friction, and are hydrophilic with excel-
lent lubrication traits. These properties support the cur-
rent trend of using larger diameter femoral heads be-
Overall wear reduction rates of 40% to 80% have been cause there is no clinically important increase in wear,
reported.32 Continued follow-up is necessary to ensure and they provide a higher resistance to fracture and less
k eers
rs
that the trend toward larger diameter femoral heads
does not lead to adverse outcomes.
k eers
r s
femoral head-liner separation caused by the wettability
of the alumina surface.47 Low wear rates, 95% good or
b ooook Ceramics
b oook
o b ooo
excellent results, minimal osteolysis, and 98% survivor-
o
ship have been reported at 10-year follow-up using
/
e e
/ eb ee/ e
/e b
Ceramics are inorganic, chemically stable material
/e/e b
ceramic-on-ceramic bearing surfaces in THA.52 A ran-
ee
/ t
///t m
structures characterized by high wear and corrosion re-
. . m
sistance, strength, biocompatibility, and wettability.
: : / t.
///t m
domized trial reported the superiority of ceramic-on-
.m
ceramic bearing surfaces over metal-on-polyethylene
s
tps : s
tps :
66
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 3
rs keerrss
b ooookHXLPE and Conventional UHMWPE Outcomes in THA
b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee e
Average
/ / e
Follow-upb
Study (Year)
t . m
.m
Number of Patients
: / ///t
Wear Rates
: / t
///t. m
. m (Years) Outcomes
Johanson et al26
s
tps :
60 randomized to
s
tps :
HXLPE = 0.005 mm/year 10 Better results found in
hhtttp hhtttp
(2012) UHMWPE or HXLPE UHMWPE = patients treated with
0.056 mm/year HXLPE and cemented stems
at up to 10 years
Mutimer et al37 122 patients, randomized HXLPE = 0.05 mm/year 5.5 61 patients in each group,
(2010) to UHMWPE or HXLPE UHMWPE = 0.26 mm/year age 45 to 75 years;
and blinded 7 dislocations and
k eers
rs k eers
r s 1 revision for polyethylene
ook ook
wear in UHMWPE group
b oo Calvert et al36 119 patients:

b oo HXLPE = 0.0239 mm/year 4
b o oo
oDecreased wear with HXLPE
/
e e
/ eb (2009) 59 HXLPE and 60
UHMWPE
e/
e e
/ e b UHMWPE =
0.1276 mm/year
ee/ e
/ e b compared with UHMWPE;
mean volumetric wear
: // t/.tm
. m : / / t
/ .
t m
. m 13.741 mm3/year versus
60.24741 mm3/year,
ss : / ss : /
hhtttp hhtttp
respectively
Bragdon et al 38
(2007) tp
182 patients (200 hips,
HXLPE), retrospective
review
28-mm headstp
0.002mm/year with
0.026 mm/year with

25 Survivorship of acetabulum
at 30 years for aseptic
loosening was 72%; no
32-mm heads osteolysis data were
reported
keerrss
Campbell et al39
(2010)
21 patients, second-
generation HXLPE
k e rrss
0.015 mm/year
e
2 Low level of wear noted with
second-generation HXLPE
bboooo k liners, prospective study
b o o
o o k b o oo
o
compared with annealed
first-generation HXLPE
/
e e
/ e Geerdink et al40
e
48 patients, 23 UHMWPE
e/ e
/ e b Moderately cross-linked =
e
8
e/ e
/ e b38% reduction in wear
(2009)
: / / t
cross-linked
/ .
t m
and 17 moderately
. m
0.088 mm/year
UHMWPE = 0.142
: / /t/.tm.m
sustained over 8-year
follow-up; less
s : /
polyethylene cases
s
mm/year
ss : / retroacetabular cyst
hhtttp
tp hhtttp
tp
analyzed formation in the
moderately cross-lined
polyethylene (12%) versus
the UHMWPE (39%)
Lachiewicz et al41 146 hips, 90 patients with Median linear wear 5.7 No difference in linear wear
(2009) follow-up, HXLPE rate = 0.028 mm/year rate with 36-mm or 40-mm
k eers
rs k e r
e s
r s heads, but there was an
increase in volumetric
bboooo k b o o
o o k b o oo
wear; caution suggested in
o
using in young or active
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
patients
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
p ss : /
surfaces, with survivorship based on liner revision of
t p t p ss : /
a ceramic ball with a metal sleeve be used with either a
p
t
hht t
98% and 91.3%, respectively.42
Early enthusiasm for ceramic-on-ceramic bearing
surfaces have been tempered by the limited intraopera-
t
hht t
new ceramic or polyethylene liner at the time of revi-
sion.
Because of the brittle nature of ceramic materials,
tive options and reports of component fracture, chip- care is needed during component insertion and impac-
ping on insertion, and squeaking.53,54 Because restoring tion; forceful impaction can chip the periphery of the
k eers
the normal anatomy and hip biomechanics are impor-
rs
tant considerations in THA, the restricted options are a
k eers
r s
liner and shatter the femoral head.54 Encasing the ce-
ramic liner within a titanium sleeve eliminates the con-
b ooook b
in 2,000 to 3,000 for ceramic femoral heads and 1 inoook
cause for concern. Fracture risk has been estimated at 1
o impingement.
b ooo
cern for insertional chipping but may create an area for
o
/
e e
/ eb ee/ e
/e b
6,000 to 8,000 for ceramic acetabular liners.42 Revision
/e/e b
Squeaking has been reported in 0.45% to 7% of pa-
ee
/ t
///t m
surgery after a fracture requires a thorough synovec-
. . m
tomy and complete debris removal. It is suggested that
: / t.
///t m
tients with alumina-on-alumina bearing surfaces.
.m
Squeaking has been linked to the microseparation of
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 4
keerrss
b ooook Ceramic Outcomes in THA
b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b Average
Follow-up
Study (Year)
t . m
.m
Number of Patients
: / ///t
Follow-up Data
: / t
///t. m
. m (Years) Outcomes
Milošev et al42
s
tps :
487 patients
s
tps :
Survival rates: 8.5 Survival for MOM was
hhtttp hhtttp
(2012) MOM = 69 hips, MOP = 98.4% substantially worse than
MOP = 200 hips COC = 95.6% for the other bearing
COC = 218 hips MOM = 87.9% surface types.
Cai et al43 (2012) 93 patients (113 hips), RCT Greater range of >3 Clinical outcomes,
COC = 51 motion (6.1°) with complications, and
COP = 62 COC larger heads radiographic outcomes
k eers
rs k eers
r s similar between groups;
ook ook
only significant difference
b oo b oo b o oo
o
noted was in range of
/
e e
/ eb Kim et al44 (2012)
e/
e e
/
127 THAs, all patientse b No osteolysis,
ee/ e
/ e b 14.6
motion.
Standard improvements in
: // t/.tm
. m
younger than 31 years
: / / t
/ .
t m
. m
squeaking, or ceramic hip scores noted, with
ss : / ss : /
fractures noted excellent longevity with
hhtttp hhtttp
stem and acetabular
Synder et al45
(2012)
tp
220 COC THAs
(188 patients)
tp
12-year survival was
86.4% for whole
19.6
components.
Very good results in 39.5%
and good results in 43.6%
prosthesis of patients.
Chen et al46 (2012) 413 COC THAs in Asian No squeaking identified >2 Four complications but no
keerrss population
k e rrss
e
in any cases squeaking-related
concerns.
bboooo k Chevillotte et al47 100 COC THAs
b o o
o o k 5% incidence of
b o oo
o
10 No component
/
e e
/ e
(2012)
ee/ e
/ e b squeaking reported
on questionnaire
ee/ e
/ e b malpositioning; all
squeaking hips occurred in
: / / t
/ .
t m
. m : / /t/.tm.m
active, heavy men; no
loosening or fractures of
ss : / ss : / the ceramic implants.
hhtttp
tp hhtttp
tp
Yeung et al48 (2012) 301 consecutive COC THAs, 2.7% underwent 10 95% of patients with
244 with 10-year data revision surgery; excellent or good results,
survival rate of 4 revision for
implants = 98% periprosthetic fracture,
1 aseptic femoral
loosening, 1 femoral
k eers
rs k e r
e s
r s shortening,
2 cup revisions.
bboooo k b o o
o o k b o oo
MOM = metal-on-metal, MOP = metal-on-polyethylene, COC = ceramic-on-ceramic, RCT = randomized controlled trial, COP = ceramic-on-polyethylene.
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m
the femoral head and liner, which results in stripe wear.
: / / t
/ .
t m
. m
bearing composed of 82% alumina, 17% zirconium
t p ss
p : /
This scenario is typically associated with acetabular
t p ss
p : / oxide, 0.3% chromium oxide, and 0.6% strontium ox-
t
hht t
malpositioning, failure to restore hip biomechanics,
and impingement.53 Retrieval studies have shown that
stripe wear and edge loading create the same milieu
t
hht t ide.42 This newer composite has greater fracture tough-
ness (150%) and burst strength (160%) and maintains
the same surface hardness as its alumina predecessors,
seen with squeaking in the laboratory (roughened artic- with availability as a bearing against polyethylene only
ular surfaces, dry ceramic-on-ceramic articulations, and in the United States.42 There have been no reported
k eers
rs
repeated forced microseparations).
k eers
r s
cases of femoral head fracture, and the heads are of-
fered with greater neck length options.
b ooook Zirconia Ceramics

The addition of zirconia to alumina ceramic bearings
b oook
o b oooo
Ceramic-on-Metal Articulations
/
e e
/ eb ee/ e
/e b
affords a material with better resistance to crack prop-
/e/e b
Combining hard-on-hard bearing materials, the Biolox
ee
/ t
///t m
agation and the ability to dissipate energy. The Biolox
. . m
delta (CeramTec Ag) is a newer composite ceramic
: : / t.
///t m
.
Forte (CeramTec Ag) alumina femoral heads were
m
tested against high-carbon-wrought cobalt-chromium
s
tps : s
tps :
68
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
alloy acetabular cups in a wear simulator study. A 100- Stainless Steel
k eers
rs ke rr
fold decrease in wear with no bedding-in period was re-
e ss Stainless steel generally contains iron, carbon, chro-
b ooook ook
ported with the ceramic-on-metal versus the metal-on-
o o
metal implants.55 No damage to the femoral heads was
b
mium, nickel, and molybdenum. The carbon is in the
b o oo
o
form of metallic carbides, which are harder than the
/
ee/e b / e e b
noted, and the surface roughness was unchanged. Be-
ee /
cause the wear rate appeared to be lower and fewer
ee/ e
/ e b
surrounding material. The addition of molybdenum
stabilizes the carbides and provides good strength to
: / t
///t. m
.m
metal particles were generated, the prevalence of ad-
: / t
///t. m
. m
the material. The chromium provides the adherent,
protective surface oxide layer that maintains its bio-
s :
verse local tissue reactions may be mitigated. A recent
tps s
tps :
hhtttp hhtttp
study reported substantially lower whole blood metal compatibility. The mechanical properties of stainless
levels of chromium in ceramic-on-metal bearing materi- steel exhibit greater ductility with elongation (threefold
als compared with modern metal-on-metal bearing sur- greater in percentage when compared with other im-
faces.56 The success of this articulation has not yet been plant metals). The disadvantages of stainless steel are
proven, and the risk of head fracture and adverse local lower biocompatibility and the creation of greater arti-
tissue reactions has not been thoroughly evaluated. fact on imaging studies.
k eers
rs k eers
r s New stainless steel alloys are engineered to increase
corrosion resistance by using a nickel-free austenitic
b ooook
Ceramic-on-Polyethylene
b ooook
Both alumina and zirconia ceramic femoral heads with
o oo
stainless alloy maintained by high nitrogen content.
b o
/
e e
/ eb e/
e e
/ e b
polyethylene liners have been used extensively in THA.
e / e
/ e b
Nickel-free steel alloys produce higher tensile yield and
fatigue strength and greater resistance to pitting and
e
: / t/.tm
Traditionally, the alumina heads had better wear rates
. m
and success because of fracture of the zirconia heads.
/ / / t
/ .
t m
crevice corrosion than nickel-containing steel alloys.
. m
Despite these new innovations, stainless steel implants
:
s : /
Current studies of ceramic-on-polyethylene bearings
s ss : /
are more susceptible to galvanic and crevice corrosion,
hhtttp
tp hhtttp
tp
have shown mixed results; however, because of the fa- which makes them a less attractive option for modular
vorable biomaterial properties of ceramic heads, this components in total joint arthroplasty. Metal-on-metal
type of bearing surface has remained an option for implants were used in early THA prostheses but were
younger patients. The risk of fracture of a ceramic fem- later abandoned because of the success of UHMWPE
oral head against a polyethylene liner appears to be and the potential tissue damage from metal debris.
rrss rrss
lower than against a ceramic liner, and it may be more Casting in early designs led to large grains and poorly
o ke
resistant to third-body wear than a cobalt-chromium
ke
head.42
o k e
k e
distributed carbides that resulted in irregular surface
oo
hardness. Design improvements have resulted in a dras-
e bboo o e b o
b o o e b o o
tic reduction in wear rates and particulate debris com-
b
/
e / e Metal-on-Metal Implants
Cobalt-Chromium
m ee/ / e m ee/ / e
pared with metal-on-polyethylene articulations. Low
wear rates are typically observed for metal-on-metal ar-
: / /
/ t
/ .
t . m
Most metal-on-metal bearing surfaces use an alloy of
: / /
/t/.t .m
ticulations and have been reported in the range of
s :
cobalt-chromium combined with another element, such
s ss :
1-5 µm per year.57 Low friction and the limited size and
hhtttp
tp hhtttp
tp
as molybdenum, which enhances the alloy by decreas- concentration of debris in metal-on-metal bearing sur-
ing grain size and increasing strength. Chromium pro- faces allow for improved implant durability58-62 (Table
vides corrosion resistance superior to steel. Cobalt- 5). Under certain conditions (component malposition,
chromium alloys are among the strongest, hardest, and hip instability, taper corrosion, lubrication breakdown,
most fatigue resistant metals used for replacement com- and ion hypersensitivity), however, accelerated wear
and corrosion can occur with modern metal-on-metal
k e s
ponents. Metallic carbides from the carbon strengthen
rrs
the metal and improve wear resistance.
e k e r
e s
r sdesigns.
The AAOS Technology Overview reported on a sys-
bboooo k
Titanium
b o o
o o k b o oo
tematic review of modern metal-on-metal hip implants
o
/
e e
/ e ee/ e
/ e
Titanium alloys have superior biocompatibility, b e e
/ e b
and made the following conclusions: (1) metal-on-
/
metal THA and resurfacing are at a greater risk for re-
e
/ / t .
t m
strength, fracture toughness, image quality, and corro-
. m
sion resistance. The ability of titanium to form a tita-
: / : / / t
/ .
t m
. m
vision than other bearing couples; (2) larger femoral
heads and older age are associated with increased rates
t p ss
p : /
nium dioxide film protects against wear caused by pit-
t p ss : /
of revision with metal-on-metal THA; (3) several stud-
p
t t
ting and granular and crevice-type corrosion. Ti6Al4V
hht
is an alloy (grade 5 titanium alloy with 6% aluminum
and 4% vanadium) that has shown increased fatigue
t
hht t
ies found a correlation between implant alignment and
wear rates, local metal debris and adverse local tissue
reactions; and (4) metal ion concentrations are elevated
strength and has 20% reduced elasticity to minimize in metal-on-metal articulations with an undetermined
the potential for stress shielding and enhance bone-to- clinical significance at this time.63
k ee s
implant load transfer. Titanium alloys have greater
rrs k e r
strength than stainless steel but have notch sensitivity
e s
r s Applications in TKA
b ooook b oook
that can make load-bearing materials more susceptible
o
to cracking and scratching and thus less optimal for use
b ooo
In the United States, there are no clinical applications
o
for metal-on-metal bearing surfaces in TKA. Although
/
e e
/ eb ee/ e
/e b
as a bearing surface. Concerns about the passive release
/e/e b
there is ongoing research aimed at improving wear
ee
/ t
///t m
of vanadium, a cytotoxic element, have led to the intro-
. . m
duction of alternative alloys, including niobium.
: : / t.
///t m
rates and longevity, no implantable metal-on-metal
.m
TKA prostheses are currently available.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 5
keerrss
b ooook Metal-on-Metal THA Outcomes
b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee e
Average
/ /
Follow-upe b
Study (Year)
t . m
.m
Number of Patients
: / ///t
Follow-up Data
: / t
///t. m
. m
(Years) Outcomes
Bosker et al58
s
tps :
MOM = 120 (119 patients)
s
tps
39% diagnosed with
: 3.6 12% revision rate; elevated
hhtttp hhtttp
(2012) pseudotumor on CT serum metal ions led to a
four times increase in the
risk of pseudotumor
Malviya et al59 MOM = 50 Greater satisfaction 2 One pseudotumor noted;
(2011) MOP = 50 with MOM; 20% with elevated metal ion levels
MOM had elevated noted
k eers
rs k eers
r s
serum ion levels
b ooook Nikolaou et al60

(2011)
MOM = 193 hips
(166 patients)
b ooook
13 hips were revised;
metal ion levels
7
b o oo
10 of 13 revisions caused by a
o manufacturing defect;
/
e e
/ eb e/
e e
/ e b increase for first 4 to
5 years
ee/ e
/ e b otherwise, 98.4%
survivorship
Grübl et al61 (2007)
/ t .
MOM = 105 hips
: / / tm
. m Survivorship 98.6%;
: / / t
/ .
t m
. m10 No evidence of malignancy
s : /
(98 patients)
s s :
good results reported
s / or renal failure; no
hhtttp
tp hhtttp
tp
difference in long-term
serum metal levels
compared with prior
follow-up values
Dorr et al62 (2000) 70 MOM THAs Mechanical failure rate 5.2 Excellent results reported
(70 patients) 2%; no significant with Harris hip scores;
keerrss k e rrss
osteolysis noted
e
similar to MOP results, with
possible wear reduction
bboooo k MOM = metal-on-metal, MOP = metal-on-polyethylene
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
Applications in THA
: / / t
/ .
t m
. m : / /t/.tm.m
block cobalt-chromium acetabular components have
ss : /
Metal-on-metal bearing surfaces have a decreased rate
: /
come under scrutiny because of complications associ-
ss
hhtttp
tp hhtttp
tp
of wear and increased toughness. This greater level of ated with poor implant fixation, possible insertional
toughness allows the use of thinner liners within the deformation, and unacceptably high rates of early fail-
same cup, affording the use of larger femoral heads and ure. These problems have led to the recall of many
associated potential advantages (favorable clearances metal-on-metal THA and surface replacement devices.
and wear rates and reduced dislocation rates). The Although patients treated with conventional metal-on-
larger the femoral head, the more likely a fluid-film polyethylene THAs have elevated metal levels from ta-
k eers
rs mode of lubrication will occur and minimize articular
surface wear. Additionally, the use of larger femoral
k e r
e s
r s per junction corrosion, these values may be increased
with metal-on-metal devices because of the added wear
bboooo k heads has spurred the more widespread use of bone-

b o o
o o k b o oo
at the articular surface.64,65 In a well-functioning THA,
o
/
e e
/ e e e
conserving hip resurfacing procedures. One potential
/ / e b
complication with the use of large metal heads relates
e e e
/ e b
serum metal levels tend to increase early, peak at 4 to
/
5 years after implantation, and then decrease to a
e
: / / / .
t m m
to higher frictional torque and corrosion at the femoral
t . : / / t
/ .
t m
. m
steady-state level.66 Elevated serum metal levels may ac-
t p ss : /
head-neck junction, which may explain the problems
seen more frequently with metal-on-metal THAs than
p t p ss : /
cumulate at distant organs but have not been shown to
be carcinogenic in patients with metal-on-metal de-
p
t
hht t
with resurfacing procedures. Such complications with
MOM THAs have been trunion corrosion (aka trun-
ionosis), pseudotumor formation, component fatigue
t
hht t
vices. Serum metal levels are associated with transpla-
cental transfer and are present in the milk of nursing
mothers but have not been linked to teratogenic ef-
fractures, aseptic loosening, and dislocation related to fects.67,68
local tissue destruction. Alternatively, in the AAOS Metallic debris is generated at a greater level in
k eers
rs Technology Overview, it was found that with hip resur-
facing, the larger the femoral head the lower the risk of
k eers
r s THAs when there is negative clearance because of com-
ponent deformation on insertion, component malposi-
b ooook such complications.63

Despite early enthusiasm, metal-on-metal THAs
b oook
o b ooo
tioning, aseptic loosening, or poor component design.
o
Subsequent accumulation can occur and result in ad-
/
e e
/ eb ee/ e
/e b
have been the subject of recent controversy because of
/e/e b
verse local tissue reactions (Figure 4). Such reactions
ee
/ t
///t m
the rising rates of catastrophic failure in several metal-
. . m
on-metal components. THA constructs using mono-
: / t.
///t m
may cover a wide spectrum of presentations, ranging
.m
from a small fluid collection to a massive destructive le-
:
s
tps : s
tps :
70
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
cess. Research efforts are in place to develop new bear-
k eers
rs keerrss ing surfaces to address the limitations of current de-
b ooook b o ook
o
vices.
b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
Key Study Points
s
tps : s
tps :
hhtttp hhtttp
• The science of articular surface wear and joint
lubrication remain at the forefront of total joint
replacement research because the bearing surface
still appears to be the weak link in the system.
The perfect bearing surface does not exist; how-
ever, recent efforts continue to focus on minimiz-
k eers
rs k eers
r s ing complications and improving the wear char-
ook ook
acteristics of articular couples.
b oo b oo •
b o oo
o
Caution must be exercised when using alterna-
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
tive bearing surfaces. Articular surface wear may
be reduced, but complications such as fracture,
: // t/.tm
. m : / / t
/ .
t m
. m
adverse local tissue reactions and aseptic loosen-
ss : / ss : /
ing are now being realized with ceramic and
hhtttp
tp hhtttp
tp metal-on-metal bearings.
• The idea of corrosion and potentiation of metal
debris formation at a distance (articular surface
from trunion) are recent concerns with modern
total joint arthroplasty. The complications and
rrss rrss
adverse responses to increasing modularity and
o ke
ke
Figure 4
o k e
k e
Photograph of an adverse local tissue reaction re-
trunionosis are becoming more prevalent, lead-
oo
ing to growing concern for new complications in
e bboo o e b o
b o
lated to a failed metal-on-metal THA. Note the
o
significant amount of purulent-like fluid at the
e b o o
total joint arthroplasty.
b
/
e / e top of the wound (arrow).
m ee/ / e m ee/ / e
: / /
/ t
/ .
t . m : / /
/t/.t .m
s :
sion.69 Large pseudotumors may result in local neuro-
s ss :
hhtttp
tp hhtttp
tp
vascular bundle compression; abductor dysfunction; Annotated References
and/or a large, potential dead space after excision.69,70
Managing these reactive masses can lead to suboptimal 1. McKellop HA, Campbell P, Park SH, et al: The origin
results, depending on the level of soft-tissue destruc- of submicron polyethylene wear debris in total hip ar-
tion. Algorithms for the evaluation of painful metal-on- throplasty. Clin Orthop Relat Res 1995;311:3-20.
e s
metal bearing surfaces are available and include the as-
rrs
sessment of serum metal levels and the use of hip
k e k e r
e s
r s 2. Cooper JR, Dowson D, Fisher J, Jobbins B: Ceramic
bboooo k
hip aspiration.69
b o o
ultrasound, metal artifact reduction sequence MRI, and
o o k o oo
bearing surfaces in total artificial joints: Resistance to
o
third body wear damage from bone cement particles.
b
/
e e
/ e / e
/ e b
Although revision rates vary with metal-on-metal
ee ee/ e
/ e b
J Med Eng Technol 1991;15(2):63-67.
/ / t .
t m
THAs, widespread warnings and recalls have led to a
. m
decrease in the use of these components.71
: /
3.
: / / t . m
. m
Silva M, Heisel C, Mckellop H, Schmalzried TP: Bear-
/ t
t p ss
p : / t p ss
p : /
ing Surfaces. Philadelphia, PA, Lippincott, Williams and
Wilkins, 2007.
Summary t
hht t t
hht t
4. Brown TD, Bartel DL; Implant Wear Symposium 2007
Engineering Work Group: What design factors influence
One of the key challenges in total joint arthroplasty is wear behavior at the bearing surfaces in total joint re-
selecting the proper bearing surface that will reduce the placements? J Am Acad Orthop Surg 2008;16(suppl 1):
k e s
need for complex revision surgeries. Wear and corro-
rrs e r
sion in total joint constructs is unavoidable and gener-
e k e s
r s S101-S106.
b ooook b oook
ates particulate debris that leads to aseptic loosening
o
and, when present in sufficient quantities, adverse local
5.
b oooo
Kurtz SM: A primer on UHMWPE, in Kurtz SM, ed:
/
e e
/ eb ee/ e
/e b
tissue reactions. Improvements in the performance of
/e/
2004, pp 1-9.
ee e b
The UHMWPE Handbook. San Diego, CA, Elsevier,
/ t
///t m
biomaterials are needed to address the pressing issues
. . m
of implant degradation and improved long-term suc-
:
6.
: / t.
///t m
.m
Bartel DL, Bicknell VL, Wright TM: The effect of con-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
formity, thickness, and material on stresses in ultra-high younger than 50 years. J Arthroplasty 2011;26(1):9-15.
k eers
rs rrs
molecular weight components for total joint replace-
kee s Ninety-four patients younger than 50 years were treated
ook ook
ment. J Bone Joint Surg Am 1986;68(7):1041-1051.
b oo b o o b o oo
with flat, wedge, tapered femoral stems and followed
o
for 11 to 18.5 years after primary THA. The authors re-
/
ee/e b 7.
ee e
/ e b
Hood RW, Wright TM, Burstein AH: Retrieval analysis
/
of total knee prostheses: A method and its application
ee/ e
/ e b
ported that 98% of the stems showed signs of osseoin-
tegration; distal femoral osteolysis was seen in one hip.
1983;17(5):829-842.
: / ///t. m
.m
to 48 total condylar prostheses. J Biomed Mater Res
t : / t
///t. m
. m
Young patients achieved excellent results at a mean of
16 years after surgery.
s
tps : s
tps :
8.
hhtttp
Crowther JD, Lachiewicz PF: Survival and polyethylene
wear of porous-coated acetabular components in pa-
hhtttp
tients less than fifty years old: Results at nine to four-
18. Lombardi AV Jr, Ellison BS, Berend KR: Polyethylene
wear is influenced by manufacturing technique in mod-
ular TKA. Clin Orthop Relat Res 2008;466(11):2798-
teen years. J Bone Joint Surg Am 2002;84(5):729-735. 2805.
k eers
rs
9. Eggli S, z’Brun S, Gerber C, Ganz R: Comparison of
k e
polyethylene wear with femoral heads of 22 mm and
ers
r s
19. Won CH, Rohatgi S, Kraay MJ, Goldberg VM, Rimnac
CM: Effect of resin type and manufacturing method on
b ooook Surg Br 2002;84(3):447-451.

b ooook
32 mm: A prospective, randomised study. J Bone Joint
b oo
wear of polyethylene tibial components. Clin Orthop
o o
Relat Res 2000;376:161-171.
/
e e
/ eb 10.
e/
e e
/ e b
Kim YH, Oh SH, Kim JS: Primary total hip arthroplasty 20.
ee/ e
/ e b
Parks NL, Engh GA, Topoleski LD, Emperado J: The
: // t/.tm
. m
with a second-generation cementless total hip prosthesis
: / / t . m
. m
Coventry Award: Modular tibial insert micromotion. A
/ t
ss /
in patients younger than fifty years of age. J Bone Joint
: ss : /concern with contemporary knee implants. Clin Orthop
hhtttp hhtttp
Surg Am 2003;85(1):109-114.
tp tp
Relat Res 1998;356:10-15.
11. Keener JD, Callaghan JJ, Goetz DD, Pederson DR, Sul- 21. Mont MA, Maar DC, Krackow KA, Jacobs MA, Jones
livan PM, Johnston RC: Twenty-five-year results after LC, Hungerford DS: Total hip replacement without ce-
Charnley total hip arthroplasty in patients less than fifty ment for non-inflammatory osteoarthrosis in patients
years old: A concise follow-up of a previous report. who are less than forty-five years old. J Bone Joint Surg
rrss rrss
J Bone Joint Surg Am 2003;85(6):1066-1072. Am 1993;75(5):740-751.
o ke
ke 12.
o k
Capello WN, D’Antonio JA, Feinberg JR, Manley MT: e
k e oo
e bboo o e b o o o
Ten-year results with hydroxyapatite-coated total hip
b
22. Jasty MJ, Floyd WE III, Schiller AL, Goldring SR, Har-
e b o o
ris WH: Localized osteolysis in stable, non-septic total
b
/
e / e ee/ e
femoral components in patients less than fifty years old:
/
A concise follow-up of a previous report. J Bone Joint
m / / e
hip replacement. J Bone Joint Surg Am 1986;68(6):
m
912-919.
ee
Surg Am 2003;85(5):885-889.
: / /
/ t
/ .
t . m : / /
/t/.t .m
ss : s
23.
s :
Muratoglu OK, Kurtz SM: Alternative Bearing Surfaces
hhtttp
tp hhtttp
tp
13. McAuley JP, Szuszczewicz ES, Young A, Engh CA Sr: in Hip Replacement. New York, NY, Marcel Dekker,
Total hip arthroplasty in patients 50 years and younger. 2002.
24. Small SR, Berend ME, Howard LA, Tunç D, Buckley
14. Singh S, Trikha SP, Edge AJ: Hydroxyapatite ceramic- CA, Ritter MA: Acetabular cup stiffness and implant
coated femoral stems in young patients: A prospective orientation change acetabular loading patterns. J Ar-
k eers
rs 1123.
k e r
ten-year study. J Bone Joint Surg Br 2004;86(8):1118-
e s
r s throplasty 2013;28(2):359-367.
bboooo k b o o
o o k Four implant designs of variable stiffness were im-
b o oo
planted into a composite pelvis at 35° or 50° of abduc-
o
/
e e
/ e
15.
ee/ / e b
Kearns SR, Jamal B, Rorabeck CH, Bourne RB: Factors
e
affecting survival of uncemented total hip arthroplasty
e / e
/ e b
tion. All specimens were loaded to simulate normal gait
patterns, and peri-implant bone strains were measured.
e
2006;453:103-109.
: / / t
/ .
t m
in patients 50 years or younger. Clin Orthop Relat Res
. m : / / t t m
Stiffer components had higher localized surface strains
. . m
and imbalanced load distributions. An increased abduc-
/
t p ss
p : / t p ss
p : /
tion angle resulted in varying amounts of peri-implant
16.
t t
Burston BJ, Yates PJ, Hook S, Moulder E, Whitley E,
hht
Bannister GC: Cemented polished tapered stems in pa-
tients less than 50 years of age: A minimum 10-year
t
hht t
25.
bone strain.
Voleti PB, Baldwin KD, Lee GC: Metal-on-metal vs con-

follow-up. J Arthroplasty 2010;25(5):692-699. ventional total hip arthroplasty: A systematic review
At a minimum 10-year follow-up, 58 consecutive pol- and meta-analysis of randomized controlled trials. J Ar-
ished tapered stems in patients younger than 50 years throplasty 2012;27(10):1844-1849.
k eers
rs rs
r
were reviewed. No stems were revised for aseptic loos-
k ee
ening, and good or excellent results were reported in s A literature review found four, level I randomized con-
ook ook
trolled trials for inclusion in a meta-analysis. No sub-
b oo b o
76% of the patients. Cup wear and failure were the pre-
o b oooo
stantial differences were found between patients treated
/
e e
/ eb ee/ e
/e b
dominant reasons for revision in this particular cohort.
e /e/e b
with metal-on-metal and conventional THAs related to
functional scores and radiographic outcomes. A 3.37
e
17.
: / t
///t. m
McLaughlin JR, Lee KR: Total hip arthroplasty with an
. m
uncemented tapered femoral component in patients
: / t.
///t m
times greater rate of complications was reported in the
.m
group treated with metal-on-metal THAs. The authors
s
tps : s
tps :
72
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
recommended caution in the routine use of metal-on- throplasty. J Bone Joint Surg Am 2007;89(10):2212-
k eers
rsmetal devices in primary THAs.
keerrss 2217.
b ooook
26.
b o ook
Johanson PE, Digas G, Herberts P, Thanner J, Kär-
o 35.
o oo
o
Blumenfeld TJ, McKellop HA, Schmalzried TP, Billi F:
b
/
ee/e b e e
/ e b
rholm J: Highly crosslinked polyethylene does not re-
/
duce aseptic loosening in cemented THA 10-year find-
e ee e
/ e b
Fracture of a cross-linked polyethylene liner: A multi-
/
factorial issue. J Arthroplasty 2011;26(4):e5-e8.
:
2012;470(11):3083-3093.
/ ///t. m
.m
ings of a randomized study. Clin Orthop Relat Res
t : / t
///t. m
. m
Fracture in a HXLPE liner is reviewed. Horizontal load-
s
tps : s
tps : ing conditions were believed to have caused the failure.
hhtttp hhtttp
Sixty patients were randomized to standard UHMWPE Liner locking mechanisms and material properties of
or HXLPE THA components and followed for 10 years HXLPE are reviewed in detail, particularly their rela-
to assess wear rates. HXLPE was found to have a wear tionship to component failure.
rate of 0.005mm/year compared with 0.056 mm/year
for conventional UHMWPE. No other clinical or radio- 36. Calvert GT, Devane PA, Fielden J, Adams K, Horne JG:
graphic parameters differed between the two groups. A double-blind, prospective, randomized controlled trial
k e
27.
ers
rs k e rs
r
Martell JM, Berdia S: Determination of polyethylene
e s
comparing highly cross-linked and conventional poly-
ethylene in primary total hip arthroplasty. J Arthro-
ook ook
wear in total hip replacements with use of digital radio-
b oo b oo
graphs. J Bone Joint Surg Am 1997;79(11):1635-1641.
b o oo
plasty 2009;24(4):505-510.
o
/
e e
/ eb 28.
e/
e e
/ e b
Goldvasser D, Noz ME, Maguire GQ Jr, Olivecrona H,
37.
/ e e b
Mutimer J, Devane PA, Adams K, Horne JG: Highly
ee /
crosslinked polyethylene reduces wear in total hip ar-
: // t/.tm m
Bragdon CR, Malchau H: A new technique for measur-
. : / / t . m
. m
throplasty at 5 years. Clin Orthop Relat Res 2010;
/ t
ss /
ing wear in total hip arthroplasty using computed to-
: ss : /468(12):3228-3233.
hhtttp hhtttp
mography. J Arthroplasty 2012;27(9):1636-1640, e1.
tp tp
A prospective, double-blinded randomized controlled
The authors describe a new technique using CT to deter- trial was conducted with 122 patients to assess the wear
mine the UHMWPE wear rates in THAs. A detailed de- of standard UHMWPE versus HXLPE. At mean
scription of the three-dimensional measuring technique follow-up of 5.5 years, lower wear rates were reported
is reviewed. for the HXLPE (0.05 mm/year) compared with the stan-
dard UHMWPE (0.26 mm/year).
rrss rrss
29. Gee AO, Lee GC: Alternative bearings in total knee ar-
o ke
ke 280-283.
o k e
throplasty. Am J Orthop (Belle Mead NJ) 2012;41(6):
k e 38. Bragdon CR, Kwon YM, Geller JA, et al: Minimum
oo
6-year followup of highly cross-linked polyethylene in
e bboo o b o
b o o
The authors present a review of HXLPE, mobile bear-
e e b o o
THA. Clin Orthop Relat Res 2007;465:122-127.
b
/
e / e / / e
ings, and other alternative bearing surfaces in TKA.
m ee 39.
m ee/ / e
Campbell DG, Field JR, Callary SA: Second-generation
30.
: / / t .
t . m
Willie BM, Foot LJ, Prall MW, Bloebaum RD: Surface
/ / : / /
/t/.t .m
highly cross-linked X3™ polyethylene wear: A prelimi-
s :
damage analysis of retrieved highly crosslinked polyeth-
s ss :
nary radiostereometric analysis study. Clin Orthop
hhtttp
tp hhtttp
tp
ylene tibial components after short-term implantation. Relat Res 2010;468(10):2704-2709.
J Biomed Mater Res B Appl Biomater 2008;85(1): Second-generation HXLPE liners in 19 patients were
114-124. evaluated to measure wear rates and clinical outcomes
and were compared with first-generation liners. Wear
31. Gordon AC, D’Lima DD, Colwell CW Jr: Highly cross- rates and head penetration were low at 1- to 2-year
linked polyethylene in total hip arthroplasty. J Am Acad follow-ups and similar to the in vitro wear rate. Level of
k eers
rs
Orthop Surg 2006;14(9):511-523.
k e r
e s
r s evidence: IV.
bboooo k
32.
o o
Muratoglu OK, Bragdon CR, O’Connor DO, Jasty M,
b o o k 40.
b o oo
Geerdink CH, Grimm B, Vencken W, Heyligers IC,
o
/
e e
/ e e / e
/ e b
Harris WH: A novel method of cross-linking ultra-high-
molecular-weight polyethylene to improve wear, reduce
e ee/ e
/ e b
Tonino AJ: Cross-linked compared with historical poly-
ethylene in THA: An 8-year clinical study. Clin Orthop
: / / t
/ t m
oxidation, and retain mechanical properties: Recipient
. . m
of the 1999 HAP Paul Award. J Arthroplasty 2001;
: / / t
/ .
t m
Relat Res 2009;467(4):979-984.
. m
16(2):149-160.
t p ss
p : / t
41.
p ss
p : /
Lachiewicz PF, Heckman DS, Soileau ES, Mangla J,
33. t
hht t
Waewsawangwong W, Goodman SB: Unexpected fail-
ure of highly cross-linked polyethylene acetabular liner.
t
hht t Martell JM: Femoral head size and wear of highly cross-
linked polyethylene at 5 to 8 years. Clin Orthop Relat
Res 2009;467(12):3290-3296.
J Arthroplasty 2012;27(2):e1-e4.
The disadvantages of HXLPE use in THA are discussed, 42. Milošev I, Kovač S, Trebše R, Levašič V, Pišot V: Com-
including a case of unexpected failure from liner frac- parison of ten-year survivorship of hip prostheses with
k eers
rs rs
r s
ture. Factors associated with the fractured liner included
k ee
decreased mechanical properties, vertical cup placement,
use of conventional polyethylene, metal-on-metal, or
ceramic-on-ceramic bearings. J Bone Joint Surg Am
b ooook and a large diameter femoral head.
b oook
o b ooo
2012;94(19):1756-1763.
o
/
e e
/ eb 34.
e / e
/e b
Tower SS, Currier JH, Currier BH, Lyford KA, Van Cit-
e e e/e b
Three different bearing surfaces, metal-on-polyethylene,
/
ceramic-on-ceramic, and metal-on-metal, were evalu-
e
/ t
///t m
ters DW, Mayor MB: Rim cracking of the cross-linked
. . m
longevity polyethylene acetabular liner after total hip ar-
: : / t.
///t m
ated in 487 THAs at an average follow-up of 8.5 years.
.m
Survivorship at 10 years for the metal-on-polyethylene,
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
ceramic-on-ceramic, and metal-on-metal devices were 138-144.
k eers
rs rrss
0.984, 0.956, and 0.879, respectively. The authors con-
kee
cluded that a metal-on-polyethylene bearing surface is
The authors clinically and radiographically reviewed
b ooook o ook
the appropriate option for older and less active patients.
b o oo
301 consecutive primary THAs. Death occurred in
o o
9.2% of patients from an unrelated cause, 2.7% under-
b
/
ee/e b Level of evidence: III.
ee/ e
/ e b ee/ e
/ e b
went revision surgery, and 95% had an excellent or
good result. The overall rate of implant survival was
43.
: / ///t. m
.m
Cai P, Hu Y, Xie J: Large-diameter Delta ceramic-on-
t
ceramic versus common-sized ceramic-on-polyethylene
: / t . m m
98%, with revision for any reason as the end point.
///t .
Level of evidence: IV.
s
tps :
bearings in THA. Orthopedics 2012;35(9):e1307-
s
tps :
hhtttp hhtttp
e1313. 49. Ezzet KA, Hermida JC, Colwell CW Jr, D’Lima DD:
A prospective, randomized controlled trial was per- Oxidized zirconium femoral components reduce poly-
formed with 93 patients to evaluate a ceramic-on- ethylene wear in a knee wear simulator. Clin Orthop
ceramic device. A control group was treated with a Relat Res 2004;428:120-124.
ceramic-on-polyethylene device. The large diameter
ceramic-on-ceramic device had 6.1° greater range of
k eers
rs k eers
r s
motion, with similar hip scores and complication rates
50. Laskin RS: An oxidized Zr ceramic surfaced femoral
component for total knee arthroplasty. Clin Orthop
ook ook
as the ceramic-on-polyethylene device at short-term
b oo
follow-up. Level of evidence: I.
b oo b o oo
Relat Res 2003;416:191-196.
o
/
e e
/ eb 44.
e/
e e
/ e b
Kim YH, Park JW, Kim JS: Cementless metaphyseal fit-
51.
/ e e b
Walter WL, O’Toole GC, Walter WK, Ellis A, Zicat BA:
ee /
Squeaking in ceramic-on-ceramic hips: The importance
: // /.tm m
ting anatomic total hip arthroplasty with a ceramic-on-
t . : / t . m
. m
of acetabular component orientation. J Arthroplasty
/ / t
ss /
ceramic bearing in patients thirty years of age or
: ss : /
2007;22(4):496-503.
hhtttp hhtttp
younger. J Bone Joint Surg Am 2012;94(17):1570-1575.
tp
A review of 127 hips was performed in patients younger
than 30 years at the time of surgery. All components,
except one acetabular component, remained well fixed.
tp52. Akagi M, Nakamura T, Matsusue Y, Ueo T, Nishijyo
K, Ohnishi E: The Bisurface total knee replacement: A
unique design for flexion. Four-to-nine-year follow-up
No cases of squeaking, fracture, or osteolysis were re- study. J Bone Joint Surg Am 2000;82(11):1626-1633.
ported. Ceramic-on-ceramic and metaphyseal filling
rrss rrss
stems appear to be successful in young patients treated 53. D’Antonio JA, Capello WN, Manley MT, Naughton M,
o ke
ke
with THA. Level of evidence: IV.
o k e
k e Sutton K: A titanium-encased alumina ceramic bearing
oo
for total hip arthroplasty: 3- to 5-year results. Clin Or-
e bboo o 45.
e b o o o
Synder M, Drobniewski M, Sibiński M: Long-term re-
b e b o o
thop Relat Res 2005;441:151-158.
b
/
e / e ee/ e
sults of cementless hip arthroplasty with ceramic-on-
/
ceramic articulation. Int Orthop 2012;36(11):2225-
m 54.
m ee/ / e
Garino J, Rhaman MN, Bal BS: Reliability of modern
2229.
: / /
/ t
/ .
t . m : /
/t/.t .m
alumina bearings in total hip replacements. Semin Ar-
/
s :
The authors reviewed 220 THAs treated with ceramic-
s ss :
throplasty 2006;17:113-119.
hhtttp
tp hhtttp
tp
on-ceramic prostheses (mean follow-up, 19.6 years).
Overall, 12-year survival rates were 89.99% for the cup 55. Isaac GH, Brockett C, Breckon A, et al: Ceramic-on-
and 91.36% for the stem. Level of evidence: IV. metal bearings in total hip replacement: Whole blood
metal ion levels and analysis of retrieved components.
46. Chen WM, Wu PK, Chen CF, Huang CK, Liu CL, Chen J Bone Joint Surg Br 2009;91(9):1134-1141.
TH: No significant squeaking in total hip arthroplasty:
k eers
rs 2012;27(8):1575-1579.
k e r
e s
A series of 413 hips in the Asian people. J Arthroplasty
r s 56. Rieker CB, Schön R, Köttig P: Development and valida-

tion of a second-generation metal-on-metal bearing:
bboooo k o o
The squeaking rate of ceramic-on-ceramic THA im-
b o o k b o oo
Laboratory studies and analysis of retrievals. J Arthro-
o
/
e e
/ e / e
/ e b
plants in an Asian population was assessed from 2003
to 2009. In 413 consecutive patients, no cases of im-
ee ee/ e
/ e b
plasty 2004;19(8, suppl 3):5-11.
: / / t
ported. Level of evidence: IV.
/ .
t m
plant squeaking and four overall complications were re-
. m
57.
: / / / .
t m
Grupp TM, Yue JJ, Garcia R Jr, et al: Biotribological
t . m
evaluation of artificial disc arthroplasty devices: Influ-
t p ss
p : / t p ss
p : /
ence of loading and kinematic patterns during in vitro
47.
t
Chevillotte C, Pibarot V, Carret JP, Bejui-Hugues J,
hht t
Guyen O: Hip squeaking: A 10-year follow-up study.
J Arthroplasty 2012;27(6):1008-1013.
t
hht t
58.
wear simulation. Eur Spine J 2009;18(1):98-108.
Bosker BH, Ettema HB, Boomsma MF, Kollen BJ, Maas

The authors reviewed 100 ceramic-on-ceramic THAs at M, Verheyen CC: High incidence of pseudotumour for-
10-year follow-up. Despite no malpositioning of the im- mation after large-diameter metal-on-metal total hip re-
plants seen on radiographs, a 5% incidence of squeak- placement: A prospective cohort study. J Bone Joint
k eers
rs in active, heavy men. Level of evidence: IV.
k eers
ing was reported. All the squeaking implants occurred
r s Surg Br 2012;94(6):755-761.
ook ook
A prospective review was performed on 120 metal-on-
b oo b oo b oooo
metal THAs with large diameter heads. The authors
/
e e
/ eb 48.
e e
/e b
Yeung E, Bott PT, Chana R, et al: Mid-term results of
/
third-generation alumina-on-alumina ceramic bearings
e e e/e b
found that 39% of the patients had a pseudotumor on
/
CT. Those with increased serum metal levels were at in-
e
/ t
///t m
in cementless total hip arthroplasty: A ten-year mini-
. . m
mum follow-up. J Bone Joint Surg Am 2012;94(2):
: : / t.
///t m
creased risk of pseudotumor development. Level of evi-
.m
dence: III.
s
tps : s
tps :
74
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
59. Malviya A, Ramaskandhan JR, Bowman R, et al: What A retrospective review of 163 prostheses was performed
k eers
rs rrs
advantage is there to be gained using large modular
kee s at a mean follow-up of 8.87 years after treatment with a

second-generation metal-on-metal THA. Survivorship
ook ook
metal-on-metal bearings in routine primary hip replace-
b oo b o
ment? A preliminary report of a prospective randomised
o b o oo
was found to be 91.3%, with revision for any reason as
o
/
ee/e b 1609.
ee e
/ e b
controlled trial. J Bone Joint Surg Br 2011;93(12):1602-
/ e / e
/ e b
the end point. Cobalt and chromium ion levels peaked
at 4 to 5 years and then gradually decreased. Level of
e
: / t . m
.m
A prospective, randomized controlled trial compared
///t
metal-on-metal THAs with a large diameter femoral
: / t
///t. m
evidence: IV.
. m
s
tps : s66.
tps : Ziaee H, Daniel J, Datta AK, Blunt S, McMinn DJ:
hhtttp hhtttp
head with conventional metal-on-polyethylene THAs
Transplacental transfer of cobalt and chromium in pa-
with a 28-mm head. No clinical or radiographic differ-
tients with metal-on-metal hip arthroplasty: A con-
ences were noted at follow-up between the groups; how-
trolled study. J Bone Joint Surg Br 2007;89(3):301-305.
ever, overall patient satisfaction was higher for the
metal-on-metal group. Twenty percent of the metal-on-
metal group had substantially elevated serum metal lev- 67. deSouza RM, Wallace D, Costa ML, Krikler SJ: Trans-
els compared with one patient in the metal-on- placental passage of metal ions in women with hip re-
k eers
rspolyethylene group. Level of evidence: I.
k eers
r s surfacing: No teratogenic effects observed. Hip Int
2012;22(1):96-99.
b ooook
60.
ooook
Nikolaou VS, Petit A, Debiparshad K, Huk OL, Zukor
b b o oo
Blood from the umbilical cord was tested in three pa-
o
/
e e
/ eb e/
e e
/ e b
DJ, Antoniou J: Metal-on-metal total hip arthroplasty—
five- to 11-year follow-up. Bull NYU Hosp Jt Dis 2011;
e e
/ e b
tients with metal-on-metal resurfacing prostheses in
/
place during pregnancy. Cobalt levels in the umbilical
e
69(suppl 1):S77-S83.
: // t/.tm
. m : / / t
/ .
t m
cord were 50% of those in the maternal blood; however,
. m
all three children were healthy and without complica-
ss : /
The authors retrospectively reviewed 166 patients (aver-
ss : /
tions. Level of evidence: IV.
hhtttp
tp hhtttp
tp
age age, 50 years) treated with metal-on-metal THAs. A
7.8% revision rate was reported. Cobalt and chromium 68. Fabi D, Levine B, Paprosky W, et al: Metal-on-metal to-
serum levels significantly increased over the first 4 to tal hip arthroplasty: Causes and high incidence of early
5 years and then stabilized before slowly decreasing.
failure. Orthopedics 2012;35(7):e1009-e1016.
Early failure of metal-on-metal THAs is reported in
80 patients. Aseptic loosening was most common in
61.
keerrss
Grübl A, Marker M, Brodner W, et al: Long-term
e
follow-up of metal-on-metal total hip replacement.
k rrss
e
56.25% of the patients. A diagnostic algorithm is re-
viewed, along with two classification schemes directing
bboooo k J Orthop Res 2007;25(7):841-848.
b o o
o o k b o oo
treatment for metal-on-metal complications.
o
/
e e
/ e 62.
e/ e
/ e b
Dorr LD, Wan Z, Longjohn DB, Dubois B, Murken R:
e 69.
e / e
/ e b
Parfitt DJ, Wood SN, Chick CM, Lewis P, Rashid MH,
e
: / t
/ .
t m
Total hip arthroplasty with use of the Metasul metal-on-
. m
metal articulation: Four to seven-year results. J Bone
/ : / /t/.tm
Evans AR: Common femoral vein thrombosis caused by
.m
a metal-on-metal hip arthroplasty-related pseudotumor.
s : /
Joint Surg Am 2000;82(6):789-798.
s ss : /
J Arthroplasty 2012;27(8):e9, e11.
hhtttp
tp hhtttp
tp The authors reported a single case of deep femoral vein
63. Bozic KJ, Browne J, Dangles CJ, et al: Modern metal- thrombosis after metal-on-metal THA. The pressure ef-
on-metal hip implants. J Am Acad Orthop Surg 2012; fect from a pseudotumor led to a serious vein thrombo-
20(6):402-406. sis and represents another potential complication of
metal-on-metal THA. Level of evidence: IV.
64. Meyer H, Mueller T, Goldau G, Chamaon K, Ruetschi
k eers
rs k e r
M, Lohmann CH: Corrosion at the cone/taper interface
e s
r
leads to failure of large-diameter metal-on-metal totals 70. Whitwell GS, Shine A, Young SK: The articular surface
bboooo k b o o
hip arthroplasties. Clin Orthop Relat Res 2012;
o o k replacement implant recall: A United Kingdom district
b o oo
hospital experience. Hip Int 2012;22(4):362-370.
o
/
e e
/ e
470(11):3101-3108.
ee/ e
/ e b
A histologic analysis of periprosthetic tissues was per-
ee/ e
/ e b
The authors review their experience with 121 ASR
(DePuy) hip components after the initiation of the prod-
: / / / .
t m m
formed to assess adverse local tissue reactions to corro-
t . : / / t
/ .
t m
. m
uct recall. One year after the recall, 23 hips had been re-
ss : /
sion products. The authors concluded that metal-on-
metal articulation wear may cause failure of the cone/
t p p t p ss
p : /
vised (an approximately 19% revision rate). Overall
5-year survivorship was 80.8%, with revision for all
t
hht t
taper fit, leading to galvanic corrosion. Level of
evidence: IV. t
hht t
71.
reasons as the end point. Level of evidence: IV.
Oskouian RJ, Whitehill R, Samii A, Shaffrey ME, John-

65. Bernstein M, Desy NM, Petit A, Zukor DJ, Huk OL, son JP, Shaffrey CI: The future of spinal arthroplasty: A
Antoniou J: Long-term follow-up and metal ion trend of biomaterial perspective. Neurosurg Focus 2004;17(3):
patients with metal-on-metal total hip arthroplasty. Int E2.
k eers
rsOrthop 2012;36(9):1807-1812.
k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 7
e rs
rs e rrss
oo
kMusculoskeletal
ook e Imaging
o k
ook
o
e o oo
o
/e/ebb C. Benjamin Ma, MD
e / e
/ b
e b
Terry C.P. Lynch, MD
e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
are trade-offs of digital radiography versus conven-
Introduction
tional film screen radiography. Film radiography has
k eerss k ee
nose musculoskeletal problems and has led to improve-rs
Imaging has significantly enhanced the ability to diag-
r r s
higher spatial resolution, but the improved contrast of
digital radiography allows it to have comparable diag-
b ooook b oook
ment in the management of musculoskeletal conditions.
o
nostic efficiency.
b o oo
o
Plain radiography and CT are imaging modalities
/
e e
/ eb e/ e
/ e b
Plain radiography allows the diagnosis of fractures, de-
formity, and arthritis, which led to improved tech-
e ee/ e
/ e b
that rely on ionizing radiation. The scientific unit of the
// t/.tm
niques in fracture fixation, deformity correction, and
. m
joint arthroplasties. MRI provides important informa-
: : / / t
/ .
t m
measurement of radiation dose, commonly referred to
. m
as the “effective dose,” is the millisievert (mSv). Other
ss : /
tion on soft-tissue condition and led to improvements
ss : /
radiation dose measurement units include rad, rem,
hhtttp
tp hhtttp
tp
in the management of ligament tears, rotator cuff inju- Roentgen, and Sievert. Daily radiation exposure occurs
ries, and cartilage abnormalities. Recent advances in from natural sources, such as the sun. The average per-
nuclear medicine will allow the evaluation of metabolic son in the United States receives an effective dose of
activity within the body, thus improving surveillance 3 mSv/year from naturally occurring radioactive mate-
and management of cancer. In this chapter, different rials and cosmic radiation. In comparison, on average,
rrss rrss
imaging modalities and their advantages and disadvan- the radiation dose of a standard chest radiograph is
o ke
ke o
cussed, along with advancements and improvements of k e
tages for musculoskeletal imaging (Table 1) will be dis-
k e 0.1 mSv.1
oo
e bboo o e b o
musculoskeletal imaging in different body regions.
b o o Computed Tomography
e b o
b o
/
e / e m ee/ / e m e / / e
The principle of CT is the use of x-ray beams to pro-
e
duce tomographic images, or slices of an object. CT
Imaging Types
: / /
/ t
/ .
t . m / /t/.t .m
comprises multiple plain radiography images reassem-
: /
ss : ss :
bled together to generate an image. These images can
hhtttp
tp hhtttp
tp
Radiography also be reconstructed to generate a three-dimensional
Since its discovery in 1895, plain radiography has al- image (Figure 1). In addition to generating tomographic
lowed the visualization of structures within the human images, CT can also be used to determine the density of
body. The image produced is a projection of the the imaged structures. X-ray densities are measured in
amount of radiation absorbed by the structures along Hounsfield units (HUs) or CT numbers. Water is as-
k eers
the course of the beam. Digital radiography is com-
rs
monly used to improve diagnostic efficiency and the
k e r
e s
r
signed a value of 0 HU; air, a value of −1,000 HU. Im-
s
ages are displayed as gray scale; denser objects are light-
bboooo k
quality of images when compared with conventional
b o o
o o k b o oo
er. Contrary to plain radiography, good soft-tissue
o
imaging is provided with CT scans; the gray scale can
/
e e
/ e e / / e b
film radiography. The process makes images portable
e
and transferable via computers or CDs. However, there
e ee/ e
/ e b
be modified (“windowed”) to show data that fall within
: / / t
/ .
t m
. m : / / t t m
a fixed range of densities, such as bone windows or lung
. . m
windows, to evaluate particular structures.
/
t p ss : /
Dr. Ma or an immediate family member serves as a paid
p t p ss
p : /
t
hht t
consultant to or is an employee of Zimmer and Mox-
imed; has received research or institutional support from
Wyeth, Histogenics, and Zimmer; and serves as a board
t
hht t
MRI and Magnetic Resonance Arthrography
MRI does not require ionizing radiation. It uses a
strong magnet that generates a magnetic field and mul-
member, owner, officer, or committee member of the tiple coils that send and/or receive radiofrequency sig-
American Orthopaedic Society for Sports Medicine, the nals. Currently, all clinical MRI scans image the pro-
k eerss
Arthroscopy Association of North America, and the In-
r k
ternational Society of Arthroscopy, Knee Surgery, and
eers
r s
tons in hydrogen. The strength of the MRI machine is
expressed in tesla (T) units. The stronger the magnet,
b ooook b ook
Orthopaedic Sports Medicine. Neither Dr. Lynch nor any
oo b oooo
the higher the tesla unit and the better the signal-to-
noise ratio. Stronger magnets can improve imaging
/
e e
/ eb e / e
/e b
immediate family member has received anything of
value from or has stock or stock options held in a com-
e
speed and resolution.
ee/e/e b
/ t
///t m
mercial company or institution related directly or indi-
. .
rectly to the subject of this chapter.
: m : / t.
///t m
Conventional MRI requires a large room that is
.m
shielded to contain the magnetic field. The machine
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook b ook
Advantages and Disadvantages of Each Imaging Modality
o o b o oo
o
/
ee/e b Advantages
ee/ e
/ e b ee e
/ e b
Disadvantages
/
Plain
radiography
/ ///t. m
Most commonly used medical imaging modality
t .m
Relatively inexpensive
: : / t
///t. m
. m
Radiation exposure
Not effective in soft-tissue imaging because of poor
s : s :
Real-time radiographic imaging, or fluoroscopy, allows
tps tps
contrast resolution
hhtttp hhtttp
instantaneous feedback on stress radiographs, Magnification of the images. Measurement
angiography, and orthopaedic interventions. “standards” can be placed with the object to
allow for determination of magnification.
Although most medical x-ray beams do not pose a
risk to a fetus, there is a small possibility that
serious illness and developmental problems can
k eers
rs k eers
r s
occur. The actual risk depends on the type of
imaging study and the trimester of pregnancy.
o
/
e e
/ eb CT
resolution
e/
e e
/ e b
Tomographic nature of the images with high contrast
ee/ e
/ e b
Much higher radiation exposure than plain
radiographs
: // /.tm m
Images are processed digitally; images in plane other
t . : /
than the one imaged can be reconstructed to give a
/ t
/ .
t m
. m
Subject to motion artifacts because each slice can
take acquisition time up to 1 sec
ss : / ss : /
different perspective of the object/tissue of interest. There is artifact with metal objects and it is difficult
hhtttp
tp hhtttp
tp
Direct measurements can be performed on the scans to image around metal prosthesis.
because there is no magnification. Scans have a weight limit because patients need to
Can be combined with arthrography or myelography to lie on a scanner table.
evaluate specific joint or spinal abnormalities. Contraindicated for pregnant patients, except in
Used for injections and biopsy to allow precise location life-threatening circumstances.
of structures.
keerrss MRI.
k rrss
Provides better delineation of bone structures than
e e
bboooo k b o o
o o k b o oo
o
/
e e
/ e MRI
/ e e b
Superior images of soft tissues, such as ligaments,
ee /
tendons, fibrocartilage, cartilage, muscle, bone / e e b
Motion blurring and metal artifacts are poorly
ee /
tolerated.
: / / t
/ .
marrow, and fat
t m
. m : / /t/.tm.m
The examination time for MRI is much longer than
ss /
MRI, similar to CT scans, has an advantage over plain
: ss : / for CT scans. Patients need to remain still
hhtttp hhtttp
radiography on obtaining tomographic images of the throughout the scanning process.
tp
object of interest.
tp
More effective than CT at detecting changes in intensity
within the bone marrow to diagnose osteomyelitis,
Sedation is often needed for pediatric patients
younger than age 7 years.
Metal screws, pellets, prostheses, and foreign
malignancy, contusions, occult fractures, and stress bodies can produce significant artifact, obscuring
fractures anatomic structures. Metal suppression sequences
MRI contrast (gadolinium) has less allergic reaction than can be used but with loss of resolution.
k eers
rs iodine-based media.
k e r
e s
r s
There is no radiation exposure to the patient.
Although MRI does not use radiation, the effect of
radiofrequency and magnetic field on the fetus is
bboooo k b o o
o o k b o oo
unknown. It is usually recommended that a
o
pregnant woman not have an MRI.
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
Ultrasound
t . m
. m
Noninvasive at the frequencies used for diagnostic
: / / / t : / / t
/ . m
. m
Image quality and interpretation depend on the
t
imaging
t p ss : /
Commonly used in the imaging of children and
p t p ss
p : / experience of the ultrasonographer and
radiologists.
t
hht t
pregnant women
t
hht t
Shows nonossified structures, such as femoral heads, to
diagnose hip dysplasia and dislocation.
Cannot image inside bone; bone cortex reflects
almost all of the sound waves.
Internal joint structures are not well visualized
Equipment is portable and inexpensive compared with unless in a superficial location.
MRI and CT equipment.
Highly echogenic structures, such as a foreign body that
k eers
rs rs
r s
may not be visible on radiographs, can be easily
detected using ultrasound.
k ee
b ooook oook
Can be used for targeted therapy, such as injections and
b o b oooo
/
e e
/ eb ablations.
e / e
/e b
Useful for injections and aspirations of fluid collections
e ee/e/e b
t
///t m
Provides dynamic assessment of structures (ie, tendon
. . m
and nerve subluxation).
: / : / t.
///t m
.m
s
tps : s
tps :
78
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 7: Musculoskeletal Imaging
k eers
Table 1
rs keerrss
b ooook b ook
Advantages and Disadvantages of Each Imaging Modality (continued)
o o b o oo
o
/
ee/e b Advantages
ee/ e
/ e b ee e
/ e b
Disadvantages
/
Nuclear medicine
: / ///t. m
Scintigraphy allows imaging of metabolic activity.
t .m : /
Most metabolic processes involving bone have slow
t
///t. m
Lack of detail and spatial resolution
. m
Limited early sensitivity to detect acute fractures in
s : s
metabolic activity compared with soft-tissue
tps tps : patients with slow bone metabolism; it may take
hhtttp hhtttp
organs, such as the kidney and the liver. several days for the bone scan to be positive to
Fortunately, most radioisotopes are relatively long diagnose an occult femoral neck fracture.
lived. Low sensitivity can occur with lytic bone lesions,
White blood cell scintigraphy can be used to such as multiple myeloma and some metastases.
diagnose osteomyelitis. Avoid in breastfeeding mothers. Nuclear agent can
Scintigraphy can be used to diagnose metastasis, pass from the mother’s milk to the child.
k eers
rs k eers
stress fracture, or occult fractures.
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs
Figure 1
scapular fracture.
k e r
e s
r s
A, AP view of the scapula showing a fracture that involves the glenoid. B, Three-dimensional CT reconstruction of a
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
/ / t .
t m
typically has a small bore or tube whereby the patient
. m
enters to have the study performed. The machine has a
: / / / t t m
MRI is well suited for the evaluation of soft tissues.
. . m
However, in certain cases, the analysis of soft tissues
: /
t p ss
p : /
weight limit, and the small bore also limits the size of
ss : /
can be improved with the use of contrast. Contrast-
t p p
t
hht t
the patient who can undergo the study. MRI takes lon-
ger to perform than CT and is subjected to motion ar-
tifact. Patients with claustrophobia may not tolerate
t
hht t
enhanced MRI is performed after the intravenous injec-
tion of a gadolinium-containing compound and is com-
monly used in the evaluation of tumors, infections, and
conventional MRI and may require anesthesia to un- inflammatory conditions. Complications associated
dergo the study. with MRI include the malfunction of electrical appli-
k e rs
Scanners with an open design are usually smaller
rs
machines with lower field strength; these images are of
e k eers
r s
ances such as pacemakers and mechanical pumps, the
potential for metal objects brought into the scanner to
b ooook b oook
lower quality and lower resolution than those of con-
o
ventional closed scanners. However, open scanners can
b ooo
become dangerous projectiles, the migration of metal
o
foreign bodies in the eye or the brain, and a reaction to
/
e e
/ eb ee/ e
/e b
accommodate claustrophobic patients. These machines
/e/e b
a patient’s existing metal implants.
ee
/ t
///t
not require as much imaging detail.1
: m
should be used for larger joints and structures that do
. . m / t.
///t m
Magnetic resonance arthrography is performed after
.m
contrast injection for specific evaluation of joints. Di-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Nuclear Medicine/Positron Emission
k eers
rs keerrss Tomography
b ooook b o ook
o b oo
Nuclear imaging involves the use of radioisotope-
o o
labeled, biologically active drugs to evaluate various
/
ee/e b ee/ e
/ e b ee/ e
/ e b
structures. The radioactive tracer serves as a marker of
biologic activity. The images produced by scintigraphy
: / t
///t. m
.m t
///t. m
. m
are a collection of the radiation emissions from the iso-
: /
s
tps : s :
topes.
tps
hhtttp hhtttp
Bone scintigraphy, commonly known as bone scans,
generally is performed using diphosphonates labeled
with radioactive technetium Tc 99m. The initial (tran-
sient) phase is characterized by tracer delivery to the
tissue, which represents the perfusion images. The sec-
ond (blood pool) phase follows the initial phase. The fi-
k eers
rs k eers
r s nal (delayed) phase shows tracer accumulation in tis-
b ooook b ooook growth and turnover.

b oo
sues with active turnover, mostly in bone undergoing
o o
/
e e
/ eb Figure 2
/ e e b
Direct magnetic resonance arthrography of the
ee /
shoulder. The contrast clearly identifies the / e e b
Positron emission tomography (PET) is used in ortho-
ee /
paedic oncology. Fluorodeoxyglucose (18F), or FDG, is
: // t/.tm m
small rotator cuff tear of the supraspinatus ten-
.
don (arrow) with communication of the gleno-
: / / t . m
. m
the metabolic tracer widely used in clinical oncology.
/ t
ss : /
humeral joint and the subacromial space.
ss : /
FDG accumulation reflects the rate of glucose utilization
hhtttp
tp hhtttp
tp
in tissue. It is transported into tissue by the same mech-
anisms of glucose transport and trapped in the tissue as
FDG-6-phosphate. The use of FDG in the evaluation of
the musculoskeletal system is based on increased glyco-
lytic rate in pathologic tissues. High-grade malignancies
tend to have higher rates of glycolysis than low-grade
keerrss rect magnetic resonance arthrography is commonly

used to diagnose labral tears in the shoulder and the
k e rrss
e
malignancies and have greater uptake of FDG than do
bboooo k b o o o k
hip joints, triangular fibrocartilage and ligament tears
o
low-grade or benign lesions. The FDG is typically in-
b o oo
jected intravenously, in a patient who has been fasting
o
/
e e
/ e e / / e b
of the wrist, collateral ligament evaluation in the elbow,
e
and postoperative evaluation of a repaired meniscus
e ee/ e
/ e b
and who has a suitably low blood glucose level. The pa-
tient must then wait for the blood sugar to distribute and
: / / / .
t m m
(Figure 2). With direct magnetic resonance arthrogra-
t . t . m.m
be taken up into organs that use glucose—a time during
: / / / t
ss /
phy, a dilute gadolinium-containing solution is injected
: ss : /
which physical activity must be kept to a minimum to
hhtttp hhtttp
into the joint. Indirect magnetic resonance arthrogra- minimize uptake of the radioactive sugar in muscles (this
tp
phy is commonly used when direct injection of a joint is
impractical. With indirect magnetic resonance arthrog- tp
causes unwanted artifacts when the organs of interest are
inside the body). The patient is then placed in the PET
raphy, gadolinium is injected intravenously and al- scanner for the actual image acquisition.
lowed to travel through the vascular system to the sy-
novium of a joint. Gadolinium contrast behaves like
k eers
rs iodinated contrast media, but patients have less allergic
reaction to gadolinium than iodine-based contrast.
k e r
e s
r s Radiation Safety
bboooo k o o o
However, its usage is contraindicated in patients with
b o k b o oo
Although imaging allows the visualization of different
o
/
e e
/ e ee/ e
/ e b
renal insufficiency. Intravenous gadolinium can lead to
irreversible renal damage, known as nephrogenic sys-
e / e
/ e b
structures, certain risks exist. Children and fetuses are
especially susceptible to ionizing radiation because of
e
t . m
. m
temic fibrosis. Intravenous gadolinium should not be
: / / / t : / / t
/ .
t m
. m
their rapidly dividing cells and growth. Radiography, CT,
and bone scintigraphy produce ions that can deposit en-
t p p : /
administered to patients on dialysis or those with a
ss
glomerular filtration rate less than 30. ss : /
ergy to organs and tissues that can damage DNA. Some
t p p
Ultrasonography
t
hht t t
hht t
tracers (such as iodine-131) have half-lives of several
days and can concentrate in excreted body fluid and
breast milk. Rapidly dividing tissues are the most sus-
Ultrasonography uses high-frequency sound waves to ceptible to radiation-induced neoplasia, such as bone
produce images. A transducer produces sound waves marrow, breast tissue, gastrointestinal mucosa, gonads,
k eers
rs
that travel through the soft tissue, and echo waves are
k e
deflected back by the tissue to the same transducer. Im-
ers
r s
and lymphatic tissue. The risk of cancer is approximately
4% per Sievert (100 rem). The greatest risk of fetal mal-
b ooook age resolution and beam attenuation depend on both
b
wavelength and frequency. Doppler ultrasonography
oook
o b ooo
formation is in the first trimester and with doses > 0.1
o
Gy (10 rad). For risk late in pregnancy (≥ 150 days post-
/
e e
/ eb ee/ e
/e b
can be used to image blood vessels for flow velocity
/e/e b
conception), childhood malignancies such as leukemia
ee
Doppler ultrasound.
: / t
///t m
and direction. Color maps can be generated for color
. . m : / t.
///t m
are of concern. When obtaining radiologic studies, sen-
.m
sitive organs such as gonads should be shielded. It is al-
s
tps : s
tps :
80
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
ways important to follow the ALARA principle (“as low
k e rs
rs
as reasonably achievable”) of dosing for pregnant
e keerrss
b ooook o ook
women and children. The exposure to radiation de-
o
creases as an inverse square of the distance from the
b b o oo
o
/
ee/e b ee/ e
/ e b
source. Medical personnel should wear lead aprons and
be monitored using devices such as film badges. Of all
ee/ e
/ e b
: / t . m
.m
imaging modalities, CT delivers the highest amount of
///t : / t
///t. m
. m
s
tps :
radiation dose (5-15 mSv versus 0.1-2.0 mSv for plain
s
tps :
hhtttp hhtttp
radiography). CT should not be performed if other com-
parable imaging modalities are available. It is also im-
portant to exercise caution in performing multiple CT
scans at different intervals in the same patient. Figure 3 A, Plain AP radiographic view of the glenohu-
meral joint showing the joint space and minimal
osteophytes. B, Weighted AP view of the gleno-
k e rs
rs
Musculoskeletal Imaging of Specific Body Parts
e k eers
r s
humeral joint of the same patient showing
bone-on-bone arthritis.
b ooook
Shoulder
b ooook b o oo
o
/
e e
/ eb / e e b
Musculoskeletal imaging is commonly used in the diag-
ee /
nosis of shoulder injuries, including fractures, arthritis,
ee/ e
/ e b
t . m
. m
and soft-tissue injuries such as rotator cuff tears and in-
: // / t : / / t
/ .
t m
. m
stability.
ss : / ss : /
Fractures
hhtttp
tp
AP and axillary lateral or scapula Y views of the shoul-
der are commonly used to rule out shoulder fractures.
hhtttp
tp
More specific views, such as AP and serendipity view
(45° tilted view) of the clavicle, West Point axillary lat-
k errss
eral to diagnose bony Bankart injuries, and the Stryker
e k e rrss
e
bboooo k b o o o k
notch view for Hill-Sachs lesions, are used in the diag-
nosis of different injuries. CT is used to evaluate the
o b o oo
o
/
e e
/ e ee/ e
/ e b
complexity of the fracture pattern, and any comminu-
tion of proximal humerus and scapula fractures. Three-
Figure 4
/ e e b
MRIs showing the modified Goutallier classifica-
ee /
tion of fatty infiltration of the rotator cuff mus-
: / / t
/ .
t m m
dimensional reconstructions can be helpful to evaluate
. : / /t/.tm.m
cle. Grading is done on the sagittal fat-sensitive
images. A, Grade 0: no fat in the muscle belly of
ss /
the joint involvement of scapular neck and body frac-
: ss : /
all muscle groups. B, Grade 2: less than 50%
hhtttp hhtttp
tures.
tp tp
fatty infiltration; muscle atrophy is present over
the supraspinatus muscle.
Arthritis
For shoulder arthritis, an AP view of the glenohumeral
joint or Grashey view and axillary lateral views of the tears and labral injuries and in determining size, retrac-
shoulder can evaluate the amount of joint space nar- tion, and the tear pattern of injury. Ultrasound can al-
k eerss
rowing. A weighted view of the AP glenohumeral joint
r k e r
e
can also evaluate signs of instability or proximal migra- s
r s low dynamic evaluation of rotator cuff injuries and bi-
ceps mobility; however, resolution is lower and
bboooo k o o o k
tion and inflammatory arthritis (Figure 3). Primary os-
b o b o oo
evaluation is more localized. Recent studies have high-
o
/
e e
/ e e e
/ e b
teoarthritis of the shoulder usually has large inferior os-
/
teophytes seen on an AP view of the glenohumeral joint
e e / e
/ e b
lighted the importance of muscle atrophy and fatty in-
filtration (Figure 4) in the muscle as negative prognos-
e
: / / / .
t m m
and posterior wear on the axillary lateral view. For in-
t .
flammatory arthritis, there is less osteophytosis, but
: / / t
/ .
t m
tic factors in outcomes following rotator cuff repairs.
. m
The Goutallier method for evaluating the quality of the
p ss : /
there will be central wear of the glenoid, osteopenia,
t p ss : /
rotator cuff muscles was introduced in 1994.2 Using
t p p
t
hht t
and subchondral cyst formation. For surgical planning,
CT or MRI can be obtained to evaluate the amount of
glenoid wear and version. MRI allows evaluation of the
t
hht t
CT images, the amount of fat present in the muscle was
estimated. This method was later adapted for grading
muscle quality on MRI scans.3 The modified Goutallier
condition of the rotator cuff tendon for surgical plan- classification system grades the muscles of the rotator
ning between conventional total shoulder replacements cuff on the amount of fat present relative to muscle vol-
k eers
versus reverse shoulder replacements. Ultrasound-
rs k e r
guided glenohumeral joint injection can increase the ac-
e s
r s
ume.
For shoulder instability, plain radiography evaluates
b ooook
curacy in intra-articular injections.
b oook
o b oooo
bony deformities, such as the Hill-Sachs lesion, and an-
terior inferior glenoid bone loss. However, the limita-
/
e e
/ eb Rotator Cuff Tears and Instability
ee/ e
/e b ee/e/e b
tion of x-ray projection makes it difficult to quantify
/ t
///t m
MRI is more effective than other modalities in the eval-
. . m
uation of soft-tissue abnormalities such as rotator cuff
: / t.
///t m
the amount of bone loss. Three-dimensional CT scans
.m
have been recommended to evaluate the amount of
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
condyles (posterior fat pad sign). Occult fractures are
k eers
rs keerrss present in a significant percentage of both pediatric and
b ooook b o ook
o
adult patients with effusions, and follow-up radio-
o oo
o
graphs are standard. Although MRI can detect occult
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
fractures and bone bruises not seen on initial radio-
graphs in patients with effusions, treatment is usually
: / t
///t. m
.m : / t
///t. m
. m
presumptive, and the utility of MRI in occult elbow
s
tps : s
tps :
fracture diagnosis is yet to be shown.6 CT with multi-
hhtttp hhtttp
planar reformations is used for treatment planning for
complex fractures of the distal humerus and the radial
head.7
Figure 5 A, T2-weighted fast spin-echo sagittal image
shows a complete tear of the distal biceps from Arthritis
the radial tuberosity. The distal tendon frag-
In the evaluation of the restricted elbow, CT can better
k eers
rs e rs
ment (arrow) is thickened and undulating from
r
retraction. Bone marrow and subcutaneous fat
k e s detect intra-articular bodies and osteophytes than con-

ook ook
are reduced in signal because of fat saturation ventional radiographs. MRI is useful in evaluating for
b oo b o
pulses, accentuating the edema in the tissues
o b o oo
intra-articular bodies and has the advantage of disclos-
o
/
e e
/ eb e/
e / e b
surrounding the torn biceps tendon. B, T2-
e
weighted fast spin-echo axial image shows a
complete tear of the distal biceps from the ra-
ee/ e
/ e b
ing soft-tissue abnormalities that may also produce
locking, such as a thickened synovial fringe or synovial
dial tuberosity.
: // t/.tm
. m plicae.8
: / / t
/ .
t m
. m
ss : / ss : /
hhtttp hhtttp
Instability and Tendinopathy
tp
glenoid bone loss when compared with other modali-
ties, such as radiographs, MRI, and CT scans.4 MRI tp
For the evaluation of elbow instability, MRI has been
established as a reliable tool in assessment of the ulnar
and direct magnetic resonance arthrography are good collateral ligament complex, the radial collateral liga-
to evaluate labral and ligament injuries. The ABER (ab- ment, the annular ligament, and the lateral ulnar collat-
duction and external rotation) sequence is specifically eral ligament.9 In addition, MRI is used to evaluate bi-
keerrss k e
tures and also the posterosuperior rotator cuff tendons rrss
performed to evaluate the anterior inferior labral struc-
e
ceps or triceps tendon tears (Figure 5) or medial or
lateral epicondylitis.10 Because of the relatively superfi-
bboooo k o o
when in contact with the posterior labrum. This mag-
b o o k b o oo
cial position of the elbow’s ligaments and tendons,
o
/
e e
/ e e e
/ e b
netic resonance sequence is helpful to confirm the diag-
/
nosis of anterior inferior labral tears and internal im-
e e e
/ e b
sonography may be used to screen for Little Leaguer’s
/
elbow and the etiology and assessment of treatment of
e
pingement syndrome.5
: / / t
/ .
t m
. m : / /t/.tm.m
tennis elbow with both mixed and promising results.11
ss : / ss : /
hhtttp hhtttp
Neuropathy Neuropathy
tp
Ganglion cysts in the shoulder can lead to nerve com-
pression and muscle weakness. The suprascapular
nerve is the nerve most often compressed in the shoul-
tp
Cubital tunnel syndrome and other neuropathies can be
evaluated with MRI, both directly visualizing the
nerves involved for signal and morphologic abnormali-
der region. Ganglion cysts that compress the nerve at ties and identifying causative factors, such as accessory
the suprascapular notch can lead to weakness in both anconeus epitrochlearis muscle, ganglion cysts, enthes-
k eers
rs the supraspinatus and infraspinatus muscles, whereas
e
cysts at the spinoglenoid notch will lead to weakness in
k r
e s
r s ophytes, or other masses compromising the volume of
the cubital tunnel.12
bboooo k b o o
the infraspinatus muscle only. Direct magnetic reso-
o o k b o oo
o
/
e e
/ e e / e
/ e b
nance arthrography can evaluate the communication
between the cyst and the joint, usually through a small
e
Wrist
Fractures
ee/ e
/ e b
: / / t
/ .
t m
labral tear. Indirect magnetic resonance arthrography
. m
can evaluate the presence of a dilated vein or aneurysm
: / / t
/ .
t m
. m
Standard plain film evaluation of the wrist includes PA,
oblique, and lateral views. A dedicated ulnar-deviated PA
t p ss
p : /
that can lead to nerve compression.
ss : /
view for specific evaluation of the scaphoid is often rou-
t p p
Elbow
Fractures
t
hht t t
hht t
tine because of the frequency and the consequences of
occult fractures of the scaphoid. A semisupinated oblique
view may reveal occult radial fractures. Secondary signs,
Standard radiographs of the elbow include an AP ex- such as obliteration or deviation of the pronator quadra-
tended and lateral flexion view. For trauma imaging, an tus fat pad on the lateral radiograph or the scaphoid fat
k eers
rs head is obtained. The presence of a joint effusion or
k eers
oblique lateral view for specific evaluation of the radial
r s
pad on the PA radiograph, can raise suspicion for occult
fractures. Because of the frequency of missed scaphoid
b ooook b oook
hemarthrosis leads to lifting of the inferior edge of the
o
fat contained within the coronoid fossa and produces
b ooo
fractures on initial radiographs, advanced imaging with
o
MRI, multidetector CT (MDCT), nuclear scintigraphy,
/
e e
/ eb ee/ e
/e b
the sail sign, whereas displacement of the fat contained
/e/e b
or tomosynthesis are being explored in the emergency
ee
/ t
///t m
within the olecranon fossa of the distal humerus allows
. . m
this fat to be visualized posterior to the distal humeral
: : / t.
///t m
setting.13 MDCT is often used for complex distal radius
.m
fractures. The addition of three-dimensional reconstruc-
s
tps : s
tps :
82
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
Figure 6 Triangular fibrocartilage central perforation. A, Extreme palmar MRI scan of the triangular fibrocartilage complex
b ooook b oook b oo
showing an intact volar radioulnar ligament. B, MRI scan of the triangular fibrocartilage complex halfway between
o o o
the extreme volar and extreme dorsal images showing almost complete loss of the triangular fibrocartilage disk
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
between the ulnar head and the ulnar-most aspect of the lunate. However, the distal fibers of the complex can be
seen attaching to the ulnar fovea and the tip of the ulnar styloid (arrow). C, Dorsal MRI scan shows an intact dor-
: // t/.tm
. m : / / t
/ .
t m
. m
sal radioulnar ligament attaching to the edge of the radius at the distal end of the sigmoid notch of the radius.
ss : / ss : /
hhtttp
tp
tions to the traditional two-dimensional sagittal and cor-
hhtttp
tpthan 1.5 T magnetic resonance arthrography.17 How-
onal reformations may better assess a coronal fracture ever, for the detection of erosions from rheumatoid ar-
line, central articular depression, and articular commi- thritis, even low field strength 0.2 T MRI is more sen-
keerrss
nution and determine the exact number of fragments and
may thus alter the surgical approach.
k e rrss
e
sitive than conventional radiography.18 CT and
tomosynthesis also have higher sensitivity.
bboooo k b o o
o o k b o oo
o
/
e e
/ e
Instability
e / e
/ e b
For evaluation of the intrinsic scapholunate and luno-
e e / e
/ e b
Tendinopathy and Neuropathy
MRI has long been used to evaluate tendinopathy of
e
: / / t
/ .
t m
triquetral ligaments of the wrist and evaluation of the
. m
triangular fibrocartilage, MDCT arthrography and
/ /t/.tm
the wrist. Increased fluid within tendon sheaths, syno-
.m
vial thickening, morphologic and signal abnormalities
:
ss : /
magnetic resonance arthrography at 3 T have higher
ss : /
of the tendons, and scarring and thickening of the ten-
hhtttp
tp
specificity and sensitivity when compared with conven-
tional MRI at 1.5 T.14 Evaluation of the triangular fi-
brocartilage complex by MRI at 1.5 T has been re-
hhtttp
tp
don sheaths all can be readily detected. Overuse syn-
dromes such as de Quervain tenosynovitis or “baby
wrist,”19 inflammatory conditions such as rheumatoid
ported with sensitivities ranging from 27% to 100% arthritis, or even infections such as tuberculosis have
and specificities from 90% to 100%. The more periph- been studied. Because of the relatively superficial ana-
eers
eral ulnar-sided tears and the noncommunicating par-
rs
tial ulnar-sided (proximal) tears, which may be more
k k e r
e s
r s
tomic position, sonography is gaining more attention in
the evaluation of conditions such as extensor carpi ul-
bboooo k b o o
o o k
clinically significant (Figure 6), are particularly prob-
lematic in detection with MRI at 1.5 T, even with indi-
b o oo
naris instability and impingement by volar plate fixa-
o
tion screws on extensor tendons.20 MRI has also been
/
e e
/ e rect arthrography.15
ee/ e
/ e b / e
/ e b
used extensively to assess median nerve pathology in
ee
: / / t
/ .
t m
The distal radioulnar joint may be evaluated reliably
. m
with plain films, provided the lateral view is well posi-
/ / t
/ t m
carpal tunnel syndrome and ulnar nerve pathology in
. . m
the Guyon canal. Ultrasound can be useful to interro-
:
t p ss
p : /
tioned, with the volar surface of the pisiform projected
ss : /
gate the wrist dynamically of superficial structures.
t p p
t
hht t
between the volar surfaces of the distal pole of the
scaphoid and the capitate and that the distal radius is
without significant fracture deformity.16
t
hht t
Tumor
Both MRI and ultrasonography can be used in the spe-
cific diagnosis of ganglion cysts, accessory muscles, for-
Arthritis eign bodies, abscess, hemangiomas, hematomas, lipo-
k eers
Evaluation of the integrity of the articular cartilage
rs k e
within the wrist remains a challenge. Sensitivities for
ers
r s
mas, tenosynovitis, tendon tears, aneurysms, and
arteriovenous malformations presenting as hand
b ooook b oook
cartilage abnormalities of the distal radius, scaphoid,
o
lunate, and triquetrum range from 10% to 52% using
b ooo
masses. Solid masses such as giant cell tumor of the ten-
o
don sheath, schwannomas, and neuromas may not
/
e e
/ eb ee/ e
/e b
either 1.5 T or 3 T MRI machines, even with additional
/e/e b
have a tissue-specific appearance, but differential possi-
ee
/ t
///t m
direct or indirect magnetic resonance arthrography. In
. . m
one study, MDCT arthrography proved more sensitive
: / t.
///t
niques.21
: m
bilities can be narrowed significantly using these tech-
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs Figure 7
k eers
r s
Intertrochanteric fracture. A, Plain film showing a displaced fracture of the greater trochanter apophysis. The ex-
tent of the lesion is underestimated by the plain film image. B, Fast spin-echo proton density-weighted coronal
b ooook b oook b oo
image shows the fracture line (arrow) extending from the base of the greater trochanter to a point midway across
o o o
the intertrochanteric line; the fracture is of greater extent than the plain film suggested. C, Fast spin-echo T2-
/
e e
/ eb e/
e e
/ e b e / e
/ e b
weighted coronal image shows the fracture line (arrow) extending from the base of the greater trochanter to a
point almost completely across the intertrochanteric line, coming just short of the medial cortex, even further de-
e
fixation.
: // t/.tm
. m : / / t
/ .
t m
lineating the full extent of the fracture line. A sliding hip screw and side plate were subsequently used for fracture
. m
ss : / ss : /
Hip
Fracture hhtttp
tp hhtttp
tp ment relative to the labrum and total femoral head dis-
placement are assessed.25 Plain film evaluation includes
an assessment of the hips in AP projection with analysis
Plain film investigation for hip fractures generally in-
cludes an AP radiograph of the pelvis and a lateral view of Shenton line, acetabular angles, the position of the
femoral head with respect to the acetabulum using Hil-
rrss rrss
of the hip of the affected side. When the plain film
o ke
ke o k e
study is negative, but there is inability to bear weight or
k e
other clinical findings that raise suspicion, MRI is often
genreiner and Perkins lines, the morphology of the ac-
etabulum, and the development and the shape of the
oo
e bboo o e b o o
used in the emergency setting with abbreviated proto-
b o e b o
b o
femoral head. In the adult, acetabular depth, inclina-
/
e / e / / e
cols to provide high sensitivity and specificity for frac-
m ee
ture (Figure 7), osteonecrosis, or muscle injury.22 When
m ee/
tion, version, center edge angle, and femoral head sphe-
/ e
ricity are analyzed on plain films.26
: /
/ t
/ .
t . m
compared with bone scans, MRI is equally accurate for
/ : / /
/t/.t .m
s :
fracture detection but provides additional diagnoses in
s ss :
Arthritis
hhtttp
tp hhtttp
tp
a substantial number of patients22 with other pelvic Osteoarthritis is suggested on plain films by joint space
fractures, such as insufficiency fractures of the sacrum narrowing, osteophytes at the femoral head neck junc-
or the acetabulum, muscle edema and tears, trochan- tion or acetabular rim, subchondral cysts, subchondral
teric bursitis, and hamstring tendinopathy. sclerosis, and eventually loss of femoral head sphericity
from subchondral collapse. In some patients, this pro-
cess can occur prematurely or quite rapidly. In prema-
k eers
rs
Osteonecrosis
After initial plain films, MRI has become the preferred
k e r
e s
r s ture osteoarthritis, preexisting abnormalities such as
developmental hip dysplasia, femoral acetabular im-
bboooo k b o o
method to diagnose suspected osteonecrosis.23 Findings
o o k
such as the characteristic double line sign consisting of
b o oo
pingement, or osteonecrosis are often present.27 In rap-
o
/
e e
/ e ee/ e
/ e b
high signal intensity paralleling a low-intensity periph-
e e
/ e b
idly occurring osteoarthritis, MRI evaluation often dis-
/
closes joint effusion, diffuse bone marrow edema in the
e
/ / t .
t m
eral rim is often seen on T2-weighted images. Increased
. m
joint fluid, which is nonspecific, can be a secondary
: / : / / t
/ .
t m
. m
femoral head and neck, femoral head flattening, and
cystlike subchondral defects. Magnetic resonance ar-
t p ss
p : /
finding. Other entities need to be considered when MRI
t p ss : /
thrography or specialized sequences may be helpful in
p
t
hht t
detects abnormalities of the proximal femur, including
transient marrow edema of the femoral head24 and sub-
chondral insufficiency fractures. Distinguishing os-
t
hht t
assessing articular cartilage damage in the hip.
Femoral Acetabular Impingement and Labral Tear

teonecrosis from a subchondral fracture can be done by The presence of a mismatch between the femoral head
observing that in osteonecrosis, the double line forms a and neck with the acetabulum resulting in abutment of
k eers
rs
continuous ring.
k eers
r s the proximal femur with the acetabulum is termed fem-
oral acetabular impingement (FAI). This condition may
b ooook Developmental Dysplasia of the Hip
b oook
o
Examination of the hip for developmental dysplasia in
b ooo
lead to premature osteoarthritis. Fibrocystic changes are
o
seen on plain films in the anterosuperior femoral neck in
/
e e
/ eb ee/ e
/e b
the pediatric population begins with dynamic and static
/e/e b
33% of the patients with FAI in one study.28 Rim ossi-
ee
/ t
///t m
ultrasound. The percentage of femoral head coverage,
. . m
labral morphology, and superior femoral head displace-
: : / t.
///t m
fication in the pincer type FAI and the pistol grip defor-
.m
mity of the femoral neck in the cam type can also be seen
s
tps : s
tps :
84
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
on plain films. MRI can assess for abnormal epiphyseal with coronal and sagittal reformations is recommended
k eers
rs ke rrs
torsion angles, labral tears, and cartilage delamination
e s for comminuted and displaced tibial plateau fractures or
b ooook b o ook
in this entity. Calculation of the alpha angle as the angle
o
subtended by the long axis femoral neck and the inter-
distal femoral fractures. Three-dimensional reconstruc-
o oo
o
tion can help provide better visualization of the de-
b
/
ee/e b / e e b
section of an idealized circle outlining the femoral head
ee /
with a bony bump on the femoral neck in a specialized / e e b
pressed articular fragments and also accurately identify
ee /
the fracture plane, such as with a Hoffa fracture of the
t . m
.m
oblique axial plane can be supportive of the diagnosis.
: / ///t : / t
///t. m
. m
distal femur. MRI can be used to evaluate soft- tissue in-
s
tps :
To evaluate hip instability or labral tears, magnetic res-
s
tps :
juries, especially meniscus injuries with tibial plateau
hhtttp hhtttp
onance arthrography with direct injection of a fractures and also associated ligament injuries.32
gadolinium-containing compound can be done.
Arthritis
Total Hip Arthroplasty For arthritis of the knee, it is important to perform
In the evaluation of the painful hip after arthroplasty, weight-bearing views to allow an indirect method of
the analysis of plain films for the development of radio- evaluating cartilage thickness. A bilateral flexion
k rs
rs
lucency between the prosthesis and bone, between the
ee k eers
r s weight-bearing PA view, or Rosenberg view, allows bet-
ook ook
cement and the prosthesis, or between the cement and ter evaluation of the posterior weight-bearing surface
b oo b o
bone should be done. Fractures of the cement, the de-
o b o oo
o
of the tibia. The flexed PA view allows the x-ray beam
/
e e
/ eb ee e
/ e b
velopment of sclerosis near the tip of the femoral stem,
/
the evidence of prosthetic movement or the presence of
ee/ e
/ e b
to project along the posterior tibial slope to clearly
evaluate the joint space. Merchant or skyline views are
: // t/.tm m
metallic beads shed from the prosthesis can all be indic-
. t . m
. m
helpful to evaluate patellofemoral joint arthritis; how-
: / / / t
ss /
ative of loosening on plain films. Plain films may also
: : /
ever, it is important that these views are obtained at ac-
ss
hhtttp hhtttp
disclose stress shielding, insufficiency fractures near the curate knee flexion angles.
tp
femoral stem, component wear, component dislocation
of the liner, or dislocation. Histiocytic response from
immune reaction to prosthetic components shows a
tp MRI has had significant improvement over the past
decade in imaging cartilage lesions. Although MRI can
evaluate focal cartilage injuries much better than plain
smooth endosteal scalloping on plain films. Arthrogra- radiography, we have also extended the use of MRI to
phy plus aspiration and synovial biopsy to exclude in- evaluate the quality of cartilage. New imaging modali-
keerrss
fection can also disclose sinus tracts or extravasation
k e
below the intertrochanteric line. Nuclear scintigraphy, rrss
e
ties such as delayed gadolinium-enhanced MRI of car-
tilage (dGEMRIC), T2 mapping, and T1rho mapping
bboooo k o o o
with indium-labeled white blood cells, immunoglobulin
b o k b o oo
allow us to directly probe the biochemical composition
o
/
e e
/ e e / / e b
G scanning, or gallium scanning can also help in the di-
e
agnosis of periprosthetic infection.29 Special techniques
e e / e
/ e b
of cartilage.33 These techniques are developed to detect
early cartilage changes, with loss of proteoglycan and
e
/ / t
/ .
t m
in MRI can be done to view the complications of total
. m
hip arthroplasty, such as muscle tears.30
: : / /t/.tm.m
organization, before loss of volume and thinning.
ss : / ss : /
dGEMRIC is an indirect magnetic resonance arthrogra-
hhtttp hhtttp
phy technique, where gadolinium is injected intrave-
Infection
tp
In the diagnosis of a septic hip, neither ultrasound nor
CT can be reliably used to exclude infection. Aspiration
tp
nously and allowed to diffuse into the joint. The
amount of contrast diffusion into the cartilage matrix
represents inversely the amount of proteoglycan in the
and synovial biopsy under either fluoroscopic guidance articular cartilage. T2 mapping measures primarily the
or ultrasonography remains essential. Work is being organization of the cartilage matrix and water content
k ee s
done using dynamic contrast-enhanced MRI to distin-
rrs k e r
e
guish septic effusions from transient synovitis in the pe-s
r s within the articular cartilage. T1rho is a novel sequence
that measures the amount of proteoglycan within the
bboooo k
diatric population.31
b o o
o o k cartilage (Figure 8).
b o oo
o
/
e e
/ e Muscles and Tendons
ee/ e
/ e b Total Knee Replacement
ee/ e
/ e b
: / / t
/ .
t m
Abductor gluteus medius, gluteus minimus, hip adduc-
. m
tor and rectus tendinopathies, bursitis, groin hernias,
/ / t
/ .
t m
Plain radiographs are commonly used in the evaluation
. m
of patients with total knee replacements. A change in
:
t p ss
p : /
aponeurosis avulsions, athletic pubalgia, stress fractures,
ss : /
the position of the prosthesis is a clear indication of
t p p
t
hht t
ischiofemoral impingement, and snapping hip can be
evaluated with MRI or, in some cases, ultrasound. t
hht t
loosening. Radiolucent lines can be present around the
prosthesis; however, the diagnosis of component loos-
ening is not as difficult as in total hip arthroplasty be-
Knee cause the joint is more superficial, and patients will ex-
Fracture hibit more localized pain along the loose prosthesis.
k eers
Knee fractures are commonly evaluated using orthogo-
rs eers
r
nal views of the tibiofemoral joint and the patella joint.
k s
The diagnosis and workup of an infected knee prosthe-
sis is similar to the methods for total hip arthroplasty
b ooook b ook
AP and lateral views of the knee help rule out most of
oo
these fractures. A Merchant or skyline view of the pa-
b oooo
Ligament and Meniscus Injuries
/
e e
/ eb ee/ e
/e b
tella can rule out dislocations or evaluate longitudinal
/e/e b
MRI has superior capabilities in the diagnosis of knee
ee
/ t
///t m
fractures of the patella. Oblique views can be performed
. . m
to evaluate fractures that are out of plane. A CT scan
: / t.
///t m
ligament and meniscus injuries. The sensitivity and the
.m
specificity for diagnosing anterior cruciate ligament in-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttpFigure 9 Osteochondritis dissecans of the talar dome.
A, Fast spin-echo T2-weighted coronal image of
the talus shows an osteochondral defect of the
k eers
rs k eers
r s
talar dome. There is poorly defined subchondral
edema with a full-thickness articular cartilage
ook ook
defect (arrow) but apparently intact cortical
b oo b oo b o oo
bone. B, Fast spin-echo T2-weighted sagittal im-
o
/
e e
/ eb Figure 8
e e
/ e b
Quantitative MRI of the knee. The color map is an
/
overlay to visually represent the T1rho measure-
e ee/ e
/ e b
age of the same talus shows an osteochondral
defect of the medial talar dome. The cortex ap-
pears slightly collapsed in the area of cartilage
: // t/ tm
ment. Warmer color (red) indicates loss of pro-
. . m
teoglycan (cartilage degeneration) whereas cold
: / / t
/ . m
. m
loss. In conjunction with the coronal images, the
t
s : /
color (blue) indicates cartilage with higher con-
s ss : / area of surface abnormality and the depth of
hhtttp hhtttp
tent of proteoglycan. White outline indicates the lesion can be ascertained.
tp
edema pattern.
tp
tocol, such as the Ottawa rules.35 Three views are rou-
juries are 85% and 94%, respectively, whereas for me- tinely obtained. The presence of a tibiotalar joint
niscus injuries the sensitivity and the specificity are 96% effusion detected as a teardrop sign at the anterior as-
keerrss and 97%, respectively.34 However, the presence of radio-

graphic abnormalities does not mean that patients have
k e rrss
e
pect of the joint on the lateral radiograph is associated
with a significant number of radiographically occult
bboooo k b o o
o o
niscus tears are present in advancing age, and arthro-k
to be symptomatic. It has been well documented that me-
b o oo
fractures, especially if larger than 13 mm.36 These oc-
o
/
e e
/ e ee/ e
/ e b
scopic surgery on asymptomatic meniscus tears or me-
e / e
/ e b
cult fracture sites include the talar dome, the tibial
overhang, the posterior rims of the distal tibia (Tillaux
e
: / / t
/ .
t m
niscus tears with no mechanical symptoms yields no
. m
benefits to placebo treatment. Clinicians must be careful
/ /t/.tm
fracture), the medial and lateral malleoli, the tibial pla-
.m
fond, and the anterior process of the calcaneus.
:
s : /
in interpreting radiographic findings and clinical symp-
s ss : /
CT with two-dimensional reconstructions can be in-
hhtttp
tp hhtttp
tp
toms. MRI, however, is not as accurate when compared strumental in detecting these injuries. Three-
with clinical examinations in the diagnosis of chronic dimensional reconstructions from MD CT data may
posterior cruciate ligament (PCL) or posterolateral cor- help in surgical planning. A significant percentage, up
ner injuries. Chronic PCL injuries can have continuity of to 45%, of occult subchondral lesions can also be de-
the PCL fibers on MRI but have clinical instability. Pos- tected using MRI, which are less well seen using CT.
k eers
rs
terolateral corner structures are quite complex, and ded-
k e
icated oblique views of the posterolateral corner of the
r
e s
r s
The relationship of these lesions and subsequent osteo-
chondral defects of the talar dome is being investi-
bboooo k knee may be needed to diagnose these injuries.
b o o
o o k gated37 (Figure 9).
b o oo
o
/
e e
/ e Foot and Ankle
ee/ e
/ e b Instability
ee/ e
/ e b
: / / t
/ .
t m
Standard radiographs of the tibia and the fibula include
. m
AP and lateral views. For the ankle, AP, mortise, and
/ / t
/ t m
In the evaluation of the ligamentous integrity of the an-
. . m
kle, one study demonstrated sensitivities for syndes-
:
t p ss
p : /
lateral views are obtained, and AP, oblique, and lateral
ss : /
motic ligament injuries ranging from 45% to 62%
t p p
t
hht t
images are usually obtained for the foot. Other com-
mon views are the Harris Beath axial views for the cal-
caneus, gravity stress views for evaluating the integrity
t
hht t
compared with arthroscopy.38 However, with added in-
direct arthrography or direct magnetic resonance ar-
thrography, this can be improved to the 91% to 95%
of ankle ligaments, and weight-bearing views of the range.38
foot for evaluating acquired or congenital deformities
k eers
rs
of the foot and for interrogation of the Lisfranc joint.
k eers
r
Specialized views are available for evaluating the calca-
s
Impingement
MRI continues to have a role in the evaluation of the
b ooook neal facets and the sesamoids.
b oook
o b oooo
various impingement syndromes.39 Soft-tissue masses
can be seen in the anterolateral gutter in patients with
/
e e
/ eb Fractures
ee/ e
/e b /e/e b
arthroscopically confirmed anterolateral impingement
ee
/ t
///t m
In the acute trauma setting, the decision to obtain ra-
. . m
diographs may be determined using a standardized pro-
: / t.
///t m
in a little less than half of patients. This sensitivity im-
.m
proves considerably (88% to 96%) if there is fluid in
:
s
tps : s
tps :
86
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
the joint, either native or injected via a magnetic reso-
k e rs
rs
nance arthrogram.40 Sonographic arthrography and
e keerrss
b ooook ook
MDCT arthrography have also been studied for antero-
o o
lateral impingement, with sensitivities of 85% and
b b o oo
o
/
ee/e b 97%, respectively.41
ee/ e
/ e b ee/ e
/ e b
Tenosynovitis
: / t
///t. m
.m : / t
///t. m
. m
s :
Because of its superior soft-tissue contrast, MRI contin-
tps s
tps :
hhtttp hhtttp
ues to predominate in the evaluation of tendon abnor-
malities. Adequate coverage is essential to include the
distal insertions of the specific tendons to be interro-
gated (ie, flexor hallucis, posterior tibial tendon, per-
oneus longus) and not just limit the study to the ankle.
Signal abnormalities within the tendons, fluid in the
k e rs
rs
tendon sheaths, and secondary edema in subjacent
e k eers
r s
b ooook b oook
bone can all be used to establish a diagnosis of tendin-
o
opathy or tenosynovitis. The amount of fluid or the ex-
b o oo
o
/
e e
/ eb e/
e e e b
tent of signal abnormality can be instrumental in distin-
/ ee/ e
/ e b
: // t/ tm
guishing normal from pathologic findings.42 Tendon
. . m
subluxation, tears, or impingement may also be evalu-
: / / t
/ .
t m
. m
ated with sonography.
ss : / ss : /
Infection
hhtttp
tp
Plain films are obtained initially in suspected osteomy-
hhtttp
tp
Figure 10 Osteomyelitis. A, Plain film of the left foot, show-
ing edema of the great toe but no periostitis,
elitis and also to confirm the presence of periostitis, fo- cortical erosion, or focal osteopenia.
cal osteopenia, cortical erosion, soft-tissue edema, or B, Fast spin-echo T2-weighted image showing
rrss rrss
soft-tissue gas or foreign bodies. Often, secondary im- fluid in the first metatarsophalangeal joint and
e e
deep marrow edema in the distal first metatar-
aging is required to definitively exclude bone infection.
o ookke
Nuclear scintigraphy with combined triple phase
o o k
o k e sal head. The cortex has a small defect at the
o oo
site of penetration by a foreign body (arrow).
/ e
/ bb
e o / / b
e o
Tc-99m bone and tagged white blood cell scans can be
e b
useful in ruling out infection, especially in cases compli-
/ e
/ b
e b o
C, T1-weighted image showing fluid in the first
metatarsophalangeal joint and deep marrow
e m ee
cated by recent fracture, recent surgery, or prostheses.
t . m t . m mee
edema in the distal first metatarsal head. Deep
. .
marrow signal loss on T1-weighted images is a
s : /
: /
/ t
MRI is also used, relying on concordant signal abnor-
/
malities within the deep bone marrow on T1-weighted
s : /
: /
/ / t
concordant finding with high signal on T2-
hhtttp
tp s
images (loss of normal fat signal), fluid sensitive se-
quences such as fat-saturated T2-weighted images or
hhtttp
tp s weighted images in the diagnosis of osteomy-
elitis. However, both of these findings represent
edema within the marrow, a nonspecific finding
seen also in trauma and tumors. D, T1-weighted
short tau inversion recovery sequences (high signal image after the intravenous injection of a
from bone marrow edema), plus enhancement after in- gadolinium-based compound shows enhance-
travenous gadolinium contrast injection on fat- ment of the deep marrow of the distal first
metatarsal, the synovium in the joint, and the
k ee s
saturated T1-weighted images (Figure 10). Excluding
rrs k e
concomitant infection in a neuropathic foot can be par-
r
e s
r s plantar subcutaneous fat deep to the first
metatarsal. These findings are all supportive of
bboooo k b o o
o
in bones may be helpful, with the signal abnormalitiesk
ticularly challenging. The pattern of signal abnormality
o tic arthritis.
b o oo
the diagnosis of osteomyelitis and possible sep-
o
/
e e
/ e ee/ e
/ e b
in the uninfected neuropathic bone confined to the im-
ee/ e
/ e b
/ / t t m
mediate subcortical bone in a thin rim pattern, whereas
. . m
infected bones have confluent deep marrow signal
: / : / / t
/ .
t m
. m
t p ss
p : /
changes. Other secondary findings, such as sinus tracts,
t p ss
Neuropathy
p : /
t t
abscesses, pressure point location, and gas in the soft
hht
tissues, also can be used to distinguish the uninfected
from the infected neuropathic foot.43
t
hht t
A variety of specific nerve neuropathies can be exam-
ined with MRI. Neuropathies affecting branches of the
posterior tibial nerve are studied, such as the medial
and lateral plantar nerves in the tarsal tunnel; Baxter
Tumors neuropathy of the inferior calcaneal nerve; and jogger’s
k e rs
Both MRI and sonography are used to characterize
rs
soft-tissue masses. Ganglion cysts, plantar fibromas,
e k eers
r s foot, which is caused by entrapment of the medial plan-
tar nerve by the abductor hallucis muscle and the mas-
b ooook
Morton neuromas, and lipomas can often be
b oook
o
specifically diagnosed with MRI (Figure 11). However,
b ooo
ter knot of Henry (chiasma plantaris), where the flexor
o
hallucis longus and flexor digitorum longus cross. Oth-
/
e e
/ eb ee/ e
/e
with Morton neuroma, recurrence of tumor may beb /e/e b
er nerves studied with both MRI and ultrasound include
ee
cess.44
: / t
///t m
difficult to distinguish from the normal scarring pro-
. . m / t.
///t m
the sural and superficial peroneal nerves. The physician
.m
should look for masses; scar tissue; thickened retinacu-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
Figure 11 Ganglion cyst. A, T1-weighted sagittal image of the ankle shows a mass, similar but slightly darker in signal than
b ooook b oook b oo
muscle, adjacent to the peroneus brevis tendon. B, Proton-weighted axial image of the ankle shows the same
o o o
mass, similar but slightly brighter in signal to muscle, adjacent to the peroneus brevis tendon. C, T2-weighted fast
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
spin-echo coronal image of the ankle shows the same mass, with homogeneous high fluid signal, adjacent to the
peroneus brevis tendon. Thin septa separate the mass into at least three compartments.
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp hhtttp
la; inflammatory conditions compressing the nerves in 2. Goutallier D, Postel JM, Bernageau J, Lavau L, Voisin
tp
confined spaces such as the tarsal tunnel; neurofibro-
mas; schwannomas of the nerves themselves; or second-
ary signs such as muscle atrophy, as in Baxter neurop-
tp MC: Fatty muscle degeneration in cuff ruptures: Pre-
and postoperative evaluation by CT scan. Clin Orthop
Relat Res 1994;304:78-83.
athy involving the abductor digiti minimi muscle.
3. Fuchs B, Weishaupt D, Zanetti M, Hodler J, Gerber C:
keerrss k e rrss
e
Fatty degeneration of the muscles of the rotator cuff:
Assessment by computed tomography versus magnetic
bboooo k Summary
b o o
o o k 599-605.
b o oo
resonance imaging. J Shoulder Elbow Surg 1999;8(6):
o
/
e e
/ e e / / e b
Musculoskeletal imaging has significantly enhanced the
e
ability to diagnose, monitor, and evaluate the healing of
e ee/ e
/ e b
/ / t
/ t m
musculoskeletal conditions. Clinicians should deter-
. . m
mine the best imaging modalities to aid in their treat-
:
4.
: / /t .tm
Rerko MA, Pan X, Donaldson C, Jones GL, Bishop JY:
.m
Comparison of various imaging techniques to quantify
/
s : /
ment of musculoskeletal disorders.
s ss : /
glenoid bone loss in shoulder instability. J Shoulder El-
hhtttp
tp hhtttp
tp bow Surg 2013;22(4):528-534.
The authors compared the ability of plain radiographs,
MRI, CT, and three-dimensional CT to quantify glenoid
Key Study Points bone loss.
k eers
rs • Understand the benefits and limitations of each
k
imaging modality: plain radiography, ultrasonog-
e r
e s
r s
5. Steinbach LS: MRI of shoulder instability. Eur J Radiol
2008;68(1):57-71.
bboooo k raphy, nuclear imaging, CT, and MRI.
b o o
o o k 6.
b o oo
o
Chapman VM, Kalra M, Halpern E, Grottkau B,
/
e e
/ e
•
ation safety.
ee e
/ b
Understand the importance of guidelines of radi-
/ e ee/ e
/ e b
Albright M, Jaramillo D: 16-MDCT of the posttrau-
matic pediatric elbow: Optimum parameters and associ-
•
: / / t
/ .
t m
. m
Understand the importance of different imaging
: / / t
/ .
t m
. m
ated radiation dose. AJR Am J Roentgenol 2005;185(2):
ss : /
modalities of different conditions and body re-
t p p t p ss
p : /
516 -521.
gions.
t
hht t t
hht t
7. Guitton TG, Ring D; Science of Variation Group: Inter-
observer reliability of radial head fracture classification:
Two-dimensional compared with three-dimensional CT.
J Bone Joint Surg Am 2011;93(21):2015-2021.
Eighty-five orthopaedic surgeons classified 12 different
k eers
k eers
r s radial head fractures using the Broberg and Morrey
modification of the Mason classification assessing frac-
b ooook b oook
o o oo
ture line, comminution, articular surface involvement,
b o
/
e e
/ eb 1.
e / e
/e b
Ma CB, Steinbach LS: Musculoskeletal imaging, in Lie-
berman JA: AAOS Comprehensive Orthopaedic Re-
e e /e/e b
articular stepoff or gap, central impaction, and the num-
ber of fragments. The use of three-dimensional recon-
e
/ t
///t
Surgeons, 2008, pp 137-142.
: m
view. Rosemont, IL, American Academy of Orthopaedic
. . m : / t.
///t m
structions results in a small but substantial decrease in
.m
interobserver variation.
s
tps : s
tps :
88
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
8. Awaya H, Schweitzer ME, Feng SA, et al: Elbow syno- 20. Bianchi S, van Aaken J, Glauser T, Martinoli C, Beau-
k eers
rsvial fold syndrome: MR imaging findings. AJR Am J
keerrss lieu JY, Della Santa D: Screw impingement on the ex-

tensor tendons in distal radius fractures treated by volar
ook ook
Roentgenol 2001;177(6):1377-1381.
b oo b o o b o oo
plating: Sonographic appearance. AJR Am J Roentgenol
o
/
ee/e b 9.
/ e e b
Potter HG, Weiland AJ, Schatz JA, Paletta GA, Hotch-
ee /
kiss RN: Posterolateral rotatory instability of the elbow:
ee e
/ e b
2008;191(5):W199-203.
/
1997;204(1):185-189.
: / t . m
.m
Usefulness of MR imaging in diagnosis. Radiology
///t
21.
: / ///t. m
. m
Bianchi S, Della Santa D, Glauser T, Beaulieu JY, van
t
Aaken J: Sonography of masses of the wrist and hand.
s
tps : s
tps : AJR Am J Roentgenol 2008;191(6):1767-1775.
10.
hhtttp
Kijowski R, De Smet AA: Magnetic resonance imaging
hhtttp
findings in patients with medial epicondylitis. Skeletal
Radiol 2005;34(4):196-202.
22. Kirby MW, Spritzer C: Radiographic detection of hip
and pelvic fractures in the emergency department. AJR
Am J Roentgenol 2010;194(4):1054-1060.
11. Struijs PA, Assendelft WJ, Kerkhoffs GM, Souer S, van The authors present a retrospective analysis of 92 pa-
k eers
rs k eers
r s
Dijk CN: The predictive value of the extensor grip test
for the effectiveness of bracing for tennis elbow. Am J
tients referred for MRI from the emergency department.
Fourteen percent of the patients with negative plain
b ooook Sports Med 2005;33(12):1905-1909.
b ooook oo
films had fractures disclosed by MRI, whereas no frac-
o o
ture was found in 12% of the patients with radiographs
b
/
e e
/ eb 12.
e/ e
/ e b
Miller TT, Reinus WR: Nerve entrapment syndromes of
e ee/ e
/ e b
suggestive of fracture. In 43 of the 59 patients without a
fracture on MRI, muscle edema or tear, trochanteric
2010;195(3):585-594.
: // t/.tm
the elbow, forearm, and wrist. AJR Am J Roentgenol
. m : / / t
/ .
t m
. m
bursitis, or hamstring tendinopathy were found to ac-
ss : / ss : /
count for patient symptoms.
hhtttp hhtttp
A review of nerve entrapment syndromes of the elbow,
tp
forearm, and wrist featuring both sonographic and MRI
imaging is presented. tp23. Beltran J, Herman LJ, Burk JM, et al: Femoral head avas-
cular necrosis: MR imaging with clinical-pathologic and
radionuclide correlation. Radiology 1988;166(1 Pt 1):
13. Nikken JJ, Oei EH, Ginai AZ, et al: Acute wrist trauma: 215-220.
Value of a short dedicated extremity MR imaging exam-
rrss rrss
ination in prediction of need for treatment. Radiology 24. Vande Berg BE, Malghem JJ, Labaisse MA, Noel HM,
o ke
ke
2005;234(1):116-124.
o k e
k e
Maldague BE: MR imaging of avascular necrosis and
oo
transient marrow edema of the femoral head. Radio-
e bboo o14.
e b o o o
Chhabra A, Soldatos T, Thawait GK, et al: Current per-
b e b o
b o
graphics 1993;13(3):501-520.
/
e / e m ee/
wrist. Radiographics 2012;32(3):879-896./ e
spectives on the advantages of 3-T MR imaging of the
25.
ee/ / e
White KK, Sucato DJ, Agrawal S, Browne R: Ultrasono-
m
/ / t
/ .
t . m
A review of the use and findings of high field strength
: / : / /t/.t .m
graphic findings in hips with a positive Ortolani sign
/
and their relationship to Pavlik harness failure. J Bone
ss :
(3 T) MRI in evaluation of the ligaments, tendons, and
ss :
hhtttp hhtttp
Joint Surg Am 2010;92(1):113-120.
15.
tp
articular cartilage of the wrist is presented.
Haims AH, Schweitzer ME, Morrison WB, et al: Inter-

tp
26. Clohisy JC, Carlisle JC, Beaulé PE, et al: A system-
atic approach to the plain radiographic evaluation of
nal derangement of the wrist: Indirect MR arthrography the young adult hip. J Bone Joint Surg Am 2008;
versus unenhanced MR imaging. Radiology 2003; 90(suppl 4):47-66.
227(3):701-707.
k eers
rs k e r
e s
r s 27. Clohisy JC, Dobson MA, Robison JF, et al: Radio-
bboooo k
16.
o o
Mino DE, Palmer AK, Levinsohn EM: Radiography and
o o k
computerized tomography in the diagnosis of incongru-
b b o oo
graphic structural abnormalities associated with prema-
o
ture, natural hip-joint failure. J Bone Joint Surg Am
/
e e
/ e ee/
J Bone Joint Surg Am 1985;67(2):247-252.e
/ b
ity of the distal radio-ulnar joint: A prospective study.
e ee/ e
/ e
2011;93(suppl 2):3-9.
b
: / / t
/ .
t m
. m : / / t
/ t m
Six hundred four patients were retrospectively analyzed
. . m
for causes of premature hip failure. Developmental hip
17.
t p : /
Moser T, Dosch JC, Moussaoui A, Dietemann JL: Wrist
ss
ligament tears: Evaluation of MRI and combined
p t p ss
p : /
dysplasia and FAI were associated with the majority of
osteoarthritic hips, with significant bilaterality associ-
t
hht t
MDCT and MR arthrography. AJR Am J Roentgenol
2007;188(5):1278-1286. t
hht t ated with FAI.
28. Leunig M, Beck M, Kalhor M, Kim YJ, Werlen S,

18. Taouli B, Zaim S, Peterfy CG, et al: Rheumatoid Ganz R: Fibrocystic changes at anterosuperior femoral
arthritis of the hand and wrist: Comparison of three im- neck: Prevalence in hips with femoroacetabular im-
k eers
rsaging techniques. AJR Am J Roentgenol 2004;182(4):
937-943.
k eers
r s pingement. Radiology 2005;236(1):237-246.
b ooook b oook
o
29.
b oooo
Keogh CF, Munk PL, Gee R, Chan LP, Marchinkow
LO: Imaging of the painful hip arthroplasty. AJR Am J
/
e e
/ eb 19.
e / e
/e b
Anderson SE, Steinbach LS, De Monaco D, Bonel HM,
Hurtienne Y, Voegelin E: “Baby wrist”: MRI of an over-
e ee/e/e b
Roentgenol 2003;180(1):115-120.
182(3):719-724.
: / t
///t m
use syndrome in mothers. AJR Am J Roentgenol 2004;
. . m 30.
: / t.
///t m
.m
Potter HG, Nestor BJ, Sofka CM, Ho ST, Peters LE,
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Salvati EA: Magnetic resonance imaging after total hip 38. Kim S, Huh YM, Song HT, et al: Chronic tibiofibular
k eers
rs rrss
arthroplasty: Evaluation of periprosthetic soft tissue.
kee
syndesmosis injury of ankle: Evaluation with contrast-
enhanced fat-suppressed 3D fast spoiled gradient-
ook ook
b oo b o o b o oo
recalled acquisition in the steady state MR imaging.
o
/
ee/e b 31.
/ e e
Kim EY, Kwack KS, Cho JH, Lee DH, Yoon SH:
ee / b
Usefulness of dynamic contrast-enhanced MRI in differ-
ee e
/ e b
Radiology 2007;242(1):225-235.
/
: / t . m
.m
entiating between septic arthritis and transient synovitis
///t
in the hip joint. AJR Am J Roentgenol 2012;198(2):
39.
: / ///t. m
. m
Donovan A, Rosenberg ZS: MRI of ankle and lateral
t
hindfoot impingement syndromes. AJR Am J Roentge-
s
tps : s
tps : nol 2010;195(3):595-604.
hhtttp hhtttp
428-433.
Eighteen patients were evaluated using dynamic Impingement syndromes of the ankle are reviewed,
showing the differing patterns of MRI abnormalities
contrast-enhanced MRI with a significant difference in
found in anterolateral, anteromedial, posterolateral,
time enhancement curves between patients with septic
posterior, and extra-articular impingment syndromes.
arthritis and transient synovitis of the hip. The optimal
time for acquisition of contrast-enhanced coronal MRI
k eers
rs guish between the two entities.
k eers
r s
to be acquired was 3.5 minutes after injection to distin- 40. Rubin DA, Tishkoff NW, Britton CA, Conti SF, Towers
JD: Anterolateral soft-tissue impingement in the ankle:
ook ook
Diagnosis using MR imaging. AJR Am J Roentgenol
b oo b oo b o oo
1997;169(3):829-835.
o
/
e e
/ eb 32.
e/ e
/ e b
Markhardt BK, Gross JM, Monu JU: Schatzker classifi-
cation of tibial plateau fractures: Use of CT and MR im-
e 41.
ee/ e
/ e b
Cochet H, Pelé E, Amoretti N, Brunot S, Lafenêtre O,
585-597.
: // t/ tm
aging improves assessment. Radiographics 2009;29(2):
. . m : / / t
/ .
t m
. m
Hauger O: Anterolateral ankle impingement: Diagnostic
ss : / ss : /
performance of MDCT arthrography and sonography.
hhtttp hhtttp
AJR Am J Roentgenol 2010;194(6):1575-1580.
33.
tp
Kurkijärvi JE, Nissi MJ, Kiviranta I, Jurvelin JS, Niem-
inen MT: Delayed gadolinium-enhanced MRI of carti-
lage (dGEMRIC) and T2 characteristics of human knee
tp Sonography and MD CT arthrography are compared in
the evaluation of anterolateral impingement. Sonogra-
phy without joint injection had a sensitivity and speci-
articular cartilage: Topographical variation and rela- ficity of 77% and 57% respectively, whereas CT ar-
tionships to mechanical properties. Magn Reson Med thrography had a sensitivity of 97% and specificity of
2004;52(1):41-46. 71% using arthroscopic findings as the reference stan-
keerrss k e rrss
e
dard.
bboooo k 34.
AJR Am J Roentgenol 2006;187(2):371-375.
b o o
Magee T, Williams D: 3.0-T MRI of meniscal tears.
o o k 42.
o oo
o
Kijowski R, De Smet A, Mukharjee R: Magnetic reso-
b
/
e e
/ e 35.
ee/ e
/ e b
Verma S, Hamilton K, Hawkins HH, et al: Clinical ap-
e e
/ e b
nance imaging findings in patients with peroneal tendi-
/
nopathy and peroneal tenosynovitis. Skeletal Radiol
e
t . m
. m
plication of the Ottawa ankle rules for the use of radi-
: / / / t : / /t/.tm.m
2007;36(2):105-114.
: /
ography in acute ankle injuries: An independent site as-
ss ss : /
hhtttp hhtttp
43. Ahmadi ME, Morrison WB, Carrino JA, Schweitzer
tp tp
sessment. AJR Am J Roentgenol 1997;169(3):825-827.
ME, Raikin SM, Ledermann HP: Neuropathic arthrop-
athy of the foot with and without superimposed osteo-
36. Clark TW, Janzen DL, Ho K, Grunfeld A, Connell DG:
myelitis: MR imaging characteristics. Radiology 2006;
Detection of radiographically occult ankle fractures fol-
238(2):622-631.
lowing acute trauma: Positive predictive value of an an-
kle effusion. AJR Am J Roentgenol 1995;164(5):1185-
k eers
rs 1189.
k e r
e s
r s
44. Espinosa N, Schmitt JW, Saupe N, et al: Morton
neuroma: MR imaging after resection—postoperative
bboooo k 37.
o
Griffith JF, Lau DT, Yeung DK, Wong MW: High-
b o
o o k MR and histologic findings in asymptomatic and symp-
b o oo
tomatic intermetatarsal spaces. Radiology 2010;255(3):
o
/
e e
/ e e e
/ e b
resolution MR imaging of talar osteochondral lesions
/
with new classification. Skeletal Radiol 2012;41(4):
e
850-856.
ee/ e
/ e b
Fibrous tissue is commonly found in postoperative inter-
387-399.
: / / t
/ .
t m
. m t . m
. m
metatarsal spaces after Morton neuroma resection and
: / / / t
t p ss : /
The authors present a retrospective review of 70 osteo-
chondral defects of the talar dome and provide a new
p t p ss
p : /
mimics the appearance of the original tumor on MRI in
both asymptomatic and symptomatic patients.
t
hht t
classification system based on high-quality images.
t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
90
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 8
e rs
rs e rrss
oo
kPatient-Centered
ook e Care:
o k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Communication t
///t. m
.mee Skills and t
///t. m
. mee
s:
s /
: s : /
:
Cultural tpCompetence
hhtttp
Hassan R. Mir, MD Raj D. Rao, MD
tps
hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Introduction
e/
e e
/ e b e / e
/ e b
centered care: “whole person” care, comprehensive
e
: // t/.tm
. m
Physicians are often attracted to the field of orthopae-
: / / t
/ t m
communication and coordination, patient support and
. . m
empowerment, and ready access.1 Holistic care and ac-
ss : / s : /
cess to care can be affected by changes in practice and
s
hhtttp hhtttp
dics because of their interest in anatomy, biomechanics,
tp
and the scientific method. However, as most experi-
enced practitioners will attest, mastery of these subjects
alone is insufficient to achieve successful outcomes. The
tp
through health policy. The issues of patient support and
empowerment and comprehensive communication re-
late directly to the interactions between physicians and
interpersonal and emotional aspects of patient care their patients and highlight the importance of physician
greatly affect every component of medical care delivery, education on a patient-centered approach to the
rrss rrss
and orthopaedic surgeons must possess effective com- physician-patient relationship.
o kee
munication skills that allow them to develop good
k o k e
k e
Health literacy, which includes patients’ understand-
oo
ing of their medical conditions and postsurgical treat-
e bboo o b o
b o o
physician-patient relationships and actively involve pa-
tients in all aspects of their care. The US Census Bureau
e e b o o
ment plans, has been linked to many aspects of individ-
b
/
e / e m e / / e
anticipates a continued increase in population diversity:
e ee/ / e
ual health and medical care, including patient
satisfaction and outcomes.2 Orthopaedic surgeons
m
/ / t
/ .
the minority population is predicted to increase from
t . m
34% in 2008 to 55% in 2050. Therefore, the ability to
: / /t . .m
should be aware that the terminology used and the
: / / / t
ss :
interact and communicate with patients must transcend
s :
manner in which the information is communicated to
s
hhtttp
tp hhtttp
tp
their patients can significantly affect patient under-
various backgrounds and any expectations that patients
standing and emotional response to healthcare deliv-
may have. ery.3,4 Publications and audiovisual materials can be
used to improve health literacy, but the content should
ensure that the information is clearly conveyed and can
Patient-Centered Care be customized to the individual patient’s level of com-
k eers
rs
Patient-centered care refers broadly to the process of
k e r
e s
r sprehension.5 Because patients respect their physicians’
knowledge and counsel, physicians should educate their
bboooo k b o o
o o
about individual treatment options. More specifically,k
involving patients and their families in decision making
b o oo
patients about diagnoses, treatments, and the risks and
o
/
e e
/ e ee/ e
/ e b
the term refers to the central role of the patient in the
e e
benefits of various options.
/ / e b
Effective communication can affect the patient’s
e
/ / t
/ t m
design of changing healthcare delivery models. Studies
. . m
of what patients and their families desire in a health-
: : / / t
/ .
t m
. m
health, functional, and emotional status. Improved pa-
ss : /
care system have identified four key features of patient-
t p p t p ss : /
tient interactions can help the physician elicit important
information that can improve diagnostic accuracy and
p
t
hht t
Dr. Mir or an immediate family member serves as a
t
hht t
enhance patient compliance by increasing the level of
trust.6,7 The physician should allow the patient to pres-
ent his or her concerns by means of open-ended ques-
board member, owner, officer, or committee member of tions and minimal interruptions. This approach may
the American Academy of Orthopaedic Surgeons Diver- help the physician gain insight into the patient’s prob-
k eerss
sity Advisory Board and the Orthopaedic Trauma Associ-
r k ee
ation Public Relations Committee. Dr. Rao or an immedi-rs
r s lems and obtain all necessary information to help nar-
row the list of differential diagnoses through subse-
b ooook b ook
ate family member serves as a board member, owner,
oo b oooo
quent directed questioning. Patients are also more
likely to trust their physician when given the opportu-
/
e e
/ eb e / e
/e b
officer, or committee member of the Lumbar Spine Re-
search Society, the Medicare Coverage and Advisory
e ee/e/e b
nity to present all of their concerns and have their ques-
/ t
///t
US Food and Drug Administration.
: m
Committee, the North American Spine Society, and the
. . m : / t.
///t m
tions answered. Additionally, many patients now use
.m
complementary and alternative medicines that can
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
affect their care, and this may be unreported without a Communication Models
k eers
rs thorough interview.8
keerrss Multiple educational models have been developed to
b ooook b o ook
From a medical-legal perspective, patient-centered
o
communication can improve the informed consent pro-
b oo
help physicians communicate and provide counsel in a
o o
more patient-centered way. The 5As model of behav-
/
ee/e b / e e b
cess and help reduce medical errors and malpractice lit-
ee /
igation risk.9,10 Many medical liability suits can be traced / e e b
ioral change is an evidence-based approach that can be
ee /
applied to a broad range of behaviors and health con-
t . m
.m
to breakdowns in communication, which can lead to a
: / ///t t
///t. m
. m
ditions.14,15 The 5As comprise the following: (1) asking
: /
tps :
difference of expectations between physicians and their
s s :
the patient about the behavior; (2) advising the patient
tps
hhtttp hhtttp
patients. Many lawsuits can be avoided by establishing about personal health risks; (3) assessing patient level
initial patient-centered communication with good bidi- of behavior, beliefs, and motivation; (4) assisting with
rectional flow of information and expectations, followed the anticipation of barriers and the development of a
by open, honest dialogue when complications occur. specific action plan; and (5) arranging follow-up sup-
A movement toward shared decision making in med- port. Assistance in problem solving and arranging
icine is occurring, with patients and their families expe-
k eers
rs riencing more active involvement in the process and
k eers
r s
follow-up have been shown to be the most important
factors that lead to lasting change, but these are also
ook ook
physician guidance.11 This change requires effective
b oo b o
patient-centered communication. Orthopaedic surgeons
o b o oo
delivered least often and may be the most challenging
o
for orthopaedic surgeons. The 5As model has been fre-
/
e e
/ eb ee e
/ e b
who have been educated in interview skills and infor-
/
mation delivery can ensure a beneficial two-way inter-
ee/ e
/ e b
quently applied to health conditions such as smoking
t
action with all of their patients.
: // /.tm
. m : / / t
/ t m
cessation and obesity, issues that often affect outcomes
. . m
in orthopaedic surgery. Similarly, the model can be ap-
ss : / s : /
plied to other health conditions that require behavioral
s
hhtttp
tp hhtttp
tp
change, including musculoskeletal conditions that are
Communication Skills in Orthopaedics managed nonsurgically, such as back pain and osteoar-
Physicians may conduct more than 100,000 patient in- thritis. Postoperative results for several procedures also
terviews during their careers, and the literature increas- depend on patient adherence to rehabilitation protocols
ingly supports the positive influence of effective com- and activity restrictions.
rrss rrss
munication on various aspects of health care. The 4Es educational model (Figure 1) has also been
o ke
ke Therefore, many organizations have educated medical
o k e
k e used to increase patient-centered communication and
oo
improve healthcare delivery.16 This model divides clini-
e bboo o e b o
b o
students, residents, and practicing physicians on com-
o
munication skills over the past 2 decades.12 Although
e b o o
cal care into communication tasks and biomedical
b
/
e / e m e / / e
medical science continues to improve, advances in tech-
e / / e
tasks, which are weighted equally. The communication
m ee
tasks—engagement, empathy, education, and enlist-
: / / t
/ .
t . m
nology are unlikely to obviate the need for and the
value of compassion and empathy in the physician-
/ : / /
/t/.t .m
ment—improve physician-patient interaction. The bio-
ss : s :
medical tasks, or the 2Fs (find it, fix it), involve making
s
hhtttp hhtttp
patient relationship. Orthopaedic surgeons and other
tp
specialists face significant daily time constraints, but
education in effective verbal and nonverbal communi-
cation skills can make the time spent with their patients
tp
a diagnosis and then treating the problem. The 4Es
model has been used more frequently than the 5As
model in the education of orthopaedic surgeons about
more effective and can improve patient relationships. patient-centered communication because it closely par-
allels how surgical issues are addressed.
k eers
rs Improving Communication
A successful patient encounter requires that the pa-
k e r
e s
r s
Engagement uses both verbal and nonverbal com-
munication skills to establish the physician-patient rela-
bboooo k b o o o k
tient’s key concerns have been solicited and directly ad-
o b o oo
tionship. Verbal interview techniques include speaking
o
calmly, asking open-ended questions, and avoiding in-
/
e e
/ e e / / e b
dressed.11 Patient concerns can vary widely and be in-
e
fluenced by their values, culture, sex, and other
e ee/ e
/ e b
terruptions.11 Nonverbal communication skills include
: / / / .
t m m
variables.13 To facilitate open communication, the phy-
t .
sician should be careful to avoid a judgmental attitude
/ / t .
t m
maintaining eye contact, smiling, and sitting instead of
. m
standing to avoid appearing rushed. Empathy uses both
: /
ss : /
and offer his or her counsel with patient feedback to
t p p t p ss
p : /
verbal and nonverbal cues to assure the patient that his
t
hht t
ensure patient involvement and understanding.
The American Academy of Orthopaedic Surgeons
(AAOS) has made substantial efforts to improve the
t
hht t
or her thoughts and feelings are understood by the sur-
geon in a compassionate manner and can help establish
a relationship of trust that facilitates increased sharing
historical patient perspective of orthopaedic surgeons of important information. Patient education should
as technically proficient but lacking empathy and com- provide information about diagnoses and treatments in
k eers
rs
munication skills. Patient surveys showed improvement
between 1998 and 2008 (Table 1). The AAOS has part-
k eers
r s
an interactive manner (using both dialogue and audio-
visual aids) and ensure that the message is understood
b ooook b ook
nered with the Institute for Healthcare Communication
oo
since 2003 to develop a mentoring program as well as a
b oooo
by the patient and that all alternatives have been re-
viewed.2,5 Enlistment allows the patient to understand
/
e e
/ eb / e
/e b
series of workshops that are available to enhance the
ee ee/e/e b
his or her active role in both the decision-making pro-
out the United States.

: / t
///t m
communication skills of orthopaedic surgeons through-
. . m / t.
///t m
cess and in the ultimate treatment outcome. Patient
.m
compliance significantly affects all treatment plans.
:
s
tps : s
tps :
92
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 8: Patient-Centered Care: Communication Skills and Cultural Competence
k eers
Table 1
rs keerrss
b ooook b ook
Results From AAOS Survey on Patient Expectations and Perceptions on Communication
o o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
1998 Results 2008 Results
Is highly trained
: / t
///t. m
Expectations That Remained the Same or Decreased
.m : / t
///t. m
. m 87% 82%
s
tps : s
tps :
hhtttp hhtttp
Listens to patients 85% 83%
Has successful medical results 84% 84%
Is caring and compassionate 77% 74%
Spends time answering questions 74% 74%
Delivers value/cost 70% 73%
k eers
rs
Easy to get appointment
k eers
r s 65% 65%
b ooook Is research oriented
b ooook 39%
b o oo
o
36%
/
e e
/ eb Is prestigious
Accepts insurance (added in 2008)
e/
e e
/ e b ee/ e
33%
/
NAe b 31%
85%
Expectations That Improved
: // t/.tm
. m : / / t
/ .
t m
. m
Is highly trained
ss : / ss : / 66% 75%
hhtttp
tp
Spends time answering questions
Has successful medical results
Is caring and compassionate
hhtttp
tp 35%
55%
35%
51%
64%
55%
Delivers value/cost 36% 50%
keerrss
Easy to get appointment
Is research oriented
k e rrss
e
28%
52%
33%
64%
bboooo k Is prestigious
b o o
o o k 61%
b o oo
o 72%
/
e e
/ e Knowledge and experience
ee/ e
/ e b ee/ e
/
60%
e b 71%
Overall performance
: / / t
/ .
t m
. m : / /t/.tm.m
57% 67%
ss / ss : /
NA = not applicable. Arrows indicate the direction of significant differences. Percentage results are based on a scale of 1 to 5, from poor to excellent.
:
hhtttp hhtttp
(Adapted from Tongue JR, Jenkins L, Wade A: Low-touch surgeons in a high-touch world. AAOS Now 2009;63[85]).
Incorporating Technology
tp tp
Technologic advances are rapidly changing the way
people interact with each other in modern society, with
k eerss
increasing rates of individual and mass communication
r
occurring via e-mail, the Internet, and social media.17
k e r
e s
r s
bboooo k
Additionally, face-to-face interactions can be inter-
b o o
o o k b o oo
o
/
e e
/ e e e
rupted frequently by using personal digital items such
/ /
as mobile phones and tablets, which distract from ver-
e e b ee/ e
/ e b
: / / / .
t m m
bal and nonverbal communication. The incorporation
t . : / / t
/ .
t m
. m
t p ss : /
of new communication technology into medicine can
be beneficial if done properly and without interfering
p t p ss
p : /
t
hht t
with the physician-patient relationship.
Patients use the Internet to gather information about
their medical conditions and healthcare providers.18
t
hht t Figure 1 Illustration of the 4Es of complete clinical care, a
model for physician patient communication.
(Reproduced with permission from Tongue JR,
The vast amount of medical knowledge increases expo- Epps HR, Forese LL: Communication skills for
patient-centered care: Research-based, easily
nentially and makes this task difficult; even physicians learned techniques for medical interviews that
k ee s
struggle to sort through all the available information.19
rrs
In response, many physicians have established an on-
k eers
r s benefit orthopaedic surgeons and their patients.
J Bone Joint Surg Am 2005;87:652-658.)
b ooook
line presence using websites and social media to edu-
b
cate patients about their practices and provide informa-oook
o b oooo
/
e e
/ eb ee/ e
/
tion about diagnoses. It is the responsibility of the
e b ee/e/e b
Electronic communication is increasing between
viewed forum is honest and accurate.

: / t
///t. m
physician to ensure that material posted in a publicly
. m : / t.
///t m
.m
physicians and patients. Although electronic forms of
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
communication such as phone calls, e-mail, texting, in-
k eers
rs stant messaging, and videoconferencing, allow the
keerrss Cultural Competence
b ooook b o ook
rapid exchange of healthcare information, caution must
o
be exercised. Physicians must be aware that nonverbal
b oo
The Office of Minority Health in the US Department of
o o
Health and Human Services defines cultural and lin-
/
ee/e b / e e b
communication plays a large role in the exchange of
ee /
medical information with audiovisual cues. This is es-
ee/ e
/ e b
guistic competence as a set of congruent behaviors, at-
: / t . m
.m
pecially important for the physical examination. Not
///t / t
///t. m
titudes, and policies that combine in a system, an
. m
agency, or among professionals that enables effective
:
tps :
all media allow every aspect of this exchange to occur.20
s s :
work in cross-cultural situations. Culture refers to inte-
tps
hhtttp hhtttp
This lack of full personal context can lead to incom- grated patterns of human behavior that include the lan-
plete information and incorrect conclusions and deci-
guage, thoughts, communications, actions, customs, be-
sions. Healthcare information exchanged via newer
liefs, values, and institutions of racial, ethnic, religious,
forms of communication may also have medical-legal
or social groups. Competence implies the capacity to
ramifications that are still being explored.
As electronic health records become more common, function effectively as an individual and as an organiza-
k eers
rs r
the use of computers and tablets in the patient exami-
k ee s
r s tion within the context of the cultural beliefs, behav-
iors, and needs presented by patients and their commu-
ook ook
nation room has increased.21 Patients are using their
b oo b o
mobile phones more frequently throughout the visit to
o b o oo
nities. The Office of Minority Health highlights social
o
/
e e
/ eb ee e
/ e b
record notes, photos, or video. Although these items
/
may have advantages, the technology cannot be al-
e / e
/ e b
groups that influence a person’s culture and self-
identity, including race, ethnicity, religion, sex, sexual
e
t . m
. m
lowed to interrupt or supersede verbal and nonverbal
: // / t : / / t
/ .
t m
. m
orientation, age, disability, and socioeconomic status.
ss /
communication, which are still central to the develop-
: ss : /
Extensive research in cognitive psychology has iden-
hhtttp hhtttp
ment of trust in the patient-physician relationship. tified the presence of bias in all individuals, as demon-
tp tp
strated by results of tests such as the Implicit Associa-
tion Test (https://implicit.harvard.edu). Studies of
Adverse Events physician attitudes reveal that very few practitioners
have explicit (conscious) bias, but all physicians are
Complications and adverse events are a reality in pa- prone to implicit (unconscious) bias. Bias affects how
keerrss tient care. Shared decision making and a comprehen-
k e
sive and objective informed consent process prepare pa- rrss
e
patients interpret and accept their physicians’ recom-
mendations for care. Bias also affects the recommenda-
bboooo k o o o k
tients for the possibility of an unplanned adverse event.
b o b o oo
tions that physicians make.25 Physicians must recognize
o
/
e e
/ e e e
/ e b
This process helps patients and their families accept the
/
complication and prepares them for the steps necessary
e ee e
/ e b
that the patient’s experiences influence their attitudes.
/
A patient’s perceptions of racism and classism experi-
: / / / .
t m m
to address the problem. Failure to obtain appropriate
t .
informed consent is frequently cited in malpractice law- t . m.m
enced in other healthcare settings may negatively influ-
: / / / t
ss : / : /
ence the affective tone of current patient-provider com-
ss
hhtttp hhtttp
suits. Even with suitable information and preparation,
tp tp
munication.26 The authors of a 2011 study showed that
the development of a complication creates a significant unconscious stereotyping and bias by healthcare pro-
amount of stress for patients, families, and physicians. viders can contribute to racial and ethnic disparities in
When a patient experiences an unplanned outcome, health care.27 An example of such bias is the common
the physician often experiences myriad emotions (sad- misperception that patients at a socioeconomic disad-
ness, guilt, and/or defensiveness) irrespective of the in-
vantage tend to sue their doctors more frequently than
k eers
rs volvement of a technical error. Similarly, the physician
must remember that although patients and their fami-
k e r
e s
r s economically advantaged patients. The authors of a re-
bboooo k b o o
o o
lies are likely to regard the complication as an error
k cent study showed the opposite to be true: poor pa-
b o oo
o
tients sue their physicians less often.28
/
e e
/ e e / / e b
and often quickly think to assign blame, they are also
e
experiencing mixed emotions of fear, confusion, and
e ee/ e
/ e b
The development of culturally competent care in a
healthcare organization can enhance medical care deliv-
/ / t
/ .
t m
anger. These situations require a heightened sense of
. m
awareness and good communication skills.
: : / / t
/ .
t m
. m
ery and outcomes in many ways through more effective
ss : /
Physicians should communicate with their team
t p p t p ss
p : /
patient-centered communication.29 Cultural compe-
t
hht t
members to gather information, contact the patient and
family, and avoid any defensive attitude.22 It is impor-
tant to discuss all aspects of the complication, including
t
tency can help physicians deal more effectively with
hht t
cultural conflicts that may occur between a patient and
the clinical team and interfere with a patient-centered
details, possible causes, and proposed treatment. An approach.30 To deliver culturally competent care, clini-
apology should be offered without accepting blame. cians must establish egalitarian goals for all of their pa-
k eers
rs
The situation may be compounded by the physician’s
e rs
r s
fear of potential litigation, but patients who receive full
k e
tients, identify commonalities with their patients to
counter stereotypical misinformation, and understand
b ooook b ook
disclosure are more likely to maintain trust and less
oo
likely to litigate.23,24 A sound strategy of information
b oooo
the perspectives of patients whose backgrounds may
differ from their own. Cultural competency interven-
/
e e
/ eb / e
/e b
gathering, direct interaction, showing empathy, ex-
ee ee/e/e b
tions, including the training of physicians and other
/ t
///t m
plaining options, and maintaining support can help
. . m
with communication in these difficult situations.
: / t.
///t m
healthcare professionals, have been proposed as a key
.m
strategy to help reduce healthcare disparities.31
:
s
tps : s
tps :
94
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Culturally Diverse Patient Populations Generational differences exist regarding cultural ed-
k eers
rs ke r
Cultural competence requires physicians to learn about
e rss ucation efforts, which may partly be the result of the
b ooook b ook
the diverse populations they serve, which increases pa-
o o
tient comfort and enhances communication. Medical
increased exposure of younger populations to diversity
b o oo
o
in schools and through mass media. Some people con-
/
ee/e b / e e b
anthropologists have criticized cultural competence ef-
ee /
forts that divide cultures into static categories with a
ee/ e
/ e b
sider generalizations such as those used in diversity ed-
ucation programs offensive.40 Additionally, as diversity
: / t
///t. m
.m
“list of traits.”32 The anthropologists argued that
: / t
///t. m
. m
increases in the audience for educational programs, em-
phasis should be placed on principles of cultural com-
s :
healthcare providers should be trained to be “open-
tps s
tps :
hhtttp hhtttp
minded” and willing to learn about different cultures petence rather than group generalizations because the
while remembering a patient’s individuality. Although target audience must not be assumed to be from a par-
this more fluid and individual approach to cultural di- ticular background. The AAOS has resources to help
versity can be beneficial to the physician-patient rela- educate physicians on principles and guidelines of cul-
tionship, it must be balanced with a framework that turally competent care when interacting with specific
helps guide physician-patient interactions and reduces patient populations.33 Also, the amount of literature on
k rs
rs
the prevalence of healthcare disparities.
ee k eers
r s interaction with groups from diverse backgrounds is in-
creasing as the population of these groups in US society
b ooook ooook
Physicians should educate themselves to effectively
communicate and treat patients with respect to race,
b
increases.41
b o oo
o
/
e e
/ eb e/
e e
/ e b
ethnicity, religion, sex, sexual orientation, age, disabil-
ity, and socioeconomic status. Both verbal and nonver-
ee/ e
/ e b
t . m
. m
bal communication can vary among culturally diverse
: // / t : / / t
/ .
t m
. m
Healthcare Disparities
ss : /
groups, and constant education and practice can help
ss : /
Disparities in healthcare delivery and differences in di-
hhtttp
tp hhtttp
tp
physicians improve their skills. Some language barriers
agnosis, treatment, and outcomes based on racial and
can be overcome through empathy and culturally ap-
ethnic backgrounds of patient populations are well es-
propriate nonverbal cues, but patients with limited En-
tablished for many common clinical conditions. Given
glish proficiency must be given proper access to trans-
the increasing evidence for inequality, the US Congress
lation services.
mandated in 2003 that the Agency for Healthcare Re-
rrss rrss
search and Quality report on progress and opportuni-
Improving Cultural Competence
o ke
ke o k e
k
Cultural competence can be taught using a fact-centered
e
ties to reduce healthcare disparities. The agency pro-
oo
duces two annual reports: the National Healthcare
e bboo o e b o
b
the recognition of variation within the group, warnso
approach based on group characteristics that emphasizes
o e b o o
Quality Report that focuses on quality, and the Na-
b
/
e / e ee/ / e
against ethnic stereotyping, and acknowledges that these
m ee/ / e
tional Healthcare Disparities Report that focuses on
prevailing disparities in healthcare delivery relevant to
m
: / / t
/ .
t . m
group characteristics serve only as a first step to learning
/
culturally competent care. This process should then /t . .m
racial and socioeconomic factors in patient popula-
: / / / t
ss : s :
tions. According to the 2011 National Healthcare Dis-
s
hhtttp hhtttp
evolve toward a more attitude- and skill-centered ap-
tp tp
parities Report, racial and ethnic minorities and low-
proach based on principles of cultural competence. It is income individuals not only experience more barriers
important to understand the differences between stereo- to care but also receive poorer quality of care when it is
types and generalizations when learning about different available (http://www.ahrq.gov). Although US health-
patient groups. Stereotypes are end points resulting from care quality and access are reported as suboptimal, es-
conventional and oversimplified conceptions and opin- pecially for minority and low-income groups, the over-
k eerss
ions that can be treacherous because they do not account
r k e
for individual differences. Generalizations use culturalr
e s
r s all progress in quality enhancement is unevenly
matched by improvements in access for minorities and
bboooo k o o o k
patterns as a starting point to help focus thought, with
b o b o oo
reductions in the disparity of quality (Figures 2 through
o
/
e e
/ e e / / e b
the realization that individuality must be acknowledged.
e
A guiding principle in cultural competency education is
e e / e
/ e b
4). Recognition of these problems has increased, and
numerous efforts to address them have been under-
e
: / /
ferently to treat them equally.33
/ .
t m m
that it may be necessary to communicate with people dif-
t . : / / t
/ .
t m
. m
taken but much work remains. Physicians can play a
ss : /
Considerable variation exists in cultural competence
t p p t p ss : /
key role in addressing disparities by practicing cultur-
ally competent care and by advocating on behalf of
p
t
hht t
education, with limited specific guidelines or validated
evaluation methods. Currently, education programs
may promote changes in providers’ knowledge and at-
t
hht t
their patients. A 2011 study showed that health infor-
mation technology has the potential to improve quality
of care and patient safety, and if carefully designed and
titudes, but little empirical evidence exists that such ef- implemented, this may also help eliminate healthcare
forts reduce indicators of disparate care.34 With in- disparities.42
k eers
creasing incorporation of cultural competence
rs k e r
education into all levels of medical and surgical educa-
e s
r s In orthopaedic surgery, the complex reasons under-
lying healthcare disparities have been increasingly stud-
b ooook b oook
tion, it is necessary to evaluate teaching methods and
o
establish recommendations to improve outcomes.35-38 In
b ooo
ied as barriers to optimal outcomes.43-45 These studies
o
have shown how patient-related factors contribute to
/
e e
/ eb ee/ e
/e b
2005, a successful educational model was developed
/e/e b
the multifaceted nature of disparities in musculoskeletal
ee
/ t
///t m
that links cultural competence with patient-centered
. . m
communication and medical education39 (Table 2).
: / t.
///t m
care. Learning more about patient-centered care
.m
through the development of communication skills and
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 2
keerrss
b ooook b ook
RESPECT Model for Patient Communication and Medical Education
o o b o oo
o
/
ee/e b Skill Definition
ee/ e
/ e b
Behavioral Description
ee/ e
Examples
/ e b Relevant Evidence
Respect:
show
A demonstrable
attitude
: / t
///t. m
.m
Nonverbal: Maintain attentive
/ t
///t
posture, appropriate eye and
: . m
“Hi, I’m Dr. X, and I’m
. m
looking forward to
Disparity: African
American, Hispanic,
s :
communicating the
tps s :
personal contact; follow cues
tps
working with you.” and Asian patients
hhtttp hhtttp
value and the regarding personal space, “What would you like reported feeling less
autonomy of the physical contact, and me to call you?” respected by their
patient and the appropriate greetings. “You overcame a lot to doctors than did
validity of his or her Verbal: Welcome patient to get here today!” white patients.
concerns. encounter, introduce self and
explain role on team, ask the
k eers
rs k eers
patient how he or she wants to
r s
be addressed, and recognize
b ooook b oook
and affirm strengths and
o
efforts.
b o oo
o
/
e e
/ eb Explanatory A patient’s
e/
e e
/ e b
Nonverbal: Give patient space to
ee/ e
/ e b
“What do you or your Patients and doctors
model: ask understanding of
: //
what causes his or
t/.tm
. m
share his or her ideas by
listening without judgment.
: / / t
/ .
t m
. m
family think is
causing your
often have different
ideas that remain
s : /
her illness or what
s s : /
Verbal: Ask patient what he or
s
symptoms?” unexplored unless
hhtttp
tp hhtttp
tp
will help it. she thinks is causing or will “Why do you think this elicited. Without
alleviate symptoms. started when it did?” discussion, patients
“What do you think leave less satisfied.
will solve the
problem?”
Social Effect of patient’s life Nonverbal: Show interest and “What should I know Low social support
keerrss context:
ask
on illness and of
illness on his or her rrss
pay attention.
e e
Verbal: Ask how patient’s illness
k
about you to care for
you best?”
predicts higher
mortality post-MI.
bboooo k life. Include stressors,

supports, strengths,
b o o
o k
affects his or her life and how
o
his or her life affects illness. you?”
b o oo
“What is hardest for
o
Negative health
consequences follow
/
e e
/ e and spiritual
resources that
ee/ e
/ e b / e e b
“Who helps you the
ee
most?”
/
death of spouse
alleviated by
: / / t
influence patient,
/ .
t m
. m : / /t/.tm.m
“What keeps you presence of
ss : /
health, or care.
ss : / going?” confiding figure.
hhtttp hhtttp
“What about religion?”
tp
Power: share Access to status,
control, resources,
options, and ability
tp
Nonverbal: Reduce physical
barriers; do not dominate the
interaction; sit.
“Beside your diabetes, Disparity: White
what else should we
talk about?”
physicians dominate
conversation more
to produce desired Verbal: Listen; limit interruptions; “What would make than nonwhite
outcomes build history rather than take your medications patients.
k eers
rs
Power gradient favors
doctors
e r s
it; use EMR to share
r s
information with patient via
k e
easier?”
“Thanks for telling me
Self-efficacy needed to
make healthy
bboooo k b o o o k
graphs, etc; invite open
discussion of disagreement;
o
that you don’t agree.
b o oo
What do you think?”
o
choices.
/
e e
/ e ee/ e
/ e b
negotiate agenda/treatment
plan by eliciting preferences;
ee/ e
/ e b
: / / t
/ .
t m
. m
empower patient, recognize
strengths.
: / / t
/ .
t m
. m
Empathy:
p ss : /
Verbal and nonverbal
t p p ss : /
Nonverbal: Listen attentively and “That must be hard;
t p
Disparity: Doctors
show
t
hht t
responses that
validate patients’
emotions and cause
t
hht
respond accordingly.
Verbal: Name and validatet
patients’ emotions; place
anyone would feel
that way.”
“This can be scary. Let’s
display less warmth
with African
American patients.
them to feel significance of patient’s talk about it.”
understood. experience into words to “The injury changed
convey specific understanding. everything for you.”
k eers
rs Concerns Worries about
k e rs
r s
Nonverbal: Head nods, etc, to
e
“What worries you the Unvoiced concerns
b ooook and/or
fears: ask
symptoms, diagnosis,
or treatment are ook
encourage patient to give
oo
details.
b
most?”
oooo
“What scares you about
b
lead to unmet needs
and patient
/
e e
/ eb often unexpressed.
ee e
/e b
Verbal: Ask open-ended
/ questions about fears or
e e/e b
the medication?”
/
“Are you worried about
e
dissatisfaction.
: / t
///t. m
. m concerns.
: / t.
///t m
.m sex after your heart
attack?”
s
tps : s
tps :
hhtttp hhtttp
(continued on next page)
96 Orthopaedic Knowledge Update 11 © 2014 American Academy of Orthopaedic Surgeons

e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 2
rs keerrss
b ooook b ook
RESPECT Model for Patient Communication and Medical Education (continued)
o o b o oo
o
/
ee/e b Skill Definition
ee/ e
/ e b Behavioral Description
ee/ e
/ e b Examples Relevant Evidence
Trust, team- Relationship built on
building, understanding,
: / ///t. m
Trust: Notice/respond to signs of
t .m
distrust; elicit and respond to
: / t
///t. m
. m
“People in my family
have had the same
Disparity: 62.8% of
African Americans
therapeutic
s
power sharing, and
tps : expectations; reassure and

s
tps : thing.” versus 38.4% of
hhtttp hhtttp
alliance: empathy; patient clarify follow-up; follow “Should we get your whites believe their
build, confident that doctor through. family involved to doctors have
don’t acts on his or her Therapeutic alliance: Find specific help us?” experimented or
assume. behalf. common goals; negotiate “We’re here when you would experiment
differences. need us.” on them without
Team building: Identify, enlist, “Let’s make sure we their consent.
k eers
rs k eers
and collaborate with potential
r s
members of healthcare team.
answer all your
questions so you feel
African American
patients receive less
o
comfortable making
your decision.”
support, partnering,
and information.
/
e e
/ eb e/
e e
/ e b e / e
/ e b
EMR-electronic medical records, MI = myocardial infarction, RESPECT = respect, explanatory model, social context, power, empathy, concerns, and trust.
e
(Adapted with permission from Mostow C, Crosson J, Gordon S, et al: Treating and precepting with RESPECT: A relational model addressing race, ethnicity, and culture in
t . m
. m
medical training. J Gen Intern Med 2010;25[suppl 2]:S146-S154.)
: // / t : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
Figure 2 Illustrations show statistics on US healthcare dis-
Figure 3 Illustrations show statistics on US healthcare dis-
parities. Population’s quality of care received
parities. Population’s access to care received was
was better than, about the same as, or worse
better than, about the same as, or worse than
k eers
rs
than that of the reference group (listed after
k
NHW = non-Hispanic white. (Adapted with per-
eers
r
″vs.). AI = American Indian, AN = Alaska Native,
s that of the reference group (listed after ″vs.″).
AI = American Indian, AN = Alaska Native, NHW
b ooook b oook
mission from the Agency for Healthcare Re-
o
search and Quality: 2011 National Healthcare
b oooo = non-Hispanic white. (Adapted with permission
from the Agency for Healthcare Research and
/
e e
/ eb / ee b
Quality and Disparities Reports. Washington,
ee /
DC, US Department of Health and Human Ser-
ee/e/e b Quality: 2011 National Healthcare Quality and
Disparities Reports. Washington, DC, US Depart-
t . m m
vices (AHRQ Publication No. 12-0006), 2012.)
: / ///t . : / t.
///t m
.m
ment of Health and Human Services (AHRQ Pub-
lication No. 12-0006), 2012.)
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
icine irrespective of technologic advances. Excellence in
k eers
rs keerrss effective communication should be a priority for ortho-
b ooook b o ook
o
paedic surgeons because it affects all aspects of clinical
care.
b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
With an increasingly diverse patient population,
physicians must become culturally competent to inter-
: / t
///t. m
.m : / t
///t. m
. m
act with patients who come from different backgrounds
and who have various expectations. This allows physi-
s
tps : s
tps :
hhtttp hhtttp
cians to treat them equally and overcome disparities in
health care.
Key Study Points
k eers
rs k eers
r s
b ooook b ooook •
b o oo
Good communication skills (verbal and nonver-
o
bal) are key in patient-physician interactions.
/
e e
/ eb e/
e e
/ e b •
e / e
/ e b
Cultural competence is necessary to practice ef-
e
: // t/.tm
. m : / / t
/ .
t m
fectively in a diverse society.
. m
ss : / ss : /
hhtttp
tp hhtttp
tp Annotated References
1. Bechtel C, Ness DL: If you build it, will they come? De-
keerrss k e rrss
e
signing truly patient-centered health care. Health Aff
(Millwood) 2010;29(5):914-920.
bboooo k Figure 4
o o o k
Illustrations show statistics on US healthcare dis-
b o b o oo
Research conducted at the National Partnership for
o
/
e e
/ e e/ / e b
parities. Population’s quality measures for
e
trends over time for disparities are improving
e
(reducing at a rate of > 1% per year), not
e / e
/ e b
Women and Families suggests that a truly patient-
centered healthcare system must be designed to incorpo-
e
t . m
. m
changing (no change or change at a rate of
: / / / t : / /t/ tm
rate features that matter to patients.
. .m
ss /
< 1% per year) or worsening (increasing at a
: 2.
ss : /
Baker DW: The meaning and the measure of health lit-
hhtttp hhtttp
rate > 1% per year). Reference group is listed
tp
after ″vs.″ AI = American Indian, AN = Alaska
Native, NHW = non-Hispanic white. (Adapted
with permission from the Agency for Healthcare
Research and Quality: 2011 National Healthcare
tp
3.
eracy. J Gen Intern Med 2006;21(8):878-883.
Bagley CH, Hunter AR, Bacarese-Hamilton IA: Pa-

Quality and Disparities Reports. Washington, tients’ misunderstanding of common orthopaedic termi-
DC, US Department of Health and Human Ser- nology: The need for clarity. Ann R Coll Surg Engl
vices (AHRQ Publication No. 12-0006), 2012.) 2011;93(5):401-404.
k eers
rs k e r
e s
r s This questionnaire-based study showed that surgeons
bboooo k cultural competency will empower orthopaedic sur-

b o o
o o k o oo
should be careful when using basic and common ortho-
o
paedic terminology to avoid misunderstanding by the
b
/
e e
/ e / e e b
geons to build physician-patient relationships based on
ee /
trust and delivery of equal-quality musculoskeletal care of practice.
ee/ e
/ e b
patient. Educating patients in the clinic is a routine part
: / / t . m
. m
to all of their patients. Although the issues of commu-
/ t : / / t
/ .
t m
. m
ss : /
nication skills and cultural competency are addressed
t p p
through educational efforts by the AAOS, they are not
t
4.
p ss
p : /
Vranceanu AM, Elbon M, Ring D: The emotive impact
of orthopedic words. J Hand Ther 2011;24(2):112-117.
t
hht t
yet universally incorporated into residency training and
continuing medical education programs.
t
hht t This article discusses the emotional effect of words used
by hand specialists, discusses the effect of the nomencla-
ture chosen to describe orthopaedic diagnoses and pro-
cedures, and provides recommendations consistent with
evidence-based practice.
k eers
rs
Summary
k eers
r s 5. Badarudeen S, Sabharwal S: Assessing readability of pa-
b ooook o
making and the healthcare system, patient-centered
b ook
As patients become more involved in medical decision
o b ooo
tient education materials: Current role in orthopaedics.
o
/
e e
/ eb / ee b
care must be formally taught. Communication skills are
ee /
important to improve the physician-patient relation-
e /e/e b
Given the variability in the capacity of individuals seek-
e
: / t
///t. m
. m
ship, which remains at the center of all aspects of med-
: / t.
///t m
ing orthopaedic care to comprehend health-related ma-
.m
terials, stratification of the contents of patient education
s
tps : s
tps :
98
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
materials at different levels of complexity likely will im- This article describes various modalities of Internet
k eers
rs rrss
prove health literacy and enhance patient-centered com-
munication.
kee
communication. The Internet is sculpting contemporary
orthodontic visage, whether it involves interacting with
b ooook b o ook
o o oo
a colleague through text, voice, or video; transferring
b o
/
ee/e b 6.
e e
/ e b
Wilson IB, Schoen C, Neuman P, et al: Physician-patient
/
communication about prescription medication nonad-
e e / e
/ e b
patient records to distant locations; or submitting man-
uscripts to journals.
e
: / ///t
Intern Med 2007;22(1):6-12. . mm
herence: A 50-state study of America’s seniors. J Gen
t . /
18.
: t
///t. m
. m
Sechrest RC: The Internet and the physician-patient re-
s
tps : s
tps : lationship. Clin Orthop Relat Res 2010;468(10):2566-
hhtttp hhtttp
7. Schattner A, Rudin D, Jellin N: Good physicians from 2571.
the perspective of their patients. BMC Health Serv Res This article reviews the development of the Internet, the
2004;4(1):26. core concepts that have driven the emergence and evo-
lution of the Internet as a mass medium of information
8. Rispler D, Sara J, Davenport L, Mills B, Iskra C: Under- exchange, and how the healthcare industry can harness
the Internet to improve the physician-patient relationship.
k eers
rs k eers
reporting of complementary and alternative medicine
r s
use among arthritis patients in an orthopedic clinic. Am
ook ook
19. Hurwitz SR, Slawson DC: Should we be teaching infor-
b oo
J Orthop (Belle Mead NJ) 2011;40(5):E92-E95.
b oo
This cross-sectional study demonstrates the prevalence
b o oo
mation management instead of evidence-based medi-
o
/
e e
/ eb /
e e
/ e b
of complementary and alternative medicine used among
e
orthopaedic patients and significant increases in comple-
ee e
/ e b
cine? Clin Orthop Relat Res 2010;468(10):2633-2639.
/
Incorporation of the best evidence of busy clinical prac-
: // t . m
. m
mentary and alternative medicine reporting on the spe-
/ t : / / t
/ .
t m
. m
tice into the real world requires the applied science of
: /
cific questionnaire than in a standard medical history.
ss ss : /information management. Clinicians must learn the
hhtttp hhtttp
techniques and skills to focus on finding, evaluating,
9.
tp
Bhattacharyya T, Yeon H, Harris MB: The medical-
legal aspects of informed consent in orthopaedic sur- tp 20.
and using information at the point of care.
Richard A: Teaching non-verbal communication skills.

gery. J Bone Joint Surg Am 2005;87(11):2395-2400.
Educ Prim Care 2011;22(6):423-424.
10. Levinson W, Roter DL, Mullooly JP, Dull VT, Frankel This study asked trainees to identify aspects of nonver-
keerrss k rrss
RM: Physician-patient communication: The relationship
e e
with malpractice claims among primary care physicians
bal communication, such as body language, tone, and
speed. The trainees showed their control and power in
bboooo k and surgeons. JAMA 1997;277(7):553-559.
b o o
o o k b o oo
directing consultation and facilitating the expression of
o
emotion during the session.
/
e e
/ e 11.
e / e
/ e b
Teutsch C: Patient-doctor communication. Med Clin
e 21.
ee/ e
/ e b
Haig SV: Ethical choice in the medical applications of
North Am 2003;87(5):1115-1145.
: / / t
/ .
t m
. m : / /t . m.m
information theory. Clin Orthop Relat Res 2010;
/ t
12.
ss : /
Tongue JR, Epps HR, Forese LL: Communication skills.
ss : /
468(10):2672-2677.
hhtttp
tp hhtttp
tp
Instr Course Lect 2005;54:3-9. Suggestions for maintaining high standards of practice
in the face of the information technology burden include
(1) increasing information technology time awareness,
13. Lewis VO, McLaurin T, Spencer HT, Otsuka NY, Jime- (2) increasing information technology goal awareness,
nez RL: Communication for all your patients. Instr and (3) determining how much information recorded is
Course Lect 2012;61:569-580. for financial instead of medical reasons.
k eers
rs k e r s
As a result of increasing malpractice litigation, physi-
r
cians need to examine their communication skills. In an
e s 22. Capozzi JD, Rhodes R: Managing medical errors.
bboooo k b o o
o k
increasingly diverse world, social and cultural beliefs,
o
attitudes, and behaviors have a considerable effect on
b o oo
o
/
e e
/ e the health of communities.
ee/ e
/ e b 23.
e / e
/ e b
Mazor KM, Simon SR, Yood RA, et al: Health plan
e
14.
/ t . m
. m
Glasgow RE, Emont S, Miller DC: Assessing delivery of
: / / t : / / t
/ .
t m
members’ views about disclosure of medical errors. Ann
. m
Intern Med 2004;140(6):409-418.
t p : /
the five “As” for patient-centered counseling. Health
ss
Promot Int 2006;21(3):245-255.
p t p ss
p : /
15.
t
hht t
The Agency for Health Care Policy and Research Smok-
t
hht t
24. Wu AW, Cavanaugh TA, McPhee SJ, Lo B, Micco GP:
To tell the truth: Ethical and practical issues in disclos-
ing medical mistakes to patients. J Gen Intern Med
ing Cessation Clinical Practice Guideline. JAMA 1996; 1997;12(12):770-775.
275(16):1270-1280.
25. Sabin J, Nosek BA, Greenwald A, Rivara FP: Physi-
k
16.
eers
rsKeller VF, Carroll JG: A new model for physician-
patient communication. Patient Educ Couns 1994;
k eers
r s cians’ implicit and explicit attitudes about race by MD
race, ethnicity, and gender. J Health Care Poor Under-
b ooook 23(2):131-140.
b oook
o o oo
served 2009;20(3):896-913.
b o
/
e e
/ eb 17.
e / e
/e b
Revankar AV, Gandedkar NH: Effective communica-
e
26.
e /e/e b
Hausmann LR, Hannon MJ, Kresevic DM, Hanusa BH,
e
2010;137(5):712-714.
: / t
///t m
tion in the cyberage. Am J Orthod Dentofacial Orthop
. . m : / t.
///t m
Kwoh CK, Ibrahim SA: Impact of perceived discrimina-
.m
tion in healthcare on patient-provider communication.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Med Care 2011;49(7):626-633. 33. Jimenez RL, Lewis VO: Culturally Competent Care
k eers
rs ke rrss
In a cross-sectional survey at an orthopaedic Veterans
e
Guidebook: Companion to the Cultural Competency
Challenge CD-ROM. Rosemont, IL, American Acad-
b ooook b ook
Affairs clinic, African American patients more often re-
o o
ported perceptions of racism and classism in previous
o oo
emy of Orthopaedic Surgeons, 2007.
b o
/
ee/e b / e e b
healthcare settings that may negatively influence the af-
ee /
fective tone of subsequent patient-provider communica- 34.
e / e
/ e b
Dykes DC, White AA III: Culturally competent care
e
tion.
: / t
///t. m
.m : / t
///t. m
. m
pedagogy: What works? Clin Orthop Relat Res 2011;
469(7):1813-1816.
s
tps : s
tps :
hhtttp hhtttp
27. Stone J, Moskowitz GB: Non-conscious bias in medical This article discusses the general approaches to cultur-
decision making: What can be done to reduce it? Med ally competent care education, the tools used in the
Educ 2011;45(8):768-776. evaluation of such endeavors, and the effect of such en-
deavors on caregivers and/or the outcomes of therapeu-
Workshops or other learning modules about noncon- tic interventions.
scious processes can provide medical professionals with
skills to reduce bias when they interact with patients
k eers
rs from a minority group.
k eers
r s
35. Butler PD, Swift M, Kothari S, et al: Integrating cultural
competency and humility training into clinical clerk-
ook ook
ships: Surgery as a model. J Surg Educ 2011;68(3):
b oo
28.
b o
McClellan FM, White AA III, Jimenez RL, Fahmy S: Do
o 222-230.
b o oo
o
/
e e
/ eb e e
/ b
poor people sue doctors more frequently? Confronting
/ e
unconscious bias and the role of cultural competency.
e ee/ e
/ e b
This review article uses surgery as a model to establish a
set of recommendations to assist clerkship directors and
: // t/.tm
. m : / / t . m
. m
curriculum committees in their efforts to ensure cultural
/ t
ss /
This review article examines the misperception that a re-
: ss : / competency and humility training in medical education
hhtttp hhtttp
lationship between patient poverty and medical mal- over the past 2 years.
tp
practice litigation may arise from unconscious physician
bias and other social variables. tp 36. Smith BD, Silk K: Cultural competence clinic: An on-
line, interactive, simulation for working effectively with
29. Shannon D: Cultural competency in health care organi- Arab American Muslim patients. Acad Psychiatry 2011;
zations: Why and how? Physician Exec 2010;36(5): 35(5):312-316.
rrss rrss
18-22. Preliminary data from this study support that an online,
o ke
ke k e e
Physician leaders need to understand the relevance of
o k
interactive patient simulation involving the care of an
oo
Arab American Muslim patient has the potential to im-
e bboo o e b o o o
cultural competence. The cultural competency of their
organizations needs to be strengthened to provide safer,
b e b o o
prove the knowledge and skills of second-year medical
b
/
e / e / / e
higher quality, and more efficient health care.
m ee ee/ / e
students regarding patient care beyond the basic cultural
competence curriculum.
m
30.
: / / t .
t . m
Fiester A: What “patient-centered care” requires in seri-
/ / : / /
/t/.t .m
s :
ous cultural conflict. Acad Med 2012;87(1):20-24.
s
37.
ss :Gustafson DL, Reitmanova S: How are we “doing” cul-
hhtttp hhtttp
tural diversity? A look across English Canadian under-
tp
The author examined the tension that occurs when cul-
turally sensitive issues of patient-centered care disrupt
the workflow of the service; require the acknowledge-
tp graduate medical school programmes. Med Teach 2010;
32(10):816-823.
ment of antithetical, unsupportable values; or entail dis- This website and literature review shows that more re-
criminatory or ad hominem practices that constitute a search is needed to map the approaches to cultural di-
versity and evaluate the effectiveness of these ap-
personal insult or affront to the provider.
k eers
rs k e r
e s
r s proaches on improving physician-patient relationships,
reducing health disparities, improving outcomes, and
bboooo k 31.
o o
o k
Like RC: Educating clinicians about cultural compe-
o
tence and disparities in health and health care. J Contin
b b o oo
producing positive learning in physicians.
o
/
e e
/ e Educ Health Prof 2011;31(3):196-206.
ee/ e
/ e b
This article overviews healthcare policy as well as legis-
38.
ee/ e
/ e b
Harris-Haywood S, Goode T, Gao Y, et al: Psychomet-
ric evaluation of a cultural competency assessment in-
/ t . m
. m
lative, accreditation, and professional initiatives relating
: / / t : / / t
/ .
t m
. m
strument for health professionals. Med Care 2012.
t p p : /
to racial and ethnic disparities in health care. Continu-
ss
ing medical education offerings on cultural competence
t p ss
p : /
This study evaluated the measurement properties of the
t
hht t
and disparities are reviewed, with examples provided of
available curricular resources and online courses. t
hht t Cultural Competence Health Practitioner Assessment
and found that it can be used to establish associations
between practitioners’ cultural and linguistic compe-
tence and health outcomes as well as evaluate interven-
32. Jenks AC: From “lists of traits” to “open-mindedness”: tions to increase competence.
Emerging issues in cultural competence education. Cult
k eers
rs Med Psychiatry 2011;35(2):209-235.
k eer
This article explains that educators of contemporarys
r s 39. Mostow C, Crosson J, Gordon S, et al: Treating and
precepting with RESPECT: A relational model address-
b ooook oook
cultural competence have rejected the list of traits ap-
b o b ooo
ing race, ethnicity, and culture in medical training.
o
J Gen Intern Med 2010;25(suppl 2):S146-S154.
/
e e
/ eb e / e
/e b
proach and instead aim to produce a new kind of
healthcare provider who is open-minded, willing to
e e /e/e b
The specific behavioral descriptions for each component
e
dividual.
: / t
///t m
learn about differences, and treats each patient as an in-
. . m : / t.
///t m
of RESPECT (respect, explanatory model, social con-
.m
text, power, empathy, concerns, and trust—an educa-
s
tps : s
tps :
100
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
tional model for patient care) make it a concrete, prac- 43. Borkhoff CM, Hawker GA, Wright JG: Patient gender
k eers
rs r
tical, integrated model for teaching patient care.
kee rss
Precepting with RESPECT fosters a safe climate for res-
affects the referral and recommendation for total joint
ook ook
arthroplasty. Clin Orthop Relat Res 2011;469(7):1829-
b oo b o
idents to partner with faculty, address challenges with
o 1837.
b o oo
o
/
ee/e b patients at risk, and improve outcomes.
ee/ e
/ e b ee/ e
/ e b
Patient sex plays an important role in the process of re-
ferral and recommendation for total joint arthroplasty.
40.
/ ///t. m
Taylor P, Keeter S: Millennials: A Portrait of Generation
t .m
Next. Washington, DC, Pew Research Center, February
: : / t . m
. m
Female sex affects multiple steps in the process, suggest-
///t
2010.
s
tps : s
tps : ing barriers unique to women exist in the patient-
hhtttp hhtttp
physician interaction.
This report on the values, attitudes, behaviors, and de-
mographic characteristics of the millennial generation
44. Katz JN, Lyons N, Wolff LS, et al: Medical decision-
was prepared by the Pew Research Center, a nonparti-
san “fact tank” that provides information on the issues, making among Hispanics and non-Hispanic whites with
attitudes, and trends shaping America and the world. chronic back and knee pain: A qualitative study. BMC
Musculoskelet Disord 2011;12:78.
k
41.
eers
rs rs
r
Hussain W, Hussain H, Hussain M, Hussain S, Attar S:
k ee s The authors assembled six focus groups of patients with
Approaching the Muslim orthopaedic patient. J Bone chronic back or knee pain to discuss the management of
b ooook Joint Surg Am 2010;92(7):e2.
b ooook b o oo
their conditions and preferred roles in medical decision
o
/
e e
/ eb e/
e e
/ e b
This paper reviews how cultural and religious consider-
ations apply to orthopaedic patients who are Muslim.
e e
/ e b
making. The findings suggested differences between His-
/
panics and non-Hispanic whites in preferred informa-
e
: // t/.tm
. m
Understanding the fundamentals of patient beliefs and
maintaining empathy to their principles will help ortho-
: / / t
/ .
t m
tion sources and decision-making roles.
. m
ss : /
paedic surgeons provide high-quality and culturally sen-
ss
45.
: /
Hausmann LR, Hanusa BH, Kresevic DM, et al: Ortho-
hhtttp
tp hhtttp
tp
sitive care to their Muslim patients. pedic communication about osteoarthritis treatment:
Does patient race matter? Arthritis Care Res (Hoboken)
42. López L, Green AR, Tan-McGrory A, King R, Betan- 2011;63(5):635-642.
court JR: Bridging the digital divide in health care: The Visits to Veterans Affairs orthopaedic clinics were coded
role of health information technology in addressing ra-
using the using the Roter Interaction Analysis System
cial and ethnic disparities. Jt Comm J Qual Patient Saf
rrss rrss
and the Informed Decision-Making model. Communica-
2011;37(10):437-445.
o ke
ke o k e
k e
Several causes for disparities are amenable to interven-
tion regarding the management of chronic knee and hip
oo
osteoarthritis did not vary by patient race. The findings
e bboo o e b o
b o
tions using health information technology, particularly
o
innovations in electronic health records. Recommenda-
e b o o
diminish the potential role of communication in Veter-
b
/
e / e m e / / e
tions regarding the healthcare system and provider and
e ee/ / e
ans Affairs clinics as an explanation for well-
documented racial disparities in arthroplasty.
m
/ / t
/ .
patient factors can help organizations address disparities
t . m
as they tailor their health information technology sys-
: / : / /
/t/.t .m
tems.
ss : ss :
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 9
e rs
rs e rrss
oo
kPolytrauma
ook e Care o k
ook
o
e o oo
o
/e/ebb Max Talbot, MD, FRCSC
e / e
/ b
e b
Greg Berry, MDCM, FRCSC
e / e
/ b
e b
Edward J. Harvey, MD, MSc
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
tration. Crystalloid and colloid resuscitation should be
Introduction conservative and limited by preestablished end points,
k eerss k eers
In general, an understanding of the physiologic process-
r r
es that affect polytraumatized patients has remained thes
such as restoration of a radial pulse. This method will
minimize dilutional coagulopathy and lessen the chance
b ooook o ook
concern of physicians other than orthopaedic surgeons.
b o b oo
of displacing established clots.
o o
After reaching the hospital, the most severely injured
/
e e
/ eb e/ e
/ e b
Increasingly, however, the need for early and aggressive
orthopaedic care of patients with multiple traumatic in-
e ee/ e
/ e b
trauma patients will benefit from a balanced transfu-
: // /.tm m
juries has made it more relevant for orthopaedic sur-
t .
geons to understand the physiologic processes involved
: / / t
/ .
t m
sion regimen that closely approximates the composition
. m
of blood. Recent wars have provided substantial expe-
ss : / s : /
rience with massive transfusion and have resulted in the
s
hhtttp hhtttp
in caring for these patients. As modern battlefield tech-
tp
niques are adopted into civilian medicine, severely in-
jured polytraumatized patients are surviving in greater
numbers. As such, the orthopaedic care of these patients
tp
current ratio-based approach. Military and civilian ret-
rospective studies have shown that the transfusion of
high ratios of fresh frozen plasma (FFP) and platelets to
requires knowledge of intensive care and global trauma packed red blood cells (PRBCs) decreases mortality in
protocols. Orthopaedic surgeons must understand and patients requiring massive transfusions.1 A prospective
trial is currently underway to validate the optimal ratio
k errss
integrate musculoskeletal protocols with the care and
e
concerns of other teams of physicians. Ongoing com-
k e rrss
e
of blood products. This transfusion strategy presents
bboooo k b o o
o o
munication and team building within the care-delivery
k not been fully resolved.
b o oo
challenges to logistics and resource allocation that have
o
/
e e
/ e
matrix is becoming increasingly important.
ee/ e
/ e b ee/ e
/ e b
It is important to note that ratio-based transfusion is
required only in a small subset of patients. Efforts have
: / / t
/ .
t m
. m t . m.m
been made to develop clinical scoring systems to pre-
: / / / t
ss /
Initial Assessment and Resuscitation
: : /
dict massive bleeding and make early determinations
ss
hhtttp
tp hhtttp
tp
about which patients will benefit from aggressive dam-
The principles of initial trauma management are intui-
age control resuscitation.2 At this time, clinical judg-
tive and have remained relatively unchanged. The clas-
ment will serve the clinician better than any individual
sic ABC mnemonic of care (airway, breathing, circula-
scoring system. Patients with more severe clinical (pro-
tion) is still valid; ideally, however, these steps should found hypovolemia with large transfusion require-
occur concurrently. If exsanguination is occurring from ments) and laboratory evidence of shock and more ex-
k ee s
a limb injury, strong consideration should be given to
rrs k e r
e
first controlling the catastrophic bleeding. A tourniquet s
r s tensive anatomic injuries will generally have a higher
risk of coagulopathy and higher transfusion require-
bboooo k b
control of massive bleeding from open extremity o o
o o
is often the most efficient method to obtain temporary
k b o oo
ments. In such instances, the clinician should consider
o
/
e e
/ e / e
/ e b
wounds. Damage-control resuscitation starts at the
ee ee e
damage control resuscitation.
/ / e b
/ / t
/ t m
point of injury, with the use of hypotensive resuscita-
. . m
tion, which aims to minimize prehospital fluid adminis-
: : / / t
/ .
t m
. m
t p ss
p : / ss : /
Trauma-Induced Coagulopathy
t p p
t
hht t
Dr. Harvey or an immediate family member has received
research or institutional support from Synthes, Stryker,
t
hht t
The observation that 25% of trauma patients have lab-
oratory evidence of coagulopathy on presentation to
the emergency department has led to a reappraisal of
Smith & Nephew, and Zimmer and serves as a board the pathophysiology of trauma-induced coagulopathy.3
member, owner, officer, or committee member of the Hypothermia, acidosis, and coagulation factor dilution
k eerss
Orthopaedic Trauma Association, the Canadian Ortho-
r k e
paedic Association, and the Orthopaedic Research Soci-
ers
r s can be aggravating factors, but it is now clear that
shock and tissue injury are the initial triggers of this
b ooook b ook
ety. Neither of the following authors nor any immediate
oo b oooo
condition.4 It is postulated that hypoperfusion induces
the expression of thrombomodulin by endothelial
/
e e
/ eb e / e
/e b
family member has received anything of value from or
has stock or stock options held in a commercial company
e ee/e/e b
cells, which leads to protein C activation, systemic
/ t
///t m
or institution related directly or indirectly to the subject
. . m
of this chapter: Dr. Talbot and Dr. Berry.
: : / t.
///t m
anticoagulation, and derepression of fibrinolysis.5 Mul-
.m
tiple studies have identified coagulopathy as an inde-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
pendent predictor of mortality in trauma.5,6 More lopathy is a prominent feature in traumatic combat in-
k eers
rs recently, coagulopathy and protein C activation have
keerrss juries, which tend to be more severe than civilian inju-
b ooook b o ook
been linked to an increase in ventilator-associated
o
pneumonia, multiple organ failure, longer mechanical
ries. The Military Application of Tranexamic Acid in
o oo
o
Trauma Emergency Resuscitation (MATTERs) study
b
/
ee/e b ee/ e
/ e b
ventilation, and longer stays in the intensive care unit.6
This new understanding of the mechanisms and the
ee/ e
/ e b
retrospectively evaluated the use of TXA in 896 com-
bat casualties requiring blood transfusions who were
t . m
.m
consequences of trauma-induced coagulopathy has led
: / ///t
to a reassessment of the importance of coagulopathy
: / t . m
. m
admitted to a medical facility at Camp Bastion, Af-
///t
s
tps : s
tps :
ghanistan, over a 2-year period.13 Despite more severe
hhtttp hhtttp
markers in trauma resuscitation. trauma, mortality in the TXA group was significantly
Two drugs with the potential to reverse traumatic lower (17.4% versus 23.9% [P = 0.03]). TXA use was
coagulopathy have been the focus of recent intense re- independently associated with lower mortality in the
search. Recombinant factor VIIa was initially devel- subset of patients requiring massive transfusions.
oped to treat patients with hemophilia who have anti- It is essential to recognize the potential for trauma-
bodies to coagulation factors VIII and IX. Its potential induced coagulopathy in severely injured patients. Vol-
k eers
rs to activate the extrinsic coagulation pathway when
k eers
r
combined with tissue factor and to activate factor X di-s ume resuscitation should be approached with the prin-
ciples of hemostatic resuscitation in mind. Institutional
b ooook b ooook
rectly at the surface of activated platelets led to its off-
o oo
massive transfusion protocols are a valuable tool in en-
b o
/
e e
/ eb e/ / e b
label use in severely traumatized patients with coagu-
e
lopathy. A randomized controlled trial initially showed
e e / e
/ e b
suring a consistent approach. The administration of
TXA should be considered as an adjunct to resuscita-
e
// t/.tm
decreased transfusion requirements in patients with
. m
blunt (nonpenetrating) trauma; however, recombinant
: : / / t
/ .
t m
. m
tion in patients with severe bleeding.
ss : /
factor VIIa had no mortality benefit.7 This finding led
ss : /
hhtttp
tp hhtttp
tp
to the widespread use of recombinant factor VIIa, par-
Treatment Patterns Driven
ticularly in those with complex war injuries.8 Early ret- by Military Experience
rospective data suggested decreased mortality in civil-
ian and military patients with traumatic injuries who The recent conflicts in Iraq and Afghanistan have given
were treated with recombinant factor VIIa, but larger military surgeons extensive experience with injuries
rrss rrss
prospective studies failed to confirm those results.9 The caused by improvised explosive devices (IEDs). The
o ke
ke
use of recombinant factor VIIa has since declined con-
o k
siderably, and it is not currently approved by the FDAe
k e
most severe injuries are sustained at close range during
oo
dismounted combat operations; multiple traumatic in-
e bboo o e b o
for treating patients with traumatic coagulopathy.
b o o e b o o
juries involving mangled limbs and amputations are
b
/
e / e ee/ e
Tranexamic acid (TXA), an inhibitor of fibrinolysis,
/
has been used extensively to decrease bleeding during
m m ee/ / e
common and are often accompanied by pelvic fractures
or intra-abdominal injuries. Advances in tactical medi-
/ t . . m
elective surgeries and other procedures. TXA is partic-
: / / / t : / /
/t/.t .m
cine and rapid air transport often allow these patients
s :
ularly attractive because of the key role of hyperfibrin-
s s :
to survive from the point of injury to a surgical facility.
s
hhtttp
tp hhtttp
tp
olysis in traumatic coagulopathy. Clinical Randomiza- Tactical care on the battlefield allows medics to treat
tion of an Antifibrinolytic in Significant Hemorrhage-2 the most common causes of preventable death in a
(CRASH-2) was a blinded randomized controlled trial protocol-driven manner. Tourniquet application and
that evaluated the role of TXA in patients with trau- wound packing with hemostatic dressings are the most
matic injuries.10 More than 20,000 patients with trau- useful interventions. Both treatments are aimed at stop-
matic injuries from centers in 40 countries who had ac- ping compressible hemorrhage, the most frequent cause
k eers
rs tive bleeding or were at risk of bleeding were included
k
in the trial. Four-week mortality from all causes was e r
e s
r s of preventable death on the battlefield.14
Contrary to past medical doctrine, the prehospital
bboooo k 14.5% in the TXA group compared with 16% in the

b o o
o o k b o oo
application of tourniquets in current conflicts has been
o
/
e e
/ e e e
/ e b
placebo group, which represents a statistically and clin-
/
ically significant reduction in mortality (P = 0.0035).
e e e
/ e b
shown to be effective at stopping blood loss and in-
/
creasing survival rates.15 Tourniquets are an integral
e
: / / / .
t m m
The risk of death caused specifically by bleeding was
t . : / / t
/ .
t m
. m
part of the damage control resuscitation-surgery contin-
t p ss : /
4.9% in the TXA group compared with 5.7% in the
placebo group. Subsequent analysis showed that TXA
p t p ss : /
uum. Complications are rare and mostly consist of
neurapraxias. An increased fasciotomy rate was report-
p
t
hht t
should be administered within 3 hours of injury.11
Based on these data, TXA could potentially save more
than 128,000 lives annually worldwide if it was given
t
hht t
ed when tourniquets were widely issued to US military
personnel in 2005;16 however, this is likely related to the
increasing number of severe injuries cause by more so-
within 1 hour of injury.12 It is noteworthy that no spe- phisticated weapons and to a lower threshold for pro-
cific screening was done for hyperfibrinolysis or coagu- phylactic fasciotomy before patients were evacuated
k eers
rs lopathy. Thromboelastography might allow clinicians
eers
r
to target this therapy to patients with hyperfibrinolysis,
k s from the combat theater. Extrapolation of these data to
civilian medicine may be difficult. The low rate of com-
b ooook b ook
potentially producing a greater treatment effect. Inter-
oo
estingly, the CRASH-2 trial showed no decrease in the
b oooo
plications from tourniquet use may not be applicable to
situations in which longer periods of time elapse be-
/
e e
/ eb number of transfusions in the TXA group.
ee/ e
/e b ee/e/e b
tween tourniquet application and hospital admission.
/ t
///t m
TXA has anti-inflammatory effects that may also
. . m
contribute to decreasing mortality.13 Traumatic coagu-
: : / t.
///t m
The resuscitation of patients with multiple traumatic
.m
amputations can be extremely challenging. An aggres-
s
tps : s
tps :
104
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 9: Polytrauma Care
sive application of damage control principles is essential ment in mortality rates until the modernization of in-
k e rs
rs
to ensure the best outcomes. Hemodynamically unsta-
e keerrss tensive care and trauma resuscitation protocols. Even
b ooook o ook
ble patients are best treated in the operating room,
o
where resuscitation and hemorrhage control can be per-
b
with better early care of these patients, unexplained
b o oo
o
morbidity and mortality existed that was sometimes at-
/
ee/e b ee/ e
/ e b
formed concurrently. The timing of CT has been stud-
ied. Preoperative or intraoperative CT is usually of little
ee/ e
/ e b
tributed to the early care itself, which turned on the
traumatic response cascade.20-22 There is ongoing de-
t . m
.m
value because most clinically important injuries can be
: / ///t : / t
///t. m
. m
bate regarding whether early care contributes to com-
plications in patients with traumatic injuries. The early
s
tps :
readily evaluated without CT.17 Postoperative CT is use-
s
tps :
hhtttp hhtttp
ful in delineating the full extent of injuries. Determining hyperinflammatory response to severe trauma, which is
the extent of anatomic involvement requires a consis- a natural part of the healing response, is followed by a
tent team approach. It is vital to swiftly control all sites hypoinflammatory phase.23,24 This biphasic response
of hemorrhage. Priority must be given to treating intra- may result in increased morbidity during the hypoin-
abdominal injuries and unstable or open pelvic frac- flammatory phase. The initial trauma can cause injury
tures. External fixation of the pelvic ring and preperito- to primary organs as well as an early hyperinflamma-
k eers
rs k eer
neal packing may be indicated for stabilizing unstable
s
r s tory response. Late, multiple organ dysfunctions are of-
ten associated with the second hit, particularly tempo-
pelvic fractures.17 It is essential to achieve vascular con-
b ooook o ook
trol of all bleeding extremities while laparotomy and
b o b o oo
ral physiologic insults that occur during the
o
/
e e
/ eb e e
/ e b
pelvic external fixation are ongoing. In most instances,
/
a pneumatic tourniquet is adequate, but surgical control
e e / e
/ e b
hypoinflammatory phase. Secondary endogenous and
exogenous factors play a crucial role in the initiation of
e
: // /.tm m
is necessary for the most proximal amputations. In
t .
some patients, proximal vascular control of the lower
: / / t
/ .
t m
posttraumatic complications. Iatrogenic second hits in-
. m
clude massive transfusions and surgical interventions
ss : /
extremities is best obtained with a laparotomy. It is im-
ss : /
that cause tissue damage, hypothermia, or blood loss.
hhtttp
tp hhtttp
tp
portant to expedite the initial surgery by simultaneously Studies have shown a higher incidence of morbidity in
performing as many of the procedures as possible.18 patients with severe pulmonary injuries or shock or in
In some instances, surgical workspace is suboptimal, otherwise unstable patients undergoing surgery. The
with two surgeons from different specialties working second hit is worsened by blood loss, sepsis, and
on each limb. Extremity procedures should be brief in a ischemia (or conditions that cause these disorders).25
rrss rrss
patient with overwhelming trauma. Physiology is the Applying the strategy of damage control surgery re-
o e
prime concern in a polytraumatized patient, not the
kke o k
complexity of the fracture. Limb injuries require con-e
k e
sulted in better survival rates in polytraumatized pa-
oo
tients with abdominal injuries.26 These principles were
e bboo o e b o o o
trol of major vessels, gross débridement, and temporary
b e b o o
expanded over time with the popularization of damage-
b
/
e / e ee/ e
external fixation. Formal revascularization or the use
/
of a temporary shunt can be considered for avascular
m m ee/ / e
control orthopaedics (DCO). The goal of DCO is to
lessen blood loss, sepsis, and ischemia. Patient selection
: /
/ t
/ .
t . m
extremities, depending on the patient’s physiology. Dé-
/ : / /
/t/.t .m
is key, with the degree of chest trauma and brain injury
s :
bridement can be complex in patients with combat in-
s s :
among other factors that are crucial in determining a
s
hhtttp
tp hhtttp
tp
juries. Extreme contamination and wounds in difficult patient’s viability and the applicability of DCO.25,27
anatomic areas are typical. An appreciation of the pa- The debate on DCO versus total early care is ongo-
tient’s physiologic status will allow the surgeon to abort ing. Patient categories have been loosely defined to aid
the débridement before the onset of profound coagu- surgeons in choosing treatment modalities. Patients can
lopathy. In patients with massive trauma, it is often im- be classified according to their overall underlying con-
possible to obtain a clean wound after the first débride- dition (Figure 1). Stable patients (grade I, cleared for
rs
rs
ment because of the need to limit physiologic insult
k ee k e r
e s
r s surgery) usually can be taken to the operating room for
early total care. Unstable patients (grade III, cardiovas-
bboooo k
from prolonged surgery. Staged procedures will follow
at higher echelons of care.
b o o
o o k b o oo
cular instability [systolic blood pressure < 90 mm Hg])
o
/
e e
/ e ee e
/ e
rates of survival can be expected when a mature b
Although war injuries are challenging to treat, high
/ e e
/ e b
are taken to the operating room for management of
/
their nonorthopaedic injuries and are treated according
e
: / / t
/ .
t m m
trauma system is in place.17,19 Severe combat injuries
. : / / t
/ .
t m
. m
to the principles of DCO. Patients in extremis (grade IV,
t p ss : /
carry useful lessons in damage control surgery for non-
military surgeons who are unlikely to see mutilating in-
p t p ss : /
acutely life-threatening injuries) are taken to the inten-
sive care unit where external fixation may be applied if
p
t
hht t
juries. In a complex case, it is easy to get drawn into
the technical aspects of limb alignment and fixation, t
hht t
possible. Patients in borderline condition (grade II, un-
certain condition with episodes of cardiovascular insta-
bility and hypoxemia) have more problems and are
but such concerns are rarely important in a true dam-
age control situation. All surgical procedures should be more difficult to treat. These patients receive acute non-
resuscitative in nature. orthopaedic care in the trauma room with the resusci-
k eers
rs k eers
r s tation protocol. If stabilization is possible, they are tak-
en to the operating room for DCO care. Early total care
b ooookExtremity Trauma and Indications

b oook
o b ooo
procedures usually are not appropriate for these pa-
o
tients regardless of the success of resuscitation.
/
e e
/ eb for Damage-Control Orthopaedics
ee/ e
/e b /e/e b
Some authors have attempted to define borderline
ee
/ t
///t m
For centuries, physicians have seen early death in poly-
. . m
traumatized patients; however, there was little improve-
: / t.
///t m
patients with objective laboratory or scoring bench-
.m
marks. Indications of a borderline patient include poly-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
Figure 1 Algorithm for classifying a patient’s condition and type of surgery. The patient’s underlying condition will determine
treatment. Borderline patients, although difficult to define, should be managed with DCO. At day 5 or later after
injury, DCO fixation methods can be converted to other fixation modalities. ETC = early total care, DCO = damage
control orthopaedics, OR = operating room, ICU = intensive care unit, ISS = Injury Severity Score, IM = intramedul-
lary. (Adapted with permission from Pape HC, Grimme K, Van Griensven M, et al: Impact of intramedullary instru-
mentation versus damage control for femoral fractures on immunoinflammatory parameters: Prospective random-
ized analysis by the EPOFF Study Group. J Trauma 2003;55[1]:7-13.)
k eers
rs k e r
e s
r s
bboooo k o o o k
trauma with an Injury Severity Score (ISS) greater than
b o b o oo
have the capability of monitoring inflammatory mark-
o
/
e e
/ e e e
/ e
abdominal and/or pelvic trauma, and hemorrhagic
e b
20 and additional thoracic trauma, polytrauma with
/ e e
/ e b
ers (interleukin [IL]-6, 8, 10, and 18), but the global
/
use of these tests is not the standard of care. The role of
e
: / / / .
t m m
shock (initial relative risk < 90 mm Hg) or an ISS
t .
greater than 40 without additional thoracic trauma.
: / / / .
t m m
these markers in determining patient viability and the
t .
applicability of DCO is likely to become more promi-
p ss : /
Bilateral lung contusions on a chest radiograph, an ini-
t p t p ss : /
nent because the markers, in particular IL-6, have been
p
t
hht t
tial mean pulmonary arterial pressure greater than
24 mm Hg, and an increase of pulmonary arterial pres-
sure of more than 6 mm Hg during intramedullary nail-
t
hht t
shown to be good indicators of systemic traumatic im-
munomodulation. High levels of inflammatory markers
at the time of surgery are indicators of complicated pa-
ing are also indicators of a patient in borderline condi- tient care and poor outcomes.30
tion.28 Longer procedures have been associated with The choice and timing of procedures are also debat-
k eers
rs
multiple organ failure. Depending on the report, it ap-
pears that extremity surgery should be delayed in pa-
k eers
r s
able. The external fixator is the primary treatment de-
vice used in DCO. External fixation decreases surgical
b ooook b oook
tients with a Glasgow Coma Scale score less than 9. In-
o
direct measures of hypoperfusion, such as lactic acid
b ooo
time and blood loss, allows better visualization of the
o
extremities, and decreases the morbidities associated
/
e e
/ eb ee/ e
/e b
levels or base excess, have shown some promise in di-
/e/e b
with skeletal fixation. Some authors have also dis-
ee
/ t
///t m
agnosing occult hypoperfusion and may play a role in
. . m
better defining the borderline patient.29 Some centers
: / t.
///t m
cussed nailing, minimally invasive plating, or various
.m
other procedures as DCO techniques.31
:
s
tps : s
tps :
106
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Regardless of the surgical technique, the timing of gastrointestinal, and musculoskeletal damage. Because
k rs
rs
DCO versus early total care is an important factor.
ee keerrss of the complex nature of these injuries, a multidisci-
b ooook b o ook
Much debate has centered on the fixation of femoral
o
shaft fractures, which are a common injury in patients
plinary approach is crucial in ensuring survival with the
lowest possible morbidity.
b o oo
o
/
ee/e b ee/ e
/ b
with polytrauma. Studies on femoral shaft fracture
e
have shown that early femoral nailing achieves better
ee/ e
/ e b
The initial emergency department evaluation should
determine possible sources of bleeding in the hemody-
t . m
.m
outcomes when polytrauma is not a factor.32 Using data
: / ///t
reported to the National Trauma Data Bank, a 2009
: / t . m
. m
namically unstable patient according to Advanced
///t
s
tps : s
tps :
Trauma Life Support principles. After thoracic, abdom-
hhtttp hhtttp
retrospective study reviewed 3,069 femoral shaft frac- inal, and limb injuries have been eliminated as origins
tures in polytraumatized patients who were treated of blood loss, the pelvis must be considered a likely
with definitive fixation.33 Definitive fixation within source in a patient with ongoing or recurrent hemody-
12 hours of hospital admission was associated with a namic instability. To save the patient’s life, arrest of
higher mortality rate. Femoral shaft fixation that was hemorrhage and mechanical stabilization are urgent
delayed beyond 12 hours reduced mortality by approx- goals. An uncommon but more lethal injury, the open
k eerss
imately 50%. This delay in treatment was particularly
r k eer
beneficial in patients with life-threatening abdominals
r s pelvic fracture, must always be considered and ruled
out in any patient with pelvic ring disruption. Physical
b ooook
injuries.
b ooook o oo
examination of the perineum, rectum, and vagina is im-
b o
/
e e
/ eb e/ / e b
A retrospective study evaluated 766 polytraumatized
e
patients with lung injuries and femoral fractures treated
e ee/ e
/ e b
portant to rule out an open pelvic fracture, which has a
higher mortality rate and may alter medical manage-
// t/.tm
with intramedullary nailing at less than or more than
. m
24 hours after injury.22 In patients with severe chest
:
ment.
: / / t
/ .
t m
. m
ss : /
trauma, there was a higher incidence of posttraumatic
ss : /
hhtttp hhtttp
Imaging
tp
acute respiratory distress syndrome (33% versus 7.7%)
and mortality (21% versus 4%) in the group treated
with early intramedullary nailing compared with the
tp
Further definition of the pelvic injury can be obtained
with inlet-outlet radiographic views and CT. Although
plain radiographs alone can be used to classify these in-
group treated after more than 24 hours. The study au-
juries, CT will better define all components of the in-
thors did not stratify the findings of different (longer)
jury.38 The Young and Burgess classification of pelvic
rrss rrss
time periods to treatment. In a 1999 retrospective anal-
fractures is based on the instability created by the force
o ke
ke o k
stitution over a 24-year period were categorized into e
ysis, 4,313 polytraumatized patients treated at one in-
k e vector applied at the moment of impact and includes four

oo
e bboo o e b o o o
groups based on the presence or the absence of multiple
b e b o
groups, which are then further subdivided. Rotationally
b o
unstable patterns include anterior-posterior compression
/
e / e ee/ e
organ failure.34 In those in whom multiple organ failure
/
developed, secondary surgery was usually performed
m m ee/ / e
(APC) injuries, which result in external rotational pelvic
/ t . . m
on days 2 to 4 after injury. Using data from a level I
: / / / t : / /
/t/.t .m
instability; lateral compression (LC) injuries, which pro-
duce internal rotation of the hemipelvis; vertical shear
s :
trauma center gathered over a 12-year period,
s ss :
hhtttp hhtttp
(VS) injuries, which are the result of an axial load
tp tp
1,362 patients with traumatic chest or head injuries
and a femoral shaft fracture were stratified into several through the pelvis resulting in vertical instability and dis-
groups based on the time of treatment. Patients who placement; and combined mechanism (CM) injuries,
were surgically treated less than 24 hours after injury which have components of the other three patterns. Al-
did the best, and treatment 2 to 5 days after injury was though this classification system cannot accurately pre-
associated with high complication rates. Early total dict a specific vascular injury, it is a useful tool in pre-
k eerss
care for polytraumatized patients with a femoral shaft
r k e
fracture should take into account the effects of the pa-r
e s
r sdicting likely resuscitative requirements and concomitant
injuries and can help direct definitive stabilization strat-
bboooo k b o o o k
tient’s physiologic state and treatment time. Early treat-
o b o oo
egies. APC injuries are more likely to be associated with
o
solid and hollow abdominal organ injury, more pro-
/
e e
/ e e e
/ b
ment may not be the best choice for a borderline pa-
/ e
tient. Procedures done between days 2 and 5 seem to be
e e / e
/ e b
found shock, sepsis, and delayed respiratory distress syn-
e
: / / t
/ .
t m
. m
undesirable. Patients surgically treated on or after
/ / t
/ t m
drome, whereas LC injuries have a higher associated in-
. . m
cidence of traumatic brain injury. Transfusion volume
:
t p ss
p : /
6 days of injury had fewer complications.35
ss : /
and mortality are highest in patients with APC injuries,
t p p
t
hht
Pelvic Ring Injuries
t t t
followed by CM, and then LC/VS mechanisms.
hht
Temporary Mechanical Stabilization
Disruption of the pelvic ring in a patient with multiple Historically, immediate external fixation of the pelvis
traumatic injuries is usually caused by the transfer of was included in the management algorithm of the
k eers
high-energy blunt force trauma to the bony and soft-
rs e
tissue components and contents of the pelvis. This in-
k ers
r s
hemodynamically unstable patient with a pelvic ring in-
jury.39 This strategy was based on the supposition that
b ooook b ook
jury is associated with a high incidence of morbidity
oo
and mortality.36,37 For a patient surviving the initial
b oooo
the increased intrapelvic volume produced in APC and
VS injuries permitted ongoing hemorrhage, which was
/
e e
/ eb / e
/e b
traumatic event, late mortality results from sepsis
ee ee/e/e b
stopped by reducing the volume available and inducing
/ t
///t m
and/or multiple organ system failure, whereas survivor
. . m
morbidity may include lasting urogenital, neurologic,
: : / t.
///t m
tamponade. Because cranial bleeding into the retroperi-
.m
toneal space is relatively unaffected by pelvic volume
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Figure 2
e e
/ e b
Typical placement of a sheet binder with clamps
/
to hold it in place. Compression takes place over
e ee/ e
/ e b
: // t/ tm
both pelvic and the greater trochanteric areas.
. . m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
reduction induced with external fixation and the time
required for the application of an external fixation
frame, formal external fixation has been largely sup-
planted by the use of pelvic orthotic devices or binders.
Pelvic orthotic devices can take the form of a simple
bed sheet or a commercial device40 (Figures 2 and 3).
keerrss These devices are simple, can be rapidly applied, and

k e rrss
e
bboooo k b o o
o
to mechanically stabilize APC, VS, and some CM inju- k
are effective at circumferentially constraining the pelvis
o
Figure 3
b o oo
Photograph of a patient with a commercially
o
available binder in place around the greater
/
e e
/ e / e e b
ries.41 Pelvic orthotic devices have been shown to effec-
ee /
tively reduce volume in APC-type injuries without / e e b
trochanters. The binder is sometimes inadver-
ee /
tently placed (arrow), but the greater tro-
: / / t . m
. m
overreducing LC injuries.42 In patients with APC inju-
/ t : / /t/.tm.m
chanter is the best site for compression and
avoiding laparotomy sites or impeding abdomi-
s : /
ries who are at higher risk of exsanguination, there is
s ss : /nal examinations.
hhtttp
tp hhtttp
tp
some evidence that these devices can reduce transfusion
requirements, the length of the hospital stay, and mor-
tality.43 vic ring, the C-clamp provides mechanical stability to
The device is placed at the level of the greater tro- allow effective preperitoneal packing. Although it can
chanters, permitting access to the groin (for interven- be applied using surface anatomy landmarks alone,
tional radiology) and the abdomen (for general sur- there is a danger of intrapelvic penetration of the pins
k eers
rs gery). The device can safely remain in place for up to
k e
190 hours without causing skin or other soft-tissue ne- r
e s
r s in the displaced pelvis. Most centers that regularly use
bboooo k b o o o k
crosis, although caution must be exercised when the in-
o b o oo
this device recommend fluoroscopic imaging to avoid
o
this complication. A safer alternative to posterior ring
/
e e
/ e e e
/ b
volved skin has been compromised by the initial in-
/ e
jury.42 Additional reduction of any pelvic external
e ee/ e
/ e b
pin placement is gluteal pillar placement with anterior
inferior iliac spine pins46 (Figure 4).
: / / / .
t m m
rotation deformity can be achieved by binding the
t . : / / t
/ .
t m
. m
knees together.
t p ss : /
Formal iliac crest or supra-acetabular external fixa-
p ss : /
Controlling Bleeding
t p p
t
hht t
tion is reserved for patients undergoing abdominal or
thoracic surgery in the operating room or as a delayed
measure to afford definitive stabilization (along with
t
hht t
In the absence of obvious sources of bleeding, an inter-
vention is needed to arrest hemorrhaging in a patient
with a pelvic ring injury and hemodynamic instability,
internal fixation, as needed) in some pelvic ring injury either ongoing or recurrent. The three potential sources
patterns. The supra-acetabular position has been of hemorrhage are arterial, venous, and fracture sur-
k eers
rs shown to be mechanically advantageous.44 The pelvic
C-clamp is an external fixation device used in some
k eers
r s
faces. Arterial bleeding is the most difficult to control
and is the primary source of lethal exsanguination. Two
b ooook b ook
centers for acute provisional stabilization of pelvic ring
oo
injuries. It differs from the other described devices in
b oooo
procedures are routinely used to treat arterial bleeding:
angioembolization or preperitoneal packing. Pelvic ar-
/
e e
/ eb / e
/e b
that it applies a compressive force on the posterior ring,
ee ee/e/e b
teriography with identification of arterial rupture and
/ t
///t m
effectively reducing fracture or dislocation seen in APC,
. . m
VS, and some CM injuries.45 In a grossly unstable pel-
: : / t.
///t m
embolization has been available since the 1990s, and it
.m
has proven to be an effective method of bleeding con-
s
tps : s
tps :
108
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
Figure 4 The use of anterior inferior iliac spine pin placement for better posterior control also avoids impingement of other
abdominal procedures, such as a colostomy (arrow).
keerrss k e rrss
e
bboooo k o o o
trol in the 3% to 10% of patients with pelvic fracture
b o k b o oo
sustained hemodynamic stability and correction of all
o
/
e e
/ e ee e
/ e b
requiring the procedure.47,48 The rate of successful
/
bleeding control is approximately 90%. Repeat angiog-
ee e
/ e b
coagulopathies have been achieved. In a small number
/
of patients, angiography and embolization will be re-
: / / t
/ .
t m m
raphy with embolization has proven worthwhile in pa-
. : / /t/.tm.m
quired after packing.54 To obtain a solid wall to pack
ss /
tients with signs of recurrent bleeding,49,50 although the
: ss : /
against, stabilization of the posterior pelvic ring can be
hhtttp hhtttp
danger of systemic embolization must be taken into ac- achieved with either a pelvic orthotic device or a pelvic
tp
count. Patients with extravasation of intravenous con-
trast material in the pelvis seen on a CT scan (blush tp
C-clamp. When compared with an angiography-
embolization protocol, a preperitoneal packing proto-
sign) and those older than 60 years with major pelvic col in pelvic ring trauma is advantageous because there
trauma may require embolization.51,52 Conversely, the is usually more ready access to the operating room than
absence of extravasation of intravenous contrast mate- to the angiography suite, and the need for transfusion
k eerss
rial on pelvic CT suggests the absence of important ar-
r
terial bleeding and negates the need for angiogra-
k e r
e s
r s is decreased.55
Pelvic trauma often results in morbidity and mortal-
bboooo k
phy.51,53
b o o
o o k b o oo
ity. Routine imaging with radiographs and CT can
o
/
e e
/ e e / / e b
Preperitoneal packing, rather than angiography and
e
embolization, is used in some centers as a routine mea-
e e / e
/ e b
guide resuscitation and initial stabilization strategies
and predicts transfusion requirements and concomitant
e
: / / / .
t m m
sure to control pelvic bleeding. In other centers, prep-
t .
eritoneal packing is reserved for patients in extremis,
: / / / .
t m m
injuries. Pelvic orthotic devices have largely supplanted
t .
standard external fixation and C-clamp fixation in the
t p ss
p : /
when treatment cannot be delayed while waiting for ac-
t p ss : /
temporary mechanical stabilization of the pelvic ring.
p
t
hht t
cess to an angiography suite. Preperitoneal packing also
can be used when pelvic hemorrhaging continues after
angiography and embolization. The technique involves
t
hht t
Institutional protocols, using angiography and embo-
lization and/or preperitoneal packing, should be estab-
lished for managing hemodynamic instability caused by
an infraumbilical midline skin and fascial incision, fol- intrapelvic hemorrhage.
lowed by packing of three to four abdominal sponges
k ee s
into the posterior pelvis at the level of the sacroiliac
rrs k ee
joints and at the pelvic cavity bilaterally to compressrs
r s Summary
b ooook b ook
the major vessels contributing to exsanguination. Prep-
oo
eritoneal packing can be done as a stand-alone proce-
b oooo
New treatment modalities and algorithms for managing
/
e e
/ eb ee/ e
/e b
dure (without violating the peritoneal cavity) or can be
/e/e b
polytraumatized patients have been recently proposed,
ee
/ t
///t m
combined with a laparotomy. The abdomen is closed
. . m
until the patient is returned to the operating room after
: / t.
///t m
mainly because of experience gained in treating injuries
.m
sustained in military combat. Newer hematologic ther-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
apies are increasingly being used in the field of trauma. 4. Frith D, Goslings JC, Gaarder C, et al: Definition and
k eers
rs There is an obvious need for transdisciplinary collabo-
keerrss drivers of acute traumatic coagulopathy: Clinical and
experimental investigations. J Thromb Haemost 2010;
b ooook o ook
ration in treating polytraumatized patients. Although
o
orthopaedic surgeons may not be knowledgeable about
b o
8(9):1919-1925.
b oo
o
/
ee/e b ee/ e
/ e b
all the nuances of resuscitation, they should be aware
of the most commonly used new therapies to ensure op-
ee/ e
/ e b
The authors discuss the development of a clinically rel-
evant definition of acute traumatic coagulopathy, an im-
juries.
: / t . m
.m
timal care of their patients with multiple traumatic in-
///t : / t
///t. m
. m
pairment of hemostasis that occurs early after injury.
s
tps : s
tps :
hhtttp hhtttp
5. Brohi K, Cohen MJ, Ganter MT, et al: Acute coagulop-
athy of trauma: Hypoperfusion induces systemic antico-
agulation and hyperfibrinolysis. J Trauma 2008;64(5):
Key Study Points 1211-1217.
• Understand the pathophysiology of posttrau- 6. Cohen MJ, Call M, Nelson M, et al: Critical role of ac-
k eers
rs matic coagulopathy and the principles of
damage-control resuscitation.
k eers
r s
tivated protein C in early coagulopathy and later organ
failure, infection and death in trauma patients. Ann
b ooook •
o ook
Recognize that there is a place for tourniquet use
b o
Surg 2012;255(2):379-385.
b o oo
o
A prospective cohort study of 203 major trauma pa-
/
e e
/ eb e e
/ b
in civilian trauma in the case of traumatic ampu-
/ e
tations or exsanguinating extremity wounds.
e ee/
protein C.e
/ e b
tients was performed to assess the activity of activated
•
/ t . m
. m
Understand the principles of DCO and how this
: / / t : / / t
/ .
t m
. m
: /
treatment fits into the overall picture of poly-
ss ss :
7.
/ Boffard KD, Riou B, Warren B, et al: Recombinant fac-
hhtttp hhtttp
tor VIIa as adjunctive therapy for bleeding control in se-
tp tp
traumatized patients.
verely injured trauma patients: Two parallel random-
ized, placebo-controlled, double-blind clinical trials.
J Trauma 2005;59(1):8-18.
8. Wade CE, Eastridge BJ, Jones JA, et al: Use of recombi-

rrss rrss
nant factor VIIa in US military casualties for a five-year
o ke
ke 1.
k
Brown JB, Cohen MJ, Minei JP, et al: Debunking the
o e
k e
period. J Trauma 2010;69(2):353-359.
oo
e bboo o e b o
b o
survival bias myth: Characterization of mortality during
o
the initial 24 hours for patients requiring massive trans-
A review of more than 2,000 patients entered in the
e b o o
Joint Theater is presented. This study was undertaken to
b
/
e / e m e / / e
fusion. J Trauma Acute Care Surg 2012;73(2):358-364.
e ee/ / e
assess how deployed physicians are using recombinant
factor VIIa and its effect on casualty outcomes.
m
: / / t
/ .
t . m
The effect on mortality of the ratio of FFP, PRBCs, and
/
platelets was analyzed in this prospective study of
: / /
/t/.t .m
ss : s9.
s : Hauser CJ, Boffard K, Dutton R, et al: Results of the
hhtttp hhtttp
1,961 adult patients with blunt trauma and hemorrhagic
tp tp
CONTROL trial: Efficacy and safety of recombinant
shock. Six hundred four patients in the cohort received a activated factor VII in the management of refractory
massive transfusion (> 10 units PRBCs) in the first 24 traumatic hemorrhage. J Trauma 2010;69(3):489-500.
hours after injury. The time course of mortality was spe-
cifically studied to rule out the possibility that a survival This phase III randomized clinical trial evaluated the ef-
bias accounted for the decreased mortality reported in ficacy and the safety of recombinant factor VIIa as an ad-
previous studies. High ratios of FFP:PRBCs and platelets: junct to direct hemostasis in patients with major trau-
k eers
rs r
PRBCs were associated with decreased mortality at all
k e e s
r
time points, suggesting that an FFP:PRBC transfusion ra-s matic injuries. The authors reported on 573 patients (481
with blunt and 92 with penetrating trauma) who bled
bboooo k tio of 1:1 is ideal.
b o o
o o k b o oo
four to eight red blood cell units within 12 hours of in-
o
jury and were still bleeding despite strict damage control
/
e e
/ e 2.
e / e
/ e b
Brockamp T, Nienaber U, Mutschler M, et al: Predict-
e / e e b
resuscitation and surgical management. Patients were as-
ee /
signed to receive recombinant factor VIIa (200 µg/kg ini-
/ / t
/ .
t m
ing on-going hemorrhage and transfusion requirement
. m
after severe trauma: A validation of six scoring systems
: : / t . m
. m
tially; 100 µg/kg at 1 hour and 3 hours) or placebo. In-
/ / t
ss : /
and algorithms on the TraumaRegister DGU®. Crit Care
t p p t p ss
p : /
tensive care unit management was standardized. Primary
outcome was 30-day mortality. Enrollment was termi-
t
2012;16(4):R129.
hht t
The authors present a retrospective internal and exter-
nal validation of six scoring systems and algorithms
t
hht t nated at 573 of 1,502 planned patients, partially because
of unexpected low mortality prompted by futility analy-
sis (10.8% versus 27.5% planned/predicted). Recombi-
(four civilian and two military systems) to predict the nant factor VIIa reduced blood product use but did not
risk of massive transfusion at a very early stage after affect mortality compared with placebo. Modern
trauma on one single data set of severely injured pa- evidence-based treatment of trauma patients lowers mor-
k eers
rs tients derived from the TraumaRegister DGU database
k eer
(2002-2010). Data from 56,573 patients were screeneds
r s tality, making outcomes studies increasingly difficult.
b ooook b oook
to extract one complete data set matching all variables
o
10.
o oo
Shakur H, Roberts I, Bautista R, et al: Effects of
b o
/
e e
/ eb ee/ e
/e b
needed to calculate all systems assessed in this study.
e /e/e b
tranexamic acid on death, vascular occlusive events, and
blood transfusion in trauma patients with significant
e
3.
: / t
///t. m
Brohi K, Singh J, Heron M, Coats T: Acute traumatic
. m
coagulopathy. J Trauma 2003;54(6):1127-1130.
: / t.
///t m
haemorrhage (CRASH-2): A randomised, placebo-
.m
controlled trial. Lancet 2010;376(9734):23-32.
s
tps : s
tps :
110
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
TXA may reduce bleeding in patients undergoing elec- ism of death in 230 of 287 patients (80%). In patients
k eers
rs rrss
tive surgery. The authors, in a randomized controlled
kee
trial, assessed the effects of the early administration of a
with hemorrhage, the bleeding body regions that ac-
ook ook
counted for mortality were the torso (48%), an extrem-
b oo b o
short course of TXA acid on death, vascular occlusive
o b o oo
ity (31%), and junctional areas (neck, axilla, and groin;
o
/
ee/e b patients.
ee e
/ e b
events, and the receipt of blood transfusion in trauma
/ e e
/ e b
21%). Fifty-one percent of the casualties presented in
/
extremis, with cardiopulmonary resuscitation at presen-
e
11.
/ t
///t. m
.m
Roberts I, Shakur H, Afolabi A, et al: The importance
: : / t
///t. m
tation. Hemorrhage is a major mechanism of death in
. m
combat injuries, underscoring the necessity for initia-
s
tps :
of early treatment with tranexamic acid in bleeding
s
tps : tives to mitigate bleeding, particularly in the prehospital
hhtttp hhtttp
trauma patients: An exploratory analysis of the environment.
CRASH-2 randomised controlled trial. Lancet 2011;
377(9771):1096-1101, e1-e2. 15. Kragh JF Jr, Walters TJ, Baer DG, et al: Survival with
The CRASH-2 trial showed that early administration of emergency tourniquet use to stop bleeding in major
TXA safely reduces mortality from bleeding in patients limb trauma. Ann Surg 2009;249(1):1-7.
with traumatic injuries. It was predicted that approxi-
k eers
rs r
mately 112,000 deaths might be averted annually if
k ee s
r s 16. Kragh JF Jr, Wade CE, Baer DG, et al: Fasciotomy rates
ook ook
trauma patients received TXA within 3 hours of injury.
b oo b oo b o oo
in operations enduring freedom and iraqi freedom: As-
o
sociation with injury severity and tourniquet use.
/
e e
/ eb 12.
e e
/ e b
Ker K, Kiriya J, Perel P, Edwards P, Shakur H,
/
Roberts I: Avoidable mortality from giving tranexamic
e ee/ e
/ e b
J Orthop Trauma 2011;25(3):134-139.
During the period of the study (between 2003 and
: // /.tm m
acid to bleeding trauma patients: An estimation based
t .
on WHO mortality data, a systematic literature review
: / / t
/ .
t m
. m
2006), fasciotomy rates increased as a result of a com-
ss : /
and data from the CRASH-2 trial. BMC Emerg Med
ss : / bination of factors: increasing injury severity, increasing
hhtttp
tp hhtttp
tp
use of tourniquets, and increased awareness of the need
2012;12:3.
to perform prophylactic fasciotomies. The authors
The CRASH-2 trial showed that early administration of concluded that further research is needed to determine
TXA safely reduces mortality from bleeding in trauma the optimum rate of fasciotomy in a combat environ-
patients. Based on data from the CRASH-2 trial, global ment.
mortality data, and a systematic literature review, the
authors estimated the number of premature deaths that
keerrss
might be averted worldwide every year with TXA.
k e rrss
e
17. Morrison JJ, Hunt N, Midwinter M, Jansen J: Associ-
ated injuries in casualties with traumatic lower extrem-
bboooo k b o o k
Based on data from the World Health Organization and
o
their systematic literature review, the authors estimated
o b o oo
ity amputations caused by improvised explosive devices.
o
Br J Surg 2012;99(3):362-366.
/
e e
/ e e e
/ b
an annual decrease of approximately 400,000 deaths in
/ e
hospitalized patients with bleeding trauma. If patients
e e / e
/ e b
IEDs pose a substantial threat to military personnel, of-
e
: / / t
/ .
t m
received TXA within 1 hour of injury, approximately
. m
128,000 deaths might be averted. If patients received
: / /t/.tm
ten resulting in lower extremity amputation and pelvic
.m
injury. CT is necessary to delineate the extent of the in-
s : /
TXA within 3 hours of injury, approximately 112,000
s ss : /
jury, but it is unclear whether CT should be performed
hhtttp
tp hhtttp
tp
deaths might be averted. Country-specific estimates during or after surgery. In this study, 278 traumatic
show that the largest numbers of averted deaths would lower extremity amputations occurred in 169 combat
occur in India and China. personnel. Sixty-nine of the personnel were killed in ac-
tion, 16 later died from their wounds, and 84 were
13. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ: wounded in action but survived. Of the 100 casualties
Military Application of Tranexamic Acid in Trauma who reached the hospital alive, 9 thoracotomies, 1 cran-
k eers
rs
Emergency Resuscitation (MATTERs) Study. Arch Surg
2012;147(2):113-119.
k e r
e s
r s iotomy, and 34 laparotomies were performed. All head
or torso injuries that required immediate surgery were
bboooo k b o o o k
This was a retrospective observational study comparing
o b o oo
clinically apparent on admission. Higher levels of ampu-
o
tation were associated with greater injury burden and
/
e e
/ e e e
/ b
TXA administration with no TXA in patients receiving
/ e
at least 1 unit of PRBCs. A subgroup of patients receiv-
e ee/ e
/ e b
mortality. Intraoperative CT had little value in identify-
ing clinically important covert injuries.
/ / t t m
ing massive transfusion (≥ 10 units of PRBCs) was also
. . m
examined. The purpose was to characterize the contem-
: / : / / t
/ .
t m
. m
ss : /
porary use of TXA in combat injury and assess the ef-
t p p t p ss
18.
p : /
Benfield RJ, Mamczak CN, Vo KC, et al: Initial predic-
t
fect of its administration on total blood product use,
hht t
thromboembolic complications, and mortality. t
hht t
tors associated with outcome in injured multiple trau-
matic limb amputations: A Kandahar-based combat
hospital experience. Injury 2012;43(10):1753-1758.
14. Eastridge BJ, Hardin M, Cantrell J, et al: Died of An early 30-day follow-up study was performed to eval-
wounds on the battlefield: Causation and implications uate combat personnel with IED injuries with bilateral
for improving combat casualty care. J Trauma 2011; lower extremity amputations, with and without pelvic
k eers
rs71(1, suppl):S4-S8.
k eers
r s and perineal involvement. The results showed that the
injuries were survivable. Standard measures of injury
ook ook
In this study, died of wounds casualties (n = 558) ac-
b oo b o
counted for 4.56% of the military personnel not return-
o b oooo
and predictors of survival bore little relationship to ob-
/
e e
/ eb e e
/e b
ing to duty because of battle injuries over the study pe-
/
riod. Traumatic brain injury was the predominant injury
e e /e/e b
served outcomes and may require reevaluation. Long-
term follow-up is needed to assess the extent of func-
e
/ t
///t m
leading to death in 83% of the patients, whereas hemor-
. . m
rhage from major trauma was the predominant mechan-
: : / t.
///t m
tional recovery and the overall morbidity and mortality
.m
of patients with these types of IED injuries.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
19. Beckett A, Pelletier P, Mamczak C, Benfield R, Elster E: 29. Crowl AC, Young JS, Kahler DM, Claridge JA,
k eers
rs rrs
Multidisciplinary trauma team care in Kandahar, Af-
kee s
ghanistan: Current injury patterns and care practices.
Chrzanowski DS, Pomphrey M: Occult hypoperfusion
ook ook
is associated with increased morbidity in patients under-
b oo
Injury 2012;43(12):2072-2077.
b o o b o oo
going early femur fracture fixation. J Trauma 2000;
o
/
ee/e b ee/ e
/ e b
The authors report on 2,599 patients with multiple
traumatic injures sustained in Afghanistan. The most
ee/ e
48(2):260-267.
/ e b
t . mm
common source of injury was an IED blasts (915 pa-
: / ///t .
tients) followed by gunshot wounds (327 patients).
30.
: / t
///t. m
. m
Sun T, Wang X, Liu Z, Chen X, Zhang J: Plasma con-
centrations of pro- and anti-inflammatory cytokines and
s
tps : s
tps :
hhtttp hhtttp
Nineteen patients had triple amputations as a result of outcome prediction in elderly hip fracture patients.
injuries from IEDs. One hundred twenty-seven patients Injury 2011;42(7):707-713.
received massive transfusions. The in-hospital mortality In elderly patients with a hip fracture, cytokine concen-
rate was 4.45%; 4,106.24 operating room hours were trations were an independent predictor of poor out-
logged to complete 1,914 patient cases. The mean num- comes. Inflammatory response played an important role
ber of procedures per case in 2009 was 1.27, compared in postoperative organ dysfunction.
with 3.11 in 2010. Multinational and multidisciplinary
k eers
rs rs
r s
care was required for the large number of severely in-
k ee 31. Higgins TF, Horwitz DS: Damage control nailing.

jured patients treated at Kandahar Airfield in Afghani-
b ooook stan.
b ooook b oo
J Orthop Trauma 2007;21(7):477-484.
o o
/
e e
/ eb 20.
e/ e
/ e b
Burch JM, Ortiz VB, Richardson RJ, Martin RR, Mat-
e
32.
ee/ e
/ e b
Reynolds MA, Richardson JD, Spain DA, Seligson D,
// t/.tm
tox KL, Jordan GL Jr: Abbreviated laparotomy and
. m
planned reoperation for critically injured patients. Ann
: : / / t
/ .
t m
Wilson MA, Miller FB: Is the timing of fracture fixation
. m
important for the patient with multiple trauma? Ann
ss :
Surg 1992;215(5):476-484.
/ ss : /
Surg 1995;222(4):470-481.
21.
hhtttp
tp
Henry SM, Tornetta P III, Scalea TM: Damage control
hhtttp
for devastating pelvic and extremity injuries. Surg Clin
North Am 1997;77(4):879-895.
tp33. Morshed S, Miclau T III, Bembom O, Cohen M, Knud-
son MM, Colford JM Jr: Delayed internal fixation of
femoral shaft fracture reduces mortality among patients
with multisystem trauma. J Bone Joint Surg Am 2009;
22. Pape HC, Auf’m’Kolk M, Paffrath T, Regel G, Sturm 91(1):3-13.
keerrss k e rrss
JA, Tscherne H: Primary intramedullary femur fixation
e 34. Pape H, Stalp M, Griensven M, Weinberg A, Dahlweit
bboooo k b o o o k
in multiple trauma patients with associated lung contu-
sion—a cause of posttraumatic ARDS? J Trauma 1993;
o b o oo
M, Tscherne H: Optimal timing for secondary surgery
o
/
e e
/ e
34(4):540-548.
ee/ e
/ e b e e
/ e b
in polytrauma patients: An evaluation of 4,314 serious-
/
injury cases. Chirurg 1999;70(11):1287-1293.
e
23.
: / / t
/ .
t m m
Pape HC, Grimme K, Van Griensven M, et al: Impact
. : / /t/.tm.m
ss : /
of intramedullary instrumentation versus damage con- 35.
ss : /
Brundage SI, McGhan R, Jurkovich GJ, Mack CD,
hhtttp hhtttp
trol for femoral fractures on immunoinflammatory pa- Maier RV: Timing of femur fracture fixation: Effect on
tp
rameters: Prospective randomized analysis by the
EPOFF Study Group. J Trauma 2003;55(1):7-13. tp outcome in patients with thoracic and head injuries.
J Trauma 2002;52(2):299-307.
24. Pape HC, Marcucio R, Humphrey C, Colnot C, Knobe 36. Demetriades D, Karaiskakis M, Toutouzas K, Alo K,
M, Harvey EJ: Trauma-induced inflammation and frac- Velmahos G, Chan L: Pelvic fractures: Epidemiology
k eers
rs
ture healing. J Orthop Trauma 2010;24(9):522-525.
e r
e s
r s
This article reviews the initial inflammatory response to
k
and predictors of associated abdominal injuries and out-
comes. J Am Coll Surg 2002;195(1):1-10.
bboooo k b o o
trauma as it pertains to musculoskeletal healing.
o o k 37.
b o oo
o
Giannoudis PV, Grotz MR, Tzioupis C, et al: Preva-
/
e e
/ e 25.
e/
contusion. Am Surg 1991;57(12):780-784.e
/ e b
Stellin G: Survival in trauma victims with pulmonary
e ee/ e
/ e b
lence of pelvic fractures, associated injuries, and mortal-
ity: The United Kingdom perspective. J Trauma 2007;
: / / t
/ .
t m
. m t . m
. m
63(4):875-883.
: / / / t
26.
t p ss
p : /
Rotondo MF, Schwab CW, McGonigal MD, et al:
″Damage control″: An approach for improved survival
t p
38. ss
p : /
Koo H, Leveridge M, Thompson C, et al: Interobserver
t
hht t
in exsanguinating penetrating abdominal injury.
J Trauma 1993;35(3):375-383.
t
hht t reliability of the Young-Burgess and Tile classification
systems for fractures of the pelvic ring. J Orthop
Trauma 2008;22(6):379-384.
27. Townsend RN, Lheureau T, Protech J, Riemer B, Simon
D: Timing fracture repair in patients with severe brain 39. Burgess AR, Eastridge BJ, Young JW, et al: Pelvic ring
k eers
rs 44(6):977-983.
k eers
injury (Glasgow Coma Scale score < 9). J Trauma 1998;
r s disruptions: Effective classification system and treat-
ment protocols. J Trauma 1990;30(7):848-856.
b ooook b oook
o b oooo
/
e e
/ eb 28.
e /e b
Pape HC, Giannoudis P, Krettek C: The timing of frac-
/ e
ture treatment in polytrauma patients: Relevance of
e
40.
e /e/e b
Routt ML Jr, Falicov A, Woodhouse E, Schildhauer TA:
Circumferential pelvic antishock sheeting: A temporary
e
183(6):622-629.
: / t
///t m
damage control orthopedic surgery. Am J Surg 2002;
. . m : / t.
///t
S3-S6.m
resuscitation aid. J Orthop Trauma 2006;20(1, suppl):
.m
s
tps : s
tps :
112
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
41. Tan EC, van Stigt SF, van Vugt AB: Effect of a new pel- 49. Fang JF, Shih LY, Wong YC, Lin BC, Hsu YP: Repeat
k eers
rs rrss
vic stabilizer (T-POD®) on reduction of pelvic volume
kee
and haemodynamic stability in unstable pelvic fractures.
transcatheter arterial embolization for the management
of pelvic arterial hemorrhage. J Trauma 2009;66(2):
b ooook Injury 2010;41(12):1239-1243.

b o ook
o
429-435.
b o oo
o
/
ee/e b / e e b
The authors describe 15 patients with a prehospital un-
ee /
treated, unstable pelvic fracture with signs of hypovo- 50.
e / e
/ e b
Shapiro M, McDonald AA, Knight D, Johannigman JA,
e
: / t
///t. m
.m
lemic shock treated with the T-POD device (Pyng Med-
ical). Application of the pelvic stabilizer provided a
: / t
///t. m
. m
Cuschieri J: The role of repeat angiography in the
management of pelvic fractures. J Trauma 2005;58(2):
s
tps : s
tps : 227-231.
hhtttp hhtttp
60% reduction in the rate of symphyseal diastasis. The
patients’ mean arterial pressure increased significantly
from 65.3 to 81.2 mm Hg (P = 0.03), and the 51. Ryan MF, Hamilton PA, Chu P, Hanaghan J: Active ex-
mean heart rate declined from 107 beats per minute to travasation of arterial contrast agent on post-traumatic
94 (P = 0.02). In the acute setting, the T-POD device has abdominal computed tomography. Can Assoc Radiol J
a clear compressive effect on pelvic volume in unstable 2004;55(3):160-169.
pelvic fractures.
k eers
rs k eers
r s 52. Kimbrell BJ, Velmahos GC, Chan LS, Demetriades D:
ook ook
42. Krieg JC, Mohr M, Ellis TJ, Simpson TS, Madey SM, Angiographic embolization for pelvic fractures in older
b oo b o
Bottlang M: Emergent stabilization of pelvic ring inju-
o b o oo
patients. Arch Surg 2004;139(7):728-733.
o
/
e e
/ eb e e
/
cal trial. J Trauma 2005;59(3):659-664.
e b
ries by controlled circumferential compression: A clini-
/ e 53.
ee/ e
/ e b
Stephen DJ, Kreder HJ, Day AC, et al: Early detection
: // t/.tm
. m : / / t
/ .
t m
. m
of arterial bleeding in acute pelvic trauma. J Trauma
43.
ss : /
Croce MA, Magnotti LJ, Savage SA, Wood GW II,
ss : /
1999;47(4):638-642.
hhtttp hhtttp
Fabian TC: Emergent pelvic fixation in patients with ex-
204(5):935-942. tp
sanguinating pelvic fractures. J Am Coll Surg 2007;
tp54. Burlew CC, Moore EE, Smith WR, et al: Preperitoneal
pelvic packing/external fixation with secondary angio-
embolization: Optimal care for life-threatening hemor-
44. Kim WY, Hearn TC, Seleem O, Mahalingam E, Ste- rhage from unstable pelvic fractures. J Am Coll Surg
phen D, Tile M: Effect of pin location on stability of 2011;212(4):628-637.
rrss rrss
pelvic external fixation. Clin Orthop Relat Res 1999; The authors found that preperitoneal pelvic packing and
o ke
ke
361:237-244.
o k e
k e
external fixation were effective in controlling hemor-
oo
rhage from unstable pelvic fractures. None of the high-
e bboo o45.
e b o o o
Ganz R, Krushell RJ, Jakob RP, Küffer J: The antishock
b e b o
b o
risk patients in this study died because of pelvic bleed-
/
e / e m ee/ / e
pelvic clamp. Clin Orthop Relat Res 1991;267:71-78.
ee/
ing. Secondary angioembolization was needed in few
/ e
patients, permitting the selective use of this resource-
m
46.
/ t .
t . m
Reynolds JH, Attum B, Acland RJ, Giannoudis P,
: / / / : / /t/.t .m
demanding intervention. In addition, preperitoneal pel-
vic packing and external fixation temporizes arterial
/
s :
Roberts CS: Anterior versus posterior pin placement of
s ss :
hemorrhage, providing valuable transfer time for facili-
hhtttp
tp hhtttp
tp
pelvic C-clamp in relationship to anatomical structures:
ties without angiography. With other urgent surgical in-
A cadaver study. Injury 2008;39(8):865-868. terventions required in more than 85% of patients,
combining these procedures with preperitoneal pelvic
47. Cook RE, Keating JF, Gillespie I: The role of angiogra- packing and external fixation for surgical control of pel-
phy in the management of haemorrhage from major vic hemorrhage appears to optimize patient care.
fractures of the pelvis. J Bone Joint Surg Br 2002;84(2):
k eers
rs
178-182.
k e r
e s
r s 55. Osborn PM, Smith WR, Moore EE, et al: Direct retro-
peritoneal pelvic packing versus pelvic angiography: A
bboooo k
48.
o o o k
Starr AJ, Griffin DR, Reinert CM, et al: Pelvic ring dis-
b o b o oo
comparison of two management protocols for haemo-
o
/
e e
/ e e / e
/ e b
ruptions: Prediction of associated injuries, transfusion
requirement, pelvic arteriography, complications, and
e
40(1):54-60.
ee/ e
/ e b
dynamically unstable pelvic fractures. Injury 2009;
: / / t
/ t m
mortality. J Orthop Trauma 2002;16(8):553-561.
. . m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 10
e rs
rs e rrss
oo
kMedical
ook e Issues for othek
ook
o Athlete
e o oo
o
/e/ebb Brian T. Feeley, MD
e / e
/ b
e b
Sarina Behera, MD
e /
Anthony C. Luke, MD e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
Physiology of Exercise
Introduction
The conversion of nutrients into energy is governed by
k eerss k eers
The day-to-day practice of sports medicine for athletes
r r
typically involves more medical issues than orthopaedic s either anaerobic or aerobic mechanisms, with consider-
able overlap between each type. With short, high-
b ooook b oook
issues. A working knowledge of these issues and of the
o b o oo
intensity athletic events such as powerlifting or sprint-
o
ing, the adenosine triphosphate/phosphocreatine
/
e e
/ eb e/ e
/ e b
protocols for risk concerns associated with each sport is
key for physicians covering athletic events. This chapter
e ee/ e
/ e b
system fuels high-intensity bursts that last 5 to 10 sec-
// t/ tm
highlights the nonorthopaedic issues that need to be con-
. . m
sidered on the field, in the training room, and at the of-
: / / t .
t m
onds. This short-term anaerobic energy system is used
. m
for activities that require up to 90 seconds of effort
: /
fice.
ss : / s : /
when adequate oxygen for aerobic activity is not avail-
s
hhtttp
tp hhtttp
tp
able. Muscle cells primarily use glycolysis as their pri-
mary energy source, but this mechanism results in a
buildup of lactate within the cells. When the lactate
Sports Nutrition
threshold level is reached, the ability of cells to work ef-
A proper nutrition regimen is nearly as important as an fectively is diminished because of increased muscle
acidity and the inhibition of fatty acid breakdown,
rrss rrss
athlete’s training and is recognized in position state-
o ke
ments by the American Dietetic Association, the Dieti-
ke o
tians of Canada, and the American College of Sports
k e
k e
causing fatigue. The aerobic energy system is primarily
used for most athletic activities. The metabolic activity
oo
e bboo o e b o o
Medicine.1 With any nutrition regimen in an athlete,
b o e b o
b o
takes place in the mitochondria, and carbohydrates,
/
e / e ee/ e
the goal is to achieve the appropriate caloric intake to
/
support daily metabolic and physical demands. The
m m ee/
fats, and proteins are used as substrates for adenosine
/ e
triphosphate in the presence of oxygen via the Krebs
: / / t
/ .
t . m
timing of caloric intake should be monitored to maxi-
/ : / /
/t/.t .m
cycle and the electron transport chain.1
ss :
mize training and competition potential, especially in
ss :
hhtttp hhtttp
elite athletes.
tp tp
Macronutrients
The current recommendation for caloric intake by Individual protein requirements vary considerably
the US Department of Health and Human Services is based on athletic activity, but generally should be
approximately 2,000 calories per day (a minimum of higher than normal in athletes to help promote and
1,200 cal/day for women and 1,800 cal/day for men). maintain adequate muscle mass (Table 1). Protein is a
For athletes, the caloric intake is much higher; men re- primary contributor to tissue repair and regeneration
k eerss
quire up to 4,000 to 5,000 cal/day, and women require
r k
up to 2,000 to 3,000 cal/day. However, athletes typi-
e r
e s
r s and is the main component of the metabolic, transport,
and hormonal systems. Well-planned vegetarian diets
bboooo k o o o
cally are unable to maintain the necessary caloric in-
b o k b o oo
seem to effectively support athletic performance; how-
o
/
e e
/ e e / / e b
take to support their energy expenditures.2 Low energy
e
intake is a major nutritional concern for female athletes
e e / e
/ e b
ever, this finding is not conclusive.4 Although most veg-
etarian diets provide the recommended amount of daily
e
/ / t
/ .
t m
because a negative energy balance can lead to weight
. m
loss and disruption of the endocrine and metabolic
: : / / t
/ .
t m
. m
protein, such diets often contain less protein than non-
ss : /
functions. The US Department of Health and Human
t p p t p ss : /
vegetarian diets, and plant-based proteins are less well
digested than animal-based proteins. Therefore, the rec-
p
t
hht t
Services provides dietary guidelines for the energy rec-
ommendations for athletes of all levels.3 t
hht t
ommended protein intake for vegetarian diets should
be approximately 10% higher. Protein consumption by
vegans is a potential concern because their diet is lim-
ited to the amino acids lysine, threonine, tryptophan,
Dr. Luke or an immediate family member has stock or and methionine.5
k eerss
stock options held in SportzPeak; and has received re-
r k
search or institutional support from Genzyme. Neither
eers
r s Ideally, carbohydrate consumption should be based
on a variety of fruits, vegetables, and grains spread out
b ooookof the following authors nor any immediate family
b oook
o b oooo
among the daily training meals. The selection of
healthy carbohydrates in modern society is made
/
e e
/ eb e / e
/e b
member has received anything of value from or has
stock or stock options held in a commercial company or
e ee/e/e b
difficult by the convenience of prepackaged foods con-
/ t
///t m
institution related directly or indirectly to the subject of
. . m
this chapter: Dr. Feeley and Dr. Behera.
: : / t.
///t m
taining carbohydrates derived from high-fructose corn
.m
syrup. Fructose-based carbohydrates can promote de
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Recommended Intake of Macronutrients
b o ook
o b o oo
o
/
ee/e b Macronutrient
ee/ e
/ e b
Recommended Intake
ee/ e
/ e b Percentage of Daily Caloric Intake
Protein
: / t
///t. m
.m
Endurance: 1.2–1.4 g/kg
Strength: 1.6–1.8 g/kg
: / t
///t. m
. m
10%–35%
s
tps : s
tps :
hhtttp hhtttp
Carbohydrate 5–10 g/kg 40%–65%
Dietary Fat 20%–35%
(Adapted from US Department of Health and Human Services. Dietary Guidelines of Americans. Washington, DC, 2005. http://www.health.gov/DietaryGuidelines.
Accessed April 8, 2013.)
k eers
rs Table 2
k eers
r s
b ooook Important Micronutrients for Athletes

b ooook b o oo
o
/
e e
/ eb Micronutrient
e/ e
/ e
Function
e b ee/ e
/ e b
B vitamins (thiamin, riboflavin,
: // t/.tm
. m : / / t
/ .
t m
. m
Involved in optimum energy production and the repair of muscle tissue. Folate and vitamin
niacin, B6, folate, B12)
ss : / s : /
B12 are required for the production of red blood cells.
s
hhtttp
tp hhtttp
tp
Vitamin D Required for calcium absorption and the regulation of serum calcium and phosphate levels.
Regulates the development and homeostasis of the bone. Low levels often found in indoor
athletes.
Vitamins C and E Antioxidants that inhibit oxidative stress on the muscles and other cells. May be beneficial in
limiting inflammation and muscle soreness.
rrss rrss
Calcium Important for bone growth and the maintenance and repair of bone tissue, blood calcium
o ke
ke o k e
levels, muscle contraction, and nerve signal generation.
k e oo
e bboo o Zinc
e b o
b o e b o
Important in the growth, building, and repair of muscle tissue, energy production, and
o b
immune status. Female athletes can have low levels.
o
/
e / e Magnesium
m ee/ / e m e / / e
Involved in the metabolism of fat and proteins, regulates membrane stability, and has
e
: / /
/ t
/ .
t . m : / /
/t/.t .m
important roles in multiple hormones. Athletes participating in wrestling, ballet,
gymnastics, and tennis often have low levels.
ss : ss :
hhtttp
tp
novo lipogenesis, dyslipidemia, and increased visceral
adiposity.6 Sport drinks and bars should be considered
hhtttp
tp Hydration
Hydration is an often overlooked aspect of nutrition,
supplemental to a well-balanced diet. especially during prolonged training regimens. The seri-
Dietary fat plays several important roles, including ous effects of dehydration, especially during hot
k eers
rs protection from injury, providing thermal insulation,
k e r
e s
r s weather, include heat stroke, heat-related illness, and
death. A loss of more than 2% of body weight as a re-
bboooo k and serving as a vitamin carrier. Fat is also the primary
o o
o
source of reserve energy in the body: plasma triglycer-
b o k b o oo
sult of dehydration can result in a decrease in athletic
o
/
e e
/ e / e
ides can supply 30% to 80% of the energy necessary
ee / e b
for sustained physical activity. The athlete should be
e e
/ e b
performance; at higher levels, this loss causes mental
/
and cognitive deficits.8 Clinically, athletes experiencing
e
: / / t . m
. m
encouraged to choose foods that contain essential fatty
/ t : / / t
/ .
t m
. m
dehydration present with muscle cramps, fatigue, and
t p ss
p : /
acids (such as omega-3 fatty acids) and have higher lev-
els of unsaturated fats instead of high levels of satu-
t p ss
p : /
dizziness. Athletes who perspire excessively, those in
hot climates, and those participating in preseason activ-
rated fats. t
hht t t
hht t ities are more likely to experience dehydration. Hy-
ponatremia (a serum sodium level < 135 mmol/L) can
result from prolonged, heavy sweating with a concom-
Micronutrients and Other Factors itant failure to replenish sodium or from overhydra-
Micronutrients play an important role in energy pro- tion.
k eers
rs
duction, maintenance of bone and muscle health, im-
mune function, and protection against oxidative dam-
k eers
r s The guidelines for adequate hydration during exer-
cise have been published by the American College of
b ooook age. Exercise adds stress to many of these pathways,
b oook
o
which requires maintaining an appropriate level of mi-
b ooo
Sports Medicine, and specific guidelines for environ-
o
mental activities also have been published.8 It is recom-
/
e e
/ eb ee/ e
/e b
cronutrients at all times for physiologic health.7 The
/e/e b
mended that fluid intake begin 4 hours before training,
ee
/ t
///t
tant for athletes are listed in Table 2.
: m
most common vitamins and minerals considered impor-
. . m : / t.
///t m
with a goal of drinking 5 to 7 mL per kg of body
.m
weight of either water or a sports beverage. No data
s
tps : s
tps :
116
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 10: Medical Issues for the Athlete
k ee s
Table 3
rrs keerrss Eating Disorders and the Female Athlete Triad
b ooookThe SCOFF Items for Screening Eating

Disorders in Primary Care
b o ook
o b oo
Female athletes who participate in sports for which
o o
body image is important, such as gymnastics, dance,
/
ee/e b ee
(1) Do you make yourself sick because you feel/ e
/ e b ee/ e
/ e b
swimming, and figure skating, have a high prevalence
of disordered eating. Eating disorders can develop in
uncomfortably full?
: / t
///t. m
.m : / t
///t. m
. m
athletes across all sports and of both sexes. The clinical
s :
(2) Do you worry that you have lost control over how much
tps s
tps : consequences of eating disorders include mental health
hhtttp hhtttp
you eat? problems, poor athletic performance, bradycardia and
(3) Have you recently lost more than 15 lb in a 3-month other arrhythmias, and the female athlete triad. Ath-
period? letes can be evaluated for eating disorders by using the
(4) Do you believe yourself to be fat when others say you are SCOFF questionnaire (Table 3), which is a brief five-
too thin? question form that reliably screens for anorexia ner-
vosa and bulimia nervosa.11
k eers
(5) Would you say that food dominates your life?
rs k eers
r s The female athlete triad represents the spectrum of
(Reproduced with permission from Morgan JF, Reid F, Lacey JH. The SCOFF
b ooook1999;319:1467-1468.)
b oook
questionnaire: Assessment of a new screening tool for eating disorders. Br Med J
o b o oo
energy availability, menstrual dysfunction, and bone
o
mineral density. The pathologic forms of this triad re-
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
sult in amenorrhea, osteoporosis, and disordered eat-
ing. Research suggests osteopenia and exercise-related
// t/.tm
. m
clearly support the use of electrolyte beverages during
: : / / t
/ .
t m
. m
menstrual changes represent early diagnostic criteria
ss : /
competition to improve athletic performance, although
ss : / for this disorder, and disordered eating is not necessar-
hhtttp
tp hhtttp
tp
ily part of the triad in all female athletes. The American
some studies suggest that these drinks help maintain College of Sports Medicine developed guidelines for the
performance during endurance exercises.8 screening, diagnosis, and treatment of the female ath-
lete triad in 1997, and updated the guidelines in
Caffeine and Other Supplements 2007.12 This model emphasizes the fact that each com-
The emphasis on the use of sports supplements to im- ponent can exist on its own, but the three are interre-
keerrss
prove performance has increased, with an overwhelm-
ing number of products that promise muscle mass in-
k e rrss
e
lated and can progress at different rates. Treatment for
athletes with disordered eating currently focuses on a
bboooo k o
crease, fast recovery, and improved outcomes in athletic
b o
o o k b o oo
team approach that includes the physician, the family,
o
/
e e
/ e
events. Despite the prevalence of these products, very
e /
few have led to improved performance. Most supple-
e e
/ e b e / e
/ e b
the coach, a bone health specialist, a dietitian, and a
mental health worker.12
e
: / / / .
t m m
ments have not shown any benefit or have dangerous
t .
side effects. Banned supplements can be identified by
: / /t/.tm.m
ss : / ss : /
hhtttp hhtttp
the World Anti-Doping Agency (http://www.wada-
tp tp
Concussion
ama.org). Other supplements, such as sports drinks,
bars, and gels, are commonly used as dietary supple- Concussion has become one of the most publicized ath-
ments to improve recovery and have mild beneficial ef- letic injuries, with long-term health consequences that
fects on sports performance outcomes. include altered cognitive status, mental illness, and
Caffeine, a naturally occurring substance that stimu- death. With the increased awareness of concussion as a
eers
lates the central nervous system, has had ergogenic ef-
rs
fects in studies across multiple sports.9 Caffeine is also
k k e r
e s
r s significant health risk, considerable effort has been in-
vested in improving the definition and the diagnosis of
bboooo k
theorized to decrease the perception of effort, thus al-
b o o
o o k b o oo
a concussion, as well as the management of postcon-
o
cussion injuries. Although knowledge regarding the
/
e e
/ e e / / e
tary person.10 Caffeine is currently on the World Anti-
e b
lowing a higher level of effort, especially in the seden-
e e / e
/ e b
short-term consequences of concussions is much im-
e
/ / t
/ t m
Doping Agency monitoring program, and the National
. . m
Collegiate Athletic Association will ban any athlete
: : / / t
/ .
t m
proved, much remains unknown about the long-term
. m
results of a single or multiple concussions.
ss : /
with a caffeine level in urine higher than 15 µg/mL.
t p p t p ss
p : /
t
hht t
High-energy drinks with excessive amounts of caffeine
have ergolytic and potentially dangerous effects, espe-
cially when mixed with other stimulants or alcohol.
t
hht t Definition and Epidemiology
A concussion is defined as a complex pathophysiologic
process induced by traumatic biomechanical forces that
Currently, creatine is the most commonly used ergo- affect the brain.13 The symptoms are often vague and
genic aid among athletes who wish to build muscle and underreported by athletes, coaches, and parents. The
k e rs
enhance recovery. Creatine effectively improves perfor-
rs
mance in high-intensity activities, such as sprinting and
e k eers
r s
self-reporting of concussions has significantly increased
the incidence of this condition.
b ooook
cramps, nausea, and diarrhea. Kidney and liver dys-
b oook
weight lifting.11 The adverse effects include fluid gain,
o b ooo
Studies conducted in recent years have explored the
o
epidemiology of concussions in athletes. In high-school
/
e e
/ eb ee/ e
/e
function have been rarely reported, although causalityb /e/e b
sports, concussions account for almost 15% of all
ee
/ t
///t
rently considered safe for healthy adults.
: m
is unclear. Despite these side effects, creatine is cur-
. . m : / t.
///t m
sports-related injuries. A review of the epidemiology of
.m
concussions in high-school athletes found that the over-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
all injury rate was 2.5 per 10,000 athletic exposures.14 from regular sports participation for at least 7 days af-
k eers
rs Concussions occurred more commonly in competition
keerrss ter symptoms have resolved, while making a gradual
b ooook o ook
than during practice, and the highest reported rates
o
were in football (47%), girls’ soccer (8%), and boys’
b
return to play. The effects of concussions can be cumu-
b o oo
o
lative, and athletes who sustain three or more concus-
/
ee/e b / e e b
wrestling (6%). Among football players, linemen had
ee /
the highest incidence of concussions, followed by tight
ee/ e
/ e b
sions are much more likely to sustain a recurrent con-
cussion, which raises questions regarding further
t . m
.m
ends, running backs, and linebackers. However, neither
: / ///t : / t
///t. m
. m
participation in contact sports.17,18
s
tps :
the impact volume nor the intensity appeared to influ-
s
tps :
Computerized concussion assessment programs have
hhtttp hhtttp
ence the concussion threshold level reported in high- been used to provide a neurocognitive baseline for de-
school football players.15 termining when athletes can return to play.19 Although
these computerized neurocognitive tests help compare
Diagnosis and Management athletes’ results with their baseline status, the long-term
The diagnosis of a concussion is made based on the efficacy of this testing method has been questioned.20
mechanism of impact and the associated symptoms.
k eers
rs k e
The signs and symptoms of a concussion are vague and
ers
r s Long-Term Effects
ook ook
The long-term effects of concussions are not well estab-
b oo
therefore are difficult to diagnose, especially in cases of
oo
a mild injury. Somatic symptoms include headache, fa-
b b o oo
lished. The long-term consequences of repeated concus-
o
/
e e
/ eb / e e b
tigue, dizziness, nausea or vomiting, visual problems,
ee /
and phonophobia. Athletes with a concussion often ex-
ee e
/ e b
sions in football players have been studied.21 Players
/
who sustained more than three concussions reported an
t . m
. m
perience cognitive changes, including amnesia, confu-
: // / t : / / t
/ .
t m
. m
increased prevalence of memory problems and mild
: /
sion, disorientation, inability to focus, delayed verbal
ss ss /
cognitive impairment compared with those who had
:
hhtttp hhtttp
fewer than three concussions. The results of other stud-
tp tp
and motor responses, drowsiness, and reports of being
“in a fog.” Emotional lability and irritability are com- ies suggested an increased incidence of clinical depres-
mon sequelae of concussion. sion in retired football players, but the association be-
The evaluation of an athlete with a concussion tween concussion and depression is not clear in those
should begin with an initial systematic field assessment. patients.22 Additional long-term prospective studies are
The physician should assess and maintain adequate air- needed.
keerrss way, breathing, and circulation on the field and per-
k e rrss
e
bboooo k form a neurologic examination to evaluate for any spi-
b o o o k
nal injury. After the athlete is on the sidelines, a more
o Stingers
b o oo
o
/
e e
/ e ee e
/ b
detailed history and physical examination are per-
/ e
formed, with attention given to any of the previously
e / e
/ e b
Stingers, also known as burners, are one of the most
e
t . m
. m
identified symptoms discussed earlier. The player’s hel-
: / / / t / /t/.tm
common sports injuries treated by physicians and ath-
.m
letic trainers. Stingers occur most commonly in football
:
ss /
met should be taken away to prevent the player from
: ss : /
and are the result of traction or a direct impact on the
hhtttp hhtttp
returning to the game. The Sport Concussion Assess-
tp
ment Tool 3rd Edition (available free online at http://
bjsm.bmj.com/content/47/5/259.full.pdf) can be used tp
nerve from the cervical root to the brachial plexus.
Mechanism of Injury
on the sidelines to assess symptoms and follow the pro-
gression or the resolution of symptoms. Serial neuro- The exact mechanism of stingers is variable; they can
logic assessments also should be performed. Instruc- be the result of tensile overload of the brachial plexus,
k eers
rs tions are provided to the athlete and family for
appropriate follow-up, including further neurocogni-
k e r
e s
r s stretching of the nerve root, or direct compression of
the nerve root and the brachial plexus. Any of these
bboooo k tive testing when appropriate.16

b o o
o o k b o oo
mechanisms likely can cause similar symptoms. The C5
o
/
e e
/ e e / e
/ e b
Determining when to return to play is one of the
most controversial aspects of concussion management.
e e / e
/ e b
nerve root is most vulnerable because it is directly
aligned with the upper trunk of the brachial plexus.
e
: / / / .
t m m
Expert consensus exists that any athlete suspected of
t .
having a concussion should not be allowed to return to
: / / t
/ .
t m
. m
Presentation and Evaluation
t p ss
p : /
play on the day of injury. Prior to any further athletic
t p ss : /
Athletes may present with a sudden stinging or burning
p
t
hht t
activity, an athlete must be entirely symptom free and
cleared for play by a physician or other qualified med-
ical professional trained in the treatment of concus-
t
hht t
in the arm after a traumatic event. The athlete often
leaves the field holding the arm and reporting a ”dead
arm” sensation. This event must be distinguished from
sions. a glenohumeral dislocation. The pain from a stinger is
Postural stability and neurocognitive function tests usually experienced in a dermatomal pattern and often
k eers
rs
are more sensitive than routine clinical examination for
k e
the detection of neurologic deficits. Initial treatment
ers
r s
lasts only seconds or minutes. The symptoms are uni-
lateral; those with bilateral symptoms should be con-
b ooook b
athlete is completely asymptomatic for at least
oook
should emphasize physical and cognitive rest. After an
o b ooo
sidered to have a spinal cord injury.
o
Patients with recurrent stingers or those with persis-
/
e e
/ eb ee/ e
/e b
24 hours, he or she may progress through a stepwise re-
/e/e b
tent symptoms warrant further evaluation. Although
ee
/ t
///t m
turn to sports. It is strongly recommended that athletes
. . m
who have sustained repeated concussions be withheld
: / t.
///t m
radiography is often the initial imaging study, the rela-
.m
tive value of this examination is limited. Radiographs
:
s
tps : s
tps :
118
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
should be evaluated for any degenerative changes, oc- sidered normal in athletes, including sinus bradycardia,
k eers
rs ke rr
cult facet injuries, and loss of cervical lordosis. The
e ss first-degree atrioventricular block, and isolated left ven-
b ooook b o ook
Torg ratio helps determine the presence of central cer-
o
vical spinal stenosis, which correlates with an increased
tricular hypertrophy.28 Echocardiography can reveal in-
o oo
o
creased muscle mass and wall thickness in the left ven-
b
/
ee/e b / e e b
risk of complications after a stinger.23 Advanced imag-
ee /
ing studies are indicated in patients with persistent / e e b
tricle with or without left ventricular dilatation in
ee /
highly trained athletes; this condition is referred to as
t . m
.m
symptoms or recurrent stingers, and MRI has the most
: / ///t : / t
///t. m
. m
athlete’s heart syndrome.29
s
tps :
definitive results. In a cohort of football players with
s
tps :
A left ventricular wall thickness greater than 13 mm
hhtttp hhtttp
chronic stingers, 93% of players had significant disk suggests hypertrophic cardiomyopathy (HCM); how-
disease or neural foraminal narrowing.24 ever, in a small number of elite athletes, left ventricular
wall thickness can range from 13 to 16 mm because of
Treatment physiologic causes. Other imaging modalities, including
Most athletes who experience a stinger need only to MRI and ultrasonography, can help distinguish ath-
rest until the symptoms resolve. Rest and NSAIDs have lete’s heart syndrome from HCM. Cessation of training
k eers
rs k e r
relieved symptoms in those with persistent pain. After
e s
r s also can help make the distinction between athlete’s
ook ook
heart syndrome (the hypertrophy resolves) and HCM
b oo
the pain has resolved, rehabilitation should focus on
oo
range of motion and strength in the affected extremity.
b b o oo
(the hypertrophy persists). In addition, significant ana-
o
/
e e
/ eb / e e b
No evidence exists that equipment modification helps
prevent recurrent symptoms.
ee / ee e
/ e b
tomic variations occur between the sexes and among
/
people of different ages and ethnicities, making it diffi-
t . m
. m
Return to play is predicated on the resolution of
: // / t : / / t
/ .
t m m
cult to use wall thickness as the criterion to distinguish
.
: /
symptoms, the restoration of full strength, and the ab-
ss ss /
athlete’s heart syndrome from HCM.
:
hhtttp
tp hhtttp
tp
sence of cervical spine symptoms. Athletes with brief
symptoms (lasting less than 15 minutes) and complete Sudden Cardiac Death
resolution of the stinger are usually allowed to return HCM is the most common cause of sudden cardiac
to play unless the condition is recurrent. If the symp- death in competitive athletes younger than 35 years, ac-
toms continue for more than 15 minutes, return to play counting for 36% of cases (Figure 1). Other causes in-
is allowed the following week. If an athlete sustains clude congenital coronary artery anomalies (17%), ar-
k errss
more than three stingers in a season, ending that season
e
and performing a complete evaluation should be con-
k e rrss
e
rhythmia syndromes (7%), and myocarditis (6%).30
When a basketball player collapses on the court or a
bboooo k
sidered.25
b o o
o o k b o oo
runner dies during a marathon, these cardiac condi-
o
/
e e
/ e ee/ e
/ e b e e
/ e b
tions should be considered in the evaluation of the ath-
/
lete and sometimes in his or her surviving family mem-
e
Cardiac Conditions in Athletes
: / / t
/ .
t m
. m : / /t/.tm.m
bers. For athletes older than 35 years, the most
ss : / ss : /
common cause of sudden cardiac death is coronary ar-
hhtttp hhtttp
Several cardiac conditions can occur in a previously tery disease.27
tp
healthy athlete during exercise and sports activity. The
initial presentation in some of these conditions can be
sudden cardiac arrest. In competitive athletes younger
tp
Hypertrophic Cardiomyopathy
HCM is an autosomal dominant condition that leads to
than 35 years, the incidence of sudden cardiac death is thickening of the walls of the heart, particularly the
estimated to be less than 1 case per 100,000 per year.26 septum. HCM generally occurs in an asymmetric man-
eers
This incidence increases with age and male sex and
rs
ranges from 1 case per 15,000 per year to 1 case per
k k e r
e s
r s ner and can lead to left ventricular outflow obstruction.
Initial presentation during exercise can include chest
bboooo k
50,000 per year in athletes older than 35 years.27
b o o
o
Among the several million asymptomatic active peopleo k b o oo
pain, palpitations, dizziness, syncope, and/or cardiac
o
/
e e
/ e e / e
/ e b
in the United States, it is difficult to determine who is at
e e / e
/ e b
arrest. Pediatric and adolescent patients tend to present
with more severe forms of HCM than adults. More
e
: / / t
/ .
t m
risk for sudden cardiac death during physical activity.
. m
Exercise is commonly prescribed by healthcare pro-
/ / t
/ .
t m
than 1,000 gene mutations have been identified in sar-
. m
comere proteins, and genetic testing can play an impor-
:
t p ss
p : /
viders to improve general wellness and cardiovascular
ss : /
tant role in the diagnosis of select cases. Genetic testing
t p p
t t
health. Reconciling the significant health benefits of
hht
physical activity for most people with the risk of sudden
cardiac death in a relatively small number of athletes is
t
hht t
identifies approximately 60% of patients with HCM
when there is a positive family history compared with
30% of patients without a positive family history.31
challenging. Some health conditions, including coronary
artery disease and hypertrophic cardiomyopathy, are as- Congenital Coronary Artery Anomalies
k eers
rs k eers
sociated with sudden cardiac death in athletes of all ages.
r s
Under normal conditions, the left main coronary artery
arises from the left aortic sinus, and the right main cor-
b ooook
Normal Cardiac Adaptation to Exercise
b oook
o
Athletes increasingly push their limits during sports
b ooo
onary artery arises from the right aortic sinus. In gen-
o
eral, if the left main coronary artery arises from the
/
e e
/ eb ee/ e
/e b
participation. Intense strength and endurance training
/e/e b
right sinus and courses between the aorta and the main
ee
/ t
///t m
can lead to changes in heart morphology and function.
. . m
Electrocardiographic changes may occur that are con-
: / t.
///t m
pulmonary artery, the risk of ischemia and cardiac ar-
.m
rest is increased. The prevalence (estimated to be be-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
Figure 1 Chart shows the distribution of cardiovascular causes of sudden death in 1,435 young competitive athletes. From
the Minneapolis Heart Institute Foundation Registry, 1980 to 2005. ARVC = arrhythmogenic right ventricular car-
diomyopathy, AS = aortic stenosis, CAD = coronary artery disease, CM = cardiomyopathy, HCM = hypertrophic car-
diomyopathy, HD = heart disease, LAD = left anterior descending, LVH = left ventricular hypertrophy, MVP = mitral
valve prolapsed. (Data from Maron BJ, Thompson PD, Ackerman MJ, et al: Recommendations and considerations
related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: A sci-
rrss rrss
entific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism. En-
o ke
ke o k e
dorsed by the American College of Cardiology Foundation. Circulation 2007;115[12]:1643-455.)
k e oo
e bboo o e b o
b o o e b o
b o
/
e / e ee/ e
tween 0.1% and 0.3%) and risk of sudden death in cor-
/
onary artery anomalies that are sometimes identified at
m
Myocarditis
m ee/ / e
The pathology of myocarditis varies from an insidious
: / / t
/ .
t . m
autopsy have been difficult to determine.32 Patients can
/ : / /
/t/.t .m
prodrome similar to the common cold and influenza to
ss :
be asymptomatic or present with angina, dizziness,
ss :
significant inflammation of the heart, including lym-
hhtttp hhtttp
and/or syncope with exercise. Arterial anomalies are an phocytic infiltration of the myocardium. Acute myo-
tp
important and surgically preventable cause of sudden
death in athletes. Without a high degree of suspicion,
tp
carditis usually has an infectious etiology and various
presentations, including chest pain, dyspnea, exercise
these anomalies can often be missed, even during intolerance, congestive heart failure, arrhythmias, and
echocardiography. cardiogenic shock.33 Athletes with myocarditis should
be restricted from sports participation for at least
k eers
rs Arrhythmia Syndromes
Arrhythmia syndromes include heterogeneous condi-
k e r
e s
r s 6 months and until the illness completely resolves. Un-
detected viral myocarditis that resolves without treat-
bboooo k b o o
o o k
tions that can present as palpitations, syncope, and/or
diomyopathy.
b o oo
ment can sometimes present later in life as dilated car-
o
/
e e
/ e e / / e b
cardiac arrest in athletes. Wolff-Parkinson-White syn-
e
drome involves an accessory pathway that can partici-
e ee/
Coronary Artery Diseasee
/ e b
/ / t
/ t m
pate in an atrioventricular reentry circuit, leading to
. . m
tachycardia.26 Long QT syndrome can be acquired or
: : / / t
/ .
t m
. m
Atherosclerotic coronary artery disease is the most
ss : /
congenital; more than 10 gene mutations have been
t p p t p ss
p : /
common underlying cardiac condition occurring in ath-
letes older than 35 years.27 Although routine cardiovas-
t
hht t
identified in ion channels that are involved in electrical
conduction and lead to changes in the cardiac action
potential.28 Some arrhythmia syndromes are purely
t
hht t
cular exercise is often prescribed as a method to de-
crease the risk factors of and improve the outcomes for
electrical disturbances and can sometimes be diagnosed coronary artery disease, intense physical exertion can
with a baseline electrocardiogram. Other conditions are transiently increase the risk of ischemia and cardiac ar-
associated with structural cardiac abnormalities and in- rest. Adults who experience sudden cardiac arrest with
k eers
rs k e
dition, ventricular arrhythmias are often the cause of
er
clude arrhythmogenic right ventricular dysplasia. In ad-
s
r s exercise often report angina and/or nonspecific symp-
toms (nausea, backache) the week before the event but
b ooook sudden cardiac death in HCM. Electrocardiography

b oook
o b ooo
may not have received adequate medical attention.34
o
/
e e
/ eb e / e
/e b
and Holter monitors are commonly used to evaluate ar-
rhythmias; however, these devices have limitations and
e ee/e/e b
Older adults with established coronary artery disease
should undergo a thorough cardiologic evaluation and
usually indicated.
: / t
///t m
careful evaluation by an experienced cardiologist is
. . m / t.
///t m
obtain expert medical advice regarding exercise restric-
.m
tions and sports participation.
:
s
tps : s
tps :
120
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Prevention of Skin Infection Outbreaks
k eerss
Infectious Diseases in Athletes
r keerrss Athletes can return to play for wrestling or other high-
b ooook
Skin Infections
b o ook
o o oo
contact sports when no new lesions develop for
o
48 hours and they have been treated with antibiotics
b
/
ee/e b Cellulitis
e / e
/ e b
Cellulitis involves a bacterial infection often resulting
e ee/ e
/ e b
for 72 hours. Any skin lesions should be reported to the
coach or the athletic trainer. To prevent the spread of
: / ///t. m
from a break in the skin or hematogenous transmis-
t .m
sion. Heightened vigilance is necessary to identify
: / t
///t. m
. m
MRSA,40 all wounds (draining, moist lesions, or heal-
s
tps : s
tps :
ing lesions) must be covered with bioocclusive prewrap
hhtttp hhtttp
community-acquired methicillin-resistant Staphylococ- and tape during competition. Athletes must practice
cus aureus (MRSA) infections, which can occur in out- good hygiene, including showering and washing with
breaks among athletes. The increase in rates of soap and water and using clean towels as soon as pos-
community-acquired MRSA is an ongoing concern. sible after play. Athletes should not share equipment,
The results of a recent population study in Pennsylva- clothing, or razors. The uniforms and shared equip-
nia suggest that the annual incidence rate of ment should be cleaned on a routine schedule and
k eerss
community-acquired MRSA increased by 34% and
r k eers
r s stored in clean, dry areas. Hot tub and regular tub use
skin and soft-tissue infections increased by 4%.35 Con- should be restricted. Research on whether athletic fields
b ooook b ooook
cern also exists about the spread of the disease from na-
o oo
may contain infectious organisms is inconclusive, and
b o
/
e e
/ eb e e
/ e b
sal carriers. The prevalence of MRSA nasal carriers in
/
the college student athlete population is approximately
e ee e
/ e b
there is no indication that antimicrobial agents should
/
be applied to playing fields.
: // /.tm m
1.8%, although it has been reported as high as 9.2% in
t . : / / t
/ .
t m
. m
ss /
some groups.36 Screening all athletes for MRSA carriers
: ss : /
Mononucleosis
hhtttp hhtttp
is not recommended. MRSA presents most often at the Mononucleosis, an infectious disease caused by the
tp
elbows and the knees as a large pustule with an ery-
thematous ring that appears aggressively and is tender tp
Epstein-Barr virus, is spread by direct contact and
through the saliva and is known to the public as “the
to the touch. This presentation also can occur any- kissing disease.” The incubation period can be long,
where on the body, more often early in the season.37 approximately 30 to 50 days. Symptoms include sore
Abrasions sustained during sports seem to be the cause throat, fever, cervical lymphadenopathy (particularly
k errss
for many skin infections. Most skin infections, includ-
e k e
ing small abscesses, are still usually due to S aureus. rrss
e
involving the posterior cervical nodes), and splenomeg-
aly. A complete blood count often shows more than
bboooo k o o o
Carbuncles develop when infected follicles coalesce to
b o k b o oo
10% atypical lymphocytes. The heterophile antibody
o
/
e e
/ e
form a deep, erythematous, painful mass.
ee/ e
/ e b
Treatment of large, painful abscesses or carbuncles re-
e e
/ e b
latex agglutination test (Monospot test) has a sensitiv-
/
ity of 87% (range, 79% to 95%) and a specificity of
e
t . m
. m
quires incision and drainage, laboratory testing of the
: / / / t : / /t/.tm.m
91% (range, 82% to 99%) in patients older than
: /
pustule because of the high risk of MRSA, adjunct treat-
ss ss /
16 years.41,42 The false-negative rate can be as high as
:
hhtttp hhtttp
25% during the first week of symptoms and can range
tp tp
ment with oral trimethoprim/sulfamethoxazole or clin-
damycin38 for 10 days, and clinical reevaluation in 24 from 5% to 10% in the second week.43
hours. Intravenous vancomycin is suggested if symptoms Symptomatic treatment of mononucleosis is recom-
do not improve or if the infection is aggressive. If the mended. The patient should avoid all forms of exercise
for the first 21 days after the onset of symptoms. The
cause is Streptococcus, cephalexin or azithromycin can
complication of greatest concern is atraumatic splenic
be used for treatment. For small, benign-appearing le-
rs
rs
sions, warm compresses can be used four times per day.
k ee k e r
e s
r srupture, which has an incidence of 0.1% to 0.2%.
Most splenic ruptures occur within the first 21 days.
bboooo k
Impetigo
b o o
o o k b o oo
Questions remain regarding the measurement of spleen
o
size using ultrasonography.42 It is recommended that
/
e e
/ e / e e b
Impetigo is caused by a skin infection resulting from
ee /
group A streptococcus or S aureus.40 Impetigo also can
ee/ e
/ e b
athletes should not return to play unless they remain
: / t
/ .
t m
. m
occur following a turf abrasion as a result of a second-
/ : / / t t m
asymptomatic for at least 21 days. Up to 30% of cases
. . m
can also have a coinfection of group A streptococcus
/
t p ss
p : /
ary infection, which can present with nonbullous pap-
ss : /
pharyngitis. This infection should be treated with peni-
t p p
t
hht t
ules, vesicles, and pustules that burst and form a
honey-colored crust. With bullous impetigo, blister-like
vesicles form, with clear fluid that becomes darker, and
t t
cillin because 80% to 90% of individuals treated with
hht
amoxicillin develop a rash.44
then rupture. Ecthyma refers to ulcerated lesions with a

raised yellow crust.39 Metabolic Diseases
k ee s
Treatment of the nonbullous form caused by S au-
rrs k e
reus includes topical mupirocin three times per day for
ers
r s Hyponatremia
b ooook b oook
10 days. Bullous impetigo caused by group A strepto-
o
coccus is treated with cephalexin or erythromycin. If
b ooo
Exercise-associated hyponatremia is defined as a serum
o
sodium level less than 135 mmol/L during or up to
/
e e
/ eb ee/ e
/e b
MRSA is suspected, then a course of trimethoprim/
/e/e b
24 hours after prolonged physical activity45 and is usu-
ee
prescribed.
: / t
///t m
sulfamethoxazole or clindamycin for 10 days can be
. . m / t.
///t m
ally seen in endurance athletes. Risk factors for
.m
exercise-associated hyponatremia include slow running
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
or a performance pace of more than 4 hours for a mar- tions, increased ocular pressure and renal medullary
k eers
rs ke
athon, female sex, low body mass index (< 20), exces-
errss carcinoma, microscopic and macroscopic hematuria,
b ooook b o ook
sive fluid consumption (> 3 L), and weight gain during
o
exercise.46 Other risk factors include event inexperi-
renal papillary necrosis, infections, or kidney stones.
o oo
o
Sickle cell crises can occur with increased intensity of
b
/
ee/e b / e e b
ence, the use of NSAIDs, and unusually hot or ex-
ee /
tremely cold environmental conditions.45 Early signs / e e b
exercise, dehydration, altitude changes, asthma, and
ee /
heat-related illnesses.
: / t . m
.m
and symptoms of exercise-associated hyponatremia can
///t : / t
///t. m
. m
s
tps :
include bloating, puffiness, nausea, vomiting, and head-
s
tps :
hhtttp hhtttp
ache.47 The athlete may appear confused and obtunded. Environmental Issues for the Athlete
The athlete often reports more fluid consumption
(3.5 L) and can gain weight.47 Low sodium levels can Heat-Related Injuries
lead to seizures and death. Treatment involves fluid re- Classification of Heat-Related Illness
striction until the onset of urination in mild cases. In se- Heat-related illnesses (Table 4) can progress along a
vere cases, transfer to a hospital and treatment with in- spectrum from mild to severe. Core temperature is reg-
k eers
rs travenous 3% saline bolus is recommended.45
k eers
r s ulated by four main mechanisms that dissipate heat:
b ooook Rhabdomyolysis
b ooook oo
conduction, convection, radiation, and evaporation.
o o
When the ambient temperature exceeds 35°C (94°F),
b
/
e e
/ eb / e e b
Rhabdomyolysis occurs in athletes when muscle fibers
ee /
break down, usually because of overexertion, dehydra- / e e b
the evaporation of sweat, which can be affected by high
ee /
humidity, becomes the most important mechanism. Pa-
: // t/.tm
. m
tion, or heat-related illness. The breakdown of muscle
: / / t . m
. m
tients at risk include young athletes (because of reduced
/ t
ss : /
cells releases myoglobin, leading to complications, in-
s : /
heat tolerance, longer acclimatization periods, and less
s
hhtttp
tp hhtttp
tp
cluding major lactic acidosis and a rapid rise in serum sweating and voluntary fluid intake), obese athletes
potassium levels, which can cause secondary lethal ar- (because of poorer thermoregulation), athletes involved
rhythmias or death from acute myoglobinuric renal fail- in outdoor sports with a long exercise duration (mara-
ure.48 The creatine kinase level is used to detect muscle thons, tennis, soccer, football), and individuals with
degeneration; however, creatine kinase levels may rise to medical conditions that can adversely affect heat toler-
approximately 5,000 U/L with exercise.48 Creatine ki- ance or cause dehydration. Drug use is also a risk fac-
keerrss nase levels can be elevated to 250,000 or higher in se-
k e rrss
e
vere cases. Patients should be transferred to the hospital
tor. Although not commonly enforced, cancellation of
outdoor events when the ambient temperature is 28°C
bboooo k o
for workup because rapid decompensation can occur.
b o
o o k b o oo
(82°F) is recommended by the American College of
o
/
e e
/ e e e
/ e b
Early treatment should include aggressive oral or intra-
/
venous rehydration. Dialysis is necessary if acute renal
e
Sports Medicine.53
ee/ e
/ e b
: / / / .
t m m
failure occurs. Usually, an athlete with a creatine kinase
t . t . m.m
Management of Heat-Related Illness in Athletes
: / / / t
ss /
level of 20,000 to 50,000 U/L who is stable and has a
: ss : /
In serious cases of heat-related illness, core temperature
hhtttp hhtttp
normal serum creatinine level and good urine output re- must be measured rectally; oral, ear, temporal artery,
Sickle Cell Disease

tp
covers with oral hydration and outpatient follow-up.49
tp
and axillary temperatures are less accurate. The treat-
ment goal is to reduce the core temperature below
40°C (104°F) as soon as possible, ideally within
Sickle cell disease involves mutations in the hemoglobin 30 minutes. Immersion in cold or ice water is the most
S gene. The prevalence of sickle cell disease is 0.2%. effective, practical means to rapidly reduce core tem-
k eers
rs Approximately 8% of African Americans, 0.5% of His-
panics, and 0.2% of Caucasians have the sickle cell
k e r
e s
r s perature. Early transfer to a hospital is necessary. To
identify end-stage organ failure, laboratory tests for
bboooo k o o o
trait,50 which protects against Plasmodium falciparum
b o k b o oo
complete blood count, coagulation panel, liver func-
o
/
e e
/ e e / e
/ e b
malaria. Hemoglobin S deoxygenates and polymerizes,
resulting in a rigid cell shape and impaired blood flow,
e e / e
/ e b
tion, electrolytes, renal function, urinalysis, and muscle
enzymes (creatine kinase) should be ordered. Aggres-
e
: / / / .
t m m
hemolysis, and vasoocclusive episodes. For those with
t .
the sickle cell trait, the condition is usually benign with
: / / / .
t m m
sive intravenous fluid rehydration can be started. Dan-
t .
trolene (for malignant hyperthermia) and benzodiaz-
t p ss
p : /
no sickle cell crises, although an association with sud-
ss : /
epine (for seizure activity) can be used. For mild
t p p
t
hht t
den death and rhabomyolysis has been reported.51,52
One study reviewed 23 athlete deaths that involved a
distinctive noninstantaneous collapse, with gradual de-
t
hht t
symptoms, the athlete should be moved to the shade,
equipment should be removed, hydration should begin,
water or ice should be applied to the groin and axilla,
terioration over several minutes associated with vigor- and the legs should be elevated to aid recovery.
ous or exhaustive physical exertion, usually during In cases of environmental changes, acclimatization
k eers
rs
football conditioning drills and often in hot weather.51
k eers
r
The sickle cell trait does not affect an athlete’s perfor-s
may take anywhere from 1 to 3 weeks. Specific preseason
acclimatization guidelines for heat-related illnesses in
b ooook b oook
mance or life expectancy. Screening athletes for the
o
sickle cell trait is recommended by the National Colle-
b ooo
football include modification of equipment and contact
o
activity for the first 14 days and avoiding twice-a-day
/
e e
/ eb ee/ e
/e b
giate Athletic Association, but is still controversial.51,52
/e/e b
practice sessions during the first week. Younger athletes
ee
/ t
///t m
Sickle cell crises can result in splenic infarctions, ve-
. . m
nous thromboembolism, pregnancy-related complica-
: / t.
///t m
are limited to a maximum of 10 hours of exertion per
.m
week and 2 hours of exertion per practice.54
:
s
tps : s
tps :
122
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 4
rs keerrss
b ooook Heat- and Cold-Related Injuries
b o ook
o b o oo
o
/
ee/e b Illness Symptoms
ee/ e
/ e b Etiology
ee/ e
/ e b Management
Heat-Related
Cramps
: / t
///t. m
.m
Presents as hyperexcitable
: / t
///t. m
. m
Unknown, although cramps seem Rehydration preferably with an
s
tps : s
tps :
hhtttp hhtttp
muscles occurring during or to be associated with salt electrolyte solution (can add
after exercise deficiency and dehydrated ¼ tsp of table salt to 300–500 mL
muscles, nonacclimatized of fluids). Treat with passive
athletes in poor condition, and stretching, rest, massage, ice, and
supplement use (particularly TENS.
stimulants and creatine)
k eers
Syncope
rs
Light-headedness or fainting
k eers
r s
Dehydration and peripheral
vasodilatation, causing venous
Remove athlete from the heat and
cool down with ice and water.
pooling in lower extremities
o
Oral rehydration first or use IV
fluids (usually normal saline).
/
e e
/ eb Exhaustion
/ e e b
Inability to continue exercise
ee /
with or without collapse / e e b
Related to dehydration and
ee /
results in central fatigue and
Remove athlete from the heat and
cool down with ice and water
: // t/.tm
. m : / / t
/ .
t m
. m
peripheral vascular dilation Oral rehydration first or use IV
ss : / ss : / fluids (usually normal saline).
hhtttp
tp hhtttp
tp
Heat stroke Dizziness, lightheaded, Core temperature > 40°C; can See text
disorientation and confusion, lead to end-stage organ failure
irritability, hyperventilation,
nausea and vomiting
particularly bad, fatigue and
collapse
keerrss
Cold-Related
k e rrss
e
bboooo k Frostbite Early pain and itching,
b o o
progressing to white, cold, firm
o o k
Freezing and thawing results in
extracellular and intracellular
Avoid refreezing injury, rewarming
b o oo
bath at 40°–42°C (104°–108°F);
o
/
e e
/ e area
ee/ e
/ e b
or hard tissue in the affected ice crystal formation and
e /
cellular dehydration; vascular
e e
/ e b
provide narcotics, NSAIDs, and
tetanus prophylaxis.
: / / t
/ .
t m
. m later stages
: / /t/.tm
stasis and ischemia can occur in
.m
ss : / ss : /
hhtttp hhtttp
Trenchfoot Pain and freezing injuries at the Recurrent wet and cold exposure Rewarm when no risk of refreezing.
tp
feet
tpto the feet causes repetitive
nonfreezing injury; typically
temperature 0°–10°C (32°–50°F)
Hypothermia
Mild Confusion “umbles”: stumbles, Core temperature: 32°–35°C Passive warming with endogenous
k eers
rs mumbles, fumbles, and
grumbles
k e r
e s
r s (89°–95°F) heat; general recovery expected
without sequelae.
bboooo k Moderate Impaired judgment and apathy,
b o o
o o k Core temperature: 28°–32°C
b o oo
o
Active rewarming often required.
/
e e
/ e stiffness
ee/ e
/ e b
shivering stops (31°C), muscle (82°–89°F)
ee/ e
/ e b
Severe
: / / / .
t m m
Loss of consciousness (30°–32°C),
t .
decreased pulse, decreased
: / / / .
t m
. m
Core temperature: < 28°C (82°F)
t 30% mortality; pulse at initial
examination indicates better
t p ss
p : /
respiratory rate, coma
t p ss
p : / survival; rapid active rewarming
. t
hht t t
hht
IV = intravenous, TENS = transcutaneous electrical nerve stimulation.
t essential
k eers
rs
Cold-Related Injury
k eers
r s and drug use (for example, anticholinergics, stimulants,
marijuana, opiates). The digits, ears, nose, cheeks, and
ook ook
Cold-related injuries can be mild to severe and can
b oo worsen in wet conditions (Table 4). Patients who are of

b oo b oooo
genitalia are particularly at risk. Frostbite is graded
/
e e
/ eb ee/
wind chill, high altitude, previous frostbite, tobaccoe
African descent are at risk; other risk factors include
/e b ee e/e b
similar to burns: first-degree frostbite presents with
/
numbness, erythema, and edema; second-degree frost-
t . m
. m
use, altered mental status, impaired thermoregulation,
: / ///t : / t.
///t m
.m
bite has clear, fluid-filled blisters; third-degree frostbite
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
shows hemorrhagic blisters; and fourth-degree frostbite Papilledema, retinal hemorrhages, and global encepha-
k eers
rs presents with mottled and frozen tissue.
keerrss lopathy can occur. High-altitude cerebral edema can be
b ooook o ook
Immediate treatment should involve protecting the
o
frozen tissue from further freezing or trauma. If hypo-
b
fatal over hours to days, especially if it occurs at an al-
b o oo
o
titude higher than 20,000 feet (also known as the death
/
ee/e b / e e b
thermia is a concern, immediate, rapid rewarming can
ee /
be accomplished with a water bath at 40°C to 42°C
ee/ e
/ e b
zone).55 Treatment involves immediate descent to a lower
altitude. If descent is not possible, the patient should be
t . m
.m
(104°F to 108°F). Medications can include topical aloe
: / ///t : / t
///t. m
. m
treated with supplemental oxygen and dexamethasone.
s
tps :
vera, oral ibuprofen, and narcotics, and an oral prosta-
s
tps :
hhtttp hhtttp
glandin to cause vasodilation should be considered. High-Altitude Pulmonary Edema
Tetanus vaccination status should be updated. Patients with high-altitude pulmonary edema present
As the core temperature decreases (33°C), the indi- with a dry cough, decreased exercise tolerance pro-
vidual may demonstrate impaired judgment and apa- gressing to respiratory distress, bloody sputum, and fe-
thy. Sometimes the athlete may display paradoxical un- ver. High-altitude pulmonary edema is more common
dressing. At 31°C, shivering stops and muscle stiffness in men than women, and recurrent episodes are likely.
k eers
rs k eers
r
ensues. Patients often lose consciousness at a core tem-
s A chest radiograph shows patchy infiltrates (alveolar
edema) most commonly in the right middle lobe.56 In

ook ook
perature lower than 30° to 32°C, demonstrate de-
b oo b o
creased pulse and respiratory rate, and may become co-
o b o oo
addition to other altitude treatments, supplemental ox-
o
/
e e
/ eb matose.
e/
e e
/ e b
The patient with severe hypothermia must be han-
e e
/ e b
ygen and careful monitoring are recommended with
/
immediate descent. Otherwise, nifedipine, glucocorti-
e
t . m
. m
dled gently and removed from the cold environment;
: // / t : / / t
/ .
t m
. m
coids, acetazolamide, and inhaled salmeterol should be
used for treatment.57
ss /
wet clothing should be removed. The patient should be
: ss : /
Acclimatization to altitude should ideally occur over
hhtttp hhtttp
monitored for oxygen saturation and undergo continu-
tp
ous electrocardiography. If the patient has no pulse and
is apneic, cardiopulmonary resuscitation can be initi- tp
10 to 14 days. If ascent is necessary despite an episode
of high-altitude pulmonary edema, increases in altitude
should be limited to 300 m per day, with rest days ev-
ated. Passive warming is performed via endogenous
heat production. When hypothermia is more moderate, ery 2 to 3 days.
active warming is performed using exogenous air-
keerrss warming blankets. Rapid, active internal rewarming is

reserved for severe hypothermia; intravenous fluids
k e rrss
e Summary
bboooo k o
warmed to 40°C to 43°C can be used, although lac-
b o
o o k b o oo
o
Medical issues are more common in sports medicine.
/
e e
/ e e e
/ b
tated Ringer solution should be avoided because a cold
/ e
liver cannot metabolize lactate. Extracorporeal re-
e ee/ e
/ e b
Much of what a team physician encounters is medical
rather than orthopaedic. A surgeon should be vigilant
: / / / .
t m m
warming using peritoneal dialysis or chest tube irriga-
t .
tion can be attempted in severe cases. If the body has
: / /t/.tm.m
for the dietary, medical, and environmental conditions
ss : / s : /
and risk factors discussed and work with the athlete’s
s
hhtttp hhtttp
been warmed to 32°C to 35°C and vital signs are ab-
tp
sent, the patient has died.
Altitude Medicine
tp
team of health providers when called for.
Acute Mountain Sickness Key Study Points

Acute mountain sickness is typically seen within the
k eers
rs first 6 to 12 hours at an altitude higher than 8,000 ft.
Symptoms of acute mountain sickness include headache
k e r
e s
r s • Recognize the symptoms of concussion and im-
plement the restrictions and the regulations for
bboooo k b o o
o o
and one of the following: gastrointestinal disturbance
k b o oo
initial concussion management.
o
/
e e
/ e e / e
/ e b
(nausea, vomiting, anorexia), dizziness, fatigue, or sleep
disturbance. The physical examination results are usu-
e
•
ee e
/ e b
Be familiar with the common cardiac causes of
/
sudden death in athletes, including HCM, congen-
/ / t
/ .
t m
ally unremarkable, and the condition is self-limited if
. m
no further ascent occurs. The initial treatment is de-
: : / / t
/ .
t m
. m
ital coronary artery anomalies, and arrhythmias.
ss : /
scent (at least 1,500 to 2,000 feet). If descent is not
t p p
•
t ss : /
Heat-related injuries during sports are common
p p
t
hht t
possible, then ascent should cease and treatment with
supplemental oxygen is recommended. Treatment in-
cludes oral analgesics for headache and acetazolamide
t
hht
and can be avoided with simple preventive mea-
t
sures, including proper hydration and early
treatment.
and/or dexamethasone for acute symptoms.55 Acetazol-
amide can be taken before ascent as a preventive mea-
k eers
rs
sure.
k eers
r s
b ooook High-Altitude Cerebral Edema
b oook
o
High-altitude cerebral edema is likely a more severe form
b oooo
/
e e
/ eb ee/ e
/e b
of acute mountain sickness. Clinical symptoms include 1.
/e e b
Rodriguez NR, Di Marco NM, Langley S; American Di-
ee /
etetic Association; Dietitians of Canada; American Col-
/ t
///t m
neurologic signs, ataxia, change in mental status, hallu-
. . m
cinations, confusion, vomiting, stupor, and/or coma.
: : / t.
///t m
.m
lege of Sports Medicine: American College of Sports
s
tps : s
tps :
124
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Medicine position stand: Nutrition and athletic perfor- 12. Nattiv A, Loucks AB, Manore MM, et al: American
k eers
rsmance. Med Sci Sports Exerc 2009;41(3):709-731.
keerrss College of Sports Medicine position stand: The female
ook ook
athlete triad. Med Sci Sports Exerc 2007;39(10):1867-
b oo 2.
o o
Lun V, Erdman KA, Reimer RA: Evaluation of nutri-
b
1882.
b o oo
o
/
ee/e b ee
Clin J Sport Med 2009;19(5):405-411./ e
/ b
tional intake in Canadian high-performance athletes.
e 13.
ee/ e
/ e b
McCrory P, Meeuwisse W, Johnston K, et al: Consensus
: / t
///t. m
.m : / t
///t. m
. m
statement on Concussion in Sport 3rd International
Conference on Concussion in Sport held in Zurich, No-
3.
s
tps :
US Department of Health and Human Services. Dietary
s
tps :
hhtttp hhtttp
Guidelines of Americans. Washington, DC, 2005. http:// vember 2008. Clin J Sport Med 2009;19(3):185-200.
www.health.gov/DietaryGuidelines. Accessed April 8,
2013. 14. Marar M, McIlvain NM, Fields SK, Comstock RD: Ep-
idemiology of concussions among United States high
4. Tipton KD, Witard OC: Protein requirements and rec- school athletes in 20 sports. Am J Sports Med 2012;
ommendations for athletes: Relevance of ivory tower ar- 40(4):747-755.
k eers
rs
guments for practical recommendations. Clin Sports
Med 2007;26(1):17-36.
k eers
r s The authors conducted a review of the epidemiology of
concussions in high school sports. Football, hockey,
b ooook5.
b ooook
Tipton KD, Elliott TA, Cree MG, Aarsland AA, Sanford
b o oo
girls’ soccer, and wrestling had high rates of concussion.
o
/
e e
/ eb /
e e
/ e b
AP, Wolfe RR: Stimulation of net muscle protein syn-
e
thesis by whey protein ingestion before and after exer- 15.
ee/ e
/ e b
Eckner JT, Sabin M, Kutcher JS, Broglio SP: No evi-
: // t/.tm
. m
cise. Am J Physiol Endocrinol Metab 2007;292(1):
: / / t
/ .
t m
. m
dence for a cumulative impact effect on concussion in-
E71-E76.
ss : / ss : /
jury threshold. J Neurotrauma 2011;28(10):2079-2090.
hhtttp
tp hhtttp
tp The results of this accelerometer study suggested that
6. Stanhope KL, Schwarz JM, Keim NL, et al: Consuming impact volume or intensity does not influence the con-
fructose-sweetened, not glucose-sweetened, beverages cussion threshold in high school football athletes. Level
increases visceral adiposity and lipids and decreases in- of evidence: II.
sulin sensitivity in overweight/obese humans. J Clin In-
vest 2009;119(5):1322-1334. 16. Guskiewicz KM, Broglio SP: Sport-related concussion:
kee
7.rrss k e rrss
e
Driskell J: Vitamins and Trace Elements in Sports Nutri-
On-field and sideline assessment. Phys Med Rehabil
Clin N Am 2011;22(4):603-617, vii.
bboooo k o o
tion. New York, NY, CRC/Taylor & Francis, 2006.
b o o k b o oo
o
The authors of this concise review explain how to assess
/
e e
/ e 8.
e / e
/ e b
Sawka MN, Burke LM, Eichner ER, et al: American
e e e
/ e b
and evaluate athletes who have sustained a concussion
/
during an athletic event. Level of evidence: V.
e
/ / t
/ .
t m
College of Sports Medicine position stand: Exercise and
. m
fluid replacement. Med Sci Sports Exerc 2007;39(2):
: : / /t/.tm.m
377-390.
ss : / 17.
ss : /
Guskiewicz KM, McCrea M, Marshall SW, et al: Cu-
hhtttp hhtttp
mulative effects associated with recurrent concussion in
9. tp
Mohr M, Nielsen JJ, Bangsbo J: Caffeine intake im-
proves intense intermittent exercise performance and re-
tp collegiate football players: The NCAA Concussion
Study. JAMA 2003;290(19):2549-2555.
duces muscle interstitial potassium accumulation. 18. Iverson GL, Gaetz M, Lovell MR, Collins MW: Cumu-
J Appl Physiol 2011;111(5):1372-1379. lative effects of concussion in amateur athletes. Brain
k eers
rs e r s
The authors found that caffeine intake enhances fatigue
r s
resistance and reduces muscle interstitial potassium dur-
k e
Inj 2004;18(5):433-443.
bboooo k b o o
o k
ing intense intermittent exercise. Level of evidence: III.
o
19.
b o oo
Broglio SP, Ferrara MS, Macciocchi SN, Baumgartner
o
TA, Elliott R: Test-retest reliability of computerized con-
/
e e
/ e 10.
/ e e b
Laurence G, Wallman K, Guelfi K: Effects of caffeine on
ee /
time trial performance in sedentary men. J Sports Sci / e e b
cussion assessment programs. J Athl Train 2007;42(4):
509-514.
ee /
2012;30(12):1235-1240.
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : /
The authors found that sedentary men could exercise
more after caffeine ingestion, without an accompanying
t p ss
p : /
20. Erdal K: Neuropsychological testing for sports-related
concussion: How athletes can sandbag their baseline
t
hht t
increase in effort sensation, suggesting that caffeine
could increase the chance that sedentary men will exer-
t
hht t testing without detection. Arch Clin Neuropsychol
2012;27(5):473-479.
cise. Level of evidence: III. The authors reviewed the factors associated with ath-
letes faking their baseline concussion test results to re-
11. Baird MF, Graham SM, Baker JS, Bickerstaff GF: main in the game. The authors conclude that it is diffi-
k eers
rsCreatine-kinase- and exercise-related muscle damage
implications for muscle performance and recovery.
k eers
r s cult to fake the results of the tests and perform poorly
on the examination. Level of evidence: III.
b ooook J Nutr Metab 2012;2012:960363.
b oook
o b oooo
/
e e
/ eb e / e
/e b
The authors reviewed the current evidence and current
opinions regarding the release of creatine kinase from
e
21.
e /e/e b
Guskiewicz KM, Marshall SW, Bailes J, et al: Associa-
tion between recurrent concussion and late-life cognitive
e
evidence: V.
: / t
///t m
skeletal muscle in response to physical activity. Level of
. . m : / t.
///t m
impairment in retired professional football players.
.m
Neurosurgery 2005;57(4):719-726.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
22. Kerr ZY, Marshall SW, Harding HP Jr, Guskiewicz Anomalous aortic origin of a coronary artery with an
k eers
rs rrss
KM: Nine-year risk of depression diagnosis increases
kee
with increasing self-reported concussions in retired pro-
interarterial course: Understanding current management
ook ook
strategies in children and young adults. Pediatr Cardiol
b oo b o
fessional football players. Am J Sports Med 2012;
o b o oo
2009;30(7):911-921.
o
/
ee/e b 40(10):2206-2212.
ee/ e
/ e b 33.
ee/ e
/ e b
Elamm C, Fairweather D, Cooper LT: Pathogenesis and
23.
: / ///t. m
.m
Torg JS, Vegso JJ, O’Neill MJ, Sennett B: The epidemi-
t
ologic, pathologic, biomechanical, and cinematographic
: / t . m
. m
diagnosis of myocarditis. Heart 2012;98(11):835-840.
///t
s
tps :
analysis of football-induced cervical spine trauma. Am J
s
tps : This report reviews the underlying causes of myocarditis
hhtttp hhtttp
and the appropriate techniques to diagnose it. Level of
Sports Med 1990;18(1):50-57.
evidence: V.
24. Levitz CL, Reilly PJ, Torg JS: The pathomechanics of
chronic, recurrent cervical nerve root neurapraxia: The 34. Parker MW, Thompson PD: Assessment and manage-
chronic burner syndrome. Am J Sports Med 1997;25(1): ment of atherosclerosis in the athletic patient. Prog Car-
73-76. diovasc Dis 2012;54(5):416-422.
k eers
rs k eers
r s This report summarizes the best techniques for diagno-
ook ook
sis and management of cardiac and peripheral arterial
b oo
25. Torg JS, Ramsey-Emrhein JA: Cervical spine and bra-
oo
chial plexus injuries: Return-to-play recommendations.
b b o oo
disease in athletes. Level of evidence: V.
o
/
e e
/ eb Phys Sportsmed 1997;25(7):61-88.
e/
e e
/ e b 35.
ee/ e
/ e b
Casey JA, Cosgrove SE, Stewart WF, Pollak J, Schwartz
26.
t . m
. m
Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller
: // / t : / / t
/ .
t m
. m
BS: A population-based study of the epidemiology and
ss /
FO: Sudden deaths in young competitive athletes: Anal-
: ss : /
clinical features of methicillin-resistant Staphylococcus
hhtttp hhtttp
ysis of 1866 deaths in the United States, 1980-2006. aureus infection in Pennsylvania, 2001-2010. Epidemiol
27.
tp
Circulation 2009;119(8):1085-1092.
Corrado D, Schmied C, Basso C, et al: Risk of sports:

tp Infect 2013;141(6):1166-1179.
This population-based study uses electronic health re-
cord data in Pennsylvania to report that the annual in-
Do we need a pre-participation screening for competi- cidence of community-associated MRSA increased by
tive and leisure athletes? Eur Heart J 2011;32(8): 34%, HA-MRSA by 7%, and skin and soft-tissue infec-
rrss rrss
934-944. tion by 4%.
o ke
ke o e
This report summarizes the advantages and disadvan-
k k e
tages of preparticipation physicals for athletes of all 36.
oo
Rackham DM, Ray SM, Franks AS, Bielak KM, Pinn
e bboo o types. Level of evidence: V.
e b o
b o o e b o o
TM: Community-associated methicillin-resistant Staph-
b
/
e / e 28.
ee/ / e
Corrado D, Pelliccia A, Heidbuchel H, et al: Recom-
m ee/ / e
ylococcus aureus nasal carriage in a college student ath-
lete population. Clin J Sport Med 2010;20(3):185-188.
m
: / /
/ t
/ .
t . m
mendations for interpretation of 12-lead electrocardio-
: / /
/t/.t .m
This cross-sectional study of college student athletes in
s :
gram in the athlete. Eur Heart J 2010;31(2):243-259.
s ss :
East Tennessee showed that the prevalence of nasal car-
hhtttp
tp hhtttp
tp
This review focuses on the differences between normal riage of community-acquired MRSA is estimated at
and abnormal electrocardiograms and the resulting clin- 1.8%, which is similar to the general population.
ical workup required for differential diagnosis and clin-
ical assessment. Level of evidence: V. 37. Bowers AL, Huffman GR, Sennett BJ: Methicillin-
resistant Staphylococcus aureus infections in collegiate
29. Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spir- football players. Med Sci Sports Exerc 2008;40(8):
k eers
rs k e r
e s
ito P: The upper limit of physiologic cardiac hypertro-
r s
phy in highly trained elite athletes. N Engl J Med 1991;
1362-1367.
bboooo k 324(5):295-301.
b o o
o o k 38.
o oo
o
Forcade NA, Wiederhold NP, Ryan L, Talbert RL, Frei
b
/
e e
/ e 30.
e / e
/ e b
Maron BJ, Thompson PD, Ackerman MJ, et al: Recom-
e ee e
/ e b
CR: Antibacterials as adjuncts to incision and drainage
/
for adults with purulent methicillin-resistant Staphylo-
: / / t
/ t m
mendations and considerations related to preparticipa-
. . m
tion screening for cardiovascular abnormalities in com-
: / / t
/ .
t m
. m
coccus aureus (MRSA) skin infections. Drugs 2012;
t p ss
p : /
petitive athletes: 2007 update. A scientific statement
from the American Heart Association Council on Nutri-
t p ss
p : /
72(3):339-351.
This systematic review presents limited evidence that
t
hht t
tion, Physical Activity, and Metabolism: Endorsed by
the American College of Cardiology Foundation. Circu-
lation 2007;115(12):1643-455.
t
hht t anti–MRSA antibacterial drugs provided a benefit over
incision and drainage alone.
39. Pecci M, Comeau D, Chawla V: Skin conditions in the

31. Ho CY: Genetic considerations in hypertrophic cardio- athlete. Am J Sports Med 2009;37(2):406-418.
k eers
rs myopathy. Prog Cardiovasc Dis 2012;54(6):456-460.
k eers
r
The authors reviewed the genetic contributions to hy-s 40. Centers for Disease Control and Prevention (CDC):
b ooook oook
pertrophic cardiomyopathy. The predominant gene mu-
b o b oooo
Methicillin-resistant Staphylococcus aureus infections
/
e e
/ eb idence: V.
ee/ e
/e b
tations are found in the sarcomere proteins. Level of ev-
e /e/e b
among competitive sports participants—Colorado, Indi-
ana, Pennsylvania, and Los Angeles County, 2000-
e
32.
/ t
///t. m
. m
Brothers J, Gaynor JW, Paridon S, Lorber R, Jacobs M:
: : / t
///t m
2003. MMWR Morb Mortal Wkly Rep 2003;52(33):
. .m
793-795.
s
tps : s
tps :
126
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
41. Ebell MH: Epstein-Barr virus infectious mononucleosis. 50. Bonham VL, Dover GJ, Brody LC: Screening student
k eers
rsAm Fam Physician 2004;70(7):1279-1287.
keerrss athletes for sickle cell trait—a social and clinical exper-
ook ook
iment. N Engl J Med 2010;363(11):997-999.
b oo 42.
o o
Putukian M, O’Connor FG, Stricker P, et al: Mononu-
b o oo
o
This reviews the National Collegiate Athletic Associa-
b
/
ee/e b / e e b
cleosis and athletic participation: An evidence-based
ee /
subject review. Clin J Sport Med 2008;18(4):309-315.
ee/ e
/ e b
tion’s approval for mandatory testing of all Division I
athletes for the sickle-cell trait.
: / t
///t. m
.m :
51.
/ t
///t. m
. m
Harris KM, Haas TS, Eichner ER, Maron BJ: Sickle cell
43.
s
tps :
Vidrih JA, Walensky RP, Sax PE, Freedberg KA: Posi-
s
tps :
hhtttp hhtttp
tive Epstein-Barr virus heterophile antibody tests in pa- trait associated with sudden death in competitive ath-
tients with primary human immunodeficiency virus in- letes. Am J Cardiol 2012;110(8):1185-1188.
fection. Am J Med 2001;111(3):192-194. This review shows that 23 of 2,462 athlete deaths oc-
curred in association with the sickle-cell trait over
44. Jaworski CA, Donohue B, Kluetz J: Infectious disease. 31 years, with a prediliction among African American
athletes.
Clin Sports Med 2011;30(3):575-590.
k eers
rs k e rs
r s
This article reviews advances in the prevention, diagno-
e
52. Harmon KG, Drezner JA, Klossner D, Asif IM: Sickle
ook ook
sis, and/or management of infectious illnesses seen in
b oo athletes.
b oo b o oo
cell trait associated with a RR of death of 37 times in
o
National Collegiate Athletic Association football ath-
/
e e
/ eb 45.
e/
e e
/ e b
Hew-Butler T, Ayus JC, Kipps C, et al: Statement of the / e e b
letes: A database with 2 million athlete-years as the de-
ee /
nominator. Br J Sports Med 2012;46(5):325-330.
: // t/.tm m
Second International Exercise-Associated Hyponatremia
. : / / t
/ .
t m
. m
This review reported that the risk of death by exertion
ss /
Consensus Development Conference, New Zealand,
: ss : /
in Division I football players with the sickle-cell trait
hhtttp hhtttp
2007. Clin J Sport Med 2008;18(2):111-121. was 1 in 827. This rate was 37 times higher than in ath-
46. tp
Almond CS, Shin AY, Fortescue EB, et al: Hypona-
tremia among runners in the Boston marathon. N Engl
tp53.
letes without the sickle-cell trait.
Armstrong LE, Casa DJ, Millard-Stafford M, et al:

J Med 2005;352(15):1550-1556. American College of Sports Medicine position stand:
Exertional heat illness during training and competition.
rrss rrss
47. Kipps C, Sharma S, Pedoe DT: The incidence of Med Sci Sports Exerc 2007;39(3):556-572.
o ke
ke o k e
k e
exercise-associated hyponatraemia in the London mara-
54.
oo
Bergeron MF, McKeag DB, Casa DJ, et al: Youth foot-
e bboo o thon. Br J Sports Med 2011;45(1):14-19.
e b o
b o o
The sodium serum results from runners in the 2006
e b o o
ball: Heat stress and injury risk. Med Sci Sports Exerc
b
/
e / e m e / / e
London Marathon showed that 12.5% of healthy vol-
e m ee/ / e
2005;37(8):1421-1430.
: / / / .
t . m
unteers developed asymptomatic hyponatremia despite
t
cool conditions, with 4 of 11 hyponatremic runners
/
55.
: / /
/t/.t .m
DeFranco MJ, Baker CL III, DaSilva JJ, Piasecki DP,
ss :
consuming more fluid and gaining more weight.
ss :
Bach BR Jr: Environmental issues for team physicians.
hhtttp
tp hhtttp
tp
Am J Sports Med 2008;36(11):2226-2237.
48. Eichner ER: Exertional rhabdomyolysis. Curr Sports
56. Swenson ER, Maggiorini M: Salmeterol for the preven-
Med Rep 2008;7(1):3-4. tion of high-altitude pulmonary edema. N Engl J Med
2002;347(16):1282-1285.
49. Clarkson PM, Eichner ER: Exertional rhabdomyolysis:
k eers
rs
ure? Curr Sports Med Rep 2006;5(2):57-60.
k e r
e s
Does elevated blood creatine kinase foretell renal fail-
r s 57. Schoene RB: Illnesses at high altitude. Chest 2008;

134(2):402-416.
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 11
e rs
rs e rrss
oo
kCoagulation,
ook e Blood o Management,
k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e and Thromboembolism t
///t. m
.mee in t
///t. m
. mee
s: /
: s : /
:
Orthopaedic tps Surgery
hhtttp
Tessa Balach, MD Jay R. Lieberman, MD
tps
hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Introduction
e/
e e
/ e b e / e
/ e b
ing the surgical patient to excessive bleeding. Etiologies
e
: // t/.tm
. m
Orthopaedic surgery patients comprise a heterogeneous
: / / t
/ t m
for coagulopathies include inherited qualitative platelet
. . m
dysfunction (for example, von Willebrand disease), the
ss : / ss : /
hemophilias, and acquired coagulopathies. Acquired
hhtttp hhtttp
population representing every age group and possess a
tp
variety of medical comorbidities. An understanding of
bleeding and coagulation, the management of intraop-
erative blood loss, and the administration of blood prod-
tp
bleeding diatheses can result from medication use (such
as aspirin or warfarin), vitamin K deficiency, or organ
dysfunction (such as advanced liver disease). Thrombo-
ucts is necessary to enhance the care of these patients. In cytopenia, a quantitative deficiency of platelets, places
addition, the ability to evaluate and recognize coagulop- a patient at increased risk of spontaneous bleeding
rrss rrss
athies preoperatively, assess patients’ risk for venous when platelet counts are less than 10,000/µL and an in-
o kee
thromboembolism (VTE), provide them with appropri-
k o k e
k e creased risk of surgical bleeding when platelet counts
oo
are less than 50,000/µL to 100,000/µL.2,3
e bboo o e b o
b o o
ate prophylaxis, and diagnose and treat VTE is essential.
e b o
b o
/
e / e m ee/ / e / / e
Evaluation of Coagulopathies
m ee
The first step in screening any surgical patient for a co-
Coagulation and Coagulopathies
: / /
/ t
/ .
t . m : / /
/t/.t .m
agulopathy is to obtain a thorough history, which
ss :
The physiologic coagulation cascade is initiated when
ss :
should include specific information about bleeding
hhtttp
tp hhtttp
tp
vascular endothelial injury occurs, resulting in bleeding. symptoms, systemic illnesses, medications, a personal
The initial response to endothelial injury is the forma- history of bleeding, and a family history of bleeding
tion of a platelet plug through platelet adhesion and ag- disorders.2-4 If a patient’s history suggests a coagulopa-
gregation. The simultaneous initiation of the coagula- thy or abnormal bleeding, further evaluation is recom-
tion cascade of procoagulant factors aids in hemostasis mended. Initial laboratory tests include a complete
k eers
by stabilizing the platelet plug with a fibrin clot.1 The
rs
balanced interaction between procoagulant and antico-
k e r
e s
r s
blood count with smear, prothrombin time (PT), partial
thromboplastin time (PTT), and international normal-
bboooo k b o o
o o
agulant factors ensures that the hemostatic effects of
the cascade are mediated and are neither insufficient k b o oo
ized ratio (INR).3 If significant abnormalities are dis-
o
covered, the patient should be referred to a hematolo-
/
e e
/ e nor excessive.
ee/ e
/ e b ee/ e
/ e b
gist for further workup of a bleeding diathesis.
/ / t
/ t m
Dysfunction of physiologic coagulation results in
. . m
disorders of clot formation and stabilization, predispos-
: / / t .
t m
. m
Perioperative Management
: /
t p ss
p : / ss : /
of Coagulopathies
t p p
t
hht t
Dr. Lieberman or an immediate family member serves as
a paid consultant to or is an employee of DePuy; has re-
t
hht t
After diagnosis of a coagulopathy, its management dur-
ing the perioperative period is essential to appropriately
control blood loss. Coagulopathies resulting from a de-
ceived research or institutional support from Amgen ficiency of coagulation factors, such as the hemophilias,
and Arthrex; and serves as a board member, owner, offi- should be treated with the replacement of missing fac-
k eerss
cer, or committee member of the American Academy of
r k
Orthopaedic Surgeons and the American Association of
eers
r s
tors. Recombinant factor VIIa is indicated for use in
patients with hemophilia (factor VII or IX inhibitors)
b ooook b ook
Hip and Knee Surgeons. Neither Dr. Balach nor any im-
oo b oooo
or in those with a congenital deficiency of factor VII.4
Medication-induced coagulopathies should be allowed
/
e e
/ eb e / e
/e b
mediate family member has received anything of value
from or has stock or stock options held in a commercial
e ee/e/e b
to reverse, if possible (for example, preoperative
the subject of this chapter.

: / t
///t m
company or institution related directly or indirectly to
. . m : / t.
///t m
discontinuation of platelet inhibitors before elective
.m
surgery). In the setting of urgent or emergent surgery,
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
some of these coagulopathies can be treated with the lizing a clot and preventing its degradation.14 The car-
k eers
rs ke rr
administration of fresh frozen plasma. Patients who re-
e ss diac surgery, arthroplasty, and spine literature have
b ooook b o ook
ceive multiple transfusions because of massive blood
o
loss during a surgical procedure should be evaluated in-
repeatedly shown tranexamic acid and aminocaproic
o oo
o
acid to significantly reduce intraoperative blood loss
b
/
ee/e b / e e b
traoperatively for the development of a dilutional coag-
ee /
ulopathy. In addition, hemostatic agents, including top- / e e b
and the subsequent need for blood transfusion.7,14,15
ee /
The potential prothrombotic effects of these medica-
t . m
.m
ical fibrin sealants, thrombin, and cellulose gels, and
: / ///t : / t
///t. m
. m
tions have not been shown to be significant. With only
s
tps :
antifibrinolytic agents, are available to help control in-
s
tps :
case reports of more serious complications, such as
hhtttp hhtttp
traoperative bleeding. stroke or renal failure, the adverse effect profiles of
both tranexamic acid and aminocaproic acid are signif-
icantly better than for aprotinin, an antifibrinolytic
Blood Management agent that is no longer available for clinical use.14,15
Further study is needed to determine optimal dosing
Management of Perioperative Blood Loss and administration regimens for these medications.
k eers
rs k eers
r
A preoperative estimation of surgical blood loss guides
s
b ooook b oook
the formation of a strategy for perioperative blood
o
management. The goals during surgery should be to
Transfusion of Blood Products
Red Blood Cells
b o oo
o
/
e e
/ eb / e e b
emphasize hemostasis and minimize bleeding whenever
ee /
possible. Intraoperative techniques and strategies such / e e b
The transfusion of red blood cells can be used to man-
ee /
age perioperative anemia. Numerous studies have
: // t/.tm
. m
as electrocautery and hypotensive anesthesia can be
: / / t
/ .
t m
. m
sought to determine the absolute levels at which red
s : /
used to achieve these goals. Intraoperative blood sal-
s ss : /
blood cells should be transfused. A randomized, multi-
hhtttp
tp hhtttp
tp
vage systems, which return autologous blood to the pa- center study of critical care patients found that 30-day
tient, can be used when significant bleeding is antici- mortality rates were similar between euvolemic patients
pated.5,6 These systems are contraindicated in the who underwent transfusion at hemoglobin levels less
setting of infection or cancer.7 than 7 g/dL compared with those who underwent
Fibrin sealants work to activate the final stages of transfusion at levels less than 9 g/dL; a more restrictive
the coagulation cascade by helping to form a more sta- transfusion strategy was advocated in patients without
keerrss ble clot but need to be applied to a tissue bed that is
k e rrss
e
acute myocardial infarction or unstable angina.16 An-
other randomized controlled trial examined the trans-
bboooo k dry and without active bleeding.4 Despite this poten-
b o o o k
tially challenging technical aspect, fibrin sealants can
o b o oo
fusion requirements in patients after cardiac surgery
o
/
e e
/ e ee e
/ e b
reduce blood loss and decrease the need for blood
/
transfusions.8 Thrombin is another topical agent that
e e
/ e b
and found that patients on a more restrictive transfu-
/
sion strategy (to maintain a hematocrit ≥ 24%) had no
e
t . m
. m
can be applied intraoperatively to wound beds.
: / / / t : / /t/.tm m
significant difference in 30-day morbidity and mortality
.
ss /
Collagen-based sponges or cellulose sheets applied top-
: ss : /
rates compared with those maintained on a more lib-
hhtttp hhtttp
ically can aid in decreasing intraoperative bleeding and eral transfusion strategy (to maintain a hematocrit
tp
are frequently combined with thrombin to further po-
tentiate the hemostatic effects of both agents. Addi- tp
≥ 30%).17 A recent Cochrane Database Review of 19
trials involving more than 6,000 patients examined
transfusion thresholds and their effect on clinical out-
tional data are needed to determine if these products
are a cost-effective means of decreasing blood loss. comes. This review found that restrictive transfusion
Another strategy for managing perioperative blood strategies did not affect the likelihood of adverse events
k eers
rs loss is to ensure a patient’s hemoglobin concentrations
k
are optimized preoperatively to better tolerate acute
e r
e s
r scompared with more liberal transfusion strategies and
supported a transfusion threshold of 7 g/dL to 8 g/dL in
bboooo k b o o
blood loss associated with surgery. The preoperative
o o k most patients.18
b o oo
o
/
e e
/ e e / e
/ e b
administration of erythropoietin in the setting of total
joint arthroplasty has been demonstrated to reduce the
e e / e
/ e b
The prophylactic transfusion of red blood cells in
patients without risk factors for ischemia with hemo-
e
: / / / .
t m m
need for postoperative blood transfusion.9,10 When
t .
combined with preoperative autologous blood dona-
: / / t
/ .
t m
globin levels greater than 8 g/dL is not recommended;
. m
those with risk factors for ischemia should be consid-
ss : /
tion, erythropoietin has been shown to be effective at
t p p t p ss
p : /
ered for prophylactic transfusion when hemoglobin lev-
t
hht t
reducing the exposure to allogeneic blood products11
and is also useful in patients who will not accept autol-
ogous or allogeneic blood transfusions, such as Jeho-
t
hht t
els are less than 10 g/dL. Risk factors for ischemia in-
clude myocardial ischemia or infarction, heart failure,
chronic pulmonary disease, and chronic renal dis-
vah’s Witnesses. In the setting of elective, noncardiac, ease.16,19-21 Euvolemic patients with symptomatic ane-
nonvascular surgery with a high risk of bleeding, eryth- mia, manifested by signs such as tachycardia, hypoten-
k eers
rs
ropoietin is indicated for patients with a hemoglobin
k e
level > 10 g/dL and ≤ 13 g/dL.12 Recent data have dem-
ers
r s
sion, or orthostatic hypotension not responsive to fluid
boluses, should be considered for the transfusion of red
b ooook b ook
onstrated that erythropoietin and/or autologous blood
oo
donation may be cost-effective in patients who are at
blood cells.20
b oooo
/
e e
/ eb risk for postoperative transfusion.13
ee/ e
/e b Platelets
ee/e/e b
/ t
///t m
Tranexamic acid and aminocaproic acid are antifi-
. . m
brinolytic medications that aid in hemostasis by stabi-
: / t.
///t m
Platelet dysfunction or thrombocytopenia can be man-
.m
aged with platelet transfusion. Patients with thrombo-
:
s
tps : s
tps :
130
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 11: Coagulation, Blood Management, and Thromboembolism in Orthopaedic Surgery
cytopenia who are scheduled for surgery should be con- philia, more specific tests are ordered to evaluate for a
k eers
rs ke rrs
sidered for prophylactic transfusion for platelet counts
e s factor V Leiden mutation, a prothrombin mutation,
b ooook b o ook
less than 50,000/µL to prevent excessive bleeding.19,20
o
In addition, patients who are at increased risk of bleed-
and the lupus anticoagulant. In addition, homocysteine,
o oo
o
antithrombin III, protein C, and protein S levels are
b
/
ee/e b mended for transfusion.20
ee/ e
/ e b
ing because of platelet dysfunction can be recom- assessed.21,23-26
ee/ e
/ e b
: / t
///t. m
.m t
///t. m
. m
VTE in Orthopaedic Surgery
: /
Plasma
s
tps : s :
Orthopaedic procedures are known to be significant
tps
hhtttp hhtttp
Plasma products such as fresh frozen plasma should be risk factors for the development of VTE. Rates of VTE
transfused in cases of massive hemorrhage and when vary considerably depending on the surgical procedure
signs of clinical coagulopathy are seen. In addition, performed, the clinical scenario, and patient character-
fresh frozen plasma can be transfused to quickly re- istics. The surgeon should be able to understand and
verse warfarin-induced or other acquired coagulopa- estimate the risk of VTE associated with these situa-
thies.19,22 tions and evaluate the patient for appropriate VTE pro-
k eers
rs k eers
r s phylaxis while weighing the associated benefits and
b ooookVenous Thromboembolic Disease
b ooook bleeding risks.
b o oo
o
The use of VTE prophylaxis in the setting of elective
/
e e
/ eb Pathophysiology
e/
e e
/ e b ee/ e
/ e b
total joint arthroplasty has been shown to decrease the
rate of deep vein thrombosis (DVT) to 3% to 12% and
: // t . m
. m
VTE can be a serious source of morbidity and mortal-
/ t : / / t
/ .
t m
. m
that of fatal pulmonary embolus (PE) to less than
s : /
ity. Virchow’s triad of venous stasis, vascular injury,
s ss : /
0.1%.27-29 There is little controversy that VTE prophy-
hhtttp
tp hhtttp
tp
and hypercoagulability has framed the approach to the laxis, in some form, should be administered to patients
evaluation and management of patients with thrombo- undergoing elective hip or knee arthroplasty. However,
embolic disease. In orthopaedic surgery, venous stasis significant debate continues about risk stratification for
and vascular injury are the most common causes of patients at risk for developing VTE, the most effective
VTE. mode of prophylaxis (chemical versus mechanical), the
Under normal physiologic conditions, and in the ab- best chemoprophylactic agent (such as low molecular
k errss
sence of a thrombophilic disorder, circulating coagula-
e k e rrss
e
weight heparin, vitamin K antagonists, factor X inhibi-
bboooo k b o o o k
tion factors are neutralized and balanced by endothelial
cell surface inhibitors and circulating antiproteinases.23
o
tors, thrombin inhibitors, and antiplatelet agents), as
b o oo
well as the duration of such treatment (10 to 14 days
o
/
e e
/ e ee e
/ e b
In the setting of VTE or in hypercoagulable states, the
/
balance between thrombus formation and clot degrada-
ee e
versus 28 days or longer).
/ / e b
The American College of Chest Physicians (ACCP)
: / / t
/ .
t m m
tion is disrupted, resulting in pathologic clot formation.
. t . m.m
has published clinical practice guidelines regarding the
: / / / t
ss /
The most common location for pathologic thrombus
: ss : /
prevention of VTE that recommended a prophylactic
hhtttp hhtttp
formation is within the veins of the lower extremity.23 regimen to prevent all thromboembolic events, includ-
tp
Deep lower extremity venous thrombi that become
symptomatic or embolize to the pulmonary vasculature
are of most concern to the practicing orthopaedic sur-
tp
ing asymptomatic DVT as well as fatal PE.30 These
guidelines focused more on efficacy than the bleeding
risks associated with some of the chemoprophylactic
geon. regimens. In response, the American Academy of Or-
thopaedic Surgeons (AAOS) developed clinical practice
k eerss
Thrombophilias
r
Patients at increased risk for VTE events should be
k e r
e s
r sguidelines that balanced both efficacy and safety con-
cerns.31
bboooo k o o o k
identified preoperatively whenever possible. The etiol-
b o b o oo
The new evidence-based AAOS guidelines were pub-
o
/
e e
/ e e e
/ e b
ogy of most thrombophilias falls into one of two major
/
categories: inherited and acquired. Among the inherited
e e / e
/ e b
lished in September 2011 and included 10 recommen-
dations (Table 1) related to the use of VTE prophylaxis
e
: / / / .
t m m
causes for hypercoagulability are deficiencies of protein
t . : / / t
/ .
t m
. m
after total joint arthroplasty. Because of a lack of evi-
dence related to the efficacy of different prophylactic
t p ss : /
C, protein S, or antithrombin III; a factor V Leiden mu-
tation; and a prothrombin gene mutation. Acquired
p ss : /
regimens in preventing symptomatic events, the guide-
t p p
t
hht t
thrombophilia can be the result of pregnancy or oral
contraceptive use, nephrotic syndrome, the lupus anti-
coagulant, malignancy, atrial fibrillation, surgery,
t
hht t
line panel was unable to recommend a specific regimen
or duration of prophylaxis. The panel did strongly rec-
ommend against screening using duplex ultrasound be-
trauma and immobilization, or obesity.3,21,23-25 Similar fore discharge. New ACCP guidelines were published
to the evaluation of patients with bleeding diatheses, a in February 2012 for a variety of orthopaedic proce-
k eers
thorough history regarding prior VTE is critical. After
rs e
referral to a hematologist for a more detailed evalua-
k ers
r s
dures (Table 2), and in a shift from prior guidelines,
recognized that the selection of a prophylactic regimen
b ooook b ook
tion of a hypercoagulable disorder, patients with a his-
oo
tory of VTE are initially evaluated with routine blood
b oooo
is a balance between efficacy and safety.32 In this
evidence-based guideline, the ACCP recommended a
/
e e
/ eb / e
/e b
work, including a complete blood count and chemistry
ee ee/e/e b
number of different chemoprophylactic agents and/or
/ t
///t m
evaluation that includes kidney and liver function tests.
. . m
When patient history suggests a hereditary thrombo-
: : / t.
///t m
mechanical compression for a minimum of 14 days
.m
rather than no prophylaxis at all.33 Both the AAOS and
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook b ook
Summary of the American Academy of Orthopaedic Surgeon’s 2011 Guideline on Preventing Venous
o o
Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty
b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
1. We recommend against routine postoperative duplex ultrasonography screening of patients who undergo elective hip or
: / t . m
.m
knee arthroplasty. (Grade of Recommendation: Strong)
///t : / t
///t. m
. m
s
tps : s :
2. Patients undergoing elective hip or knee arthroplasty are already at high risk for VTE. The practitioner might further assess
tps
hhtttp hhtttp
the risk of VTE event by determining whether these patients had a previous VTE. (Grade of Recommendation: Weak)
Current evidence is not clear about whether factors other than a history of previous venous thromboembolism increase the
risk of VTE in patients undergoing elective hip or knee arthroplasty; therefore, we cannot recommend for or against
routinely assessing these patients for these factors. (Grade of Recommendation: Inconclusive)
3. Patients undergoing elective hip or knee arthroplasty are at risk for bleeding and bleeding-associated complications. In the
absence of reliable evidence, it is the opinion of this work group that patients be assessed for known bleeding disorders like
k eers
rs k eers
r s
hemophilia and for the presence of active liver disease, which further increase the risk for bleeding and bleeding-associated
complications. (Grade of Recommendation: Consensus) Current evidence is not clear about whether factors other than the
b ooook b oook b oo
presence of a known bleeding disorder or active liver disease increase the chance of bleeding in these patients; therefore,
o o o
we are unable to recommend for or against using them to assess a patient’s risk of bleeding. (Grade of Recommendation:
/
e e
/ eb Inconclusive)
e/
e e
/ e b ee/ e
/ e b
// t tm
. m
or knee arthroplasty. (Grade of Recommendation: Moderate)
: / : / / t
/ t m
4. We suggest that patients discontinue antiplatelet agents (for example, aspirin, clopidogrel) before undergoing elective hip
. . . m
ss : / ss : /
hhtttp hhtttp
5. We suggest the use of pharmacologic agents and/or mechanical compressive devices for the prevention of VTE in patients
tp tp
undergoing elective hip or knee arthroplasty and who are not at elevated risk beyond that of the surgery itself for VTE or
bleeding. (Grade of Recommendation: Moderate) Current evidence is unclear about which prophylactic strategy (or
strategies) is/are optimal or suboptimal. Therefore, we are unable to recommend for or against specific prophylactics in
these patients. (Grade of Recommendation: Inconclusive) In the absence of reliable evidence about how long to employ
these prophylactic strategies, it is the opinion of this work group that patients and physicians discuss the duration of
prophylaxis. (Grade of Recommendation: Consensus)
keerrss e rrss
6. In the absence of reliable evidence, it is the opinion of this work group that patients undergoing elective hip or knee
k e
bboooo k (Grade of Recommendation: Consensus)
b o o
o o k
arthroplasty, and who have also had a previous VTE, receive pharmacologic prophylaxis and mechanical compressive devices.
b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
7. In the absence of reliable evidence, it is the opinion of this work group that patients undergoing elective hip or knee
arthroplasty, and who also have a known bleeding disorder (for example, hemophilia) and/or active liver disease, use
t . m
. m t . m.m
mechanical compressive devices for preventing VTE. (Grade of Recommendation: Consensus)
: / / / t : / / / t
s : / s : /
8. In the absence of reliable evidence, it is the opinion of this work group that patients undergo early mobilization following
s s
hhtttp
tp hhtttp
tp
elective hip and knee arthroplasty. Early mobilization is of low cost, minimal risk to the patient, and consistent with current
practice. (Grade of Recommendation: Consensus)
9. We suggest using neuraxial (such as intrathecal, epidural, and spinal) anesthesia for patients undergoing elective hip or
knee arthroplasty to help limit blood loss, even though evidence suggests that neuraxial anesthesia does not affect the
occurrence of venous thromboembolic disease. (Grade of Recommendation: Moderate)
10. Current evidence does not provide clear guidance about whether inferior vena cava (IVC) filters prevent pulmonary
k eers
rs r s
r s
embolism in patients undergoing elective hip and knee arthroplasty who also have a contraindication to chemoprophylaxis
k e e
and/or known residual venous thromboembolic disease. Therefore, we are unable to recommend for or against the use of
bboooo k b o o
such filters. (Grade of Recommendation: Inconclusive)
o o k b o oo
o
/
e e
/ e Orthop Surg 2011;19[12]:768-776.)
ee/ e
/ e b ee/ e
/ e b
(Adapted from Mont MA, Jacobs JJ, Boggio LN, et al: Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : /
the ACCP guidelines were in agreement in recommend-
t p ss
p : / garding the use of thromboprophylaxis. Several studies
t
hht t
ing against VTE screening at the time of hospital dis-
charge. The ACCP guidelines also made several sugges-
t
hht t have found rates of DVT from less than 1% to 6% and
that of PE to be less than 1% in a variety of foot and
tions, including using low-molecular-weight heparin as ankle surgeries ranging from trauma to arthro-
a chemoprophylactic agent because of its established plasty.34-37 All recommended against the routine use of
track record with respect to efficacy, combining chemo- thromboprophylaxis for these patients and emphasized
k eers
rs prophylaxis with mechanical compression for prophy-
k eers
r s the need for well-designed prospective investigations to
b ooook laxis, and continuing prophylaxis for 35 days.
b oook
o
This debate is not confined to the arthroplasty liter-
b oooo
provide more definitive guidelines for VTE prophylaxis
in this subgroup of patients.34-36
/
e e
/ eb / ee b
ature. Recent studies in the foot and ankle literature at-
ee /
tempted to determine the rate of VTE associated with
ee/e e b
Similarly, the incidence of VTE after arthroscopy has
/
been examined, with rates of VTE in both knee and
t
///t. m
. m
these procedures while making recommendations re-
: / : / t.
///t m
.mshoulder arthroscopy most recently reported to be less
s
tps : s
tps :
132
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp Chapter 11: Coagulation, Blood Management, and Thromboembolism in Orthopaedic Surgery tps
hhtttp
k eers
Table 2
rs keerrss
b ooook b ook
Summary of the American College of Chest Physicians 2012 Evidence-Based Clinical Practice
o o
Guidelines for Prevention of Venous Thromboembolism in Orthopaedic Surgery, ed 9
b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
2.1.1 In patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA), we recommend use of one of the
: / t
///t. m
.m : / t
///t. m
. m
following for a minimum of 10 to 14 days rather than no antithrombotic prophylaxis: low-molecular-weight heparin
(LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin (LDUH), adjusted-dose
s
tps : s
tps :
hhtttp hhtttp
vitamin K antagonist (VKA), aspirin (all grade 1B), or an intermittent pneumatic compression device (IPCD) (Grade 1C).
2.1.2 In patients undergoing hip fracture surgery (HFS), we recommend use of one of the following rather than no
antithrombotic prophylaxis for a minimum of 10 to 14 days: LMWH, fondaparinux, LDUH, adjusted-dose VKA, aspirin (all
grade 1B), or an IPCD (Grade 1C).
2.2 For patients undergoing major orthopaedic surgery (THA, TKA, HFS) and receiving LMWH as thromboprophylaxis, we
recommend starting either 12 h or more preoperatively or 12 h or more postoperatively rather than within 4 h or less
k eers
rs k eers
r s
preoperatively or 4 h or less postoperatively (Grade 1B).
ook ook
2.3.1 In patients undergoing THA or TKA, irrespective of the concomitant use of an IPCD or length of treatment, we suggest
b oo b oo b o oo
the use of LMWH in preference to the other agents we have recommended as alternatives: fondaparinux, apixaban,
o
/
e e
/ eb 2.4
e/
e e
/ e b ee/ e
/ e b
dabigatran, rivaroxaban, LDUH (all grade 2B), adjusted-dose VKA, or aspirin (all grade 2C).
For patients undergoing major orthopaedic surgery, we suggest extending thromboprophylaxis in the outpatient period
: // t/.tm m : / / t
/ .
t m
. m
for up to 35 days from the day of surgery rather than for only 10 to 14 days (Grade 2B).
.
2.5
s : / s : /
In patients undergoing major orthopaedic surgery, we suggest using dual prophylaxis with an antithrombotic agent and
s s
hhtttp
tp hhtttp
tp
an IPCD during the hospital stay (Grade 2C).
2.6 In patients undergoing major orthopaedic surgery and increased risk of bleeding, we suggest using an IPCD or no
prophylaxis rather than pharmacologic treatment (Grade 2C).
2.7 In patients undergoing major orthopaedic surgery and who decline or are uncooperative with injections or an IPCD, we
recommend using apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are
unavailable) rather than alternative forms of prophylaxis (all grade 1B).
keerrss
2.8
e rrss
In patients undergoing major orthopaedic surgery, we suggest against using inferior vena cava (IVC) filter placement for
k e
bboooo k o o
o o k
pharmacologic and mechanical thromboprophylaxis (Grade 2C).
b b o oo
primary prevention over no thromboprophylaxis in patients with an increased bleeding risk or contraindications to both
o
/
e e
/ e 2.9
ee/ e
/ e b
(DUS) screening before hospital discharge (Grade 1B).
ee/ e
/ e b
For asymptomatic patients following major orthopaedic surgery, we recommend against Doppler (or duplex) ultrasound
3.0
/ / t
/ .
t m
. m / /t/.tm.m
We suggest no prophylaxis rather than pharmacologic thromboprophylaxis in patients with isolated lower-leg injuries
: :
s : /
requiring leg immobilization (Grade 2C).
s ss : /
hhtttp
tp hhtttp
tp
4.0 For patients undergoing knee arthroscopy without a history of prior VTE, we suggest no thromboprophylaxis rather than
prophylaxis (Grade 2B).
(Reproduced with permission from Falck-Ytter Y, Francis CW, Johanson NA, et al: Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention
of Thrombosis, ed 9. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141[Suppl 2]:e278S-e325S.)
k eers
rs
than 1%.38-40 A Cochrane Database Review showed a
k e r
e s
r s thromboprophylactic regimen in the setting of surgery
bboooo k
VTE rate of less than 1% following knee arthroscopy
b o o
o o k b o oo
for bone and soft-tissue sarcomas or surgery for bony
o
/
e e
/ e
and found no strong evidence to recommend the rou-
e / e
/ e
tine administration of thromboprophylaxis in these pa-
e b e / e
/ e b
metastases.42-45
The safety and efficacy of VTE prophylaxis balanced
e
tients.41
: / / t
/ .
t m
. m
Oncology patients represent a unique subgroup of
: / / t
/ .
t m
. m
with the risk of bleeding associated with prophylaxis is
t p ss : /
orthopaedic patients who are considered to be at in-
p t p ss
p : / of significant concern for patients undergoing spine sur-
gery. The risk of bleeding and the development of a
t
hht t
creased risk of VTE because of their cancer diagnosis.
In addition, they experience increased morbidity and
mortality associated with VTE.42 In the setting of
t
hht t postoperative epidural hematoma can result in signifi-
cant and potentially irreversible neurologic injury. A re-
cent meta-analysis of VTE after elective spine surgery
surgery for bone/soft-tissue sarcoma or metastatic bone
disease, the risk of VTE must be balanced with the risk found the rate of DVT to be low (1.09%) and the rate
of PE to be even lower (0.06%). The rate of epidural
k ee s
of hematoma and the resultant seeding of tumor cells.
rrs
Rates of VTE in this population have been reported to
k eers
r s hematoma was 0.4%, but 38% of those patients suf-
b ooook
range from 0% to 4% in patients managed with a
variety of prophylactic regimens ranging from no
b oook
o b oooo
fered a permanent neurologic deficit.46 Data from more
recent studies confirm the risk of epidural hematoma in
/
e e
/ eb prophylaxis to mechanical prophylaxis alone to
ee/ e
/e b ee/e/e b
the setting of chemoprophylaxis and suggest the need
/ t
///t m
chemoprophylaxis.42-45 None of these studies provides
. . m
strong recommendations for or against a specific
: : / t.
///t m
.m
for well-designed, randomized trials to determine the
role of chemoprophylaxis in spine surgery.46-50
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Thromboembolic Prophylaxis
k eers
rs ke
There are several options for providing patients with
errss Management of Thromboembolic Events
b ooook thromboembolic prophylaxis. A range of pharmaco-
b o ook
o
logic agents is available for VTE prophylaxis. Warfarin,
Diagnosis
b o oo
o
/
ee/e b / e e b
a vitamin K antagonist, leads to decreased production
ee /
of factors II, VII, IX, and X, in addition to proteins C
e / e
/ e b
The clinical diagnosis of VTE is unreliable because the
signs and symptoms of DVT or PE are often nonspe-
e
: / t
///t. m
.m
and S. Challenges with the administration of warfarin
/ t
///t. m
cific. Possible signs and symptoms of DVT include
. m
acute calf pain, leg swelling, and a positive Homan
:
s :
revolve around dosing, its significant drug and dietary
tps s
tps :
sign. The presence of these findings during the acute
hhtttp hhtttp
interactions, and the monitoring required to achieve postsurgical period should prompt more objective eval-
and maintain an adequate level of anticoagulation.49 uation for DVT. PE can often be asymptomatic but,
Warfarin can be reversed with the administration of vi- when of significant size, may manifest with symptoms
tamin K and overcome with plasma transfusions. Low- of dyspnea, pleuritic chest pain, or syncope. Clinical
molecular-weight heparins (for example, enoxaparin signs may include transient or sustained hypoxemia,
and dalteparin) and fondaparinux (an indirect factor
k eers
rs Xa inhibitor) are administered subcutaneously once or
k eers
r s
tachypnea, and persistent tachycardia.
Objective diagnostic tests should be performed for
b ooook b ooook
twice daily and do not routinely require serum moni-
toring. Both fondaparinux and low-molecular-weight
b oo
patients in whom there is sufficient clinical suspicion
o o
for VTE. Although invasive venography remains the
/
e e
/ eb e/
e e
/ b
heparins have a low risk of heparin-induced thrombo-
e
cytopenia.4 New oral anticoagulants, which include
ee/ e
/ e b
gold standard for evaluating venous thrombosis, ve-
nous ultrasonography has been demonstrated to be suf-
: // t/.tm
. m
factor Xa inhibitors (such as rivaroxaban) and direct
: / / t
/ .
t m
. m
ficiently sensitive and specific for diagnosis and is the
ss : /
thrombin inhibitors (such as dabigatran), are a class of
s : /
test of choice for evaluating DVT. Similarly, direct visu-
s
hhtttp
tp hhtttp
tp
agents that do not require monitoring and may have alization of the pulmonary vasculature with angiogra-
less risk of bleeding compared with low-molecular- phy remains the gold standard for diagnosing PE; how-
weight heparins.51,52 The safety of these drugs needs to ever, less invasive procedures with fewer associated
be determined in orthopaedic clinical practice.51 Aspi- risks have been developed and validated. Spiral CT of
rin, an antiplatelet agent, is an orally administered the chest has now become the imaging study of choice
medication that reduces platelet adhesion and seems to in evaluating these patients. Although this test has a
keerrss reduce the rate of symptomatic VTE. Aspirin is a less
k
powerful anticoagulant agent than the other chemopro-
e rrss
e
high sensitivity and specificity for PE, a recent study
bboooo k b o o o k
phylactic drugs but seems to have a lower bleeding risk.
o
suggests it may be too sensitive.56 The spiral CT scan
b o oo
o
may reveal small emboli in the pulmonary vasculature
/
e e
/ e ee e
/ e b
Intermittent pneumatic compression devices are a
/
mechanical option to prevent VTE predominantly by
ee/ e
/ e b
that are not clinically relevant. The ventilation-
perfusion (V/Q) scan compares the available ventilation
: / / t
/ .
t m m
working to decrease venous stasis. There is evidence to
. t . m.m
capacity of the lungs with that portion of the lung be-
: / / / t
ss /
support that activation of the fibrinolytic system occurs
: ss : /
ing perfused using a radioactive tracer. A normal scan
hhtttp hhtttp
with intermittent pneumatic compression devices, but it excludes PE, but an abnormal result is nonspecific. The
tp
is unknown to what degree this action is clinically ef-
fective.53 The benefits of this nonpharmacologic, nonin- tp
V/Q scan is still indicated for patients who are unable
to undergo spiral CT (for example, in those with con-
vasive means of prophylaxis are that they are not asso- trast allergy or renal dysfunction).22,57
ciated with an increased risk of bleeding. Compliance
with these devices is the most significant challenge as- Treatment
k eers
rs sociated with their use. Early mobilization and ambula-
tion should also be considered important components
k e r
e s
r s
The goals of treatment of VTE are to prevent PE-
associated mortality and decrease the morbidity associ-
bboooo k o o o k
of the prophylactic regimen. The availability of mobile
b o b o oo
ated with DVT. Prolonged systemic chemical anticoag-
o
/
e e
/ e e / / e b
compression devices now allows for this type of pro-
e
phylaxis to be used during ambulation and after dis-
e e / e
/ e b
ulation is the preferred method of treatment. The most
immediate methods of achieving therapeutic anticoagu-
e
charge from the hospital.
: / / t
/ .
t m
. m
Inferior vena cava (IVC) filters are another nonphar-
: / / t
/ .
t m
. m
lation are with intravenous unfractionated heparin,
ss : /
macologic but infrequently used option in the prophy-
t p p t p ss : /
low-molecular-weight heparin, or fondaparinux. In the
immediate postoperative period, rapid therapeutic anti-
p
t
hht t
laxis of PE. The indications for the use of these devices
are extremely limited. Patients who cannot tolerate phar-
macologic agents, who remain at high risk despite phar-
t
hht t
coagulation can be associated with an increased risk of
bleeding and should be avoided, if possible. Achieving
more gradual therapeutic anticoagulation with the use
macologic anticoagulation, and in whom pharmacologic of an unbolused heparin drip may avoid the increased
anticoagulation has failed may be among the small group risk of bleeding associated with the use of low-
k eers
rs
in whom IVC filters may be considered.4,54 Historically,
permanent IVC filters have been placed but have been
k eers
r s molecular-weight heparin, fondaparinux, or heparin
boluses to achieve therapeutic anticoagulation.
b ooook b oook
associated with complications such as IVC thrombosis,
o
erosion of the filter through the IVC walls, and the de-
b ooo
Concomitant administration of an oral anticoagu-
o
lant is initiated. Long-term anticoagulation is most fre-
/
e e
/ eb ee/ e
/e b
velopment of DVT. Retrievable filters have been devel-
/e/e b
quently accomplished by using warfarin. New oral an-
ee
/ t
///t m
oped to provide temporary prophylaxis, and early stud-
. . m
ies have shown them to be safe and effective.54,55
: / t.
///t m
ticoagulants, including dabigatran and rivaroxaban
.m
may become substitutes for warfarin.57
:
s
tps : s
tps :
134
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
The duration of treatment depends on the type and 3. Schafer AI: Approach to the patient with bleeding and
k rs
rs
the extent of thromboembolic disease. A venous throm-
ee keerrss thrombosis, in Cecil RL, Goldman LMD, Schafer AI,
eds: Goldman’s Cecil Medicine, ed 24. Philadelphia, PA,
b ooook o ook
bosis in the deep veins proximal to the popliteal vein is
o
treated with oral anticoagulation for 3 to 6 months,
b o oo
Elsevier/Saunders, 2012, pp 1121-1124.
b o
/
ee/e b ee/ e
/ e b
whereas the management of more distal thrombi is con-
troversial. Perioperative PE in the absence of other risk
ee e
/ e b
A review of the evidence-based evaluation and diagnosis
/
of abnormalities in bleeding and coagulation is presented.
t . m
.m
factors for recurrent VTE is managed with 3 to
: / ///t
6 months of oral anticoagulation. PE in patients with
:
4.
/ t
///t. m
. m
Reding MT, Key NS: Bleeding and thrombosis, in Hoff-
s
tps : s
tps :
hhtttp hhtttp
hypercoagulable states or in those who have experi- man R, ed: Hematology: Basic Principles and Practice,
enced recurrent PE should be managed with lifetime ed 5. Philadelphia, PA, Churchill Livingstone/Elsevier,
2009, pp 2369-2383.
anticoagulation.21,23,26 For patients who cannot tolerate
anticoagulation or for those whose bleeding risk is too
5. Waters JH, Dyga RM, Waters JF, Yazer MH: The vol-
significant, the placement of an IVC filter may be indi-
ume of returned red blood cells in a large blood salvage
cated. Although the IVC filter will do little to treat ex- program: Where does it all go? Transfusion 2011;
k eerss
isting PE, it may help to prevent future emboli.
r k eers
r s 51(10):2126-2132.
b ooook b ooook b oo
This study analyzed the volume of red blood cells re-
o o
turned with blood salvage systems. Although that volume
/
e e
/ eb Summary
e/
e e
/ e b ee/ e
/ e b
is high, the authors recommended selective utilization to
improve efficiency and return significant volumes to a
// t/.tm
Safe and effective treatment of orthopaedic patients de-
. m
mands an understanding of bleeding, coagulation, and
: : / t . m
. m
greater proportion of patients. Level of evidence: III.
/ / t
ss : /
blood management. Disorders of the normal coagulation
ss : /
hhtttp hhtttp
6. Tse EY, Cheung WY, Ng KF, Luk KD: Reducing peri-
tp
cascade may predispose patients to increased bleeding or
put them at risk for pathologic thrombosis. VTE and its
sequelae can impose morbidity and mortality on pa-
tp operative blood loss and allogeneic blood transfusion in
patients undergoing major spine surgery. J Bone Joint
Surg Am 2011;93(13):1268-1277.
tients. Future study will likely focus on further charac- Multiple techniques exist in spine surgery to decrease in-
terization of risk factors for the development of VTE as- traoperative blood loss. Hypotension, tranexamic acid,
rrss rrss
sociated with specific procedures, improved methods of and intrathecal morphine pumps seem to be among the
o ke
ke
and most effective prophylactic regimens.
o k e
VTE risk assessment, and the determination of the safest
k e best techniques.
oo
e bboo o e b o
b o o 7.
e b o o
Keating EM, Meding JB: Perioperative blood manage-
b
/
e / e m ee/ / e ee/ / e
ment practices in elective orthopaedic surgery. J Am
Acad Orthop Surg 2002;10(6):393-400.
m
Key Study Points
: / /
/ t
/ .
t . m : / /
/t/.t .m
ss : 8.
ss :
Thoms RJ, Marwin SE: The role of fibrin sealants in or-
hhtttp hhtttp
• Risk factors for ischemia should be considered
tp tp
thopaedic surgery. J Am Acad Orthop Surg 2009;
before the prophylactic transfusion of red blood 17(12):727-736.
cells in patients with asymptomatic anemia.
• AAOS guidelines for VTE prophylaxis recom- 9. Faris PM, Ritter MA, Abels RI; the American Erythro-
mend using VTE prophylaxis after total joint ar- poietin Study Group: The effects of recombinant human
throplasty. erythropoietin on perioperative transfusion require-
k
•
eers
rs
The ideal perioperative VTE prophylactic regi-
k e r
e s
r s ments in patients having a major orthopaedic operation.
bboooo k men remains controversial.
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b 10.
e / e
/ e b
Feagan BG, Wong CJ, Kirkley A, et al: Erythropoietin
with iron supplementation to prevent allogeneic blood
e
: / / t
/ .
t m
. m : / / t
/ t m
transfusion in total hip joint arthroplasty: A random-
. . m
ized, controlled trial. Ann Intern Med 2000;133(11):
t p ss
p : / t p ss
p : /
845-854.
1. t
hht t
Furie B, Furie BC: Molecular basis of blood coagula-
tion, in Hoffman R, ed: Hematology: Basic Principles
t
hht
11.t Bezwada HP, Nazarian DG, Henry DH, Booth RE Jr:
Preoperative use of recombinant human erythropoietin
and Practice, ed 5. Philadelphia, PA, Churchill before total joint arthroplasty. J Bone Joint Surg Am
Livingstone/Elsevier, 2009, pp 1819-1836. 2003;85(9):1795-1800.
A review of the molecular biology of coagulation factors
k eers
rsand the coagulation cascade is presented.
k eers
r s 12. Epogen [prescribing information]. Amgen Inc., Thou-
sand Oaks, CA, May 2012. http://pi.amgen.com/
b ooook2.
oook
Boller BS, Schneiderman PI: The bleeding history and
b o b oooo
united_states/epogen/epogen_pi_hcp_english.pdf. Ac-
/
e e
/ eb e / e
/e b
differential diagnosis of purpura, in Hoffman R, ed: He-
matology: Basic Principles and Practice, ed 5. Philadel-
e ee/e/e b
cessed Sept 2, 2013.
1876.
: / ///t. m
phia, PA, Churchill Livingstone/Elsevier, 2009, pp 1851-
t . m
13.
: / t.
///t m
Green WS, Toy P, Bozic KJ: Cost minimization analysis
.m
of preoperative erythropoietin vs autologous and alloge-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
neic blood donation in total joint arthroplasty. J Arthro- Med 2008;29(1):25-39.
k eers
rs plasty 2010;25(1):93-96.
keerrss
b ooook b ook
The authors examined the effectiveness and cost associ-
o o
ated with perioperative blood management with eryth-
22.
o oo
Thakur NA, Czerwein JK, Butera JN, Palumbo MA:
o
Perioperative management of chronic anticoagulation in
b
/
ee/e b / e e b
ropoietin, autologous blood donation, and allogeneic
ee /
blood transfusion. Level of evidence: IV.
ee e
/ e
18(12):729-738.b
orthopaedic surgery. J Am Acad Orthop Surg 2010;
/
14.
: / t
///t. m
.m
Eubanks JD: Antifibrinolytics in major orthopaedic sur-
: / t
///t. m
. m
The authors discuss recommendations for the manage-
s
tps : s
tps : ment of chronic anticoagulation in the perioperative pe-
hhtttp hhtttp
gery. J Am Acad Orthop Surg 2010;18(3):132-138. riod.
The antifibrinolytic agents aminocaproic acid and
tranexamic acid can be used in total joint arthroplasty 23. Lim W, Crowther MA, Ginsberg JS: Venous thrombo-
and during pediatric and adult spine surgeries to de- embolism, in Hoffman R, ed: Hematology: Basic Princi-
crease intraoperative blood loss. ples and Practice, ed 5. Philadelphia, PA, Churchill
Livingstone/Elsevier, 2009, pp 2043-2054.
k eers
rs 15.
k eers
Yang ZG, Chen WP, Wu LD: Effectiveness and safety of
r s
tranexamic acid in reducing blood loss in total knee ar- 24. Bauer KA: Hematology: Basic Principles and Practice,
b ooook 2012;94(13):1153-1159.
b oook
throplasty: A meta-analysis. J Bone Joint Surg Am
o b o oo
ed 5. Philadelphia, PA, Churchill Livingstone/Elsevier,
o
2009, pp 2021-2041.
/
e e
/ eb e/ e
/ e b
This meta-analysis of randomized controlled trials
e 25.
ee/ e
/ e b
Schafer AI: Hypercoagulable states, in Cecil RL, Gold-
// t/.tm
showed tranexamic acid to be safe and effective for re-
. m
ducing intraoperative blood loss and the need for blood
: : / / t . m
. m
man LMD, Schafer AI, eds: Goldman’s Cecil Medicine,
/ t
s : /
transfusions in total joint arthroplasty. Level of evi-
s ss : /ed 24. Philadelphia, PA, Elsevier/Saunders, 2012, pp
hhtttp hhtttp
1148-1154.
16.
dence: I.
tp
Hébert PC, Wells G, Blajchman MA, et al: A multi-
tp The authors provide an evidence-based approach to the
diagnosis and the management of hypercoagulable
states.
center, randomized, controlled clinical trial of transfu-
sion requirements in critical care: Transfusion require-
ments in critical care investigators, Canadian Critical 26. Chong LY, Fenu E, Stansby G, Hodgkinson S; Guideline
keerrss Care Trials Group. N Engl J Med 1999;340(6):409-417.
k e rrss
e
Development Group: Management of venous thrombo-
embolic diseases and the role of thrombophilia testing:
bboooo k 17.
o o o k
Hajjar LA, Vincent JL, Galas FR, et al: Transfusion re-
b o e3979.
b o oo
Summary of NICE guidance. BMJ 2012;344(344):
o
/
e e
/ e e e
/ b
quirements after cardiac surgery: The TRACS random-
/ e
ized controlled trial. JAMA 2010;304(14):1559-1567.
e ee/ e
/ e b
Guidelines and recommendations about the evaluation
t . m
. m
This randomized controlled trial examining transfusion
: / / / t : / /t/ t
sented.m
and the treatment of thrombophilias and VTE are pre-
. .m
ss /
strategies in cardiac surgery patients found a more re-
: ss : /
hhtttp hhtttp
strictive strategy was not inferior to a more liberal one
tp tp
27. Keeney JA, Clohisy JC, Curry MC, Maloney WJ: Effi-
in regard to 30-day morbidity and mortality. Level of
cacy of combined modality prophylaxis including short-
evidence: I.
duration warfarin to prevent venous thromboembolism
after total hip arthroplasty. J Arthroplasty 2006;21(4):
18. Carson JL, Carless PA, Hebert PC: Transfusion thresh- 469-475.
olds and other strategies for guiding allogeneic red
blood cell transfusion. Cochrane Database Syst Rev
k eers
rs 2012;4:CD002042.
k e r
e s
r s 28. Pellegrini VD Jr, Donaldson CT, Farber DC, Lehman
EB, Evarts CM: The John Charnley Award: Prevention
bboooo k b o o
o k
This Cochrane Database Review examining transfusion
o
strategies supported the application of restrictitve trans-
b o oo
of readmission for venous thromboembolic disease after
o
total hip arthroplasty. Clin Orthop Relat Res 2005;441:
/
e e
/ e / e e b
fusion protocols in most patients, including those with a
history of cardiovascular disease.
ee / 56-62.
ee/ e
/ e b
: / / t
/ .
t m
. m 29.
: / / t
/ .
t m
. m
Won MH, Lee GW, Lee TJ, Moon KH: Prevalence and
19.
t p : /
Goodnough LT: Transfusion medicine, in Cecil RL,
ss
Goldman LMD, Schafer AI, eds: Goldman’s Cecil Med-
p t p ss
p : /
risk factors of thromboembolism after joint arthroplasty
without chemical thromboprophylaxis in an Asian pop-
t
hht t
icine, ed 24. Philadelphia, PA, Elsevier/Saunders, 2012,
pp 1148-1154. t
hht t ulation. J Arthroplasty 2011;26(7):1106-1111.
The authors find that patients at high risk for VTE
A clinical update on trends and indications regarding the should be provided with thromboprophylaxis after total
transfusion of blood and blood products is presented. joint arthroplasty. Level of evidence: III.
k eers
rs 20. Milward PA, Brecher ME: Conn’s Current Therapy.
Philadelphia, PA, WB Saunders, 2012, pp 866-869.
k eers
r s 30. Geerts WH, Bergqvist D, Pineo GF, et al: Prevention of
venous thromboembolism: American College of Chest
b ooook oook
The authors review the clinical application and admin-
b o b ooo
Physicians Evidence-Based Clinical Practice Guidelines
o
/
e e
/ eb istration of blood and blood products.
ee/ e
/e b ee/e/e b
(8th Edition). Chest 2008;133(6, suppl):381S-453S.
21.
: / t
///t. m
Whitlatch NL, Ortel TL: Thrombophilias: When should
. m
we test and how does it help? Semin Respir Crit Care
31.
: / t
///t m
Johanson NA, Lachiewicz PF, Lieberman JR, et al: Pre-
. .m
vention of symptomatic pulmonary embolism in pa-
s
tps : s
tps :
136
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
tients undergoing total hip or knee arthroplasty. J Am 2011;20(5):764-770.
k eers
rsAcad Orthop Surg 2009;17(3):183-196.
keerrss The rate of thromboembolism is examined in patients
b ooook
32.
b o ook
o
Falck-Ytter Y, Francis CW, Johanson NA, et al: Preven-
o oo
undergoing shoulder surgery. The authors concluded
o
that the rate of DVT and PE was too low to recommend
b
/
ee/e b ee e
/ e b
tion of VTE in orthopedic surgery patients: Antithrom-
/
botic Therapy and Prevention of Thrombosis, 9th ed:
ee/ e
/ e b
the routine use of thromboprophylaxis for these pa-
tients. Level of evidence: II.
: / ///t. mm
American College of Chest Physicians Evidence-Based
t .
Clinical Practice Guidelines. Chest 2012;141(2, suppl):
:
39.
/ t
///t. m
. m
Randelli P, Castagna A, Cabitza F, Cabitza P, Arri-
e278S-e325S.
s
tps : s
tps :
hhtttp hhtttp
goni P, Denti M: Infectious and thromboembolic com-
Recommendations of the ACCP for thromboembolic pro- plications of arthroscopic shoulder surgery. J Shoulder
phylaxis in orthopaedic surgery patients are presented. Elbow Surg 2010;19(1):97-101.
Infectious and thromboembolic complications after
33. Mont MA, Jacobs JJ, Boggio LN, et al: Preventing ve- shoulder arthroscopy are examined. The rate of DVT
nous thromboembolic disease in patients undergoing was low and not further decreased with the use of
k eers
rsSurg 2011;19(12):768-776.
k eers
elective hip and knee arthroplasty. J Am Acad Orthop
r s
thromboprophylaxis. Level of evidence: III.
b ooook is presented.
b oook
A summary of the AAOS guidelines on preventing VTE
o
40.
b o oo
Maletis GB, Inacio MC, Reynolds S, Funahashi TT: In-
o
cidence of symptomatic venous thromboembolism after
/
e e
/ eb e/
e e
/ e b ee/
94(8):714-720.e
/ e b
elective knee arthroscopy. J Bone Joint Surg Am 2012;
34.
: // t/ tm
Saragas NP, Ferrao PN: The incidence of venous throm-
. . m
boembolism in patients undergoing surgery for acute
: / / t
/ .
t m
. m
This meta-analysis examined the rate of symptomatic
s : /
Achilles tendon ruptures. Foot Ankle Surg 2011;17(4):
s ss : /
VTE after knee arthroscopy. The authors found the rate
hhtttp
tp hhtttp
tp
263-265. to be very low and found no significant evidence to rec-
This study examines the rate of venous thromboembolic ommend the routine use of thromboprophylaxis in these
patients. Level of evidence: II.
disease after surgical treatment of Achilles tendon rup-
tures. The authors conclude that the rate of VTE is too
low to recommend routine thromboprophylaxis in these 41. Ramos J, Perrotta C, Badariotti G, Berenstein G: Inter-
patients. Level of evidence: III. ventions for preventing venous thromboembolism in
rrss rrss
adults undergoing knee arthroscopy. Cochrane Data-
o kee
35.
k k e e
Pelet S, Roger ME, Belzile EL, Bouchard M: The inci-
o k
base Syst Rev 2008;4:CD005259.
oo
e bboo o b o
b o
dence of thromboembolic events in surgically treated
o
ankle fracture. J Bone Joint Surg Am 2012;94(6):
e
42.
e b o o
Ramo BA, Griffin AM, Gill CS, et al: Incidence of
b
/
e / e 502-506.
m ee/ / e ee/ / e
symptomatic venous thromboembolism in oncologic pa-
tients undergoing lower-extremity endoprosthetic ar-
m
/ / t
/ .
t . m
This study demonstrated that patients with surgically
treated ankle fractures experience a rate of VTE that is
: / /t . .m
throplasty. J Bone Joint Surg Am 2011;93(9):847-854.
: / / / t
ss :
low and not affected by the addition of thromboprophy-
ss :
The rate of VTE is evaluated in orthopaedic oncology
hhtttp
tp hhtttp
tp
laxis. The authors recommend consideration of throm- patients. The rate of thromboembolism in this patient
boprophylaxis only in high-risk patients. Level of evi- population was low, and there was no difference in that
dence: III. rate among different modes of thromboprophylaxis.
36. Jameson SS, Augustine A, James P, et al: Venous throm-
boembolic events following foot and ankle surgery in 43. Mitchell SY, Lingard EA, Kesteven P, McCaskie AW,
k eers
rs
Br 2011;93(4):490-497.
k e r
e s
the English National Health Service. J Bone Joint Surg
r s Gerrand CH: Venous thromboembolism in patients
with primary bone or soft-tissue sarcomas. J Bone Joint
bboooo k b o o o k
The rate of thromboembolism is examined in patients
o b o oo
Surg Am 2007;89(11):2433-2439.
o
/
e e
/ e e e
/ b
undergoing a variety of foot and ankle surgeries. The
/ e
authors concluded that the rate of VTE was too low to
e
44.
ee/ e
/ e b
Damron TA, Wardak Z, Glodny B, Grant W: Risk of
/ / t
/ .
t m
recommend the routine use of thromboprophylaxis for
. m
these patients. Level of evidence: III.
: : / / t
/ .
t m
venous thromboembolism in bone and soft-tissue
. m
sarcoma patients undergoing surgical intervention: A re-
t p ss
p : / t p ss
p : /
port from prior to the initiation of SCIP measures.
J Surg Oncol 2011;103(7):643-647.
37.
t
hht t
Barg A, Henninger HB, Hintermann B: Risk factors for
symptomatic deep-vein thrombosis in patients after to-
tal ankle replacement who received routine chemical
t
hht t This study set out to evaluate the risk of thromboembo-
lism in patients with sarcomas. The authors identified a
thromboprophylaxis. J Bone Joint Surg Br 2011;93(7): trend toward a decreased risk of VTE with the use of
921-927. chemoprophylaxis. Level of evidence: III.
The authors reviewed the rate of VTE after ankle ar-
k eers
rs r
throplasty and found it to be approximately 4% when
k ee s
r
low molecular weight heparin was used. Level of evi- s 45. Ruggieri P, Montalti M, Pala E, et al: Clinically signifi-
cant thromboembolic disease in orthopedic oncology:
b ooook dence: IV.
b oook
o b ooo
An analysis of 986 patients treated with low-molecular-
o
weight heparin. J Surg Oncol 2010;102(5):375-379.
/
e e
/ eb 38.
e / e
/e b
Jameson SS, James P, Howcroft DW, et al: Venous
e e /e/e b
This is a retrospective review of VTE in oncology pa-
e
/ t
///t m
thromboembolic events are rare after shoulder surgery:
. . m
Analysis of a national database. J Shoulder Elbow Surg
: : / t.
///t m
tients treated wtih endoprosthetic reconstruction and
.m
low molecular weight heparin. The authors found the
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
rate of thromboemolism to be low with this prophylac- 51. Ageno W, Gallus AS, Wittkowsky A, et al: Oral antico-
k eers
rs tic regimen. Level of evidence: III.
keerrss agulant therapy: Antithrombotic Therapy and Preven-
ook ook
tion of Thrombosis, 9th ed: American College of Chest
b oo
46.
o
Sansone JM, del Rio AM, Anderson PA: The prevalence
b o b o oo
Physicians Evidence-Based Clinical Practice Guidelines.
o
/
ee/e b e e
/ e b
of and specific risk factors for venous thromboembolic
/
disease following elective spine surgery. J Bone Joint
e ee e
/ e b
Chest 2012;141(2, suppl):e44S-e88S.
/
The authors provide an evidence-based review of the use
Surg Am 2010;92(2):304-313.
: / t
///t. m
.m
In this meta-analysis aimed at determining the rate of
: / t
///t. m
. m
and pharmacology of oral anticoagulants, including
s
tps : s
tps : warfarin and the new factor Xa inhibitors.
hhtttp hhtttp
venous thromboembolic disease in elective spine surgery,
the authors found a low rate of VTE. The use of chemo-
52. Raskob GE, Gallus AS, Pineo GF, et al: Apixaban ver-
prophylaxis improved that rate, but with a higher risk
sus enoxaparin for thromboprophylaxis after hip or
of epidural hematoma. Level of evidence: II.
knee replacement: Pooled analysis of major venous
thromboembolism and bleeding in 8464 patients from
47. Ploumis A, Ponnappan RK, Sarbello J, et al: Thrombo-
the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint
prophylaxis in traumatic and elective spinal surgery:
k eers
rs k eers
r s
Analysis of questionnaire response and current practice Surg Br 2012;94(2):257-264.
ook ook
of spine trauma surgeons. Spine (Phila Pa 1976) 2010; This comparison of an oral factor Xa inhibitor, apixa-
b oo
35(3):323-329.
b oo b o oo
ban, to enoxaparin found that apixaban was more effec-
o
/
e e
/ eb / e e b
This study examined the preference of surgeons regard-
ee /
ing prophyalxis and attempted to report a consensus
e e
/ e b
tive at preventing VTE than enoxaparin with a de-
/
creased risk of bleeding. Level of evidence: I.
e
: // t/.tm m
protocol for thromboprophylaxis in the setting of spine
. : / / t
/ .
t m
. m
ss : /
trauma and elective spine surgery. Level of evidence: V. 53.
ss : /
Macaulay W, Westrich G, Sharrock N, et al: Effect of
hhtttp hhtttp
pneumatic compression on fibrinolysis after total hip ar-
48.
tp
Glotzbecker MP, Bono CM, Wood KB, Harris MB:
Postoperative spinal epidural hematoma: A systematic
review. Spine (Phila Pa 1976) 2010;35(10):E413-E420.
tp54.
throplasty. Clin Orthop Relat Res 2002;399:168-176.
Van Ha TG, Chien AS, Funaki BS, et al: Use of retriev-

This study defined the incidence of epidural hematoma able compared to permanent inferior vena cava filters:
after spine surgery to be small (< 1%) and attempted to A single-institution experience. Cardiovasc Intervent
rrss rrss
determine the effect of thromboprophylaxis on the risk Radiol 2008;31(2):308-315.
o ke
ke
of its development. Level of evidence: IV.
o k e
k e oo
e bboo o 49.
e b o o o
Cheng JS, Arnold PM, Anderson PA, Fischer D, Dettori
b
55. Strauss EJ, Egol KA, Alaia M, Hansen D, Bashar M,
e b o
b o
Steiger D: The use of retrievable inferior vena cava fil-
/
e / e e
Pa 1976) 2010;35(9, suppl):S117-S124.
m e/ e
JR: Anticoagulation risk in spine surgery. Spine (Phila
/ / / e
ters in orthopaedic patients. J Bone Joint Surg Br 2008;
m ee
90(5):662-667.
: /
/ t
/ .
t . m
This meta-analysis examined the risk of VTE in patients
/ : / /
/t/.t .m
s :
after spine surgery and found the rates to be low overall,
s 56.
ss :
Parvizi J, Smith EB, Pulido L, et al: The rise in the inci-
hhtttp
tp hhtttp
tp
with trauma patients having an increased risk. Level of
dence of pulmonary embolus after joint arthroplasty: Is
evidence: III.
modern imaging to blame? Clin Orthop Relat Res
2007;463:107-113.
50. Smith JS, Fu KM, Polly DW Jr, et al: Complication rates
of three common spine procedures and rates of
thromboembolism following spine surgery based on 57. Weitz JI: Pulmondary embolism, in Cecil RL, Goldman
k eers
rs
108,419 procedures: A report from the Scoliosis Re-
search Society Morbidity and Mortality Committee.
k e r
e s
r s
LMD, Schafer AI, eds: Goldman’s Cecil Medicine, ed
24. Philadelphia, PA, Elsevier/Saunders, 2012, pp 596-
bboooo k Spine (Phila Pa 1976) 2010;35(24):2140-2149.
b o o
o o k
The authors present a retrospective review of data from
603.
b o oo
o
A review of the evaluation and treatment of PE is pre-
/
e e
/ e ee/ e
/ e b
a database and found the rates of VTE after a variety of
spine surgeries to be 2% to 7%. Level of evidence: III.
sented.
ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
138
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 12
e rs
rs e rrss
oo
kWork-Related
ook e Illness,
o k
ook
o Cumulative
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Trauma, and t
///t. m
.mWorkers’
ee t
///t. m
. mee
s: /
: s : /
:
Compensationtps
hhtttp
Peter J. Mandell, MD
tps
hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Introduction
e/
e e
/ e b e / e
/ e b
work injury for government workers (federal, state,
e
: // t/.tm
. m
One hundred years ago, the United States had devel-
: / / t
/ t m
county, city, public schools), including law enforcement
. . m
and firefighters, was approximately two thirds higher
ss : / ss : /
than for private sector workers. Government landscap-
hhtttp hhtttp
oped the world’s largest economy and was still rapidly
tp
expanding its wealth. To continue that expansion, the
nation needed a way to compensate employees injured
at work. A no-fault workers’ compensation insurance
tp
ers with at least 1 day lost from work sustained 250%
more reported injuries than comparable occupations in
the private sector. Government janitorial workers sus-
program, commonly referred to as a “grand bargain,” tained almost 300% more injuries, with at least 1 lost
filled that need. Workers did not have to prove employ- day from work, than their private sector counterparts.
rrss rrss
ers were at fault to receive speedy and fully funded For police officers, leading injury events were violent
o kee
treatment, temporary cash wage replacement payments,
k o k e
k e
acts (such as apprehending combative suspects) and
oo
transportation incidents (such as motorcycle accidents
e bboo o and permanent disability awards. Employers were
b o
b o o
spared the uncertainty of civil court trials. Wisconsin
e e b o o
while controlling traffic). For warehouse workers, con-
b
/
e / e m e / / e
was the first state to enact such a program in 1911, and
e ee/ / e
tact with objects and equipment (for example, lacera-
tions, punctures, being struck or crushed by an object)
m
/ / t
/ .
Mississippi was the last in 1948.1 In effect, these laws
t . m
constituted “...the first and most enduring tort reform
: / /t . .m
and overexertion were the most common accidents.
: / / / t
measure[s] in the US.”2
ss : s :
Overexertion also was a leading event in injuries sus-
s
hhtttp
tp hhtttp
tp
tained by nursing aides, janitors, and truck drivers. In
2010, sprains, strains, and tears comprised 40% of the
injuries that resulted in at least 1 day off work; more
The Burden of Work-Related Musculoskeletal than one third of those were back injuries.4 One eighth
Ailments of sprain, strain, and tear cases involved the shoulder,
and shoulder cases required more than twice as much
k e s
Approximately 116 million individuals had full-time
rrs
jobs in the United States in July 2012; the unemploy-
e k e r
e s
r s
time off work as the median of other sprain, strain, and
tear cases.
bboooo k
ment rate was 8.2%.3 Based on 2010 US Department
b o
of Labor data,4 approximately 1,370,000 workers ino
o o k b o oo
Workers age 16 to 19 years, 25 to 34 years, and 45
o
/
e e
/ e ee/ e
/ e b
the United States sustained nonfatal work injuries and
e e
/ e b
to 54 years had work injury rates of 1.17%, 1.06%,
/
and 1.3%, respectively.4 The injury rate was 1.28% for
e
/ / t t m
illnesses severe enough to require 1 or more days away
. . m
from work. The overall incidence of significant work
: / : / / t
/ .
t m
. m
men and 1.06% for women. Of workers injured in
ss : /
injuries among full-time employees in the United States
t p p t p ss : /
2010, 41% were Caucasian, 11% were Hispanic, 8%
were African American, and the rest were not reported.
p
t t
was 1.2%. Seven occupations were associated with a
hht
more than 3% incidence of work injuries: nursing aide,
orderly, light/delivery truck driver, warehouse worker,
t
hht t
Many studies have been published regarding the al-
location of limited healthcare resources to several dif-
ferent diseases,5 but few such studies focused on work-
construction laborer, big rig truck driver, and janitor. related events. The task is difficult because studies of
Of these seven occupations, warehouse workers had industrial accident records indicate that 25% to 50%
k eers
the highest number of lost workdays. The incidence of
rs k eers
r sof nonfatal injuries and approximately 90% of deaths
related to occupational disease go unreported.6,7 The
b ooook b oook
o b ooo
US Department of Labor data intentionally exclude
o
farmers, farm workers, and self-employed individuals
/
e e
/ eb e / e
/e b
At the time this chapter was written, Dr. Mandell or an
immediate family member serves as a board member,
e ee/e/e b
or adjustments for underreporting such groups. Cor-
thopaedic Association.
: / t
///t m
owner, officer, or committee member of the Western Or-
. . m : / t.
///t m
recting for those factors, it is estimated that there were
.m
approximately 8.5 million US industrial injuries in
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
2007, of which 2.5 million were serious enough to health care and information, psychologic stress, cul-
k eers
rs r
result in lost work days.5 Approximately 5,600 fatali-
kee rss ture, lifestyle, and community environment.9
b ooook o ook
ties were reported. It is estimated that the US cost of
o
occupational injuries in 2007 was $250 billion (ap-
b b o oo
o
/
ee/e b ee/ e
/ e b
proximately 1.8% of the gross domestic product), in-
cluding direct and indirect costs. In comparison, total
ee/ e
/ e b
Treatment Outcomes in Workers’ Compensation
t . m
.m
costs were $432 billion for cardiovascular disease and
: / ///t
$219 billion for cancer.5 Total workers’ compensation
Cases
: / t
///t. m
. m
Numerous studies going back several years have re-
s
tps : s
tps :
hhtttp hhtttp
payouts for medical and wage replacement expenses in ported that treatment outcomes in workers’ compensa-
2007 were $55.4 billion. The $195 billion difference tion cases are worse than when that same disease or in-
between total costs and payouts to workers is one indi- jury is treated in a nonwork injury setting. A recent
cation that workers’ compensation systems do not study reported that lumbar fusions for diagnoses of
cover the full costs of industrial accidents and illnesses.5 disk degeneration, disk herniation, and/or radiculopa-
State laws rarely, if ever, allow wage loss repayments to thy in a workers’ compensation setting are associated
k eers
rs exceed 70% of preinjury base income.
k eers
r s with a significant increase in disability, opiate use, pro-
longed work loss, and poor return-to-work status.10
Another study indicated that workers’ compensation
b o
/
e e
/ eb Culture and Injury at Work
e/
e e
/ e b e / e
/ e b
patients achieved significantly less improvement after
posterolateral lumbar fusion surgery than those not in-
e
: // t/.tm
A 2002 analysis of a national population–based survey
. m
examined risk factors associated with work injuries.8
/ / t
/ .
t m
jured at work.11 A detailed discussion about lumbar
. m
disk herniations can be found in chapter 52, Degenera-
:
ss : /
Past studies had shown a greater incidence of work in-
ss : /
tive Disk Disease and Pain in the Lumbar Spine, Ortho-
hhtttp
tp hhtttp
tp
juries among workers with characteristics such as low paedic Knowledge Update 11.
family income, rural residence, high levels of physical A 2010 study determined how workers’ compensa-
effort, and a history of working in awkward positions tion accidents affected the results of shoulder decom-
(such as frequent stooping). The study concluded that pression or rotator cuff repair.12 Patients in both treat-
in well-run companies, which placed few constraints on ment groups had significant improvement irrespective
rrss rrss
their employees, workers experienced one third fewer of their workers’ compensation status. The results
o ke
ke
work injuries than expected. If an employee deemed his
o k
or her work environment to be safe, injuries again de-e
k e showed that although injured workers reported a sig-
oo
nificantly higher level of disability both before and af-
e bboo o e b o o o
creased by one third. Conversely, work-family interfer-
b e b o o
ter shoulder surgery, they still had statistically signifi-
b
/
e / e ee/ / e
ence increased the risk of work injuries by more than
one third. Also, the study concluded from the survey
m m ee/ / e
cant improvement 1 year after the operation.
/ t . . m
that injury risk differs as a function of race. Caucasians
: / / / t : / /
/t/.t .m
s :
were injured 67% more frequently than African Amer-
s ss :
Writing an Independent
hhtttp
tp hhtttp
tp
icans. Those in a group titled “Other” (including His- Medical Examination Report
panics, Native Americans, and Asian Americans) were
injured almost 60% more often than Caucasians. These Although the concept of a workers’ compensation pro-
results may have been skewed because the survey in- gram ensures that injured workers do not have to prove
cluded only English-speaking adults. their employers were at fault to receive workers’ com-
A 2010 study reported on clinically based evidence pensation benefits, they do need to prove that work
k eers
rs k e
fractures.9 In general, both African Americans and His- r
of ethnic differences in recovery following distal radial
e s
r s was, at least, a partial cause of the injury. Causation re-
quirements are easily met when a connection is made
bboooo k o
panics showed poorer ultimate function and greater
b o
o o k b o oo
between a distinct event and bodily damage: for exam-
o
/
e e
/ e e e
/ e b
pain scores than whites. After adjusting for sociodemo-
/
graphic factors and injury characteristics, the dispari-
e e e
/ e b
ple, a trip and fall at work that causes an acute lumbar
/
compression fracture. Causation is more difficult to
e
: / / / .
t m m
ties for Hispanics persisted for both pain and function,
t . : / / t
/ .
t m
. m
prove when that same worker has osteoporosis and
t p ss : /
whereas the outcome disparities for African Americans
were no longer significant. Ethnic disparities occurred
p t p ss : /
prior healed spinal compression fractures.
An orthopaedic surgeon needs to obtain a special-
p
t
hht t
in both workers’ compensation patients and those not
injured at work. The authors suggested that education,
body mass index, age, and sex may affect the different
t
hht t
ized history and perform a physical examination to de-
termine whether a particular injury or illness is com-
pensable, requires further medical treatment, and has
outcomes. The authors also found that workers’ com- left the employee with residual impairment. In obtain-
pensation patients had significantly more pain and less ing a history, the physician must record in detail how
k eers
rs function than their nonwork injured counterparts.
Twenty-six percent of African Americans, 14% of His-
k eers
r s the injury occurred. Timing can be everything in the de-
termination of the cause for a workers’ compensation
b ooook b ook
panics, and 6% of whites reported that their fractures
oo
occurred at work—a significant difference (P < 0.001).
b oooo
case. The physician must determine if the patient re-
ported the injury immediately or later. Researchers
/
e e
/ eb / e
/e b
Other studies have suggested that the explanation of
ee ee/e/e b
have noted for some time that more claims for indus-
/ t
///t m
ethnic differences in disease outcomes is multifaceted
. . m
and includes factors such as poverty, lack of access to
: : / t.
///t m
trial injuries are made on Mondays (25%) than on Fri-
.m
days (16%), an observation known as the “Monday ef-
s
tps : s
tps :
140
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 12: Work-Related Illness, Cumulative Trauma, and Workers’ Compensation
fect.”13 Some researchers think that a subset of workers and motor and sensory function must be quantified,
k rs
rs
who injure themselves on the weekend wait until they
ee keerrss not just estimated. Tape measures, goniometers, and
b ooook b o ook
get to work on Monday to report a claim, thus receiv-
o
ing health coverage and wage replacement benefits. The
well-calibrated grip strength devices should be used so
o oo
o
that objective results can be obtained. The injured and
b
/
ee/e b ee/ e
/ e b
Monday effect is more likely to occur with easily con-
cealed injuries, such as back sprains and shoulder ten-
ee/ e
/ e b
uninjured sides should be compared, when possible, to
better gauge the patient’s loss of particular normal
t . m
.m
dinitis, than with more obvious injuries, such as cuts
: / ///t
and fractures. The Monday effect has long raised suspi-
function.
: / t
///t. m
. m
During the physical examination, the physician
s
tps : s
tps :
hhtttp hhtttp
cions of worker fraud. should consider a thorough differential diagnosis. Cer-
The patient’s current complaints should be docu- vical disk disease can cause shoulder pain, lumbar disk
mented carefully. The physician needs to determine the disease can produce hip symptoms, and hip pathology
source of any pain on the date of the injury and assess can give rise to knee discomfort. The reliability of the
current pain symptoms. Close attention should be given patient’s physical findings should be evaluated.
to spreading symptoms. If the patient’s records report Whether the objective findings support the patient’s
k eerss k
now also reports neck, elbow, wrist, and hand symp-
eers
the initial injury as a shoulder sprain but the patient
r r s subjective complaints should be addressed. Nonorganic
findings, such as a positive result from Waddell tests,
b ooook b ooook
toms during physical examination, the causes of pain in should be noted.14
b o oo
o
/
e e
/ eb e/ e
/ e b
the later reported areas should be explored in detail.
Understanding the mechanism of injury may help deter-
e e / e
/ e b
The patient’s current and future medical treatment
needs to be discussed. In many jurisdictions, final reso-
e
: // t/.tm
mine the cause of delayed symptoms in initially unre-
. m
ported areas. The patient’s current physical limitations
/ / t
/ .
t m
lution of the claim includes ongoing medical interven-
. m
tions to cure—or at least relieve—the effects of the
:
ss : /
must be distinguished from limitations on the date of
ss : /
employee’s work injury. Medical treatment recommen-
hhtttp
tp hhtttp
tp
injury. How the injury has affected the worker’s activi- dations should be evidence-based when possible.
ties of daily living must be determined. The physician
should consider the reliability of the original diagnosis.
For the patient who seems to exhibit wandering pain, a Cumulative Trauma
list of all current complaints must be carefully compiled
rrss rrss
to avoid confusion. The worker’s statements about his Cumulative trauma and repetitive motion injuries are
o ke
or her injuries should be compared with statements in
ke
the medical records.
o k e
k e
also referred to as musculoskeletal disorders or work-
oo
related musculoskeletal disorders. These terms connote
e bboo o e b o o o
The patient’s history can provide important clues
b e b o o
an array of afflictions that seem to result from repeti-
b
/
e / e ee/ e
about diagnosis, causation, and prognosis—all of
/
which the physician is expected to explore for the
m ee/ / e
tive or strenuous movements: overexertion; assuming
constrained, unusual, and/or prolonged postures; and
m
: / /
/ t
/ .
t . m
workers’ compensation system. Did the patient sustain
/t . .m
other overuse events. In return for workers giving up
: / / / t
s :
prior injuries to the same body part or region? Did the
s s :
their right to sue their employers for work-related inju-
s
hhtttp
tp hhtttp
tp
patient undergo prior relevant surgeries? Did he or she ries, employers agreed to accept responsibility for such
receive prior disability awards? Did the patient have conditions unless convincing evidence of other non–
sports-related or other non–work-related injuries that work-related causes exists. Some states have since lim-
could have increased his or her vulnerability to the ited musculoskeletal disorder claims after the grand
work injury? Does the patient have a family history of bargain was established, but other states continue to
lumbar disk disease, knee instability, hand arthritis, or accept them. Other causes for claimed cumulative
k eerss
other issues? The patient should be assessed for other
r k e
diseases and habits that can affect the musculoskeletal r
e s
r strauma injuries may include concurrent work with a
different employer, strenuous sports activities, and
bboooo k o o o
system, such as obesity, arthritis, diabetes, smoking,
b o k non–work-related accidents.
b o oo
o
/
e e
/ e
and significant alcohol consumption.
e / e
/ e b
A detailed work history is also important informa-
e e e
/ e b
Whether repetitive stress consistently and predict-
/
ably causes musculoskeletal disorders is a topic of on-
e
: / / / .
t m m
tion for the independent medical examination report.
t . : / / t
/ .
t m
. m
going debate in the literature. Carpal tunnel syndrome
t p ss : /
The physician needs to know the patient’s work envi-
ronment and activities to not only assess causation but
p t p ss : /
has been well studied, but the results still are not clear-
cut. A scientific research paper for the German govern-
p
t
hht t
also gauge the potential for modified work. The physi-
cian should determine the patient’s length of current
employment, previous work experience, job satisfaction
t
hht t
ment was published in 2009 that supported categoriz-
ing carpal tunnel syndrome as an occupational
disease.15 The authors concluded that repetitive manual
or recent job-related changes (such as increased work- work tasks that involve flexion and extension at the
load because of downsizing), and the existence of con- wrist, forceful gripping, and using vibratory tools can
k eers
flicts with supervisors or fellow employees or job-
rs
related stress.
k eers
r s damage the median nerve and cause carpal tunnel syn-
drome.15 Also, a considerable discrepancy was noted in
b ooook b oook
For workers’ compensation cases, the physical ex-
o
amination, including the history and physical reports, is
b ooo
the results regarding computer work as a cause of car-
o
pal tunnel syndrome. Systematic and other reviews had
/
e e
/ eb ee/ e
/e b
legal evidence that is subject to great scrutiny and may
/e/e b
not shown any increase in carpal tunnel risk to date.
ee
/ t
///t m
have a profound effect on a patient’s future. During the
. . m
physical examination, the range of motion, atrophy,
: / t.
///t m
Cumulative trauma conditions generally have similar
.m
characteristics: the neck, shoulder, carpal tunnel, back,
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
male workers. Although musculoskeletal disorders oc-
k eers
rs
Table 1
keerrss cur at higher rates in transportation, maintenance, con-
b ooook Physical Examination Tests

for Feigned Weakness
b o ook
o
struction, and manufacturing industries than in service
b o oo
o
occupations, 55% of carpal tunnel syndrome cases oc-
/
ee/e b Test Patient Response
ee/ e
/ e b ee/ e
/ e b
cur in the manufacturing and office work industries.
The drop test

: / t
///t. m
.m
With the patient supine, the physician
: / t
///t. m
. m
s
tps : s :
Malingering and Somatization
tps
hhtttp hhtttp
drops the weak or paralyzed arm
over the patient’s face and observes
Malingering is at the extreme end of a spectrum of con-
that the limb does not hit the
patient. cepts that have been termed symptom magnification,
exaggeration, submaximal, insincere or low effort, in-
The pain test The physician surprises the patient appropriate pain or illness behavior, and nonorganic
with discomfort and observes that
findings. When an orthopaedic surgeon uses such
k eers
rs
the weak or paralyzed limb moves
normally.
k eers
r s terms, the implication is that something about the pa-
tient’s presentation is inconsistent.
b ooook The Hoover test
b oook
The physician places one hand under
o
the heel of the patient’s normal leg
o oo
Most studies over the past 35 years list the incidence
b o
/
e e
/ eb / e e b
while pressing down on the weak
ee /
leg and then asks the patient to lift
e / e
/ e b
of malingering as quite low. A survey of 48 orthopaedic
surgeons and 57 neurosurgeons across the United
e
t . m
. m
the weak leg against resistance. If
: // / t / / t
/ .
t m
States reported that 60% of the surgeons agreed that
. m
malingering occurred in 5% or fewer of their patients
:
ss /
the physician feels no
: ss : /
with low back pain.19 However, 15% of the survey re-
hhtttp hhtttp
counterpressure under the normal
The hysterical gait

observation
tp
heel, the patient is not trying.
The patient shows foot dragging
rather than lifting or sudden knee
tp
spondents estimated that more than 20% of their pa-
tients were feigning illness. Considerable literature ex-
ists on how to document patients who describe
buckling without falling. symptoms with little or no physical basis. An approach
has been established using physical signs for low back
rrss rrss
conditions that has gained widespread acceptance.14
o ke
ke knees, and feet are commonly involved. These charac-
o k e
k e
The shortcomings of the physical tests were empha-
oo
sized, and isolated false-positive signs may occur. For
e bboo o e b o
teristics are often nonspecific and poorly localized.16
b o o e b o o
example, stocking hypesthesia may be a symptom of
b
/
e / e ee/
Usually, the onset of symptoms occurs gradually over
/
months or years and can often require extended time
m e ee/ / e
vascular disease, and widespread tenderness may be a
symptom of osteoporosis. Isolated nonorganic signs
m
: / / t
/ .
t . m
for improvement. Cumulative trauma disorders may go
/
unreported because workers do not associate their /t . .m
should be ignored and significance associated with mul-
: / / / t
ss : s :
tiple positive signs.
s
hhtttp hhtttp
symptoms with job-related activities.16 In many states,
tp tp
The notion of inappropriate behavior during illness
part of the grand bargain encompasses certain statuto- has been studied.20 In addition to the classic signs such
rily defined diagnoses that are presumed correct, in- as stocking hypesthesia and collapsing weakness, the
cluding the “gun belt presumption” for police officers authors noted that bizarre pain drawings showing total
who have chronic low back pain and the industrially body pain among other things could be used to docu-
caused “cancer presumption” for firefighters who have ment nonorganicity. The timing of a symptom is also
k eers
rs been exposed to smoke and other toxic substances
throughout their work lives.
k e r
e s
r s important. Pain usually varies in patients with a physi-
cal disease, but patients with nonorganic symptoms
bboooo k Musculoskeletal disorders involve an average of 9

b o o
o o k have no pain-free intervals.
b o oo
o
/
e e
/ e e e
days off work compared with 7 days off for other work
/ / e b
injuries.17 However, the work injury rate, as measured
e e e
/ e b
Pseudoneurologic findings have been discussed.21 Pa-
/
tients with feigned weakness usually showed an abrupt
e
: / / / .
t m m
by missed workdays between 1992 and 2007, de-
t .
creased by slightly more than 50%. For musculoskele-
: / / t
/ .
t m
. m
and stepwise loss of strength. For patients with organic
t p ss : /
tal disorders, it decreased by 57%.17 Some authors refer
p t p ss : /
weakness, the loss of resistance is smooth. Physical
tests for feigned weakness are presented in Table 1.
p
t
hht t
to cumulative trauma disorders as a modern-day epi-
demic, yet Ramazzini, the father of occupational medi-
cine, observed in 1713 that scribes doing repetitive
t
hht t
With feigned sensory loss, numbness often follows the
patient’s own concept of his or her anatomy.21 Almost
all sensory modalities of pain, touch, and propriocep-
tasks reported “...intense fatigue in the whole arm but tion disappear at a discrete border, such as the midline
no remedy could relieve this and finally the whole right or a joint. Some tests that may help document feigned
k eers
rs
arm became paralyzed.”18
More than 50% of sprain, strain, and tear injuries
k eers
r s sensory loss are listed in Table 2. The five-rung test
(also called the five-handle position grip strength test)
b ooook culoskeletal disorders. Approximately 67% of all

b oook
resulting in days away from work are classified as mus-
o b ooo
and rapid exchange grip strength tests are ways to doc-
o
ument low effort.22 The five-rung test involves a patient
/
e e
/ eb ee/ e
/e b
workers with musculoskeletal disorders are male; how-
/e/e b
squeezing a hand dynamometer as hard as possible at
ee
/ t
///t m
ever, approximately 75% of carpal tunnel syndrome
. . m
cases and 60% of tendinitis cases are reported by fe-
: / t.
///t m
each of the five grip settings, from smallest to largest. A
.m
normal response produces a bell-shaped strength curve.
:
s
tps : s
tps :
142
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
increases in force during submaximal effort (69%) than
k ee s
Table 2
rrs keerrss during maximal effort (28%). This test effectively de-
b ooookPhysical Examination Tests for Feigned

Sensory Loss
b o ook
o
tected submaximal effort levels.
b o oo
o
Other conditions can resemble malingering but are
/
ee/e b ee/ e
/ e b
The physician applies painful stimuli to a numb area and
ee/ e
/ e b
quite different and are termed somatoform pain disor-
ders.25 Some psychiatrists estimate that at least one half
t . m
.m
observes the normal heart rate increase of 20 to 30 beats
per minute.
: / ///t t . m
. m
of patients seeking primary care have somatic pain as a
: / ///t
manifestation of psychosocial distress. Most patients in
s
tps : s
tps :
hhtttp hhtttp
The physician surprises the patient with discomfort to a the United States with somatization disorder are fe-
numb limb and notes withdrawal. male. Typical somatization symptoms include head-
The physician applies tuning fork vibration to the numb half ache, fibromyalgia, and back pain.
of a cavity, such as the thorax or skull. Because of bone In somatization, the body is used for psychologic
conduction, the patient should feel the vibration on the purposes.26 People who cannot engage in or whose cul-
normal side. tures do not allow open expression of psychic difficul-
k eers
rs k eers
r
The physician tests the great toe for proprioception and
s ties often communicate such issues through sometimes
powerful physical symptoms.
ook ook
notes that the patient answers the up or down questions
b oo b o
wrongly 100% of the time. By chance, a 50% correct
o b o oo
Some patients consciously produce their disease but
o
/
e e
/ eb answer rate is expected.
e/
e e
/ e b e / e
/ e b
are motivated by unconscious reasons. These patients
are similar to individuals who fear heights or crowded
e
: // t/.tm
. m / / t
/ .
t m
places but don’t know why. Such patients have facti-
. m
tious disorders, perhaps the most famous of which is
:
s : /
Sincere patients usually have a large variance in re-
s ss : /
Munchausen syndrome. Those with a factitious disor-
hhtttp
tp hhtttp
tp
sponse among the five squeezes, peaking at the second der have a psychologic need to assume the role of the
or third rungs and dropping off significantly at the first sick patient. As noted in a classic study: “Patients with
and fifth. Low-effort patients produce a flat or flatter factitious disorders can and have produced signs and
curve with less deviation among the five attempts. symptoms of virtually any disease. The level of produc-
Rapid exchange gripping also has been used to fur- tion can vary from a purely fictitious medical history
ther enhance the recognition of low-effort patients.22
rrss rrss
(lying about symptoms), a simulation of signs or symp-
The test used the rung on which the patient had the
o ke
ke
most strength during the five-rung study. A computer
o k e
k e
toms (such as heating a thermometer), to the actual
oo
production of disease states (administering bacterial
e bboo o e b o
recorded grip strength measurements as the patient
b o o e b o o
cultures intravenously to produce septicemia). Almost
b
/
e / e ee/
switched hands every 1.5 seconds for a total of eight
/ e
times with each hand. Sincere patients had no signifi-
m ee/ / e
all laboratory abnormalities can be produced facti-
tiously. The only limits to factitious disorders are those
m
: / / t
/ .
t . m
cant differences between peak scores on the five-rung
/
test and their results for the rapid exchange grip test. /t . .m
of human creativity.”27 In more than three fourths of
: / / / t
ss : s :
factitious disorder cases, the patient or a family mem-
s
hhtttp hhtttp
Low-effort patients had significantly greater grip
tp tp
ber works in the healthcare field.27 Those with a facti-
strength with the rapid exchange test. Accurate identi- tious disorder are often nurses, ward clerks, medical re-
fication of 91% of sincere patients and 82% of low- ceptionists, and laboratory technicians.
effort patients was reported; however, the use of any Authors of a 2010 study noted that childhood
single measurement to label a patient as low effort is events, specifically abuse and emotional trauma, have
not advocated. Combining the results of the rapid ex- profound and enduring effects on the neuroregulatory
k eerss
change grip, the five-rung grip, and clinical impressions
r
(that is, Waddell-like findings seen on examination)
k e r
e s
r s systems that mediate illness, as well as on behavior in
both childhood and adult life.28 These authors docu-
bboooo k
produced a more accurate characterization of low-
b o o
o o k b o oo
mented relationships between traumatic stress in child-
o
/
e e
/ e
effort patients than just a single test.
e / e
/ e b
A study of the five-rung test23 concluded that the
e e e
/ e b
hood and the leading causes of morbidity, mortality,
/
and disability in the United States, such as cardiovascu-
e
: / / / .
t m m
shape of the curve was strength dependent; thus, the
t .
five-rung test may yield biased results during the assess-
: / / t
/ .
t m
. m
lar disease, depression, obesity, smoking, alcohol and
t p ss : /
ment of sincere effort in patients with weakened hands.
p t p ss : /
drug abuse, and chronic pain. These conclusions are
based on findings from the Adverse Childhood Experi-
p
t
hht t
The five-rung test was less effective for women. How-
ever, the authors of a 2012 study offered the visual tar-
get grip test as an accurate evaluation of sincerity of ef-
t
hht t
ences (ACE) Study, an epidemiologic inquiry providing
retrospective and prospective analyses of more than
17,000 obese patients in a medically supervised weight-
fort.24 The test tricks a patient into exerting maximal loss program at Kaiser Permanente in San Diego, Cali-
effort by providing incorrect visual feedback. The test fornia. The study scrutinized the effect of traumatic ex-
k eers
displays a target line on a monitor and instructs the
rs k eers
r
participant to reach for it with each grip repetition. The s periences during the first 18 years of life on adolescent
and adult medical and psychiatric disease, sexual be-
b ooook b oook
line’s position is then secretly changed, which requires
o
doubling the force necessary to reach it. Accordingly,
b ooo
havior, healthcare costs, and life expectancy.28
o
In the study, 80% of the participants were Cauca-
/
e e
/ eb ee/ e
/e b
participants are tricked into exerting more force than
/e/e b
sian and Hispanic, 10% were African American, and
ee
/ t
///t m
intended to reach the deceptive target line. Providing
. . m
incorrect visual feedback caused significantly greater
: / t.
///t m
10% were Asian American; 74% had attended college;
.m
and their mean age was 57 years. Almost one half of
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
guard against getting well and is left with no honorable
k eers
rs
Table 3
keerrss way to recover from illness.”30 In the legal system,
b ooook Types of Adverse Childhood Experiences
b o ook
o
which is often adversarial, the patient is challenged re-
o oo
o
peatedly to prove permanent illness. Consciously or
b
/
ee/e b Category
ee/ e
/ e b
Percentage
ee/ e
/ e b
subconsciously, such patients may develop a heightened
awareness to the normal, minor aches and pains of
Abuse
: /
Emotional—recurrent threats, t
///t. m
.m 11
: / t
///t. m
. m
daily life to justify the existence of lingering injury. A
less severe interpretation of claimant behavior is of-
s
tps : s
tps :
hhtttp hhtttp
humiliation fered: “Human nature being what it is, there is a ten-
Physical—beating, not spanking 28 dency for the injured person to make the most (of) any
Contact sexual abuse 22 complaints that he may have when examined for possi-
ble compensation.... The injured person in these cir-
For women 28
cumstances has a different approach to that of a sick
For men 16 person coming for treatment to heal his illness. The in-
k eers
rs Household Dysfunction
k eers
r s jured person aims to ‘sell his disability’ and make it as
large as he can to claim as much compensation as pos-
b ooook Mother treated violently

Household member was alcoholic or
b ooook
13
27
o oo
sible...this approach is understandable and to be ex-
b o
/
e e
/ eb drug user
e/
e e
/ e b e / e
/
merges into malingering.”20
e e b
pected. When this tendency is grossly exaggerated, it
Household member was imprisoned
: // t/.tm
. m
6
: / / t
/ .
t m
. m
ss /
Household member was chronically
:
17
ss : /
hhtttp hhtttp
depressed, suicidal, mentally ill, or in Summary
a psychiatric hospital
tp
Not raised by both biologic parents 23 tp
The treatment and the evaluation of workers’ compen-
sation patients gives the orthopaedic surgeon the op-
Neglect
portunity to assist the patient with his or her health and
Physical 10 job: two of the most important aspects of life. This
rrss rrss
Emotional 15 unique aspect of medicine requires the blending of
o ke
ke o k e
k e
medical and legal skills. Patients who are both ill and
oo
out of work experience added stress that can alter their
e bboo o e b o
b o
the patients were men; all of the patients were middleo e b o o
responses to physical examinations, laboratory tests,
b
/
e / e ee/ / e
class. The 10 categories of ACEs studied and the per-
m ee/ / e
and medical treatment. The doctor-patient relationship,
although paramount, is shared with the employer and,
m
: / / t
/ .
t m
centage of occurrence among the 17,000 patients are
/ .
found in Table 3. The ACE score for each patient was
/t . .m
many times, a lawyer. Attention to detail in the diagno-
: / / / t
ss : s :
sis and the examination findings is essential. The final
s
hhtttp hhtttp
established based on how many of the 10 different en-
tp tp
goals are to restore the patient’s health and allow him
vironments each individual experienced during the first or her to return to work.
18 years of life. Approximately 33% of the patients
had an ACE score of zero, but these categories were so
profound that of the patients who had experienced one
ACE, almost 90% had also experienced one or more
k eers
rs additional ACE. Approximately 17% of the patients
had an ACE score of 4 or higher; 11% had an ACE
k e r
e s
r
Key Study Points
s
bboooo k score of 5 or higher. Women were 50% more likely
b o o
o o k •
b o oo
Work-related orthopaedic injuries are common
o
/
e e
/ e e / / e
of ACE. The authors concluded that high ACE scores
e b
than men to have experienced five or more categories
e economy.
ee/ e
/ e b
and affect the health of US workers and the
: / / / .
t m m
were the key to what, in mainstream epidemiology, ap-
t .
pears as the natural propensity for women to have ill-
•
t . m
. m
Patients who sustain a work-related injury may
: / / / t
t p ss : /
defined health conditions, such as fibromyalgia,
p t p ss
p : /
respond differently to orthopaedic treatment but
can benefit from such treatment.
t
hht t
chronic fatigue syndrome, obesity, and chronic pain
syndromes.28
A clear relationship exists between the number of
• t
hht t
When patients do not respond as expected, the
reason may be somatization.
unexplained symptoms a patient has and his or her
ACE score.29 A particular patient’s current complaint is
k eers
rs
often only a surrogate for the real issue. The author of
a classic study concluded that most behavior regarding
k eers
r s
b ooook b ook
exaggerated illness in compensation cases results from
oo
suggestion or rationalization as well as somatization,29
b oooo
/
e e
/ eb / e
/e
and reasoned that “because any improvement in the
ee b ee/e/e b
/ t
///t m
claimant’s health condition may result in denial of dis-
. . m
ability status in the future, the claimant is compelled to
: : / t.
///t m
.m
s
tps : s
tps :
144
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
ment of some chronic diseases. This study indicates that
k eerss
r keerrss recovery from distal radial fracture is different between
groups as well. These disparities may result from multi-
b ooook1.
o ook
Greenwood JG: Disability Evaluation. St. Louis, MO,
b o o oo
factorial sociodemographic factors that are present both
b o
/
ee/e b Mosby, 1996, p. 7.
ee/ e
/ e b ee/ e
/ e b
before and after treatment. Level of evidence: II.
2.
: / ///t. m
Hashimoto DM: The future role of managed care and
t .m
capitation in worker’s compensation. Am J Law Med
10.
: / t
///t. m
. m
Nguyen TH, Randolph DC, Talmage J, Succop P, Tra-
vis R: Long-term outcomes of lumbar fusion among
1996;22(2-3):233-261.
s
tps : s
tps : workers’ compensation subjects: A historical cohort
hhtttp hhtttp
study. Spine (Phila Pa 1976) 2011;36(4):320-331.
3. Statista: Monthly number of full-time employees in the Lumbar fusion for the diagnoses of disk degeneration,
United States from July 2012 to July 2013 (in millions, disk herniation, and/or radiculopathy in a workers’
unadjusted). http://www.statista.com/statistics/192361/ compensation setting is associated with significant in-
unadjusted-monthly-number-of-full-time-employees-increase in disability, opiate use, prolonged work loss, and
the-us. Accessed January 18, 2013. poor return-to-work status.
k eers
rs k eers
r s
This website provides up-to-date, seasonally adjusted
ook ook
full-time employment (> 35 hours/week) and unemploy-
b oo
ment data on a monthly basis.
b oo
11.
o oo
Carreon LY, Glassman SD, Kantamneni NR, Mugavin
o
MO, Djurasovic M: Clinical outcomes after posterolat-
b
/
e e
/ eb 4.
e/ e
/ e b
US Department of Labor: Bureau of Labor Statistics:
e ee/ e
/ e b
eral lumbar fusion in workers’ compensation patients: A
case-control study. Spine (Phila Pa 1976) 2010;35(19):
// /.tm m
Nonfatal Occupational Injuries and Illnesses Requiring
t .
Days Away From Work, 2011. http://www.bls.gov/
: : / / t
/ .
t m
. m
1812-1817.
ss : /
news.release/osh2.nr0.htm. Accessed January 18, 2013.
ss : /
After controlling for covariates known to affect out-
hhtttp hhtttp
comes following lumbar fusion, patients who receive
tp
These data provide extensive information on the inci-
dences, case counts, diagnoses, and trends in work inju-
ries. Figures on job types, employer categories, and the
tp workers’ compensation have significantly less improve-
ment. Amelioration in back pain was similar between
the two groups, but workers’ compensation patients re-
effects of age on injury rates are provided. tained a higher level of disability after their surgeries.
5. Leigh JP: Economic burden of occupational injury and
keerrss
illness in the United States. Milbank Q 2011;89(4):
k e rrss
e
12. Holtby R, Razmjou H: Impact of work-related compen-
bboooo k 728-772.
b o o
o o k
This study presents estimates of the national price of oc-
o oo
sation claims on surgical outcome of patients with rota-
o
tor cuff related pathologies: A matched case-control
b
/
e e
/ e / e e b
cupational injuries and illnesses in 2007. Although such
ee /
costs are sizable and as high as cancer costs, workers’
ee/ e
/ e b
study. J Shoulder Elbow Surg 2010;19(3):452-460.
One hundred ten work-related shoulder decompressions
: / / t
/ .
t m m
compensation insurance covers less than one fourth of
. : / /t . m.m
(60%) or cuff repairs (40%) were compared with 110
/ t
the total cost.
ss : / ss : /
non–work-injured historical controls with similar diag-
hhtttp hhtttp
noses and treatments. Both groups significantly im-
6.
tp
Bonauto DK, Fan JZ, Largo TW, et al: Proportion of
workers who were work-injured and payment by work-
ers’ compensation systems—10 states, 2007. MMWR
tp proved after surgery, although the non–work-injured
group had better results. Level of evidence: III.
Morb Mortal Wkly Rep 2010;59(29):897-900. 13. Campolieti M, Hyatt DE: Further evidence on the
The proportion of individuals injured at work in the “Monday effect” in workers’ compensation. ILR Rev
k eers
r
12 months of this study ranged from 4.0% to 6.9%, but
s e
insurance paid for medical treatment in only 47% to
k r
e s
r s
2006;59(3):438-450.
bboooo k need to be examined.

b o o
o k
77% of the states studied. The reasons for nonpayment
o
14.
b o oo
Waddell G, McCulloch JA, Kummel E, Venner RM:
o
Nonorganic physical signs in low-back pain. Spine
/
e e
/ e 7.
ee/ e
/ e b
Leigh JP, Robbins JA: Occupational disease and work- / e e b
(Phila Pa 1976) 1980;5(2):117-125.
ee /
: / / t
/ .
t m
. m
ers’ compensation: Coverage, costs, and consequences. 15.
: / / t
/ .
t m
. m
Giersiepen K, Spallek M: Carpal tunnel syndrome as an
t p ss
p : /
Milbank Q 2004;82(4):689-721.
t p ss
p : /
occupational disease. Dtsch Arztebl Int 2011;108(14):
238-242.
8.
t
hht t
Smith TD, DeJoy DM: Occupational injury in America:
An analysis of risk factors using data from the General
Social Survey (GSS). J Safety Res 2012;43(1):67-74.
t
hht t Carpal tunnel syndrome caused by work, either alone or
in combination with other factors, has been well docu-
mented by epidemiologic data and is pathophysiologically
The authors identified race, occupational category, and plausible. However, working at a computer keyboard
work-family interference as risk factors and safety cli- does not seem to raise a patient’s risk for this condition.
k eers
rstors for work injury.
k eers
mate and organizational effectiveness as protective fac-
r s 16. Armstrong TJ: Disability Evaluation, ed 2. St. Louis,
b ooook9.
b oook
o
Walsh M, Davidovitch RI, Egol KA: Ethnic disparities
b oooo
MO, Mosby, 2003, pp 178-190.
/
e e
/ eb / ee b
in recovery following distal radial fracture. J Bone Joint
Surg Am 2010;92(5):1082-1087.
ee / 17.
e /e/e b
Injuries, in The Burden of Musculoskeletal Diseases in
e
/ t
///t. m
. m
Ethnic disparities have been demonstrated in the treat-
: : / t.
///t m
the United States. Rosemont, IL, American Academy of
.m
Orthopaedic Surgeons, 2011, pp 129-143.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
A recently updated overview of the spectrum of muscu- tively detected submaximal effort, although it is not safe
k eers
rs rrss
loskeletal injuries in the United States, with data on
kee
prevalence, trends, location, causes, injury sites, out-
for patients during initial therapy but may be appropri-
ook ook
ate for patients who can safely exert maximal grip force.
b oo b o
comes, and the demographic characteristics of work-
o b o oo
o
/
ee/e b place injuries.
ee/ e
/ e b 25.
ee/ e
/ e b
Goldberg RJ: Current Diagnosis in Neurology. St.
Louis, MO, Mosby 1994, pp 300-304.
18.
/ ///t. m
Ramazzini B: De morbis artificum diatriba [diseases of
t .m
workers]: 1713. Am J Public Health 2001;91(9):1380-
: : /
26. t
///t. m
. m
Ford CV: The Somatizing Disorders: Illness as a Way of
1382.
s
tps : s
tps :
hhtttp hhtttp
Life. New York, NY, Elsevier Science Publishing Com-
pany, 1983, pp 1-2.
19. Leavitt F, Sweet JJ: Characteristics and frequency of
malingering among patients with low back pain. Pain
27. Eisendrath SJ: Factitious physical disorders. West J Med
1986;25(3):357-364.
1994;160(2):177-179.
20. Waddell G, Bircher M, Finlayson D, Main CJ: Symp-
k eers
rs k eers
r s
toms and signs: Physical disease or illness behaviour? 28. Felitti VJ, Anda RF: The relationship of adverse child-
hood experiences to adult medical disease, psychiatric
ook ook
Br Med J (Clin Res Ed) 1984;289(6447):739-741.
b oo b oo b o oo
disorders, and sexual behavior: Implications for health-
o
/
e e
/ eb 21.
e/
e e
/ e b
Shaibani A, Sabbagh MN: Pseudoneurologic syn-
dromes: Recognition and diagnosis. Am Fam Physician
e / e
/ e b
care, in Lanius RA, Vermetten E, Pain C, eds: The Im-
pact of Early Life Trauma on Health and Disease—The
e
1998;57(10):2485-2494.
: // t/.tm
. m : / / t t m
Hidden Epidemic. Cambridge, United Kingdom, United
. . m
Kingdom University Press, 2010, pp 77-87.
/
ss : / ss : /T.S Eliot’s haunting phrase “In my beginning is my end”
hhtttp hhtttp
22. Stokes HM, Landrieu KW, Domangue B, Kunen S:
tp
Identification of low-effort patients through dynamom-
etry. J Hand Surg Am 1995;20(6):1047-1056. tp capsulizes the effect of adverse childhood experiences.
This chapter documents that depression, suicide,
chronic pain, alcoholism, and lives cut short by two de-
23. Gutierrez Z, Shechtman O: Effectiveness of the five- cades can all be traced back to the worst secrets of
handle position grip strength test in detecting sincerity childhood.
rrss rrss
of effort in men and women. Am J Phys Med Rehabil
o ke
ke
2003;82(11):847-855.
o k e
k e
29. Hicks A: Problems in writing medico-legal reports: I.
Clinical exaggeration and malingering. East Afr Med J
oo
e bboo o 24.
e b o o o
Shechtman O, Sindhu BS, Davenport PW: Using the “vi-
b
1988;65(1):51-56.
e b o
b o
/
e / e ee/ e
sual target grip test” to identify sincerity of effort dur-
/
ing grip strength testing. J Hand Ther 2012;25(3):
m
30.
ee/ / e
Bellamy R: Compensation neurosis: Financial reward
m
320-329.
: / /
/ t
/ .
t . m : / /
/t/.t .m
for illness as nocebo. Clin Orthop Relat Res 1997;336:
s :
Participants were tricked into exerting more force than
s ss :
94-106.
hhtttp
tp hhtttp
tp
intended to reach a deceptive target line. This test effec-
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
146
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 13
e rs
rs e rrss
oo
kLevels
ook e of Evidence o and
k
ook
o
e Grades o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e of Recommendation t
///t. m
.mee t
///t. m
. mee
s: /
: s : /
:
tps
hhtttp tps
hhtttp
Brad Petrisor, MSc, MD, FRCSC Mohit Bhandari, MD, PhD, FRCSC
k eers
rs k eers
r s system, and these systems do not always agree.3 A
b ooook b o oo
level I (high-quality) study in one system may not cor-
o
relate with a level I study in another system. Different
/
e e
/ eb e/ e
/ e b
Evidence-based medicine requires the integration of
clinical judgment and acumen, recommendations based
e ee/ e
/ e b
raters may place the same study at a different level
: // t/.tm
on the best available evidence, and the incorporation of
. m
the patient’s values and preferences.1 The term best
/ / t .
t m
within the same system. The interrater reliability for
. m
determining the levels of evidence in the American vol-
: /
ss : / s : /
ume of the Journal of Bone and Joint Surgery was de-
s
hhtttp hhtttp
available evidence implies that there is a hierarchy of
tp
evidence, with studies ranging from high quality to low
quality.1 Clinical trials and research studies attempt to
identify underlying truths about disease or disease pro-
tp
termined to be high (intraclass coefficient, 0.61-0.75),
but agreement was much higher for reviewers trained
in epidemiology.5 For this reason, the principles of
cesses; however, clinical research must overcome two study design and quality in generic terms will be dis-
main factors—bias and random chance—in the quest to cussed. Another potential pitfall of reporting the level
of evidence of clinical trials is that it may give readers a
k errss k
deviate from the truth, and, unlike random chance, bias rrss
identify these truths.2 Bias is the systematic tendency to
e e e
false sense of security in incorporating the trial results
bboooo k b o o
is a modifiable factor. High-quality methodology in
o o k into practice. It should be remembered that a high-
b o oo
o
quality level I therapeutic study does not necessarily
/
e e
/ e e / / e b
clinical trials reduces the introduction of bias, which
e
can cause investigators to deviate from their attempts
e ee/ e
/ e b
translate into a high-quality recommendation grade for
clinical practice. This requires that the study ask an im-
at identifying the truth.
/ / t
/ .
t m
. m
This chapter will discuss the methodologic safe-
: t . m.m
portant clinical question, assess the totality of the liter-
: / / / t
ss : /
guards that can be incorporated into clinical research
ss /
ature, and incorporate patients’ values and preferences.
:
hhtttp hhtttp
Methods for developing grades of recommendation us-
tp
to increase the quality of the research and move the re-
search to a higher level in the hierarchy of evidence. Re-
search studies can become more internally valid by re-
tp
ing the Grading of Recommendations Assessment, De-
velopment, and Evaluation (GRADE) system also are
presented in this chapter.3
ducing potential sources of bias as much as possible.
Historically, there have been several different systems
k ee s
designed to classify the hierarchy of evidence.3 The
rrs
Journal of Bone and Joint Surgery (American volume)
k e r
e s
r s Study Designs
bboooo k
and many other orthopaedic journals have incorpo-
b o o
o o k b o oo
There are several categories of surgical literature. Some
o
/
e e
/ e e / e
/ e b
rated a level of evidence rating for all published trials
and studies.4 However, there is more than one rating
e e / e
/ e b
studies try to answer a question about a therapy,
whereas others may seek to answer questions about a
e
: / / t
/ .
t m
. m / / t
/ .
t m
prognosis, diagnosis, harm, or economic analysis. Each
. m
area of the literature has its own hierarchy of evidence.
:
t p ss : /
Dr. Petrisor or an immediate family member is a member
p t p ss
p : /
Studies that are termed level I or the highest quality ev-
t
hht t
of a speakers’ bureau or has made paid presentations
on behalf of Stryker; serves as a paid consultant to or is
an employee of Stryker; has received research or institu-
t
hht t
idence in one particular category, such as therapy, may
not be the highest quality evidence in the categories of
prognosis or diagnosis.6 This chapter will focus on the
tional support from Stryker and Synthes; and has re- evidence hierarchy in the category of therapy because it
ceived nonincome support (such as equipment or encompasses most of the major study designs and is
k eers
rs k eer
services), commercially derived honoraria, or other non–
research-related funding (such as paid travel) from Syn-s
r s
more common in orthopaedic literature.5
b ooookthes. Dr. Bhandari or an immediate family member
b oook
o
Randomized Controlled Trial
b oooo
Therapy studies can be broadly categorized as those
/
e e
/ eb e / e
/e b
serves as a paid consultant to or is an employee of Am-
gen, Eli Lilly, Stryker, Smith & Nephew, and Zimmer and
e ee/e/e b
having an experimental design or those with an obser-
Smith & Nephew and DePuy.

: / t
///t m
has received research or institutional support from
. . m : / t.
///t m
vational nature. The highest level of evidence in a
.m
therapy study is the randomized controlled trial, which
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
is an experimental study design. This type of design has patients who have a particular disease or outcome and
k eers
rs ke
several important methodologic safeguards to minimize
errss then identify control subjects (patients who do not have
b ooook b o ook
bias, with the process of randomization itself being the
o
foremost safeguard. Randomization attempts to bal-
the disease or outcome). Study investigators assess the
o oo
o
odds of having a risk factor associated with the identi-
b
/
ee/e b / e e b
ance the prognosis between groups within a trial. The
ee /
process balances for any known prognostic variables / e e b
fied outcome. This type of design is necessarily retro-
ee /
spective because the disease or the outcome has already
t . m
.m
and, more importantly, also balances for unknown
: / ///t : / t
///t. m
. m
occurred, and the investigators must look back in time
s
tps :
prognostic variables.7,8 Some clinical trials have used
s
tps :
to identify the risk factors. This trial design can pro-
hhtttp hhtttp
even or odd numbers or chart numbers to randomize duce findings and help identify associations between
patients; however, these methods would at best be disease and risk factors, and it is a very powerful tool
termed pseudorandomization.9 Randomization in and when the disease incidence is low or when the outcome
of itself is vital to reduce the bias that can be intro- of interest takes a long time to develop. Other potential
duced into a trial with an imbalance of prognosis. In benefits of the case-control design are that it is less ex-
addition to randomization, concealment in the alloca- pensive to conduct than a randomized controlled trial
k eers
rs rs
r s
tion of treatment groups is needed; that is, the investi-
k ee
and can be done more quickly. However, the findings
gators should be unable to determine the group to

ook ook
are only associations, meaning that investigators are
b oo b o
which a particular patient would be randomly assigned.
o b o oo
not able to identify causative factors or causation per se
o
/
e e
/ eb ee e
/ e b
If allocation is not concealed, the investigators could
/
enroll patients or choose not to enroll patients based on of disease.
ee e
/ e b
between risk factors and the subsequent development
/
: // t/.tm m
the group to which the patients would be randomly as-
. : / / t
/ .
t m
. m
ss /
signed. This methodology would necessarily lead to
: ss : /
Cohort Design
hhtttp hhtttp
prognostic imbalance and undermine the process of
tp tp
The cohort study is the next design above the case-
randomization.10 control study in the design hierarchy. The cohort design
After the patients have been randomized, it is vital to is observational in nature but can be very similar to the
maintain the prognostic balance with the process of randomized trial design without the random assign-
blinding. When possible, all members of the investiga- ment of treatments. A simple cohort trial identifies two
tive team should be blinded to treatment allocation.10-12 groups of patients who differ in an exposure or a treat-
keerrss k e rrss
Clearly, it is not possible to blind surgeons to the treat-
e
ment group, and, in many instances, it is not possible to
ment. It can be used when it would be considered un-
bboooo k b o
blind patients to the received treatment. However,
o
o o k ethical to randomize patients to a particular treatment
b o oo
or exposure. For example, a prospective cohort trial
o
/
e e
/ e e / / e b
other people involved in the study can be blinded, in-
e
cluding the therapy staff, the clinical staff, the outcome
e ee/ e
/ e b
could be used to assess the effect of smoking on frac-
ture nonunion. One group of patients with a fracture
mittee.13
: / / t
/ .
t m
adjudicators, the data analysts, and the writing com-
. m t . m.m
who are smokers can be matched and compared with
: / / / t
ss : / ss : /
another group of patients with a fracture who are non-
hhtttp hhtttp
smokers. The patients are matched based on known
Case Series
tp
The case series or case report is at the lowest level of
the hierarchy for formal data collection. The case series
tp
prognostic factors, such as age, fracture type, or treat-
ment, with the groups differing only in the selected ex-
posure. Another example is the comparison of one sur-
is the most common study type in the orthopaedic lit- geon’s treatment of tibial fractures with a second
erature.5,14 Case series are observational and lack a con- surgeon’s treatment protocol. However, unknown prog-
k eers
rs trol group. Most case series are often retrospective in
k e r
e
nature and by necessity must resort to historical or lit- s
r s nostic factors are not controlled for in this type of
study design, and there may be some prognostic imbal-
bboooo k b o o
o o k
erature comparisons. Reducing bias in the case series is
possible by prospectively collecting the data, asking an
b o oo
ance between the groups that can affect the ultimate
o
/
e e
/ e e / e
/ e b
appropriate question, using validated outcomes, and
e e e
/ e b
outcome of the trial. An imbalance in prognosis can re-
/
sult in an overestimation or an underestimation of the
e
/ / t
/ t m
using unbiased outcome measures and adjudicators. At
. . m
best, conclusions drawn from a case series are hypoth-
: : / / / .
treatment effect.2
t t m
. m
ss : /
eses for generating future clinical research.15
t p p t p ss
p : /
Case-Control Study t
hht t
Above the case series in the quality hierarchy is the
t
hht t
Study Quality
There is a hierarchy of study quality within the hierar-
case-control design, an observational and retrospective chy of study designs. One randomized trial may be
study design. One of the main strengths of the case- more methodologically sound than another, and it is
k eers
rs
control design is that it is useful for rare outcomes or
diseases that have a low incidence rate. In many in-
k eers
r s
possible that the less robust randomized trial may be
downgraded to a lower quality level in the study design
b ooook b ook
stances, the study is designed to identify the risk factors
oo
present in the development of a disease. Similarly, the
b oooo
hierarchy. For example, trial A is a randomized trial
with computer randomization and complete conceal-
/
e e
/ eb / e
/e b
study can be used to identify prognostic factors that
ee ee/e/e b
ment of the treatment allocation. The trial also blinds
/ t
///t m
may modify the way a disease progresses. This design is
. . m
retrospective in nature because investigators identify
: : / t.
///t m
the patient, the data collectors, the nursing teams, the
.m
physiotherapy teams, the outcomes adjudicators, and
s
tps : s
tps :
148
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 13: Levels of Evidence and Grades of Recommendation
the writing committee. The outcomes observed are potential outcome events will be lost or not observed.
k eers
rs ke rrss
clearly defined and objective (for example, revision sur-
e
Patients may not complete follow-up assessments be-
b ooook o ook
gery or validated functional outcome measures, both
o
generic and disease specific). The study is appropriately
b
cause of a differential in treatment effect; if a large
b o oo
o
number of patients in one group do not complete
/
ee/e b / e e b
powered to identify a clinically important difference in
ee /
outcomes. This type of study can be contrasted to
ee/ e
/ e b
follow-up, an unknown prognostic reason could be in-
volved. By convention, a minimum 80% follow-up rate
t . m
.m
trial B, a randomized trial that used a coin flip for ran-
: / ///t : / t
///t. m
. m
is considered respectable for a clinical trial. However,
s
tps :
domization, no blinding of personnel involved in treat-
s
tps :
methodologists suggest that this rate is inadequate, and
hhtttp hhtttp
ment allocation, and no blinding of patients. The sur- all trialists should strive to approach 100% follow-up.16
geon investigator collects the outcome data using The effect of the follow-up rate is illustrated by the
nonvalidated outcomes (the patient is doing excellent, following example. In a trial, 200 patients are random-
good, fair, or poor). Trial A is more internally robust ized to two groups (A and B) of 100 patients each. In
with respect to its methodology and has used appropri- group A, 85 patients complete follow-up; there are five
ate techniques to minimize bias. Trial B is likely to events in that group. In group B, 90 patients complete
k rs
rs
overestimate or underestimate the truth.
ee k eers
r s follow-up; there are eight events in that group. This
Randomization and concealment of allocation are would lead to an event rate of 6% in group A and 9%
b ooook o ook
important factors in obtaining prognostic balance be-
b o b o oo
in group B (P > 0.05), which is not a statistically signif-
o
/
e e
/ eb ee e
/ e b
tween groups in a randomized controlled trial. Blinding
/
plays the important role of maintaining this prognostic
e e
/ e b
icant difference between the groups. However, if there
/
are just two more patients in group B who have an
e
: // t/.tm m
balance by ensuring that the groups in the trial are
. : / / t
/ .
t m
. m
event that is not assessed at follow-up, these two addi-
ss /
treated in the same manner by different members of the
: ss : /
tional events could potentially shift the trial outcome to
hhtttp hhtttp
care and investigative teams. Other factors, including a statistically significant result. In small trials, which
tp
the lack of an intention-to-treat analysis or the absence
of appropriate follow-up, also can downgrade the qual-
ity and evidence level of a study.
tp
are common in orthopaedic studies (average, 80 to
100 patients), events that are undetected because of
loss of follow-up can profoundly affect the result.17 If
patients are enrolled in trials to observe outcomes, it is
Intention-to-Treat Analysis essential that the patients complete follow-up so that
k errss
An intention-to-treat analysis analyzes patients in the
e
groups to which they were randomized, despite the
k e rrss
e
the outcomes of interest can be observed.
bboooo k b o o o k
treatment that they received. This type of analysis con-
o b o oo
o
/
e e
/ e e e
/ e b
trasts with the per protocol analysis in which investiga-
/
tors analyze patients to the treatment they received
e
Grading the Evidence
ee/ e
/ e b
: / / / .
t m m
regardless of their randomized allocation. Intention-to-
t . : / / /.
The GRADE Approach
t tm.m
ss /
treat analysis is important for maintaining prognostic
: ss : /
The GRADE Working Group was formed in 2000 to
hhtttp hhtttp
balance. For example, if a trial is devised randomizing standardize the levels of evidence and the formulation
tp
patients with wrist fractures to treatment with Kirsch-
ner wire fixation versus locking volar plate fixation,
there may be a subset of patients randomized to the
tp
of grades of recommendation.3 The working group is
composed of healthcare workers, researchers, and opin-
ion leaders in evidence-based medicine. The GRADE
Kirschner wire fixation who instead are treated with system provides a framework for the development of
plate fixation (the surgeon may believe that a patient’s guidelines in a structured manner3 (Figure 1). To de-
eers
bone is too osteopenic or the fracture pattern is not
rs
amenable to Kirschner wire fixation). Using the
k k e r
e s
r svelop a guideline, it is necessary to ask a well-
structured question, choose an appropriate outcome,
bboooo k b o o
o o
then be analyzed in the original treatment allocation k
intention-to-treat analysis, this subset of patients would
b o oo
evaluate the literature, and then incorporate patients’
o
/
e e
/ e e / e
/ e b
group. The reason for this methodology is that there
e e / e
/ e b
values and preferences into a clinically relevant recom-
mendation.3 In some instances, the orthopaedic surgery
e
: / / t
/ .
t m
may be some unknown prognostic factor linking these
. m
patients that is associated with being nonamenable to
/ / t
/ t m
literature has a paucity of high-quality evidence avail-
. . m
able for evaluation; however, the GRADE system will
:
t p ss
p : /
wire fixation. The intention-to-treat analysis provides a
ss : /
work regardless of the type of evidence used for the rec-
t p p
t
hht t
more conservative estimate of the treatment effect,
whereas a per-protocol analysis in this example may
overestimate or underestimate the treatment effect.
t t
ommendation.
hht
Rating the Evidence
However, it is often useful to do both analyses so that Evidence is most commonly acquired by performing a
the reader can assess the results of each. systematic review, with a focused question and a repro-
k e rs
rs
Completion of Follow-up
e k eers
r s ducible literature search that identifies all the literature
relevant to the focused question.18 The patient popula-
b ooook b oook
The percentage of patients with completed follow-up is
o
also a vital component in assessing the quality of a
b ooo
tion, intervention, comparator, and outcomes (known
o
by the acronym PICO) system provides a common
/
e e
/ eb ee/ e
/e b
trial. For example, if only 50% of the patients return
/e/e b
framework for question development.19 The patient
ee
/ t
///t m
for a final assessment of functional outcomes or have
. . m
unreported revision procedures, a significant number of
: / t.
///t m
population for whom the guideline is being developed
.m
must be determined. Defining the population may in-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k Figure 1
b o o
o k b o oo
Illustration of the guideline development process and the role of GRADE. (Reproduced with permission from
o o
Guyatt G, Oxman AD, Akl EA, et al: GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of
/
e e
/ e ee e
/ e b
findings tables. J Clin Epidemiol 2011;64[4]:383-394.)
/ ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss : /
clude factors such as mean age, fracture type, and re-
source status (resource-rich or resource-poor patients).
p t p ss : /
appropriate outcome also may be difficult. For exam-
ple, when assessing pelvic fracture outcomes, several
p
t
hht t
For example, asking a question about the use of bio-
logic therapies as adjuncts to fracture repair may not
have an effect in those patients who are unable to pro-
t
hht t
different functional outcome measures have been re-
ported in the literature, with no standard measure used
by all studies.20 This problem is also seen in other spe-
cure the use of those therapies or in healthcare systems cialties, such as foot and ankle and hip and knee
that cannot afford their use. reconstruction.21-24
k eers
rs The potential of several interventions for many given
orthopaedic problems can confound the development
k eers
r s When developing a guideline, it is necessary to assess
all patient-important outcomes as well as any potential
b ooook b oook
of guidelines. Much of the orthopaedic literature also
o
lacks an appropriate comparison group; therefore, it
b ooo
adverse effects of various treatments.25 It is important
o
for content experts to formulate clinically relevant and
/
e e
/ eb ee/ e
/e b
may be difficult to ascertain the appropriate compara-
/e/e b
appropriate questions and discuss all important out-
ee
/ t
///t m
tor. In many trials in the literature, there is neither an
. . m
intervention nor a comparison group. Determining the
: / t.
///t
velopment.26
: m
comes and harms before the initiation of guideline de-
.m
s
tps : s
tps :
150
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Risk of Bias Consistency
k eers
rs ke rr
After the question has been determined, it is necessary
e ss Inconsistency refers to the inherent heterogeneity be-
b ooook b ook
to evaluate the literature surrounding it. The GRADE
o o
Working Group suggests that the levels of evidence be
b o oo
tween studies. Systematic reviews show that several
o
randomized controlled trials on a particular subject and
/
ee/e b / e e b
ranked as follows: high quality, moderate quality, low
ee / ee/ e
/ e b
having the same outcome can produce differing results.
This can be caused by many factors, including differ-
t
///t m
quality, and very low quality. Randomized trials are
. .m
graded as high quality or moderate quality, although
: / : / t
///t. m
. m
ences in the patient populations, the quality of the trial,
s :
some trials could be further downgraded if necessary.18
tps s
tps :
the application of an intervention, or the outcomes be-
hhtttp hhtttp
Observational studies are considered low quality or ing assessed. An exploration of the heterogeneous fac-
very low quality. Individual studies can be downgraded tors may reveal the reason for the inconsistency; how-
based on their risk of bias, and the total evidence can ever, if the inconsistency remains unexplained, the body
be downgraded for a lack of consistency, directness, of literature can be downgraded for the lack of consis-
and precision or a risk of publication bias. Evidence tency.30 The presence of inconsistency is important be-
cause it can decrease confidence in the estimate of the
k e s
rs e
dose-response effect.27 However, when discussing the
e k ers
can by upgraded if there is a large treatment effect or a
r r s effect. For example, if four randomized control trials
result in two trials with treatment effects in support of
b ooook b oook
quality of the evidence in the makeup of guidelines, the
o
GRADE Working Group also uses the concept of qual- o oo
a given therapy and two trials with treatment effects
b o
/
e e
/ eb e/
e e
/ e b
ity in the form of totality of evidence. For example, sev-
ee/ e
/ e b
against the same therapy, this type of inconsistency
would undermine confidence in this body of literature.
// t/ tm
eral high-quality randomized trials with a low risk of
. . m
bias or high internal validity may provide inconsistent
: : / / t
/ .
t m
. m
The literature could be downgraded for the lack of con-
ss : /
or imprecise evidence for a particular outcome when
ss /
sistency.30
:
hhtttp
tp hhtttp
tp
the trials are compared with each other or when all the Imprecision
trials are evaluated together.18 In general, precision is quantified by assessing the con-
fidence interval (CI). With a 95% CI, the true treat-
Directness ment effect will lie within the interval 95% of the time.
Direct evidence as defined by the GRADE Working If a CI is significantly wide, it is an imprecise measure
keerrss
Group is evidence that applies directly to an investiga-
k e
tor’s question or the question put forward by the guide-rrss
e
of the treatment effect. In individual trials, if the confi-
dence limits cross the line of no effect, the treatment
bboooo k o o o k
line committee.28 It directly relates to the patient popu-
b o b o oo
may be beneficial, may not be beneficial, or may be po-
o
/
e e
/ e e e
/ e b
lation of interest, compares the interventions of
/
interest, and evaluates the patient groups with consid-
e e e
/ e b
tentially harmful. Using the GRADE system of guide-
/
line development, if the confidence limits of a pooled
e
: / / / .
t m m
eration of outcomes that are important to patients. In-
t . : / /t/.tm.m
estimate of effect cross a clinical threshold for recom-
ss /
directness can be introduced into a trial when there are
: ss : /
mending or not recommending a treatment, then there
hhtttp hhtttp
differences in the trial population and the population of is a lack of precision.31 In trials with a lack of precision,
tp
interest or when the trial has no control group for com-
parison of outcomes. This is particularly relevant in the tp
the evidence may be downgraded one or two levels. It
has been suggested that with few events and confidence
limits that suggest either benefit or harm, the evidence
orthopaedic literature because many trials lack a con-
trol group.14 should be downgraded by two levels for imprecision.31
The potential for indirect evidence is illustrated by
k eerss
the following example. The American Academy of Or-
r
thopaedic Surgeons (AAOS) developed a clinical prac-
k e r
e s
r sPublication Bias
Some studies with negative results or results perceived
bboooo k o o o
tice guideline on the Diagnosis and Treatment of Acute
b o k b o oo
as uninteresting may not be published or may be sub-
o
/
e e
/ e ee/ e
Achilles Tendon Rupture based on many studies in
/ e b
which the patients were not high-performance ath-
e / e
/ e b
ject to lag bias (delayed publication because of multiple
rejections, with subsequent publication in more obscure
e
t . m
. m
letes.29 If the recommendations of this AAOS guideline
: / / / t / / t
/ .
t m
journals).32 Other authors choose to publish trials in
. m
foreign language journals. Less-than-rigorous literature
:
t p p : /
are applied to a population of high-performance ath-
ss
letes, there would be some indirectness in extrapolating ss : /
search strategies may overlook these types of studies. If
t p p
t
hht t
the results. If the differences in the patient populations
are too great, the evidence could be downgraded be-
t
hht t
systematic reviews report on only positive studies, this
can introduce publication bias and can lead to an over-
estimation of the treatment effect.33 There may be a
cause of this indirectness. However, caution should be greater risk of publication bias with multiple, smaller
exercised in downgrading a study for indirectness in randomized trials because larger trials are more likely
study populations, unless there is some plausible bio-
k eers
rs k e
logic rationale that one population may behave differ-
ers
r s
to be published. Statistical methods for determining
publication bias include the use of a funnel plot and
b ooook ook
ently than another.28 Another example of indirect evi-
oo
dence is applying the results of studies assessing
b b oooo
statistical tests for asymmetry.32
/
e e
/ eb / ee b
hardware failure in osteopenic or osteoporotic patients
to adolescent patients.
ee / Clinical Example
ee/e/e b
: / t
///t. m
. m / t.
///t m
The following clinical question was formulated using
.m
the PICO format. In adult patients with a displaced
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook in Displaced Distal Radius Fracturesa
b ook
Summary of Findings Table: Internal Fixation Versus External Fixation
o o b o oo
o
/
ee/e b ee/ e
/ e b
Population: Adult Patients With Unstable Distal Radius Fractures
ee/ e
/ e b
Intervention: Internal Fixation
: / t
///t. m
.m : / t
///t. m
. m
Comparison: External Fixation
s
tps : s
tps :
No. of Studies
Outcomes (Design)
11 (8 RCTs)
hhtttp Limitations
Yes, 3 observational
hhtttp
Inconsistency
Serious inconsistency,
Indirectness
No serious indirectness
Imprecision
Some
Functional outcome studies, RCTs with multiple patient-
(DASH score) some limitations reported outcomes
k eers
rs 9 (6 RCTs) Yes, 3 observational
k eers
r s
used
Serious inconsistency, No serious indirectness Some
b ooook Objective (grip

strength)
studies, RCTs with
some limitations
b ooook different measures
obtained between
b o oo
o
/
e e
/ eb e/
e e
/ e b trials
ee/ e
/ e b
6 (4 RCTs)
Radiographic
: // t/.tm
Yes, 3 observational
. m
studies, RCTs with
: / / / .
t m
No serious inconsistency No serious indirectness
t . m
Some
(volar tilt)
ss : /
some limitations
ss : /
hhtttp
tp hhtttp
tp
a
For dichotomous outcomes, a presentation of both relative risks and absolute risks would be included. RCT = randomized controlled trial, DASH = Disabilities of the Arm,
Shoulder, and Hand. Standardized mean difference is a measure of treatment effect with positive values favoring internal fixation and negative values favoring external
fixation.
(Data from Wei DH, Poolman RW, Bhandari M, Wolfe VM, Rosenwasser MP: External fixation versus internal fixation for unstable distal radius fractures: A systematic review
and meta-analysis of comparative clinical trials. J Orthop Trauma 2012;26[7]:386-394.)
keerrss distal radius fracture requiring surgical fixation, does

k e rrss
e would likely go ahead with the procedure; however,
bboooo k o
internal fixation versus external fixation improve func-
b o
o o k b o oo
this would not negate the necessary conversation with
o
/
e e
/ e e e
tional outcomes?34 From this clinical question, a sys-
/ / e b
tematic literature review was identified and used to ini-
e e e
/ e b
the patient to offer treatment alternatives. A recom-
/
mendation to “probably do it” would mean a more ex-
e
: / / / .
t m
tiate the GRADE approach. From the systematic
t . m : / /t/.tm.m
tensive discussion of options and a potentially greater
incorporation of the patient’s values and preferences
ss /
review, a table with an evidence profile and a summary
: ss : /
hhtttp hhtttp
of findings was created (Table 1). The table outlines the into the decision.35
tp
sources of the potential study limitations, inconsisten-
cies, indirectness, and imprecision. A full summary of
findings table also contains the relevant results (includ-
tp Returning to the clinical example, Table 1 suggests
low-quality research supporting the use of internal
locked volar plating over external fixation for treating
ing relative risks and absolute risks for dichotomous an unstable distal radius fracture in terms of the out-
outcomes) for each patient-important outcome. A qual- come of function, grip strength, and radiographic volar
k eers
rs ity rating for the evidence can then be obtained for each
outcome.
k e r
e s
r s tilt. The systematic review by the study investigators
does not provide information on the risks associated
bboooo k b o o
o o k b o oo
with plate fixation (for example, a larger incision or ex-
o
/
e e
/ e Strength of a Recommendation
ee/ e
/ e b e / e
/ e b
tensor tendon rupture) versus the risks associated with
external fixation (for example, pin tract infection).34
e
/ / t
/ .
t m
. m
When making a recommendation, several factors, in-
: : / / t
/ .
t m
The grade of the recommendation in favor of plate fix-
. m
ation would be “probably do it”; however, the treating
t p ss
p : /
cluding a measure of beneficial and harmful effects, the
t p ss
p : / surgeon should be aware that further high-quality re-
t
hht t
quality of the evidence, a translation of the evidence
into the clinical situation, and the baseline risk of the
population in question, must be taken into account ac-
t
hht t search could change the recommendation, and the risks
and benefits of plate fixation should be discussed with
the patient, and his or her values and preferences
cording to the GRADE Working Group. The strength should influence the treatment decision.
of the recommendations can then be categorized as The GRADE system has been incorporated by sev-
k eers
rs
strong or weak.26 Because the GRADE Working Group
states that “a recommendation is intended to facilitate
k eers
r s
eral organizations that develop guidelines, including the
World Health Organization, the Cochrane Collabora-
b ooook an appropriate decision in an individual patient or a

population,” the actual recommendation would be to
b oook
o b ooo
tion, and the US Preventative Task Force.36 The
o
GRADE system uses a systematic framework for guide-
/
e e
/ eb ee/ e
/e b
do it or do not do it (strong), or probably do it or prob-
e /e/e b
line development from the initiation of an appropriate
e
/ t
///t m
ably do not do it (weak).3 A recommendation to “do
. . m
it” would mean that most well-informed patients
: : / t.
///t m
.m
clinical question to an evaluation of the literature and
subsequent formulation of the guideline.37
s
tps : s
tps :
152
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 1
rs keerrss
b ooook b
in Displaced Distal Radius Fracturesa (continued)ook
Summary of Findings Table: Internal Fixation Versus External Fixation
o o b o oo
o
/
ee/e b ee/ e
/ e b
Population: Adult Patients With Unstable Distal Radius Fractures
ee/ e
/ e b
Intervention: Internal Fixation
: / t
///t. m
.m : / t
///t. m
. m
Comparison: External Fixation
s
tps : s
tps :
Publication Bias
None detected
hhtttp
No. of Patients
(Internal Fixation)
316
hhtttp
No. of patients
(External Fixation)
289
Standardized Mean
Difference (95% CI)
0.28
Quality
Low
(0.03, 0.53)
None detected 372 356 −0.28 Low
k eers
rs k eers
r s (−0.57, 0.00)
ook ook
None detected 255 244 0.43 Low
b oo b oo
(0.11, 0.75)
b o oo
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m 2.
: / / t .
t m
. m
Chu R, Walter SD, Guyatt G, et al: Assessment and im-
/
Summary
ss : / ss : /
plication of prognostic imbalance in randomized con-
hhtttp
tp hhtttp
tp
A number of study designs exist, each with its own trolled trials with a binary outcome—a simulation
strengths and weaknesses. Within studies of therapy, study. PLoS One 2012;7(5):e36677.
the randomized controlled trial is at the top level, or This study assessed the potential for prognostic imbal-
considered best evidence as it incorporates methodol- ance between two arms of a randomized controlled
ogy to reduce bias, randomization being but one trial. The authors concluded that the probability of
prognostic balance between the two arms can be sub-
rrss rrss
method. By understanding study design and study qual-
stantial in small trials.
o ke
ke o
evidence. Once this is done, by incorporating the for-
k e
ity, it is possible to rank studies of therapy into levels of
k e oo
e bboo o e b o o
mat of GRADE, it is then possible to formulate a grade
b o 3.
e b o
Atkins D, Eccles M, Flottorp S, et al; The GRADE
b o
Working Group: Systems for grading the quality of evi-
/
e / e ee/ e
of recommendation for a given treatment and the sub-
/
sequent formation of clinical care guideline to aid in
m m ee/ / e
dence and the strength of recommendations I: Critical
/ t
the evidence-based care of patients.
: / / / .
t . m : / /t/.t .m
appraisal of existing approaches. BMC Health Serv Res
2004;4(1):38.
/
ss : ss :
hhtttp
tp hhtttp
tp
4. Wright JG, Swiontkowski MF, Heckman JD: Introduc-
Key Study Points ing levels of evidence to the journal. J Bone Joint Surg
Am 2003;85(1):1-3.
• Gain understanding about how the GRADE 5. Bhandari M, Swiontkowski MF, Einhorn TA, et al: In-
working group incorporates the hierarchy of ev-
k eers
rs
idence.
k e r
e s
r s
terobserver agreement in the application of levels of ev-
idence to scientific papers in the American volume of
bboooo k
• Gain understanding about how the GRADE
working group method is used to develop a
b o o
o o k o
Am 2004;86(8):1717-1720.
b oo
the Journal of Bone and Joint Surgery. J Bone Joint Surg
o
/
e e
/ e grade of recommendation.
ee/ e
/ e b 6.
ee/ e
/ e b
Oxman AD, Sackett DL, Guyatt GH; The Evidence-
•
/ / t
/ t m
Gain understanding about how the incorpora-
. . m
tion of patients’ preferences and values is done
: t . m
. m
Based Medicine Working Group: Users’ guides to the
: / / / t
ss : /
within the GRADE system for the development
t p p t p ss
p : /
medical literature: I. How to get started. JAMA 1993;
270(17):2093-2095.
t
hht t
of grades of recommendation.
t
hht7.t Farrokhyar F, Karanicolas PJ, Thoma A, et al: Random-
ized controlled trials of surgical interventions. Ann Surg
2010;251(3):409-416.
The authors identify potential methodologic challenges
k eers
rs
k eers
r s in conducting surgical randomized trials and discuss
strategies to overcoming the challenges.
b ooook b oook
o b oooo
/
e e
/ eb 1.
e / e
/e b
Sackett DL, Rosenberg WM, Gray JA, Haynes RB,
Richardson WS: Evidence based medicine: What it is
e
8.
e /e b
Bhandari M, Guyatt GH, Swiontkowski MF: User’s
/e
guide to the orthopaedic literature: How to use an arti-
e
: / ///t. m
and what it isn’t. BMJ 1996;312(7023):71-72.
t . m : / t.
///t m
cle about a surgical therapy. J Bone Joint Surg Am
.m
2001;83(6):916-926.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
9. Bhandari M, Guyatt GH, Lochner H, Sprague S, Tor- Epidemiol 2011;64(4):401-406.
k eers
rs rrss
netta P III: Application of the Consolidated Standards
kee
of Reporting Trials (CONSORT) in the fracture care lit-
The authors of this part of the GRADE guideline series
b ooook o ook
erature. J Bone Joint Surg Am 2002;84(3):485-489.
b o b oo
discuss the issues involved in rating evidence for quality.
o o
The GRADE approach attempts to separate the quality
/
ee/e b 10.
ee/ e
/ e b
Savović J, Jones H, Altman D, et al: Influence of re-
ee/ e
/ e b
of the evidence from the grade of the recommendation.
: / ///t. mm
ported study design characteristics on intervention effect
t .
estimates from randomised controlled trials: Combined
19.
: / t . m
. m
Guyatt GH, Oxman AD, Kunz R, et al: GRADE guide-
///t
lines: 2. Framing the question and deciding on impor-
s
tps :
analysis of meta-epidemiological studies. Health Tech-
s
tps :
hhtttp hhtttp
tant outcomes. J Clin Epidemiol 2011;64(4):395-400.
nol Assess 2012;16(35):1-82.
The authors of this part of the GRADE guideline series
This study assessed the potential for bias within se- highlight the methodology behind framing a good clini-
quence generation, concealment of allocation, and cal question for the development of a guideline. The
blinding. The authors identified that bias in relationship method includes identifying the patient population, the
to unclear or inadequate sequence generation, conceal- interventions, the comparison groups, and all important
ment of allocation, and blinding can potentially result in
k eers
rs k eers
r
an overestimation or an underestimation of treatment
s
outcomes.
ook ook
effects.
b oo b oo
20.
b o oo
Lefaivre KA, Slobogean GP, Valeriote J, O’Brien PJ,
o
Macadam SA: Reporting and interpretation of the func-
/
e e
/ eb 11.
e e
/ e b
Devereaux PJ, Bhandari M, Montori VM, Manns BJ,
/
Ghall WA, Guyatt GH: Double blind, you have been
e ee/ e
/ e b
tional outcomes after the surgical treatment of disrup-
tions of the pelvic ring: A systematic review. J Bone
5(2):36-37.
: // /.tm m
voted off the island! Evid Based Ment Health 2002;
t . : / / t
/ .
t m
. m
Joint Surg Br 2012;94(4):549-555.
ss : / ss : /
This study illustrates that there is substantial variability
hhtttp
tp hhtttp
tp
12. Montori VM, Bhandari M, Devereaux PJ, Manns BJ, in the functional outcome scores used in reporting the
Ghali WA, Guyatt GH: In the dark: The reporting of surgical treatment of pelvic fractures. Some outcome
blinding status in randomized controlled trials. J Clin scores had not been validated.
Epidemiol 2002;55(8):787-790.
21. Goldstein CL, Schemitsch E, Bhandari M, Mathew G,
Petrisor BA: Comparison of different outcome instru-
rrss rrss
13. Devereaux PJ, Bhandari M, Montori VM, Manns BJ,
ments following foot and ankle trauma. Foot Ankle Int
o ke
ke est link—good-bye! ACP J Club 2002;136(1):A11.
o k e
Ghali WA, Guyatt GH: Double blind, you are the weak-
k e 2010;31(12):1075-1080.
oo
e bboo o e b o
b o o e b o
b o
The authors assessed different foot and ankle outcome
scores and correlated foot- and ankle-specific outcome
/
e / e 14.
ee/ e
Mundi R, Chaudhry H, Sharma R, Schemitsch E, Bhan-
/
dari M: What is the quality of the orthopaedic litera-
m m ee/ / e
measures with validated generic functional outcome
103-109.
: / / t
/ .
t . m
ture? J Long Term Eff Med Implants 2007;17(2):
/ : / /
/t/.
scores.
t .m
ss : ss :
hhtttp hhtttp
22. Farrugia P, Goldstein C, Petrisor BA: Measuring foot
15.
tp
Guyatt GH, Sackett DL, Cook DJ; Evidence-Based
Medicine Working Group: Users’ guides to the medical
literature: II. How to use an article about therapy or
tp and ankle injury outcomes: Common scales and check-
lists. Injury 2011;42(3):276-280.
The authors provide an update on the types of func-
prevention: A. Are the results of the study valid? JAMA tional outcome measures used to assess ankle injury and
1993;270(21):2598-2601. review specific validated foot and ankle outcome mea-
k eers
rs 16.
e r
e s
r s
Akl EA, Briel M, You JJ, et al: Potential impact on esti-
k
sures.
bboooo k b o o
o k
mated treatment effects of information lost to follow-up
o
in randomised controlled trials (LOST-IT): Systematic
23.
b o oo
Lau JT, Mahomed NM, Schon LC: Results of an Inter-
o
net survey determining the most frequently used ankle
/
e e
/ e review. BMJ 2012;344:e2809.
ee/ e
/ e b / e e b
scores by AOFAS members. Foot Ankle Int 2005;26(6):
479-482.
ee /
: / / t
/ t m
This study attempted to assess the reporting, extent, and
. . m
actions of trialists to manage follow-up loss. The au-
: / / t
/ .
t m
. m
ss : /
thors concluded that if different assumptions were made
t p p
about patients lost to follow-up, those assumptions
24.
t p ss
p : /
Bryant DM, Sanders DW, Coles CP, Petrisor BA, Jeray
KJ, Laflamme GY: Selection of outcome measures for
t
hht t
could change the interpretation of the trial results.
t
hht t patients with hip fracture. J Orthop Trauma 2009;
23(6):434-441.
17. Thorlund K, Imberger G, Walsh M, et al: The number
of patients and events required to limit the risk of over- 25. Guyatt GH, Alonso-Coello P, Vandvik PO: Experience
estimation of intervention effects in meta-analysis—a with GRADE. J Clin Epidemiol 2012;65(12):1243-
k eers
rs simulation study. PLoS One 2011;6(10):e25491.
k eers
r s
This study found that meta-analyses of small trials can
1244.
This article is an introduction to the series of GRADE
b ooook oook
introduce random error, which may result in the overes-
b o b oooo
articles in the Journal of Clinical Epidemiology. It high-
/
e e
/ eb ee/ e
/e b
timation of the identified effects of interventions.
/e/e
grading system.
ee b
lights the reasons for the development of a standardized
18.
/ t
///t m
Balshem H, Helfand M, Schünemann HJ, et al: GRADE
. . m
guidelines: 3. Rating the quality of evidence. J Clin
:
26.
: / t.
///t m
.m
Guyatt GH, Oxman AD, Vist GE, et al: GRADE: An
s
tps : s
tps :
154
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
emerging consensus on rating quality of evidence and 32. Guyatt GH, Oxman AD, Montori V, et al: GRADE
k eers
rsstrength of recommendations. BMJ 2008;336(7650):
keerrss guidelines: 5. Rating the quality of evidence—publica-
ook ook
924-926. tion bias. J Clin Epidemiol 2011;64(12):1277-1282.
b oo b o o b o oo
o
The authors discuss the GRADE system, with a specific
/
ee/e b 27.
/ e e b
Guyatt GH, Oxman AD, Sultan S, et al: GRADE guide-
ee /
lines: 9. Rating up the quality of evidence. J Clin Epide-
ee/ e
/ e b
focus on publication bias and how it can affect the de-
velopment of guidelines. Some approaches for uncover-
miol 2011;64(12):1311-1316.
: / t
///t. m
.m : / ///t. m
. m
ing publication bias are detailed.
t
s :
The authors discuss the GRADE system of creating
tps s
tps :
hhtttp hhtttp
33. Montori VM, Smieja M, Guyatt GH: Publication bias:
guidelines and specifically look at how the system al-
A brief review for clinicians. Mayo Clin Proc 2000;
lows the quality of evidence to be uprated. The criteria
75(12):1284-1288.
used to uprate the quality of observational studies is
specifically described.
34. Wei DH, Poolman RW, Bhandari M, Wolfe VM, Rosen-
wasser MP: External fixation versus internal fixation
28. Guyatt GH, Oxman AD, Kunz R, et al: GRADE guide-
k eers
rs k eers
r s
lines: 8. Rating the quality of evidence—indirectness.
for unstable distal radius fractures: A systematic review
and meta-analysis of comparative clinical trials. J Or-
J Clin Epidemiol 2011;64(12):1303-1310.
b ooook b ooook
This paper, the eighth in the series by the GRADE au-
thop Trauma 2012;26(7):386-394.
b o oo
o
The authors performed a systematic review and meta-
/
e e
/ eb ee e
/ b
thors, highlights and explains the GRADE system. It
/ e
specifically discusses the GRADE concept and the as-
ee/ e
/ e b
analysis assessing external and internal fixation in treat-
ing unstable distal radius fractures. They concluded that
sessment of indirectness.
: // t/.tm
. m : / t . m
. m
there may be some improvement in functional outcomes
/ / t
ss : / ss : /
with internal fixation but also suggest that both tech-
hhtttp hhtttp
29. Chiodo CP, Glazebrook M, Bluman EM, et al: Ameri- niques may be viable. Level of evidence: II.
tp
can Academy of Orthopaedic Surgeons clinical practice
guideline on treatment of Achilles tendon rupture.
tp35. Brozek JL, Akl EA, Compalati E, et al: Grading quality
of evidence and strength of recommendations in clinical
practice guidelines—part 3 of 3: The GRADE approach
The authors discuss the development of the AAOS
to developing recommendations. Allergy 2011;66(5):
guideline on the treatment of Achilles tendon rupture.
588-595.
keerrss
Guidelines are provided on nonsurgical and surgical
k e
management of Achilles tendon rupture based on a fo-rrss
e
The authors discuss the GRADE approach for develop-
bboooo k b o o
o o k
cused question and a rigorous search of the literature.
b o oo
ing clinical practice guidelines. Two examples of guide-
o
lines that have used the GRADE approach in the field of
/
e e
/ e 30.
e / e
/ e b
e ee/ e
/ e b
allergy are discussed.
/ / t
/ .
t m
lines: 7. Rating the quality of evidence—inconsistency.
. m
J Clin Epidemiol 2011;64(12):1294-1302.
:
36.
: t . m.m
Guyatt G, Oxman AD, Akl EA, et al: GRADE guide-
/ / / t
ss : / ss : /
lines: 1. Introduction—GRADE evidence profiles and
hhtttp hhtttp
The authors discuss the GRADE system of guideline de- summary of findings tables. J Clin Epidemiol 2011;
tp
velopment and specifically address the issue of consis-
tency. Criteria for evaluating consistency are discussed,
including the assessment of the similarity of point esti-
tp 64(4):383-394.
This paper provides an introduction to the GRADE ap-
proach to guideline development. The authors outline
mates and the amount of overlap between CIs. the development of the system and specifically discuss
how to develop evidence profiles and tables that sum-
31.
k eers
r
s e
lines 6: Rating the quality of evidence—imprecision.
k r
e s
r s
marize the findings of research studies.
bboooo k J Clin Epidemiol 2011;64(12):1283-1293.
b o o
o o
The GRADE system of guideline development is dis- k 37.
b o oo
GRADE Working Group website. http://www.
o
gradeworkinggroup.org. Accessed May 3, 2013.
/
e e
/ e e/ e
/ e b
cussed. The authors discuss the use and the assessment
e
of CIs and how the quality of the evidence can be rated
ee/ e
/ e b
This website is available as a resource for understanding
GRADE as well as providing tools for using GRADE in
/ t . m
. m
up or down depending on the precision of the measure
: / / t : / / t . m
. m
making recommendations.
/ t
of effect.
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 14
e rs
rs e rrss
oo
kOrthopaedic
ook e Research:o k
ook
o
e Health o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Research Methodology,t
///t. m
.m ee Outcomes, t
///t. m
. mee
s: /
: s : /
:
tps
and Biostatistics
hhtttp
Jesse Slade Shantz, MD, MBA
tps
hhtttp
Saam Morshed, MD, PhD, MPH
k eers
rs k eers
r s
o
/
e e
/ eb Introduction
e/
e e
/ e b e / e
/ e b
More generally, biomedical ethics are an essential
e
: // t/.tm
. m
Orthopaedic surgeons must understand the conduct of
: / / t
/ t m
starting point for the design and performance of clini-
. . m
cal research. Clinical trials must respect the principles
ss : / s : /
of autonomy, beneficence, and nonmaleficence and
s
hhtttp hhtttp
research and the analysis of results to appropriately ap-
tp
ply available evidence to effectively treat patients. Clin-
ical studies become increasingly important if no evi-
dence exists to guide treatment. As consumers and
tp
place participants at minimal risk of harm.3 These eth-
ical principles do not limit the scope of research ques-
tions but may influence the study design that is chosen
producers of clinical evidence, it is essential that ortho- to answer a given research question. Ethical standards
paedic surgeons understand that clinical research in- are upheld on an institutional level by committees ded-
rrss rrss
volves a compromise between the limitation of bias and icated to the protection of human subjects. Although
o kee k e
the maintenance of study feasibility. This chapter uses
k o k e
such a protection committee is tasked to oversee an in-
oo
stitution’s research activities, the final responsibility lies
e bboo o b o
b o o
the example of Achilles tendon rupture to highlight the
basic principles of research ethics, appropriate trial de-
e e b o o
with investigators to uphold ethical standards in their
b
/
e / e sign, and data analysis.1
m ee/ / e research.
ee/ / e
A data safety and monitoring board, an independent
m
: / /
/ t
/ .
t . m /t . .m
board appointed by the study’s investigators to review
: / / / t
ss : s :
interim study results and incident complications, pro-
s
hhtttp hhtttp
Ethics and Evidence-Based Medicine
tp tp
vides an additional level of patient protection in clinical
trials. The data safety and monitoring board should not
Clinical problems without literature support for a sin-
include investigators or those with conflicts of interest
gle diagnostic or treatment approach are common. Al-
in the study outcome and should be given the power to
though the absence of evidence can result in marked
discontinue the study based on explicit a priori cessa-
variability and inefficiencies in the delivery of health
tion rules. The description of committees used to mon-
k e s
care, the embrace of this uncertainty represents the
rrs
foundation of clinical equipoise—a state in which phy-
e k e r
e s
r s itor and report complications has been variable in or-
thopaedic trials.4
bboooo k b o o
o k
sicians are sufficiently ambivalent in preference to pre-
o
scribe one of two or more available options.2 Equipoise
b o oo
o
/
e e
/ e ee/ e
/ e b
is an important consideration to ethical and unbiased
ee/ e
/ e b
Formulating a Research Question
/ / t t m
clinical research. In the example of an Achilles tendon
. . m
rupture, equipoise would be satisfied if practitioners
: / : / / t
/ .
t m
. m
ss : /
were willing to provide either nonsurgical or surgical
t p p t p ss : /
A testable question based on a clinical problem without
a satisfactory answer in the current literature provides
p
t t
care after reviewing the available literature. It follows
hht
that it is ethical to randomize patients to either treat-
ment, with the goal of determining the more efficacious
t
hht t
the foundation for clinical research. The clear defini-
tion of several components of a clinical question is es-
sential for the appropriate design of clinical research
treatment. studies. These components include the study popula-
tion, the intervention(s) being studied, the comparison
k eers
rs k e
Dr. Morshed or an immediate family member has received
ers
r s or control group (if any), and the outcome to be mea-
sured.
b ooook b ook
research or institutional support from Stryker and Synthes.
oo b oooo
The question, once carefully crafted, will drive the
study design in several ways. In the example of an
/
e e
/ eb e / e
/e b
Neither Dr. Shantz nor any immediate family member has
received anything of value from or has stock or stock op-
e ee/e/e b
Achilles tendon rupture, there has been considerable
/ t
///t m
tions held in a commercial company or institution related
. . m
directly or indirectly to the subject of this chapter.
: : / t.
///t m
debate in the field of orthopaedic surgery about the
.m
best treatment.1 The central question is whether surgi-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
strategy must be designed, papers should be reviewed
k eers
rs keerrss for exclusions, relevant data from each included study
b ooook b o ook
o
should be abstracted, and results from studies should
o oo
o
be synthesized and applied to practice.5
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
Inclusion and exclusion criteria will be mainly deter-
mined by the research question. The main goal of re-
: / t
///t. m
.m : / t
///t. m
. m
stricting studies included in a systematic review is to
ensure that the patients represented by the study are
s
tps : s
tps :
hhtttp hhtttp
similar to the target population desired by the investi-
gator. Exclusion criteria limit the review of papers that
investigate outmoded treatments or use lower quality
study designs.
The target population is defined by characteristics of
interest in that particular clinical situation and is a sub-
k eers
rs k eers
r s set of the entire population6 (Figure 1). For example, a
surgeon prescribing a therapy plan for an elite athlete
b ooook Figure 1
b ooook
Diagram illustrating the generalized process of
b o oo
with an Achilles tendon rupture might be interested in
o
/
e e
/ eb / e e b
clinical research. A study population is sampled,
ee /
allowing the collection and analysis of data. An-
e / e
/ e b
early rehabilitation protocols. The surgeon would want
to focus on trials of early rehabilitation in athletes
e
: // /.tm m
alytic approaches allow inferences to be drawn
t .
regarding the target population.
/ / t
/ .
t m
rather than diluting the quality of data with studies in-
. m
cluding nonathletes. Failing to set focused criteria re-
:
ss : / ss : /
sults in confusion in interpreting the outcomes of a sys-
hhtttp
tp hhtttp
tp
tematic review, which can be seen in a 2010 Cochrane
cal repair or nonsurgical management of Achilles ten- review of the treatment of Achilles tendon ruptures.7
don ruptures leads to better outcomes. This question This review did not allow the separation of active and
seems simple; however, this chapter will detail how the sedentary participants and led to difficulty in applying
perspective of the investigator and the target popula- the results to each patient group.
tion (for example, patients with diabetes; healthy, rec-
rrss rrss
Building a search strategy is the next component of
o ke
ke o
study design. Each of these patient populations has
k e
reational athletes; or professional athletes) drives the
k e
the systematic review.8 The goal of the investigator
oo
should be to include all relevant studies from all juris-
e bboo o e b o o o
unique attributes that necessitate a specific approach to
b e b o o
dictions; this often requires collaboration with a medi-
b
/
e / e ee/ e
treatment to ensure optimal outcomes with the fewest
/
complications. For an athlete, rerupture of the tendon,
m ee/ / e
cal librarian. In this way, no studies addressing the
question of interest will be excluded from the analysis.
m
: / /
/ t
/ .
t . m
the length of the rehabilitation period, and the amount
/t . .m
It is important to register the review on an interna-
: / / / t
s :
of time before return to play would be outcomes of in-
s s :
tional database, such as the International Prospective
s
hhtttp
tp hhtttp
tp
terest that would influence an investigator to choose a Register of Systematic Reviews (PROSPERO).9
comparative trial. In diabetic patients, complications After assembling the potentially relevant literature,
can represent a limb-threatening event, although they several reviewers must apply the predefined inclusion
occur with low frequency. This factor would influence and exclusion criteria to all papers and manually search
investigators to consider case-control study designs be- through the reference lists of reviewed papers for any
cause of their statistical efficiency. Given the frequency missed studies. In general, reviewers should confer on
k eers
rs of Achilles tendon ruptures in recreational athletes, a
k e
cost-effectiveness analysis comparing surgical and non- r
e s
r s the interpretation of criteria before their review and
then independently evaluate each study. All disagree-
bboooo k o o
surgical management might provide useful information
b o o k b o oo
ments should be settled by consensus. A flowchart illus-
o
/
e e
/ e e e
/ e b
for physicians and policymakers to best allocate finite
/
resources efficiently. Each of these examples suggests
e e e
/ e b
trating this process as mandated by the Preferred
/
Reporting Items for Systematic Reviews and Meta-
e
: / / / .
t m m
only a few variables and illustrates that small altera-
t . : / / t
/ .
t m
. m
Analyses (PRISMA)10 statement is shown in Figure 2.
design.
t p ss
p : /
tions in the aims of the investigator may alter the study
t p ss : /
After the review, data abstraction and synthesis are
generally accomplished using forms specifically de-
p
t
hht t t
hht t
signed to limit bias. The ultimate goal is to decide if the
available studies are similar enough to allow statistical
pooling of data or meta-analysis. Pooling similar stud-
Systematic Search of the Literature
ies combines data from multiple smaller studies with a
A key component that allows the practice of evidence- high likelihood of false-negative results and achieves an
k eers
rs based medicine is the ability to draw on previous re-
k eers
r
search relevant to answering current clinical questions.5 s adequately powered analysis. Often, the differences in
methodology and outcome measurements make the
b ooook b oook
More specifically, an investigator must efficiently and
o
thoroughly search for relevant literature to avoid re- meta-analyses.
b ooo
pooling of data difficult and limit the ability to perform
o
/
e e
/ eb ee/ e
/e b
peating studies that have already been done. To accom-
/e/e b
Despite rigorous methodology, the clinical usefulness
ee
/ t
///t m
plish this goal, the inclusion criteria and data to ab-
. . m
stract must be predefined, a comprehensive search
: / t.
///t m
of systematic reviews is ultimately determined by the
.m
quality of the included studies and the validity of infer-
:
s
tps : s
tps :
158
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 14: Orthopaedic Research: Health Research Methodology, Outcomes, and Biostatistics
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
Figure 2
/ / t
/ .
t m
. m / /t/.tm.m
A generic example of a flow diagram of the process used in reporting systematic reviews as specified by the Pre-
ferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Reproduced with permis-
: :
s : / s : /
sion from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Sys-
s s
hhtttp
tp hhtttp
tp
tematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6) e1000097.
dol:10.1371/journal.pmed1000097.)
ences relevant to the target population chosen by the Selection Bias

investigator. If the included studies are retrospective or Selection bias refers to systematic error in the ascertain-
k eerss
poor in quality, the conclusions that are drawn must be
r k
cautiously interpreted. Similarly, if the patients in-
e r
e s
r s ment of study subjects, leading to a false association
between an exposure and an outcome.11 For example,
bboooo k b o o
o o
cluded in the reviewed studies do not match the target
k b o oo
in a study examining the association between Achilles
o
/
e e
/ e e / e
/ e b
population of the investigator, the study results may
not accurately predict the clinical response to treat-
e e / e
/ e b
tendon rerupture and basketball participation, selection
bias would be introduced by using patients ascertained
e
: / / t
/ .
t m
ment. A well-designed search strategy may find no pa-
. m
pers that adequately answer the clinical question. This
: / / t
/ .
t m
. m
from a sports medicine clinic and a control group
drawn from the general population. In this example,
t p ss
p : /
situation provides the opportunity for a study that can
t p ss : /
the characteristics of patients referred to a tertiary care
p
t
hht t
help guide clinical decision making.
t
hht t
sports clinic may be different from those of the general
population, putting them at a higher risk for rerupture
independent of their exposure status.
Bias Reduction in Clinical Research Differential loss to follow-up, a similar phenomenon
in which there is a systematic deviation in the propor-
k eers
To estimate a valid and precise answer to the study
rs k e
question, research studies should be designed to limit
ers
r s
tion of patients from study groups lost to follow-up,
can potentially alter study conclusions. In the preceding
b ooook b oook
bias. Bias is defined as a systematic deviation from the
o
true study results.11 Unrecognized bias will result in a
b ooo
example, patients involved in competitive sports may
o
be more likely to attend future clinic appointments
/
e e
/ eb ee/ e
/e b
tendency toward erroneous study results. The most
/e/e b
than patients drawn from the general population. This
ee
/ t
///t
bias, and confounding bias (Table 1).
: m
common types of bias are selection bias, information
. . m / t.
///t m
could artificially increase the association between bas-
.m
ketball participation and tendon rerupture.
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Types of Bias in Clinical Trials
b o ook
o b o oo
o
/
ee/e b Type of Bias Example(s)
ee/ e
/ e b ee/ e
/ e b
Information
/ ///t. m
Patients fail to recall exposure (recall
t .m
bias) or more complete records exist
: : / t
///t. m
. m
s :
for patients with more severe
tps s
tps :
hhtttp hhtttp
disease (reporting bias).
An assessor systematically
underestimates range of motion
using a goniometer.
Selection Patients treated nonsurgically fail to
attend follow-up appointments
k eers
rs when rerupture occurs.
k eers
r s
b ooook Confounding
oook
Competitive sports participation
o
increases the chances of surgical
b b o oo
o
/
e e
/ eb of rerupture.
ee e
/ b
treatment and increases the chances
/ e Figure 3
ee/ e
/ e b
An example of a causal inference diagram show-
: // t/.tm
. m : / / t
/ .
t m
. m
ing the relationship of a confounding factor to
an exposure treatment and outcome of interest.
ss : / ss : /
hhtttp
tp hhtttp
tp
Selection bias can be limited by facility-based con-
trol selection, in which the control group is drawn from In this case, the association between corticosteroid
the same patient population as the study group, thereby treatment and the treatment choice and the potential
increasing the likelihood that potential confounding for corticosteroids to impact healing and complication
variables are similar in the two groups. Every effort rates makes corticosteroid use a potential confounder
rrss rrss
should be made to prevent loss to follow-up. of the relationship between the treatment technique
o ke
ke Information Bias
o k e
k e
and the outcome.
oo
An important goal of clinical epidemiology is to de-
e bboo o e b o o o
Information bias results from the inaccurate classifica-
b e b o o
scribe an unbiased association that an exposure (such
b
/
e / e / / e
tion of outcomes or flawed data collection resulting in
m ee
inaccurate results.11 Spurious conclusions resulting
m ee/ / e
as the injury, the medical treatment, or the surgical pro-
cedure) may have with an outcome of interest. This re-
: / /
/ t
/ .
t . m
from measurement bias can be avoided by designing
: / /
/t/.t .m
lationship may be considered causal under certain strict
s :
specific and reproducible information systems for data
s s :
conditions, with the most stringent being appropriate
s
hhtttp
tp hhtttp
tp
collection. Training of the study staff will increase the temporal ordering.13 To satisfy these conditions, inves-
reproducibility of the data collected, and blinding of tigators attempt to minimize selection and information
the assessor and the subject will improve the objectivity bias through rigorous study design. Randomization, re-
of measurements.12 For example, a research coordina- striction of enrollment, and matching are three meth-
tor may believe that surgery provides better recovery of ods that allow the control of confounding variables in
clinical trials.11
k eers
rs
ankle plantar flexion strength after Achilles tendon
k e
rupture. This belief may result in increased encourage- r
e s
r s The process of randomization, given a large sample,
results in the equal allocation of known and unknown
bboooo k b o o
o k
ment for surgically treated participants during postop-
o
erative strength testing if the participant’s group assign-
b o oo
confounding factors to different treatment groups. As
o
/
e e
/ e ee/ e
/ e
ment is known. With blinding, the predetermined b e e
/ e b
the incidence of a confounding factor decreases, there is
/
a risk of unequal distribution of participants with the
e
/ / t t m
beliefs of the outcome assessor cannot influence the
. . m
collection of outcome data. Blinding of assessors of
: / : / / t
/ .
t m
. m
confounding variable to treatment groups; therefore,
ss : /
outcomes should be achieved wherever possible in clin-
t p p t p ss : /
stratification becomes necessary. Stratification involves
the separate randomization of participants with and
p
Confounding Bias
t
hht t
ical research studies to limit information bias.
t
hht t
without a given confounding factor to ensure equal
distribution of that factor among treatment groups
(Figure 4). Restriction involves the elimination of the
Confounding bias occurs when a noncausal relation- effect of a confounding factor by limiting the partici-
ship is seen between the exposure and the outcome as a pants to those with a single state of the confounding
k eers
rs of variables.13 A confounding variable is associated
k eers
result of mixing associations with a third variable or set
r s variable. For example, in a study of wound complica-
tions after the surgical treatment of Achilles tendon
b ooook b oook
with both the risk factor and the outcome under study
o
(Figure 3). For example, a study shows an association
b ooo
ruptures, including only those patients currently taking
o
corticosteroids would eliminate the use of corticoster-
/
e e
/ eb ee/ e
/e b
between the percutaneous treatment of Achilles tendon
/e/e b
oids as a confounding factor.
ee
/ t
///t m
ruptures and wound complications. Most of the pa-
. . m
tients treated percutaneously are taking corticosteroids.
: / t.
///t m
Matching is another means of neutralizing con-
.m
founding factors. This method involves selecting con-
:
s
tps : s
tps :
160
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
Figure 4 Illustration of the types of randomization possible in randomized controlled trials.
keerrss k e rrss
e
bboooo k
Table 2
b o o
o o k b o oo
o
/
e e
/ e / e e b
Comparison of Analysis Methods for the Post Hoc Control of Bias in Clinical Studies
ee / ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m Assesses Multiple
ss : /
Assesses Categorical
ss : /
Assesses Continuous Confounding Variables
hhtttp hhtttp
Method of Analysis Confounding Variables Confounding Variables Simultaneously
Stratified
Multiple regression
tp Yes
Yes
No
Yes
tp No
Yes
rs
rs
trol subjects based on similar characteristics. Matching
k ee k e r
e s
r s Observational Studies
bboooo k
can be based on one or several cofactors, such as be-
o o
o
tween treated and nontreated patients in a prospective
b o k b o oo
In observational studies, participants are not randomly
o
assigned to a treatment group. Participants are identi-
/
e e
/ e / e e b
study or between participants with a positive or a neg-
ee /
ative outcome in a retrospective, case-controlled study. / e e b
fied based on their exposure to a predetermined factor
ee /
and then followed forward in time to determine the re-
: / / t
/ .
t m
. m
Age, sex, and disease severity are often used as match-
: / / t
/ .
t m
. m
lationship between that factor and an outcome of inter-
ss : /
ing criteria. Confounding also can be addressed at the
t p p t p ss
p : /
est (cohort study). Participants also can be identified
t t
analysis phase of clinical research, as will be discussed
hht
later in this chapter (Table 2). t
hht t
based on an outcome, after which their exposure histo-
ries are ascertained to assess the associations of interest
(case-control study). There are several types of observa-
tional study designs, each balancing the need for data
Types of Studies and the risk of bias. In contrast, in randomized con-
trolled trials, participants with a given set of character-
k e rs
rs
In general, two main types of clinical studies are used
e k eers
r s istics are identified, and a treatment is randomly as-
b ooook b
and randomized controlled trials (Figure 5). Study ook
to investigate treatment effects: observational studies
oo b oooo
signed to each participant.14
/
e e
/ eb / e
/e b
types are also discussed in chapter 13, Levels of Evi-
ee ee/e/e b
Randomized Controlled Trials
Knowledge Update 11.

: / t
///t m
dence and Grades of Recommendation, Orthopaedic
. . m / t.
///t m
The randomized controlled trial is the current standard
.m
for determining causal relationships of a treatment ef-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e
Figure 5
ee/ e
/ e b e / e
/ e b
Illustration of study designs available to clinical investigators. Retrospective (usually case series and case-control
studies) and prospective (usually prospective cohort studies and randomized controlled trials) designs are con-
e
trials.
: / / t
/ .
t m
. m : / /t/.tm
trasted for clarity. Randomization is the main differentiating factor between cohort and randomized controlled
.m
ss : / ss : /
hhtttp
tp
fect in clinical medicine.15 In this study design, the inves-
tigator assigns each participant to a treatment group hhtttp
tp A recent randomized controlled trial of surgical ver-
sus nonsurgical management of Achilles tendon rup-
through a process of randomization, meaning that each tures used the outcome of rerupture as a primary end
participant has an equal chance of being assigned to all point.17 In this study, treatment variables were con-
trolled by using identical rehabilitation protocols for
k eers
rs
treatment arms.16 Concealment of randomization is a
e
core property of comparative trials because this process
k r
e s
r s the surgically and nonsurgically treated patients. Con-
bboooo k b o o
o k
limits the bias of the investigator and the treating med-
o
ical team with respect to the allocation of participants to
b o oo
cealed randomization resulted in the equal distribution
o
of known confounding factors; however, blinding of
/
e e
/ e / e e b
treatment groups. This process does not eliminate the
ee / / e e b
outcome assessors was not achieved because the treat-
ee /
ing surgeon assessed the primary outcome measure of
: / / t
/ t m
possibility of information bias if outcome assessors are
. . m
not properly blinded. Randomization is intended to
: / / t
/ .
t m
. m
rerupture. This may have resulted in bias in assessing
ss : /
equally distribute (at least probabilistically) all known
t p p t p ss
p : /
rerupture; the primary outcome measure would have
groups.13 t
hht t
and unknown confounding factors among treatment
Randomized controlled trials, despite their method-

t
hht
been better assessed by a blinded assessor. The study
t
authors also acknowledged that the sample size may
have been insufficient to detect a difference in out-
ological strengths, have several drawbacks. Performing comes between the two treatments.
a rigorous comparative study involves great costs and a
Economic Analysis and
k eers
rs
commitment of time. It is often difficult to enroll pa-
tients in studies comparing surgical and nonsurgical
k eers
r s Comparative Outcomes Research
b ooook b oook
treatments or in studies in which patients have precon-
o
ceived treatment preferences. Randomized controlled
b ooo
Opportunity cost is used in the economic analysis com-
o
paring healthcare services and treatments. Essentially,
/
e e
/ eb ee/ e
/e b
trials often include an overly homogeneous group of
/e/e b
economic analysis attempts to ensure that the program
ee
diverse patient groups.
: / t
///t m
patients, which makes it difficult to apply findings to
. . m / t.
///t m
under study is the best way to allocate finite healthcare
.m
dollars. This can be measured by analyzing cost, cost-
:
s
tps : s
tps :
162
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 3
rs keerrss
b ooookComparison of Economic Analysis Study Designs
b o ook
o b o oo
o
/
ee/e b Allows Comparison of
ee/ e
/
Two Treatments of the e b Requires Clinical
ee
Randomized e
/ e b
Can Be Paired With
/ Comparable Across
Type of Analysis
t .
Same Condition
: / ///t m
.m Outcome Measures
: / t . m
. m
Controlled Trials
///t
Healthcare Domains
Cost Yes
s
tps : No
s
tps : Yes Yes/No
Cost-effectiveness
Cost utility hhtttp
Yes
Yes
Yes
Yes hhtttp Yes
Yes
No
Yes
k e rs
effectiveness, and cost utility (Table 3). The perspective
rs
taken is one of the fundamental decisions in economic
e k eers
r s
Prospective cohort studies are similar to randomized
controlled trials in all but one important characteristic:
b ooook b ooook
analysis. Depending on the audience and the aims of the
study, the investigator usually determines if a patient, a
b oo
treatments are not randomly assigned. Safeguards
o o
against selection and information biases should be in-
/
e e
/ eb e/
e e
/ e b
hospital, a health system, or a societal perspective is
/ e
/ e b
stituted a priori, and information should be collected
ee
taken.
: // t/.tm
. m
Cost analysis involves comparing the total cost of
: / / t
/ t m
on all known and measurable confounding variables
. . m
for later stratification or statistical adjustment. Using
s : /
treatments and assumes that the efficacy of those treat-
s s : /
these methods, research questions that do not lend
s
hhtttp
tp hhtttp
tp
ments is equivalent. The units of comparison are typi- themselves to randomization because of ethical or other
cally currency. Only costs that are unique to one or the reasons can be investigated using a cohort study design.
other treatment are considered in this analysis because One drawback of a prospective cohort study is the need
common costs cancel each other. This type of analysis to wait for outcomes of interest to occur. This often
is useful for comparing two treatments of the same dis- takes a considerable amount of time, incurs substantial
ease; however, it has limited use when attempting to in- expense, and presents difficulties with participant attri-
keerrss
fluence policy regarding budget allocations between
k e rrss
e
tion.
bboooo k
two unique clinical problems.
o o
o
Cost-effectiveness studies incorporate clinical out-
b o k A 2009 study comparing techniques of Achilles ten-
o oo
o
don repair prospectively enrolled patients treated with
b
/
e e
/ e ee/ e
/
pressed as cost per natural outcome unit. The moree b
comes into the analysis. Units of measure tend to be ex-
ee/ e
/ e b
either an open or a mini-open surgical tendon repair.20
Patients were not randomly allocated to the two treat-
: / / t
/ .
t m
. m
general the measure of outcome, the more easily treat-
t . m.m
ment groups; however, they were recruited prospec-
: / / / t
ss /
ments can be compared across diseases and specialties.
: ss : /
tively based on reported inclusion and exclusion crite-
hhtttp hhtttp
Cost-utility analysis takes this concept one step fur- ria. The lack of randomization may have led to bias by
tp
ther and expresses the results in quality-adjusted life-
years, a clinical measure that can be applied across pro- tp
the treating surgeons based on some known or un-
known confounding factor, and such bias would cast
grams and diseases. The quality-adjusted life-year doubt on the validity of the study’s conclusions.
represents 1 year in perfect health; any impairment in
function or health status decreases the value of that Case-Control Studies
k eerss
year by a given fraction. For example, in one study,
r
1 year lived with hip arthritis would be valued at
k e r
e s
r s
Case-control studies are retrospective studies in which
the participants are chosen based on the presence or the
bboooo k o
0.49 quality-adjusted life-years based on responses by
b o
o o k b o oo
absence of an outcome of interest.21 In this sense, the
o
/
e e
/ e
patients older than 65 years to the EuroQol Five Di-
e / e
/ e b
mension (EQ-5D) questionnaire.18 Cost-benefit analysis
e e / e
/ e b
process of a case-control study, which identifies the
presence of the outcome before the determination of
e
/ / t
/ .
t m
expresses the benefits of a health program in currency
. m
units. This allows the direct comparison of costs and
: : / / t
/ .
t m
. m
factors affecting that outcome, is the reverse of a pro-
ss : /
benefits but presents the difficult task of fully valuing
t p p t p ss : /
spective study. This retrospective design allows the
study of rare outcomes or those with prolonged latency
p
t
hht t
the monetary benefits of programs.
Prospective Cohort Studies

t
hht t
periods that would not be feasible with other study de-
signs. In this research process, cases are first identified
retrospectively based on an outcome, and predeter-
In a prospective cohort study, several groups are identi- mined characteristics (for matching) of interest are in-
fied based on differences in an exposure of interest. The cluded. A strict a priori definition of the methods of as-
k eers
exposure can be a specific injury, a particular proce-
rs
dure, or a patient characteristic. The presence of a
k eers
r s certainment of the outcome and the exposure is
imperative. Control groups are composed of partici-
b ooook b oook
group with the exposure of interest and a control group
o
is the main prerequisite for a prospective cohort study
b ooo
pants with similar characteristics who lack the outcome
o
of interest. The composition of the control group often
/
e e
/ eb ee/ e
/e b
and differentiates this study design from the case series.
/e/e b
involves a compromise between rigor and feasibility be-
ee
/ t
///t m
Follow-up is carried out on the identified cohort of par-
. . m
ticipants to look for outcomes of interest.19
: / t.
///t m
cause matching multiple characteristics will limit the
.m
number of eligible participants in the control group.
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
One limitation of case-control studies is the ability to tant difference, which is defined as the difference, from
k eers
rs ke r
study only one outcome of interest. There is a risk of
e rss a patient’s perspective, that would result in a noticeable
b ooook o ook
bias in the data collected because of poor recall during
o
patient interviews (a form of information bias) and an
b
change of outcomes for the target population. The min-
b o oo
o
imally clinically important difference is a value estab-
/
ee/e b / e e b
unequal allocation of certain factors to one of the
ee /
groups (confounding bias). These limitations make it
ee/ e
/ e b
lished by clinicians based on their own experience in
measuring outcomes in the condition of interest. The
t . m
.m
difficult to draw causal relationships between expo-
: / ///t : / t
///t. m
. m
outcome measure must be validated for patients similar
to the study’s sample to ensure that the outcome con-
s
tps :
sures and outcomes using case-control studies; how-
s
tps :
hhtttp hhtttp
ever, this study design allows exploration of relation- struct measures the aspect of the outcome that the in-
ships between variables with maximal statistical vestigators intended to measure.26
efficiency, making the study of rare outcomes feasible. The simplest outcomes to conceptualize are proba-
A 2012 case-control study looked at the occurrence bly dichotomous outcomes, situations in which the out-
of pulmonary emboli and deep vein thromboses after come of interest is either present or absent. Examples
Achilles tendon rupture to identify risk factors for these are union, reoperation, infection, and survival. Many
k eers
rs k eers
r
rare adverse events.22 A database of 1,172 patients who
s of these seemingly objective outcomes involve some
judgment in the diagnosis; this introduces the risk of
ook ook
had been treated for Achilles tendon rupture allowed a
b oo b o
more precise estimation of the rate of deep vein throm-
o b o oo
bias into the study. For that reason, it is desirable to as-
o
/
e e
/ eb ee e
/ e b
bosis and pulmonary embolism after injury with mini-
/
mal data collection. In this study, only nine patients
e / e
/ e b
semble an adjudication committee that is blinded to
treatment allocation (if possible) to democratically de-
e
t . m
. m
had the outcome of interest, which suggests that a pro-
: // / t / / t
/
complication.
: .
t m
termine the presence or the absence of an outcome or a
. m
ss /
spective study to assess the association between rupture
: ss : /
Patient-centered outcome measures involve deter-
hhtttp hhtttp
and thromboembolic complications would not be feasi-
ble.
tp tp
mining function and the health-related quality of life.27
Many of the current measurement instruments are self-
or interview-administered questionnaires that have
Case Series been rigorously validated for use in patients similar to
The case series reports on the outcomes of a group of the study population. Traditional health-related
patients with similar traits who receive the same treat-
rrss rrss
quality-of-life measures were surgeon administered,
ment.23 Because these descriptive and often retrospec-
o ke
ke k
tive studies lack a control or comparison group, only
o e
k e
such as the Constant score for measuring shoulder
oo
function or the Harris hip score. Allowing the treating
e bboo o e b o
b o
specific inferences can be drawn from the results. Case
o
series can be affected by selection bias because the cri-
e b o o
surgeon to assess outcome introduces bias. Current
b
/
e / e ee/ / e
teria for choosing cases often are not explicitly stated.
m ee/ / e
outcome instrument administration is standardized to
decrease bias by facilitating the blinding of the assessor.
m
: / / t
/ .
t . m
Measurement bias is an important concern because the
/
outcome measurement is rarely blinded in case series, /t . .m
Both generic and joint disease–specific instruments
: / / / t
ss : s :
are available. Generic instruments, such as the Medical
s
hhtttp hhtttp
leading to potentially flawed outcome assessments. De-
tp tp
Outcomes Study 36-Item Short Form and the EQ-5D,
spite these drawbacks, case series serve a purpose in the measure the overall health status of the participant and
initial trial of a new implant or technique and may help provide an estimate of the patient’s functional level in
identify safety concerns before widespread implementa- society.28,29 Each instrument has been validated in vari-
tion. The results can be used to provide an estimate of ous age groups and disease states, allowing compari-
sample size for a future randomized controlled trial. sons across procedures and specialties. Joint disease–
k eers
rs The case series can report on the natural history of a
k e
disease by reporting on disease progression in patients r
e s
r sspecific measures include the Western Ontario
McMaster Universities Osteoarthritis Index for the hip
bboooo k with a specific diagnosis.

b o o
o o k b o oo
and the knee; the Disabilities of the Arm, Shoulder and
o
/
e e
/ e e e
/ e b
A 2010 case series reported the results of a group of
/
nonsurgically treated patients with Achilles tendon rup-
e e e
/ e b
Hand questionnaire for the upper extremity; and the
/
Oswestry Low Back Pain Disability Questionnaire. All
e
: / / / .
t m m
ture who were managed with a functional rehabilita-
t .
tion protocol.24 Functional recovery, clinical outcome,
: / / t
/ .
t m
. m
of these instruments incorporate questions that address
t p ss : /
and complications were reported by the study authors;
p t p ss : /
limitations imposed by specific joint dysfunctions. Al-
though these instruments are less generalizable to con-
p
t
hht t
however, it is difficult to state the superiority of this
method or compare the results with those of another
similar study by other authors because these investiga-
t
hht t
ditions outside the anatomic focus of the questionnaire,
these measures are generally more sensitive to changes
in function than generic outcome measures and may
tors did not evaluate a comparison treatment.25 not be subject to the ceiling effect noted with many ge-
neric outcome instruments.
k eers
rs Outcome Measures
k eers
r s The time horizon over which measurements are
taken is one consideration in outcome measurements.
b ooook b oook
o
Detecting treatment effects starts with selecting relevant
b ooo
Clinically, surgeons can intuitively decide on the rele-
o
vant time horizon for an outcome measurement based
/
e e
/ eb ee/ e
/e b
and precise outcome measures. Treatment effects are
/e/e b
on the recovery time expected for a procedure and the
ee
/ t
///t m
generally quantified statistically; however, clinicians
. . m
should be aware of the concept of a clinically impor-
: / t.
///t m
expected durability of the results. For example, measur-
.m
ing health-related quality-of-life changes after anterior
:
s
tps : s
tps :
164
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 4
rs keerrss
b ooookTypes of Data and Common Statistical Tests
b o ook
o b o oo
o
/
ee/e b Dependent Variable
ee/ e
/ e b ee e
/ e b
Independent Variable
/
Categorical
: / t
///t. m
.m
Two Groups
: / t
///t
Chi-square test, Fisher exact test . m
. m
Multiple Groups (>3)
Chi-square
s
tps : s
tps :
hhtttp hhtttp
Numerical Mann-Whitney U test, Wilcoxon signed Kruskal-Wallis test
rank test
Continuous Student’s t test Analysis of variance
k eerss k eer
cruciate ligament reconstruction at only 3 month post-
r s
r
operatively would not be sensible because the rehabili- s the separation between values is equal (for example,
four injections is twice as many as two injections,
b ooook b oook
tation period is often from 6 to 9 months. Similarly, re-
o b o oo
whereas stage IV cartilage lesions are not necessarily
o
/
e e
/ eb e/ e
/ e b
porting primary total hip arthroplasty survival data at
5 years does not reflect the expected 15-year survival of
e e / e
/ e b
twice as bad as stage II lesions).
Continuous data are obtained through measurement
e
: // t/.tm
modern implants. Longer time horizons, however, lead
. m
to increasing challenges in patient follow-up and repre-
: / / t
/ .
t m
and can take on any measurable value based on the
. m
precision of the measuring device. Data with consistent
ss : /
sent another instance of balancing the integrity of re-
ss : /
hhtttp hhtttp
intervals that demonstrate a normal distribution are
tp
sults with trial feasibility.
tpconsidered normally distributed. Joint range of motion
measurements determined with a goniometer are exam-
ples of continuous data. Parametric data that approxi-
Analyzing Study Results mate a normal distribution with interval consistency
can be illustrated by Medical Outcomes Study 36-Item
rrss rrss
After completing follow-up on all participants or the Short Form scores of physical function. Nonnormally
o ke
ke o k
able. Data can take many forms, including categorical e
review of the last chart, a large amount of data is avail-
k e distributed numerical data such as time measurements
oo
e bboo o e b o
and numerical data. Each type of data and research
b o o require special consideration and statistical procedures
e b o
b o
that do not depend on the assumption of normally dis-
/
e / e m ee/ / e
methodology requires appropriate statistical interroga-
tion to draw the most accurate conclusions possible30 U test).
m e / / e
tributed data (Wilcoxon rank-sum test, Mann-Whitney
e
(Table 4).
: / /
/ t
/ .
t . m : / /
/t/.t .m
ss : ss :
Estimation and Hypothesis Testing
hhtttp
tp hhtttp
tp
Categorical Data Statistical analysis of study data allows the inferences
Measurements containing two or more categories are from a sample of subjects to be applied to a population
called categorical data. This concept can be conceptual- of similar patients. To make such inferences, investiga-
ized as buckets into which observations fit, such as tors and readers of scientific literature rely on estima-
dead or alive; male or female; and mild, moderate, and tion and hypothesis testing. With all statistical ap-
k e s
severe disease. The simplest form of categorical data is
rrs
binary data that has only two observed states, such as
e k e r
e s
r s proaches, study subjects become proxies for the target
population. To provide an estimate of effect, these ap-
bboooo k
survival data (dead or alive).
b o o
o o
Categorical data with more than two categories may k b o oo
proaches attempt to show differences or associations
o
/
e e
/ e ee/ e
/ e b
be ordinal or nominal. Ordinal data have an obvious
e / e
/ e b
among variables of interest.
The process of estimation focuses on presenting the
e
/ / t .
t m
order and are exemplified by disease severity descrip-
. m
tors such as mild, moderate, and severe. Nominal data
: / / / t
/ t m
magnitude of an effect and the precision of that esti-
. . m
mate (the sample mean and confidence interval [CI], re-
:
t p ss
p : /
do not have an obvious order. An example of nominal
ss : /
spectively). Results are presented as a mean difference,
t p p
t
hht t
data is the location of a fracture (proximal, midshaft,
or distal) because these categories do not lend them-
selves to a natural order.
t
hht t
a relative risk, or an odds ratio with a CI. A CI is a
range of values that contain the target population mean
with a given certainty (for example, the estimated
quantity of interest will be contained within the inter-
Numerical Data val 95 of 100 times for a 95% CI). The width of the CI
k e rs
Numerical data can be classified as either discrete or
rs
continuous, with the main distinction between the two
e k eers
r s
will be determined by standard error, which is an esti-
mate of the population standard deviation derived from
b ooook b ook
forms being the restriction of values in discrete data.
oo
An example of discrete data in orthopaedic surgery tri-
b oooo
variability in the sample mean estimates.
Hypothesis testing (significance testing) is based on
/
e e
/ eb / e
/e b
als is counting events, such as readmissions to a hospi-
ee ee/e/e b
the concept of testing the null hypothesis that the effect
/ t
///t m
tal or the number of intra-articular steroid injections.
. . m
The important characteristic of this type of data is that
: / t.
///t m
is zero against the alternative hypothesis that the effect
.m
is not zero. The ensuing analysis evaluates the probabil-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
ity (P value) that the data obtained could have occurred able, this method is much more statistically efficient
k eers
rs ke rrs
by chance. Smaller P values indicate a smaller probabil-
e s than stratified analyses. A 2012 study investigating the
b ooook b o ook
ity that the observed results could have occurred by
o
chance. Although the P value provides a test of the
b oo
association of Achilles tendon rupture with pulmonary
o o
embolism and deep vein thrombosis used logistic re-
/
ee/e b / e e b
plausibility of the null and alternative hypotheses, it
ee /
does not indicate the magnitude of the effect. The test / e e b
gression to estimate the effect of various factors on the
ee /
occurrence of thromboembolic events.22 The indepen-
t . m
.m
statistic provides only a probability that the observed
: / ///t t
///t. m
. m
dent variables in the model were chosen by first per-
: /
tps :
value, or one even farther from the null hypothesis,
s s :
forming bivariable analyses of associations with the
tps
hhtttp hhtttp
could occur by chance. outcome. The independent variables with sufficiently
The precision of estimates and the cutpoints chosen strong associations were used to build the multivariable
for hypothesis testing are intended to limit the chance model. One measure of a regression model’s explana-
of error in terms of extrapolating study results to a tion of the variability in the observed data (a surrogate
population of interest. Two main types of error are en- of robustness of the model) is expressed by the coeffi-
countered in data analysis: type I (alpha) and type II cient of determination (R2) value. Other diagnostic pro-
k eers
rs rs
r s
(beta) errors. Type I errors are finding an effect where,
k ee
cedures for assessing model goodness-of-fit are avail-
ook ook
in fact, no effect exists (a false-positive result). To limit
b oo b o
the chance of a type I error, a 95% CI or a P value of
o b o oo
able and important for determining confidence in the
o
estimates provided by a multivariable regression model.
/
e e
/ eb ee e
/ b
0.05 are customarily selected, these values allow a 5%
/ e
chance of a type I error. Type II errors, which are com-
ee/ e
/ e b
An explanation of these procedures is beyond the scope
of this chapter. Consultation with a statistician is rec-
: // t/.tm
. m
mon in orthopaedic trials, involve finding no difference
: / / t
/ .
t m
. m
ommended when using multiple variable regression
ss /
where a difference exists (a false-negative result).31 In
: s : /
analysis.
s
hhtttp hhtttp
study design, a 10% to 20% chance of a type II error is
generally accepted.
tp
Power is defined as the probability that the study re- tpSummary
sults will reject the null hypothesis if the null hypothe-
sis is actually false. Power is related to the sample size Searching and evaluating the current literature is an es-
of the study. When a lack of association or effect is re- sential part of evidence-based orthopaedic care. If no
keerrss ported, the reader should consider whether too few pa-
k e
tients were enrolled to detect the effect or associationrrss
e
relevant evidence exists, it is important for investigators
bboooo k of interest.
b o o
o o k b o oo
to develop clinical research studies to provide valid in-
o
ferences regarding associations and causal relationships
/
e e
/ e Statistical Approaches for Reducing
ee/ e
/ e b ee/ e
/ e b
that will guide decision making. Increasing the method-
Confounding Bias
: / / t
/ .
t m
. m : / /t/ tm
ologic quality will decrease bias at all levels of the hier-
. .m
archy of evidence. Properly conducted statistical analy-
ss /
Confounding bias can result when extraneous factors
: s : /
ses clearly describe data and relationships and
s
hhtttp hhtttp
influence the observed effect of an exposure on an out-
tp
come of interest. Although rational study design can
limit the effects of confounding, it is sometimes neces- tp
ultimately allow conclusions to be drawn that pertain
to the target population from which the study sample
originated. Clinical study design and implementation is
sary to apply post hoc control for confounding vari-
ables. Subgroup analysis involves performing separate a complex process that requires a nuanced knowledge
data analyses of groups within the larger study sample. of the clinical dilemma along with the principles of ep-
k eers
rs k e
rerupture of the Achilles tendon after surgical or non- r
For example, if an investigator believes that the risk of
e s
r s
idemiology and biostatistics. To achieve work of the
highest possible quality, investigators should enlist the
bboooo k b o o o k
surgical treatment is influenced by sex, separate analy-
o edge exist.
b o oo
collaboration of experts in areas where gaps in knowl-
o
/
e e
/ e e / / e b
ses of rerupture rates for males and females would be
e
appropriate. If the mean differences in rerupture rates
e ee/ e
/ e b
: / / / .
t m m
in the male and female groups are found to be different,
t .
then statistical interaction is present, and a single, sum-
: / / t
/ .
t m
. m
t p ss : /
mary estimate of effect may not be appropriate. With
p t p ss
p : /
Key Study Points
t
hht t
an increasing number of confounding variables, data in
each stratum become sparse and limit the use of this
type of analysis.
t
hht•
t Research methodology attempts to limit bias, a
systematic deviation from the truth.
Multiple variable regression analysis provides an- • The basis of a good comparative research ques-
other method of controlling confounding factors in re- tion includes a well-defined study population, an
intervention, a comparison group, and a vali-
k eers
rs
search studies. Regression analysis produces a linear
e
model of data that quantifies the effect of a unit in-
k ers
r s dated outcome measure.
b ooook b oook
crease of each included independent variable on the de-
o
pendent variable or the outcome of interest. Both con-
•
b oooo
Outcome measures should be selected carefully
to ensure that they measure the effects of treat-
/
e e
/ eb ee/ e
/e b
tinuous and categorical independent variables can be
/e/e b
ment that interest the investigator and matter to
ee
/ t
///t. m
included in regression models, and, although some pre-
. m
cision of effect estimates is lost with each included vari-
: : / t.
///t m
patients.
.m
s
tps : s
tps :
166
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
12. Poolman RW, Struijs PA, Krips R, et al: Reporting of
k eerss
r keerrss outcomes in orthopaedic randomized trials: Does blind-
ook ook
ing of outcome assessors matter? J Bone Joint Surg Am
b oo
1.
b o
Chiodo CP, Glazebrook M, Bluman EM, et al: Diagno-
o o oo
2007;89(3):550-558.
b o
/
ee/e b e
Acad Orthop Surg 2010;18(8):503-510.
e/ / e b
sis and treatment of acute Achilles tendon rupture. J Am
e 13.
ee/ e
/ e b
Jewell NP: Statistics for Epidemiology: Texts in Statisti-
/ ///t. m
.m
A narrative review of the current treatment options for
t
Achilles tendon rupture. Level of evidence: V.
: : / t
///t. m
. m
cal Science Series. Boca Raton, FL, Chapman & Hall/
CRC, 2004, vol 58.
s
tps : s
tps :
hhtttp hhtttp
2. Freedman B: Equipoise and the ethics of clinical re- 14. Katz JN, Wright JG, Losina E: Clinical trials in ortho-
search. N Engl J Med 1987;317(3):141-145. paedics research: Part II. Prioritization for randomized
controlled clinical trials. J Bone Joint Surg Am 2011;
3. WMA Declaration of Helsinki: Ethical Principles for 93(7):e30.
Medical Research Involving Human Subjects. 2008.
The authors review the process of taking a clinical ques-
World Medical Association website. http://
k eers
rswww.wma.net/en/30publications/10policies/b3.
k e rs
r
Ac-
e s tion from creation to answer and focus on the creation

of randomized controlled trials in orthopaedic surgery.
ook ook
cessed September 3, 2012.
b oo b oo b o oo
Subjects requiring comparative trials are explored for
o
orthopaedic subspecialties.
/
e e
/ eb 4.
e e
/ e b
Goldhahn S, Sawaguchi T, Audigé L, et al: Complica-
/
tion reporting in orthopaedic trials: A systematic review
e ee/ e
/ e b
2009;91(8):1847-1853.
: // t/.tm
. m
of randomized controlled trials. J Bone Joint Surg Am 15.
: / / t t m
Bederman SS, Chundamala J, Wright JG: Randomized
. . m
clinical trials in orthopaedic surgery: Strategies to im-
/
ss : / ss : /
prove quantity and quality. J Am Acad Orthop Surg
hhtttp
tp hhtttp
tp
5. Egger M, Smith GD, Altman DG: Systematic Reviews in 2010;18(8):454-463.
Health Care: Meta-Analysis in Context, ed 2. London, This article summarizes the challenges faced by ortho-
England, BMJ, 2001. paedic surgeons attempting to plan and execute ran-
domized controlled trials. Rather than focusing only on
6. Bhandari M, Joensson A: Clinical Research for Sur- the specific elements of methodology, the authors cata-
geons. New York, NY, Thieme, 2009. log cultural, educational, and attitudinal reasons for the
keerrss k e rrss
e
paucity of level I evidence to guide orthopaedic sur-
geons.
bboooo k
7.
b o o o k
Khan RJ, Carey Smith RL: Surgical interventions for
treating acute Achilles tendon ruptures. Cochrane Data-
o b o oo
o
/
e e
/ e
base Syst Rev 2010;9:CD003674.
ee/ e
/ e b
In the latest update in the Cochrane library on the treat-
16.
e e
/ e b
Boutron I, Ravaud P, Nizard R: The design and assess-
/
ment of prospective randomised, controlled trials in or-
e
t . m
. m
ment of acute Achilles tendon rupture treatment, the au-
: / / / t : / /t/.t
858-863.m.m
thopaedic surgery. J Bone Joint Surg Br 2007;89(7):
ss /
thors conclude that the rerupture rate is lower in surgi-
: ss : /
hhtttp hhtttp
cally repaired Achilles tendons with a corresponding
tp
increase in the rate of wound complications. Level of ev-
idence: I. tp
17. Willits K, Amendola A, Bryant D, et al: Operative ver-
sus nonoperative treatment of acute Achilles tendon
ruptures: A multicenter randomized trial using acceler-
8. Gillespie LD, Gillespie WJ: Finding current evidence: ated functional rehabilitation. J Bone Joint Surg Am
Search strategies and common databases. Clin Orthop 2010;92(17):2767-2775.
k eers
r
Relat Res 2003;413:133-145.
s k e r
e s
r s
A recent randomized controlled trial compared surgical
and nonsurgical treatment of Achilles tendon rupture.
bboooo k
9.
o o
o k
National Institute for Health Research: PROSPERO: In-
o
ternational Prospective Register of Systematic Reviews.
b b o oo
The main outcome measure was rerupture rate as deter-
o
mined by the treating surgeon. Randomization method-
/
e e
/ e ee/ e
/ b
York, England, PROSPERO, 2012. http://www.crd
e
.york.ac.uk/Prospero. Accessed December 22, 2012.
ee/ e
/ e b
ology, stratification, and blinding of assessors are all de-
tailed in the methods section. Level of evidence: II.
t . m
. m
Website of the PROSPERO register of systematic re-
: / / / t : / / t
/ .
t m
. m
t p ss /
views. This project attempts to catalogue all systematic
:
reviews and standardize the way in which they are pro-
p
18.
t p ss
p : /
Lawless BM, Greene M, Slover J, Kwon Y-M, Malchau
H: Does age or bilateral disease influence the value of
10.
duced.
t
hht t
Liberati A, Altman DG, Tetzlaff J, et al: The PRISMA
t
hht t hip arthroplasty? Clin Orthop Relat Res 2012;470(4):
1073-1078.
This article discusses the value of a total hip arthro-
statement for reporting systematic reviews and meta-
plasty. A decision analysis was used to allow the calcu-
analyses of studies that evaluate healthcare interven-
lation of cost-effectiveness of the procedure. By deter-
k eers
rs
tions: Explanation and elaboration. BMJ 2009;339:
b2700.
k eers
r s mining a cost per quality-adjusted life-year, this
procedure can be compared to other, nonmusculoskele-
b ooook
11.
b oook
o
Szklo M, Nieto FJ: Epidemiology: Beyond the Basics,
b ooo
tal medical interventions. Level of evidence: IV.
o
/
e e
/ eb / ee b
ed 2. Sudbury, MA, Jones and Bartlett Publishers, 2007.
ee / 19.
e /e/e b
Bryant DM, Willits K, Hanson BP: Principles of design-
e
: / t
///t. m
. m : / t.
///t m
ing a cohort study in orthopaedics. J Bone Joint Surg
.m
Am 2009;91(suppl 3):10-14.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
20. Bhattacharyya M, Gerber B: Mini-invasive surgical re- 26. Poolman RW, Swiontkowski MF, Fairbank JC,
k eers
rs pair of the Achilles tendon—does it reduce post-
keerrss Schemitsch EH, Sprague S, de Vet HC: Outcome instru-
ook ook
operative morbidity? Int Orthop 2009;33(1):151-156. ments: Rationale for their use. J Bone Joint Surg Am
b oo b o o b o oo
2009;91(suppl 3):41-49.
o
/
ee/e b 21.
e e
/ e b
Busse JW, Obremskey WT: Principles of designing an
/
orthopaedic case-control study. J Bone Joint Surg Am
e 27.
ee/ e
/ e b
Shearer D, Morshed S: Common generic measures of
2009;91(suppl 3):15-20.
: / t
///t. m
.m : / t . m
. m
health related quality of life in injured patients. Injury
///t
2011;42(3):241-247.
s
tps : s
tps :
hhtttp hhtttp
22. Patel A, Ogawa B, Charlton T, Thordarson D: Inci- The authors describe and detail the appropriate applica-
dence of deep vein thrombosis and pulmonary embo-
tion of validated clinical outcome measures for injured
lism after Achilles tendon rupture. Clin Orthop Relat
patients.
Res 2012;470(1):270-274.
An example of a large, retrospective analysis of a cohort 28. Ware JE Jr, Sherbourne CD: The MOS 36-item short-
identified by using an administrative database. The au- form health survey (SF-36): I. Conceptual framework
k eers
rs e rs
thors employ regression models to identify factors asso-
r s
ciated with thromboembolic events in Achilles tendon
k e
and item selection. Med Care 1992;30(6):473-483.
b ooook repairs. Level of evidence: III.
b ooook 29.
o oo
EuroQol—a new facility for the measurement of health-
b o
/
e e
/ eb 23.
/ e e b
Kooistra B, Dijkman B, Einhorn TA, Bhandari M: How
ee /
to design a good case series. J Bone Joint Surg Am
e e
/ e b
related quality of life: The EuroQol Group. Health Pol-
/
icy 1990;16(3):199-208.
e
2009;91(suppl 3):21-26.
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / 30.
ss : /
Dowrick AS, Tornetta P III, Obremskey WT, Dirschl
hhtttp hhtttp
24. Karkhanis S, Mumtaz H, Kurdy N: Functional manage- DR, Bhandari M: Practical research methods for ortho-
tp
ment of Achilles tendon rupture: A viable option for
non-operative management. Foot Ankle Surg 2010;
16(2):81-86.
tp paedic surgeons. Instr Course Lect 2012;61:581-586.
This review article provides a brief review of research
methods and related topics.
An example from the Achilles tendon literature of a
large case series. Level of evidence: IV. 31. Lochner HV, Bhandari M, Tornetta P III: Type-II error
keerrss 25. Majewski M, Schaeren S, Kohlhaas U, Ochsner PE:

k e rrss
e
rates (beta errors) of randomized trials in orthopaedic
trauma. J Bone Joint Surg Am 2001;83(11):1650-1655.
bboooo k b o o
o k
Postoperative rehabilitation after percutaneous Achilles
o
tendon repair: Early functional therapy versus cast im-
b o oo
o
/
e e
/ e / e e b
mobilization. Disabil Rehabil 2008;30(20-22):1726-
1732.
ee / ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
168
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 15
e rs
rs e rrss
oo
kCare
ook e of the Geriatric o k
ook
o Patient
e o oo
o
/e/ebb Eric Meinberg, MD
e / e
/ b
e b
Simon C. Mears, MD, PhD
e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
than 65 years who report fair or poor health, and in-
Introduction creasing numbers of patients have heart disease, hyper-
k eerss
The aging of the baby boomer generation (individuals
r
born between 1946 and 1965) means that the older
k eers
r s
tension, and/or diabetes; have survived cancer; or are
obese.2 Arthritis is the most common chronic health
b ooook o ook
segment of the population is the fastest growing. This
b o
condition, reported by 50%.1
b o oo
o
Although many older patients have chronic health
/
e e
/ eb e/ e
/ e b
situation presents the orthopaedic surgeon with many
challenges, including caring for frail patients and those
e ee/ e
/ e b
problems, there is also a substantial proportion of this
: // /.tm m
with many medical comorbidities as well as taking care
t .
of patients with osteoporotic bones, which make repair
: / / t
/ .
t m
population that remains very active. Forty percent of
. m
individuals older than 65 years report their health as
ss : / s : /
very good or excellent; 35% of persons age 65 to 74
s
hhtttp hhtttp
more difficult. A knowledge of basic geriatric principles
tp
is important to any orthopaedic surgeon caring for ag-
ing patients. tp
years and 24% older than 74 years report regular phys-
ical activity. Many continue to participate in high-
demand activities, such as alpine skiing, cycling, swim-
ming, and mountain climbing,3 and there is an
increasing recognition of sports injuries in the aging
Demographics population.4,5
keerrss
Because of the aging of the baby boomers, coupled
k e rrss
e
bboooo k b o o
o o
with the increased life expectancy of American adults,
k Preoperative Evaluation
b o oo
o
/
e e
/ e e / / e b
an ever-increasing number of geriatric patients will re-
e
quire management of elective and emergent orthopae-
e ee/ e
/ e b
Before orthopaedic surgery is performed, older patients
/ / t
/ .
t m
dic conditions. By 2030, all baby boomers will be at
. m
least 65 years old and will fall into the geriatric age
: t . m.m
should undergo a thorough medical evaluation to min-
: / / / t
ss : /
group. This segment of the population can be expected
ss : /
imize perioperative risk. The preoperative evaluation
hhtttp
tp hhtttp
tp
before orthopaedic surgery is individualized and de-
to increase by 31%, more than double the rate of pends on the surgical team’s routine practice, hospital
younger age groups.1 Because of better health manage- policies, medical risk factors, and the urgency of the
ment and decreased smoking, a woman age 65 years in procedure. A more thorough evaluation is warranted in
2009 can expect to live an additional 20 years. This de- patients with multiple comorbid conditions and when
mographic shift continues in that the number of people the procedure is elective, whereas a targeted evaluation
k ee s
living beyond 100 years has increased 53% in the past
rrs
20 years and is expected to grow (Figure 1).
k e r
e s
r sand intervention is needed to appropriately mitigate
risk in urgent and emergent procedures.
bboooo k b o o
o o k
However, despite an increase in life expectancy, there
is a significant increase in the number of comorbidities
b o oo
The goal of the preoperative evaluation is simple:
o
/
e e
/ e e / e
/ e b
that can negatively affect an individual’s health and sur-
e e e
/ e b
identify abnormalities that can be corrected to reduce
/
the risks of surgery and shorten the subsequent recov-
e
: / / t
/ t m
gical outcomes. There are 24.4% of Americans older
. . m : / / t
/ .
t m
. m
ery period. The cornerstone of this evaluation is a thor-
t p ss
p : / t p ss : /
ough history and physical evaluation and a review of
the patient’s medications. After key areas of concern
p
t
hht t
Dr. Meinberg or an immediate family member is a mem-
ber of a speakers’ bureau or has made paid presenta-
tions on behalf of Synthes and Medtronic; serves as a
t
hht t
are identified, targeted testing can be done to evaluate
and improve modifiable conditions that the patient
may have. A good preoperative evaluation should in-
paid consultant to or is an employee of Amgen, clude recommendations to manage the patient’s medi-
Medtronic, and Synthes; and serves as a board member, cal conditions and pain after the procedure. The rou-
k eerss
owner, officer, or committee member of the Northern
r k e
California Chapter of the Western Orthopaedic Associa-
ers
r s tine ordering of laboratory tests and diagnostic studies,
such as an electrocardiogram (ECG), without indica-
b ooook b ook
tion. Neither Dr. Mears nor any immediate family mem-
oo b oooo
tion is of little diagnostic value and is not recom-
mended because of its low yield.6 Additionally, spurious
/
e e
/ eb e / e
/e b
ber has received anything of value from or has stock or
stock options held in a commercial company or institu-
e ee/e/e b
positive results can lead to further testing and diagnos-
chapter.
: / t
///t m
tion related directly or indirectly to the subject of this
. . m : / t.
///t m
tic dilemmas that may not benefit the patient or alter
.m
the course of care. Although abnormal test results in el-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
Figure 1
/ / t
/ .
t m
. m
The aging population based on US census results.
: : / /t/.tm.m
s : / s : /
(http://www.agingstats.gov/Main_Site/Data/2012_Documents/Population.aspx)
s s
hhtttp
tp
derly patients are often found, they do not correlate
with the risk of complications. However, simpler mea-
hhtttp
tp
14 that were abnormal and for which management was
changed.11 It is unclear whether routine chest radio-
sures, such as the patient’s American Society of Anes- graphs are beneficial, but they should be obtained in
thesiologists physical status classification, risk of the patients with a history of cardiopulmonary disease.
k eers
rs k e
procedure, and congestive heart failure, are predictive
r
e s
r s
bboooo k of postoperative complications.7,8
b o o
o o k b o oo
o
Diseases Requiring Special Consideration
/
e e
/ e Electrocardiogram
ee/ e
/ e
The 2007 American College of Cardiology/American
b ee/ e
/ e b
: / t
/ .
t m
. m
Heart Association guidelines on perioperative cardio-
/
Cardiac Disease
: / / t .
t m
. m
As outlined in Table 1, patients with significant or un-
/
t p ss
p : /
vascular evaluation recommend a preoperative 12-lead
ss : /
stable cardiac disease require further evaluation and
t p p
t
hht t
ECG in patients scheduled to undergo surgery with any
of the risk factors listed in Table 1.9 t t
workup. This group includes those who have had a re-
hht
cent myocardial infarction or unstable angina. If stress
testing does not demonstrate myocardial tissue at risk,
Chest Radiograph surgery can proceed safely with little risk. However,
An abnormal chest radiograph is more likely to be those with a positive stress test will require revascular-
k eers
rs
found in older patients than in the general population,
e
especially those with a history of cardiac or pulmonary
k ers
r s
ization before any elective orthopaedic procedure.
Cardiac patients without active symptoms and good
b ooook b ook
disease. In one study, only 1 of 368 patients who under-
oo
went a routine screening chest radiograph had an ab-
b oooo
functional capacity (ability to climb a flight of stairs)
do not require evaluation beyond an ECG. Those with
/
e e
/ eb / e
/e b
normal study.10 A meta-analysis of routine preoperative
ee ee/e/e b
two risk factors from Table 1 also can safely undergo
/ t
///t m
chest radiographs involving almost 15,000 patients
. . m
demonstrated only 140 unexpected abnormalities and
: / t.
///t m
surgery without further workup unless it will alter
.m
management. Those with three or more risk factors,
:
s
tps : s
tps :
170
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 15: Care of the Geriatric Patient
k eers
Table 1
rs keerrss
b ooookPerioperative Cardiovascular Risk
b ook
American College of Cardiology/American Heart Association Clinical Predictors of Increased
o o b o oo
o
/
ee/e b ee/ e
/
Major Predictors That Require Intensive Managemente b ee/ e
/ e b
t
///t. m
.m t
///t. m
. m
and May Lead to Delay or Cancellation of the Surgical Other Clinical Predictors That Warrant Careful
: / : /
Procedure Unless Emergent
s
tps : s
tps :
Assessment of Current Status
Unstable angina
Severe angina
hhtttp
Unstable coronary syndromes
hhtttp History of ischemic heart disease
Recent myocardial infarction

Decompensated congestive heart failure History of cerebrovascular disease
k e s
New York Heart Association class IV
rrs
Worsening heart failure
e k eers
r s
b ooook New-onset heart failure
Significant arrhythmias
b ooook b o oo
o
History of compensated heart failure or prior heart failure
/
e e
/ eb High-grade atrioventricular block
Symptomatic ventricular arrhythmias
e/
e e
/ e b ee/ e
/ e b
Symptomatic bradycardia
: // t/.tm
. m : / / t
/ .
t m
. m
New ventricular tachycardia
ss : / ss : /
hhtttp
tp hhtttp
tp
Severe heart disease Diabetes mellitus
Severe aortic stenosis
Symptomatic mitral stenosis
Renal insufficiency
(Reproduced with permission from Fleisher LA, Beckman JA, Brown KA, et al: ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac
rrss rrss
surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on
Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear
o kee k e e
Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and
k o k
Biology, and Society for Vascular Surgery. Circulation 2007;116[17]:e418-e499.)
oo
e bboo o e b o
b o o e b o
b o
/
e / e m ee/ / e m ee/ / e
/ / t
/ .
however, should undergo further noninvasive testing if
t . m
it will alter management of the cardiac disease.9
: / : / /
/t/.t .
preoperative evaluation to identify reversible causes of
m
postoperative pulmonary complications.14 Alternatives
ss :
Patients who had recent revascularization with a
ss : to general anesthesia, such as regional blocks and epi-
hhtttp
tp
stent deserve special consideration. The risk of death or
postoperative myocardial infarction is increased in
those who stop antiplatelet therapy for surgery, espe-
hhtttp
tp dural or spinal anesthesia, may be especially beneficial
to patients with severe pulmonary disease to reduce
postoperative complications. Smoking cessation more
cially if they have a drug-eluting stent because of a de- than 8 weeks before an elective surgery has resulted in
lay in coronary artery endothelization. Ideally, discon- a substantial reduction in pulmonary complications.
eers
tinuation of antiplatelet drugs should be delayed
rs
12 months but, if necessary, can be stopped at 3 to
k k e r
e s
r s
Paradoxically, those who stop smoking less than
8 weeks before surgery have an increased risk of com-
bboooo k
6 months. Those who receive a bare metal stent can
b o o
o
stop antiplatelet therapy 4 weeks after stenting.12 All of o k b o oo
plications.14,15
o
/
e e
/ e ee/ e
/ e b
these patients should continue with full-strength aspirin
e / e
/ e b
Renal Disease
e
: / / t
/ .
t m
throughout the surgical procedure and refrain from the
. m
antiplatelet drugs for as short a time as possible. Pa-
: / / t
/ .
t m
It is estimated that 5% of the US population has
. m
chronic renal disease. Geriatric patients may have acute
t p ss
p : /
tients with drug-eluting stents are at the highest risk of
t p ss
p : / or chronic renal failure or a combination of both con-
t t
thrombotic events if antiplatelet therapy is stopped. Ac-
hht
cording to a guideline paper, a multidisciplinary team
should measure the risk of stopping antiplatelet therapy
t
hht t ditions. It is important to note that chronic renal dis-
ease can affect both metabolic function through elec-
trolyte imbalances and hematopoietic function,
versus the risk of bleeding if surgery must proceed.13 resulting in anemia and coagulopathy.
Acute renal failure must be treated before surgery
k e rs
Pulmonary Disease
rs
Patients who are being treated for asthma or chronic
e k eers
r s
and assessed by a urologist or nephrologist, and may be
prerenal, intrinsic, or postrenal.
b ooook
obstructive pulmonary disease (COPD) should be
maintained on their regular medication regimens
b oook
o b ooo
Prerenal failure causes include hypovolemia or hy-
o
potension, which result in decreased perfusion of other-
/
e e
/ eb ee/ e
/e
throughout the perioperative period. Those with severeb ee/e/e b
wise normal functioning kidneys. Hypovolemia may be
/ t
///t m
COPD or asthma with physical examination findings
. . m
such as wheezing, rhonchi, or rales should undergo a
: : / t.
///t m
.m
treated with an intravenous (IV) fluid bolus or a more
liberal nothing-by-mouth status, allowing the patient to
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
drink clear liquids up to 3 hours before surgery. Preop- tion of beta blockers may cause rebound ischemia and
k eers
rs ke r
erative hypotension resulting in renal dysfunction de-
e rss complications when used for ischemic heart disease.
b ooook an urgent or elective basis.

b o ook
serves a thorough evaluation before surgery, whether of
o b oo
These effects are not as significant when beta blockers
o o
are used for hypertension or migraine headaches. As a
/
ee/e b ee/ e
/ b
Intrinsic renal disease may result from infection,
e
ischemia, or the use of nephrotoxic substances, such as
ee/ e
/ e b
result, all patients who are on beta blockers should re-
main on them throughout the perioperative period and
t . m
.m
aminoglycoside antibiotics or IV contrast. Treatment
: / ///t t
///t. m
. m
should receive them on the day of surgery, if possible. If
: /
tps :
consists of discontinuation of the toxic substance or
s s :
it is determined that a patient would benefit from beta
tps
hhtttp hhtttp
treating the infection that is affecting the kidney. blockade during the perioperative period, it should be
Postrenal failure is caused by downstream obstruc- started early enough to be titrated to blood pressure
tion of the kidneys. Causes include renal caliculi or and heart rate.18 The use of additional beta blockade in
bladder or prostate dysfunction. Clearance of the ob-
patients undergoing high-risk surgical procedures is
struction will result in the release of a large volume of
controversial and may lead to high rates of periopera-
urine and allow for the recovery of renal function.
k eers
rs k eers
Chronic renal failure is defined as a glomerular fil-
r s
tive mortality and stroke.19
tration rate of less than 60 mL/min and has profound
b ooook b ooook
effects on perioperative morbidity and mortality.
o oo
Other Antihypertensive Medications
b o
/
e e
/ eb e/ e
/ e b
Chronic renal failure and many of its associated mani-
festations, including anemia, coagulopathies, and dia-
e
Alpha-2
ee/
agonists,
e
/ e b
calcium channel blockers,
angiotensin-converting enzyme (ACE) inhibitors, and
: // /.tm m
betes, have been identified as significant risk factors in
t . t . m
. m
diuretics may be safely continued until the day of sur-
: / / / t
ss /
comorbidity and mortality following total joint arthro-
: : /
gery, unless there is an obvious reason, such as hy-
ss
hhtttp hhtttp
plasty.16 Efforts should be made to correct or normalize
tp tp
potension or hypovolemia, for them to be discontinued.
the metabolic and physiologic manifestations of Alpha-2 agonists have been shown to decrease the
chronic renal failure. Patients with anemia should
stress response to intubation and act as a mild anx-
maintain blood hemoglobin levels higher than 8 to 10
iolytic agent during the perioperative period. Continu-
g/dL in the perioperative period. Serum potassium
should remain less than 5.5 mmol/L to reduce the risk ation of ACE inhibitors to the time of surgery increases
the risk of intraoperative hypotension. Oral diuretics
keerrss of arrhythmias; if hemodialysis is required to achieve

this, the procedure should be performed 1 day before
k e rrss
e
may affect the ability of the anesthesiologist to manage
bboooo k b o o
o
reviewed with a pharmacist or an internist to ensureo k
surgery to minimize fluid shifts. Medications should be
b o oo
the patient’s fluid balance intraoperatively, so these
o
medications should be held the morning of surgery un-
/
e e
/ e e / e
/ e b
that there will be no medication-induced complications.
e ee/ e
/ e b
til the patient is able to tolerate oral intake postopera-
Diabetes Mellitus
: / / t
/ .
t m
. m : / /t/ tm
tively. Intravenous diuretics can be substituted in the
. .m
perioperative period.
ss : /
Diabetes is one of the most common comorbidities and
ss : /
hhtttp
tp
has reached pandemic status in the United States. Or-
thopaedic disorders such as Charcot arthropathy have
been attributed to it, and a multitude of orthopaedic
hhtttp
tp
Corticosteroids
Surgeons who will be operating on patients who are
taking glucocorticoids such as prednisone need to take
conditions are exacerbated by diabetes. Osteoporosis is special precautions before surgery. Even if taking gluco-
the most common metabolic bone disease in patients
corticoids for relatively minor indications such as pso-
k eers
rs
with diabetes, and the cause is multifactorial. Bone
mass is reduced in patients with diabetes because they
k e r
e s
r sriasis or asthma, patients may have suppression of the
bboooo k b o
may contribute to lower bone vascularity and mass,o
tend to be more sedentary, peripheral vascular disease
o o k hypothalamic-pituitary axis and are at risk for an adre-
o oo
o
nal crisis if the steroids are abruptly withdrawn or a
b
/
e e
/ e ee/ e
/ e b
and insulin’s anabolic effect is absent. In addition, the
ee/ e
/ e b
supplemental replacement is not in place to account for
the added stress of surgery. The following are general
/ / t t m
effects of peripheral neuropathy and muscle decondi-
. . m
tioning contribute to an increased fall risk.17 Reports of
: / : / / t . m
. m
guidelines, but the patient should be evaluated by his or
/ t
ss : /
increased infections and other major complications are
t p p t p ss
p : /
her internist for specific treatment recommendations:
t
hht t
noted throughout the literature on fracture, spine, ar-
throplasty, hand, and sports. Correcting associated
metabolic abnormalities and normalizing blood glucose
t
(1) Patients who have taken glucocorticoids for less
hht t
than 3 weeks or have taken chronic alternate-day ther-
apy are at low risk for adrenal suppression and should
in the perioperative period can minimize complications. continue on their typical dose perioperatively. (2) Those
who have taken the equivalent of 20 mg/day of pred-
nisone for more than 3 weeks or have a cushingoid ap-
k eers
rs Medications That Require Special Consideration
k eers
r s pearance should receive an additional perioperative
b ooook Beta Blockers

b oook
o b ooo
stress dose of steroids. (3) Patients who have taken low
o
doses of prednisone (5 to 20 mg/day) for more than
/
e e
/ eb / e
/e b
Beta-blocker medications have many potential periop-
ee ee/e/e b
3 weeks should undergo further testing to evaluate the
/ t
///t m
erative benefits. They prevent or control arrhythmias
. . m
and decrease myocardial oxygen demand. Discontinua-
: / t.
///t m
hypothalamic-pituitary axis to determine whether they
.m
require additional stress-dose steroids.
:
s
tps : s
tps :
172
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Thyroxine Anesthetic Choices and Indications
k eers
rs ke
Patients with hypothyroidism who receive chronic thy-
errss Choices are available for anesthesia in the geriatric pa-
b ooook b o ook
roxine therapy should continue to receive therapy in
o
the perioperative period. Patients may go up to 5 to
b oo
tient. Traditionally, the type of anesthetic used has not
o o
been observed to make a difference in patient out-
/
ee/e b / e e b
7 days without supplementation, but if this time is ex-
ee /
ceeded, they should receive intravenous or intramuscu- / e e b
comes.20 It has become clear, however, that significant
ee /
confounders exist in the literature. Patients with spinal
: / t
///t. m
.m
lar thyroxine at 80% of their oral dose until they are
t
///t. m
. m
anesthesia are commonly given enough supplemental
: /
s :
able to resume taking oral medications.
tps s :
medicines to also be deeply sedated at the time of their
tps
hhtttp hhtttp
procedures.21 In a recent randomized study, deep seda-
Antiplatelet Drugs tion was shown to be significantly associated with de-
Many geriatric patients take medications that affect the lirium when compared with light sedation.22
normal hemostatic balance. In addition to aspirin, plate- The use of regional anesthesia to augment standard
let receptor blockers such as clopidogrel and ticlopidine techniques is also becoming popular. These techniques
are administered to an increasing number of patients allow for lower doses of narcotics with fewer associ-
k eers
rs k e r
with a history of cardiac or thrombolic events. In pa-
e s
r s ated adverse effects. The use of nerve blocks in the
b ooook oook
tients who have received drug-eluting coronary artery
o
stents, there is significant concern regarding catastrophic
b
emergency department for patients with hip fracture
b o oo
o
has been shown to reduce the need for narcotics.23 Nar-
/
e e
/ eb / e e b
thrombosis with discontinuation before reendothelializa-
ee /
tion occurs approximately 12 months after placement.
ee/ e
/ e b
cotic medicines in elderly patients lead to urinary reten-
tion, constipation, and delirium; the reduction of nar-
t . m
. m
In these patients, it is recommended that platelet recep-
: // / t : / / t
/ .
t m
. m
cotics may reduce complications and improve outcomes
: /
tor blockers be continued except in emergencies; if dis-
ss ss : /
as long as pain control is maintained.
hhtttp
tp hhtttp
tp
continued, they should be restarted as quickly as possi- Overall, the role of the anesthesiologist has ex-
ble. This group of patients should be on an aspirin panded, and the type of anesthesia selected can affect
regimen during this period. Because most urgent ortho- outcomes and minimize complications after surgery; a
paedic procedures, such as fracture fixation, do not re- one-size-fits-all approach is no longer applicable. Com-
sult in critical blood loss, it is generally considered safe munication between the anesthesiologist, the surgeon,
to continue therapy in the perioperative period. and the medical team is essential to allow for efficient
keerrss
Bisphosphonates
k e rrss
e
care of the geriatric patient. Communication will lessen
delays and lessen the number of cases that are can-
bboooo k o o
o
Many postmenopausal women are treated with bisphos-
b o k celled.
b o oo
o
/
e e
/ e ee/ e
/ b
phonates for chronic management of osteoporosis. The
e
extremely long half-life of these drugs creates unique
e / e
/ e b
Mitigation and Management of Blood Loss
e
t . m
. m
challenges in their management. Continuous use of bis-
: / / / t : / /t/.tm.m
Geriatric patients, especially those who are frail, are
ss /
phosphonates after surgery is considered safe but may
: ss : /
more likely to have chronic anemia. During major or-
hhtttp hhtttp
be discontinued during the perioperative period if not thopaedic procedures, anemia is a major risk factor for
tp
well tolerated without any ill effects. Those who re-
quire initiation of bisphosphonate treatment following tp
postoperative blood transfusion.24 The trigger for trans-
fusion after surgery has been a subject of debate. The
a fragility fracture may be started on this regimen im- old standard was a goal hemaglobin of 10 g/dL. The re-
mediately without any demonstrated alteration of bone cent Functional Outcomes in Cardiovascular Patients
healing or remodeling. Currently, it is unclear whether Undergoing Surgical Hip Fracture Repair (FOCUS)
k eerss
patients who have sustained an atypical femur fracture
r
due to chronic bisphosphonate use would benefit from
k e r
e s
r s trial has provided some information that a trigger of
8.5 g/dL is safe in elderly patients after hip fracture re-
bboooo k o o
a “drug holiday” to allow for recovery of osteoclast
b o o k b o oo
pair.25 The need for blood transfusion should be based
o
/
e e
/ e
function.
ee/ e
/ e b e / e
/ e b
on symptomatic anemia. This should be individualized
in patients with severe coronary disease, renal failure,
e
: / / t
/ .
t m
. m value.
: / / t
/ .
t m
. m
or other comorbidities that may need a higher trigger
Surgical Treatment
t p ss
p : / t ss : /
Mitigation of blood loss should be considered
p p
t
hht t
Surgical treatment of geriatric patients presents the or-
thopaedic surgeon with many challenges to reduce peri-
operative morbidity and mortality. These patients typi-
t
hht t
throughout a surgical procedure. The use of tranexamic
acid during major surgeries seems safe and may de-
crease the need for blood transfusions after surgery.26
cally have more comorbidities and frailty. Surgeries are The surgeon should pay careful attention to detail dur-
most commonly of an urgent nature and must be per- ing surgery and exercise efficiency to shorten the proce-
k eers
formed quickly to reduce complications. Cognitive im-
rs
pairment can limit the types of rehabilitation with
k eers
r s
dure in the geriatric patient. This should affect surgical
decision making in the frail, elderly patient who may
b ooook b ook
which a patient can comply. Osteoporosis is often pres-
oo
ent, and poor bone quality may affect the surgical pro-
b oooo
not tolerate an extensive and extended surgery.
Blood loss should first be treated with fluid manage-
/
e e
/ eb / e
/e b
cedure that is chosen. Because of patient frailty, there is
ee ee/e/e b
ment. Patients are often dehydrated when they have re-
/ t
///t m
great pressure for the surgeon to perform successful
. . m
surgery and reduce the risk of reoperation.
: : / t.
///t m
frained from eating or drinking overnight. This prob-
.m
lem is compounded in urgent or emergent procedures.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Patients with hip fractures are typically severely dehy- tentially as little as 1 to 2 hours, increasing the risk of
k eers
rs rrss
drated at admission. IV fluid repletion is essential pre-
kee
decubitus in patients who cannot move. Ulcerations
b ooook operatively and intraoperatively.27
b o ook
o
may occur on the heels or buttocks or from the edge of
o oo
o
a splint, a cast, or a brace.
b
/
ee/e b Thermoregulation
ee/ e
/ e b
All patients get cold in the operating room. The frail
ee/ e
/ e b
Pressure ulcers may develop in one third of elderly
patients with hip fracture.31 These ulcers often require
t
///t. m
.m
patient with little body mass is more prone to a low-
: / : / t
///t. m
. m
months of healing and sometimes additional proce-
s :
ered core temperature. Cold temperatures are associ-
tps s
tps :
dures. The expense related to management is tremen-
hhtttp hhtttp
ated with complications, including higher infection dous to the healthcare system; ulcers are often the rea-
rates. Particular care must be taken with elderly pa- son for nonpayment of the hospital by Medicare as a
tients in the operating room to ensure that they remain “never” event.32 Prevention is the mainstay of treat-
covered and warm. The use of air-warming devices is ment. It has been suggested that patients be turned ev-
necessary and attention to detail is paramount to en- ery 2 hours.33 In particular, splinted or numbed extrem-
sure the patient keeps his or her temperature at an op- ities (after the administration of a regional anesthetic)
k eers
rs timum level throughout the procedure.
k eers
r s are susceptible to ulcers and must be watched. The use
of prophylactic padding with a hydrocolloid dressing in
b ooook Consideration of Tissue Quality

b ooook b o oo
high-risk patients should be considered.
o
/
e e
/ eb and Robust Repair
e/
e e
/ e b
Both soft tissue and bone are weakened in the elderly Infection
ee/ e
/ e b
t . m
. m
patient. Periosteum and soft tissues are thinner and
: // / t : / / t
/ .
t m
. m
Infection is a feared complication in all patients; how-
: /
weaker in elderly patients than in younger patients.
ss ss /
ever, elderly patients are unable to tolerate the extra an-
:
hhtttp hhtttp
Frailty is associated with muscle weakness and sarcope- tibiotics needed to fight infection or additional surger-
tp
nia, and bones often are osteoporotic. All of these fac-
tors make rehabilitation more difficult and surgical
tp
ies. Excessive or inappropriate use of antibiotics may
lead to devastating Clostridium difficile overgrowth. As
planning important in elderly patients. The surgeon in all patients, the use of perioperative antibiotics and
needs to recognize that fixation that may be sufficient excellent surgical technique is needed for infection pre-
in a younger patient may not be feasible in a geriatric vention. Foley catheters should be removed the day af-
keerrss patient, affecting surgical decision making and possibly
k e
changing the type of repair offered. The elderly patientrrss
e
ter surgery to reduce the risk of urinary tract infection.
Mobilization and early incentive spirometry will help
bboooo k o o
may do better with replacement rather than fracture
b o o k b o oo
to decrease the risk of pneumonia and atelectasis.
o
/
e e
/ e e / / e b
fixation. These factors need to be recognized and surgi-
e
cal plans changed according to the individual patient.
e Deep Vein Thrombosis
ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
The geriatric patient is at risk of deep vein thrombosis
ss : / ss : /
after major limb surgery or trauma, especially in the
hhtttp hhtttp
lower extremity. The American College of Chest Physi-
tp tp
Postoperative Treatment
cians Evidence-Based Clinical Practice Guidelines and
Prevention of Complications the American Academy of Orthopaedic Surgeons
The prevention of complications is probably the most (AAOS) guidelines recommend prophylaxis, particu-
important aspect of the care of the geriatric patient. Be- larly in patients undergoing hip and knee replacement
cause of their frail condition, elderly patients will more or hip fracture repair.34,35 These recommendations also
k eers
rs poorly tolerate errors compared with younger pa-
k e r
e s
r
tients.28,29 Each organ system is susceptible to iatrogenic s should be followed for patients who are immobilized or
who have lower extremity trauma. Care must be taken
bboooo k b o o o k
injury during routine hospital care. Medicine selection
o b o oo
in selecting agents when patients are already on blood
o
/
e e
/ e e / e
/ e b
must be assessed to avoid renal damage. The frail pa-
tient is unable to tolerate reoperation. Surgery should
e e / e
/ e b
thinners for other purposes. No information is avail-
able for those who must also continue on antiplatelet
e
/ / t
/ .
t m
provide a reliable, long-lasting solution so that only
. m
one procedure is necessary for treatment. Some surgical
: : / / t
/ .
t m
agents, although it is known that patients on oral anti-
. m
coagulants for atrial fibrillation and antiplatelet drugs
ss : /
complications are common in elderly patients and are
t p p t p ss
p : /
for a coronary stent are at high risk of bleeding.36 In
Decubitus Ulcers
t
hht t
described in the following sections.
t
hht t
these cases, the risks of excessive bleeding must be
weighed against the risk of deep vein thrombosis and
individual decisions made.
The skin of the elderly patient is more susceptible to
pressure ulcers because of the absence of protective sen- Delirium
k eers
rs sation secondary to pain, delirium, or dementia and
thinner subcutaneous fat layers and hypoperfusion. A
k eers
r s The most common complication in the perioperative
period for the geriatric patient is delirium. Delirium oc-
b ooook b ook
higher Braden scale rating predicts pressure ulcer for-
oo
mation.30 The Braden scale is commonly used by nurs-
b oooo
curs twice as often in the patient with cognitive dys-
function27 as in those with normal cognitive function.
/
e e
/ eb / e
/e b
ing staff and evaluates sensory perception, activity, mo-
ee ee/e/e b
Delirium has been shown to increase the length of hos-
/ t
///t m
bility, and nutrition, as well as moisture and friction at
. . m
the potential ulcer site. The time to dermal injury is po-
: : / t.
///t m
pital stay as well as morbidity and mortality.37 The pre-
.m
vention of delirium in elderly patients is multifactorial.
s
tps : s
tps :
174
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Surgical delays in fracture patients should minimized.
k eers
rs ke r
Careful attention to medications to prevent iatrogeni-
e rss
Table 2
b ooook b ook
cally caused delirium is important. Medications have
o o
been classified by the American Geriatric Society Beers
b o oo
Confusion Assessment Method
o
/
ee/e b / e e b
Criteria to help practitioners avoid potential unfriendly
ee /
medications to the geriatric population.38 The Ameri- 2. Inattention
ee e
/ e b
1. Acute onset and fluctuating course
/
: / t
///t. m
.m
can Geriatrics Society has made an easy-to-use pocket
/ t
///t. m
. m
3. Disorganized thinking
:
s :
list of these criteria to help avoid medications that
tps s
tps :
hhtttp hhtttp
4. Altered level of consciousness
cause delirium or other preventable side effects. In par-
ticular, anticholinergic medicines are commonly used
and have a high potential for delirium in elderly pa-
tients. Attention to detail is the most important means Rehabilitation Goals
of prevention. Other strategies to reduce delirium rates
k eers
include normalization of the hospital environment, de-
rs k e
creased sounds, and promoting sleep at night; surgery
ers
r s Early Mobilization, Weight Bearing, and
Range of Motion
b ooook
performed in a timely manner and reduced waiting
times also decrease delirium rates.
b ooook b o oo
The goal of rehabilitation in the elderly patient is to re-
o
/
e e
/ eb e/ e
/ e b
The careful selection of a pain management protocol
e e / e
/ e b
store function to the preoperative level. Because frail
patients do not tolerate immobility well, every attempt
e
: // t/.tm
appropriate for the geriatric patient is important to
. m
minimize pain while minimizing the adverse effects of
/ / t
/ .
t m
should be made to allow patients to bear weight fully
. m
and have full range of motion after surgery. All patients
:
ss : /
narcotic medicines. Many elderly patients also have
ss : /
with hip fractures should be allowed to fully bear
hhtttp
tp hhtttp
tp
cognitive impairment that affects both measurements of weight after surgery.39 Periprosthetic fractures, ankle
pain and influences patterns of pain medicine prescrip- fractures, and intra-articular fractures are problematic
tion. Fixed doses of acetaminophen are a useful adjunct in this regard. If weight-bearing restrictions are re-
to decrease pain without increasing the likelihood of quired, long-term nursing care may be needed for el-
delirium. Low-dose oxycodone (2.5 to 5.0 mg) can be derly patients. Immobility leads to worse outcomes. El-
k errss
added as needed for pain control. Care should be taken
e
with additional medications to avoid polypharmacy
k e rrss
e
derly patients have difficulty restricting weight bearing,
and every attempt should be made to improve surgical
bboooo k b o o
and other potential drug interactions in elderly pa-
o o k b o oo
fixation to allow for weight bearing as tolerated after
o
surgical repair. Rehabilitation should not be delayed af-
/
e e
/ e
tients.
e / e
/ e b
The Confusion Assessment Method is used to diag-
e ee/ e
/ e b
ter surgery, and specialized approaches elderly patients
: / / t
/ .
t m m
nose delirium (Table 2). The key features of delirium
.
are helpful.40
: / /t/.tm.m
ss /
are a change in mental status that is acute and fluctu-
: ss : /
Osteoporosis Evaluation and Management
hhtttp hhtttp
ates. Hypoactive delirium is common and not diag-
tp
nosed as often as hyperactive delirium. Although diffi-
cult to diagnose, delirium occurs often in patients with
tp
Osteoporosis is a common condition in frail, elderly
patients. All patients older than 50 years who have had
a fracture should be evaluated for osteoporosis, begin-
dementia. A key factor in diagnosis is examining the
ning with a dual-energy x-ray absorptiometry scan to
patient over time and referring to caregivers to help un-
assess bone density and an assessment of vitamin D lev-
derstand baseline status.
k eers
rs k e r
e s
r
If delirium is recognized, the first action should be a
s
els. Patients with osteoporosis should be treated using a
team approach. Because most patients want to avoid
bboooo k o o o k
determination of the cause with rectification. Electro-
o
lyte abnormalities, excessive pain, infection, or acute
b b o oo
additional medications and are therefore reluctant to
o
treat osteoporosis, typical compliance rates are 20%.
/
e e
/ e / e e b
medical conditions should be treated. Narcotics over-
ee /
use should be addressed. Delirium at night should be
ee/ e
/ e b
Comprehensive programs have significantly affected
: / / t
/ .
t m
. m
treated with nonpharmacologic interventions. The pa-
: / / t
/ t m
the rates of compliance. A strategy for the treatment of
. . m
osteoporosis in patients with fracture needs to be coor-
t p ss
p : /
tient should not be left alone at night so that the use of
ss : /
dinated. This can be by the orthopaedic surgeon, by a
t p p
t
restraints can be avoided; the environment should re-
hht t
main familiar. Eyeglasses and hearing aids should be
used by the patient if needed.
t
hht t
metabolic bone clinic, or through the patient’s primary
care physician. Best results have been seen in managed
care situations where pathways are used to encourage
After a careful examination and laboratory and patients to undergo osteoporosis diagnosis and man-
medication reviews have been performed and if non- agement.41
k e s
pharmacologic interventions have failed, the use of
rrs
low-dose haloperidol can be considered. Dosage should
e k eers
r s
b ooook b ook
start at 0.5 mg orally. Higher doses will lead to seda-
oo
tion and then a rebound effect with even worse delir-
Comanaged Care
b oooo
/
e e
/ eb / e
/e b
ium that may last for weeks. Long-acting benzodiaze-
ee
Rationale
ee/e/e b
/ t
///t m
pams should be avoided because these will sedate the
. . m
patient and lead to long-lasting delirium.
: : / t.
///t m
The care of the elderly patient is often difficult because
.m
of multiple system failures and the many medications
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
such patients are sometimes required to take. Thus, the
k eers
rs ke
prevention of complications is paramount. A team ap-
errss Key Study Points
b ooook o
management approach that allows orthopaedic sur-
b ook
proach to care through different models, with the co-
o
•
o oo
Preoperative evaluation in the geriatric patient
b o
/
ee/e b / e e b
geons to team with a hospitalist,42 a medical doctor, or
ee /
a geriatrician, has been found to have significant ad-
e e
/ e b
should identify conditions that will affect surgery
/
and then optimize the patient in a timely manner.
e
t . m
.m
vantages for the patient.43 Both teams must agree on
: / ///t •
: t
///t. m
. m
Geriatric patients do not tolerate complications
/
tps :
those items for which they are responsible. For exam-
s s
tps :
(either medical or surgical), and the practitioner
hhtttp hhtttp
ple, the orthopaedic surgeon may be in charge of the must pay attention to detail to avoid postopera-
surgical wound, the surgery, weight bearing, and reha- tive problems.
bilitation as well as deep vein thrombosis prophylaxis. • A comanaged approach to the geriatric patient
The medical side of the team is responsible for making will improve results and reduce costs of care.
sure the patient is adequately prepared for surgery,
fluid therapy, medication reconciliation, and medical
k eers
rs management. In the comanaged care model, both teams
k eers
r s Annotated References
ook ook
can write orders for the patient. Communication and
b oo b o
the use of pathways are essential to success. Communi-
o b o oo
o
/
e e
/ eb e/
e e
/ e b
cation needs to occur several times each day between
teams. Weekly meetings need to occur to review care
1.
e / e
/ e b
Administration on Aging: A Profile of Older Americans.
United States Department of Health and Human Ser-
e
and fine-tune management.
: // t/.tm
. m : / / t
/ t m
vices, 2011.
. . m
This report from the Administration on Aging reviews
ss : / ss : /
data from the 2010 census regarding older adults in the
hhtttp hhtttp
Improved Outcomes
tp
Comanaged care has been shown to save money and
improve quality and outcomes in patients who have
tp
2.
United States.
National Center for Health Statistics: Health, United

had a hip fracture or have undergone joint arthro- States, 2011: In Brief. Hyattsville, MD, 2012.
plasty.44,45 A shorter length of hospital stay and de- This report from the Centers for Disease Control and
creased complications have been shown using a hospi- Prevention is an annual update on health statistics
keerrss talist as well as with geriatric models. Comanagement
k
has been implemented in different countries with simi-
e rrss
e
across the United States.
bboooo k o o o k
lar results and seems to be a robust addition to the care
b o
3.
b o oo
Kammerlander C, Braito M, Kates S, et al: The epidemi-
o
/
e e
/ e e e
/ e b
of the elderly patient. A key element of this approach is
/
buy-in from the hospital. An important aspect of a co-
e e e
/ e b
ology of sports-related injuries in older adults: A central
/
European epidemiologic study. Aging Clin Exp Res
e
: / / / .
t m m
managed service is routine outcome collection and the
t . : / /t/.tm.m
2012;24(5):448-454.
ss /
use of this information to prove to hospital administra-
: ss : /
This retrospective study analyzes the cause of sports in-
hhtttp hhtttp
tion that better, cheaper care is being provided. juries seen in 2,635 patients older than 65 years be-
High-Energy Trauma tp tptween 1994 and 2008. The authors emphasize that
older adults remain active, and the prevention of injury
in older adults needs to be considered.
High-energy trauma is a particularly dangerous occur-
rence in the geriatric patient. Mortality rates have been 4. Prescott JW, Yu JS: The aging athlete: Part 1, “boomer-
found to be three times higher than in younger patients, itis” of the lower extremity. AJR Am J Roentgenol
k eers
rs and even minor injuries, such as clavicle fractures, can
k
be fatal.46 Pelvic fractures, which would be benign in
e r
e s
r s 2012;199(3):W294-306.
bboooo k b o o o k
the younger patient, may be lethal in the geriatric pa-
o b o oo
This review describes sports injury patterns in the lower
o
extremity of older patients.
/
e e
/ e sive blood loss and mortality.
ee e
/ b
tient. Lateral compression injuries may lead to exten-
/ e 5.
ee/ e
/ e b
Quatman C, Yu JS: The aging athlete: Part 2, “boomer-
: / / t
/ .
t m
. m t . m
. m
itis” of the upper extremity. AJR Am J Roentgenol
: / / / t
Summary
t p ss
p : / t p ss
p : /
2012;199(3):W307-321.
t
hht t
The practicing orthopaedic surgeon needs to know ba-
sic geriatric principles. In the future, the fastest growing
t
hht t
This review describes sports injury patterns in the upper
extremity of older patients.
6. Hepner DL: The role of testing in the preoperative eval-

patient population in the area of trauma will be the ge- uation. Cleve Clin J Med 2009;76(suppl 4):S22-S27.
riatric patient. The avoidance of geriatric-unfriendly
k eers
rs
medications, early surgery, and medical comanagement
are important to achieve optimal outcomes in this
k eers
r s 7. Dzankic S, Pastor D, Gonzalez C, Leung JM: The prev-
alence and predictive value of abnormal preoperative
b ooook growing patient population. Reoperation must be
b oook
o
avoided. A team approach to care is essential to im-
b oooo
laboratory tests in elderly surgical patients. Anesth An-
/
e e
/ eb / e
/e b
prove quality, which in turn lowers costs. This includes
ee ee/e/e b
alg 2001;93(2):301-308.
ter fractures.
: / t
///t m
postfracture care and the treatment of osteoporosis af-
. . m
8.
/ t.
///t m
Liu LL, Dzankic SS, Leung JM: Preoperative electrocar-
.m
diogram abnormalities do not predict postoperative car-
:
s
tps : s
tps :
176
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
diac complications in geriatric surgical patients. J Am 16. Bozic KJ, Lau E, Kurtz S, et al: Patient-related risk fac-
k eers
rsGeriatr Soc 2002;50(7):1186-1191.
keerrss tors for periprosthetic joint infection and postoperative

mortality following total hip arthroplasty in Medicare
b ooook9.
o ook
o
Fleisher LA, Beckman JA, Brown KA, et al: ACC/AHA
b b o oo
patients. J Bone Joint Surg Am 2012;94(9):794-800.
o
/
ee/e b e e
/ e b
2007 guidelines on perioperative cardiovascular evalua-
/
tion and care for noncardiac surgery: A report of the
e ee/ e
/ e b
In 40,919 Medicare patients undergoing hip arthro-
plasty, rheumatologic disease (hazard ratio [HR] =
/ ///t. m
.m
American College of Cardiology/American Heart Asso-
t
ciation Task Force on Practice Guidelines (Writing
: : / t
///t. m
. m
1.71), obesity (HR = 1.73), coagulopathy (HR = 1.58),
and preoperative anemia (HR = 1.36) were found to be
s
tps :
Committee to Revise the 2002 Guidelines on Periopera-
s
tps : significant risk factors for periprosthetic infection.
hhtttp hhtttp
tive Cardiovascular Evaluation for Noncardiac Surgery)
developed in collaboration with the American Society of 17. Hofbauer LC, Brueck CC, Singh SK, Dobnig H: Osteo-
Echocardiography, American Society of Nuclear Cardi- porosis in patients with diabetes mellitus. J Bone Miner
ology, Heart Rhythm Society, Society of Cardiovascular
Res 2007;22(9):1317-1328.
Anesthesiologists, Society for Cardiovascular Angiogra-
phy and Interventions, Society for Vascular Medicine
k eers
rsColl Cardiol 2007;50(17):e159-e241.
k eers
and Biology, and Society for Vascular Surgery. J Am
r s
18. Marsland D, Colvin PL, Mears SC, Kates SL: How to
optimize patients for geriatric fracture surgery. Osteo-
poros Int 2010;21(suppl 4):S535-S546.
o o
This review paper discusses the preoperative manage-
/
e e
/ eb 10.
/ e
/ e b
Rucker L, Frye EB, Staten MA: Usefulness of screening
chest roentgenograms in preoperative patients. JAMA
ee ee/ e
/ e b
ment of geriatric patients undergoing urgent surgery.
1983;250(23):3209-3211.
: // t/.tm
. m 19.
: / / t . m
. m
Flynn BC, Vernick WJ, Ellis JE: β-Blockade in the peri-
/ t
11.
s : /
Archer C, Levy AR, McGregor M: Value of routine pre-
s ss : /operative management of the patient with cardiac dis-
hhtttp hhtttp
ease undergoing non-cardiac surgery. Br J Anaesth
tp
operative chest x-rays: A meta-analysis. Can J Anaesth
1993;40(11):1022-1027. tp 2011;107(suppl 1):i3-i15.
This article reviews the literature addressing the use of
12. Vandvik PO, Lincoff AM, Gore JM, et al: Primary and β-blockade for patients with coronary disease who re-
secondary prevention of cardiovascular disease: Anti- quire surgery. Although initial studies showed this
thrombotic therapy and prevention of thrombosis, 9th method to improve outcomes, more recent studies have
keerrss
ed. American College of Chest Physicians Evidence-
k e rrss
e
Based Clinical Practice Guidelines. Chest 2012;141(2,
shown that the complications of beta blockade may out-
weigh the benefits.
bboooo k suppl):e637S-e668S.
b o o
o o k 20.
b o oo
o
Neuman MD, Silber JH, Elkassabany NM, Ludwig JM,
/
e e
/ e e e
/ b
Current guidelines for patients with coronary artery dis-
/ e
ease are reviewed. Single antiplatelet drug therapy is rec-
e ee/ e
/ e b
Fleisher LA: Comparative effectiveness of regional ver-
sus general anesthesia for hip fracture surgery in adults.
/ / t t m
ommended for patients with coronary artery disease,
. . m
whereas dual platelet therapy is recommended for pa-
: / : / /t . m.m
Anesthesiology 2012;117(1):72-92.
/ t
s : /
tients within 1 year of stent procedures.
s ss : /
In a retrospective cohort review of 18,158 patients, the
hhtttp
tp hhtttp
tp
authors show an advantage to regional anesthesia over
13. Korte W, Cattaneo M, Chassot PG, et al: Peri-operative general anesthesia for elderly patients undergoing hip
management of antiplatelet therapy in patients with cor- fracture repair.
onary artery disease: Joint position paper by members
of the working group on Perioperative Haemostasis of 21. Sieber FE, Gottshalk A, Zakriya KJ, Mears SC, Lee H:
the Society on Thrombosis and Haemostasis Research General anesthesia occurs frequently in elderly patients
k eers
rs
(GTH), the working group on Perioperative Coagula-
k e r
e s
r s
tion of the Austrian Society for Anesthesiology, Resusci-
during propofol-based sedation and spinal anesthesia.
J Clin Anesth 2010;22(3):179-183.
bboooo k b o o
tation and Intensive Care (ÖGARI) and the Working
o o k
Group Thrombosis of the European Society for Cardiol-
b o oo
In a prospective observational study of 40 patients un-
o
/
e e
/ e / e e b
ogy (ESC). Thromb Haemost 2011;105(5):743-749.
ee / e / e
/ e b
dergoing hip fracture repair with spinal anesthesia and
propofol-based sedation, electroencephalographic moni-
e
: / / t
/ t m
A consensus position is presented for antiplatelet ther-
. . m
apy in the perioperative period. The group recommends
: / / t
/ .
t m
toring using a bispectral index showed routine sedation
. m
levels consistent with general anesthesia.
t p ss
p : /
a multidisciplinary review of each patient to optimize
the risks and the benefits of continuing or stopping an-
t p ss
p : /
t
hht t
tiplatelet therapy for surgery.
t
hht t
22. Sieber FE, Zakriya KJ, Gottschalk A, et al: Sedation
depth during spinal anesthesia and the development of
postoperative delirium in elderly patients undergoing
14. Edrich T, Sadovnikoff N: Anesthesia for patients with hip fracture repair. Mayo Clin Proc 2010;85(1):18-26.
severe chronic obstructive pulmonary disease. Curr In this prospective randomized clinical study, light seda-
Opin Anaesthesiol 2010;23(1):18-24. tion with spinal anesthesia reduced postoperative delir-
k eers
rslung disease who require surgery is presented.
k eers
An evidence-based approach for managing patients with
r s ium by 50% when compared to deep sedation in elderly
patients undergoing hip fracture repair.
b ooook b oook
o b oooo
/
e e
/ eb 15.
e e
/e b
Bushnell BD, Horton JK, McDonald MF, Robertson
/
PG: Perioperative medical comorbidities in the ortho-
e
23.
e /e/e b
Luger TJ, Kammerlander C, Gosch M, et al: Neuroaxial
versus general anaesthesia in geriatric patients for hip
e
216-227.
: / t
///t m
paedic patient. J Am Acad Orthop Surg 2008;16(4):
. . m : / t.
///t m
fracture surgery: Does it matter? Osteoporos Int 2010;
.m
21(suppl 4):S555-S572.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
This review discusses the pros and cons of anesthetic 32. Rosenthal MB: Nonpayment for performance? Medi-
k eers
rs choices for hip fracture repair.
keerrss care’s new reimbursement rule. N Engl J Med 2007;
ook ook
357(16):1573-1575.
b oo 24.
o o
Vochteloo AJ, Borger van der Burg BL, Mertens B, et al:
b b o oo
o
/
ee/e b ee e
/ e b
Outcome in hip fracture patients related to anemia at
/
admission and allogeneic blood transfusion: An analysis
33.
e e
/ e b
Rich SE, Margolis D, Shardell M, et al: Frequent man-
/
ual repositioning and incidence of pressure ulcers
e
Disord 2011;12:262.
: / ///t. m
.m
of 1262 surgically treated patients. BMC Musculoskelet
t : / t
///t. m
. m
among bed-bound elderly hip fracture patients. Wound
Repair Regen 2011;19(1):10-18.
s
tps : s
tps :
hhtttp hhtttp
This retrospective study shows that preoperative and This retrospective study questions the efficacy of fre-
postoperative anemia are independent risk factors for quent repositioning in preventing decubitus ulcers in
poor outcomes after hip fracture repair. nursing home patients.
25. Carson JL, Terrin ML, Noveck H, et al: Liberal or re- 34. Falck-Ytter Y, Francis CW, Johanson NA, et al: Preven-
strictive transfusion in high-risk patients after hip sur- tion of VTE in orthopedic surgery patients: Antithrom-
k eers
rs gery. N Engl J Med 2011;365(26):2453-2462.
k eers
r s
botic Therapy and Prevention of Thrombosis, 9th ed.
American College of Chest Physicians Evidence-Based
The prospective randomized FOCUS trial shows that a
b ooook o ook
restrictive transfusion threshold of 8 g/dL does not
b o e278S-e325S.
b oo
Clinical Practice Guidelines. Chest 2012;141(2, suppl):
o o
/
e e
/ eb more liberal threshold of 10 g/dL.
ee e
/ b
change mortality or morbidity when compared with a
/ e ee/ e
/ e b
Guidelines are presented by the American College of
Chest Physicians based on evidence-based approaches
26.
: // t/.tm
. m
Yang ZG, Chen WP, Wu LD: Effectiveness and safety of
: / / t
/ .
t m
. m
for preventing thrombotic events after orthopaedic sur-
ss : /
tranexamic acid in reducing blood loss in total knee ar-
ss : /
gery.
hhtttp
tp hhtttp
tp
throplasty: A meta-analysis. J Bone Joint Surg Am 35. Mont MA, Jacobs JJ, Boggio LN, et al: Preventing ve-
2012;94(13):1153-1159. nous thromboembolic disease in patients undergoing
This meta-analysis shows that tranexamic acid is safe elective hip and knee arthroplasty. J Am Acad Orthop
and reduces blood loss after knee replacement. Surg 2011;19(12):768-776.
Guidelines are presented to prevent thrombotic events
rrss rrss
27. Lee HB, Mears SC, Rosenberg PB, Leoutsakos JM, after hip and knee replacement surgery in an evidence-
o ke
ke o k e
Gottschalk A, Sieber FE: Predisposing factors for post-
k e
operative delirium after hip fracture repair in individu-
based guideline approach by the AAOS.
oo
e bboo o e b o o o
als with and without dementia. J Am Geriatr Soc 2011;
b
36.
e b o o
Gutierrez A, Rao SV: Atrial fibrillation and percutane-
b
/
e / e 59(12):2306-2313.
m ee/ / e
In this retrospective review of patients undergoing hip
m ee/ / e
ous coronary intervention: Stroke, thrombosis, and
bleeding. Curr Treat Options Cardiovasc Med 2011;
: / /
/ t
/ .
t . m
fracture repair, preexisting dementia changes the risk
: / /
/t/.t .m
13(3):203-214.
s :
factors for developing delirium after surgery.
s ss :
This review examines the use of antiplatelet medicines
hhtttp
tp hhtttp
tp
in patients undergoing coronary stent procedures who
28. Makary MA, Segev DL, Pronovost PJ, et al: Frailty as a must be on other anticoagulants.
predictor of surgical outcomes in older patients. J Am
Coll Surg 2010;210(6):901-908. 37. Marcantonio ER, Flacker JM, Michaels M, Resnick
NM: Delirium is independently associated with poor
This prospective study shows that frailty predicts length functional recovery after hip fracture. J Am Geriatr Soc
k eers
rs derly patients undergoing surgery.
k e r
e s
of stay, complications, and discharge disposition in el-
r s 2000;48(6):618-624.
bboooo k 29.
b o o
o o k
Higuera CA, Elsharkawy K, Klika AK, Brocone M, Bar-
38.
o oo
American Geriatrics Society 2012 Beers Criteria Update
b o
/
e e
/ e / e e b
soum WK: 2010 Mid-America Orthopaedic Association
ee /
Physician in Training Award: Predictors of early adverse
ee/ e
/ e b
Expert Panel: American Geriatrics Society updated
Beers Criteria for potentially inappropriate medication
: / / t
/ .
t m m
outcomes after knee and hip arthroplasty in geriatric
. : / / t
616-631.
/ t m
use in older adults. J Am Geriatr Soc 2012;60(4):
. . m
1400.
t p ss
p : /
patients. Clin Orthop Relat Res 2011;469(5):1391-
t p ss
p : /
The American Geriatric Society uses an evidence-based
t
hht t
This prospective study examines risk factors for compli-
cations in elderly patients undergoing hip and knee re-
t
hht t approach to list medicines with potentially undesirable
adverse effects in elderly patients.
placement. 39. Koval KJ, Sala DA, Kummer FJ, Zuckerman JD: Post-
operative weight-bearing after a fracture of the femoral
30. Braden BJ, Maklebust J: Preventing pressure ulcers with neck or an intertrochanteric fracture. J Bone Joint Surg
k eers
rs k eers
r s
the Braden scale: An update on this easy-to-use tool that
assesses a patient’s risk. Am J Nurs 2005;105(6):70-72.
Am 1998;80(3):352-356.
b ooook b oook
o o oo
40. Bachmann S, Finger C, Huss A, Egger M, Stuck AE,
b o
/
e e
/ eb 31.
e / e
/e b
Baumgarten M, Margolis DJ, Orwig DL, et al: Pressure
ulcers in elderly patients with hip fracture across the
e e /e/e b
Clough-Gorr KM: Inpatient rehabilitation specifically
designed for geriatric patients: Systematic review and
e
863-870.
: / t
///t m
continuum of care. J Am Geriatr Soc 2009;57(5):
. . m : / t.
///t m
meta-analysis of randomised controlled trials. BMJ
.m
2010;340:c1718.
s
tps : s
tps :
178
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
This meta-analysis examines rehabilitation protocols for 45. Kates SL, Mendelson DA, Friedman SM: Co-managed
k eers
rspatients after hip fracture repair.
keerrss care for fragility hip fractures (Rochester model). Os-
ook ook
teoporos Int 2010;21(suppl 4):S621-S625.
b oo
41.
b o
Dell R: Fracture prevention in Kaiser Permanente
o b o oo
o
This article provides the nuts and bolts behind establish-
/
ee/e b 457-460.
ee e
/ b
Southern California. Osteoporos Int 2011;22(suppl 3):
/ e ee/ e
/ e b
ing a comanaged hip fracture program. The authors
show dramatic reductions in cost and improvements in
t . m
.m
A 10-step program for osteoporosis treatment is pre-
: / ///t
sented that, when used in an effective healthcare organi-
: / t .
care.
///t m
. m
s
tps : s
tps :
hhtttp hhtttp
zation, has led to a 40% reduction in fractures. 46. Keller JM, Sciadini MF, Sinclair E, O’Toole RV: Geriat-
ric trauma: Demographics, injuries, and mortality. J Or-
42. Phy MP, Vanness DJ, Melton LJ III, et al: Effects of a thop Trauma 2012;26(9):e161-e165.
hospitalist model on elderly patients with hip fracture.
Arch Intern Med 2005;165(7):796-801. This retrospective review of elderly patients who sustain
high energy trauma shows high mortality and morbidity
rates in this group.
k
43.
eers
rs
Friedman SM, Mendelson DA, Kates SL, McCann RM:
e rs
r s
Geriatric co-management of proximal femur fractures:
k e
b ooook oook
Total quality management and protocol-driven care re-
o
sult in better outcomes for a frail patient population.
b b o oo
o
/
e e
/ eb / e
J Am Geriatr Soc 2008;56(7):1349-1356.
ee / e b ee/ e
/ e b
44.
t . m
. m
Kammerlander C, Roth T, Friedman SM, et al: Ortho-
: // / t : / / t
/ .
t m
. m
ss /
geriatric service—a literature review comparing differ-
: ss : /
hhtttp hhtttp
ent models. Osteoporos Int 2010;21(suppl 4):S637-
S646.
tp
This review examines the concept of the orthogeriatric
service in several patient care models.
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook Section 2 b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
e rs
rs Systemic Disorders
errss
o k
ook e oook
ok e o oo
/ e
/ b
eb o / e
/ b
e b / e
/ b
e b o
e t m
.t.mee t . m mee
s : /
:// / s : /
: /
/ / t .
t t
hhtt pp s hhtttp
tp s
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
b oooo k b o o
o o k b o oo
o
/e b
e/e . m mee/ e
/ e b
. m mee/ e
/ e b
Section Editor:
ss: /
: /
/ t
/ t .
Javad Parvizi, MD, FRCSC
ss: /
: /
/ t
/ t .
t
hht t p
t p t
hhtt p
t p
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 16
e rs
rs e rrss
oo
kDisease
ook e Footprints: o Genomics,
k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Proteomics,/t.and m.mee Metabolomics /t.m . mee
s: /
: / / t s : /
: / / t
tps
hhtttp tps
hhtttp
Joseph A. Karam, MD Javad Parvizi, MD, FRCS
k eers
rs k eers
r s approaches could not. Metabolomic-based studies have
b ooook b o oo
offered means of objectively diagnosing diseases such
o
as schizophrenia, a disease whose diagnosis currently
/
e e
/ eb e/ e
/ e b
Since the launch of the Human Genome Project, studies
have abounded and numerous efforts have been in-
e ee/ e
/ e b
relies on history taking and subjective assessment, with
: // /.tm m
vested to establish the genetic basis of multiple diseases
t .
and reveal new methods of prevention, diagnosis, and
: / / t
/ .
t m
a characteristic fingerprint plasma profile.1
. m
Genomic, proteomic, and metabolomic studies have
ss : / ss : /
contributed to the understanding of diseases. Although
hhtttp hhtttp
treatment. However, the time is long past the simple
tp
discovery of a genetic locus responsible for a disease
trait that follows classic mendelian inheritance. With
the advent of new technology able to perform genome-
tp
fields such as oncology have extensively benefited from
such investigations, musculoskeletal pathology has ac-
quired a benefit that is relatively more limited. How-
wide explorations, studies have aimed to explain the ever, conditions such as osteoarthritis (OA), idiopathic
genetic basis of more complex diseases. Recent investi- osteonecrosis of the femoral head, or idiopathic scolio-
rrss rrss
gations in molecular medicine have followed a compre- sis have an obviously significant genetic predisposition
o kee
hensive systematic approach in the study of genomics
k o k e
k e
and require further efforts to better characterize their
underlying pathophysiology.
oo
e bboo o e b o
and proteomics. Genomic studies evaluate the whole
b o
genome of a cell, and proteomic studies characterizeo e b o
b o
/
e / e m e / / e
and quantify the complete protein content of a biologic
e m ee/ / e
. m
sample. An even more contemporary approach, metab-
t .
Genomics
t . .m
2: Systemic Disorders
: / /
/ / t
olomics, has consisted of profiling the metabolic con-
s : s : /
: /
/ / t
hhtttp
tp s
tent of biologic samples. Metabolites are downstream
from genes and proteins, are closer to the expressed
phenotype, and can provide information that previous hhtttp
tp s
Genomics for Understanding
Disease Pathophysiology
In classic genetic diseases with mendelian inheritance, a
mutation in the gene is necessary and sufficient for the
expression of the mutated phenotype. Various genetic
Dr. Parvizi or an immediate family member is a member diseases present with major musculoskeletal manifesta-
k rs
rs
ee k e r
e s
r stions; a 2001 study provided an exhaustive report on
genetic skeletal disorders.2 This report included 456 ge-
bboooo k b o o o k
on behalf of Cadence; serves as a paid consultant to or
is an employee of 3M, Cadence, Ceramtec, Pfizer, Salient
o b o oo
netic conditions involving the musculoskeletal system
o
/
e e
/ e ee e
/ e b
Surgical, Smith & Nephew, TissueGene, and Zimmer; has
/
received research or institutional support from 3M, Bax-
e / e
/ e b
and described their inheritance pattern, locus, gene,
and gene product (protein). Table 1 provides a selection
e
: / / t
/ .
t m m
ter, DePuy, the Musculoskeletal Transplant Foundation,
. / / t
/ t m
of genetic skeletal diseases with their characteristics
. . m
based on this report. Even though mendelian genetics
:
t p ss : /
the National Institutes of Health (NIAMS & NICHD),
Smith & Nephew, Stryker, and Zimmer; and serves as a
p ss : /
can explain the inheritance pattern of specific and often
t p p
t
hht t
board member, owner, officer, or committee member of
the American Association of Hip and Knee Surgeons, the
American Board of Orthopaedic Surgery, the British Or-
t
hht t
rare genetic diseases, there is no explanation of the
transmission of more frequent affectations that seem to
cluster in families without a clear inheritance pattern.
thopaedic Association, CD Diagnostics, the Eastern Or- Hence, the concept of multifactorial inheritance was in-
thopaedic Association, the Hip Society, the Orthopaedic troduced, where subjects have a genetic predisposition
k eers
Research and Education Foundation, the Orthopaedic
rs k e
Research Society, the Philadelphia Orthopedic Society,
ers
r s
for a disease, which often involves multiple genetic loci,
and environmental factors (usually unidentified) influ-
b ooook b ook
SmartTech, and United Healthcare. Neither Dr. Karam
oo b oooo
ence the expression of these genes. This pattern of in-
heritance has been suggested for conditions such as es-
/
e e
/ eb e / e
/e b
nor any immediate family member has received any-
thing of value from or has stock or stock options held in
e ee/e/e b
sential hypertension, diabetes, and obesity and even to
/ t
///t m
a commercial company or institution related directly or
. . m
indirectly to the subject of this chapter.
: : / t.
///t m
explain morphologic characteristics, such as height. It
.m
is also the model proposed for various musculoskeletal
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
Section 2: Systemic Disorders tps
hhtttp
k eers
rs
Table 1
keerrss
b ooook b ook
o
Locus, Implicated Gene, and Gene Product (ie, Protein)
b oo
Select Skeletal Genetic Disorders Following Mendelian Heredity, With Their Mode of Inheritance,
o o o
/
ee/e b Disease
ee/ e
/ e b Mode of Inheritance Locus
ee/ e
/ e b Gene/Protein
Achondroplasia
: / t
///t. m
.m AD
: / t
///t. m
. m
4p16.3 FGFR3: Fibroblast growth factor
s
tps : s
tps :
hhtttp hhtttp
receptor 3
Marfan syndrome AD 15q21.1 FBN1: Fibrillin 1
McCune-Albright syndrome AD 20q13 GNAS1: Guanine nucleotide binding
(polyostotic fibrous dysplasia) protein, α stimulating activity,
polypeptide 1
Multiple epiphyseal dysplasia type 1 AD 19p13.1 COMP: Cartilage oligomeric matrix
k eers
rs k eers
r s protein
b ooook Multiple epiphyseal dysplasia type 5

Multiple epiphyseal dysplasia type 6
b ooook AD
AD
2p23-24
6q13
b o oo
o
MATN3: Matrilin 3
COL9A1: Collagen type 9, α1 chain
/
e e
/ eb Severe neonatal osteopetrosis
e/
e e
/ e b AR 11q13
ee/ e
/ e b TCIRG1: Subunit of ATPase proton
: // t/.tm
. m : / / t
/ .
t m
. m
pump
Late-onset osteopetrosis type 2
ss : / AD
ss : / 16p13 CLCN7: Chloride channel 7
hhtttp hhtttp
COL1A1: Collagen type 1, α1 chain;
tp tp
Osteogenesis imperfecta type 1 AD 17q21.3
COL1A2: Collagen type 1, α2
chain
Osteogenesis imperfecta type 4 AD, AR
AD = autosomal dominant, AR = autosomal recessive
(Based on data presented by Warman et al.2)
keerrss k e rrss
e
bboooo k b o
disorders (such as adolescent idiopathic scoliosis, hipo
o o k b o oo
o
can thus be mapped through linkage analysis in these
/
e e
/ e / e e b
dysplasia, and myelomeningocele) that have a relatively
ee / / e
/ e b
cases, compared with late-onset OA where this ap-
ee
significant genetic component.
t . m
. m t m
proach has been of very low yield.5 Indeed, mutations
. .m
s : /
: /
/ / t
Genetic linkage analysis and gene sequencing al-
lowed the identification of the genetic basis of most
s : : /
/ t
in genes such as SMAD3 (SMAD family member 3) and
/ /
TRPV4 (Transient Receptor Potential cation channel,
hhtttp
tp s
single-gene diseases; however, studying the underlying
genetic basis of multifactorial inheritance conditions is
hhtttp
tp ssubfamily V, member 4) have been found to be respon-
sible for syndromes in which OA is a major manifesta-
more complex. These have recently benefited from the tion. GWAS brought more insight into the etiopatho-
implementation of genome-wide association studies genesis of late-onset OA. A very large GWAS recently
(GWAS), which are able to assay hundreds of thou- included more than 7,000 unrelated patients with OA
k eers
rs
sands of genetic markers, usually single nucleotide
polymorphisms (SNPs), using a stringent significance
k e r
e s
r s
and revealed five loci that were linked to OA with a
genome-wide significance (P < 10-8).4 These genes are
bboooo k tion between common variants in diseased patients

b o o
threshold (P < 5 × 10-8).3 By identifying a high correla-
o o k b o oo
implicated in posttranslational modifications, such as
o
protein glycosylation and sulfonation, that may affect
/
e e
/ e / e e b
(linkage disequilibrium), a genetic region linked to the
ee /
disease is identified. Sequencing and detailed study of
ee/ e
/ e b
cartilage proteins, collagen type XII composition, endo-
: / t
/ .
t m
. m
that region, more specifically of the genes included in
/ : / / t t m
chondral ossification, and skeletal development. One
. . m
mutated gene coded for a missense variant of nu-
/
t p ss
p : /
it, further delineate the biologic mechanisms involved
t p ss
p : /
cleostemin, a protein that regulates the mesenchymal
t
in disease pathophysiology.
hht
Genomics for Understanding
t t
hht t cell cycle and has been found to be increased in chon-
drocytes of osteoarthritic joints, thus shedding light on
a possible etiopathogenetic role for this pathway in
Musculoskeletal Pathologies OA.
OA is a typical example of a musculoskeletal condition Several other musculoskeletal conditions have also
k eers
rs
that has benefited from GWAS. The role of predispos-
ing genetic factors is thought to amount to 50% of the
k eers
r s
been evaluated by GWAS, such as idiopathic scoliosis,
osteoporosis, and determinants of bone mineral density
b ooook risk of developing OA.4 Underlying biologic pathways
b oook
o
involved in the etiopathogenesis are very poorly under-
b oooo
(BMD).6,7 The most recent and widest meta-analysis on
GWAS identifying candidate loci for determination of
/
e e
/ eb / e
/e
stood. Early-onset OA usually presents with a mono-
ee b ee/e/e b
BMD reported 56 loci that were highly correlated with
/ t
///t m
genic mendelian inheritance pattern and is generally
. . m
part of a syndrome.5 Underlying genetic disturbances
: : / t.
///t m
BMD.7 The regions incriminated were involved in re-
.m
ceptor activator of nuclear factor kappa-B ligand osteo-
s
tps : s
tps :
184
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 16: Disease Footprints: Genomics, Proteomics, and Metabolomics
protegerin (OPG) pathways, mesenchymal cell differen- dose, as is routinely done in clinical practice. The most
k eers
rs ke
tiation, endochondral ossification, and Wnt signaling
errss significant difference in predicting the ideal warfarin
b ooook
bility to fractures.
b o ook
pathways. Six genes were also correlated with suscepti-
o
dose was observed in patients who ultimately required
o oo
o
low-dose (≤ 21 mg/week) or high-dose (≥ 49 mg/week)
b
/
ee/e b / e e b
Even though GWAS have offered major advances in
ee /
understanding the genetic basis of several diseases, a / e e b
warfarin treatment. However, even in those patients,
ee /
the prediction of the ideal dose was not very reliable:
t . m
.m
large part of disease heritability still remains unex-
: / ///t : / t
///t. m
. m
only 35% and 32.8% of estimations fell within 20% of
s
tps :
plained. Moreover, many outcomes have not been re-
s
tps :
the ideal treatment dose in patients requiring low-dose
hhtttp hhtttp
produced in independent GWAS, possibly as a result of and high-dose warfarin treatment, respectively. Several
ethnic variability and disease heterogeneity. Some au- studies have attempted to test the external validation of
thors have concluded that these studies may not have a this algorithm, as well as other pharmacogenomic-
major effect on predictive medicine, but their main con- based algorithms, and found grossly similar results.11,12
tribution would be to better understand disease biology Furthermore, it has been shown that the routine use of
and lead to the development of new targeted therapies.3 genotypic testing before warfarin administration would
k eers
rs k eers
r s not be a cost-effective approach.13
b ooook
Genomics in Disease Management:
Pharmacogenomics
b ooook b o oo
o
/
e e
/ eb / e e b
Genomic studies have provided the medical community
ee /
with the means for personalized medicine, delivering
Proteomics
ee/ e
/ e b
: // t . m
. m
the adapted treatment based on a patient’s own genet-
/ t : / / t
/ .
t m m
The human body is thought to contain more than
.
s : /
ics. A person’s metabolism of a drug, as well as drug ef-
s ss /
1 million proteins, compared with the reportedly only
:
hhtttp hhtttp
40,000 genes comprising the human genome.14 In addi-
tp
ficacy for the same disease in different individuals, have
been shown to be associated with certain SNPs. Identi-
fying the patient’s haplotype (set of alleles, or SNPs, on
tp
tion to alternative splicing, more than 300 posttransla-
tional modifications have been identified. Furthermore,
compared with genomic studies, which evaluate a static
the same chromosome) might help in selecting drug
material that is the same in all the cells of the body,
treatment and appropriate doses.8
protein analysis is a dynamic phenomenon. Protein ex-
The most relevant clinical application of pharmaco-
rrss rrss
pression varies with time and differs in quality and in
genomics in orthopaedics currently concerns warfarin
o ke
ke o k e
k
therapy. This drug is routinely used after major ortho-
e quantity between different cells or fluids of the body
oo
and between diseased and healthy states.
e bboo o e b o
paedic surgery to prevent or treat venous thromboem-
b o o
bolic events. The metabolism of this drug is infamous
e b o
b o
/
e / e ee/ / e
for its unpredictability among different individuals and
m / / e
Proteomics for Biomarker Identification
m ee
Several biomarkers are used in medical practice to diag-
t . . m
for its susceptibility to external factors, such as changes
t . .m
s : /
: /
/ / t
in diet or medication intake. The therapeutic index is
s : /
: /
/ t
nose diseases and monitor the response to treatment.
/
For example, inflammatory biomarkers such as
hhtttp
tp s
very narrow and subtherapeutic treatment can lead to
fatal thromboembolic events, whereas overdosage can
lead to highly morbid and sometimes fatal bleeding hhtttp
tp s
C-reactive protein (CRP) are widely used to quantify
systemic inflammation and assess the activity of inflam-
matory disorders. Studies evaluating these markers as
events. The cytochrome P450 2C9 complex has been diagnostic tools generally quantify their specificity and
shown to have a major role in warfarin metabolism, sensitivity by comparing them with the gold standard,
and most drug interactions occur when there is interfer- which is usually very invasive, is expensive, or presents
k eerss
ence with this enzymatic complex.9 Moreover, polymor-
r
phisms in CYP2C9, the gene coding for the cytochrome
k e r
e s
r s at a late stage. Target-specific investigations have been
bboooo k b o o
P450 2C9 complex, as well as in other genes such as
o o k used to analyze specific predetermined proteins that are
b o oo
o
thought to be implicated in the pathophysiologic pro-
/
e e
/ e
VKORC1 (vitamin K epoxide reductase complex sub-
e / e
/ e b
unit 1) have been shown to widely influence the metab-
e ee/ e
/ e b
cess of the disease based on previous scientific knowl-
edge. Recent applications in musculoskeletal pathology
: / / / .
t m m
olism of warfarin. Consequently, several teams have
t .
studied these polymorphisms and introduced algo-
: / / t
/ .
t m
. m
targeted molecular markers for periprosthetic joint in-
ss : /
rithms for the optimal warfarin dose depending on the
t p p t p ss : /
fection (PJI). The diagnosis of this disease poses many
challenges, and even though recent diagnostic criteria
p
t
hht t
patient’s genetic profile for these enzymes. The Interna-
tional Warfarin Pharmacogenetics Consortium pub-
lished the results of a pharmacogenomics-based algo-
t
hht t
have been established by the Musculoskeletal Infection
Society (MSIS), many equivocal cases are encoun-
tered.15,16 Two recent studies have evaluated synovial
rithm to determine the accurate dose of warfarin fluid markers in PJI.17,18 Candidate markers were pro-
treatment.10 The study included 5,700 subjects and led teins known to be involved in inflammatory pathways.
k ee s
to an algorithm based on clinical data, including demo-
rrs k e
graphics and the intake of enzymatic inducers, as well
ers
r s Marker profiles were found to be significantly different
in PJI cases compared with controls, and several mark-
b ooook b oook
as genetic data, comprising the six possible genotypes
o
for CYP2C9 and the three possible genotypes for the
b ooo
ers outperformed classic diagnostic tests, such as eryth-
o
rocyte sedimentation rate (ESR) and CRP. One study
/
e e
/ eb ee/ e
/e
rs9923231 polymorphism of VKORC1. This pharma- b /e/e b
reported 100% sensitivity and specificity for synovial
ee
/ t
///t m
cogenomic model performed better than a model based
. . m
on clinical data alone or starting the patients on a fixed
: / t.
///t m
fluid interleukin-1 and interleukin-6 in differentiating
.m
PJI from controls.17
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Another approach in biomarker identification re- their underlying biochemical pathways may help find
k eers
rs ke r
sorts to a more comprehensive analysis by establishing
e rss novel therapeutic targets.
b ooook used with complex diseases such as OA, where the

b ook
complete proteomic profiling. This process has been
o o b o oo
o
/
ee/e b / e e b
pathophysiology is still not entirely elucidated. A pro-
ee /
teomic study of chondrocytes harvested from patients
Metabolomics
ee/ e
/ e b
: / t
///t. m
.m
undergoing total joint arthroplasty was conducted, and
t
///t. m
. m
Complementing Genomics and Proteomics
: /
s :
the profiles were compared with cells from normal sub-
tps s :
With the introduction of large-scale genomic studies,
tps
hhtttp hhtttp
jects.19 Twenty-eight proteins showed significantly dif- several predisposing genetic profiles are being discov-
ferent concentrations between the two groups. A par- ered for different conditions. However, the link be-
ticularly high abundance of “stress-response” proteins tween the genetic variant and the phenotype still largely
was found, shedding more light on the cellular response remains a mystery. Metabolomics is the study of the
to injury in osteoarthritic joints. Two anti- closest biochemical molecules to the phenotypic expres-
sion: metabolites. The authors of a 2003 study pro-
k eers
rs
inflammatory mediators also were shown to be ele-
e
vated, manifesting an attempt of the organism to pro-
k ers
r s vided an example, whereby metabolomics helped eluci-
b ooook b oook
tect itself from excessive inflammation in OA. Another
o
study compared the proteome of osteoarthritic chon-
b o oo
date the path from genetic mutation to phenotypic
o
expression by studying the oncogenetic effect of isoci-
/
e e
/ eb e/
e e
/ e b
drocytes with normal chondrocytes, but regional
ee/ e
/ e b
triate dehydrogenase-1 (IDH-1) mutation in glioblasto-
mas.23 This mutation is known to have a major role in
// t tm
changes in osteoarthritic joints also were evaluated
. . m
(normal versus damaged cartilage in the same joint).20
: / t . m
. m
the progression of high-grade gliomas to glioblastomas;
: / / / t
s : /
The differences found between normal chondrocytes
s ss : /
nevertheless, the underlying pathophysiology is un-
hhtttp
tp hhtttp
tp
and those harvested from apparently normal cartilage known. The mutation leads to a loss of the ability of
the enzyme to transform isocitrate to α-ketoglutarate.
in an osteoarthritic joint confirmed that preclinical per-
However, a heterozygotic mutation is found in cancer
turbations in the cartilage are present and can be used
cells, which would not be expected to affect the equilib-
to screen for OA in the preclinical stage. rium of tricyclic acid (TCA) substrates. These authors
In contrast with these tissue studies, a proteomic undertook metabolic profiling of glioblastoma cells to
keerrss analysis of the serum and synovial fluid of patients

with different stages of OA was performed, and four
k e rrss
e
further examine the effect of this mutation, and, as
expected, TCA species were not found to be signifi-
bboooo k b o o
o o
biomarkers that significantly correlated with OA were
k b o oo
cantly affected. However, an unexpected substance,
o
/
e e
/ e e / / e b
discovered.21 Three of these markers were greatly ele-
e
vated in the serum and synovial fluid of patients with
e e / e
/ e b
2-hydroxyglutarate, was found to be substantially more
abundant in mutated cells. The mutation actually con-
e
t . m
OA compared with healthy controls and patients with
. m t . m.m
ferred a gain of function, allowing the enzyme to re-
s : /
: /
/ / t
rheumatoid arthritis. The values of these markers also
s : / / / t
duce α-ketoglutarate into 2-hydroxyglutarate. This me-
: /
hhtttp
tp s
correlated with Kellgren-Lawrence stage, showing
higher levels with more severe disease. The fourth
marker, possibly belonging to a proinflammatory path- hhtttp
tp s
tabolomic study not only contributed to further
clarification of disease pathophysiology but also identi-
fied a biomarker for disease prognosis (because brain
way, was significantly decreased in patients with OA. tumors with IDH-1 mutations have a different behav-
ior) and established a potential therapeutic target for
Proteomic Profiling in brain tumors.
k eers
rs Musculoskeletal Oncology
k
Proteomic markers also have been used to evaluate the
e r
e s
r sMethods in Metabolomics
bboooo k o o
genetic expression of tumors and thereby distinguish
b o o k b o oo
Analyzing the metabolome poses several difficulties, es-
o
/
e e
/ e e / / e b
different types of tumor cells that would be expected to
e
have a varying response to treatment. As a result of the
e e / e
/ e b
pecially because the target molecules are too small and
very similar in structure. Metabolomic-based analyses
e
: / / / .
t m m
wide success of proteomic profiling via mass spectrom-
t .
etry (MS) in non–small-cell lung cancer and glioblas-
: / / / .
t m m
are generally centered on nuclear magnetic resonance
t .
or MS. MS represents a more sensitive technique, capa-
t p ss
p : /
toma multiforme, matrix-assisted laser desorption ion-
t p ss : /
ble of analyzing a higher number of molecules; it can
p
t
hht t
ization MS was used to establish proteomic profiling of
soft-tissue sarcoma.22 Histologic analysis fails to reli-
ably differentiate high-grade from low-grade soft-tissue
t
hht t
discriminate different isotopes and can more easily be
coupled to chromatography. Most of the current me-
tabolomic studies resort to MS coupled with a
sarcoma, thus justifying the need for objective and reli- chromatography-based technique (gas chromatography,
able biomarkers. Three proteins were found to be sig- liquid chromatography, or capillary electrophoresis) to
k eers
rs
nificantly overexpressed in high-grade lesions: calcy-
clin, macrophage inhibitory factor, and calgranulin.
k eers
r s provide a very powerful and high resolution analysis.
Other recent technologic advances that further en-
b ooook b oook
Subsequent immunohistochemistry validated the over-
o
expression of calcyclin in high-grade lesions, providing
b ooo
hanced the performance of these analyses include the
o
use of tandem MS detectors and electrospray ionization
/
e e
/ eb ee/ e
/e b
a means to reliably predict tumor behavior and thus
/e/e b
interfaces. After sample analysis, each metabolite is
ee
/ t
///t m
guide therapeutic management. In addition, further ex-
. . m
ploration of the identified overexpressed proteins and
: : / t.
///t m
identified based on established reference libraries that
.m
are continuously updated.
s
tps : s
tps :
186
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Metabolomics for Biomarker Identification a mouse model.27 Fifty-two serum metabolites were
k eers
rs ke
The authors of a 2012 study attempted to establish a
errss found to have significantly different expression patterns
b ooook b ook
metabolic profile of synovium to identify OA at an
o o
early stage and objectively assess the severity of the dis-
in mice with osteosarcoma compared with controls, but
b o oo
o
most importantly, 56 metabolites were significantly dif-
/
ee/e b / e e b
ease.24 They compared synovial tissue samples from pa-
ee /
tients undergoing total knee arthroplasty for end-stage / e e b
ferent after the development of lung metastases com-
ee /
pared with the premetastatic stage. The detailed study
t
///t. m
.m
OA to those obtained from subjects undergoing nonre-
: / : / t
///t. m
. m
of the dynamic changes in the serum metabolome thus
s :
constructive knee surgery (meniscal or ligamental re-
tps s
tps :
provides biomarkers indicative of tumor behavior, pro-
hhtttp hhtttp
pair) and who presented minimal to no signs of OA. vides information about the metabolic alterations lead-
Among the 105 metabolites that were detected in the ing to tumor invasion and metastasis, and identifies po-
harvested synovial tissues, 11 showed significantly dif- tential therapeutic targets. The activity of IDH was also
ferent concentrations between the 2 groups. These found to correlate with tumor behavior in osteosar-
included biomarkers of collagen turnover (propyl- coma. IDH activity was downregulated during the tu-
hydroxyproline), cellular energetic pathways (acetyl- mor growth phase and was upregulated in the meta-
k rs
rs
carnitine, succinate, glutamine) and branched-chain
ee k eers
r s static phase, accompanied by an increase in
ook ook
amino acid catabolism. Moreover, the authors identi- 2-hydroxyglutarate, similar to what was observed in
b oo b oo
fied several metabolites that were in significantly differ-
b o oo
glioblastoma (discussed previously).23 This pathway
o
/
e e
/ eb e/
e e
/ e b
ent concentrations in synovial tissue compared with
control media, thus shedding new light on normal sy-
ee e
/ e b
seems to have a major role in the progression of tumors
/
to a more aggressive stage and might be the target of
t . m
. m
novial physiology and characterizing the biochemical
: // / t : / / t
/ .
t m
. m
future cancer therapies. The elevation of serum choles-
: /
properties of synovial cells. A particular finding was el-
ss ss /
terol and arachidonic acid levels indicated an important
:
hhtttp hhtttp
role of lipid metabolism disruption in metastatic osteo-
tp tp
evated levels of kynurenine, a metabolite of trypto-
phan, which is altered in several human diseases, espe- sarcoma, corroborating previous studies where inhibit-
cially neoplasias and neurologic disorders. ing cholesterol and arachidonic acid synthesis was
After preliminary studies revealing a characteristic found to prevent the metastatic progression of tu-
metabolic profile in the urine of guinea pigs with OA, a mors.28,29 A recent study showed an inverse dose-
human study was conducted in which the metabolic dependent effect between the amount of statin use and
k errss
profiles of urine from patients with hip and/or knee OA
e
were compared, selected from the Johnston County OA
k e rrss
e
the risk of prostate cancer, and clinical trials are ongo-
ing to evaluate the potential use of statins in prostate
bboooo k o o o
project, to those of sex-, age-, height-, and weight-
b o k cancer management.30
b o oo
o
/
e e
/ e e e
/ b
matched controls.25 They were able to identify a meta-
/ e
bolic fingerprint of OA in urine. Metabolic patterns
e e / e
/ e b
Metabolomics for Optimization of Disease
e
. m m
were also correlated to OA severity based on Kellgren-
t . t . m m
Treatment: Pharmacometabolomics
.
s : /
: /
/ / t
Lawrence grades. Because nuclear magnetic resonance
: / /
/ / t
Even though pharmacogenomics has played a major
s :
hhtttp
tp s
spectroscopy (not MS) was used, they were unable to
fully identify all the markers that yielded different sig-
nals between the two groups. Nonetheless, they demon- hhtttp
tp s
role in individualized drug treatments, it is associated
with many shortfalls, including the recognition of a
patient-specific effect on drug pharmacokinetics and
strated altered energy utilization and decreased levels of pharmacodynamics. Pharmacogenomic approaches
histidine in OA. Alterations in branched-chain amino have failed to reliably identify patients predisposed to
acid metabolism in OA has also been recently demon- drug-induced liver injury, and susceptibility seems to be
eers
strated in a 2010 study, whereby serum metabolic pro-
rs
files of patients with knee OA were compared to those
k k e r
e s
r s related to environmental factors in addition to genetic
predisposition.31 Thus, the pharmacometabolomic ap-
bboooo k b o o
o o
of controls.26 The authors found branched-chain amino
k
acid (valine, leucine, and isoleucine) to histidine ratios
b o oo
proach, was introduced, which assesses the environ-
o
/
e e
/ e e / e
/ e b
to be a highly reliable serum marker for knee OA.
e e / e
/ e b
mental influences on drug absorption, metabolism, and
excretion, in addition to genetic variation.32 Metabolic
e
: / / t
/ .
t m
Metabolomics-based studies performed on different
. m
biologic samples—including tissue, serum, and urine—
: / / t
/ .
t m
. m
profiling of rat urine was used before and after the ad-
ministration of toxic doses of acetaminophen, one of
t p ss
p : /
have established a metabolic fingerprint of OA. This
ss : /
the most common causes of drug-induced liver injury
t p p
t t
will enable the early diagnosis of OA in the orthopae-
hht
dic community by using easily accessible fluid samples.
It might also be useful to monitor the response to treat-
t
hht t
and a widely used drug in patients suffering from
chronic musculoskeletal pain. Specific urinary meta-
bolic profiles before drug administration were proven
ment, but more importantly, it contributes to under- to reliably predict drug metabolism as well as liver
standing of the underlying pathophysiology of the dis- damage. Based on these findings, the benefits of a phar-
k e rs
ease, guiding research studies on potential preventive
rs
treatments and disease-modifying agents for OA.
e k eers
r s
macometabolomic approach were projected to select
drug class and drug dose based on a patient’s metabolic
b ooook
Metabolomics in Cancer Management
b oook
o b ooo
phenotype. Researchers later conducted the first phar-
o
macometabolomic study in humans, but this time using
/
e e
/ eb ee/ e
/e b
The authors of a 2011 study have resorted to metabo-
/e/e b
a standard therapeutic dose.33 The urine levels of a co-
ee
/ t
///t m
lomic analysis to characterize osteosarcoma tumor cells
. . m
that become invasive and lead to lung metastases using
: / t.
///t m
lonic bacterial cometabolite, p-cresol, was found to sig-
.m
nificantly predict the extent of acetaminophen metabo-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
lism by sulfonation. It was concluded that p-cresol and dissecting the pathophysiology of complex diseases,
k eers
rs acetaminophen both compete for the same enzyme and
keerrss where multiple genetic and environmental factors are
b ooook b o ook
sulfate donor for sulfonation. By its large effect on the
o
sulfonation capacity of the body, p-cresol, and thus the
interlinked. Recent advances have been possible with
o oo
o
the benefit of high-end technology such as MS, which is
b
/
ee/e b ee/ e
/ e b
gut bacteria (host microbiome), may have a substantial
effect on the metabolism of several drugs (minoxidil,
ee/ e
/ e b
capable of detecting and characterizing a very large
number of molecules in a sample, as well as cutting-
t . m
.m
tamoxifen, and apomorphine) and hence partly explain
: / ///t
the individual variability in drug metabolism. Further- t . m
. m
edge bioinformatics systems capable of analyzing com-
: / ///t
plex data. Moreover, joint efforts among different insti-
s
tps : s
tps :
hhtttp hhtttp
more, many molecules in the body undergo sulfona- tutions on a global level have provided very powerful
tion, such as chondroitin sulfate, an important compo- studies with large sample sizes. Even though these ap-
nent of hyaline cartilage, and p-cresol might be linked proaches have substantially contributed to understand-
to a variety of diseases by acting on the metabolism of ing complex diseases, there is still a long way to go, es-
these molecules. High urinary levels have been associ- pecially in the field of musculoskeletal pathology. With
ated with the progression of multiple sclerosis, and re- additional technologic advances, and, most impor-
k eers
rs duced sulfonation of acetaminophen has been reported
k eer
in patients with chronic neurologic diseases and rheu-s
r s tantly, with increasingly common efforts among differ-
ent research teams, it is hoped that the understanding
b ooook matoid arthritis.34-36

b ooook o oo
of musculoskeletal disease pathology will evolve to al-
b o
/
e e
/ eb e/
e e
/ e b e / e
/ e b
low for identification of disease in early stages with re-
liable biomarkers and provide the means to administer
e
Future Trends
: // t/.tm
. m / / t
/ .
t m
personalized treatments, adapted to each individual pa-
. m
tient, with optimal chances of cure and minimal risk of
:
ss : /
Genomics-based studies will probably greatly benefit
ss : /
adverse effects.
hhtttp
tp hhtttp
tp
from next-generation sequencing technology, which is
able to provide a complete report of all variants associ-
ated with a certain disease instead of relying on a very
limited amount of common variants and on linkage dis-
equilibrium associations.5 Other fields of genomics that
rrss rrss
are on the horizon include epigenetic studies, which in-
o ke
ke o k e
vestigate the modifications that control the expression
k
of genetic material rather than the genetic information e oo
e bboo o e b
itself. DNA methylation, micro RNAs, and histone
o
b o o e b o
b o
/
e / e ee/ / e
acetylation have been suggested to play a substantial
role in the genetic basis of OA and are worthy of more
m
Key Study Points
m ee/ / e
t . . m t . .m
exploration.37-39
s : /
: /
/ / t
The future of proteomics will mainly benefit from
•
s : : /
/ / t
Genomics, proteomics, and metabolomics consti-
/
tute systematic approaches that evaluate the
hhtttp
tp s
technologic advances to optimize protein microarray
and chip technology.40 Even though DNA and RNA mi-
hhtttp
tp s
whole genetic, protein, or metabolic content of a
biologic sample. Studies based on these ap-
croarrays have been available for some time, and have proaches enrich knowledge about normal physi-
been widely used in cancer research, protein microar- ology, shed more light on disease pathophysiol-
rays are still not in widespread use. However, with the ogy, identify biomarkers able to detect diseases
increased proteins identified to play a role in various at an early stage or confirm disease diagnosis in
k eers
rs diseases and the intensive use of MS-based analysis,
k e
protein microarrays should witness significant progress r
e s
r s dubious cases, and establish therapeutic targets
bboooo k o o
and might prove to be essential in establishing pro-
b o o k •
that constitute the basis of modern therapies.
b o oo
o
Commonly encountered musculoskeletal pathol-
/
e e
/ e
teomic profiling of diseases.
e / e
/ e b
Metabolomics seem to have a very promising destiny
e ee/ e
/ e b
ogies, such as osteoarthritis, idiopathic scoliosis
or osteoporosis, follow a multifactorial genetic
: / / / .
t m m
in medicine. With the current heterogeneity of tech-
t . : / / t
/ .
t m
. m
inheritance pattern that cannot be explained by
t p ss : /
niques for sample analysis and software used for data
handling among different studies, future efforts should
p t ss : /
traditional genetics and that may greatly benefit
p p
t
hht t
focus on unifying study methods.41 Furthermore, many
metabolic markers reported to characterize certain dis-
eases still have not been properly identified, and efforts
t
hht
•
from studies based on these systematic ap-
t
proaches.
Pharmacogenomics, pharmacoproteomics, and
should be made toward populating metabolomic refer- pharmacometabolomics are being developed to
ence libraries and combining different libraries. provide the means for personalized treatment
k eers
rs k eers
r s
strategies. These studies would be adapted to
each individual patient, in addition to being tai-
b ooook Summary
b oook
o b ooo
lored to the nature and the severity of the dis-
o
ease, thus delivering the most effective cures with
/
e e
/ eb / e
/e b
The systemic approaches that profile the whole genetic,
ee ee/e/e b
the fewest adverse effects.
/ t
///t m
protein, or metabolic content of a biologic sample have
. . m
constituted the core of recent investigations aimed at
: : / t.
///t m
.m
s
tps : s
tps :
188
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
The authors review the identified effects of CYP2C9
k eerss
r keerrss polymorphisms on drug metabolism.
b ooook1.
b o ook
He Y, Yu Z, Giegling I, et al: Schizophrenia shows a
o 10.
o oo
o
Klein TE, Altman RB, Eriksson N, et al: Estimation of
b
/
ee/e b chiatry 2012;2:e149.
ee/ / e b
unique metabolomics signature in plasma. Transl Psy-
e ee/ e
/ e b
the warfarin dose with clinical and pharmacogenetic
data. N Engl J Med 2009;360(8):753-764.
: / ///t. mm
The authors used targeted metabolomics to show that
t .
metabolic deviations seen in plasma can be biomarkers
: /
11. t
///t. m
. m
Roper N, Storer B, Bona R, Fang M: Validation and
s
tps :
to help diagnose schizophrenia.
s
tps :
hhtttp hhtttp
comparison of pharmacogenetics-based warfarin dosing
algorithms for application of pharmacogenetic testing.
2. Warman ML, Cormier-Daire V, Hall C, et al: Nosology J Mol Diagn 2010;12(3):283-291.
and classification of genetic skeletal disorders: 2010 re-
vision. Am J Med Genet A 2011;155A(5):943-968. The authors performed an external validation of four
previously reported algorithms for warfarin dosing
The authors present a comprehensive list of genetic skel- based on a pharmacogenetics-based approach, including
k eers
rspattern, locus, gene, and protein.
k eers
etal disorders classified in 40 groups, with inheritance
r s the algorithm proposed by the International Warfarin

Pharmacogenetics Consortium.
b ooook3.
ooook
Hirschhorn JN, Gajdos ZK: Genome-wide association
b b o oo
o
/
e e
/ eb e/ e
/ e b
studies: Results from the first few years and potential
implications for clinical medicine. Annu Rev Med 2011;
e
12.
/ e
/ e b
Marin-Leblanc M, Perreault S, Bahroun I, et al: Valida-
tion of warfarin pharmacogenetic algorithms in clinical
ee
62:11-24.
: // t/.tm
. m : / / t
/ t m
practice. Pharmacogenomics 2012;13(1):21-29.
. . m
This paper evaluated the performance of four warfarin
ss : /
The authors review the outcomes of GWAS in recent
ss : / pharmacogenetic algorithms, including the one estab-
hhtttp hhtttp
years and their potential application in the clinical set-
4.
ting.
tp
Zeggini E, Panoutsopoulou K, Southam L, et al: Identi-
tp lished by the International Warfarin Pharmacogenetic
Consortium.
fication of new susceptibility loci for osteoarthritis 13. You JH, Tsui KK, Wong RS, Cheng G: Potential clinical
(arcOGEN): A genome-wide association study. Lancet and economic outcomes of CYP2C9 and VKORC1
genotype-guided dosing in patients starting warfarin
rrss rrss
2012;380(9844):815-823.
o ke
ke o
tifying five loci with genome-wide significance.
k e
This is the widest and most recent GWAS on OA, iden-
k e
therapy. Clin Pharmacol Ther 2009;86(5):540-547.
oo
e bboo o e b o
b o o 14.
o o
Melton L: Protein arrays: Proteomics in multiplex. Na-
e b b
/
e / e 5.
ee/ / e
van Meurs JB, Uitterlinden AG: Osteoarthritis year
2012 in review: Genetics and genomics. Osteoarthritis
m m ee/ / e
ture 2004;429(6987):101-107.
t . . m t . .m
15. Parvizi J, Ghanem E, Menashe S, Barrack RL, Bauer
s : /
: /
Cartilage 2012;20(12):1470-1476.
/ / t
The authors review the most recent advances in the ge-
s : /
: /
/ / t
TW: Periprosthetic infection: What are the diagnostic
6.
netics of OA.
hhtttp
tp s
Gorman KF, Julien C, Moreau A: The genetic epidemi- hhtttp
tp s challenges? J Bone Joint Surg Am 2006;88(suppl 4):
138-147.
ology of idiopathic scoliosis. Eur Spine J 2012;21(10): 16. Parvizi J, Zmistowski B, Berbari EF, et al: New defini-
1905-1919. tion for periprosthetic joint infection: From the Work-
The authors review the studies addressing the genetic group of the Musculoskeletal Infection Society. Clin Or-
k eers
rs k e
encountered in identifying the genes involved in ther
e s
r s
basis of idiopathic scoliosis and underline the difficulties thop Relat Res 2011;469(11):2992-2994.
This paper reports the new definition criteria for PJI es-
bboooo k pathophysiology of this disease.
b o o
o o k b o oo
tablished by the MSIS workgroup.
o
/
e e
/ e 7.
e / e
/ e b
Estrada K, Styrkarsdottir U, Evangelou E, et al:
e
17.
e / e
/ e b
Deirmengian C, Hallab N, Tarabishy A, et al: Synovial
e
: / t
/ .
t m
Genome-wide meta-analysis identifies 56 bone mineral
. m
density loci and reveals 14 loci associated with risk of
/ : / / t
/ .
t m
fluid biomarkers for periprosthetic infection. Clin Or-
. m
thop Relat Res 2010;468(8):2017-2023.
t p ss
p : /
fracture. Nat Genet 2012;44(5):491-501.
t p ss
p : /
The authors evaluated 23 potential synovial fluid bio-
t t
The authors present the results of the largest meta-
hht
analysis performed on GWAS attempting to identify the
genes implicated in the determination of BMD and the
t
hht t
18.
markers for accurately diagnosing PJI.
Jacovides CL, Parvizi J, Adeli B, Jung KA: Molecular

risk of low-trauma fracture.
markers for diagnosis of periprosthetic joint infection.
8. Hood E: Pharmacogenomics: The promise of personal- J Arthroplasty 2011;26(6, suppl):99, e1.
k eers
rsA581-A589.
k eer
ized medicine. Environ Health Perspect 2003;111(11):
s
r s The authors evaluated 46 synovial fluid proteins for ac-
curately diagnosing PJI.
b ooook b oook
o b oooo
/
e e
/ eb 9.
e e
/e b
He S-M, Zhou Z-W, Li X-T, Zhou S-F: Clinical drugs
/
undergoing polymorphic metabolism by human cyto-
e
19.
e /e/e b
Ruiz-Romero C, Carreira V, Rego I, Remeseiro S,
López-Armada MJ, Blanco FJ: Proteomic analysis of hu-
e
/ t
///t m
chrome P450 2C9 and the implication in drug develop-
. . m
ment. Curr Med Chem 2011;18(5):667-713.
: : / t.
///t m
man osteoarthritic chondrocytes reveals protein changes
.m
in stress and glycolysis. Proteomics 2008;8(3):495-507.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
20. Lambrecht S, Verbruggen G, Verdonk PC, Elewaut D, 30. Murtola TJ, Tammela TL, Määttänen L, et al: Prostate
k eers
rs rr
Deforce D: Differential proteome analysis of normal
kee ss cancer and PSA among statin users in the Finnish pros-
ook ook
and osteoarthritic chondrocytes reveals distortion of vi- tate cancer screening trial. Int J Cancer 2010;127(7):
b oo b o
mentin network in osteoarthritis. Osteoarthritis Carti-
o
1650-1659.
b o oo
o
/
ee/e b lage 2008;16(2):163-173.
ee/ e
/ e b ee/ e
/ e b
The authors evaluated the effect of cholesterol lowering
drugs on PSA levels and the incidence of prostate cancer
21.
t . m
.m
de Seny D, Sharif M, Fillet M, et al: Discovery and bio-
: / ///t
chemical characterisation of four novel biomarkers for
: / t . m
. m
in a cohort of 23,320 men who underwent screening for
///t
s
tps : s
tps : prostate cancer.
hhtttp hhtttp
osteoarthritis. Ann Rheum Dis 2011;70(6):1144-1152.
The authors sought biomarkers for OA by comparing 31. O’Connell TM, Watkins PB: The application of metab-
serum proteomic profiles between patients with differ- onomics to predict drug-induced liver injury. Clin Phar-
ent stages of OA, normal controls, and patients with macol Ther 2010;88(3):394-399.
rheumatoid arthritis.
The authors review the pharmaco-metabolomic ap-
proaches to predict drug-induced liver injury.
k eers
rs 22.
k eers
Holt GE, Schwartz HS, Caldwell RL: Proteomic profil-
r
ing in musculoskeletal oncology by MALDI mass spec- s
b ooook o ook
trometry. Clin Orthop Relat Res 2006;450:105-110.
b o
32.
oo
Clayton TA, Lindon JC, Cloarec O, et al: Pharmaco-
o o
metabonomic phenotyping and personalized drug treat-
b
/
e e
/ eb 23.
e/ e
/ e b
Dang L, White DW, Gross S, et al: Cancer-associated
e ee/ e
/ e b
ment. Nature 2006;440(7087):1073-1077.
2009;462(7274):739-744.
: // t/.tm
IDH1 mutations produce 2-hydroxyglutarate. Nature
. m 33.
: / / t
/ .
t m
. m
Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson
ss : / ss : /
JK: Pharmacometabonomic identification of a signifi-
hhtttp
tp hhtttp
tp
cant host-microbiome metabolic interaction affecting
24. Adams SB Jr, Setton LA, Kensicki E, Bolognesi MP, human drug metabolism. Proc Natl Acad Sci USA
Toth AP, Nettles DL: Global metabolic profiling of hu-
2009;106(34):14728-14733.
man osteoarthritic synovium. Osteoarthritis Cartilage
2012;20(1):64-67.
34. Bradley H, Waring RH, Emery P, Arthur V: Metabolism
The authors undertook metabolic profiling of cultured of low-dose paracetamol in patients with rheumatoid
rrss rrss
synovial tissue from osteoarthritic joints and joints with arthritis. Xenobiotica 1991;21(5):689-693.
o ke
ke nature of OA.
o k e
no evidence of OA, aiming to identify a biochemical sig-
k e oo
e bboo o e b o
b o o 35.
e b o
Steventon GB, Heafield MT, Waring RH, Williams AC,
b o
Sturman S, Green M: Metabolism of low-dose paraceta-
/
e / e 25.
ee/ e
Lamers RJ, van Nesselrooij JH, Kraus VB, et al: Identi-
/
fication of an urinary metabolite profile associated with
m m ee/ / e
mol in patients with chronic neurological disease. Xen-
t . . m . m
obiotica 1990;20(1):117-122.
t .
762-768.
s : /
: /
osteoarthritis. Osteoarthritis Cartilage 2005;13(9):
/ / t s : /
: /
/ / t
26.
hhtttp
tp s
Zhai G, Wang-Sattler R, Hart DJ, et al: Serum
branched-chain amino acid to histidine ratio: A novel hhtttp
36.
tp s Cao L, Kirk MC, Coward LU, Jackson P, Whitaker JN:

p-cresol sulfate is the dominant component of urinary
myelin basic protein like material. Arch Biochem Bio-
metabolomic biomarker of knee osteoarthritis. Ann phys 2000;377(1):9-21.
Rheum Dis 2010;69(6):1227-1231.
37. Barter MJ, Bui C, Young DA: Epigenetic mechanisms in
The authors identified specific changes in serum meta-
k eers
rs bolic profiles in patients with OA.
k e r
e s
r s
cartilage and osteoarthritis: DNA methylation, histone
modifications and microRNAs. Osteoarthritis Cartilage
bboooo k 27.
o o
o o k
Hua Y, Qiu Y, Zhao A, et al: Dynamic metabolic trans-
b
2012;20(5):339-349.
b o oo
o
/
e e
/ e ee e
/ e b
formation in tumor invasion and metastasis in mice
/
with LM-8 osteosarcoma cell transplantation. J Pro-
e / e
/ e b
The authors review current evidence on epigenetic phe-
nomena in the pathogenesis of OA.
e
: / / t
teome Res 2011;10(8):3513-3521.
/ .
t m
. m 38.
/ / t
/ .
t m
. m
Gabay O, Sanchez C: Epigenetics, sirtuins and osteoar-
:
t p p : /
The authors undertook serum metabolic profiling in an
ss
osteosarcoma mice model. Characteristic changes were
t p ss
p : /
thritis. Joint Bone Spine 2012;79(6):570-573.
t
hht t
found in the serum metabolome at different stages of tu-
mor progression. t
hht t The authors review the role of chromatin-modifying en-
zymes in the pathogenesis of OA.
28. Kort WJ, Hülsmann WC, Stehman TE: Modulation of 39. Reynard LN, Loughlin J: Genetics and epigenetics of os-
metastatic ability by inhibition of cholesterol synthesis. teoarthritis. Maturitas 2012;71(3):200-204.
k eers
rs Clin Exp Metastasis 1989;7(5):517-523.
k eers
r s The authors review the role of epigenetics in the patho-
genesis of OA.
b ooook 29.
oook
Suzuki I, Iigo M, Ishikawa C, et al: Inhibitory effects of
b o b oooo
/
e e
/ eb e / e
/e b
oleic and docosahexaenoic acids on lung metastasis by
colon-carcinoma-26 cells are associated with reduced
e
40.
e /e/e b
Gobezie R, Millett PJ, Sarracino DS, Evans C, Thornhill
TS: Proteomics: Applications to the study of rheumatoid
e
cer 1997;73(4):607-612.
: / t
///t m
matrix metalloproteinase-2 and -9 activities. Int J Can-
. . m : / t.
///t m
arthritis and osteoarthritis. J Am Acad Orthop Surg
.m
2006;14(6):325-332.
s
tps : s
tps :
190
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
41. Zhang A, Sun H, Wang X: Serum metabolomics as a
k eers
rs keerrss
novel diagnostic approach for disease: A systematic re-
ook ook
view. Anal Bioanal Chem 2012;404(4):1239-1245.
b oo b o o
The authors provide a comprehensive review of serum
b o oo
o
/
ee/e b ee/ e
/ e b
metabolomic analysis and highlight its role in identify-
ing disease biomarkers and diagnosing diseases at a very
ee/ e
/ e b
early stage.
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / /t/.tm.m
ss : / ss : /
hhtttp
tp hhtttp
tp
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 17
e rs
rs e rrss
oo
kBone
ook e and Calcium o Metabolism
k
ook
o
e o oo
o
/e/ebb Parth A. Vyas, MD
e / e
/ b
e b
Anish Potty, MD
e
Vinay Aggarwal, BA
/ e
/ b
e b
Gregg Klein, MD Joseph M. Lane, MD
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
gen and noncollagenous proteins, such as osteopontin,
Introduction osteocalcin, fibronectin, thrombospondin, bone sialo-
k eerss k ee
of biologic activity. The human skeleton serves uniquers
Bone is a specialized connective tissue with a high level
r r s
protein, growth hormones, and cytokines.2 The inor-
ganic portion is composed of hydroxyapatite crystals,
b ooook o ook
and vital mechanical and biologic functions, which in-
b o b oo
with the composition Ca10(PO4)6(OH)2. Hydroxyapa-
o o
tite consists of 65% to 70% of the dry weight of bone,
/
e e
/ eb e e
/ e b
clude but are not limited to providing supporting
/
framework; protecting vital organs; providing attach-
e ee/ e
/ e b
is responsible for its mechanical properties, and is the
: // t/.tm
. m
ment sites to ligaments and muscles; storing minerals
: / / t
/ t m
primary reservoir of calcium and phosphorus.1
. . m
ss /
such as calcium, phosphorus, and sodium; and provid-
: ss : /
hhtttp hhtttp
ing space for hematopoietic and lymphopoietic activi-
tp
ties. To meet these functions effectively, bone has two
distinct structural components. Cortical or compact tpCellular Regulation of Bone
and Calcium Metabolism
bone is responsible for strength and resistance to tensile Osteoprogenitor cells are mesenchymal stem cells
and sheer forces, whereas cancellous or trabecular bone found near all bony surfaces. When stimulated by
has a higher surface area and is mainly responsible for Runt-related transcription factor 2/core-binding factor
k errss
metabolic and biologic functions.1
e k e rrss
e
subunit α-1 (RUNX2/CBFA1) transcription factor net-
bboooo k b o o
o o k work and the Wnt/β-catenin signaling pathway, these
b o oo
o
cells are capable of differentiation to osteoblasts.
/
e e
/ e Composition of Bone
ee/ e
/ e b ee/ e
/ e b
Osteoblasts synthesize, transport, and arrange the
many proteins of matrix and initiate the process of
t . m m
Bone is composed of organic matrix and inorganic min-
. t . m.m
mineralization. Osteoblasts have receptors that bind
s : /
: /
/ / t
erals. The organic matrix is composed of type 1 colla-
: / /
/ / t
regulatory hormones (parathyroid hormone [PTH], vi-
s :
hhtttp
tp s hhtttp s
tamin D, leptin, and estrogen), cytokines, growth fac-
tp
tors, and extracellular matrix proteins and, in turn, ex-
press several factors that regulate the differentiation
Dr. Klein or an immediate family member is a member of
a speakers’ bureau or has made paid presentations on be- and function of osteoclasts. Osteoblasts surrounded by
half of Zimmer; serves as a paid consultant to or is an em- newly deposited organic matrix transform into osteo-
ployee of Biomet and Zimmer; has received research or in- cytes; alternatively, osteoblasts remaining on the bone
k rs
rs
stitutional support from Zimmer; and serves as a board
ee k e r
e s
r s surface may become flattened and quiescent bone-
lining cells.1
bboooo k
member, owner, officer, or committee member of the
b o o
American Academy of Orthopaedic Surgeons. Dr. Lane or
o o k b o oo
Osteocytes communicate with each other and the
o
/
e e
/ e ee e
/ e b
an immediate family member is a member of a speakers’
/
bureau or has made paid presentations on behalf of Am-
e e
/ e b
cells on the bone surface via an intricate network of cy-
/
toplasmic processes known as canaliculi, and they help
e
: / / t
/ .
t m m
gen, Eli Lilly, Novartis, and Weber Chilcott; serves as a paid
. : / / t
/ .
t m
. m
control calcium and phosphate levels in the microenvi-
ronment and detect and translate mechanical forces
t p ss : /
consultant to or is an employee of Amgen, CollPlant, Bone
Therapeutics, SA, BioMimetics, DFine, Graftys, and Zim-
p t p ss : /
into biologic activity (mechanotransduction).
p
t
hht t
mer; has received research or institutional support from
Amgen; and serves as a board member, owner, officer, or
committee member of the Orthopaedic Research Society,
t
hht t
Osteoclasts are the cells responsible for bone resorp-
tion and are derived from the same hematopoietic pro-
genitor cells that also give rise to monocytes and mac-
the Musculoskeletal Tumor Society, the American Acad- rophages. The cytokines and growth factors that
emy of Orthopaedic Surgeons, the Association of Bone regulate human osteoclast differentiation and matura-
k eers
and Joint Surgeons, the American Orthopaedic Associa-
rs k e
tion, and the American Society for Bone and Mineral Re-
ers
r s
tion include macrophage colony-stimulating factor
(M-CSF), interleukin-1 (IL-1), and tumor necrosis fac-
b ooook b ook
search. None of the following authors nor any immediate
oo b oooo
tor (TNF). Mature multinucleated osteoclasts (contain-
ing 6 to 12 nuclei) form from the fusion of circulating
/
e e
/ eb e / e
/e b
family member has received anything of value from or has
e ee/e/e b
mononuclear precursors and have a limited life span
/ t
///t m
. . m
this chapter: Dr. Vyas, Dr. Potty, and Mr. Aggarwal.
: : / t.
///t m
(approximately 2 weeks). The osteoclast signaling path-
.m
way involves three factors: (1) the transmembrane re-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
ceptor activator of nuclear factor-κB (RANK), which is liver, and 25 hydroxy vitamin D is converted to 1,25 di-
k eers
rs expressed on osteoclast precursors; (2) RANK ligand
keerrss hydroxyvitamin D (the active form) in the kidneys. Vi-
b ooook o ook
(RANKL), which is expressed on osteoblasts and mar-
o
row stromal cells; and (3) osteoprotegerin (OPG), a se-
b
tamin D stimulates the synthesis of calcium-binding
b o oo
o
proteins in the gut and the kidneys and promotes cal-
/
ee/e b ee/ e
/ e b
creted “decoy” receptor made by osteoblasts and sev-
eral other types of cells that can bind RANKL and thus
ee/ e
/ e b
cium absorption at these sites. It also promotes phos-
phate absorption from the gut and mineralization of
t . m
.m
short-circuit its interaction with RANK. When stimu-
: / ///t : / t
///t. m
. m
the skeleton. The effects of vitamin D are not limited to
bones. Recently, its influence on immunology, muscle
s
tps :
lated by RANKL, RANK signaling activates the trans-
s
tps :
hhtttp hhtttp
cription factor NF-κB, which is essential for the gener- function, and pathogenesis of some tumors has been
ation and the survival of osteoclasts. A second identified. 25 hydroxyvitamin D level in serum is the
important pathway involves M-CSF produced by osteo- preferred laboratory assay to evaluate vitamin D sta-
blasts and the M-CSF receptor, which is expressed by tus.5
osteoclast progenitors. Activation of the M-CSF recep- The role of FGF-23 in bone biology was first identi-
tor stimulates a tyrosine kinase activity that is also cru- fied in human genetic and acquired rachitic diseases,
k eers
rs k
pathway is the Wnt/β-catenin pathway. Wnt proteins
eers
r s
cial for the generation of osteoclasts. The other notable such as autosomal dominant hypophosphatemic rick-
ets, tumor-induced osteomalacia, and X-linked hypo-
b ooook o ook
produced by marrow stromal cells bind to the low-
b o b o oo
phosphatemic rickets. In these conditions, increased
o
/
e e
/ eb e e
/ e b
density lipoprotein receptor-related protein 5 (LRP5)
/
and LRP6 receptors on osteoblasts and thereby trigger
e e / e
/ e b
levels of the protein are accompanied by impaired tu-
bular phosphate reabsorption, hypophosphatemia, low
e
: // t/.tm
the activation of β-catenin and the production of OPG.
. m
Osteoclasts share many characteristics of foreign body
: / / t
/ .
t m
(or inappropriately normal) levels of 1,25 dihydroxyvi-
. m
tamin D, and impaired skeletal mineralization (rickets
ss : /
giant cells, such as their common origin from
ss : /
or osteomalacia). More recently, FGF-23 has also been
hhtttp
tp hhtttp
tp
monocyte-macrophage lineage and their response to in- shown to regulate PTH metabolism based on observa-
flammatory cytokines such as TNF and IL-1. They bind tions that it can suppress PTH secretion both in vitro
to the bone surface via integrins, where they form an and in vivo.6
underlying resorption pit. The cell membrane overlying
the resorption pit is thrown into numerous folds (the
rrss rrss
ruffled border). The osteoclast removes the mineral by Bone Quality and Density
o ke
ke generating an acidic environment using a proton pump
o k
system and digests the organic component by releasing e
k e oo
The optimal health of the skeleton relies on both qual-
e bboo o proteases.3
e b o
b o o e b o o
ity and quantity of bone. Bone resorption and forma-
b
/
e / e m ee/ / e ee/ / e
tion are closely coordinated procedures that assist in
the growth, development, and repair of microdamage
m
t . . m t . .m
s :
Hormonal Regulation of Bone
/
: /
/ / t s : /
: /
to bone. Bone formation predominates during the first
/ / t
two to three decades of life, and peak bone mass is
and Calcium Metabolism
hhtttp
tp s
All the aforementioned cellular activities are closely
hhtttp
tp s
achieved in the third decade of life. After the fourth de-
cade of life, bone resorption predominates, and a con-
regulated by hormonal influences. PTH, vitamin D, and stant decrease in bone mass is observed. In females, a
calcitonin are major hormones involved in bone min- precipitous decrease in bone mass occurs around meno-
eral homeostasis, but other factors such as thyroid, in- pause because of the lack of anabolic effects of estro-
sulin, insulin-like growth factor, growth hormone, and gen. In addition to hormonal factors, other factors such
k eers
rs prostaglandins also play some part. The role of fibro-
k
blast growth factor-23 (FGF-23) is being discussed in
e r
e s
r s as polymorphisms in the receptors for vitamin D and
LRP5/6, nutrition, physical activity, and age can also
bboooo k o
relation to bone mineralization and some hypophos-
b o
o o k b o oo
influence bone mass and bone mineral density.1
o
/
e e
/ e
phatemic conditions.
e / e
/ e b
Parathyroid glands identify low calcium levels in ex-
e e e
/ e b
Bone quality is an important and independent pa-
/
rameter of bone health. Inadequate mineralization,
e
: / / / .
t m m
tracellular fluid and respond by secreting PTH, which
t . : / / t
/ .
t m
. m
most commonly a result of vitamin D deficiency, is an
t p ss : /
then increases calcium reabsorption and decreases
phosphate reabsorption in renal tubular cells. PTH also
p t p ss : /
important bone quality issue encountered in routine
clinical practice. Accumulation of microdamage as a re-
p
t
hht t
increases calcium absorption from the gut through
an increased conversion of vitamin D into the active
1,25-OH metabolite. It stimulates osteoblasts directly
t
hht t
sult of the inability to repair bone wear and tear is an
important bone quality issue in patients on long-term
antiresorptive therapy, although bone quantity and
and osteoclasts indirectly through osteoblasts. The ef- density can be normal in such patients.
fect of PTH on bone is dual and complex, but it ulti-
k eers
rs mately increases bone resorption. The net effect of PTH
k eers
r
is an increase in serum calcium level, when it is contin- s Osteopenia and Osteoporosis
b ooook test to evaluate PTH status in the body.

b ook
uously released.4 Intact PTH is the preferred laboratory
oo b oooo
Reduced bone mineral density (BMD) is prevalent in el-
/
e e
/ eb ee/ e
/e b
Vitamin D is either generated from the diet or is syn-
/e/e b
derly individuals. Because of increased life expectancy,
ee
/ t
///t m
thesized in the skin because of the effect of ultraviolet
. . m
light. It is converted into 25 hydroxyvitamin D in the
: / t.
///t m
BMD issues can be major public health liabilities. For
.m
instance, the estimated lifetime risk of having a hip
:
s
tps : s
tps :
194
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 17: Bone and Calcium Metabolism
fracture and a vertebral fracture in a 50-year-old Amer- trasonography are described in the literature, but a lack
k eers
rs ke
ican woman is 17.5% and 15.6%, respectively. Accord-
errss of standards for comparison limits their use in clinical
b ooook o ook
ing to World Health Organization (WHO) guidelines,
o
osteoporosis is defined as having a BMD of 2.5 stan-
b
practice.
b o oo
o
/
ee/e b ee/ e
/ b
dard deviations below the young normal mean, and os-
e
teopenia is defined as BMD between −1 to −2.5 stan- / e
Fracture Risk Assessment
ee / e b
BMD is an excellent tool for detecting osteoporosis and
t . m
.m
dard deviations from the young normal mean.7
: / ///t t
///t. m
. m
is an effective predictor of fracture risk. Despite the
: /
s
tps : s :
high specificity of BMD, the sensitivity of DEXA is low.
tps
hhtttp hhtttp
Risk Factors for Low BMD In addition to BMD measured by DEXA, several other
Several factors are found to have a role in the develop- factors affect an individual’s probability of having a
ment of osteoporosis. Calcium intake, physical activity, fracture. A history of low-energy fracture is a strong
early menarche, and late menopause are associated predictor of future fractures. In a patient with a verte-
with higher BMD, whereas smoking,8 family history, bral fracture, the probability of experiencing another
white race, low body weight, and glucocorticoid intake vertebral fracture during the first year is 19.2%, and
k rs
rs rs
r
are considered significant risk factors for the develop-
ee k ee s having a vertebral fracture at baseline increases the
ook ook
ment of osteopenia or osteoporosis. Multiparity, lacta- probability of having another in 1 year by fivefold.10
b oo b o
tion, caffeine intake, and alcoholism are also consid-
o b o oo
o
Another study has shown that persons with prior hip
/
e e
/ eb lacking.7
ee e
/ b
ered important risk factors, but conclusive evidence is
/ e ee/ e
/ e b
fractures are at three times higher risk and those hospi-
talized with other nonhip fractures are at 1.8 times
: // t/.tm
. m t . m
. m
higher risk of subsequent fractures.11 Other significant
: / / / t
ss : /
Screening and Detection Strategies
: /
risk factors include low body mass index, glucocorti-
ss
hhtttp
tp hhtttp
tp
Screening of elderly individuals for the presence of os- coid exposure, a parental history of hip fracture, smok-
teoporosis or osteopenia is considered an effective ing, excessive intake of alcohol, and rheumatoid arthri-
strategy to prevent potentially hazardous complica- tis.
tions, such as fractures. Considerable controversies ex- WHO has developed an online fracture risk assess-
ist regarding the optimum testing interval. Dual energy ment tool (FRAX) that incorporates all the aforemen-
x-ray absorptiometry (DEXA) scans are usually re- tioned risk factors and calculates the probability of an
k errss
peated at 2-year intervals in all patients and at 1 year
e k
intervals in patients who have a change in treatment.7
e rrss
e
individual having an osteoporotic fracture in 10 years.
Treatment should be considered for patients with os-
bboooo k o o o k
Considerable data are in support of longer testing inter-
b o b o oo
teopenia in whom the 10-year risk of hip fracture is 3%
o
/
e e
/ e score greater than −1.5).9
ee e
/ e b
vals in people with normal or slightly low BMD (T-
/ e e
/ e b
or the 10-year risk of a major osteoporosis-related frac-
/
ture is 20% as assessed with FRAX.12 The National
e
t . m
. m t . m.m
Osteoporosis Foundation (NOF) estimates that 10 mil-
Indications for BMD Testing
s : /
: /
/ / t s : /
: /
/ / t
lion people in the United States have osteoporosis, and
hhtttp
tp s
BMD testing is indicated in women at least 65 years of
age and men at least 70 years of age regardless of clin-
ical risk factors; younger postmenopausal women and hhtttp
tp s
almost 34 million more are at increased risk because of
osteopenia and other associated risk factors that may
impair bone quality.7 Thus, most patients with in-
men age 50 to 69 years about whom there is concern creased fracture risk are osteopenic, but not osteoporo-
based on their clinical risk factor profile; women in the tic. It is the large population of osteopenic patients in
menopausal transition phase if there is a specific risk which it is difficult to make treatment-related decisions;
k eers
rs
factor associated with increased fracture risk, such as
low body weight, prior low-trauma fracture, or medi-
k e r
e s
r
thus FRAX is an extremely helpful tool.
s
bboooo k b o o o
cation for high risk; adults who have a fracture after
o k b o oo
Treatment of Osteoporosis and Osteopenia
o
/
e e
/ e e e
/ e b
age 50 years; adults with a condition (such as rheuma-
/
toid arthritis) or who are taking medication (for exam-
e e / e
/ e b
The primary goal of the treatment of osteoporosis is
prevention of fragility fractures and the potential dev-
e
: / / t
/ .
t m
ple, glucocorticoids in a daily dose ≥ 5 mg prednisone
. m
or equivalent for ≥ 3 months) associated with low bone
: / / t
/ .
t m
. m
astating complications resulting in increased morbidity
and mortality and decreased function. Because osteopo-
t p ss : /
mass or bone loss; anyone being considered for phar-
p t p ss
p : /
rosis is a generalized problem (throughout the skele-
t
hht t
macologic therapy for osteoporosis; anyone being
treated for osteoporosis to monitor treatment effect;
and anyone not receiving therapy in whom evidence of
t
hht t
ton), it can influence both management and outcome of
almost all orthopaedic conditions, which mainly in-
clude degenerative spine and joint disorders.
bone loss would lead to treatment.7 DEXA is currently There is sufficient evidence that osteoporosis treat-
the most widely used method and gold standard for os- ment is most effective in terms of patient compliance
k eers
teoporosis detection and follow-up. A DEXA scan is
rs e
done on the hips, lumbar spine, and forearm. A periph-
k ers
r s
when it is initiated by orthopaedic surgeons. According
to a randomized controlled study, adherence to treat-
b ooook b ook
eral DEXA scan has also been suggested because it re-
oo
duces radiation exposure. The accuracy and the preci-
b oooo
ment occurred in 58% of patients when treatment was
initiated and followed by an orthopaedic surgical team
/
e e
/ eb / e
/e
sion of a peripheral DEXA scan in fracture risk
ee b ee/e/e b
compared with 29% when primary care physicians ini-
/ t
///t m
prediction is yet to be established.7 In addition to
. . m
DEXA, other methods such as quantitative CT and ul-
: : / t.
///t m
tiated the treatment.13 In another study of BMD testing,
.m
discussion about osteoporosis and the initiation of
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
Pharmacologic Interventions
k eers
rs
Table 1
keerrss
Drugs are considered the most predictable method for
b ooook Antiosteoporotic Drugs
b o ook
o
treating osteoporosis (Table 1). The NOF recommends
o oo
o
drug interventions in people with a hip or vertebral
b
/
ee/e b Antiresorptive Agents Anabolic Agents
ee/ e
/ e b ee e
/ e b
(clinical or morphometric) fracture, a T-score ≤ −2.0 at
/
the femoral neck or spine after appropriate evaluation
Bisphosphonates
Calcitonin
: / ///t.
PTH 1-84 m
Teriparatide (PTH 1-34)
t .m : / t
///t. m
. m
to exclude secondary causes, low bone mass (T-score
between −1.5 and −2.0 at the femoral neck or spine),
Estrogen
s
tps :
Strontium ranelate
s
tps :
hhtttp hhtttp
Estrogen agonists/ (notapproved by FDA) and a 10-year probability of a hip fracture ≥ 3% or a
antagonists 10-year probability of a major osteoporosis-related
Denosumab fracture ≥ 20% based on the United States-adapted
PTH = parathyroid hormone.
WHO algorithm.
In routine clinical practice, antiresorptive agents are
usually used first to treat osteoporosis. Four bisphos-
k eers
rs k eers
r s
phonates are approved by the FDA for osteoporosis
management. Alendronate, risedronate, and ibandro-
b ooook oo
treatment were three times higher in patients in whom
b ook b o oo
nate are orally administered, whereas zolendronic acid
o
/
e e
/ eb e/
e e
BMD testing was ordered by a treating orthopaedic
/ e b
surgeon than in patients for whom a letter was sent to
e / e
/ e b
is administered intravenously. Both alendronate and
risedronate treatment can reduce vertebral and hip
e
t . m
. m
their primary care physician by the treating orthopae-
: // / t / / t
/ .
t m
fractures by approximately 45%. Risedronate can re-
. m
duce the incidence of vertebral and hip fractures, by
:
ss : /
dic surgeon after a distal end radius fracture.14 General
ss : /
70% and 41%, respectively. Ibandronate is adminis-
hhtttp
tp hhtttp
tp
guidelines for treatment are discussed in this section, tered as a monthly oral tablet and is comparable to
but it is important to understand that an individualized alendronate and risedronate for preventing vertebral
approach is required for optimum management. fractures, but its efficacy for hip fracture is yet to be
proven. Fracture risk reduction with zolendronic acid is
Nonpharmacologic Intervention 35% for all fractures and 70% for vertebral fractures.
Because osteoporosis is a multifactorial disorder, its
rrss rrss
Zolendronic acid is administered intravenously once
o ke
ke
treatment requires a careful mixture of lifestyle inter-
ventions.
o k e
k
per year to avoid unpleasant gastric side effects and
e oo
esophagitis, and compliance is ensured. The deposition
e bboo o Diet is an important factor in maintaining bone

e b o
b o o e b o o
of bisphosphonates in long bones and a long physio-
b
/
e / e 1,200 mg and vitamin D intake between 600 and
m ee/ e
health. In general, calcium intake between 1,000 and
/ m ee/ / e
logic half-life are responsible for a small incidence of
atypical fractures.16 Estrogen and estrogen-like agents
t . . m t . .m
s : : /
/ t
800 IU is recommended to maintain positive calcium
/ /
balance and reduce bone loss. A diet high in fiber and
s : /
: /
in females can prevent bone loss, but the benefits
/ / t
should be carefully weighed against the potential risk
hhtttp
tp s
sodium can reduce calcium absorption, and the dose of
calcium should be adjusted accordingly. In addition to
hhtttp
tp s
for gynecologic malignancies. Of the selective estrogen
receptor modulators currently approved for clinical
calcium and vitamin D, magnesium, boron, vitamin C, use, only raloxifene has been approved for the preven-
and vitamin K are important for skeletal health, but tion and treatment of osteoporosis. Raloxifene has con-
routine supplementation for these nutrients is not rec- sistently proven to increase BMD in the lumbar spine
ommended. It is worth noting that calcium and vitamin and the femoral neck by 2% to 3% and decrease levels
k eers
rs D requirements in elderly individuals vary considerably
k e r
e s
r s
of bone-turnover markers by 30% to 40% (levels com-
parable with mean levels found in premenopausal
bboooo k b o
underlying malabsorption; thus, it is important to mon-o
based on diet, ultraviolet light exposure, medicines, and
o o k b o oo
women). Raloxifene can significantly reduce the risk of
o
/
e e
/ e / e e b
itor the serum levels of calcium, 25-hydroxyvitamin D,
ee / e e
/ e b
vertebral fracture, but its efficacy for the prevention of
/
hip fractures has not yet been proven.16 Estrogen can
e
: / / t
/ t m
and PTH and periodically adjust the doses.15
. . m
Exercise is important in building and maintaining
: / / t
/ .
t m
. m
increase bone mass and reduce fracture risk, but it is no
ss : /
peak bone mass.7 A general recommendation is that ex-
t p p t p ss : /
longer used in the management of osteoporosis because
it is associated with an increase in the incidence of
p
t t
ercises should be performed two to three times per
hht
week and must include weight bearing and impact ex-
ercises. During the exercise program, care should be
t
hht t
breast and endometrial cancers.
Denosumab is a fully human monoclonal antibody
against RANKL that prevents the interaction of
taken to assign loading exercises to the areas that are RANKL with its receptor (RANK) on osteoclasts and
prone to fragility fractures, particularly the spine and osteoclast precursors and reversibly inhibits osteoclast-
k eers
rs
the hip. Fall prevention strategies, such as balance and
gait training; tai-chi; muscle conditioning; and the use
k eers
mediated bone resorption. Denosumab can effectively
r s
reduce the risk of vertebral fracture by 68% and hip
b ooook of appropriate assisting devices, hip protectors, and
b oook
o
protective flooring can make a difference in an individ-
b ooo
fracture by 40%. Denosumab is promptly reversible
o
but is also associated with atypical fractures and jaw
/
e e
/ eb ee/ e
/e b
ual’s probability of having a fragility fracture. Neuro-
/e/e
necrosis with prolonged use.17
ee b
should be adequately treated.
: / t
///t m
logic disorders such as dementia and parkinsonism
. . m / t.
///t m
Calcitonin-salmon is FDA approved for the treat-
.m
ment of osteoporosis in women who are at least 5 years
:
s
tps : s
tps :
196
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
postmenopause. Calcitonin was found to exert its anti- Over-the-counter preparations are half the weight of
k rs
rs rrss
resorptive effects via directly reducing osteoclastic re-
ee kee
the recommended dose, and citrate contains half the el-
b ooook b o ook
sorption and thus leads to an increase in BMD and
o
bone strength. Furthermore, calcitonin appears to
emental strontium than ranelate, and thus its efficacy in
o oo
o
antiosteoporosis treatment is doubtful.
b
/
ee/e b ee/ e
/ e b
mainly target the most active osteoclasts; in contrast to
most other antiresorptive agents, it does not reduce the
ee/ e
/ e b
Monitoring of the patient for response to treatment
is of vital importance to prevent adverse effects and en-
t . m
.m
number of osteoclasts. Its action on osteoclasts is re-
: / ///t
versible; although attenuating resorption, calcitonin t . m
. m
sure patient compliance. Both laboratory parameters
: / ///t
and BMD should be periodically measured in patients
s
tps : s
tps :
hhtttp hhtttp
treatment does not interfere markedly with bone for- on drug therapy. For treatment monitoring, the NOF
mation, in contrast to other currently available antire- recommends that a central DEXA scan be done at
sorptive agents.18 Calcitonin reduces the risk of verte- 2-year intervals, with reduction in the screening inter-
bral fracture, but evidence regarding its efficacy in the val if found necessary by the clinician. All the DEXA
reduction of risk for hip fractures is weak.19 It is mostly scans should be done at the same place with the same
used in patients with active vertebral fracture because it technology and should be read by the same person to
k eerss
benefit of pain relief.20
k eers
does not inhibit fracture healing and has an additional
r r s make valid comparisons. Quantitative CT can also be
helpful in this regard. Peripheral DEXA or quantitative
b ooook b ooook
Teriparatide is indicated for use in patients in whom
o oo
ultrasonography do not change predictably in patients
b o
/
e e
/ eb e/ e
/ e b
first-line agents fail, those with an active fracture, and
for low turnover osteoporosis. Teriparatide is PTH 1-
e e / e
/ e b
undergoing treatment and thus are not recommended.
Laboratory tests should be done to measure calcium
e
: // t/.tm
34, which is genetically engineered fractionated PTH.
. m
When administered intermittently, both PTH 1-34 and
/ / t
/ .
t m
and vitamin D levels. PTH level can also be a useful
. m
guide to judge serum calcium and vitamin D levels.
:
ss : /
PTH 1-84 stimulate osteoblasts and produce anabolic
ss : /
Bone-specific alkaline phosphatase, osteocalcin, and
hhtttp
tp hhtttp
tp
effects on bone. After prolonged treatment, PTH also N-terminal peptide of type 1 collagen are markers of
stimulates osteoclasts, but anabolic action still predom- osteoblastic function and should be elevated in patients
inates, and the ultimate effect is bone formation.4 The being treated by anabolic agents. Urinary N-terminal
increase in BMD by PTH 1-34 daily subcutaneous dose telopeptide or serum C-terminal telopeptide are the
is 13% every 2 years.21 The risk of vertebral fracture markers of bone resorption and should decrease in pa-
rrss rrss
and nonvertebral fracture is reduced by 65% and 53%, tients on antiresorptive drugs. It is worth mentioning
o ke
ke o k e
respectively. Teriparatide can also reverse potential ad-
k
verse effects of long-term bisphosphonate therapy, such e
that to be valid, these tests should be done in the morn-
oo
ing after fasting overnight and preferably at the same
e bboo o e b o o o
as osteonecrosis of the jaw and stress reaction in the
b
laboratory every time.7
e b o
b o
/
e / e ee/ e
cortex of the femur. It has a potential risk for osteosar-
/
coma, proven in animal studies at doses 30 to 40 times
m ee/ / e
An intelligent combination of pharmacologic and
nonpharmacologic interventions, nutritional interven-
m
t . . m t . .m
s : /
: /
higher than the dose in humans, but so far it has not
/ / t
been found to increase the risk of osteoporosis in hu-
s : /
: /
tions, and patient education are necessary to treat an
/ / t
individual with osteoporosis in an optimum manner.
hhtttp
tp s
mans using the therapeutic dose for osteoporosis. It is
common practice to follow teriparatide treatment with
hhtttp
tp s
an antiresorptive agent for 1 to 2 years to prevent loss Osteomalacia and Rickets
of newly deposited bone.
Strontium ranelate is one of the anabolic agents with Vitamin D deficiency has protean manifestations broadly
proven antifracture activity used in the treatment of termed as osteomalacia in adults and rickets in growing
k eerss
postmenopausal osteoporosis. Its mechanism of action
r k e
makes it different from other drugs because it simulta- r
e s
r s children. Vitamin D deficiency and insufficiency are an
underestimated problem among orthopaedic surgeons,
bboooo k o o o
neously stimulates two reverse processes: bone forma-
b o k b o oo
but as many as 70% of orthopaedic trauma patients have
o
/
e e
/ e e e
/ e b
tion and bone resorption. The action of the agent de-
/
pends on various mechanisms, including the activation
e e e
/ e b
low vitamin D levels when they are evaluated. Consid-
/
erable controversies exist regarding optimum vitamin D
e
: / / / .
t m m
of calcium receptors, localized on osteoblasts and os-
t . : / / t
/ .
t m
. m
levels; a serum level of 12.5 ng/mL or below is consid-
t p ss : /
teoclasts, and the influence on the OPG/RANKL sys-
tem. The drug effectively prevents spinal, hip, and ex-
p t p ss : /
ered deficient. However, vitamin D insufficiency exists
when levels of vitamin D are not frankly depleted but
p
t
hht t
travertebral fractures. The agent’s antifracture efficacy
within the spine does not depend on the patient’s age,
base BMD values, or the concentration of bone metab-
t
hht t
are associated with increased levels of PTH (secondary
hyperparathyroidism). In this state, low levels of 1,25 vi-
tamin D lead to a decrease in serum calcium, which stim-
olism markers. As to the antifracture efficacy in the hip, ulates the parathyroid gland and leads to the production
it affects women with an increased bone fracture risk. and secretion of more PTH. PTH endeavors to return se-
k eers
Strontium ranelate increases BMD within the lumbar
rs k ee
spine and the hip, decreases the concentrations of boners
r s rum calcium levels to normal by increasing
1-hydroxylase activity and tubular reabsorption of cal-
b ooook b oook
resorption markers, and increases the concentrations of
o
bone formation markers.22 The drug is administered in
b ooo
cium in the kidney and by enhancing osteoclastic bone
o
resorption, thus releasing calcium stores from the bone.
/
e e
/ eb ee/ e
/e b
a daily 2.0-g oral dose. Although strontium ranelate
/e/e b
Currently, vitamin D levels greater than 30 ng/mL are
ee
/ t
///t m
use is not approved by the FDA, strontium salts are
. . m
available in the United States as strontium citrate.
: / t.
///t m
considered adequate in general, but some researchers
.m
even advocate levels closer to 50 ng/mL.23
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 2
keerrss
b ooook Classification of Rickets
b o ook
o b o oo
o
/
ee/e b Type 1 Type 2
ee/ e
/ e b ee/ e
/ e b
Vitamin D deficiency or
abnormal vitamin D
: / ///t. m
Renal tubular disorders
t .m
leading to defective
: / t
///t. m
. m
metabolism leading to
s
tps : phosphate reabsorption
s
tps :
hhtttp hhtttp
deficiency of active vitamin (Fanconi syndrome, familial
D (dietary deficiency or hypophosphatasia,
1-hydroxylase deficiency) X-linked hypophos-
phatamic rickets)
k eers
rs k eers
r s
Vitamin D deficiency in children manifests as rickets,
b ooook b oook
which is characterized by the inability to mineralize
o
bone generated by the growth plate, leading to charac-
b o oo
o
/
e e
/ eb / e e b
teristic changes and deformities in the growth plate.
ee /
Malnutrition and a lack of sunlight exposure are the
ee/ e
/ e b
: // t/.tm
. m
most common causes of rickets, but other causes exist24
: / / t
/ .
t m
. m
(Table 2).
ss : / ss : /
hhtttp
tp hhtttp
tp
The clinical signs of rickets depend on the age of on-
set and the severity of the deficiency. Rickets will be at Figure 1 AP radiograph of both tibias in a child with rick-
its most severe when the deficiency coincides with a pe- ets, widening of the growth plates, and lateral
riod of rapid growth. Poor mineralization of the skele- bowing of the tibias. (Courtesy of Robert
ton leads to skeletal deformities that are more common Schneider, MD, Department of Radiology, Hospi-
tal for Special Surgery, New York, NY.)
in infancy, when affected children develop deformities
keerrss of their weight-bearing limbs. Crawling children tend

k e rrss
e
bboooo k to develop forearm deformities, whereas toddlers de-
o
velop genu varum (bow legs) or genu valgum (knock
b o
o o k b o oo
pared with the distal ulna, as most of the growth of the
o
/
e e
/ e ee/ e
/ e b
knees). Other clinical signs include retarded growth;
swelling of the wrists, knees, and ankles; and frontal
e / e
/ e b
radius arises from this growth plate (Figure 1).
Radiographs of the skeleton in patients with os-
e
t . m
. m
bossing of the skull. The costochondral junctions of the
t . m
teomalacia tend to be normal, although subperiosteal
.m
: / /
/ / t
anterior ribs can also be affected (rickety rosary). Tooth
s : s : / / / t
erosions because of secondary hyperparathyroidism can
: /
hhtttp
tp s
eruption can be delayed, and if tooth enamel develops
at a time of moderate hypocalcemia, it is hypoplastic.
In addition, muscle weakness leads to hypotonia, and hhtttp
tp s
be seen on radiographs of the hand. Cortical bone may
appear lamellated because of increased porosity. The
classic radiographic sign of osteomalacia is a pseudo-
affected children are often irritable. Where vitamin D fracture, or a Looser transformation zone: narrow ra-
deficiency is the sole abnormality, skeletal development diolucent bands composed of unmineralized osteoid,
is not unduly delayed, but if the cause of rickets is the that extend in a perpendicular fashion across the cor-
k eers
rs skeletal maturity is delayed.25
k e r
result of renal disease or intestinal malabsorption, then
e s
r s tex. There may be an overall reduction in bone density,
but equally there is often a coarsening of trabeculae.
bboooo k b o o o k
In adults, vitamin D deficiency results in impaired
o b o oo
The vertebral bodies may have an amorphous ground-
o
/
e e
/ e e e
/ e b
mineralization of bone, leading to osteomalacia. Sec-
/
ondary hyperparathyroidism leads to bone resorption
e e / e
/ e b
glass appearance. Lateral spinal radiographs may reveal
a banded sclerosis seen in vertebral bodies. Condensa-
e
: / / / .
t m m
and accelerated osteoporosis and increases the risk of
t .
fragility fractures. In adults, vitamin D deficiency is
: / / t
/ .
t m
tion of trabecular bone adjacent to the vertebral end
. m
plates occurs, and this imparts an appearance of alter-
t p ss : /
subtle and often missed because unless it is severe, it is
p t p ss
p : /
nating bands of increased and diminished density (rug-
t
hht t
radiologically and clinically silent. Apart from vitamin
D deficiency, renal failure and oncogenic osteomalacia
as a result of FGF-23 overproduction are important
t
hht t
ger jersey spine). This feature is secondary to hyper-
parathyroidism and not specific to osteomalacia26
(Figures 2 and 3). If bone densitometry is performed,
causes of osteomalacia in adults. BMD will be reduced. In addition, in the elderly, this
In addition to generalized osteopenia, the classic ra- reduction in BMD may also be a consequence of an as-
k eers
rs e
eal plates, with associated fraying and cupping of the
k ers
diologic features of rickets are widening of the epiphys-
r s
sociated osteoporosis.
The diagnosis of rickets is based mainly on a classic
b ooook b ook
metaphyses of the long bones. Because long bones de-
oo
velop at different stages, signs of rickets will vary in in-
b oooo
radiologic and clinical picture. Vitamin D levels in se-
rum can be confirmatory. Increased bone-specific alka-
/
e e
/ eb / e
/e b
tensity in different parts of the skeleton. A radiograph
ee ee/e/e b
line phosphatase and secondary hyperparathyroidism
/ t
///t m
of the wrist usually shows these characteristic changes.
. . m
Rickets is more pronounced at the distal radius com-
: : / t.
///t m
are expected. Serum phosphorus level should be mea-
.m
sured to rule out hypophosphatemia.
s
tps : s
tps :
198
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
Figure 2 AP radiographs of the femur showing Looser
zones (arrows). (Courtesy of Robert Schneider,
MD, Department of Radiology, Hospital for Spe-
cial Surgery, New York, NY.)
keerrss
The most reliable diagnostic procedure, but one that
k e
is rarely indicated clinically, is bone biopsy and bone rrss
e
Figure 3 Lateral radiograph of the spine showing rugger
bboooo k b o o
histomorphometry. Excessive unmineralized matrix is
o o k b o oo
jersey appearance caused by hyperparathyroid-
o
ism. (Courtesy of Robert Schneider, MD, Depart-
/
e e
/ e
diagnostic of osteomalacia and rickets.
e / e
/ e b
The treatment of both rickets and osteomalacia in-
e e
New York, NY.)
e e
/ e b
ment of Radiology, Hospital for Special Surgery,
/
. m m
volves dosing with vitamin D, either as D3 or D2. Vita-
t . t . m.m
: / /
/ / t
min D3 is the preferred form for supplementation be-
s : s : /
: /
/ / t
hhtttp
tp s
cause it is better absorbed. Varying doses and treatment
regimens have been described, but the aim is to achieve
a 25-hydroxyvitamin D level between 20 and 50 ng/ hhtttp
tp s
occur in 1% to 2% of the general US population, with
increasing prevalence in older age groups and in men.28
Paget disease of bone does not affect children, and the
mL. Supplementation with calcium is also helpful, par- disorder juvenile Paget disease (hyperphosphatasia) is
ticularly in elderly individuals, to suppress the raised unrelated to the pathogenesis of adult Paget disease.
PTH levels and expedite the healing process, particu- Current research suggests a combination of environ-
k eerss
larly in those with a poor calcium intake. Hypophos-
r
phatemia should be corrected with phosphorus supple-
k e r
e s
r s
mental and genetic influences in the development of
Paget disease of bone. Environmental factors such as a
bboooo k b o o
ments to correct underlying metabolic abnormalities
o o k b o oo
viral etiology have been discussed, but further study is
o
still required. Various gene mutations have been corre-
/
e e
/ e
caused by hypophosphatemic rickets.27
e / e
/ e b
Surgical management is rarely required in the form
e ee/ e
/ e b
lated with the development of Paget disease, with the
ets with deformities.

: / / t
/ .
t m
of corrective osteotomies except in cases of severe rick-
. m / / t .
t m
alteration in the SQSTM1 gene most strongly linked,
. m
although its specific role in bone metabolism is not yet
: /
t p ss
p : / ss : /
fully understood.29 It is suspected that the effect of gene
t p p
Paget Disease
t
hht t t
hht t
mutations results in overactive osteoclast and osteo-
blast activity, with reports of bone formation rates six
to seven times greater than normal.30 Although bone
Paget disease of bone, also known as osteitis defor- formation is increased, the resulting lamellar structure
mans, is characterized by an accelerated rate of abnor- is abnormal and mechanical strength is diminished.
k e rs
mal bone remodeling leading to overgrowth at focal
rs
sites and mechanical bone weakness. Although capable
e k eers
r s
Most patients with Paget disease are asymptomatic,
and the diagnosis is most often made incidentally with
b ooook b ook
of affecting any bone, there is a predilection for the
oo
skull, spine, pelvis, and long bones of the lower extrem-
b oooo
elevated serum alkaline phosphatase or a radiograph
performed for another reason. Bone biopsy is not typi-
/
e e
/ eb / e
/e b
ity. Paget disease is the second most common metabolic
ee ee/e/e b
cally needed for diagnosis. However, classic histologic
/ t
///t m
bone disease after osteoporosis and most commonly af-
. . m
fects individuals older than 55 years. It is estimated to
: : / t.
///t m
findings include an increased number of osteoclasts and
.m
newly formed bone with widened lamellae and irregu-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
lar cement lines, producing the characteristic mosaic sis, the most common being a defect in the osteoclast-
k eers
rs pattern. The normal fatty or hematopoietic marrow
keerrss specific proton-pump subunit (TCIRG1).32 The genetic
b ooook b o ook
spaces are also replaced by loose, highly vascularized fi-
o
brous connective tissue. Osteoclastic and osteoblastic
defects ultimately lead to diminished function of osteo-
o oo
o
clast carbonic anhydrase, which would normally acid-
b
/
ee/e b ee/ e
/ e b
activities eventually decrease, leaving sclerotic and de-
formed bones. Patients suspected of having Paget dis-
ee/ e
/ e b
ify the region deep to osteoclasts and therefore allow
for dissociation and resorption of the mineralized ma-
t . m
.m
ease should undergo bone scintigraphy to evaluate the
extent of disease.
: / ///t t . m
. m
trix. The decrease in osteoclastic activity leads to an ab-
: / ///t
normally high bone mass and density, but a decrease in
s
tps : s
tps :
hhtttp hhtttp
The most common symptom is bone pain that is of- mechanical bone strength leads to increased fractures.
ten worse at rest and relieved with movement. The pain The improper resorption of bone can also cause bone
may originate from the bone lesion itself or from bone growth within the medullary cavity, leaving limited
overgrowth, leading to osteoarthritis or nerve impinge- space for hematopoietic cells. Thus, osteopetrosis is not
ment. One of the most common symptoms is low back solely an orthopaedic condition but may involve medi-
pain because of spinal stenosis. Paget disease in the cal conditions such as bone marrow suppression that
k eers
rs skull may also lead to hearing loss. True malignancy
k eer
may develop, but the incidence is low (< 1%).29 In pa-s
r s lead to pancytopenia and immune deficiency.
The mode of inheritance is dependent on the type of
b ooook b ooook
tients with asymptomatic Paget disease, pharmacologic
o oo
osteopetrosis. There are three primary types: rapidly
b o
/
e e
/ eb e/ e
/ e b
treatment is not generally necessary but patients should
be monitored yearly for signs of progressive disease or
e e / e
/ e b
progressing congenital or infantile autosomal recessive,
intermediate autosomal recessive, and chronic adult au-
e
: // t/.tm
impairment. Generally, therapy is indicated for asymp-
. m
tomatic patients when alkaline phosphatase is two to
/ / t
/ .
t m
tosomal dominant.33 The congenital form is the most
. m
severe and is often lethal because of the absence of
:
ss : /
four times above the upper limit of normal.
ss : /
bone remodeling that results in severe bone marrow
hhtttp
tp hhtttp
tp
The gold standard treatment of Paget disease of suppression. It is characterized by hepatosplenomegaly,
bone is with newer-generation nitrogen-containing bis- thrombocytopenia, cranial and optic nerve palsy, osteo-
phosphonates, which are capable of producing long- myelitis, and immune deficiency. Intermediate auto-
term remission without the toxic effects of inhibiting somal recessive osteopetrosis is characterized by recur-
mineralization seen in earlier-generation bisphospho- rent fractures, short stature, neuropathies, tetanic
rrss rrss
nates. Bisphosphonates reduce bone turnover by inhib- seizures secondary to hypocalcemia, and pancytope-
o ke
ke
iting osteoclastic bone resorption. Although bone le-
o k e
k
sions on radiographs rarely fully return to normal, the e
nia.34 The autosomal dominant form occurs more often
oo
in adults and is less severe than the congenital form.
e bboo o e b o o
reduced bone turnover allows for new bone formation
b o e b o o
Adult forms may be asymptomatic but bone healing is
b
/
e / e ee/ e
in normal lamellar structure.31 Recent studies indicate
/
that although intensive bisphosphonate therapy is effec-
m ee/ / e
delayed, fragility fractures occur, and the incidence of
osteomyelitis, especially in the jaw, is increased.
m
t . . m t . .m
s : /
: /
tive in drastically normalizing serum alkaline phos-
/ / t
phatase levels, there is no clinical advantage when com-
s : /
: /
The diagnosis of osteopetrosis primarily is made
/ / t
clinically with radiographic evaluation. There is a char-
hhtttp
tp s
pared with symptom-driven management with less
aggressive bisphosphonate therapy. Calcitonin, an anti-
hhtttp
tp s
acteristic bone within a bone appearance and diffuse
sclerosis affecting the skull, the spine, and the pelvic
resorptive agent, is now infrequently used with the ad- and appendicular bones. The diagnosis can be con-
vent of newer-generation bisphosphonates and is typi- firmed with genetic testing, but it is not mandatory for
cally reserved only when bisphosphonates are not diagnosis. Treatment of congenital osteopetrosis in-
tolerated. Analgesics are commonly used as adjunctive volves bone marrow transplantation from an HLA-
k eers
rs therapy to bisphosphonates, in addition to physical
therapy, bracing, and walking aids.
k e r
e s
r smatched donor, which may potentially resolve the he-
matologic abnormalities and be life saving. For patients
bboooo k o o o k
The role of surgery in Paget disease includes correc-
b o b o oo
who are not candidates for bone marrow transplanta-
o
/
e e
/ e e e
/ e b
tive osteotomy for long bone deformity, fracture fixa-
/
tion, joint arthroplasty, spinal decompression, and the
e e e
/ e b
tion and have severe symptoms, interferon gamma-1b
/
reportedly is an effective alternative.35 Treatment of
e
: / / / .
t m m
resection of bone tumors. Few patients require surgical
t . : / / t
/ .
t m
. m
adult-onset osteopetrosis is largely symptomatic, and
t p ss : /
treatment with the success of newer-generation bis-
phosphonates and effective pain management. Patients
p t p ss : /
life expectancy is normal. Fractures and arthritis are
prevalent in the adult-onset type, and surgical interven-
p
t
hht t
who undergo surgery are at increased risk for intraop-
erative complications such as increased blood loss be-
cause the bone has become abnormally hypervascular.
t
hht t
tion with specialized drills for the unique bone type
may be required to prevent delayed union or nonunion
of fractures and osteomyelitis.36
However, patients who undergo surgery have reported The increased bone density seen in osteopetrosis can
improved quality of life. also result from other pathologically and pharmacolog-
k eers
rs k eers
r s ically induced processes. For example, with pycnodys-
ostosis, a lysosomal storage disease, a cysteine protease
b ooook Osteopetrosis
b oook
o b ooo
found in osteoclasts known as cathepsin K is deficient
o
because of a mutation at chromosome 1q21.37 Cathep-
/
e e
/ eb ee/ e
/e b
Osteopetrosis is a rare, heritable metabolic disorder
/e/e b
sin K is responsible for the osteoclast’s degradation of
ee
/ t
///t m
caused by defective bone resorption by osteoclasts.
. . m
There are multiple gene mutations linked to osteopetro-
: / t.
///t m
type I collagen and other proteins in the bone matrix.38
.m
In pycnodysostosis, therefore, bone is characteristically
:
s
tps : s
tps :
200
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
atric symptoms such as anxiety, depression, and aches
k eers
rs keerrss and pains.
b ooook b o ook
o
When an elevated PTH level in serum is secondary
o oo
o
to low calcium and vitamin D levels or chronic renal
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
diseases, it is termed secondary hyperparathyroidism.
In patients with chronic long-standing secondary hyper-
: / t
///t. m
.m : / t
///t. m
. m
parathyroidism, regulation over secretion of PTH
sometimes is lost and hypercalcemia and high PTH lev-
s
tps : s
tps :
hhtttp hhtttp
els coexist. This condition is termed tertiary hyperpara-
thyroidism and is most often seen in people with
chronic renal diseases, but it is also seen in those with
hypophosphatemic rickets.40
The skeletal changes are sometimes striking, with ra-
diographs demonstrating osteopenia and subperiosteal
k eers
rs k eers
r s resorption of the tufts and digits of the hands and feet.
Brown tumor is a classic manifestation of hyperpara-
thyroidism and can be confused with other lytic lesions,
b o
/
e e
/ eb e/
e e
/ e b e / e
/ e b
including tumors and cysts41 (Figure 4).
Diagnosis and differentiation between different types
e
: // t/.tm
. m / / t
/ .
t m
of hyperparathyroidism can be made by serum levels of
. m
intact PTH, ionized calcium, phosphorus, and vitamin
:
ss : / ss : /
D. High PTH level with hypercalcemia is either pri-
hhtttp
tp hhtttp
tp
mary or tertiary hyperparathyroidism. High PTH level
with low or normal serum calcium levels is usually
Figure 4 AP radiograph of phalanges showing subperios-
teal bone resorption on the radial aspects of
secondary hyperparathyroidism. Response to supple-
the middle phalanges, and arterial calcification mentation with calcium and vitamin D will help differ-
in hyperparathyroidism from renal failure. entiate between primary and secondary hyperparathy-
rrss rrss
(Courtesy of Robert Schneider, MD, Department roidism.
e e
of Radiology, Hospital for Special Surgery, New The treatment of primary hyperparathyroidism is
o ookke York, NY.)
o o k
o k e o oo
mainly surgical, characterized by the removal of ade-
/ e
/ bb
e o / e
/ b
e b o / e
/ b
e o
noma or adenomas or the removal of the ectopic gland.
b
In patients who do not meet surgical criteria, bisphos-
e . m me
osteosclerotic and prone to fractures, particularly at the
e
extremities and the clavicle. Other signs of the disease
t t . m mee
phonates can be administered for suppression of osteo-
. .
s : /
: /
/ / t
include unusually short distal phalanges, delayed clo-
clasts.
s : /
: /
/ / t
Secondary hyperparathyroidism is usually reversible,
hhtttp
tp s
sure of skull sutures leading to a prolonged opening of
the infantile fontanelle, and short stature.37,38 Research
enhancing the understanding of the role of cathepsin K hhtttp
tp s
provided the underlying cause is corrected. Supplemen-
tation of calcium and vitamin D is usually sufficient in
most cases. Correction of underlying renal disease or
in bone metabolism has led to pharmacologic develop- malabsorption syndrome should be considered when
ments that exploit the inhibition of the osteoclast pro- feasible. In cases of renal failure, the active form of vi-
tease to treat pathologic bone diseases. A new drug, tamin D (1,25 vitamin D) should be used for supple-
k eerss
odanacatib, is a cathepsin K inhibitor that has passed
r k e r
e
phase III clinical trials for the treatment of osteoporo- s
r s mentation.42 Tertiary hyperparathyroidism occurs when
prolonged states of secondary hyperparathyroidism
bboooo k o o o
sis. Based on its mechanism of action, odanacatib pro-
b o k b o oo
cannot be changed by elevating the calcium level. These
o
/
e e
/ e e / / e b
duces a transient pycnodysostotic state and may ulti-
e
mately prove useful for treating other diseases of low
e e / e
/ e b
situations often involve hypertrophy of all four glands.
The treatment of this condition is the same as that for
e
: / / t
/ .
t m
bone density or osteolysis. The drug shows significant
. m
promise for mainstream use in the treatment of osteo-
: / / t
/ .
t m
. m
primary hyperparathyroidism.
porosis by 2015.39
t p ss
p : / t p ss
p : /
t
hht t t
hht t
Renal Osteodystrophy
The kidneys are the major regulators of mineral ho-
Hyperparathyroidism
meostasis, a target organ for PTH and vitamin D, and
The clinical picture resulting from elevated PTH levels also a manufacturing site for the active form of vitamin
k eers
in the serum is called hyperparathyroidism. Overac-
rs k e
tivity of the parathyroid gland that is responsible for
ers
r s D. Skeletal manifestation of vitamin D can result from
different mechanisms. High-turnover renal osteodystro-
b ooook b oook
elevated PTH level in the serum is called primary hy-
o
perparathyroidism. Examples of conditions causing pri-
b ooo
phy results from secondary hyperparathyroidism be-
o
cause of a lack of active 1,25 D3 dihydroxyvitamin.
/
e e
/ eb ee/ e
/e b
mary hyperparathyroidism are parathyroid adenoma,
/e/e b
PTH activates osteoclast production, and excessive
ee
/ t
///t m
hyperplasia, or ectopic glands. Clinical features include
. . m
nephrolithiasis, proximal muscle weakness, and psychi-
: / t.
///t m
bone resorption occurs. The pathologic picture of pa-
.m
tients with high-turnover renal osteodystrophy is typi-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
cal of hyperparathyroidism and ranges from excessive
k eers
rs bone resorption to osteitis fibrosa cystica. Low-
keerrss
b ooook o ook
turnover renal osteodystrophy, which is now seen with
o
increasing frequency, is mainly caused by aluminum
b b o oo
o
/
ee/e b ee/ e
/ e b
toxicity, is more prevalent in patients undergoing peri-
toneal dialysis, and is characterized by osteomalacia.
ee/ e
/ e b
t . m
.m
Clinical symptoms include bone pain, muscle weakness,
: / ///t
skeletal deformities, and reduced BMD with an in-
: / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
creased risk of fractures. In children, the typical symp-
toms of rickets are not unusual.
Radiologically, renal osteodystrophy may present as
osteomalacia, osteosclerosis, fracture, amyloid deposi-
tion, and soft-tissue calcification and bone resorption.
This clinical picture is not specific, and varieties of
k eers
rs manifestations are common with hyperparathyroidism
and rickets in children.43
k eers
r s
b ooook o ook
Medical management of renal osteodystrophy con-
b o b o oo
o
/
e e
/ eb e/ e
/ e b
sists of limitation of phosphorus intake in diet, the ad-
ministration of an aluminum chelating agent (defarox-
e ee/ e
/ e b
// t/.tm
amine), and supplementation of vitamin D in its active
. m
form (calcitriol). Surgical management includes renal
: : / / t
/ .
t m
. m
ss : /
transplant, the fixation of pathologic fractures, reduc-
ss : /
hhtttp
tp hhtttp
tp
tion and fixation of slipped capital femoral epiphysis,
and appropriate correction of the deformities. Multi-
modality management is required to treat the skeletal
Figure 5 Lateral radiograph of the spine showing osteopo-
complications of renal osteodystrophy.44 rosis with severe compression fractures of T10
and T12, and mild compression fracture of T6.
rrss rrss
(Courtesy of Robert Schneider, MD, Department
o ke
ke Cushing Syndrome
o k e
k e
of Radiology, Hospital for Special Surgery, New
York, NY.)
oo
e bboo o e b o o o
Cushing syndrome refers to altered health secondary to
b e b o
b o
/
e / e ee/ e
prolonged exposure to elevated levels of corticoster-
/
oids. Corticosteroids have profound implications on
m m ee/ / e
health. Stress causes insufficient bone to fail earlier as
t . . m t . .m
compared with equivalent loads in the normal popula-
s : /
: /
collagen and mineral metabolism. The loss of skeletal
/ / t
mass may occur early in the course of glucocorticoid
s : /
: /
/ / t
tion. The most common insufficiency is osteoporosis,
hhtttp
tp s
therapy and appears to be related to the cumulative
dose of steroids, as well as to the usual risk factors for
hhtttp
tp s
followed by vitamin D deficiency. Osteoporotic frac-
tures most often occur in the spine (Figure 5), the hip,
and the distal end of the radius. Fatigue fracture, a vari-
osteoporosis. The direct effects of overproduction of
glucocorticoid include (1) the suppression of intestinal ant of stress fracture, often occurs in athletes or mili-
calcium absorption, (2) decreased renal tubular calcium tary recruits and is most common in the metatarsals,
resorption with increased urinary calcium excretion, the femoral neck, the tibia, and the pars interarticularis
k eers
rs and (3) suppressed osteoblast function and decreased
k
bone formation. The indirect effects of steroids occure r
e s
r sof the spine.
The mainstay of management of stress and insuffi-
bboooo k o o
via secondary hyperparathyroidism. Calcium and vita-
b o o k b o oo
ciency fractures is identification and treatment of un-
o
/
e e
/ e e e
/ e b
min D supplementation and antiresorptive agents have
/
been used extensively to treat steroid-induced osteopo-
e e e
/ e b
derlying pathology. Complete workup for metabolic
/
bone diseases is essential. Treatment consists of correct-
e
: / / / .
t m m
rosis. Teriparatide, a synthetic PTH analogue, is effec-
t . : / / t
/ .
t m
. m
ing the underlying insufficiency along with orthopaedic
management of fractures. Fracture healing in these pa-
t p ss : /
tive in the treatment of steroid-induced osteoporosis;
osteoblast dysfunction is responsible for low-turnover
p t p ss : /
tients is challenging. PTH 1-84 has been shown to in-
p
t
hht t
osteoporosis in this situation.45
t
hht t
crease the rate of fracture healing in pelvic fractures,
and the rate of union at 8 weeks was 100% in the PTH
1-84 treated group compared with 9% in the control
Stress Fractures and Insufficiency Fractures group.46 In another randomized controlled study, daily
subcutaneous injection of teriparatide (PTH 1-34) in-
k eers
rs Fractures that occur in the absence of a preceding trau-
matic event pose unique management challenges for an
k eers
r s creased the rate of healing for distal radius fractures.47
Osteoclasts play an important role in fracture heal-
b ooook b ook
orthopaedic surgeon, and underlying metabolic bone
oo
diseases may be a factor. When bone is subjected to ex-
b oooo
ing, and inhibition of osteoclasts by bisphosphonates is
not recommended until fracture healing is evident. In-
/
e e
/ eb / e
/e b
cessive stress, it is likely to accumulate microdamage
ee ee/e/e b
travenous zolendronic acid at 6 weeks of fracture does
/ t
///t m
and ultimately fail. The capacity to withstand stress de-
. . m
pends on the underlying metabolic condition and bone
: : / t.
///t m
not seem to inhibit fracture healing and reduces the
.m
mortality rate by 23%.
s
tps : s
tps :
202
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
A task force appointed by the American Society for
k eers
rs keerrss Bone and Mineral Research defined major and minor
b ooook b o ook
o oo
features of complete and incomplete atypical femoral
o o
fractures. According to the task force, all major fea-
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
tures, including their location in the subtrochanteric re-
gion and the femoral shaft, transverse or short oblique
: / t
///t. m
.m t
///t. m
. m
orientation, minimal or no associated trauma, a medial
: /
s
tps : s :
spike when the fracture is complete, and absence of
tps
hhtttp hhtttp
comminution, must be present to designate a femoral
fracture as atypical. Minor features include fracture as-
sociation with cortical thickening, a periosteal reaction
of the lateral cortex, prodromal pain, bilaterality, de-
layed healing, comorbidities, and concomitant drug ex-
posures including bisphosphonates, other antiresorp-
k eers
rs k eers
r s tive agents, glucocorticoids, and proton pump
ook ook
inhibitors.48 Typical radiologic features of these frac-
b oo b oo b o oo
o
tures are cortical thickening in the lateral side of the
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
subtrochanteric region, a transverse fracture, and a me-
dial cortical spike (Figure 6). Bilateral involvement is
: // t/.tm
. m t . m
. m
seen in at least 9% of people (can be a higher percent-
: / / / t
ss : / ss : /
age depending on the series), and 76% of patients have
hhtttp hhtttp
prodromal pain.49 These fractures are slow to heal and
tp tp
are associated with a higher rate of complications.
Treatment with prophylactic surgical fixation in se-
lected cases and teriparatide to increase bone turnover
is recommended and has been successful. With the in-
creasing awareness about this condition among clini-
keerrss k e rrss
e
cians, bisphosphonate therapy is closely monitored and
is interspersed with drug holidays. Because bisphospho-
bboooo k b o o
o o k b o oo
nates prevent a large number of fragility fractures and
o
/
e e
/ e
Figure 6
e e
/
features of an atypical fracture.
e e b
AP radiograph of the femur showing the classic
/ e / e
/ e b
the risk of atypical fracture is very low, they will likely
remain part of osteoporosis treatment at least for the
e
t . m
. m near future.
t . m.m
s : /
: /
/ / t s : /
: /
/ / t
tp s
Biologic agents, such as bone morphogenetic protein
hhtttp
and dimineralized bone matrix in conjunction with bone
marrow stem cells, can enhance fracture union. These hhtttp
tp
Summary
s
agents are advantageous over conventional bone graft- Bone is a specialized connective tissue that not only
ing because they often can be injected into the fracture provides mechanical support but also plays a critical
site percutaneously, thus avoiding extensive surgery. role in mineral homeostasis. Disorders of bone mass
k eers
rs k e r
e s
r sand/or bone quality result in compromised bone
strength as manifested by low-energy fragility fractures.
bboooo k
Bisphosphonate-Related Fractures
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b
Bisphosphonates are the most common agents used to
Key Study Points
ee/ e
/ e b
/ / t t m
treat osteoporosis and many other metabolic bone dis-
. . m
orders. Growing evidence favors the relationship of bis-
: / : / / t
/ .
t m
. m
ss : /
phosphonates with atypical subtrochanteric femur frac-
t p p
•
t p ss
p : /
A low-energy fragility fracture implies enhanced
risk for additional fractures and requires treat-
t t
tures. The estimated incidence of atypical femoral
hht
fractures increases progressively from 2 per 100,000
cases per year for 2 years of bisphosphonate use to 78
t
hht
•
t
ment.
Altered bone quality diminishes bone strength
per 100,000 cases per year for 8 years of bisphospho- independent of bone mass.
nate use.48 In a case-control study, bisphosphonate use • Both normal bone mass and bone quality depend
k e s
was associated with fractures of the shaft and subtro-
rrs
chanteric region of the femur more than intertrochan-
e k eers
r s on adequate calcium and vitamin D intake.
ook ook
• Both anticatabolic (bisphosphonates, selective es-
b oo
teric and femoral neck fracture, with an odds ratio of
b oo
4.44.49 The underlying mechanism is unclear, but the
b oooo
trogen receptor modulators, denosumab, and
/
e e
/ eb ee/ e
/e b
inability to repair wear and tear by remodeling caused
ee/e/e b
calcitonin) and anabolic (teriparatide and stron-
tium ranelate) drugs can correct osteoporosis
/ t
///t m
by osteoclast dysfunction leads to accumulation of mi-
. . m
crodamage and ultimately a stress fracture results.
: t. mm
and diminish the risk for low-energy fractures.
: / ///t .
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
12. Unnanuntana A, Gladnick BP, Donnelly E, Lane JM:
k eers
keerrss The assessment of fracture risk. J Bone Joint Surg Am
ook ook
2010;92(3):743-753.
b oo
1.
b o
Rosenberg AE: Robbins and Cotran Pathologic Basis of
o o oo
o
The authors discuss BMD, chemical risk factors for
b
/
ee/e b 2005, pp 1274-1278.
ee/ / e b
Disease, ed 7. Philadelphia, PA, Elsevier Saunders,
e ee/ e
/ e b
fracture with the use of FRAX, and bone turnover
markers in the prediction of fracture risk and evaluation
2.
/ t
///t. m
.m
Boskey AL: Noncollagenous matrix proteins and their
: : / ///t. m
. m
of patients with osteoporosis.
t
s :
role in mineralization. Bone Miner 1989;6(2):111-123.
tps s
tps :
hhtttp hhtttp
13. Miki RA, Oetgen ME, Kirk J, Insogna KL, Lindskog
DM: Orthopaedic management improves the rate of
3. Suda T, Kobayashi K, Jimi E, Udagawa N, Taka- early osteoporosis treatment after hip fracture: A ran-
hashi N: The molecular basis of osteoclast differentia- domized clinical trial. J Bone Joint Surg Am 2008;
tion and activation. Novartis Found Symp 2001;232: 90(11):2346-2353.
235-250.
k eers
rs 4. Misiorowski W: Parathyroid hormone and its ana-
k eers
r s
14. Rozental TD, Makhni EC, Day CS, Bouxsein ML: Im-
proving evaluation and treatment for osteoporosis fol-
ook ook
logues—molecular mechanisms of action and efficacy in lowing distal radial fractures: A prospective randomized
b oo b o
osteoporosis therapy. Endokrynol Pol 2011;62(1):
o b o oo
intervention. J Bone Joint Surg Am 2008;90(5):
o
/
e e
/ eb 73-78.
e/
e e
/ e b
This article discusses the mechanism of action of PTH
953-961.
ee/ e
/ e b
: // t/.tm
. m
and its genetically engineered analogue PTH 1-34. The 15.
: / / t
/ .
t m
. m
Mawer EB, Davies M: Vitamin D nutrition and bone
ss /
anabolic action of PTH, which is the most important
: ss : /
disease in adults. Rev Endocr Metab Disord 2001;2(2):
hhtttp hhtttp
desired action when its analogues are used therapeuti- 153-164.
5.
tp
cally, is discussed in detail. Level of evidence: V.
Norman AW, Roth J, Orci L: The vitamin D endocrine

tp16. Gehrig L, Lane J, O’Connor MI: Osteoporosis: Man-
agement and treatment strategies for orthopaedic sur-
system: Steroid metabolism, hormone receptors, and bi- geons. J Bone Joint Surg Am 2008;90(6):1362-1374.
ological response (calcium binding proteins). Endocr
Rev 1982;3(4):331-366.
rrss rrss
17. Cummings SR, San Martin J, McClung MR, et al: De-
o ke
ke 6.
o k
Wesseling-Perry K: FGF-23 in bone biology. Pediatre
k e
nosumab for prevention of fractures in postmenopausal
oo
women with osteoporosis. N Engl J Med 2009;361(8):
e bboo o Nephrol 2010;25(4):603-608.
e b o
b o o 756-765.
e b o
b o
/
e / e 7.
ee/ / e
National Osteoporosis Foundation: The Clinician’s
m
18.
ee/ / e
Karsdal MA, Henriksen K, Arnold M, Christiansen C:
m
t . . m t . .m
Calcitonin: A drug of the past or for the future? Physi-
Guide to Prevention and Treatment of Osteoporosis
: / /
/ / t
(2010). Washington, DC, National Osteoporosis Foun-
s : s : /
: /
/ / t
ologic inhibition of bone resorption while sustaining os-
dation, 2010.
hhtttp
tp s
The NOF is a body of experts that sets forth guidelines
from time to time for clinical practice. This guide dis- hhtttp
tp s teoclast numbers improves bone quality. BioDrugs
2008;22(3):137-144.
cusses recent advances and the latest recommendations 19. Kanis JA, Johnell O, Gullberg B, et al: Evidence for ef-
in the management of osteoporosis. Level of evidence: V. ficacy of drugs affecting bone metabolism in preventing
hip fracture. BMJ 1992;305(6862):1124-1128.
k eers
rs 8.
e
on bone health. Clin Sci (Lond) 2007;113(5):233-241.
k r
Wong PK, Christie JJ, Wark JD: The effects of smoking
e s
r s 20. Knopp-Sihota JA, Newburn-Cook CV, Homik J, Cum-
bboooo k b o o
o o k b o oo
mings GG, Voaklander D: Calcitonin for treating acute
o
and chronic pain of recent and remote osteoporotic ver-
/
e e
/ e
9.
ee/ / e b
Gourlay ML, Fine JP, Preisser JS, et al: Bone-density
e
testing interval and transition to osteoporosis in older
ee/ e
/ e b
tebral compression fractures: A systematic review and
meta-analysis. Osteoporos Int 2012;23(1):17-38.
/ / t
/ t m
women. N Engl J Med 2012;366(3):225-233.
. . m
This study demonstrates that mild forms of osteopenia
: : / / t
/ .
t m
. m
This meta-analysis of 13 randomized trials demon-
ss : /
(T-score = −1.5) rarely progress to osteoporosis, and sur-
t p p t p ss
p : /
strated pain relief for acute compression fractures but
provided no support for the use of calcitonin for the
t
hht t
veillance testing should be prolonged. Controversy ex-
ists about whether a 15-year testing interval is correct,
but the idea of extending the time between retesting is
t
hht t treatment of chronic pain. Level of evidence: I.
well accepted. 21. Han SL, Wan SL: Effect of teriparatide on bone mineral
density and fracture in postmenopausal osteoporosis:
10. Lindsay R, Silverman SL, Cooper C, et al: Risk of new Meta-analysis of randomised controlled trials. Int J Clin
k eers
rs JAMA 2001;285(3):320-323.
k eer
vertebral fracture in the year following a fracture.
s
r s
Pract 2012;66(2):199-209.
This is a meta-analysis of eight randomized controlled
b ooook b oook
o b ooo
trials evaluating the efficacy of once-daily subcutaneous
o
injection of teriparatide in the treatment of postmeno-
/
e e
/ eb 11.
e e
/e b
Lyles KW, Schenck AP, Colón-Emeric CS: Hip and
/
other osteoporotic fractures increase the risk of subse-
e ee/e/e b
pausal osteoporosis. Level of evidence: I.
Int 2008;19(8):1225-1233.
: / t
///t m
quent fractures in nursing home residents. Osteoporos
. . m : / t.
///t m
.m
s
tps : s
tps :
204
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
22. Przedlacki J: Strontium ranelate in post-menopausal os- 33. Shapiro F: Osteopetrosis: Current clinical consider-
k eers
rsteoporosis. Endokrynol Pol 2011;62(1):65-72.
keerrss ations. Clin Orthop Relat Res 1993;294:34-44.
b ooook b o ook
The antifracture efficacy of strontium ranelate was com-
o
pared with that of other agents with antifracture activ- 34.
b o oo
o
Stark Z, Savarirayan R: Osteopetrosis. Orphanet J Rare
/
ee/e b contraindication are discussed.
ee/ e
/ e b
ity. Its indications for therapy and side effects/
ee/ e
Dis 2009;4:5.
/ e b
: / t
///t. m
.m 35.
: / t . m
. m
Key LL Jr, Rodriguiz RM, Willi SM, et al: Long-term
///t
treatment of osteopetrosis with recombinant human in-
23.
s
tps :
Binkley N, Ramamurthy R, Krueger D: Low vitamin D
s
tps :
hhtttp hhtttp
status: Definition, prevalence, consequences, and correc- terferon gamma. N Engl J Med 1995;332(24):1594-
tion. Endocrinol Metab Clin North Am 2010;39(2): 1599.
287-301.
This review article discusses metabolism, mechanism of 36. Landa J, Margolis N, Di Cesare P: Orthopaedic man-
agement of the patient with osteopetrosis. J Am Acad
action, and skeletal effects of vitamin D. Topics includ-
ing the normal level of vitamin D and optimum thera- Orthop Surg 2007;15(11):654-662.
k eers
rsdiscussed. Level of evidence: V.
k eers s
peutic strategies to treat vitamin D deficiency also are
r 37. Gelb BD, Shi GP, Chapman HA, Desnick RJ: Pycnodys-
ostosis, a lysosomal disease caused by cathepsin K defi-
o o
ciency. Science 1996;273(5279):1236-1238.
/
e e
/ eb 24.
e e
/ e b
Rajah J, Thandrayen K, Pettifor JM: Clinical practice:
/
Diagnostic approach to the rachitic child. Eur J Pediatr
e ee/ e
/ e b
2011;170(9):1089-1096.
: // t/.tm
. m
38.
: / / t
/ t m
Motyckova G, Fisher DE: Pycnodysostosis: Role and
. . m
regulation of cathepsin K in osteoclast function and hu-
ss /
This article discusses the clinical presentation, labora-
: ss : /
man disease. Curr Mol Med 2002;2(5):407-421.
hhtttp hhtttp
tory tests, and the radiologic picture of rickets and out-
tp
lines the diagnostic approach for a child with rickets.
Level of evidence: V. tp39. Gauthier JY, Chauret N, Cromlish W, et al: The discov-
ery of odanacatib (MK-0822), a selective inhibitor of
cathepsin K. Bioorg Med Chem Lett 2008;18(3):
25. Unuvar T, Buyukgebiz A: Nutritional rickets and vita- 923-928.
min D deficiency in infants, children and adolescents.
rrss rrss
Pediatr Endocrinol Rev 2010;7(3):283-291.
40. Fraser WD: Hyperparathyroidism. Lancet 2009;
o ke
ke k e e
This article discusses clinical features, diagnosis, and
o k
374(9684):145-158.
oo
e bboo o ferent age groups. Level of evidence: V.
e b b o o
management of vitamin D deficiency and rickets in dif-
o 41.
e b o
b o
Silverberg SJ, Shane E, de la Cruz L, et al: Skeletal dis-
/
e / e 26.
m ee/ / e
Reginato AJ, Coquia JA: Musculoskeletal manifesta-
m e / / e
ease in primary hyperparathyroidism. J Bone Miner Res
e
t . . m . m
1989;4(3):283-291.
t .
s : /
: /
/
Rheumatol 2003;17(6):1063-1080.t
tions of osteomalacia and rickets. Best Pract Res Clin
/ s : /
: /
/ / t
27.
hhtttp
tp s
Berry JL, Davies M, Mee AP: Vitamin D metabolism,
hhtttp
42.
tp s Unnanuntana A, Rebolledo BJ, Khair MM, DiCarlo EF,

Lane JM: Diseases affecting bone quality: Beyond osteo-
porosis. Clin Orthop Relat Res 2011;469(8):2194-
rickets, and osteomalacia. Semin Musculoskelet Radiol 2206.
2002;6(3):173-182. This review article discusses metabolic bone diseases
other than osteoporosis that can impair the quality of
28.
k eers
r
Altman RD, Bloch DA, Hochberg MC, Murphy WA:
s k e
Prevalence of pelvic Paget’s disease of bone in the
r
e s
r s
bone and predispose an individual to fragility fractures.
Level of evidence: V.
bboooo k b o o
o k
United States. J Bone Miner Res 2000;15(3):461-465.
o 43.
o oo
o
Tejwani NC, Schachter AK, Immerman I, Achan P: Re-
b
/
e e
/ e 29.
/ e e b
Lodish H, Berk A, Zipursky S, Matsudaira P, Balti-
ee /
more D, Darnell J: The fibrous proteins of the matrix, in
e
14(5):303-311.
e/ e
/ e b
nal osteodystrophy. J Am Acad Orthop Surg 2006;
t . m
. m
Molecular Cell Biology, ed 4. New York, NY, WH Free-
: / / / t : / / t
/ .
t m
. m
man, 2000.
t p ss
p : / 44.
t p ss
p : /
Elder G: Pathophysiology and recent advances in the
management of renal osteodystrophy. J Bone Miner Res
30.
t
hht t
Otto F, Thornell AP, Crompton T, et al: Cbfa1, a can-
didate gene for cleidocranial dysplasia syndrome, is es-
sential for osteoblast differentiation and bone develop-
t
hht t 2002;17(12):2094-2105.
45. Hodgson SF: Corticosteroid-induced osteoporosis. En-

ment. Cell 1997;89(5):765-771. docrinol Metab Clin North Am 1990;19(1):95-111.
k
31.
eers
rs k eers
Komori T, Yagi H, Nomura S, et al: Targeted disruption
r
of Cbfa1 results in a complete lack of bone formation s 46. Peichl P, Holzer LA, Maier R, Holzer G: Parathyroid
hormone 1-84 accelerates fracture-healing in pubic
b ooook 89(5):755-764.
b oook
owing to maturational arrest of osteoblasts. Cell 1997;
o b ooo
bones of elderly osteoporotic women. J Bone Joint Surg
o
Am 2011;93(17):1583-1587.
/
e e
/ eb ee/ e
/e b e /e/e b
This is a prospective, randomized controlled study to
e
32.
/ t
///t. m
Tolar J, Teitelbaum SL, Orchard PJ: Osteopetrosis.
. m
N Engl J Med 2004;351(27):2839-2849.
: : / t.
///t m
evaluate the effect of PTH 1-84 on the course of pelvic
.m
fracture healing and functional outcomes in postmeno-
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
pausal women. Twenty-one of 65 patients with pelvic force of the American Society for Bone and Mineral Re-
k eers
rs rrss
fractures received PTH 1-84, and the rest served as con-
kee
trols. The rate and speed of healing was significantly
search. J Bone Miner Res 2010;25(11):2267-2294.
b ooook o ook
higher in the treatment group. Level of evidence: I.
b o b oo
A multidisciplinary expert group reviewed pertinent
o o
published reports concerning atypical femur fractures,
/
ee/e b 47.
e / e
/ e b
Aspenberg P, Genant HK, Johansson T, et al: Teri-
e / e e b
as well as preclinical studies that could provide insight
ee /
into their pathogenesis, and a case definition was devel-
/ ///t. m
paratide for acceleration of fracture repair in humans: A
t .m
prospective, randomized, double-blind study of 102
: : / t . m
. m
oped to correctly identify these fractures. Level of evi-
///t
s :
postmenopausal women with distal radial fractures.
tps s
tps : dence: V.
hhtttp hhtttp
J Bone Miner Res 2010;25(2):404-414.
49. Lenart BA, Neviaser AS, Lyman S, et al: Association of
The role of a 20-µg daily subcutaneous dose of teri- low-energy femoral fractures with prolonged bisphos-
paratide in acceleration of fracture healing in conserva-
phonate use: A case control study. Osteoporos Int 2009;
tively treated distal end radius fracture is discussed.
Level of evidence: I. 20(8):1353-1362.
k eers
rs 48.
rs
r s
Shane E, Burr D, Ebeling PR, et al: Atypical subtrochan-
k ee
ook ook
teric and diaphyseal femoral fractures: Report of a task
b oo b oo b o oo
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
206
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 18
e rs
rs e rrss
oo
kArthritis
ook e and Other o Cartilage
k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e Disorders /t.m .mee t
///t. m
. mee
s: /
: / / t s : /
:
tps
hhtttp tps
hhtttp
Brian A. Klatt, MD Antonia Chen, MD, MBA Rocky S. Tuan, PhD
k eers
rs k eers
r s (RA), but there are numerous other types of inflamma-
b ooook b o oo
tory processes that result in arthritis. This traditional
o
classification will serve as the structure for the chapter,
/
e e
/ eb e/ e
/ e b
Recent surveys performed by the Centers for Disease
Control and Prevention estimate that joint disorders
e ee/ e
/ e b
but it should be noted that there is also an inflamma-
: // t/.tm
and arthritis affect 21% of the US population
. m
(69.9 million people).1 Approximately 16.9 million US
/ / t .
t m
tory component to OA. It is debated whether the in-
. m
flammatory component of OA is part of the progres-
: /
ss : / s : /
sion of the disease or the initiating event.
s
hhtttp hhtttp
adults (7.9%) reported arthritis-attributable activity
tp
limitations in 2003.2 This number was projected to in-
crease to 17.6 million by 2005 and to 25 million (9.3%
of the US adult population) by 20302. Projections are
tp
An understanding of the various types of arthritis
will enable the orthopaedic surgeon to properly care
for these patients.
based on increases in the number of patients who will
suffer from arthritis as a result of an aging population
k errss
and an obesity epidemic. In 2030, it is expected that a
e k e
diagnosis of arthritis will be made in 67 million adultsrrss
e
Osteoarthritis
bboooo k
(25% of the US adult population).2
b o o
o o k OA, also known as degenerative joint disease, is the
b o oo
o
most common cartilage disorder, and continues to be
/
e e
/ e e / / e b
Cartilage plays a critical role in the normal function
e
of articular joints. The synovial joints are lined with
e ee/ e
/ e b
the leading cause of disability and impaired quality of
life in developed countries.3 OA is defined as the pro-
t . m
hyaline cartilage, which provides a low friction surface
. m t . m.m
gressive loss of cartilage structure and function.
s : /
: /
/ / t
for smooth and painless movement. Articular cartilage
: / /
/ / t
Primary OA is an idiopathic process of cartilage de-
s :
hhtttp
tp s
is composed of chondrocytes and the matrix that they
maintain. This matrix is composed of collagens, pro-
teoglycans, and noncollagenous proteins. A complete hhtttp
tp s
generation that occurs with normal use. This wear and
tear of the joint becomes more prevalent with advanc-
ing age. Secondary OA is the development of OA be-
and thorough discussion of the properties and function cause of an insult or injury that initiates and accelerates
of articular cartilage can be found in chapter 3, Articu- the degenerative process of OA. The age of incidence of
lar Cartilage and Intervertebral Disk, Orthopaedic secondary OA depends on the disease process that ini-
k ee s
Knowledge Update 11.
rrs
Cartilage becomes damaged and loses its function
k e r
e s
r stiates cartilage degeneration. It can be the result of in-
fection; traumatic joint injury; osteonecrosis; and a va-
bboooo k b o o
o o k
through a variety of processes. Traditional classifica-
b o oo
riety of hereditary, developmental, metabolic, and
o
/
e e
/ e e / e
/ e b
tions have divided cartilage disorders into osteoarthritis
(OA; noninflammatory) or inflammatory arthritis. The
e e / e
/ e
ondary OA is shown in Table 1.
e b
neurologic disorders.4 An extensive list of causes of sec-
: / / t
/ t m
prototype inflammatory arthritis is rheumatoid arthritis
. . m : / / t
/ .
t m
. m
Osteoarthritis Disease Progression
t p ss
p : / t p ss : /
Changes to Cartilage
p
t
hht t
Dr. Klatt or an immediate family member has received
research or institutional support from DePuy and serves
t
hht t
The progressive loss of cartilage is a process that in-
volves three overlapping stages: cartilage matrix dam-
age or alteration, chondrocyte response to tissue dam-
ber of American Academy of Orthopaedic Surgeons. age, and decline of the chondrocyte synthetic response
Dr. Chen or an immediate family member serves as a with progressive loss of tissue.
k eerss
paid consultant to or is an employee of Novo Nordisk.
r
Dr. Tuan or an immediate family member serves as a
k eers
r s The first phase can result from a mechanical insult,
such as a traumatic high-energy impact. There is loss of
b ooook b ook
paid consultant to or is an employee of Alacer Technolo-
oo b oooo
proteoglycan content, and proteoglycans are found in
an unaggregated form that is not bound to hyaluro-
/
e e
/ eb e / e
/e b
gies and serves as a board member, owner, officer, or
committee member of the American Society for Matrix
e ee/e/e b
nate. This disrupts the matrix macromolecular frame-
cine International Society.

: / t
///t m
Biology Tissue Engineering and the Regenerative Medi-
. . m : / t.
///t m
work, which makes the extracellular matrix (ECM)
.m
more permeable. The water content of the cartilage
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook b ook
Known Causes of Joint Degeneration (Secondary Osteoarthrosis)
o o b o oo
o
/
ee/e b Cause
ee/ e
/ e b ee e
/ e b
Presumed Mechanism
/
Intra-articular fracture
: /
High-intensity-impact joint loading t
///t. m
.m : / t
///t. m
.
Damage to articular cartilage or incongruity of joint or both
m
Damage to articular cartilage or subchondral bone or both
s
tps : s
tps :
hhtttp hhtttp
Ligament injuries Instability of the joint
Dysplasia of joint and cartilage (developmental and Abnormal shape of joint or abnormal articular cartilage or
hereditary) both
Aseptic necrosis Bone necrosis leads to collapse of articular surface and
incongruity of joint
k eers
rs
Acromegaly
k eers
r s
Overgrowth of articular cartilage produces incongruity or
joint or abnormal cartilage or both
b ooook Paget disease
b ooook o oo
Distortion or incongruity of joint as a result of bone
b o
/
e e
/ eb Ehlers-Danlos syndrome
e/
e e
/ e b e / e
/ e b
remodeling
Instability of joint
e
t . m
. m
Gaucher disease (hereditary deficiency of enzyme
: // / t : / / t
/ .
t m
. m
Bone necrosis or pathological fracture leads to incongruity of
ss /
glucocerebrosidase, leading to accumulation of
: ss : / joint
hhtttp hhtttp
glucocerebroside)
tp
Stickler syndrome (progressive, hereditary
arthro-ophthalmopathy) tp Abnormal development of joint or articular cartilage or both
Infection of joint (inflammation) Destruction of articular cartilage

Hemophilia Multiple joint hemorrhages
keerrss Hemochromatosis (excess deposition of iron in multiple

tissues)
k e rrss
e
Mechanism unknown
bboooo k o
Ochronosis (hereditary deficiency of enzyme homogentisic
b o
o o k b o oo
Deposition of homogentisic acid polymers in articular
o
/
e e
/ e Calcium pyrophosphate deposition disease
ee/ e
/ e b
acid oxidase leading to accumulation of homogentisic acid) cartilage
ee/ e
/ e b
Accumulation of calcium pyrophosphate crystals in articular
t . m
. m t . m.m
cartilage
: /
: /
/ / t
Neuropathic arthropathy (Charcot joints due to syphilis,
s s : /
: /
/ / t
Loss of proprioception and joint sensation results in increased
hhtttp
tp s
diabetes mellitus, syringomyelia, myelomeningocele,
leprosy, congenital insensitivity to pain, amylodosis)
hhtttp
tp s impact loading and torsion, instability of joint, and
intra-articular fracture
(Buckwalter JA: Articular cartilage II: Degeneration and osteoarthrosis, repair, regeneration, and transplantation. J Bone Joint Surg Am 1997;79[4]:612-632.)
k eers
rs
matrix increases, which decreases matrix stiffness. This
softening of the cartilage is clinically identified as chon-
k e r
e s
r s
matrix metalloproteinases (MMPs) that further degrade
the matrix macromolecules. As the collagen network
bboooo k dromalacia. These changes cause the cartilage surface
b o
to fray and fibrillate, which increases the vulnerabilityo
o o k b o oo
degrades, upregulation of molecules such as aggrecan,
o
aggrecanase-2, c-fos, c-jun, and fibronectin occur,
/
e e
/ e of the joint to further mechanical insult.5
ee/ e
/ e b ee/ e
/ e b
which further weakens the mechanical properties of
: / / t
/ .
t m
The second phase involves the cellular response of
. m
chondrocytes to the mechanical changes. When chon-
: / / t
/ .
t m
cartilage by destabilizing the type II collagen fiber net-
. m
work.7 To combat this cartilage degradation, there is a
t p ss
p : /
drocytes recognize tissue damage and changes to the
t p ss
p : / small repair component associated with the second
t
hht t
ECM, they release or upregulate mediators that initiate
a cellular response. Static and dynamic loading of car-
tilage results in an increase in the reactive oxygen spe-
t
hht t stage of OA that stimulates chondrocytes to synthesize
macromolecules and proliferate. The repair can coun-
teract some of the effects of the inflammatory response,
cies nitric oxide (NO), which increases chondrocyte although chondrocytes have minimal capability to re-
apoptosis and premature senescence. Premature senes- produce.
k eers
rs
cence is a pathologic process characterized by short-
ened telomeres, decreased amount of adenosine
k eers
r s
The third stage of OA occurs when cartilage is un-
able to respond to and recover from the mechanical
b ooook triphosphate (ATP) produced by the mitochondria, and

increased β-galactosidase.6 NO also inhibits collagen
b oook
o b ooo
and chemical insult of catabolic factors, including other
o
inflammatory mediators, such as IL-6, IL-8, and pros-
/
e e
/ eb ee/ e
/e
and proteoglycan synthesis by inducing the production b e /e/e b
taglandin E2. Age leads to a decline in the anabolic re-
e
/ t
///t m
of the cytokines interleukin-1 (IL-1) and tumor necrosis
. . m
factor-α (TNF-α), which stimulate the production of
: : / t.
///t m
.m
sponse of chondrocytes, and thus OA is seen more
commonly in the elderly.8
s
tps : s
tps :
208
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 18: Arthritis and Other Cartilage Disorders
Changes to Bone medication. As the disease progresses, the symptoms
k eers
rs ke rrss
As the cartilage degenerates, there is increased exposure
e
can become quite life altering. Joints will be more stiff
b ooook b o ook
of the subchondral bone. As the pressure of the cyclical
o
joint loading impacts bone, subchondral bone increases
with initial motion, and there will be pain with activi-
o oo
o
ties of daily living, such as walking up and down stairs.
b
/
ee/e b / e e b
in density and becomes sclerotic. With the exposed sub-
ee /
chondral bone, cysts may form in the bone, which can / e e b
With hip arthritis, stiffness in the joints can limit the
ee /
ability to do simple tasks, such as putting on shoes.
t . m
.m
contain myxoid, fibroid, or cartilaginous tissues. Be-
: / ///t : / t
///t. m
. m
Much of the current research effort to treat OA re-
s
tps :
cause cartilage tissue does not easily regenerate, the
s
tps :
volves around early diagnosis and treatment.17 Re-
hhtttp hhtttp
joint may form osteophytes from mesenchymal stem search has been focused on the means to identify early
cells that originate from periosteal tissue that are fi- OA, and some experimental techniques may gain clini-
brous, bony, and cartilaginous outgrowths.9 These os- cal use in the evaluation of cartilage. Several new MRI
teophytes can help create joint space in joints such as techniques have been used to assess the biochemical in-
the hip or restrict joint motion and cause contractures. tegrity of articular cartilage, including T1rho, T2 map-
They can be a source of pain at the limits of joint mo- ping, sodium MRI, and delayed gadolinium enhanced
k rs
r
tion.
ee s k eers
r s MRI of cartilage (dGEMRIC).18 T2 mapping and
ook ook
dGEMRIC have become the most commonly used im-
b oo Changes to Periarticular Tissues

b oo b o oo
aging modalities in the clinical setting. T2 mapping is
o
/
e e
/ eb e/
e e
/ e b
The soft tissues of the joint react to changes and the
loss of cartilage. The synovium can become inflamed
ee e
/ e b
useful in evaluating cartilage after reparative proce-
/
dures because it can determine if the expected normal
t . m
. m
from the release of inflammatory factors from chondro-
: // / t : / / t
/ .
t m
. m
zonal variations in healthy articular cartilage have been
ss /
cytes and release further chemokines and MMPs. Syno-
: ss : /
restored. dGEMRIC requires high doses of gadolinium
hhtttp hhtttp
vium can release collagenase and hydrolytic enzymes to contrast but has been able to show the glycosaminogly-
tp
further break down cartilage and stimulate vascular hy-
perplasia.10 With chronic OA, the joint capsule and the tp
can (GAG) concentration of cartilage. One study found
that changes seen on dGEMRIC correlated well with
ligaments become tightened and contracted. Range of the development of knee OA in the future.19 In addition
motion is decreased. Muscle can also undergo atrophy to MRI techniques, optical coherence tomography
with the relative inactivity of the joint because of pain. (OCT) may allow arthroscopic evaluation of cartilage
keerrss
Changes to Alignment
k e rrss
e
by performing microscopic cross-sectional imaging of
articular cartilage.20,21
bboooo k b o o o
It has been shown that abnormal hip-knee-ankle align-
o k b o oo
o
/
e e
/ e e e
/ e b
ment can accelerate structural changes in osteoarthritic
/
knees; varus malalignment increases medial compart-
e ee e
Treatment of Osteoarthritis
/ / e b
The treatment of OA is multifaceted and can be divided
. m m
ment disease fourfold, and valgus malalignment in-
t . t . m m
into seven main categories: patient education and life-
.
s : /
: /
/ / t
creases lateral compartment disease twofold.11 Align-
: / /
/ / t
style modification, rehabilitation, complementary and
s :
hhtttp
tp s
ment is affected by multiple factors in the joint,
including meniscal degeneration or previous menisec-
tomy, incompetent anterior cruciate ligament, osteo- hhtttp
tp s
alternative therapy, pain relievers, intra-articular injec-
tions, needle lavage, and surgical intervention. The lit-
erature for categories was evaluated in depth by a
phytes, and incongruous tibiofemoral contact.12 workgroup of specialists and was compiled into the
Whether malalignment is associated with the develop- clinical practice guidelines for the treatment of knee
ment of OA13 or if malalignment is a result of OA14 is OA by the American Academy of Orthopaedic Sur-
eers
still a topic of debate. However, it has been demon-
rs
strated that malalignment can affect more than carti-
k k e r
e s
r sgeons (AAOS).22 The levels of evidence of studies were
evaluated, and recommendations were graded: A was
bboooo k b o
bone marrow lesions.15 One study has demonstrated o
lage because malalignment predisposes OA patients to
o o k the best, and C was the worst.
b o oo
o
/
e e
/ e e / e
/ e b
that greater bone marrow edema is correlated with in-
e
Lifestyle Modification
ee/ e
/ e b
creased pain from OA.16
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
For early arthritis, symptoms can be treated with pa-
tient lifestyle modification. Self-management education
t p ss
Diagnosis of Osteoarthritis
p : / ss : /
and self-care programs are recommended to gain un-
t p p
t
hht t
Osteoarthritis is classically diagnosed by clinical exam-
ination and with plain radiographs. Physical examina-
tion of a joint with OA reveals joint pain, loss of mo-
t
hht t
derstanding of the disease process and suggest ways to
modify activity. Specific physical therapy and exercises
are also recommended, including low-impact aerobic
tion, crepitus, joint effusion, and deformity. Findings of fitness, range-of-motion exercises, and muscle strength-
OA on radiographs include joint-space narrowing, ening. For patients who are overweight and have a
k eers
osteophytes, subchondral sclerosis, and bone cysts
rs
(Table 2). The severity of symptoms does not always
k eers
r s
body mass index of greater than 25 kg/m2, weight loss
is recommended using diet and exercise to unload some
b ooook
correlate well with radiographic findings.
b oook
o
Patients in the early stages of OA usually have min-
b ooo
of the forces on the arthritic joint (Grade A recommen-
o
dation with Level I evidence).
/
e e
/ eb ee/ e
/e b
imal signs and symptoms, but there may be soreness
/e/e b
In terms of mechanical intervention, the use of an as-
ee
/ t
///t m
and pain after excessive activity that resolves with sev-
. . m
eral days of rest or a short course of anti-inflammatory
: / t.
///t m
sistive walking device such as a cane or a walker can
.m
unload the joint, provide stability, and improve pain
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
and function. Studies have shown that patellar taping ication. Acetaminophen is only an analgesic; it does not
k eers
rs ke rr
may be beneficial for short-term relief of pain associ-
e ss possess any anti-inflammatory effects. NSAIDs can
b ooook b ook
ated with OA.23,24 However, it is not recommended that
o o
patients use lateral heel wedges for treating medial uni-
provide good pain relief for the inflammation from
b o oo
o
OA. However, the side effects associated with NSAIDs
/
ee/e b / e e
compartmental OA (Grade B recommendation with
ee / b
Level II evidence), and there is inconclusive advice on
ee/ e
/ e b
can present challenges in the treatment of elderly pa-
tients. The gastrointestinal effects are the most signifi-
: / t
///t
the use of offloading knee braces.
. m
.m : / t
///t. m
. m
cant because NSAIDs are associated with the develop-
ment of ulcers, and there are increased bleeding risks
s
tps : s
tps :
hhtttp hhtttp
Pharmacologic Methods with long-term NSAID use. Although selective
None of the pharmacologic methods of treatment is cyclooxygenase-2 inhibitors may have less gastrointesti-
nal and bleeding side effects, they have been associated
able to restore or regenerate cartilage. Medications that
with increased cardiovascular events. The use of
are used to treat patients with OA are aimed at treating
acetaminophen and NSAIDs is recommended by the
symptoms. Acetaminophen is a good pain control med- AAOS workgroup (Grade B). Oral steroid medications
k eers
rs k eers
r s
b ooook Table 2
b ooook b o oo
o
/
e e
/ eb Kellgren Scale of Osteoarthritis
e/
e e
/ e b ee/ e
/ e b
Radiograph
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
Grade 0
s : /
: /
/ / t I II
s : /
: /
/ / t III IV
Classification
Description
hhtttp
Normal
tp s
No osteoarthritis
Doubtful
Minimal joint space
narrowing and hhtttp
tp s
Definite
Possible mild joint
space narrowing
Moderate
Moderate joint
space narrowing,
Severe
Severe joint space
narrowing, large
minute and definite moderate multiple osteophytes,
osteophytes osteophytes osteophytes, some severe sclerosis,
sclerosis deformity of
k eers
rs k e r
e s
r s
bone contour
bboooo k Table 3
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b
Viscosupplementation for the Treatment of Osteoarthritis
ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
Trade Name
t p ss : /
Generic Name
p
Source
t p ss
p : / Number of
Injections
Dosage per
Injection
Euflexxa t
hht t1% sodium hyaluronate Synthetic t
hht t 3 20 mg
Hyalgan Sodium hyaluronate Chicken combs 3-5 20 mg
k eers
rs Orthovisc High molecular weight
hyaluronan
k eers
r s
Synthetic 3-4 30 mg
b ooook b oook
o b oooo
/
e e
/ eb Supartz
Synvisc
Sodium hyaluronate
Hylan G-F 20
ee/ e
/e b Chicken combs
Chicken combs
5
e
3
e/e/e b 25 mg
16 mg
: / t
///t. m
. m : / t.
///t m
.m1 48 mg
s
tps : s
tps :
210
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
are not routinely used to treat OA. Oral glucosamine OA. However, if there are primary symptoms of a torn
k eers
rs ke
and oral chondroitin have not demonstrated any effect
errss meniscus or a loose body, then a partial menisectomy
b ooook
in restoring cartilage, and the AAOS workgroup
b o ook
o
strongly recommends against prescribing them (Grade
or loose body removal may be warranted (Grade C).
o oo
o
For osteotomies, the AAOS workgroup had no con-
b
/
ee/e b A).
ee/ e
/ e b
Injections of glucocorticoids and hyaluronic acid
ee/ e
/ e b
clusion on whether to perform a tibial tubercle osteot-
omy for symptomatic patients with isolated patellofem-
t . m
.m
(HA) are sometimes used to mitigate the symptoms of
: / ///t : / t
///t. m
. m
oral disease. However, the workgroup did support a
s
tps :
OA (Table 3). The AAOS workgroup recommends us-
s
tps :
realignment, or high tibial, osteotomy to treat active
hhtttp hhtttp
ing corticosteroids for short-term pain relief, but the patients with malalignment and unicompartimental OA
findings were inconclusive regarding the use of HA. In (Grade C).
theory, the use of viscosupplementation, such as HA, Implants have been used to treat OA if there is par-
may increase the viscosity of the existing synovial fluid tial joint OA or tricompartmental OA. The AAOS
and may reduce the degradation of hyaluronan in syno- workgroup did not recommend using a free-floating in-
vium and cartilage. However, studies have shown that terpositional device to treat unicompartmental OA.22
k eerss k eer
cluding erythema, effusion, swelling, and pain.25 Somes
the use of HA can cause a localized joint reaction, in-
r r s The only reliable method of using implants to effec-
tively treat advanced OA is by total joint arthroplasty,
b ooook b ooook
literature also warns of the hazards of using analgesic
o oo
where the osteoarthritic articular surfaces of a joint are
b o
/
e e
/ eb e e
/ e b
injection medications, such as bupivacaine, because
/
they may be chondrotoxic.26 With severe, advanced dis-
e e e
/ e b
replaced by metal and a spacer is used to facilitate ar-
/
ticulation. Joint arthroplasty is an option in patients
e
: // /.tm m
ease, the risk of damage from injections should not be
t . : / / t
/ .
t m
. m
with functional limitations for whom conservative mea-
ss /
of great concern. The therapeutic benefit of HA injec-
: ss : /
sures have failed.
hhtttp hhtttp
tions remains somewhat controversial.27 In theory, ex-
tp
ogenous HA reduces proinflammatory mediators and
MMPs and stimulates chondrocytes to synthesize en-
dogenous HA and proteoglycans.28 However, there is a
tp
Cartilage Regeneration and Stem Cell Therapy
Biologic solutions through cartilage regeneration may
be the future treatment of OA. Research is under way
common misperception among patients that HA injec- to find the appropriate cell source, the scaffold to sup-
tions restore cartilage. port and organize these cells, and bioactive factors and
keerrss
Surgical Intervention
k e rrss
e
bioreactors to support cartilage growth.
Tissue engineering seeks to form new cartilage by us-
bboooo k b o o
o o k
Traditional surgical treatments of smaller cartilage de-
b o oo
ing chondrocytes and other renewable cell sources,
o
/
e e
/ e e / e
/ e
and autologous chondrocyte implantation.29 These
e b
fects include microfracture, cartilage transplantation,
e / e
/ e b
such as mesenchymal and pluripotent stem cells. Pluri-
potent stem cells, such as embryonic stem cells (ESCs),
e
t . m
techniques have provided temporary relief in the resto-
. m t m
have the potential for indefinite self-renewal and can
. .m
s : /
: /
/ / t
ration of small cartilage defects, but the tissue gener-
ated is fibrocartilage and is not identical to articular
s : /
: /
/ / t
differentiate into multiple cell types.30 However, there
are ethical concerns for using the inner cell mass of
hhtttp
tp s
cartilage. The relief provided by these treatments is
temporary.
hhtttp
tp s
these blastocysts from embryos. Another alternative is
to use a patient’s own cells and use gene transduction
There are certain scenarios for considering arthros- with ESC-specific transcription factors to create ESC-
copy as a treatment option for OA. There are high lev- like stem cells, otherwise called induced pluripotent
els of evidence (I and II) to recommend against per- stem cells. However, like ESCs, these cells are undiffer-
forming arthroscopy for débriding or lavaging knee entiated and can develop into tumors.31 There are no
k eers
rs k e r
e s
r s
bboooo k
Table 3
b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b
Viscosupplementation for the Treatment of Osteoarthritis (continued)
ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
Duration of Pain
Relief
t p ss : /
Molecular Weight Elasticity
(million daltons) (Pa at 2.5 Hz)
p
Viscosity
t p ss :
(Pa at 2.5 Hz)
p / Adverse Events
12 weeks t
hht t
2.4-3.6 92 37 t
hht t Effusion, swelling, and gastrointestinal
complaints
3 to 60 days, 0.5-0.7 0.6 3 Swelling, injection site pain, and
5 to 6 months gastrointestinal complaints
k eers
rs
22 weeks 1-2.9 60
k eers
r s 46 Swelling, effusion, arthralgia, edema,
injection site erythema, and injection
b ooook b oook
o b oooo
site pain
/
e e
/ eb 6 months
6 months
0.6-1.2
6
ee/
9
e
/
111
e b 16
25
ee /e b
Arthralgia, injection site pain
/e
Effusion, injection site pain
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
current studies examining the use of pluripotent stem the usefulness of the product in the treatment of OA.
k eers
rs ke rr
cells in the treatment of cartilage damage, but studies
e ss There are multiple vectors that can be used to deliver
b ooook and macular degeneration.

b o ook
are currently using stem cells to treat spinal cord injury
o
genes, and they are divided into nonviral and viral vec-
b o oo
o
tors. Nonviral vectors include plasmids, liposomes, na-
/
ee/e b / e e b
Whatever cells are chosen must be introduced on a
ee /
tissue scaffold. Tissue scaffolds are biomaterials that
ee/ e
/ e b
ked DNA, and complexed DNA. Unfortunately, these
vectors are transient, but they are noninfectious. Viral
t . m
.m
establish a three-dimensional structure to retain the
: / ///t : / t
///t. m
. m
vectors, such as adenovirus, adeno-associated virus,
lentivirus, herpes simplex virus, and foamy virus, de-
s
tps :
cells and provide mechanical support to enable carti-
s
tps :
hhtttp hhtttp
lage development over time. There are four main liver the genes directly into DNA and provide stable
groups of scaffolding that may be applied for cartilage gene expression. However, host DNA is altered, the
tissue engineering: (1) protein-based polymers, (2) car- host can react to the infectious proteins, and there can
bohydrate-based polymers, (3) synthetic polymers, and be insertional mutagenesis.
(4) composite polymers, which combine biomaterials
from the other three categories.32
k eers
rs rs
r s
To stimulate cells to grow within scaffolds, bioactive
k ee
Inflammatory Arthritis
ook ook
factors are endogenous polypeptide molecules that can
b oo b o
be applied to constructs. Transforming growth factor-β
o b o oo
Inflammatory arthritis is a large collection of different
o
/
e e
/ eb ee e
/ e b
(TGF-β) is the most common growth factor used to
/
stimulate chondrogenesis, ECM matrix production,
e / e
/ e b
diseases that cause joint inflammation. The diagnosis
requires a complete review of the disease process pro-
e
t . m
. m
and mesenchymal stem cells.33 Other members of the
: // / t / / t
/ .
t m
file. There are no simple clinical tests that can be used
. m
to diagnose these diseases, thus the rheumatologic his-
:
ss /
TGF superfamily are also responsible for stimulating
: ss : /
tory and physical examination play a critical role in di-
hhtttp hhtttp
cartilage repair, including TGF-β1, bone morphogenetic
tp
proteins (BMP-2 and BMP-7), TGF-β3, and cartilage-
derived morphogenetic proteins (CDMP-1 and CDMP- tp
agnosis and treatment. The location of the problems
and the symmetry of presentation are important disease
features. For example, RA has a predilection for the
2). TGF-β or BMP-7 can be used with insulin growth
factor-1 (IGF-1) to stimulate anabolic cartilage path- wrists and the proximal joints of the hands and feet,
whereas psoriatic arthritis involves the distal interpha-
ways and decrease catabolic pathways. Fibroblast
rrss rrss
langeal joint of the hands. The physical findings with
growth factors (FGF), specifically FGF-2 and FGF-18,
o ke
ke k e
bind to cell surface receptors to promote anabolic path-
o k e
RA tend to be symmetric, whereas other inflammatory
oo
arthritis conditions are not. Onset and chronology of
e bboo o e b o
b o
ways and downregulate aggrecanase.34 Platelet-derived
o
growth factor attracts mesenchymal stem cells and can
e b o o
the disease are important features. The onset of RA
b
/
e / e m e / / e
stimulate proteoglycan production and chondrocyte
e ee/ / e
tends to present in a subacute manner, whereas septic
arthritis has a rapid onset in several hours. Age, sex,
m
. m
proliferation.35 Platelet-rich plasma contains growth
t . t . .m
s : /
: /
/ / t
factors that may serve as an adjunct to treating OA, but
s : /
: /
and precipitating factors can also aid in diagnosis. The
/ / t
medical treatment of all of these diseases is beyond the
hhtttp
tp s
too few studies have been conducted to make any
meaningful conclusions in OA patients.
Finally, bioreactors are chambers that mimic physio- hhtttp
tp s
expertise of the orthopaedic surgeon, and, in most
cases, the involvement of a rheumatologist is essential
for the proper care of the inflammatory arthritis.
logic conditions to facilitate chondrogenesis of a three-
dimensional construct. Automated bioreactors provide
mechanobiologic activation of the scaffolds seeded with
k eers
rs cells. There are three main bioreactors that are cur-
k
rently used: hydrostatic, dynamic loading, and hydro-
e r
e s
r s
Rheumatoid Arthritis
Rheumatoid factor (RF) is a set of self-reactive anti-
bboooo k dynamic bioreactors.
b o o
o o k b o oo
immunoglobulin G antibodies that are detected in the
o
/
e e
/ e Gene Therapy
ee/ e
/ e b e e
/ e b
blood of 80% of those with RA. RA is the most com-
/
mon inflammatory arthritis. The incidence of RA in the
e
: / / / .
t m m
The use of gene therapy was first proposed to treat
t .
rheumatoid arthritis.36 For OA, five gene therapeutic
: / / t
/ .
t m
. m
United States is 25 per 100,000 for men and 54 per
ss : /
targets that enhance chondrogenesis have been exten-
t p p t p ss : /
100,000 for women.37 The definitive cause of this dis-
ease has not been determined, but the most common
p
t
hht t
sively studied: (1) growth factors: including TGF-β,
BMP, FGF, IGF-1β, and epidermal growth factor
(EGF); (2) transcription factors: SOX9; (3) signal trans-
t
hht t
theory is that it is an autoimmune disease that can be
stimulated in genetically susceptible individuals. An en-
vironmental antigen can trigger the initiation of the re-
duction molecules: SMADS; (4) proinflammatory cyto- sponse. Rheumatoid factor is a set of self-reactive anti-
kine inhibition: TNF-α and IL-1; and (5) apoptosis or immunoglobulin G antibodies that are detected in the
k eers
rs
senescence inhibition: Bcl-2, Bcl-XL, and inducible ni-
k e
tric oxide synthase (iNOS). TNF-β1 has been studied in
ers
r s blood of 80% of those with RA. With RA, joint de-
struction begins with leukocyte infiltration of the syno-
b ooook b oook
a phase I clinical trial examining the efficacy of
o
TissueGene-C (TG-C, TissueGene Inc.), a cell-mediated
b ooo
vium, which activates type B synoviocytes that are part
o
of the synovial pannus. This then activates transcrip-
/
e e
/ eb ee/ e
/e b
gene therapy system that contains allogenic chondro-
/e/e b
tion pathways of nuclear factor (NF)-κB, signal trans-
ee
/ t
///t m
cytes that express TGF-β1. The safety of this product
. . m
was established, and further studies seek to determine
: / t.
///t m
ducers and activators of transcription (STATs), and
.m
mitogen-activated protein kinases, which enable the up-
:
s
tps : s
tps :
212
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
regulation of cytokines, such as TNF-α, IL-1, IL-6, and steroids include osteoporosis, hypertension, diabetes,
k rs
rs rrss
IL-17. In response to this cytokine release, multiple de-
ee kee
and cataracts. Lower doses have fewer side effects, so
b ooook b o ook
structive enzymes, including MMPs (collagenase and
o
gelatinase), cathepsins, and serine proteases (trypsin),
low-dose oral steroids remain a part of RA medical
o oo
o
therapy. The dosage of treatment determines whether
b
/
ee/e b ee/ e
/ e b
act to destroy cartilage. Bone destruction is also acti-
vated by the same cytokines (TNF-α, IL-1, and IL-17)
ee/ e
/ e b
or not a stress dose of steroids is required on the day of
surgery to prevent adrenal insufficiency. Patients who
t . m
.m
that upregulate receptor activator of nuclear factor-κB
: / ///t
ligand (RANKL). With increased expression of t . m
. m
take low-dose steroids (less than 7.5 mg/day) or have
: / ///t
taken steroids for a short duration of time (less than 3
s
tps : s
tps :
hhtttp hhtttp
RANKL on T cells and fibroblast-like cells, more osteo- weeks) do not require a stress dose. Patients with
clasts are activated, which leads to bony erosions. This higher dosages or longer duration of treatment should
inflammation and invasion of the synovial pannus into receive 50 to 100 mg of stress dose steroids on the day
articular cartilage and bone leads to the destruction of of surgery.
joints and causes pain and deformity. Biologic agents have revolutionized the treatment of
The most common patient presentation is that of RA. TNF-α antagonists have not only had substantial
k eerss k
develops over weeks or months, where symptom dura-
eers
r s
joint pain and swelling that is insidious in nature. This
r
benefits on the signs and symptoms of RA but also are
able to retard the radiographic progression of joint dam-
b ooook b ooook
tion of greater than 6 weeks is a cutoff point. Morning
o oo
age. These drugs work by different mechanisms, includ-
b o
/
e e
/ eb e/ e
/ e b
stiffness that lasts more than 1 hour is a hallmark
symptom of RA. Joint involvement is usually symmet-
e e / e
/ e b
ing acting as a monoclonal antibody against TNF-α or
mimic the receptor for TNF-α to prevent TNF-α from
e
: // t/.tm
ric in nature. RA is commonly polyarticular and often
. m
involves the wrist, the proximal interphalangeal joints
/ / t
/ .
t m
working. Etanercept, infliximab, and adalimumab are
. m
TNF inhibitors approved for use in RA. Anakinra is a
:
ss : /
of the hands, the metacarpophalangeal joints, the meta-
ss : /
human recombinant anti-IL-1 receptor antagonist. Re-
hhtttp
tp hhtttp
tp
tarsophalangeal joints, the elbow, the knee, the ankle, sponse rates to this drug were only 38%, and only mod-
and the cervical spine. Involvement of greater than est reductions in radiographic disease progression were
10 joints with at least one small joint increases the like- seen.39,40 The use of this drug in patients with RA is lim-
lihood of RA. As for laboratory diagnosis, patients may ited to those with refractory disease. Abatacept and
be positive for rheumatoid factor or anticitrullinated rituximab are approved for patients with active RA who
rrss rrss
protein antibody, and they may have an elevated eryth- have had inadequate response to other disease-modifying
o ke
rocyte sedimentation rate (ESR) or C-reactive protein
ke o k e
k
(CRP). The criteria for diagnosing RA is multifactorial.e
antirheumatic drugs or in whom treatment with an anti-
TNF-α agent has failed.41
oo
e bboo o e b o
The American College of Rheumatology and the Euro-
b o o e b o o
If medical treatment fails, those with advanced joint
b
/
e / e ee/ e
pean League Against Rheumatism devised a classifica-
/
tion criteria for RA. Patients who have one joint with
m ee/ / e
damage from RA may benefit from surgical treatment.
Total joint arthroplasty is a reasonable and effective
m
t . . m t . .m
s : /
: /
clinical synovitis or patients with synovitis that does
/ / t
not have another disease explanation should be tested.
s : /
: /
surgical option. Because the entire joint is affected by
/ / t
the inflammatory process of RA, replacement of the en-
hhtttp
tp s
Patients are scored on a numerical scale based on the
following criteria, and a score of greater than 6/10 is
hhtttp
tp s
tire joint is recommended even if degeneration is pres-
ent in only one or two compartments.
the diagnosis of RA. The more joints involved, the
higher the numerical score; one large joint = 0 points, 2
to 10 large joints = 1 point, one to three small joints = Juvenile Idiopathic Arthritis
2 points, 4 to 10 small joints = 3 points, and 10 joints
k eerss k e
tients with negative rheumatoid factor or high-positive r
with at least 1 small joint = 5 points. For serology, pa-
r e s
r s Juvenile idiopathic arthritis (JIA) is a term that encom-
passes arthritis conditions in children younger than
bboooo k o o o k
ACPA receive 3 points. If the level is elevated, patients
b o b o oo
16 years where there is no known cause. Classically, the
o
/
e e
/ e e e
/ e b
receive 1 point. Finally, if the duration of symptoms is
/
under 6 weeks, patients receive no points, but if the du-
e e e
/ e b
term was used to classify all idiopathic arthritis condi-
/
tions in patients younger than 16 years according to the
e
: / / / .
t m m
ration of symptoms are equal to or greater than 6
t . : / / t
/ .
t m
. m
American College of Rheumatology criteria developed
t p ss : /
weeks, then patients receive 1 point.38
Treatment of RA has evolved over the past decade as
p t p ss : /
in 1997.42 This classification scheme divided childhood
arthritis into three categories—pauciarticular, polyar-
p
t
hht t
new disease-modifying antirheumatic drugs have been
introduced (Table 4). Historically, NSAIDs and oral
corticosteroids played a large role in the treatment of
t
hht t
ticular, and systemic. This classification was expanded
by the International League of Associations for Rheu-
matology in 2001 to include the following categories:
RA, but there are significant side effects associated with systemic, polyarticular, oligoarticular, enthesitis-related,
these medications. NSAIDs have a potent role in block- and psoriatic.43 Undifferentiated JIA is an additional
k eers
ing the production of prostaglandins, but gastrointesti-
rs
nal side effects and nephrotoxicity limit the use of
k eers
r s category if the presenting JIA does not fit into any of
the above categories or if the presenting JIA spans mul-
b ooook b oook
NSAIDs. Additionally, NSAIDs are anticoagulants, so it
o
is recommended that all NSAIDs be stopped 1 week be-
tiple categories.
b oooo
The epidemiology of JIA is variable, given differ-
/
e e
/ eb ee/ e
/e b
fore surgery. Corticosteroids inhibit the production of
/e/e b
ences in diagnostic criteria and the low frequency of the
ee
/ t
///t m
prostaglandins and leukotrienes. They can significantly
. . m
decrease inflammation, but the side effects of cortico-
: / t.
///t m
disease.44 Studies have shown that the incidence ranges
.m
from 0.008 to 0.226 per 1,000 patients and the preva-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 4
keerrss
b ooook Agents for Treating Rheumatoid Arthritis
b o ook
o b o oo
o
/
ee/e b Trade Name Generic Name
ee/ e
/ e b Mechanism of Action
ee/ e
/ e b Perioperative Dosage
: / ///t. m
Corticosteroids
t .m / t
///t.
and leukotrienes
: m
Decrease production of prostaglandins
. m
≤ 7.5 mg/day = no stress dose
s
tps : s
tps :
hhtttp hhtttp
Treatment < 3 weeks = no stress dose
≥ 7.5 mg/day = 50-100 mg stress dose
on the day of surgery
Treatment > 3 weeks = 50-100 mg
stress dose on the day of surgery
NSAIDs Prostaglandin and COX inhibitor Stop 1 week before surgery
k eers
rs Actemra Tocilizumab
k eers
r sAntibody against IL-6 receptor Stop 4 weeks before surgery; resume
o
1-2 weeks after surgery
/
e e
/ eb Arava Leflunomide
e/
e e
/ e b / e
/ e b
Inhibits pyrimidine synthesis by
targeting rapidly dividing cells
ee
Minor procedures—Continue
Major procedures—Stop 2 days before
: // t/.tm
. m : / / t
/ .
t m
. m
surgery; resume 2 weeks after
surgery
Azulfidine
ss : /
Sulfasalazine
ss : /
Reduces the synthesis of inflammatory Continue for all procedures
hhtttp
tp hhtttp
tp
mediators
Cimzia Certolizumab Monoclonal antibody against TNF-α Stop 4 weeks before surgery; resume
Cytoxan Cyclophosphamide Causes DNA cross-linking Stop 4 weeks before surgery; resume
keerrss Enbrel Etanercept
k e rrss
e
Mimics the receptor for TNF-α Stop 2 weeks before surgery; resume
bboooo k Humira Adalimumab

b o o
o o k o
Monoclonal antibodies against TNF-α
b oo
o
Stop 2 weeks before surgery; resume
/
e e
/ e Imuran Azathioprine
ee/ e
/ e b e
Purine synthesis inhibitor
e/ e
/ e b 1-2 weeks after surgery
Stop 2 days before surgery; resume
t . m
. m t . m.m 1-3 days after surgery
Kineret
s : /
: /
/ /
Anakinrat s : /
: /
/ / t
IL-1 receptor antagonist Stop 1-2 days before surgery; resume
Orencia
hhtttp
tp sAbatacept
hhtttp
tp s
Downregulates T cell lymphocytes
Stop 4 weeks before surgery; resume
Plaquenil Hydroxychloroquine Inhibits toll-like receptor 9 family Continue for all procedures
receptors
k eers
rs
Remicade Infliximab
k e r
e s
Monoclonal antibody against TNF-α
r s
Stop 4-6 weeks before surgery; resume
bboooo k Rheumatrex Methotrexate
b o o
o o k Folate analog that inhibits purine
metabolism or T cell activation
b o oo
o
Continue for all procedures
/
e e
/ e Rituxan Rituximab
ee/ e
/ e b e / e
/ e
Anti B cell monoclonal antibody to
e b Hold until B cells return to normal
: / / t
/ .
t m
. m
CD-20
: / / t
/ .
t m
. m
before surgery (may take up to
1 year), resume 4-6 weeks after
t p ss
p : / t p ss
p : / surgery after wound heals
Simponi
t
hht t Golimumab
t
hht t
Monoclonal antibody against TNF-α
COX = cyclooxygenase; IL = interleukin; TNF = tumor necrosis factor.

Stop 4-6 weeks before surgery; resume
k eers
rs lence ranges from 0.07 to 4.01 per 1,000 patients.45-47 It
k eers
r s of symptoms must last at least 6 weeks. The diagnosis
b ooook is one of the most common chronic childhood illnesses;
b oook
o
it affects a similar number of patients as juvenile diabe-
of JIA is one of exclusion; there are many other causes
oooo
of childhood arthritis, and there are no specific labora-
b
/
e e
/ eb / ee b
tes and four times as many patients who have cystic fi-
ee /
brosis or sickle cell anemia.48 Patients must be younger /e e b
tory tests for JIA.
ee /
The most common JIA category is oligoarthritis JIA
: / t
///t. m
. m
than 16 years at the time of diagnosis, and the duration
: / t.
///t m
.m
(oJIA),49 which is further divided into persistent and ex-
s
tps : s
tps :
214
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
tended subcategories. For the persistent category, four Arthritis and psoriasis are diagnosed in patients with
k rs
rs rrs
or fewer joints are affected during the disease process,
ee kee s psoriatic JIA, although the characteristic rash may not
b ooook b o ook
but for the extended category, four or more joints are
o
affected after 6 months. Persistent oJIA often affects
appear for many years after the presentation of arthri-
o oo
o
tis. A diagnosis is made when arthritis and at least two
b
/
ee/e b ee/ e
/ e b
one joint, which is most commonly the knee, and these
patients often have a very mild disease pattern, present-
ee/ e
/ e b
of the following disease processes are present: nail pit-
ting (two pits or more in one or more nails) or onychol-
t . m
.m
ing with joint swelling and some loss of motion in the
: / ///t
knee. However, extended oJIA is more severe, and it t . m
. m
ysis (partial or full detachment of the nail from the nail
: / ///t
bed), dactylitis (asymmetric joint swelling in a digit), or
s
tps : s
tps :
hhtttp hhtttp
symmetrically affects more joints (hands, wrist, and psoriasis diagnosed in a first-degree relative. The arthri-
ankle), may present with chronic eye inflammation, tis is often asymmetric and peripheral, and it often
and may also have elevated ESR and antinuclear anti- affects the small joints of the hands and feet, ankles,
body. and knees. Approximately 20% of these patients may
Polyarthritis JIA (poJIA) can be differentiated from present with chronic anterior chamber uveitis. Table 5
oJIA in that five or more joints are affected in the first summarizes the differences among the different catego-
k eerss
6 months of the disease. There are two subcategories
r k eers
r
that are divided by the presence or the absence of rheu-s ries of JIA.50
Because JIA is a diagnosis of exclusion, all other
b ooook b ooook
matoid factor: poJIA rheumatoid factor-positive pa-
o oo
forms of arthritis must be ruled out before the diagno-
b o
/
e e
/ eb e/ e
/ e b
tients must have two positive laboratory tests at least
3 months apart during the first 6 months of the disease.
e e / e
/ e b
sis of JIA, and these patients should be followed clini-
cally for a long period (minimum 6 weeks). After JIA is
e
: // t/.tm
Patients positive for rheumatoid factor tend to be older
. m
females who present with symmetric small joint arthri-
/ / t
/ .
t m
diagnosed, these patients should undergo laboratory
. m
testing and should be routinely seen in a clinic. It is also
:
ss : /
tis and are often HLA-DR4 positive. Their presentation
ss : /
recommended that patients with JIA, except those with
hhtttp
tp hhtttp
tp
is similar to adult patients with RA. The presentation systemic JIA, undergo routine eye examinations every
of patients negative for poJIA rheumatoid factor is 6 months for 4 years and annually thereafter.
variable and can include fatigue, growth retardation, Treatment of JIA is similar to the anti-inflammatory
anemia, osteopenia, delay in sexual maturation, and and immune modulator medications used to treat RA,
malnutrition. The poJIA rheumatoid factor-negative dias described before. In children, special consideration
rrss rrss
agnosis is more common, and these patients tend to do should be taken to limit the use of oral systemic corti-
o ke
clinically better than rheumatoid factor-positive pa-
ke
tients.
o k e
k e
costeroids because their use can stunt growth and bone
oo
development. Intravenous immunoglobulin can also be
e bboo o e b o o o
Systematic JIA is characterized by the presence of a
b e b o o
used to treat patients, although specific immunoglobu-
b
/
e / e ee/ e
cyclical fever that rises above 39°C and goes below
/
37°C for at least 2 weeks. The fever must also be ac-
m ee/ / e
lins targeting cytokines currently are more commonly
being used. Medications such as rilonacept and canaki-
m
t . . m t . .m
s : /
: /
companied by at least one of the following clinical pre-
/ / t
sentations: rheumatoid rash (nonpuritic, macular, or
s : /
: /
numab target IL-1, and tocilizumab targets IL-6. These
/ / t
biologic therapies reduce inflammation and are being
hhtttp
tp s
maculopapular), generalized lymphadenopathy, serosi-
tis (peritoneal, pleural, or pericardial), and splenomeg-
hhtttp
tp s
used to treat the different forms of JIA.51
aly and/or hepatomegaly. These patients often have el-

evated acute-phase reactants, such as elevated ESR, Seronegative Spondyloarthropathies
CRP, and white blood cell (WBC) count, and rarely
have positive rheumatoid factor or uveitis. Systematic Seronegative spondyloarthropathy (or seronegative
k eerss
JIA often occurs in patients younger than 6 years old
r
and equally affects boys and girls.
k e r
e s
r s spondyloarthritis) is a group of diseases that involves
the axial skeleton and has negative rheumatoid factor.
bboooo k o o o
The two categories that separate JIA from juvenile
b o k b o oo
These diseases have a different pathophysiologic mech-
o
/
e e
/ e e e
/ e b
RA are the addition of enthesis-related arthritis and
/
psoriatic arthritis. Patients with enthesis-related arthri-
e e e
/ e b
anism of disease than what is commonly seen in RA.
/
The prototypical disease in this group is ankylosing
e
: / / / .
t m m
tis present with inflammation of soft tissue (ligaments,
t . : / / t
/ .
t m
. m
spondylitis. Other diseases that are classified as
t p ss : /
tendons, fascia, or joint capsule) attached to bone and
arthritis, or enthesis or arthritis with at least two of the
p t p ss : /
seronegative spondyloarthropathies include reactive ar-
thritis (Reiter syndrome), psoriatic arthritis, entero-
p
t
hht t
following criteria: symptomatic anterior uveitis, sacro-
iliac (SI) joint tenderness, or lumbosacral pain, positive
human leukocyte antigen (HLA)-B27, a family history
t
hht t
pathic arthritis, and juvenile-onset spondyloarthropa-
thies.
These diseases are associated with HLA genes of the
of positive HLA-B27, or the patient is a male older major histocompatibility complex, and this genetic
than 6 years at the time of onset of enthesis and/or ar- component is associated with familial aggregation.
k eers
rs k eers
thritis. Most of these patients have arthritis in the pe-
r
ripheral joints, in comparison to the axial skeleton, and s These arthritis diseases generally present with oligoar-
thritis with asymmetric presentation, as well as sacroil-
b ooook b oook
these patients may have inflammatory bowel disease.
o
Laboratory tests for antinuclear antibody and RF are
b ooo
iitis and spondylitis. Enthesitis, or inflammation of the
o
insertion sites of tendons or ligaments, is also a feature
/
e e
/ eb ee/ e
/e b
commonly negative, and imaging rarely shows changes
/e/e b
of these diseases. Extra-articular features, such as in-
ee
disease process.
: / t
///t m
in the SI joint or lumbosacral region until later in the
. . m / t.
///t
are common.
: m
volvement of the eyes, skin, and the genitourinary tract,
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 5
keerrss
b ooook Classification of Juvenile Idiopathic Arthritis
b o ook
o b o oo
o
/
ee/e b Number
of Duration of
ee/ e
/ e b Laboratory
ee/ e
/ e b
Classification Joints Symptoms
: / t
///t. m
.m Tests
: / t
///t. m
. m
Clinical Features Familial Trait Other
Systematic ≥1
s
tps :6 weeks Elevated ESR,
s
tps : Fever (≥ 39°C), rheumatoid
hhtttp hhtttp
CRP, and WBC rash (nonpuritic, pale
pink, blanching, and
transient), serositis,
generalized
lymphadenopathy,
splenomegaly, or
k eers
rs ≥5
k eers
r s hepatomegaly
ook ook
Polyarthritis 6 months Negative RF Females, fatigue, anemia, More common
b oo
RF negative
b oo b o oo
growth retardation,
o
than
/
e e
/ eb e/
e e
/ e b e e
/ e b
osteopenia,
/
malnutrition, and delay
e
polyarthritis RF
positive
≥5
: // t/.tm
. m : / / t
/ .
t m
.
in sexual maturation
m
Polyarthritis
ss : /
6 months Positive RF
ss : / Females with later onset Resembles adult
hhtttp hhtttp
RF positive HLA-DR4 (≥ 8 years old), RA
tp tp symmetric small joint

arthritis, and poor
function outcomes
Oligoarthritis, ≤4 6 months Monoarticular involvement Most common
persistent (knee) JIA, best
rrss rrss
outcome of JIAs
o ke
ke Oligoarthritis,
extended
≥4 6 months
o k e
k
ANA e
Elevated ESR and Polyarticular involvement
oo
(hand, wrist, or ankle),
Most common JIA
e bboo o e b o
b o o e b
younger, female, and
o
b o
/
e / e m ee/ / e chronic eye
inflammation
m ee/ / e
t . . m t . .m
Enthesitis-related ≥ 1
arthritis
s : /
: /
/ / t
6 weeks HLA-B27,
negative ANA
s : /
: /
/ / t
Anterior uveitis, sacroiliac
tenderness, lumbosacral
HLA-B27″-associated
disease in a
hhtttp
tp s and RF
hhtttp
tp s pain, and male ≥ 6 years
old,
first or second
degree relative
Psoriatic ≥1 6 weeks Dactylitis, nail Psoriasis in a
arthritis abnormalities first-degree
(onycholysis or pitting); relative
psoriatic rash may
k eers
rs k e r
e s
r s appear after 16 years
old; peripheral and
bboooo k b o o
o o k b o oo
asymmetric arthritis of
o
the ankles, knees, and
/
e e
/ e ee/ e
/ e b ee/ e
/
and/or feet e b
small joints of the hands
Undifferentiated ≥ 1
: / / t
/ .
t
6 weeks m
. m : / / t
/ .
t m
. m Does not fit any
t p ss
p : / t p ss
p : / of the other
categories, or
t
hht t t
hht t the arthritis fits
into more than
one category
ANA = Antinuclear antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; RF = rheumatoid
factor; WBC = white blood cell count.
k eers
rs k eers
r s
b ooook Ankylosing Spondylitis
b oook
o b oooo
the sacroiliac joints. Normally this disease presents in
/
e e
/ eb / e
/e
Ankylosing spondylitis is the most common and typical
ee b ee/e/e b
the third decade of life with inflammatory back pain
/ t
///t m
form of the seronegative spondyloarthropathies; it is a
. . m
chronic inflammatory disease that affects the spine and
: : / t.
///t m
.m
that is insidious in onset. Ankylosing spondylitis is di-
agnosed by clinical features, and the presenting features
s
tps : s
tps :
216
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
of the disease are nonspecific. The central feature of an- Psoriatic arthritis affects both the peripheral joints
k eers
rs ke rr
kylosing spondylitis is inflammation at the entheses.41
e ss and the axial skeleton. There are multiple disease pre-
b ooook b o ook
Radiographs of the SI joints show the hallmark sclero-
o
sis and erosion associated with ankylosing spondylitis.
sentations: distal, oligoarthritis, polyarthritis, back
o oo
o
alone, back plus distal, back plus oligoarthritis, back
b
/
ee/e b / e e b
Other manifestations, such as acute anterior uveitis, a
ee /
positive family history of seronegative spondyloarthri- / e e b
plus polyarthritis, remission, and arthritis mutilans.
ee /
Dactylitis, or sausage digit, is a typical feature of psori-
t . m
.m
tis, and a strong association with the HLA-B27 allele
: / ///t : / t
///t. m
. m
atic arthritis41 and refers to the inflammation of an en-
s
tps :
support the diagnosis of ankylosing spondylitis.
s
tps :
tire digit.
hhtttp hhtttp
The cornerstone of therapy for all patients with an- The treatment of psoriatic arthritis is similar to OA
kylosing spondylitis is physical therapy, exercise, and in some ways. Exercise and activity modification can
education. Regular exercise is crucial to maintain help. For more severe symptoms, NSAIDs can be con-
proper spine function and posture. Decreased motion sidered. Traditional disease-modifying drugs, such as
of the spine and kyphosis lead to significant morbidity. methotrexate, sulfasalazine, and cyclosporine, still play
Pharmacologic treatment can address stiffness and a role, but TNF-α antagonists are now approved for
k rs
rs
muscle spasms. NSAIDs, analgesics, and muscle relax-
ee k eers
r
ants all play a role in treating the symptoms of ankylo-s the treatment of psoriasis and psoriatic arthritis.
b ooook b ooook
sing spondylitis. Because inflammation plays a role in Enteropathic Arthritis
b o oo
o
/
e e
/ eb ee e
/ b
disease progression, TNF-α antagonists, including etan-
/ e
ercept, infliximab, and adalimumab, are approved for
ee/ e
/ e b
This type of arthritis accompanies inflammatory bowel
disease. Enteropathic arthritis occurs in 10% to 22%
: // t/.tm m
the treatment of ankylosing spondylitis.
. t . m
. m
of patients with inflammatory bowel disease, with a
: / / / t
ss : / : /
higher prevalence in those with Crohn disease than
ss
hhtttp hhtttp
Reactive Arthritis
tp tp
with ulcerative colitis.41 The peripheral arthritis is typi-
Reactive arthritis, also known as Reiter syndrome, is an cally in the lower extremity, but it can manifest as an
autoimmune sterile synovitis triggered by an infection of axial arthritis that is indistinguishable from ankylosing
the genitourinary or the gastrointestinal tract. Data in- spondylitis. The axial form has an association with
dicate that approximately 50% of reactive arthritis and HLA-B27. Treatment with NSAIDs mimics that of the
undifferentiated oligoarthritis cases can be attributed to other seronegative spondyloarthropathies.
k errss
a specific pathogen by a combination of culture and se-
e k
rology.41 The most common intestinal organisms include
e rrss
e
bboooo k o o
Salmonella, Shigella, or Campylobacter, and sexually
b o o k b
Crystal Deposition Diseases
o oo
o
/
e e
/ e e e
/ b
transmitted organisms include Chlamydia trachomatis or
/ e
Neisseria gonorrhoeae. Reactive arthritis characteristi-
e e / e
/ e b
The deposition of microcrystals into joints can result in
e
. m m
cally involves the joints of the lower extremities in an
t . . m m
damage to cartilage through acute or chronic synovitis.
t .
s : /
: /
/ / t
asymmetric, oligoarticular pattern, and enthesopathy of
: / /
/ / t
The two most common crystals present in crystal ar-
s :
hhtttp
tp s
the Achilles tendon is common. The features of anterior
uveitis, urethritis (men) or cervicitis (women), and oli-
goarthritis are all characteristics of Reiter syndrome. hhtttp
tp s
thropathies are monosodium urate (MSU) and calcium
pyrophosphate dihydrate (CPPD). Less frequently, cal-
cium apatite and calcium oxalate crystal deposition can
Psoriatic-like cutaneous manifestations, such as circinate cause arthritis. Diagnosis is confirmed in the aspirate of
balanitis and keratoderma blennorrhagica, can support synovial fluid. Polarized light microscopy is used to de-
the diagnosis. Reactive arthritis can be self-limiting, but termine the difference between gout and pseudogout.
eers e
acute inflammation. The role of antibiotics in prevent-
k k r
chronic arthritis can develop. NSAIDs are therapeutic for
rs e s
r s Gout
bboooo k b o o
o o
ing the development of chronic synovitis is not clear.
k b o oo
Gout is a disease caused by the deposition of MSU crys-
o
/
e e
/ e Psoriatic Arthritis
ee/ e
/ e b e / e
/ e b
tals in the joints and soft tissues of the body, and it is
associated with hyperuricemia. MSU crystals are nega-
e
: / / / .
t m m
Psoriatic arthritis is an inflammatory condition that is
t .
associated with psoriasis. The presence of skin manifes-
: / / / .
t m m
tively birefringent needle-shaped crystals. The arthritis
t .
is more common in men and postmenopausal women,
t p ss
p : /
tations of psoriasis is needed to reach the diagnosis.
ss : /
and it is both acute and chronic. Acute gouty arthritis
t p p
t
hht t
The classic findings of skin lesions, nail pitting, ony-
cholysis, and chronic uveitis are other manifestations
that can help with the diagnosis.
t
hht t
presents with the rapid development of warmth, swell-
ing, erythema, and pain in the involved joint. The first
attack occurs in the metatarsophalangeal joint of the
Up to one third of those with psoriasis develop in- great toe in almost 50% of the cases. Other joints that
flammatory arthritis. This can cause pain and stiffness are commonly involved include the midfoot, the ankle,
k eers
in the involved joints. Only 4% to 5% of those with
rs k eers
r
psoriatic arthritis are positive for rheumatoid factor.52 s
the heel, and the knee. Chronic tophaceous gout usu-
ally develops after 10 years or more of acute intermit-
b ooook b oook
Psoriatic arthritis is classified among the seronegative
o
spondyloarthropathies as a result of negative rheuma-
b ooo
tent gout. Joints become persistently uncomfortable
o
and swollen, and there are no more pain-free periods.
/
e e
/ eb ee/ e
/e b
toid factor, spinal involvement, the pattern of joint in-
/e/e b
The treatment of gout with colchicine and indo-
ee
extra-articular features.41
: / t
///t m
volvement, the association with HLA-B27, and the
. . m / t.
///t m
methacin results in quick resolution of the acute, pain-
.m
ful symptoms. Maintenance therapy with allopurinol
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
can reduce further attacks by decreasing the deposition countered is Staphylococcus aureus, but group A strep-
k eers
rs of crystals in the joint.
keerrss tococcus and Enterobacter are also commonly respon-
b ooook Pseudogout
b o ook
o
sible for nongonococcal septic arthritis. Gonococcal
b o oo
o
arthritis differs from nongonococcal arthritis with re-
/
ee/e b / e e b
Pseudogout is a disease caused by the deposition of
ee /
CPPD crystals in articular tissues. The name is derived
ee/ e
/ e b
gard to organism and presentation. The responsible or-
ganism is Neisseria gonorrhoeae, and gonococcal ar-
: / t
///t. m
.m
from the symptoms of acute inflammation that can re-
: / t
///t. m
. m
thritis is a migratory arthritis and tenosynovitis with or
without skin lesions. Patients are usually healthy,
s :
semble a gouty attack. The deposition of crystals is
tps s
tps :
hhtttp hhtttp
usually asymptomatic, but there can be multiple pre- young, sexually active adults. Gonococcal cultures are
sentations. In one presentation, CPPD crystals can lead often taken at extra-articular sites, and the joint fluid
to an exacerbation of OA in the involved joint. culture and Gram stain are typically negative.
Pseudogout can also result in a severe destructive pat- Other less common causes of infectious arthritis
tern that resembles neuropathic arthropathy or produce should be kept in mind. Mycobacterial, fungal, and
a symmetric proliferative synovitis such as RA. parasitic arthritis tend to present as subacute or chronic
k eers
rs k eers
r s
Fluid analysis of the joint reveals positively birefrin- monoarticular arthritis. Viral arthritis can also result
after a viral illness.
b ooook oook
gent rhomboid-shaped crystals. The knee is the most
o
commonly involved joint. Chondrocalcinosis in the me-
b o oo
Lyme disease is an Ixodes tick-borne infection
b o
/
e e
/ eb / e e b
nisci can be seen on radiographs of the knee, which is
indicative of CPPD crystals.
ee / e / e
/ e b
caused by spirochetes (Borrelia burgdorferi). Patients
present with symptoms at one of three stages. In the
e
t . m
. m
The treatment of acute symptoms involves the ad-
: // / t / / t
/ .
t m
early localized phase, patients often present with classic
. m
erythema migrans. In the early disseminated phase, pa-
:
ss : /
ministration of NSAIDs and/or intra-articular steroid
ss : /
tients commonly present with Lyme carditis or neuro-
hhtttp
tp hhtttp
tp
injections. There is no maintenance therapy to reduce
logic symptoms, such as sixth or seventh nerve palsy, or
further attacks. lymphocytic meningitis. Lyme arthritis is a late mani-
festation of Lyme disease, where patients often present
with fever and monoarticular arthritis of the knee.54
Infectious Arthritis However, Lyme arthritis can also be found in the hip,
rrss rrss
the ankle, the wrist, or elbow. These synovial joints are
Infectious arthritis is classified as both an inflammatory
o ke
ke k e e
cause of arthritis and a secondary cause of OA. It is the
o k
affected because spirochetes invade the synovium and
oo
stimulate an immune response, which includes the ac-
e bboo o e b o
b o
acute process that defines it as an inflammatory arthri-
o
tis. Acute infectious arthritis is also called septic arthri-
e b o o
cumulation of cytokines, neutrophils, immune com-
b
/
e / e ee/ / e
tis. The destruction of cartilage occurs through the ac-
m ee/ / e
plexes, and complement. The spirochete also induces
vascularity proliferation, induces synovial hypertrophy,
m
t . m
tivation of an acute inflammatory process, such as the
. t . .m
s : /
: /
/ / t
activation of T cells, and the production of toxins and
s : /
: /
and stimulates chondrocytes to produce MMPs.55
/ / t
In the classic arthritis presentation of Lyme arthritis,
hhtttp
tp s
enzymes by bacteria that in turn activates proteases
such as collagenase, hyaluronidase, elastase, lipopro-
teinase, and lipase. If the acute process is left untreated, hhtttp
tp s
patients present with episodic synovitis that lasts less
than 1 week and involves one to four joints; there are
asymptomatic periods of 2 or more weeks between ep-
it can progress to complete cartilage loss in 4 weeks. isodes. The acute pauciarticular presentation involves
Even if the acute arthritis is halted, secondary arthritis one to four joints continuously for less than 4 weeks.
can result from damage to the cartilage. Three other clinical presentations of Lyme arthritis in-
k eers
rs Infection is usually a monoarticular process but can
k e
be oligoarticular or polyarticular. Diagnosis depends onr
e s
r s clude migratory, polyarticular, and chronic pauciarticu-
lar presentations.56
bboooo k o o o k
an aspiration of the joint fluid and the analysis of this
b o b o oo
The diagnosis of Lyme disease starts with a high
o
/
e e
/ e e / / e b
fluid. Greater than 50,000/mm3 nucleated cells with
e
90% neutrophils is usually considered diagnostic. In
e e / e
/ e b
clinical suspicion for the disease given the geographic
distribution of the tick. Serological laboratory diagno-
e
: / / / .
t m m
one study, however, greater than 50% of culture posi-
t .
tive aspirates had synovial nucleated cell counts less
: / / t
/ .
t m
. m
sis of Lyme disease is performed using enzyme-linked
than 28,000/mm3.53
t p ss
p : / t p ss : /
immunosorbent assay and Western blot.
When a patient presents with an acutely painful na-
p
t
hht t
Infection in a synovial joint occurs when bacteria
gain access to the joint space. Bacteria can spread to the
joint through direct access from trauma or surgery,
t
hht t
tive joint with a high suspicion for infectious arthritis,
specific laboratory tests, including serum WBC count,
ESR, and CRP, should be performed. The joint should
through hematogenous spread, or through local tissues be aspirated and sent for cell count, where special at-
from cellulitis or osteomyelitis. Adults who develop tention is paid to the synovial WBC count and differen-
k eers
rs
acute septic arthritis often have an impaired immune
k eers
r
system. RA, liver cirrhosis, chronic renal failure, malig-s tial, culture, and crystals. Patients with nongonococcal
septic arthritis should be urgently treated, but the treat-
b ooook b oook
nancy, hemodialysis, HIV infection, and organ trans-
o
plantation are among the immune-altering diseases that
b ooo
ment method is controversial. Good results have been
o
reported for serial aspiration, arthroscopic débride-
/
e e
/ eb ee/ e
/e b
place patients at a higher risk of septic arthritis.
/e/e b
ment, and arthrotomy with débridement. Antibiotics
ee
/ t
///t m
Nongonococcal septic arthritis is the most serious
. . m
infectious arthritis. The most common organism en-
: / t.
///t m
should be administered based on culture results.
.m
Culture-negative aspirates in children require aggressive
:
s
tps : s
tps :
218
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
treatment, even if an organism is not found. For gono- tor of osteoclastogenesis and is essential in osteoclast
k rs
rs r
coccal infections, antibiotic therapy without drainage
ee kee rss formation and modulation.22 There is research to sup-
b ooook b o ook
usually suffices. Finally, for Lyme arthritis, treatment is
o
most successful with oral antibiotics, including doxycy-
port the loss of the negative-feedback mechanism in pa-
o oo
o
tients with diabetes. Neuropathy decreases the avail-
b
/
ee/e b ee/ e
/ e b
cline, tetracycline, amoxicillin, or cefuroxime. Intrave-
nous antibiotics, including ceftriaxone, cefotaxime, and
ee/ e
/ e b
able amounts of calcitonin gene-related peptide and
endothelial NOS that, in turn, activates RANKL.22 Ele-
t
penicillin G, can also be used.57
: / ///t. m
.m : / t . m
. m
vated glucose levels form advanced glycation end prod-
///t
ucts, and the lack of a receptor for these end products
s
tps : s
tps :
hhtttp hhtttp
leads to an increase in RANKL.6,22
Neuropathic Arthritis With improved understanding of the molecular pro-
cess that results in neuropathic arthritis, new treat-
Neuropathic arthritis is a synonym for Charcot ar- ments are being considered. Because of the role of
thropathy, neurotrophic arthropathy, and neuroar- IL-1β and TNF-α that results in aggressive and unre-
thropathy. In the setting of neurologic damage, neuro- mitting inflammation, one potential future treatment of
k eerss k eers
pathic arthritis is a destructive process that involves
r r
fractures, subluxation, and dislocation of the articulars neuropathic arthritis is anti-TNF therapy. Bisphospho-
nates may decrease IGF-1 and help regulate RANKL,
b ooook b ooook
structures. Two consistent clinical features of neuro-
o oo
but their clinical efficacy remains to be proven.22 Drugs
b o
/
e e
/ eb e/ e
/ e b
pathic arthritis are the presence of significant sensory
deficit and a lesser degree of pain than would be ex-
e e / e
/ e b
that increase receptors for advanced glycation end
product levels, such as angiotensin-converting enzyme
e
on radiographs.41
: // t/.tm
pected considering the amount of joint destruction seen
. m / / t
/ .
t m
inhibitors, statins, and glitazones, may be useful in pre-
. m
venting or suppressing neuropathic arthritis.22
:
ss : /
Historically, neuropathic arthritis was seen in ter-
ss : /
hhtttp
tp hhtttp
tp
tiary syphilis (tabes dorsalis). Contemporary common
causes of neuropathic arthritis are diabetes, syringomy- Summary
elia, spina bifida, and brain or spinal cord trauma. The
typical pattern of anatomic involvement depends on the Arthritis affects about one fifth of the US population.
location of the neurologic impairment. In patients with OA is the most common arthritis, and the aging popu-
rrss rrss
diabetes, the foot is most commonly involved. Syringo- lation and the increase in obesity are expected to lead
o ke
myelia involves the upper extremity, and patients with
ke o k
spina bifida have knee, hip, ankle, and spine involve-e
k e
to an epidemic of OA in the next 20 years. New under-
oo
standing of the diagnosis and the pathology of OA will
e bboo oment.
e b o
b o o e b o o
hopefully lead to treatments that can lessen the effect of
b
/
e / e ee/ e
The diagnosis of neuropathic arthritis is a clinical
/
one. Plain radiographs, bone scans, and indium-111-
m
OA.
ee/ / e
Inflammatory arthritis is a large collection of disease
m
t . . m t . .m
s : /
: /
labeled WBC scans can be useful in the diagnosis. In es-
/ / t
tablished disease, bone fragmentation, periarticular de-
s : /
: /
processes that destroy joint cartilage and lead to dis-
/ / t
ability. Biologic agents are already changing the course
hhtttp
tp s
bris formation, and joint subluxation occur.41
Neuropathic arthritis can be confused with infection,
hhtttp
tp s
and severity of these diseases. Research holds great
hope to treat and cure these inflammatory diseases.
fracture, gout, pseudogout, osteonecrosis, or OA be-
cause affected joints often present with a fluid collec-
tion. Aspiration of a joint with neuropathic arthritis
will reveal a noninflammatory fluid, and aspirates com-
k eerss
monly produce hemorrhagic fluid.
r
The pathogenesis of neuropathic arthritis has not
k e r
e s
r s Key Study Points
bboooo k o o o
been clearly defined. The answer seems to be a combi-
b o k •
b o oo
o
An in-depth understanding of the process of car-
/
e e
/ e e e
/ b
nation of two separate theories. A neurovascular theory
/ e
postulates that denervation alters blood flow from
e ee/ e
/ e b
tilage degeneration in OA is leading to research
that detects and treats arthritis at earlier stages,
: / / / .
t m m
changes in the sympathetic regulation, and this upsets
t . : / / t . m
. m
when intervention could prevent progression.
/ t
t p ss /
the balance in bone resorption and formation.41 The
:
neurotraumatic theory proposes that repeat events of
p
•
t ss : /
Clinical practice guidelines with regard to the
p p
t
hht t
minor trauma without the protection of normal pain
leads to damage from further trauma and inadequate
repair.41 Recent studies have started to reveal the patho-
t
hht t
treatment of knee OA have been developed by
the AAOS, and orthopaedic surgeons need to be-
come familiar with this information. Conserva-
genesis of neuropathic arthritis at a molecular level. tive treatment must be initiated first before surgi-
Uncontrolled inflammation leads to an imbalance in os- cal options are considered.
k ee s
teoclasts and osteoblasts.22 Several studies have shown
rrs k ee
that TNF-α and interleukins are involved in the processrs
r s • Cartilage regeneration and gene therapy are the
latest frontier in joint preservation research.
b ooook b ook
of bone resorption by promoting osteoclast recruit-
oo
ment, proliferation, and differentiation.58 Monocytes
b oooo
Knowing the challenges that are encountered in
/
e e
/ eb ee/ e
/e b
found in neuropathic arthritis express higher levels of
e /e/e b
engineering solutions will help orthopaedic sur-
geons answer patient questions about coming in-
e
/ t
///t. m
proinflammatory cytokines.5 RANKL also plays a role
. m
in neuropathic arthritis, which is an important media-
:
novations.
: / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
11. Cerejo R, Dunlop DD, Cahue S, Channin D, Song J,
k eers
keerrss Sharma L: The influence of alignment on risk of knee

osteoarthritis progression according to baseline stage of
b ooook 1.
o ook
Bolen J, Schieb L, Hootman JM, et al: Differences in the
b o o oo
disease. Arthritis Rheum 2002;46(10):2632-2636.
b o
/
ee/e b e / / e b
prevalence and severity of arthritis among racial/ethnic
e
groups in the United States, National Health Interview
e 12.
e / e
/ e b
Hunter DJ, Sharma L, Skaife T: Alignment and
e
7(3):A64.
: / t
///t m
Survey, 2002, 2003, and 2006. Prev Chronic Dis 2010;
. .m : / t
///t. m
. m
osteoarthritis of the knee. J Bone Joint Surg Am 2009;
91(suppl 1):85-89.
s
tps :
The authors describe the prevalence of doctor-diagnosed
s
tps :
hhtttp hhtttp
arthritis and its effect on activities, work, and joint pain 13. Brouwer GM, van Tol AW, Bergink AP, et al: Associa-
for six racial/ethnic groups. Data are drawn from the tion between valgus and varus alignment and the devel-
2002, 2003, and 2006 National Health Interview Sur- opment and progression of radiographic osteoarthritis
veys (n = 85,784). of the knee. Arthritis Rheum 2007;56(4):1204-1211.
2. Hootman JM, Helmick CG: Projections of US preva-
k eers
rs k eers
r s
lence of arthritis and associated activity limitations.
14. Hunter DJ, Niu J, Felson DT, et al: Knee alignment does
not predict incident osteoarthritis: The Framingham os-
ook ook
Arthritis Rheum 2006;54(1):226-229. teoarthritis study. Arthritis Rheum 2007;56(4):1212-
b oo b oo 1218.
b o oo
o
/
e e
/ eb 3.
e e
/ e b
Centers for Disease Control and Prevention (CDC):
/
Prevalence of disabilities and associated health condi-
e 15.
ee/ e
/ e b
Hunter DJ, Zhang Y, Niu J, et al: Increase in bone mar-
: // /.tm m
tions among adults—United States, 1999. MMWR
t .
Morb Mortal Wkly Rep 2001;50(7):120-125.
: / / t
/ .
t m
. m
row lesions associated with cartilage loss: A longitudi-
ss : / ss : / nal magnetic resonance imaging study of knee osteoar-
hhtttp hhtttp
thritis. Arthritis Rheum 2006;54(5):1529-1535.
4.
tp
Buckwalter JA, Mankin HJ: Articular cartilage: Degen-
eration and osteoarthritis, repair, regeneration, and
transplantation. Instr Course Lect 1998;47:487-504.
tp 16. Felson DT, McLaughlin S, Goggins J, et al: Bone mar-
row edema and its relation to progression of knee osteo-
arthritis. Ann Intern Med 2003;139(5, pt 1):330-336.
5. Uccioli L, Sinistro A, Almerighi C, et al: Proinflamma-
rrss rrss
tory modulation of the surface and cytokine phenotype 17. Chu CR, Williams AA, Coyle CH, Bowers ME: Early
o ke
ke
of monocytes in patients with acute Charcot foot.
Diabetes Care 2010;33(2):350-355.
o k e
k e
diagnosis to enable early treatment of pre-osteoarthritis.
oo
Arthritis Res Ther 2012;14(3):212.
e bboo o e b o o
The authors studied the role of proinflammatory
b o e b o o
The authors review recent advances in imaging and bio-
b
/
e / e pathogenesis of acute Charcot foot.
m ee/ e
changes in the immune phenotype of monocytes in the
/ / / e
chemical biomarkers suitable for characterization of the
ee
preosteoarthritic joint. They discuss the implications for
m
t . . m t . .m
6.
s : /
: /
/ / t
Witzke KA, Vinik AI, Grant LM, et al: Loss of RAGE
s : /
: /
developing effective early treatment strategies.
/ / t
hhtttp
tp s
defense: A cause of Charcot neuroarthropathy? Diabe-
tes Care 2011;34(7):1617-1621.
hhtttp
tp s
18. Jazrawi LM, Alaia MJ, Chang G, Fitzgerald EF, Recht
MP: Advances in magnetic resonance imaging of articu-
lar cartilage. J Am Acad Orthop Surg 2011;19(7):
The authors compared healthy controls to patients with
type 2 diabetes with and without Charcot neuropathy. 420-429.
Patients with Charcot neuropathy had significantly The authors review biochemical-based MRI techniques;
lower soluble receptor for advanced glycation end prod- T2 mapping, T1rho, sodium MRI, and dGEMRIC. By
k eers
rs duced bone stiffness.
k e r
ucts, increased serum markers of osteocalcin, and re-
e s
r s imaging the biochemical composition of cartilage, the
hope is to detect pathology earlier, intervene earlier, and
bboooo k 7.
b o o
o o
Lee JH, Fitzgerald JB, Dimicco MA, Grodzinsky AJ: k b o oo
thus shift management to joint preservation.
o
/
e e
/ e / e
/ e b
Mechanical injury of cartilage explants causes specific
ee
19.
ee/ e
/ e b
Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahl-
: / / t
/ t m
time-dependent changes in chondrocyte gene expres-
. . m
sion. Arthritis Rheum 2005;52(8):2386-2395.
: / / t
/ .
t m
berg LE: Association between findings on delayed
. m
gadolinium-enhanced magnetic resonance imaging of
t p ss
p : / t p ss
p : /
cartilage and future knee osteoarthritis. Arthritis Rheum
2008;58(6):1727-1730.
8.
t
hht t
Mankin HJ, Grodinsky AJ, Buckwalter JA: Articular
cartilage and osteoarthritis, in Einhorn TA, O’Keefe RJ,
Buckwalter JA (eds): Orthopaedic Basic Science, ed 3.
t
hht t
20. Chu CR, Lin D, Geisler JL, Chu CT, Fu FH, Pan Y: Ar-
Rosemont, IL, American Academy of Orthopaedic Sur- throscopic microscopy of articular cartilage using opti-
geons, 2007, pp 161-174. cal coherence tomography. Am J Sports Med 2004;
32(3):699-709.
k eers
rs 9.
k e
evance and biology. Osteoarthritis Cartilage 2007;
er
van der Kraan PM, van den Berg WB: Osteophytes: Rel-
s
r s 21. Chu CR, Williams A, Tolliver D, Kwoh CK, Bruno S III,
b ooook 15(3):237-244.
b oook
o b oooo
Irrgang JJ: Clinical optical coherence tomography of
early articular cartilage degeneration in patients with
/
e e
/ eb 10.
e / e
/e b
Krasnokutsky S, Attur M, Palmer G, Samuels J, Abram-
e /e e b
degenerative meniscal tears. Arthritis Rheum 2010;
ee /
62(5):1412-1420.
/ t
///t m
son SB: Current concepts in the pathogenesis of osteoar-
. . m
thritis. Osteoarthritis Cartilage 2008;16(suppl 3):S1-S3.
: : / t.
///t m
.m
The authors compare arthroscopic evaluation, OCT,
s
tps : s
tps :
220
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
and T2-weighted MRI. They conclude that OCT can be Mechanisms of action. Arthritis Res Ther 2003;5(2):
k eers
rs rrss
used clinically to provide qualitative and quantitative
kee
assessments of early articular cartilage degeneration that
54-67.
b ooook b o
strongly correlate with arthroscopy results.
ook
o 29.
o oo
o
Ventura A, Memeo A, Borgo E, Terzaghi C, Legnani C,
b
/
ee/e b 22.
e / e
/ e b
Richmond J , Hunter D, Irrgang J, et al: American
e e e
/ e b
Albisetti W: Repair of osteochondral lesions in the knee
/
by chondrocyte implantation using the MACI® tech-
e
/ ///t. m
.m
Academy of Orthopaedic Surgeons clinical practice
t
guideline on the treatment of osteoarthritis (OA) of the
: : / ///t. m
. m
nique. Knee Surg Sports Traumatol Arthrosc 2012;
t
20(1):121-126.
s
tps :
knee. J Bone Joint Surg Am 2010; Apr 92(4):990-3.
s
tps :
hhtttp hhtttp
The authors conclude, through a restrospective cohort
study, that matrix-induced autologous chondrocyte im-
23. Peter WF, Jansen MJ, Hurkmans EJ, et al: Physiother- plantation has proven to be a safe and effective proce-
apy in hip and knee osteoarthritis: Development of a dure to treat cartilage defects.
practice guideline concerning initial assessment, treat-
ment and evaluation. Acta Reumatol Port 2011;36(3): 30. Odorico JS, Kaufman DS, Thomson JA: Multilineage
268-281.
k eers
rs e rs
r s
A guideline steering committee consisting of 10 physio-
k e
differentiation from human embryonic stem cell lines.
Stem Cells 2001;19(3):193-204.
b ooook b ooook
therapists looked at 11 topics in the areas of initial as-
sessment, evaluation, and treatment. The following rec- 31.
b o oo
o
Kurtz S, Ong K, Lau E, Mowat F, Halpern M: Projec-
/
e e
/ eb / e e b
ommendations were made for OA patients: education
ee /
and self-management, exercise and manual therapy, su- / e e b
tions of primary and revision hip and knee arthroplasty
ee /
in the United States from 2005 to 2030. J Bone Joint
: // t/.tm m
pervised exercise therapy, postoperative exercise ther-
. : / t . m
. m
Surg Am 2007;89(4):780-785.
/ / t
apy, and patellar taping.
ss : / ss : /
hhtttp
tp hhtttp
tp
32. Safran MR, Kim H, Zaffagnini S: The use of scaffolds in
24. Hochberg MC, Altman RD, April KT, et al: American the management of articular cartilage injury. J Am Acad
College of Rheumatology 2012 recommendations for Orthop Surg 2008;16(6):306-311.
the use of nonpharmacologic and pharmacologic thera-
pies in osteoarthritis of the hand, hip, and knee. Arthri- 33. Fortier LA, Barker JU, Strauss EJ, McCarrel TM, Cole
tis Care Res (Hoboken) 2012;64(4):465-474. BJ: The role of growth factors in cartilage repair. Clin
keerrss
of OA of the hip, knee, and hand using systematic
k e rrss
The authors provide up-to-date guidelines on treatments
e
Orthop Relat Res 2011;469(10):2706-2715.
The authors performed a PubMed search using chon-
bboooo k b o o
o k
evidence-based literature reviews. Nonpharmacologic
o
treatment recommendations included exercise and weight
b o oo
drocyte or cartilage in combination with growth factors
o
/
e e
/ e / e e b
loss for hip and knee OA patients and joint protection
ee /
and thermal treatment of hand OA patients. Pharmaco-
ee/ e
/ e b
and their ability to synthesize extracellular growth ma-
trix. The main growth factors that were discussed were
t . m
. m
logic treatments of all OA included acetaminophen, top-
t . m
the TGF-β superfamily, IGF-1, the FGF family, and
.m
: / /
/ / t
ical and oral NSAIDs, tramadol, and intra-articular in-
s : s : : /
/ t
platelet-derived growth factor.
/ /
hhtttp s
jections. Opioids were recommended only if patients had
tp
a contraindication to total joint arthroplasty.
hhtttp
tp
34.
s Chia SL, Sawaji Y, Burleigh A, et al: Fibroblast growth
factor 2 is an intrinsic chondroprotective agent that sup-
presses ADAMTS-5 and delays cartilage degradation in
25. Webber TA, Webber AE, Matzkin E: Rate of adverse re- murine osteoarthritis. Arthritis Rheum 2009;60(7):
actions to more than 1 series of viscosupplementation. 2019-2027.
Orthopedics 2012;35(4):e514-e519.
k eers
rs k e r
The authors performed a retrospective study and found
e s
r
that patients who receive more than one series of visco-s 35. Schmidt MB, Chen EH, Lynch SE: A review of the ef-
fects of insulin-like growth factor and platelet derived
bboooo k b o o
supplementation have few adverse reactions, which
o o k
were defined as acute pain and swelling in the knee.
b o oo
growth factor on in vivo cartilage healing and repair.
o
Osteoarthritis Cartilage 2006;14(5):403-412.
/
e e
/ e 26.
ee/ e
/ e b
Chu CR, Coyle CH, Chu CT, et al: In vivo effects of
ee/ e
/ e b
: / / t
/ .
t m
. m
single intra-articular injection of 0.5% bupivacaine on
36.
: / / t
/ t m
Evans CH, Robbins PD, Ghivizzani SC, et al: Gene
. . m
transfer to human joints: Progress toward a gene ther-
599-608.
t p p : /
articular cartilage. J Bone Joint Surg Am 2010;92(3):
ss t p ss
p : /
apy of arthritis. Proc Natl Acad Sci U S A 2005;
102(24):8698-8703.
t
hht t
This in vivo study in rats showed reduced chondrocyte
density without cartilage tissue loss six months after a
t
hht t
37. Firestein G: Kelly’s Textbook of Rheumatology, ed 7.
single intra-articular injection of 0.5% bupivacaine. Philadelphia, PA, WB Saunders, 2005, pp 996-1042.
They conclude that this suggests bupivacaine toxicity.
38. Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid
k
27.
eers
rsLo GH, LaValley M, McAlindon T, Felson DT: Intra-
k eers
r s
articular hyaluronic acid in treatment of knee osteoar-
arthritis classification criteria: An American College of
Rheumatology/European League Against Rheumatism
b ooook b ook
thritis: A meta-analysis. JAMA 2003;290(23):3115-
oo 2569-2581.
b oooo
collaborative initiative. Arthritis Rheum 2010;62(9):
/
e e
/ eb 3121.
ee/ e
/e b e /e/e b
The most recent classification of RA updated the 1987
e
28.
/ t
///t. m
Moreland LW: Intra-articular hyaluronan (hyaluronic
. m
acid) and hylans for the treatment of osteoarthritis:
: : / t.
///t m
American College of Rheumatology classification by fo-
.m
cusing on the early stages of the disease. Definite RA
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
was defined with synovitis in at least one joint without 50. Gowdie PJ, Tse SM: Juvenile idiopathic arthritis. Pedi-
k eers
rs rrss
an alternate diagnosis and the following minor criteria:
kee
the site and number of joints involved, serologic find-
atr Clin North Am 2012;59(2):301-327.
b ooook o ook
ings, elevation of acute phase reactants, and the dura-
b o oo
The authors provide a comprehensive review article on
o o
JIA, detailing the causes, the epidemiology, clinical man-
b
/
ee/e b tion of symptoms.
ee/ e
/ e b ee/ e
/ e b
ifestations, classifications, developments in manage-
ment, complications, and long-term outcomes of JIA.
39.
/ ///t. m
.m
Cohen SB, Moreland LW, Cush JJ, et al: A multicentre,
t
double blind, randomised, placebo controlled trial of
: : /
51. t
///t. m
. m
Ruth NM, Passo MH: Juvenile idiopathic arthritis:
s :
anakinra (Kineret), a recombinant interleukin 1 receptor
tps s
tps :
hhtttp hhtttp
Management and therapeutic options. Ther Adv Muscu-
antagonist, in patients with rheumatoid arthritis treated loskelet Dis 2012;4(2):99-110.
with background methotrexate. Ann Rheum Dis 2004;
63(9):1062-1068. There have been great developments in the management
of patients with JIA; an improved classification system,
patient assessment, imaging, and gene profiling have
40. Bresnihan B, Newmark R, Robbins S, Genant HK: Ef- helped develop more specific treatments. Older treat-
fects of anakinra monotherapy on joint damage in pa-
k eers
rs k ee
randomized, placebo-controlled trial. J Rheumatolrs
r s
tients with rheumatoid arthritis: Extension of a 24-week
ments, including NSAIDs and methotrexate, are being
supplemented with biologic treatments such as TNF-α
b ooook 2004;31(6):1103-1111.
b ooook oo
inhibitors, IL-1 and IL-6 blockade, selective B cell
o o
blockade, and selective costimulation modulators.
b
/
e e
/ eb 41.
e/ e
/ e b
Klippel JH, Stone JH, Crofford LJ, White PH: Primer
e 52.
ee/ e
/ e b
Taylor W, Gladman D, Helliwell P, et al: Classification
Springer, 2008.
: // t/.tm
on the Rheumatic Diseases, ed 13. New York, NY,
. m : / / t
/ .
t m
. m
criteria for psoriatic arthritis: Development of new cri-
ss : / ss : /teria from a large international study. Arthritis Rheum
hhtttp hhtttp
2006;54(8):2665-2673.
42.
tp
Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson
DT, Martini A: Preliminary definition of improvement
in juvenile arthritis. Arthritis Rheum 1997;40(7):1202-
tp 53. McCutchan HJ, Fisher RC: Synovial leukocytosis in in-
fectious arthritis. Clin Orthop Relat Res 1990;257:
1209. 226-230.
43. Petty RE, Southwood TR, Manners P, et al: Interna-
rrss rrss
54. Smith BG, Cruz AI Jr, Milewski MD, Shapiro ED: Lyme
tional League of Associations for Rheumatology classi-
o ke
ke o k e
k e
fication of juvenile idiopathic arthritis: Second revision,
disease and the orthopaedic implications of lyme arthri-
oo
tis. J Am Acad Orthop Surg 2011;19(2):91-100.
e bboo o e b o
Edmonton, 2001. J Rheumatol 2004;31(2):390-392.
b o o e b o o
This review article evaluates the orthopaedic complica-
b
/
e / e 44.
ee/ / e
Manners PJ, Bower C: Worldwide prevalence of juvenile
m ee/ / e
tions of Lyme disease, which should be considered in
patients with mono-or pauciarticular joint pain or effu-
m
. m
arthritis why does it vary so much? J Rheumatol 2002;
t . t . .m
sion, especially in areas with endemic Lyme disease.

29(7):1520-1530.
s : /
: /
/ / t s : / /
/ / t
Treatment with antibiotics and arthroscopic synovec-
:
45.
hhtttp
tp s
Manners PJ, Diepeveen DA: Prevalence of juvenile
chronic arthritis in a population of 12-year-old childrenhhtttp
tp
55.
s tomy in severe cases lead to a good prognosis.
Puius YA, Kalish RA: Lyme arthritis: Pathogenesis, clin-

in urban Australia. Pediatrics 1996;98(1):84-90. ical presentation, and management. Infect Dis Clin
North Am 2008;22(2):289-300, vi-vii.
46. Mielants H, Veys EM, Maertens M, et al: Prevalence of
k eers
rs
inflammatory rheumatic diseases in an adolescent urban
k e r
student population, age 12 to 18, in Belgium. Clin Exp
e s
r s
56. Rose CD, Fawcett PT, Eppes SC, Klein JD, Gibney K,
Doughty RA: Pediatric Lyme arthritis: Clinical spectrum
bboooo k Rheumatol 1993;11(5):563-567.
b o o
o o k b o oo
and outcome. J Pediatr Orthop 1994;14(2):238-241.
o
/
e e
/ e 47.
/ e e b
Tayel MY, Tayel KY: Prevalence of juvenile chronic ar-
ee /
thritis in school children aged 10 to 15 years in Alexan-
57.
ee/ e
/ e b
Wormser GP, Dattwyler RJ, Shapiro ED, et al: The clin-
ical assessment, treatment, and prevention of lyme dis-
: / / t
/ .
t m
. m
dria. J Egypt Public Health Assoc 1999;74(5-6):
: / / t . m
. m
ease, human granulocytic anaplasmosis, and babesiosis:
/ t
529-546.
t p ss
p : / t p ss
p : /
Clinical practice guidelines by the Infectious Diseases
Society of America. Clin Infect Dis 2006;43(9):1089-
48.
t
hht t
Gortmaker SL, Sappenfield W: Chronic childhood dis-
orders: Prevalence and impact. Pediatr Clin North Am
1984;31(1):3-18.
t
hht t 1134.
58. Baumhauer JF, O’Keefe RJ, Schon LC, Pinzur MS:

Cytokine-induced osteoclastic bone resorption in char-
49. Hofer M, Southwood TR: Classification of childhood cot arthropathy: An immunohistochemical study. Foot
k eers
rs
arthritis. Best Pract Res Clin Rheumatol 2002;16(3):
379-396.
k eers
r s
Ankle Int 2006;27(10):797-800.
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
222
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 19
e rs
rs e rrss
oo
kExtracellular
ook e Matrix o k
ook
o
e o oo
o
/e/ebb / e
/ b
e b / e
/ b
e b
e and Collagen t
///t. m
.mDisorders
ee t
///t. m
. mee
s: /
: s : /
:
tps
hhtttp tps
hhtttp
William V. Arnold, MD, PhD Andrzej Fertala, PhD
k eers
rs k eers
r s cortex of bone is synthesized by osteoblasts derived
b ooook b o oo
from the midshaft region. Subsequently, the secondary
o
ossification centers are created in a process that in-
/
e e
/ eb e/ e
/ e b
The extracellular matrix (ECM) is composed of a large
number of protein molecules that are secreted by cells,
e ee/ e
/ e b
volves removal of part of the embryonic cartilage. The
: // /.tm m
with much of the three-dimensional assembly of these
t .
molecules occurring extracellularly. The ECM may be
: / / t
/ .
t m
growth plate or physis remains between structures
. m
formed within the primary and secondary ossification
ss : / ss : /
centers. The cartilage growth plate includes well-
hhtttp hhtttp
envisioned as a scaffold that holds together the cellular
tp
components of tissues and organs, but the function of
the ECM goes well beyond this simple concept. Colla-
gen proteins play a predominant role in orthopaedic-
tp
defined subpopulations of chondrocytes that form rest-
ing, proliferative, and hypertrophic zones characterized
by a columnar arrangement of cells that form them
related issues because they are the main ECM constitu- (Figures 1 and 2). The biologic activity of the growth
ent of bone and cartilage. A classic example of how plate chondrocytes is part of the mechanism that con-
rrss rrss
collagen defects can cause human disease is demon- trols bone growth and mineralization.1,3,4
o kee k e e
strated by mutations in type I collagen that cause osteo-
k o k
During the physiologic process of bone development
oo
and growth, chondrocytes produce and secrete extra-
e bboo o b o
b o o
genesis imperfecta (discussed in chapter 66, Skeletal
Dysplasias, Connective Tissue Diseases, and Other Ge-
e e b o o
cellular macromolecules that form the architecture of
b
/
e / e m e / / e
netic Disorders, Orthopaedic Knowledge Update 11).
e / / e
the cartilaginous ECM, signal cells via specific recep-
m ee
tors, and serve as a reservoir for various growth factors
t .
However, aberrations of other ECM components can
. m t . .m
s : / / / t
also contribute to orthopaedic diseases. Understanding
: / s : /
: /
/ t
that regulate bone development.5 In pathologic situa-
/
tions caused by mutations in genes encoding these mac-
tp s
these diseases at the molecular level, and specifically
hhtttp
how these diseases affect the ECM, may help direct fu-
ture treatments of these disorders. hhtttp
tp s
romolecules, the processes of bone formation and
growth are altered. Clinically, these pathologic situa-
tions are recognized as chondrodysplasias, a group of
rare, inherited disorders of skeletal development and
linear growth.6 The clinical aspects of these chondro-
Chondrodysplasias: A Broad Spectrum of
k eers
rs
Diseases of Skeletal Growth
k e r
e s
r s
dysplasias are discussed in chapter 66, Skeletal Dyspla-
sias, Connective Tissue Diseases, and Other Genetic
bboooo k b o
skeleton during fetal development is a complex ando
o k
The patterning and formation of the architecture of the
o b o oo
Disorders, Orthopaedic Knowledge Update 11. The
o
pathomechanisms of these diseases include the intracel-
/
e e
/ e ee/ e
/ e b
highly regulated process.1,2 One of its initial stages in-
/ e e b
lular processes of biosynthesis and secretion and the ex-
ee /
tracellular processes of the formation of biologic scaf-
/ / t t m
volves the condensation of mesenchymal cells at sites of
. . m
bone formation (Figure 1). In this process, mesenchy-
: / : / / t
/ .
t m
. m
folds, receptor-mediated cell-matrix interactions, and
ss : /
mal cells differentiate into chondrocytes, which form
t p p t p ss
p : /
an enzyme-dependent turnover of elements of the ECM
t t
primordial cartilage. Subsequently, the primary ossifi-
hht
cation centers are formed by degradation and mineral-
ization of the center of the primordial cartilage. The
t
hht t
(Figure 3).
Chondrodysplasias Associated With

Mutations in Collagens of Cartilage
The structural integrity of cartilage and its ability to
k eerss
Dr. Arnold or an immediate family member serves as a
r k
paid consultant to or is an employee of Merck and URL
eers
r s
fulfill specific mechanical and biologic functions is fa-
cilitated by the presence of a unique extracellular scaf-
b ooook b ook
Pharma; has stock or stock options held in Merck and
oo b oooo
fold formed by various macromolecules produced by
chondrocytes (Figure 2). Such a scaffold not only de-
/
e e
/ eb e / e
/e b
URL Pharma; and has received research or institutional
support from Stryker. Dr. Fertala or an immediate family
e ee/e/e b
fines the physical characteristics of cartilage but also
from Mentor Worldwide, LLC.

: / t
///t m
member has received research or institutional support
. . m : / t.
///t m
provides a platform for the receptor-mediated attach-
.m
ment of cells. The biologic scaffold of cartilage is a
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
Figure 1
hhtttp
tp hhtttp
tp
An illustration showing the major steps in endochondral ossification.
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
Figure 2
ss : / ss : /
A, A representation of the organization of collagenous matrices in the growth plate; a paradigm of a mouse
t p p t p p
t t t t
joint. The growth plate (B) is characterized by the presence of well-defined groups of chondrocytes. These
hht hht
chondrocytes (C) are surrounded by a fibrillar network (D), whose main components are collagen fibrils (E). En-
largements of the boxed areas are indicated by leader lines. CH = chondrocyte; CF = collagen fibrils.
dynamic structure whose homeostasis is maintained by proteins; the homotypic and heterotypic assembly of
k eers
rs the balanced processes of synthesis and degradation of
k e
its individual elements. The processes of biosynthesis
ers
r s these proteins into extracellular structures; and the en-
zymatic degradation, turnover, and modification of
b ooook b oook
and degradation are strictly regulated at different bio-
o o oo
these extracellular structures.7
b o
/
e e
/ eb e e
/e b
logic levels that include gene expression; gene transla-
/
tion; the posttranslational modification of ECM pro-
e e e/e b
Mutations associated with elements of the biologic
/
scaffold of cartilage may affect each of these stages,
e
: / ///t. m
. m
teins; intracellular transport and secretion of these
t : / t.
///t m
.m
thereby leading to chondrodysplasias.6 Focusing on the
s
tps : s
tps :
224
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 19: Extracellular Matrix and Collagen Disorders
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
Figure 3
: // t/. m
. m : / / t . m
. m
A schematic illustrating the main intracellular and extracellular steps leading to the formation of heterotypic fibrils
t / t
of cartilage.
ss : / ss : /
hhtttp
tp
biosynthesis of collagen II, the main structural protein
of cartilage, helps to illustrate the complex mechanisms
hhtttp
tp
involved in the pathology of diseases such as chondro-
dysplasias and exemplifies the challenges in developing
k errss
molecular-based therapies for these diseases.6,8,9
e k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e Intracellular Processes of Synthesis
of Procollagen II
ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
Biosynthesis of Individual
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
Procollagen II Chains
tp s
Collagen II belongs to a group of fibril-forming colla-
gens with which it shares several biochemical and bio- hhtttp
tp s
physical characteristics.7 The collagen II protein that is
assembled into the ECM is first produced as a larger, Figure 4 A depiction of the structure of procollagen II
soluble procollagen II molecule that is encoded by the molecules. A, An electron microscopy image of
k eerss
COL2A1 gene. Procollagen II is produced by chondro-
r k
cytes in the form of a homotrimeric protein with indi-
e r
e s
r s
human procollagen II molecules purified from
cultures of cells that produce them. The insert
bboooo k b o o o
vidual procollagen II chains that are characterized by
o k b o oo
depicts a procollagen II molecule in which the
o
positions of the propeptides are indicated. Note
/
e e
/ e
the presence of an extended triple-helical domain
e
flanked by the N (amino)-terminal and the C
e/ e
/ e b e / e
/ e b
a readily visible C-terminal propeptide. B, A
computerized model of a fragment of the colla-
e
: / / / .
t m m
(carboxyl)-terminal globular propeptide domains (Fig-
t .
ures 3 and 4). The telopeptides are short regions that
: / / t
/ .
t m
gen triple helix. This fragment consists of three
. m
individual chains, each consisting of eight ca-
ss : /
separate the extended triple-helical collagen domain
t p p t p ss
p : / nonical -G-X-Y- triplets. A cross-section view in-
dicates a central position of the glycine
t
hht t
from the propeptide domains. A critical characteristic
that defines the key region, namely the extended triple-
helical domain, is the presence of consecutive repeats of
t
hht t residues.
approximately 300 amino acid triplets characterized as ent at the Y positions of the -G-X-Y- triplets and glyco-
-G-X-Y-, in which G is the amino acid glycine, the X sylation of some lysine residues. Critical processes of
k eers
position is frequently occupied by the amino acid pro-
rs
line, and the Y position is frequently occupied by hy-
k eers
r s
hydroxylation are catalyzed by prolyl and lysyl hydrox-
ylases, enzymes whose specific activities depend on the
b ooook b ook
droxyproline, a hydroxylated form of the amino acid
oo
proline7 (Figures 3 and 4). Before folding into a triple-
b oooo
presence of ascorbic acid and iron ions.10,11
/
e e
/ eb / e
/e b
helical structure, the nascent procollagen II molecules
ee ee/e/e b
Assembly of the Triple-Helical Structure
/ t
///t m
undergo posttranslational modifications that mainly in-
. . m
clude hydroxylation of proline and lysine residues pres-
: / t.
///t m
Concomitant with the biosynthesis and posttransla-
.m
tional modifications of the nascent procollagen II
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss Figure 5
e rrss
Ultrastructural assays of growth plates from mice harboring the R992C substitution. A, C, E, G, and I, Wild-type
k e
bboooo k b o o
o o k b o oo
mouse cartilage. B, D, F, H, and J, Mutant mouse cartilage. A and B, Hematoxylin and eosin staining of the growth
plates. In the mutant growth plate, the columnar arrangement of chondrocytes is altered. C and D, TdT-mediated
o
/
e e
/ e ee e
/ e b e e
/ e b
dUTP nick-end labeling (TUNEL) of fragmented DNA. Positive labeling seen in D indicates the presence of frag-
/ /
mented DNA, an indication of apoptosis. A, B, C, and D, The dashed lines identify the hypertrophic zones of the
e
t m
. m t m
growth plates. E, F, G, and H, Results of the immunostaining for cleaved caspase 3, yet another apoptotic marker,
. . .m
: / /
/ / : / /
shown at two different magnifications. F and H, Cleaved caspase 3-positive cells are apparent in the proliferative
t / / t
zone. The asterisks indicate cleaved caspase 3-positive cells. I and J, Subcellular features of chondrocytes from wild
s : s :
hhtttp
tp s hhtttp
tp s
type and mutant mice, respectively. Dilated ER is present in chondrocytes harboring the R992C mutant. (Repro-
duced with permission from Hintze V, Steplewski A, Ito H, Jensen DA, Rodeck U, Fertala A: Cells expressing par-
tially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo
apoptosis. Hum Mutat 2008;29:841-851.)
chains is their assembly into a triple-helical structure, a cules is a prerequisite for their efficient secretion from
k eers
rs hallmark of collagenous proteins. This process is initi-
k e r
e
ated by the site-specific interactions of distinct domains s
r s cells. Misfolded molecules are excessively accumulated
bboooo k localized at the C-termini of the procollagen II

b o o
o o k intracellularly in the endoplasmic reticulum (ER). Such
b o oo
o
an excessive accumulation of proteins destined for se-
/
e e
/ e e e
/ b
chains7,11 (Figure 3). The assembly of individual chains
/ e
is assisted by protein chaperones that prevent any pre-
e / e b
cretion may cause ER stress, a process that frequently is
ee / e
associated with apoptosis of cells producing the aber-
: / / / .
t m m
mature nonspecific aggregation of the nascent procolla-
t . : / / t . m
. m
rant proteins8,9,14-17 (Figure 5).
/ t
t p ss : /
gen II chains. The most prominent chaperones that par-
ticipate in procollagen folding are heat shock protein
p t p ss
p : /
t
hht t
47 (HSP47), protein disulfide isomerase, and binding
immunoglobulin protein (BiP).9,12,13 Correctly folded
procollagen molecules are characterized by the stable
t
hht t
Extracellular Procollagen II Processing and
Self-Assembly of Collagen II Into Fibrils
structure of the triple-helical domain whose thermosta-
bility depends on the presence of numerous hydrogen Processing of Procollagen Propeptides
Upon secretion from cells, the N-terminal propeptide of
k eers
rs bonds between individual procollagen II chains. Al-
though the formation of such hydrogen bonds depends
k eers
r s procollagen II is cleaved by a group of enzymes that in-
b ooook b ook
on the presence of hydroxylated proline residues, the
oo
tight packing of the procollagen II chains into a triple
b oooo
cludes a disintegrin and metalloprotease with thrombo-
spondin motifs (ADAMTS)-2, -3, and -14.18,19 At the
/
e e
/ eb / e
/e b
helix is possible because of the presence of the glycine
ee ee/e/e b
same time, the C-terminal propeptide is cleaved by en-
/ t
///t m
residues in the repeating -G-X-Y- triplet of the collagen
. . m
chain (Figure 4). Correct folding of procollagen mole-
: : / t.
///t m
zymes belonging to the tolloid family of zinc metallo-
.m
proteinases, in which procollagen C-proteinase, also
s
tps : s
tps :
226
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
described as bone morphogenetic protein-1, plays a key ples, it can be postulated that COL2A1 mutations may
k eers
rs ke rrss
role.20,21 Enzymatic cleavage of propeptides represents a
e
be an important element of the pathomechanism of os-
b ooook
(Figure 3).
b ook
critical step in the process of collagen fibril formation
o o
teoarthritis.26
b o oo
o
/
ee/e b Formation of Homotypic and Heterotypic
ee/ e
/ e b ee/ e
/ e b
Molecular and Cellular Mechanisms
of Diseases Associated With Mutations
Collagen Fibrils
: / t
///t. m
.m t
///t
in COL2A1
: / . m
. m
s :
Enzymatic cleavage of procollagen II propeptides ex-
tps s :
Anatomically, a common characteristic of chondrodys-
tps
hhtttp hhtttp
poses the telopeptide region of the molecule and trig- plasias associated with mutations in COL2A1 are aber-
gers the self-assembly of collagen II molecules into rations of skeletal growth accompanied by develop-
highly ordered collagen fibrils.11 The formation of col- mental abnormalities of the growth plates. The
lagen fibrils is a spontaneous process driven by site- molecular pathomechanisms underlying these anatomic
specific interactions occurring between defined regions changes are complex and involve intracellular processes
of interacting molecules.11,22 Electrostatic and hydro- of synthesis and transport of procollagen molecules and
k eers
rs k e rs
r s
phobic interactions play a critical role in the formation
e
extracellular processes of fibril formation and cell-
b ooook b ooook
of highly ordered fibrils whose distinctive morphologic
feature is a well-defined periodicity (Figures 2 and 3). oo
matrix interaction.9 The following sections describe the
o o
major changes observed at the molecular, cellular, and
b
/
e e
/ eb / e e b
During this process, collagen II molecules coassemble
ee /
with collagen IX and collagen XI to form heterotypic / e e b
extracellular levels in cartilage of affected patients as
ee /
well as in experimental conditions that include in vitro
: // t/.tm
. m
fibrils of cartilage. After fibrils are assembled, they are
: / / t . m
. m
and in vivo models.
/ t
: /
stabilized by covalent cross-links formed primarily with
ss ss : /
hhtttp
tp hhtttp
tp
the involvement of lysine and hydroxylysine residues Effects of Mutations on Individual
present in the triple helical regions and the telopeptides Procollagen II Molecules
of cross-linked collagen molecules. The cross-linking Although there are more than 100 missense/nonsense
process depends on the enzymatic activity of copper- mutations reported for COL2A1, no clear genotype-
dependent lysyl oxidase, an enzyme that catalyzes the phenotype correlation has been established. Most single
formation of aldehydes from peptidyl lysine and hy- amino acid substitutions within the triple helical region
k errss
droxylysine residues.23 Properly assembled and cross-
e k e rrss
e
linked heterotypic collagen fibrils constitute a critical
of procollagen II are changes for glycine residues.27 In
bboooo k
structural element of cartilage ECM (Figure 3).
b o o
o o k b o oo
addition, several mutations that change codons for the
o
arginine residue present at the Y position of a -G-X-Y-
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
triplet have also been described. Substitutions at the X
positions are rarely reported, and this type of mutation
t . m
. m t . m.m
is frequently associated with Stickler syndrome. Prema-
s : /
: /
Collagen II–Associated Diseases
/ / t : /
: /
/ / t
ture stop codons in the regions of COL2A1 that en-
s
hhtttp
tp s
Mutations in COL2A1 are associated with chondro-
dysplasias, with severities ranging from profound
dwarfism and lethality in utero to mild phenotypes hhtttp
tp s
code the N-propeptide and the triple helix are also as-
sociated with Stickler syndrome, whereas those within
the region that encodes the C-propeptide were found in
characterized by precocious osteoarthritis. According spondyloperipheral dysplasia and the Torrance type of
to the revised classification of the genetic skeletal disor- platyspondylic skeletal dysplasia.
ders proposed by the International Skeletal Dysplasia Overall, it is difficult to predict the specific molecu-
eers
Society (ISDS), COL2A1-associated diseases belong to
rs
the type II collagen and similar disorders group of
k k e r
e s
r s lar consequences of mutations in collagen II. These
consequences are broad and may cause the following
bboooo k b o
forms of the COL2A1-associated chondrodysplasias. o
chondrodysplasias.24,25 Table 1 summarizes the main
o o k b o oo
conditions: (1) posttranslational overmodifications,
o
/
e e
/ e ee/ e
/ e b e e
/ e b
which include overhydroxylation of proline and lysine
/
residues and overglycosylation of the nascent procolla-
e
Early-Onset Osteoarthritis
: / / t
/ .
t m
. m
Czech dysplasia, Stickler syndrome, osteonecrosis of
: / / t
/ .
t m
. m
gen II chains; (2) a decrease in the thermostability of
ss : /
the femoral head, spondyloepiphyseal dysplasia (SED),
t p p t p ss : /
procollagen II that prevents proper formation of the
triple-helical structure at physiologic temperatures;
p
t
hht t
and Kniest dysplasia are recognized as type II collag-
enopathies with an arthritis phenotype. The results of a
2010 study26 suggested that premature osteoarthritis
t
hht t
(3) alterations of the geometry of individual procolla-
gen II molecules by introducing a kink at the site of the
mutation; (4) misalignment of individual procollagen II
represents a distinct phenotype associated with muta- chains; and (5) the production of truncated chains as a
tions in COL2A1. In addition, it is suggested that pre- result of the introduction of a premature stop codon in
k eers
cocious osteoarthritis may develop in patients with the
rs k eer
absence of any other characteristics indicating collagens
r s protein synthesis. Because of the possible intracellular
degradation of misfolded or truncated mutant mole-
b ooook b oook
II–related disorders. The authors of this study reported
o
cases of early-onset osteoarthritis in individuals harbor-
b ooo
cules, these changes may contribute to a decrease in the
o
overall amount of collagen II in cartilage. Because not
/
e e
/ eb ee/ e
/e b
ing the glycine to alanine substitution at amino acid site
/e/e b
all mutations lead to an accelerated degradation of af-
ee
/ t
///t m
204 and the glycine to serine amino acid substitution at
. . m
amino acid site 393. Based on these and other exam-
: / t.
///t m
fected molecules, certain collagen II mutants are se-
.m
creted from cells but result in the formation of aberrant
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook b ook
Overview of Diseases Associated With Mutations in Collagen II
o o b o oo
o
/
ee/e b Gene/
ee/ e
/ e bReported
Mutation
ee/ e
/ e b Detected Molecular and
Disorder/MIM#
t
Inheritance
: / ///t. m
.m Type(s)
: t . m
. m
Observed Clinical Features Histologic Changes
/ ///t
Achondrogenesis
s
tps :
COL2A1/AD Missense
s
tps :
Severe micromelic dwarfism Significantly reduced amount of
hhtttp hhtttp
type II and Small chest cartilage collagen II
hypochondro- Prominent abdomen Overmodification of collagen II
genesis/200610 Incomplete ossification of the Increased amount of collagen I
vertebral bodies and collagen III
Disorganization of the
costochondral junction
Osteonecrosis of COL2A1/AD Missense Progressive pain in the groin Suggested changes in the fibril
k eers
rs femoral
head/608805
k eers
r s Mechanical failure of the
subchondral bone
structure and interactions
with other macromolecules of
ook ook
Degeneration of the hip joint cartilage
b oo Kniest COL2A1/AD
b oo
Missense, splice, Short stature
b o oo
o Overmodification of collagen II
/
e e
/ eb dysplasia/156550
e/
e e
/ e b deletion
depression
ee e
/ e b
Round face with central
/
Degeneration of chondrocytes
Presence of cytoplasmic
: // t/.tm
. m t . m
Prominent eyes
. m
Enlargement and stiffness of
: / / / t
inclusions
Abnormal collagen fibrils
ss : / ss /
joints
:
Contractures of fingers
hhtttp
tp hhtttp
tp
Bell-shaped chest
Myopia
Platyspondylic COL2A1/AD Missense, Wafer-like vertebral bodies, Chondro-osseous histology is
dysplasia, nonsense, Severe hypoplasia of the characterized by
Torrance deletions lower ilia hypercellularity with slightly
type/151210 within the C Short long bones with ragged large chondrocytes in the
propeptide metaphyses resting cartilage
rrss rrss
Bowing of the radius Normal columnization with
o ke
ke o k e
k e oo
incorporation of cartilage into
bone at the chondro-osseous
e bboo o Spondyloepi- COL2A1/AD

e b o
b o o
Missense
e b o
b o
junction
Disproportionate short stature Dilated endoplasmic reticulum
/
e / e metaphyseal
dysplasia
m ee/ / e Scoliosis
m e
Pectus carinatum
e/ / e
Strudwick
t . . m t . .m
Dappled metaphyses
type/184250
s : /
: /
/ / t : / /
/ / t
Retinal detachment
s :
dysplasia
congenita/
183900 hhtttp
Spondyloepiphyseal COL2A1/AD
tp s deletion,
insertion
hhtttp
Missense, splice,
s
Short stature
tp
Shortening of proximal
extremities
Kyphoscoliosis and lordosis
Decrease of the thermostability
of collagen II mutants
Atypical formation of a kink in
some collagen II mutants
Platyspondyly Excessive intracellular
Coxa vara accumulation of some
Myopia thermolabile mutants
Hearing loss Apoptosis of cells harboring
k eers
rs k e r
e s
r s
some misfolded mutant
collagen II
Aberrations of formation of
bboooo k b o o
o o k b o oo
o
homotypic and heterotypic
collagen fibrils
/
e e
/ e Spondylo-
peripheral
COL2A1/AD
ee/ e
/ e b
Nonsense in the
C-terminal
Platyspondyly
e
Severe hip changes
e/ e
/ e b Alteration of C
propeptide-dependent
dysplasia/271700
: / / t
/ .
t m
. m propeptide
: / / t
/ .
Brachydactyly
t m
. m
Distal shortening of ulna
association of procollagen II
chains
t p ss
p : / t p ss
Myopia
p : /
Hearing loss
Excessive intracellular
accumulation of mutant
Stickler syndrome
type I/108300
t
hht t
COL2A1/AD Missense,
deletions,
t
hht t
High myopia
Vitreoretinal degeneration
molecules
Truncated forms of collagen II
chains
splice, Retinal detachment
nonsense Cataracts
Midline clefting-Pierre Robin
k eers
rs k eers
r s
sequence
Flat midface
Sensorineural or conductive
b ooook b oook
o
hearing loss
Mild SED
b oooo
/
e e
/ eb e / e
/e b
AD = autosomal dominant, SED = spondyloepiphyseal dysplasia.
e ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
228
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
extracellular fibrillar structures.9,17,28-33 ful to the tissue than their negative influence on cell
k eers
rs keerrss functions. This concept is supported by studies that
b ooook
Effects of Mutations in COL2A1 On Cells
Harboring Abnormal Procollagen Molecules
b o ook
o
demonstrated that thermostable mutants harboring the
b o oo
o
R75C and R519C substitutions do not cause detectable
/
ee/e b ee/ e
/ e b
The intracellular formation of the correct triple-helical
ee/ e
/ e b
ER stress.31 Although these mutant collagens are incor-
porated into the ECM, their presence is associated with
t
///t m
structure of procollagen II is essential for its secretion
. .m
to the extracellular space.9,17,31 Mutations associated
: / : / t . m
. m
mild rather than severe forms of dysplasias.
///t
s :
with misfolding of the nascent chains, however, lead to
tps s
tps :
hhtttp hhtttp
the excessive accumulation of affected molecules in the Extracellular Effects of Mutations in COL2A1
endoplasmic reticulum (ER), thereby causing ER stress, Electron microscopy observations of cartilage from
a process that may trigger the unfolded protein re- mice and affected patients harboring mutant collagen II
sponse (UPR; Figure 5). The UPR involves the interac- frequently demonstrate a decrease in the number of col-
tion of lumenal BiP with transmembrane stress sensors lagen fibrils present in the extracellular space. Detailed
such as IRE1, ATF6, and PERK. During this process, assays show that although not all mutations alter the
k e rs
rs
BiP dissociates from the BiP/sensor complexes and
e k eers
r s ability of affected collagen molecules to self-assemble
b ooook b oook
translocates into the ER lumen, where it interacts with
o
misfolded mutants. Dissociation of BiP activates the
b o oo
into fibrils, some single amino acid substitutions com-
o
pletely prevent fibril formation or alter the kinetics of
/
e e
/ eb / e e b
stress sensors and triggers downstream events that in-
ee /
clude Xbp-1 splicing and ATF6 cleavage. At the same / e e b
self-assembly. In addition, the presence of mutant
ee /
molecules in a fibril negatively affects its ability to form
: // t . m
. m
time, accelerated biosynthesis of BiP and other molecu-
/ t : / / t
/ .
t m
. m
heterotypic assemblies with wild type collagen
s : /
lar chaperones, such as protein disulfide isomerase,
s ss : /
IX.9,17,30-33,39-41 Complex changes in the structure of the
hhtttp
tp hhtttp
tp
stimulates the folding of mutant molecules, whereas the ECM formed in the presence of collagen II mutants also
overall production of proteins decreases mainly altered receptor-mediated cell-matrix interactions,
through eIF2α-dependent suppression. If the biologic thereby negatively affecting cartilage homeostasis.9
events of the UPR cannot attenuate the effects of ER
stress, the affected cells may undergo apoptosis.34,35 For
instance, studies have demonstrated that the presence
rrss rrss
Collagen VI, Collagen IX, Collagen XI,
of misfolded thermolabile R789C and R992C collagen
o ke
ke
II mutants associated with SED in humans and mice,
o k e
k e
and Collagen XXVII
oo
e bboo o e b o
b
and apoptosis9,17,31 (Figure 5). Radiographic measure-o
respectively, triggers the processes of ER stress, UPR,
o e b o
In addition to collagen II, other collagen types provide
b o
additional structural elements of cartilage ECM. Colla-
/
e / e ee/ /
ments of bones from mice harboring a spontaneous
m e m e / / e
gen VI, a heterotrimer whose individual chains are en-
e
t . . m
R992C substitution demonstrate altered growth.36
t . .m
coded by the COL6A1, COL6A2, and COL6A3 genes,
: / /
/ / t
These data exemplify the complex pathomechanism of
s : s : /
: /
/ / t
is present in the pericellular region surrounding chon-
hhtttp
tp s
chondrodysplasias associated with mutations in colla-
gen II and point toward the existence of a domino ef-
fect triggered by a change at the gene level and leading hhtttp
tp s
drocytes. The role of this protein in cartilage is not fully
defined, but hypotheses have been made that it partici-
pates in the transduction of biomechanical signals.42,43
to pathologies seen phenotypically at the level of bone. Analyses of mice with a deletion of COL6A1 indicate
In addition to causing ER stress, the presence of mis- that they develop osteoarthritis, thereby suggesting the
folded procollagen II chains in the ER leads to atypical critical role of collagen VI in maintaining the integrity
k eerss
interactions of these procollagens with other proteins.
r
For example, the R789C collagen mutant binds with
k e r
e s
r s
of cartilage.43 In addition, mutations in COL6A1 are
also associated with ossification of the posterior longi-
bboooo k b o o o
normal fibronectin, thereby trapping this extracellular
o k tudinal ligament of the spine.44
b o oo
o
/
e e
/ e e / e
/ e b
protein inside cells and disturbing the correct formation
of ECM.37 Considering these and similar examples, it
e e / e
/ e b
Collagen IX is a heterotrimer encoded by the
COL9A1, COL9A2, and COL9A3 genes. Together
e
: / / / .
t m m
becomes quite clear that ER stress and the UPR are im-
t .
portant consequences of mutations in genes encoding
: / / t
/ .
t m
with collagen II and collagen XI, this protein partici-
. m
pates in the formation of heterotypic fibrils, a main ar-
ss : /
cartilage macromolecules that contribute to the patho-
t p p t p ss
p : /
chitectural element of the cartilage ECM. Electron mi-
t
hht t
genesis of chondrodysplasias.9,14,16,17,31
The existence of the ER-related pathomechanisms
offers a new possible target for developing treatment
t
hht t
croscopy shows that collagen IX decorates the surface
of collagen II fibrils. Biochemical assays have deter-
mined that both collagen types are chemically cross-
strategies for chondrodysplasias. Specifically, chemical linked, thereby forming structurally stable collagen ma-
chaperones with the potential to promote folding and trices. Chondrodysplasias associated with mutations in
k e rs
the secretion of misfolded collagen II mutants were
rs
proposed as a new method to reduce ER stress.38 Al-
e k eers
r s
collagen IX are classified as the “multiple epiphyseal
dysplasia and pseudoachondroplasia” group24 (Table
b ooook b ook
though the chaperone approach will not eliminate the
oo
mutant molecules from affected tissues, it may still of-
2).
b oooo
Yet another component of such complex fibrils is
/
e e
/ eb / e
/e b
fer significant therapeutic benefits. This notion is based
ee ee/e/e b
collagen XI. This heterotrimeric protein is encoded by
/ t
///t m
on the possibility that the “actions” of some mutant
. . m
molecules in the extracellular space may be less harm-
: : / t.
///t m
the COL11A1, COL11A2, and COL11A3/COL2A1
.m
genes. Although the α3 (XI) chain is encoded by
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 2
keerrss
b ooook b ook
Chondrodysplasias Associated With Collagen IX, Collagen X, or Collagen XI Mutations
o o b o oo
o
/
ee/e b Gene/
ee/ e
/ e b
Reported
Mutation
ee/ e
/ e b Detected Molecular and
Disorder/MIM#
t
Inheritance
: / ///t. m
.m Type(s)
: / t . m
. m
Observed Clinical Features Histologic Changes
///t
Multiple epiphyseal Col9A1/AD
s
tps : Insertion
s
tps : Early osteoarthritis Possible alterations of formation
hhtttp hhtttp
dysplasia type 6/ Schmorl’s nodes of functional collagen IX
614135 End plate irregularities
Anterior osteophytes in the
thoracolumbar vertebrae
Normal hips
Stickler syndrome COL9A1/AR Nonsense, Moderate to severe Possible functional knockout of
type IV/614134 insertion sensorineural hearing loss all collagen IX chains
k eers
rs k eers
r s Moderate to high myopia
with vitreoretinopathy
ook ook
Epiphyseal dysplasia
b oo Multiple epiphyseal COL9A2/AD

b oo
Splice
b o oo
o
Joint pain and stiffness In-frame deletion
/
e e
/ eb dysplasia type 2/
600204
e/
e e
/ e b e e
/ e b
Mild short stature
/
Degenerative joint disease
e
Some variation in a muscle fiber
size
: // t/.tm
. m : / t m
Onset usually in childhood
. . m
Mild myopathy
/ / t
Stickler syndrome
s :
COL9A2/AR
s / Deletion
ss : /
High myopia Premature termination
hhtttp hhtttp
type 5/614284 Vitreoretinal degeneration
tp tp Retinal detachment
Mild to moderate
sensorineural hearing loss
Short stature in childhood
Multiple epiphyseal COL9A3/AD Splice Early-onset short stature In-frame deletion
dysplasia type 3/ Waddling gait
rrss rrss
600969 Stiffness and pain in the knees
and other joints
o ke
ke Susceptibility to COL9A2;
o k
Missensee
k e Degeneration of
oo Not reported
e bboo o lumbar disk

disease/603932
COL9A3;
COL11A1/AD
e b o
b o o e b o
intervertebral disks
b o
/
e / e Metaphyseal
chondrodysplasia,
COL10A1/AD
m ee/ / e
Missense,
nonsense, e / / e
Irregularities of the
m e
metaphyseal ends of bones
Expansion of hypertrophic zone
Expanded ER
t . . m t . .m
Schmid
type/156500
s : /
: /
/ / t deletion
s : /
: /
/ / t
of the extremities
Fibrochondro-
genesis-1/
228520
hhtttp
tp s
COL11A1/AR Duplication,
missense
(ref.thompson)
hhtttp
tp s Flat midface with a small nose Fibroblastic appearance of
Significant shortening of all chondrocytes
limb segments but relatively Irregular collagen fibrils
normal hands and feet
Bell-shaped thorax with a
protuberant abdomen
Marshall syndrome/ COL11A1/AD Splicing Flat or retracted midface Possible truncated forms of
k eers
rs
154780
k e r
e s
r s
affected chains
Suggested incomplete formation
of a triple helix
bboooo k Stickler syndrome COL11A1/AD

o o
o o
Deletion
b k Flat mala
b o oo
o Predicted shortening of collagen
/
e e
/ e
type 2/604841
ee/ e
/ e b Abnormal vitreous
e
architecture
e/ e
/ e b
Congenital, nonprogressive
chains
: / / t
/ .
t m
. m : t . m
. m
myopia of a high degree
/ / / t
Fibrochondro-
genesis-2/
t p p : /
COL11A2/AD, AR
ss
Splice, deletion,
insertion,
t p ss
p : /
Midface hypoplasia with a
small nose
Not reported
614524
t
hht t missense,
nonsense t
hht t Significant shortening of all
limb segments with
relatively normal hands and
feet
Small thorax with protuberant
abdomen
s s
AD = autosomal dominant; AR = autosomal recessive, ER = endoplasmic reticulum.
k eerrs k eerr s
b ooook COL2A1, the same gene that encodes procollagen II
b oook
o b oooo
greater than that determined for the collagen II chain. It
/
e e
/ eb e / e
/e
chains, it has been determined that the extent of hy-
e b e /e/e b
has been shown that by forming an inner core of colla-
e
: / t
///t. m
droxylation and glycosylation of the α3 (XI) chain is
. m : / t.
///t m
gen II fibrils, collagen XI contributes to the structural
.m
s
tps : s
tps :
230
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
integrity of the cartilage fibrillar system.45 The Interna- sis of mice deficient in CRTAP revealed the
k eers
rs ke rrs
tional Skeletal Dysplasia Society classifies chondrodys-
e s development of a severe osteochondrodysplasia charac-
b ooook b o ook
plasias associated with collagen XI as the type XI col-
o
lagen group of genetic skeletal disorders24 ( Table 2).
terized by the shortening of long bones and osteope-
nia.13
b o oo
o
/
ee/e b / e e b
Collagen XXVII is a homotrimer encoded by the
ee /
COL27A1 gene. During development, this collagen
ee/ e
/ e b
Discoidin Domain Receptor 2
t . m
.m
type is expressed in the skin, lung, aorta, stomach, and
: / ///t t
///t. m
. m
Heterotypic collagen fibrils formed by the coassembly
: /
tps :
teeth, but its expression is most notable in the prolifer-
s s :
of collagen II, collagen IX, and collagen XI are not only
tps
hhtttp hhtttp
ative zone of the growth plate. Studies in transgenic a critical structural element of cartilage but also an im-
mouse models suggest that certain mutations within the portant component of a signaling mechanism that reg-
triple-helical region of collagen XXVII are associated ulates the function and the behavior of chondrocytes.
with chondrodysplasia. Electron microscopy of carti- One of the receptors engaged in this cell-matrix interac-
lage isolated from mice harboring mutant collagen tion is discoidin domain receptor 2 (DDR2), a protein
XXVII molecules indicates that this protein plays an that belongs to a group of receptor tyrosine kinases.
k rs
rs rs
r
important role in organizing the pericellular matrix in
ee k ee s This receptor is characterized by its specificity for bind-
ook ook
the growth plate.46 ing well-defined domains of the triple-helical regions of
b oo b oo b o oo
o
several collagen types, including collagen II and colla-
/
e e
/ eb Structural Aberrations of Selected
e/
e e
/ e b ee/ e
/ e b
gen X. Inactivation of DDR2 in mice alters skeletal
growth with long bone shortening. In humans, muta-
: // t
Macromolecules That Interact With
/.tm
. m : / / t
/ .
t m
. m
tions in DDR2 are associated with spondylometa-
Cartilaginous Collagens
ss : / ss : /
epiphyseal dysplasia, short limb-hand type (MIM#
hhtttp
tp hhtttp
tp
271665). The main clinical characteristics of this dys-
In addition to chondrodysplasias caused by mutations plasia include disproportionate short stature with short
in the cartilage collagens, aberrations of proteins whose limbs, a narrow chest with pectus excavatum, brachy-
biologic activities require interactions with collagens dactyly in the hands and feet, a characteristic craniofa-
may also alter the development of skeletal tissues. The cial appearance, and developmental delay in some but
following examples illustrate this problem. not all patients.52
keerrss
Heat Shock Protein 47
k e rrss
e
A role for DDR2 has also been postulated in the
progression of osteoarthritis. It has been suggested that
bboooo k o o
HSP47 is a critical chaperone protein whose role has
b o o k b o oo
collagen II fragments generated during cartilage degra-
o
/
e e
/ e e / / e b
been well recognized in the intracellular folding of col-
e
lagen I. Recently, it has been determined that a muta-
e e / e
/ e b
dation seen in osteoarthritis are able to bind to DDR2
and trigger a cascade of biologic events that leads to an
e
. m m
tion of SERPINH1, a gene that encodes HSP47, is re-
t . . m m
increased synthesis of proinflammatory interleukin-6
t .
: / / / t
sponsible for an autosomal recessive form of
s : / : / /
/ / t
and matrix-degenerating matrix metalloproteinase
s :
hhtttp
tp s
osteogenesis imperfecta type X, thereby indicating the
importance of this chaperone in bone development.47
The potential role of HSP47 in chondrodysplasias was hhtttp
tp s
(MMP) 13. Such an involvement of DDR2 in the
pathogenesis of osteoarthritis renders it a potential
therapeutic target for limiting the progression of carti-
investigated in a mouse model. It has been demon- lage degeneration.53,54
strated that chondrocyte-specific inactivation of HSP47
causes a chondrodysplasia phenotype and results in Matrix Metalloproteinases 9 and 13
ee s
pathologic endochondral bone formation. Assays of
rrs e
cartilage from affected mice showed a significant reduc-
k k r
e s
r s Homeostasis of skeletal tissues is maintained by the
balanced physiologic processes of synthesis and degra-
bboooo k
role of HSP47 in cartilage development.12
b o o
o o k
tion of collagen fibrils, thereby indicating the critical
b o oo
dation. Both of these processes are active during the de-
o
/
e e
/ e ee/ e
/ e b e / e
/ e b
velopment of skeletal tissues, and factors that disturb
them can contribute to skeletal aberrations. Proteolytic
e
Cartilage-Associated Protein
: / / t
/ .
t m
. m
The hydroxylation of proline residues present at the Y
: / / t
/ .
t m
. m
enzymes play a critical role in the remodeling of skele-
tal tissues during their development, growth, and differ-
t p ss
p : /
position of -G-X-Y- triplets is critical for the stability of
ss : /
entiation. Matrix metalloproteinases form a group of
t p p
t
hht t
collagen triple-helical domains. However, the role of
the enzyme prolyl-3-hydroxylase in the hydroxylation
of proline residues present at selected X positions is less
t
hht t
zinc-dependent enzymes whose common characteristic
is proteolytic degradation of various ECM molecules.
The critical biologic functions of this group of enzymes
understood. One of the elements of the complex needed include the degradation of collagenous matrices and the
to hydroxylate these X-positioned proline residues is activation of various growth factors. Mutations in
k eers
cartilage-associated protein (CRTAP).48-50 Although this
rs k eers
r s
protein is found in several tissues, its presence is partic-
MMP-9 and MMP-13 cause metaphyseal anadysplasia
type 2 (MIM#613073) and type 1 (MIM#602111), re-
b ooook b oook
ularly prominent in the developing skeleton.51 Recently,
o
mutations in CRTAP were described in a family with
b ooo
spectively. These are diseases that are classified as the
o
metaphyseal dysplasias group24 and are characterized
/
e e
/ eb ee/ e
/e b
osteogenesis imperfecta type VII, suggesting the impor-
/e/e b
by severe skeletal changes that, unlike most progressive
ee
/ t
///t m
tant role of the hydroxylation of selected proline resi-
. . m
dues in the development of skeletal tissues.50 An analy-
: / t.
///t m
chondrodysplasias, resolve spontaneously. It was deter-
.m
mined that the loss of function of MMP-9 or MMP-13
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
is associated with autosomal recessive forms of meta- is based on the possibility that the actions of some mu-
k eers
rs physeal anadysplasia, whereas dominant missense mu-
keerrss tant molecules in the extracellular space may be less
b ooook autodegradation of this enzyme.55

b o ook
tations in MMP-13 cause intracellular activation and
o
harmful to the tissue than their negative influence on
o oo
o
intracellular functions. This notion is further supported
b
/
ee/e b ee/ e
/ e b ee/ e
/ e b
by studies demonstrating that thermostable mutants
with R>C substitutions in positions R75C and R519C
/ t
///t
Experimental Approaches to Treat
: . m
.m : / t
///t. m
. m
are present in the ECM but do not cause detectable ER
s :
Chondrodysplasias Caused by Mutations
tps s
tps :
stress, and their presence is associated with mild rather
hhtttp hhtttp
in Collagen Genes than severe dysplasias.31
It has been suggested that gene-based and cell-based
therapies may counterbalance the pathologic changes
caused by the presence of mutant collagen mole- Chondrodysplasias: A Member of the Rare
Diseases Group
cules.13,56 Although experimental models and limited
k eers
rs these proposed approaches, currently there are no
k eers
r s
clinical trials have demonstrated the potential utility of Chondrodysplasias represent a group of rare diseases
for which no therapeutic treatments currently exist.
b ooook b oook
treatments available to eliminate the molecular effects
o o oo
The National Institutes of Health and the FDA recog-
b o
/
e e
/ eb e/ e
/ e b
of mutations in collagen genes. The main factors that
hamper the effective implementation of proposed ther-
e e / e
/ e b
nize the growing need to intensify the basic research to
identify the mechanisms behind these rare diseases and
e
: // t/.tm
apies include the inability to deliver potential blockers
. m
that would prevent the expression of these mutant pro-
/ / t
/ .
t m
design approaches to their treatments. The urgency to
. m
move forward with research on rare diseases is not only
:
ss : /
teins or vectors harboring a DNA construct that en-
ss : /
justified by the fact that they are devastating and as a
hhtttp
tp hhtttp
tp
codes the wild-type normal variants of these genes. group affect a significant percentage of the US popula-
Moreover, the delivery of therapeutic cells to the af- tion but also because there are no treatments available
fected connective tissues in amounts relevant for suc- for most of them. Although individually uncom-
cessful therapies also presents a major challenge. In ad- mon—by definition a specific rare disease affects fewer
dition, it is unclear what therapeutic goals need to be than 200,000 people in the United States—collectively
rrss rrss
reached as a result of cell and gene therapies to achieve these diseases are prevalent in society and contribute to
o ke
ke
a regression of pathologic changes formed in affected
o k
tissues in the presence of mutant collagen molecules. e
k e
major health and socioeconomic problems. Almost
oo
7,000 rare diseases have been identified, and they affect
e bboo o e b o o
Experiments have been described that determined the
b o e b o o
18 to 25 million people or 6% to 8% of the US popu-
b
/
e / e ee/ e
minimal change in the ratio of wild-type to mutant col-
/
lagen II needed to reduce the deleterious effects caused
m ee/ / e
lation alone.57 In the context of other diseases recog-
nized as devastating in the US population, the percent-
m
t . . m t . .m
s : /
: /
by the presence of the R789C and R992C mutants as-
/ / t
sociated with SED.9 It was demonstrated that the mea-
s : /
: /
age of patients with rare diseases equals that reported
/ / t
for patients with cancer and coronary heart disease
hhtttp
tp s
surable attenuation of both intracellular and extracellu-
lar aberrations caused by the presence of these
hhtttp
tp s
(8.5% and 6.7% in 2010, respectively58). For approxi-
mately 7,000 rare diseases recognized to date, there are
collagen II mutants is only possible by eliminating their only about 250 treatments available, and the actual
expression entirely. Consequently, these results suggest causes are known for only about 4,000 of them. The
that eliminating the pathologic intracellular and extra- pursuit of understanding and treating these rare dis-
cellular consequences of the presence of thermolabile eases is not purely academic. Often the insights pro-
k eers
rs collagen mutants with increased intracellular accumula-
k
tion may not be possible by using approaches that only
e r
e s
r svided by research into such rare diseases can contribute
significantly to understanding other more common dis-
bboooo k o o
partially reduce the amount of mutant collagen mole-
b o o k b o oo
orders. It is not unreasonable to postulate that informa-
o
/
e e
/ e
cules in affected tissues.
e / e
/ e b
Because of these challenges, novel approaches are
e e e
/ e b
tion obtained from studying rare chondrodysplasias
/
may someday contribute to a better understanding of
e
: / / / .
t m m
needed. Altering the processes that contribute to ER
t . : / / t
/ .
t m
. m
osteoarthritis. The problems in treating these rare dis-
t p ss : /
stress caused by the excessive intracellular accumula-
tion of mutant collagens presents a promising therapeu-
p t p ss : /
eases include a poor understanding of their pathomech-
anisms, difficulties in identifying suitable therapeutic
p
t
hht t
tic opportunity. Specifically, using chemical chaperones,
compounds with the ability to prevent the misfolding
of mutant collagens, may be possible to reduce ER
t
hht t
targets, and the fact that this group of diseases includes
extremely diverse members, thereby requiring unique
sets of complex scientific tools, models, skills, and ex-
stress and avoid apoptosis. In contrast to genetic ap- perimental approaches to study each disease.
proaches, chemical chaperones will not block the ex- Mutations in genes encoding extracellular molecules
k eers
rs pression of misfolded mutant collagen molecules. They
may, however, facilitate their folding and secretion,
k eers
r s of cartilage present a significant medical problem. For
instance, mutations in the COL2A1 are not only asso-
b ooook b oook
thereby decreasing mutant-associated intracellular
o
stress. Such an effect has already been seen in studies
b ooo
ciated with skeletal abnormalities but also with Stickler
o
dysplasia type I, a disease associated with hearing loss,
/
e e
/ eb ee/ e
/e b
performed in a cell-based model.38 Although the chap-
/e/e b
joint problems, and progressive myopia beginning in
ee
/ t
///t m
erone approach will not eliminate mutant molecules, it
. . m
may still be beneficial for affected tissues. This notion
: / t.
///t m
the first decade of life and causing retinal detachment
.m
and blindness.59 In addition, mutations in collagen II
:
s
tps : s
tps :
232
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
have been associated with osteonecrosis of the femoral
k eers
rs keerrs
head. All patients with familial osteonecrosis according
s Annotated References
b ooook o ook
to one study60 carried COL2A1 mutations. Given the
o
prevalence of osteonecrosis in total hip arthroplasty,
b
1.
o oo
Lefebvre V, Bhattaram P: Vertebrate skeletogenesis.
b o
/
ee/e b ee/ e
/ e b
such a finding is certainly provocative. Such opportuni-
ties to potentially apply basic science findings toward
ee/ e
/ e b
Curr Top Dev Biol 2010;90:291-317.
The authors review current molecular pathways that
t . m
.m
understanding more common clinical entities points to
: / ///t
the great importance of developing gene-based etiolo-
: / t
///t
ment.. m
. m
contribute to vertebrate skeletal formation and develop-
s
tps : s
tps :
hhtttp hhtttp
gies for several skeletal diseases and further justifies the
need to intensify relevant studies in cell-based and ani- 2. Baldridge D, Shchelochkov O, Kelley B, Lee B: Signaling
mal models. pathways in human skeletal dysplasias. Annu Rev Ge-
nomics Hum Genet 2010;11:189-217.
The authors review molecular signaling pathways that
are required for skeletogenesis and how genetic muta-
Summary
k eers
rs k e
Collagens are the most abundant proteins of bone and
ers
r s
tions can affect these pathways.
b ooook o ook
cartilage. These proteins have a typical triple-helical
b o
3.
b oo
Späth SS, Andrade AC, Chau M, Nilsson O: Local reg-
o o
ulation of growth plate cartilage. Endocr Dev 2011;21:
/
e e
/ eb e/ e
/ e b
structure and are produced by cells in a complex step-
wise fashion that requires essential intracellular and ex-
e
12-22.
ee/ e
/ e b
// t/.tm
tracellular processes. Mutations in either the collagen
. m
molecules themselves or in one of the host of other
: : / / t
/ .
t m
The authors review the current understanding of the
. m
growth plate and the molecular signals that help to reg-
ss : /
molecules that are important in collagen assembly can
ss : /
ulate this process.
hhtttp
tp hhtttp
tp
adversely affect skeletal tissues. Numerous examples of
such mutations and their subsequent effects have been 4. Mackie EJ, Tatarczuch L, Mirams M: The skeleton: A
multi-functional complex organ. The growth plate
presented. The treatment of the diseases that result chondrocyte and endochondral ossification. J Endocri-
from these mutations is challenging from both a clinical nol 2011;211(2):109-121.
and a basic science perspective. However, the continued
The authors review the current understanding of the
rrss rrss
study of these mutations holds the promise of not only
role of chondrocytes in the growth plate and their con-
o ke
ke o k
the molecular basis of normal skeletal development ande
treating these diseases but also providing insight into
k e tribution to endochondral ossification.

oo
e bboo o e b o o
function and possibly further understanding of more
b o 5.
e b o
b o
Umlauf D, Frank S, Pap T, Bertrand J: Cartilage biol-
/
e / e common diseases such as osteoarthritis.
m ee/ / e m ee/ / e
ogy, pathology, and repair. Cell Mol Life Sci 2010;
t . . m t .
67(24):4197-4211.
.m
s : /
: /
/ / t s : / /
/ / t
The authors review current findings about cartilage bi-
:
Key Study Points
hhtttp
tp s hhtttp
6. tp s
ology and pathology and discuss potential therapies.
Carter EM, Raggio CL: Genetic and orthopedic aspects

of collagen disorders. Curr Opin Pediatr 2009;21(1):
• Collagen biosynthesis is a complex process that 46-54.
includes the enzymatic processing and posttrans-
lational modification of nascent collagen chains,
k eers
rs
which are then deposited in the extracellular ma-
k e r
e s
r s
7. Ricard-Blum S: The collagen family. Cold Spring Harb
Perspect Biol 2011;3(1):a004978.
bboooo k trix as fibrils that provide the mechanical
o o
o o k
strength of skeletal tissues and serve as a binding
b b o oo
The author discusses the 28 members of the collagen
o
family of triple-helical proteins, along with the struc-
/
e e
/ e ee/ e
/ b
platform for tissue-specific cells and proteins. Er-
e
rors in any step of this process can result in dis-
ee/ e
/ e b
tural and functional aspects of these proteins. In addi-
tion, genetic and acquired diseases associated with col-
ease.
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
lagens are presented.
•
t p ss
p : /
Aberrations in the structure of collagens may be
8.
t p ss
p : /
Bateman JF, Boot-Handford RP, Lamandé SR: Genetic
t
hht t
caused not only by mutations in the genes encod-
ing individual collagen chains but also mutations
of the genes encoding proteins involved in colla-
t
hht t diseases of connective tissues: Cellular and extracellular
effects of ECM mutations. Nat Rev Genet 2009;10(3):
gen production or processing. 173-183.
• Alterations of collagen structure are associated 9. Jensen DA, Steplewski A, Gawron K, Fertala A: Persis-
k eers
r
with several skeletal diseases, whose spectrum of
s k e
severity includes mild and lethal forms. To date,
ers
r s tence of intracellular and extracellular changes after in-
completely suppressing expression of the R789C
b ooook b oook
no successful therapies exist to counterbalance
o
the pathological effects of mutations affecting
b ooo
(p.R989C) and R992C (p.R1192C) collagen II mutants.
o
Hum Mutat 2011;32(7):794-805.
/
e e
/ eb ee/ e
/e b
the structure of collagen matrices of skeletal tis-
e /e/e b
The authors developed a molecular system in which the
e
sues.
: / t
///t. m
. m : / t.
///t m
production of mutant collagen II could be controlled.
.m
The affected cell/matrix systems functioned normally
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
only when the mutant collagen production was com- 20. Muir A, Greenspan DS: Metalloproteinases in Droso-
k eers
rs pletely shut off.
keerrss phila to humans that are central players in developmen-
ook ook
tal processes. J Biol Chem 2011;286(49):41905-41911.
b oo 10.
b o
Gorres KL, Raines RT: Prolyl 4-hydroxylase. Crit Rev
o b o oo
o
The authors review the role of metalloproteinase en-
/
ee/e b Biochem Mol Biol 2010;45(2):106-124.
ee/ e
/ e b
The authors review the current understanding of the en-
ee/ e
/ e b
zymes in embryonic patterning and ECM formation.
t . m
.m
zyme prolyl 4-hydroxylase and its role in protein modi-
fication.
: / ///t
21.
: / t . m
. m
Li SW, Sieron AL, Fertala A, Hojima Y, Arnold WV,
///t
Prockop DJ: The C-proteinase that processes procolla-
s
tps : s
tps :
hhtttp hhtttp
gens to fibrillar collagens is identical to the protein pre-
11. Shoulders MD, Raines RT: Collagen structure and sta- viously identified as bone morphogenic protein-1. Proc
bility. Annu Rev Biochem 2009;78:929-958. Natl Acad Sci USA 1996;93(10):5127-5130.
12. Masago Y, Hosoya A, Kawasaki K, et al: The molecular 22. Orgel JP, San Antonio JD, Antipova O: Molecular and
chaperone HSP47 is essential for cartilage and endo- structural mapping of collagen fibril interactions. Con-
k eers
rs 1118-1128.
k eers
chondral bone formation. J Cell Sci 2012;125(pt 5):
r s
nect Tissue Res 2011;52(1):2-17.
The authors review the binding characteristics of the
b ooook o ook
Chondrocyte expression of the HSP47 gene was condi-
b o b oo
fibrillar form of collagen to other ligands in the ECM.
o o
/
e e
/ eb ized chondrodysplasia.
e/
e / e b
tionally inactivated in mice, resulting in severe general-
e 23.
e / e
/ e b
Nishioka T, Eustace A, West C: Lysyl oxidase: From ba-
e
13.
// t/.tm
. m
Forlino A, Cabral WA, Barnes AM, Marini JC: New
: : / / t
/ .
t m
sic science to future cancer treatment. Cell Struct Funct
. m
2012;37(1):75-80.
s : /
perspectives on osteogenesis imperfecta. Nat Rev Endo-
s ss : /
hhtttp hhtttp
The authors discuss the role of lysyl oxidase and lysyl
tp
crinol 2011;7(9):540-557.
The authors review the current understanding of auto-
somal dominant and autosomal recessive forms of os-
tp oxidase-like proteins in tumor biology, along with the
role of these proteins in the ECM and how this may af-
fect metastases.
teogenesis imperfecta.
24. Warman ML, Cormier-Daire V, Hall C, et al: Nosology
14. Boot-Handford RP, Briggs MD: The unfolded protein and classification of genetic skeletal disorders: 2010 re-
keerrss k e rrss
response and its relevance to connective tissue diseases.
e
vision. Am J Med Genet A 2011;155A(5):943-968.
bboooo k Cell Tissue Res 2010;339(1):197-211.
b o o
o o k
The authors review the role of ER stress in connective
b o oo
The authors present a classification of genetic disorders
o
involving the skeletal system. The classification is based
/
e e
/ e / e e b
tissue diseases and the role of the unfolded protein re-
sponse to counter this stress.
ee / / e e b
on the clinical and radiographic features of these disor-
ee /
ders as well as their molecular pathogenesis. The classi-
t . m
. m t . m m
fication includes 456 conditions placed into 40 groups.
.
15.
: /
: /
/ / t
Piróg-Garcia KA, Meadows RS, Knowles L, et al: Re-
s s : /
: /
/ / t
hhtttp s
duced cell proliferation and increased apoptosis are sig-
tp
nificant pathological mechanisms in a murine model of
mild pseudoachondroplasia resulting from a mutation hhtttp
25.
tp s Krakow D, Rimoin DL: The skeletal dysplasias. Genet

Med 2010;12(6):327-341.
The authors review the current knowledge regarding the
in the C-terminal domain of COMP. Hum Mol Genet more than 350 disorders grouped together as skeletal
2007;16(17):2072-2088. dysplasias.
k eers
rs
16. Rajpar MH, McDermott B, Kung L, et al: Targeted in-
k e r
duction of endoplasmic reticulum stress induces carti-
e s
r s 26. Kannu P, Bateman JF, Randle S, et al: Premature arthri-
tis is a distinct type II collagen phenotype. Arthritis
bboooo k b o o
lage pathology. PLoS Genet 2009;5(10):e1000691.
o o k b o oo
Rheum 2010;62(5):1421-1430.
o
/
e e
/ e 17.
/ e e b
Chung HJ, Jensen DA, Gawron K, Steplewski A, Fer-
ee /
tala A: R992C (p.R1192C) substitution in collagen II
e / e
/ e b
Mutations resulting in glycine substitutions in the triple-
helical domain of collagen II were found in two Austra-
e
: / / t . m
. m
alters the structure of mutant molecules and induces the
/ t / / t
/ t m
lian families with an isolated arthritis phenotype. Level
. . m
of evidence: V.
:
306-318.
t p p : /
unfolded protein response. J Mol Biol 2009;390(2):
ss t p ss
p : /
18.
t
hht t
Apte SS: A disintegrin-like and metalloprotease
t
hht t
27. Kannu P, Bateman J, Savarirayan R: Clinical pheno-
types associated with type II collagen mutations. J Pae-
diatr Child Health 2012;48(2):E38-E43.
(reprolysin-type) with thrombospondin type 1 motif
(ADAMTS) superfamily: Functions and mechanisms. The authors reviewed the molecular bases and pheno-
J Biol Chem 2009;284(46):31493-31497. typic characteristics of diseases associated with muta-
tions in collagen II. They recognized that autosomal
k eers
rs 19. Verma P, Dalal K: ADAMTS-4 and ADAMTS-5: Key
k eers
r s dominant mutations in collagen II result in a spectrum
ook ook
of disease presentations ranging from early-onset short
b oo
enzymes in osteoarthritis. J Cell Biochem 2011;112(12):
3507-3514.
b oo b oooo
stature to later-onset mild phenotypes such as premature
/
e e
/ eb e / e
/e
The authors review the role of ADAMTS-4 and
e b e /e/e b
osteoarthritis. In addition, the authors pointed to the
clinical importance of diagnosing collagen II mutations
e
thritis.
: / t
///t m
ADAMTS-5 proteinases in a human model of osteoar-
. . m : / t.
///t m
for accurately determining risks for affected individuals
.m
and their family members.
s
tps : s
tps :
234
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
28. Fertala A, Ala-Kokko L, Prockop DJ: Characterization Single amino acid substitutions in the C-terminus of col-
k eers
rs rr
of recombinant human collagen II with Arg519-to-Cys
kee ss lagen II alter its affinity for collagen IX. Biochem Bio-
ook ook
substitution. Ann N Y Acad Sci 1996;785:251-253. phys Res Commun 2005;335(3):749-755.
b oo b o o b o oo
o
/
ee/e b 29.
ee e
/ e b
Fertala A, Ala-Kokko L, Wiaderkiewicz R, Prockop DJ:
/
Collagen II containing a Cys substitution for arg-
41.
e e
/ e b
Arita M, Li SW, Kopen G, Adachi E, Jimenez SA, Fer-
/
tala A: Skeletal abnormalities and ultrastructural
e
: / ///t. m
.m
alpha1-519: Homotrimeric monomers containing the
t
mutation do not assemble into fibrils but alter the self-
: / t
///t. m
. m
changes of cartilage in transgenic mice expressing a col-
lagen II gene (COL2A1) with a Cys for Arg-alpha1-519
s
tps :
assembly of the normal protein. J Biol Chem 1997;
s
tps : substitution. Osteoarthritis Cartilage 2002;10(10):
hhtttp hhtttp
272(10):6457-6464. 808-815.
30. Fertala A, Sieron AL, Adachi E, Jimenez SA: Collagen II 42. Guilak F, Alexopoulos LG, Upton ML, et al: The peri-
containing a Cys substitution for Arg-alpha1-519: Ab- cellular matrix as a transducer of biomechanical and
normal interactions of the mutated molecules with col- biochemical signals in articular cartilage. Ann N Y Acad
lagen IX. Biochemistry 2001;40(48):14422-14428. Sci 2006;1068:498-512.
k eers
rs k eers
r s
b ooook
31.
oook
Hintze V, Steplewski A, Ito H, Jensen DA, Rodeck U,
o
Fertala A: Cells expressing partially unfolded R789C/
b
43.
o oo
Christensen SE, Coles JM, Zelenski NA, et al: Altered
o
trabecular bone structure and delayed cartilage degener-
b
/
e e
/ eb e e
/ e b
p.R989C type II procollagen mutant associated with
/
spondyloepiphyseal dysplasia undergo apoptosis. Hum
e ee e
/ e b
ation in the knees of collagen VI null mice. PLoS One
/
2012;7(3):e33397.
Mutat 2008;29(6):841-851.
: // t/.tm
. m : / / t . m
. m
The authors compared the morphology and physical
/ t
ss : / ss : / properties of bone and cartilage in mice that expressed
hhtttp hhtttp
32. Steplewski A, Ito H, Rucker E, et al: Position of single collagen VI compared with mice without collagen VI ex-
tp
amino acid substitutions in the collagen triple helix de-
termines their effect on structure of collagen fibrils.
J Struct Biol 2004;148(3):326-337.
tp pression. Greater effects were seen with knee joint struc-
tures with relatively minimal effects on the properties of
cartilage.
33. Steplewski A, Majsterek I, McAdams E, et al: Thermo- 44. Stetler WR, La Marca F, Park P: The genetics of ossifi-
rrss rrss
stability gradient in the collagen triple helix reveals its cation of the posterior longitudinal ligament. Neurosurg
o ke
ke
multi-domain structure. J Mol Biol 2004;338(5):
989-998.
o k e
k e
Focus 2011;30(3):E7.
oo
e bboo o e b o
b o o The authors review the current understanding regarding
e b o o
the genetic factors contributing to ossification of the
b
/
e / e 34.
ee/ / e
Schröder M, Kaufman RJ: ER stress and the unfolded
protein response. Mutat Res 2005;569(1-2):29-63.
m m ee/ / e
posterior longitudinal ligament.
t . . m t . .m
35.
: /
: /
/ / t
Schröder M, Kaufman RJ: The mammalian unfolded
s
45.
s : /
: /
/ t
Yingst S, Bloxham K, Warner LR, et al: Characteriza-
/
tion of collagenous matrix assembly in a chondrocyte
36. hhtttp
tp s
protein response. Annu Rev Biochem 2005;74:739-789.
Donahue LR, Chang B, Mohan S, et al: A missense mu- hhtttp

tp s model system. J Biomed Mater Res A 2009;90(1):
247-255.
tation in the mouse Col2a1 gene causes spondy- 46. Plumb DA, Ferrara L, Torbica T, et al: Collagen XXVII
loepiphyseal dysplasia congenita, hearing loss, and ret- organises the pericellular matrix in the growth plate.
inoschisis. J Bone Miner Res 2003;18(9):1612-1621. PLoS One 2011;6(12):e29422.
k e
37.
ers
rs k e r
e s
r
Ito H, Rucker E, Steplewski A, et al: Guilty by associa-s Mice in which the cartilage-targeted expression of a mu-
tant collagen XXVII in which an 87-amino-acid se-
bboooo k b o o
o o k
tion: Some collagen II mutants alter the formation of
ECM as a result of atypical interaction with fibronectin.
b o oo
quence was deleted were analyzed. The resulting mice
o
/
e e
/ e J Mol Biol 2005;352(2):382-395.
ee/ e
/ e b e / e
/ e b
were severely dwarfed. The mutation resulted in a dis-
ruption of the pericellular matrix of the proliferative
e
38.
: / / t
/ .
t m
. m
Gawron K, Jensen DA, Steplewski A, Fertala A: Reduc-
: / / t
/ t m
chondrocytes in the growth plate.
. . m
t p ss
p : /
ing the effects of intracellular accumulation of thermo-
labile collagen II mutants by increasing their thermosta-
t
47.
p ss
p : /
Christiansen HE, Schwarze U, Pyott SM, et al: Homozy-
t
hht t
bility in cell culture conditions. Biochem Biophys Res
Commun 2010;396(2):213-218.
t
hht t gosity for a missense mutation in SERPINH1, which en-
codes the collagen chaperone protein HSP47, results in
severe recessive osteogenesis imperfecta. Am J Hum
Glycerol and trimethylamine N-oxide were used to sta- Genet 2010;86(3):389-398.
bilize two thermolabile collagen II mutants and thereby The authors report an autosomal recessive mutation in
improved cell survival by decreasing the intracellular ac- the SEPINH1 gene that encodes the HSP47 protein.
k eers
rscumulation of these mutant collagens.
k eers
r s Loss of this protein results in the accumulation of pro-
collagen I intracellularly and in the secretion of a pro-
b ooook
39.
b ook
Steplewski A, Hintze V, Fertala A: Molecular basis of
oo
organization of collagen fibrils. J Struct Biol 2007;
o oo
collagen I that is protease sensitive. Level of evidence: V.
b o
/
e e
/ eb 157(2):297-307.
ee/ e
/e b 48.
e /e/e b
Morello R, Rauch F: Role of cartilage-associated pro-
e
40.
/ t
///t. m
. m
Steplewski A, Brittingham R, Jimenez SA, Fertala A:
: : / t
///t m
tein in skeletal development. Curr Osteoporos Rep
. .m
2010;8(2):77-83.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
The authors review recent findings regarding the role of The authors present research suggesting that a decrease
k eers
rs keerr
CRTAP in collagen prolyl 3-hydroxylation and review
ss
how mutations in this protein can contribute to reces-
in the expression of DDR2 correlates with a delayed de-
velopment of cartilage degeneration in a mouse model
b ooook sive forms of osteogenesis imperfecta.
b o ook
o o oo
of osteoarthritis.
b o
/
ee/e b 49.
e / e
/ e b
Fratzl-Zelman N, Morello R, Lee B, et al: CRTAP defi-
e
54.
e / e
/ e b
Klatt AR, Zech D, Kühn G, et al: Discoidin domain re-
e
/ t
///t. m
ciency leads to abnormally high bone matrix mineraliza-
.m
tion in a murine model and in children with osteogene-
: : / ///t. m
. m
ceptor 2 mediates the collagen II-dependent release of
t
interleukin-6 in primary human chondrocytes. J Pathol
s
tps :
sis imperfecta type VII. Bone 2010;46(3):820-826.
s
tps : 2009;218(2):241-247.
hhtttp hhtttp
The authors report increased highly mineralized bone
matrix in mice and children affected by a mutation in 55. Lausch E, Keppler R, Hilbert K, et al: Mutations in
CRTAP, leading to findings similar to classical osteogen- MMP9 and MMP13 determine the mode of inheritance
esis imperfecta. Level of evidence: III. and the clinical spectrum of metaphyseal anadysplasia.
Am J Hum Genet 2009;85(2):168-178.
50. Morello R, Bertin TK, Chen Y, et al: CRTAP is required
k eers
rs rs
r s
for prolyl 3-hydroxylation and mutations cause reces-
k ee
56. Forlino A, Marini JC: Osteogenesis imperfecta: Pros-
ook ook
sive osteogenesis imperfecta. Cell 2006;127(2):291-304. pects for molecular therapeutics. Mol Genet Metab
b oo b oo b o oo
o
2000;71(1-2):225-232.
/
e e
/ eb 51.
e/
e e
/ e b
Fernandes RJ, Farnand AW, Traeger GR, Weis MA,
Eyre DR: A role for prolyl 3-hydroxylase 2 in post- 57.
ee/ e
/ e b
Office of Rare Diseases Research of the National Center
: // /.tm m
translational modification of fibril-forming collagens.
t . : / / t
/ .
t m
. m
for Advancing Translational Sciences: Rare diseases.
ss /
J Biol Chem 2011;286(35):30662-30669.
: ss : /http://rarediseases.info.nih.gov. Accessed November 4,
hhtttp hhtttp
The authors report the results of cell culture experi- 2013.
tp
ments demonstrating differential preference in the
3-hydroxylation of proline at three different sites in col-
lagen.
tp 58. Centers for Disease Control and Prevention (CDC):
http://www.cdc.gov.
52. Bargal R, Cormier-Daire V, Ben-Neriah Z, et al: Muta- 59. National Center for Biotechnology Information: Online
rrss rrss
tions in DDR2 gene cause SMED with short limbs and Mendelian Inheritance in Man. http://www.ncbi
o ke
ke 80-84.
o k e
abnormal calcifications. Am J Hum Genet 2009;84(1):
k e
.nlm.nih.gov/entrez/query.fcgi?db=OMIM.
November 4, 2013.
oo
Accessed
e bboo o e b o
b o o e b o
b o
/
e / e 53.
ee/ / e
Xu L, Servais J, Polur I, et al: Attenuation of osteoar-
thritis progression by reduction of discoidin domain re-
m
60.
m ee/
Liu YF, Chen WM, Lin YF, et al: Type II collagen gene
/ e
variants and inherited osteonecrosis of the femoral
t . m
ceptor 2 in mice. Arthritis Rheum 2010;62(9):2736-
. t . m
head. N Engl J Med 2005;352(22):2294-2301.
.
2744.
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
236
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 20
e rs
rs e rrss
oo
kMuscle
ook e Disorders o k
ook
o
e o oo
o
/e/ebb George C. Babis, MD, PhD
e / e
/ b
e b
Vasileios I. Sakellariou, MD, PhD
e / e
/ b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
the cell is stimulated, ionic calcium (Ca2+) is released by
Introduction the sarcoplasm and interacts with troponin, which sub-
k eerss k eer
The internal architecture of skeletal muscles has been
r s
r s
found to play a substantial role in the functionality and
sequently regulates the movement of tropomyosin and
the exposure of myosin-binding sites on actin. Shorten-
b ooook o ook
the effectiveness of contracture. Novel methods of
b o b oo
ing of muscle then occurs as a result of adenosine
o o
triphosphate (ATP)-dependent cross-bridge cycling of
/
e e
/ eb e/ e
/ e b
studying fascicle architecture and identifying functional
subunits within muscle have been presented. New
e
myosin and actin.
ee/ e
/ e b
: // /.tm m
pathophysiologic mechanisms have been identified, and
t .
the genetic basis of most muscle disorders has been de-
: / / t
/ .
t m
The muscle fibers are categorized according to the
. m
type of myosin that is present (fast or slow) and the de-
ss : / s : /
gree of oxidative phosphorylation of each fiber. Thus,
s
hhtttp hhtttp
coded.
tp tp
three basic muscle types I, IIA, and IIB can be recog-
nized. Type I fibers are slow-twitch oxidative and ap-
pear red as a result of the presence of myoglobin (oxy-
Muscle Architecture and Function gen binding protein). Type I fibers predominantly exist
Skeletal muscles constitute 40% to 45% of total body in postural muscles, and they are well suited for endur-
ance by aerobic metabolism through the generation of
k errss
weight. Macroscopically, each skeletal muscle consists
e e
of parallel (biceps, triceps) or convergent (pectoralis
k rrss
e
ATP. They are characterized by a slow contraction rate
bboooo k b o o
o o
major) fascicles that originate from bone and adjacent
k b o oo
and a relatively low strength of contraction. Type II
o
muscle fibers are fast twitch and appear white as a re-
/
e e
/ e e / / e b
connective tissue and have a tendinous insertion into
e
bone. Microscopically, skeletal muscles are composed
e ee/ e
/ e b
sult of the absence of myoglobin. They have a fast rate
of contraction and a relatively high strength of contrac-
t m
of myocytes that are formed from the fusion of myo-
. . m t . m.m
tion. Type II fibers are further subdivided into IIA and
s : /
: /
/ / t
blasts (progenitor cells of muscle cells), which are mul-
: /
: /
/ / t
IIB, depending on their mode of energy utilization.
s
hhtttp
tp s
tinucleated cells composed of myofibrils. Each myofi-
bril is composed of the cytoplasmic proteins actin and
myosin, which are arranged in a repeating unit called a hhtttp
tp s
Type IIA fibers (also called fast twitch A) are character-
ized by their high capacity for generating ATP by oxi-
dation. These are resistant to fatigue but not as much
sarcomere, which is the basic functional unit of the
as low oxidative fibers. However, type IIB fibers (also
muscle fiber and is responsible for muscle contraction. called fast twitch B) are fast glycolytic and are thus pri-
Skeletal muscle fibers also contain the regulatory pro- marily anaerobic. Type IIB fibers have low myoglobin
k ee s
teins troponin and tropomyosin, which are necessary
rrs
for muscle contraction to occur.1
k e r
e s
r s and high creatine phosphate content. They are common
in muscles that require a rapid generation of power, but
bboooo k b o o
o o
Muscle contraction occurs in response to an impulse
transmitted via nerve fibers through the neuromusculark b o oo
they fatigue easily because of lactic acid production.2,3
o
/
e e
/ e ee/ e
/ e b
junction. Acetylcholine, a neurotransmitter, is released
e e
/ e b
The force of the muscle contraction is proportional
/
to the number of motor units that are activated each
e
/ / t
/ t m
at the neuromuscular junction by motor neurons that
. . m
cause depolarization of the skeletal muscle cells. After
: : / / t
/ .
t m
. m
time. The size of the motor unit depends on the number
t p ss
p : / t p ss : /
of muscle fibers that are innervated by the nerve fiber.
electromyography (EMG)-driven models can be used to
p
t
hht t
Dr. Babis or an immediate family member is a member
t
hht t
assess the force of muscle contraction. Moreover, the
internal architecture of a skeletal muscle plays a signif-
icant role in its functionality.1 The authors of a 2010
on behalf of Bristol-Myers Squibb and Pfizer Alliance; study presented a novel method of studying fascicle ar-
serves as a paid consultant to or is an employee of chitecture in relaxed and contracted muscles, which
k eerss
Bristol-Myers Squibb and Pfizer Alliance; and has re-
r k ee
ceived research or institutional support from Bayer andrs
r s helps to identify functional subunits within the muscle.4
In a 2011 study, the three-dimensional muscle architec-
b ooook b ook
Amgen. Neither Dr. Sakellariou nor any immediate fam-
oo b oooo
ture of the human muscle was determined in vivo by
using two-dimensional ultrasound and a three-
/
e e
/ eb e / e
/e b
ily member has received anything of value from or has
e ee/e/e b
dimensional position tracker system, which enabled
this chapter.
: / t
///t m
. . m : / t.
///t m
quantification of muscle architecture with short scan
.m
times in comparison with diffusion tensor MRI.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 1
keerrss
b ooook Common Types of Inflammatory Myopathies
b o ook
o b o oo
o
/
ee/e b Muscle Disorder Etiology
ee/ e
/ e b ee/ e
/ e b
Clinical Findings
Dermatomyositis
: / ///t. m
Autoimmune reaction
t .m : /
Infection (usually from the Epstein-Barr virus
t
///t. m
Gottron lesions: erythematous eruptions or
. m
patches overlying the elbows, the knees, and
s
tps : s :
and rarely from spirochete or Lyme disease)
tps
the metacarpal and interphalangeal joints
hhtttp hhtttp
Rhabdomyolysis as a result of statin use Muscle weakness symmetric proximal
Paraneoplasmatic phenomena Severity ranges from simple deterioration to
paralysis
Dysphagia
Pain
Interstitial lung disease
k eers
rs Polymyositis
infectious pathogens
k eers
r s
Lyme disease, toxoplasmosis, and other Muscle loss around the shoulder and the pelvis
Weakness
b ooook Autoimmune factors
b ooook Pain
b o oo
o
/
e e
/ eb Genetic factors
e/
e e
/ e b
Increased expression of MHC-I molecules on
/ e
/
Drop foot
ee e b
Sclerodactyly
: // t/.tm
the surface of myocytes
. m
Attracted CD8 cytotoxic T cells destroy the
: / / t
/ .
t m
Dysphagia
. m
Increased incidence of malignancies (lung,
ss : /
myocytes
ss : / pancreas, and ovaries)
hhtttp
tp hhtttp
tp
Inclusion body myositis Inflammation-immune reaction caused by Progressive muscle weakness
an undetermined trigger (probably a virus Frequent tripping and falling
or an autoimmune disorder) Drop foot
Abnormal accumulation of pathogenic Difficulties in hand tasks and dysphagia
proteins (amyloid-β, phosphorylated tau
protein, and others) in aging myofibers
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
with polymyositis. Autoimmune and genetic factors
/
e e
/ e
Muscle Disorders
ee/ e
/ e b ee/ e
/ e b
have also been recognized. An increased expression of
major histocompatibility complex-I molecules on the
Inflammatory Myopathies
t . m
. m t . m.m
s : / / / t
The term inflammatory myopathy is synonymous with
: / s : /
: /
surface of myocytes attracts CD8 cytotoxic T cells that
/ / t
subsequently destroy the myocytes. Pain, weakness,
hhtttp
tp s
dermatopolymyositis, which includes three related dis-
eases: dermatomyositis, polymyositis, and inclusion
body myositis (IBM)6 (Table 1). hhtttp
tp s
and/or muscle loss around the shoulder and the pelvis
are common clinical signs. Sclerodactyly, drop foot,
and dysphagia are usual features. Polymyositis is also
Dermatomyositis is a connective tissue disease of un- associated with increased incidence of several malig-
known etiology. A history of an autoimmune reaction nancies, especially lung, pancreas, and ovarian cancers.
or an infection (usually from the Epstein-Barr virus and Interstitial lung disease is also a concern and should be
k eers
rs rarely from spirochete or Lyme disease) is identified.
Rhabdomyolysis as a result of statin use and paraneo-
k e r
e s
r s periodically evaluated.7
IBM is another form of inflammatory myopathy. It
bboooo k b o o
plasmatic phenomena have also been indicated as pos-
o o k b o oo
is characterized by a different pattern of muscle weak-
o
/
e e
/ e
sible causative factors.7
e / e
/ e b
The clinical manifestations include skin lesions, mus-
e e / e
/ e b
ness and wasting, which compromises both the proxi-
mal and the peripheral muscle groups.
e
/ / t
/ t m
cle weakness, and/or pain. The skin lesions consist of
. . m
erythematous eruptions or patches overlying the el-
: : / / t
/ .
t m
. m
Two types of IBMs exist: sporadic and hereditary.9
ss : /
bows, the knees, and the metacarpal and interphalan-
t p p t p ss : /
Several theories have been presented regarding the eti-
ology of each type. With sporadic IBM, the
p
t t
geal joints, which are also known as Gottron lesions.
hht
Dermal calcinosis (or calcinosis cutis) is more often
seen in the juvenile form of dermatomyositis. The mus-
t
hht t
inflammation-immune reaction caused by an undeter-
mined trigger (probably a virus or an autoimmune dis-
order) appears to cause muscle degeneration. Other au-
cle weakness is usually symmetric and proximal, and its thors think that an abnormal accumulation of
severity ranges from simple deterioration to paralysis. pathogenic proteins (such as amyloid-β or phosphory-
k eers
rs
Dysphagia may occur in one third of the cases. Patients
k e r
should also be evaluated for the presence of interstitial
e s
r s lated tau protein) in aging myofibers may have a caus-
ative effect in immune system deregulation.10 However,
b ooook and polymyositis.8

b oook
lung disease, which is frequent in both dermatomyositis
o b ooo
it is confusing that immunosuppressive medications do
o
not improve the symptoms of sporadic IBM, as would
/
e e
/ eb ee/ e
/e
Polymyositis is an inflammatory myopathy withb /e/e b
be expected for a disease with an autoimmune etiology.
ee
/ t
///t m
multifactorial etiology. Lyme disease, toxoplasmosis,
. . m
and other infectious pathogens have been associated
: / t.
///t m
The clinical manifestations of sporadic IBM consist of
.m
progressive muscle weakness, which initially presents as
:
s
tps : s
tps :
238
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 20: Muscle Disorders
k eers
Table 2
rs keerrss
b ooook b ook
Etiologic Factors and Clinical Findings of Most Common Muscular Dystrophies
o o b o oo
o
/
ee/ e
/ e b ee/ e
/ e b
Clinical Findings
Duchenne muscular
dystrophy (DMD)
: / ///t. m
Absence of the protein dystrophin
t .m
Chromosome X (Xp21 gene)
: / t
///t. m
.
Progressive proximal muscle weakness
m
Positive Gowers sign
s
tps :Sporadic mutations
s
tps : Walking aids are required by age 10 years
hhtttp hhtttp
Most patients wheelchair dependent by age 12
years
Pseudohypertrophy of the calf and deltoid
muscles
Muscle wasting and replacement of the necrotic
muscle fibers by adipose and connective tissue
k eers
rs
Becker muscular dystrophy
recessive pattern)
k eers
r s
Mutation in the dystrophin gene (X-linked Less severe clinical manifestation
Longer longevity
b ooook o ook
Production of a partially functional form
b o b o oo
o
/
e e
/ eb Congenital muscular
of dystrophin
e/ e
/ e b
Autosomal recessive disease
e e / e
/ e b
Muscle weakness
e
dystrophy (CMD)
: // /.tm m
Mutations in genes encoding LARGE, fukutin,
t .
and fukutin-related proteins
: / / t
/ .
t m
. m
Joint deformities that progress slowly
Severe brain malformations (lissencephaly and
ss : / ss : / hydrocephalus)
dystrophy
hhtttp
Emery-Dreifuss muscular
tp SYNE2, and FHL1
hhtttp
tp
Mutations in the genes EMD, LMNA, SYNE1,
Absence of a transmembrane protein of the

Joint contractures of elbows, ankles, and neck
Progressive muscle wasting and weakness of
the upper arms and lower legs
inner nuclear membrane named emerin Severe cardiac problems
Distal muscular dystrophy Mutation in the DYSF gene at the Slow progress and a relatively late age of onset
rrss rrss
2p13.3-p13.1 locum (varies from 20 to 60 years)
o ke
ke o k e
Miyoshi myopathy: mutation of DYSF gene
k
at the 2p13.3-p13.1 locum
e
Muscles of hands, forearms, and lower legs
oo
usually affected
e bboo o Facioscapulohumeral Autosomal dominant

e b o
b o o e b o o
Affects teenagers
b
/
e / e muscular dystrophy
Landouzy-Dejerine syndrome region 4q35
m ee/ / e
Deletion of D4Z4 repeats at the subtelomeric
/ / e
Weakness of the muscles of the face and the
m ee
shoulder girdle
t . . m t . .m
s : /
: /
Toxic gain of function of a putative gene
/ / t
called DUX4
s : /
: /
/ / t
dystrophy
hhtttp
Limb-girdle muscular
tp s hhtttp
tp
Autosomal recessive, autosomal dominant
and X-linked types
Defective proteins participating in the
s Both upper arms and legs affected
Muscle weakness proximal and slowly
progressive
formation of a dystrophin-glycoprotein Cardiopulmonary complications
complex Death from the disease quite unusual
Oculopharyngeal muscular Autosomal dominant Weakness of the extraocular muscles
k eers
rs
dystrophy
k e r
e s
r s
Trinucleotide repeat disorder associated with
expansion of (GCN)10 to (GCN)11-17 at the 5'
Blepharoptosis
Dysphagia
bboooo k b o o
o o k
end of the coding region for PABPN1
b o oo
Proximal limb and facial weakness (later stages
o
of the disease)
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss : /
frequent tripping and falling, or drop foot. Difficulties
with hand tasks and dysphagia usually occur during
p t p ss : /
also a hereditary type related to Paget disease of bone
and frontotemporal dementia caused by a mutation in
p
t
hht t
later stages of the disease.
The hereditary type comprises both autosomal dom-
t
hht t
a gene located at 9p13-p12 on chromosome 9.11
Pathognomonic clinical signs and symptoms of the he-
inant and recessive disorders. In the autosomal domi- reditary type include loss of balance, difficulties with
nant form (IBM1), the quadriceps is the first muscle to heel walking and running, and weakness in the index
be affected. In many Asian, Middle Eastern, and Jewish finger.
k rs
rs
populations, the autosomal recessive form (IBM2),
ee k eers
r s
b ooook
which is also known as distal myopathy with rimmed
b oook
o
vacuoles, usually spares the quadriceps and mostly af-
Muscular Dystrophies
b oooo
Duchenne muscular dystrophy (DMD), which is caused
/
e e
/ eb / ee b
fects the leg muscles. IBM3 is associated with muta-
ee /
tions in gene locum 17p13.1 that encodes myosin /e e b
by the absence of the protein dystrophin, is the most
ee /
common form of this group of diseases (Table 2). Dys-
: / t
///t. m
. m
heavy chain II proteins on chromosome 17. There is
t.
///t m
.m
trophin is part of a protein complex named dystrophin-
: /
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
glycoprotein complex that promotes the anchoring of 2p13.3-p13.1 locum.20 Muscles of the hands, forearms,
k eers
rs rrs
cytoskeleton within the muscle cells, through the sarco-
kee s and lower legs are usually affected.
b ooook b o ook
lemma, and to the extracellular matrix that surrounds
o
each cell. Because of defects in this assembly, contrac-
Facioscapulohumeral muscular dystrophy, also
o oo
o
known as Landouzy-Dejerine syndrome, is a type of
b
/
ee/e b ee/ e
/ b
tion of the muscle leads to disruption of the outer mem-
e
brane of the muscle cells and eventual weakening and
ee/ e
/ e b
muscular dystrophy that occurs in both sexes. It has an
autosomal dominant pattern of inheritance, but sponta-
wasting of the muscle.12
: / t
///t. m
.m
The production of dystrophin is regulated by a gene,
: / t . m
. m
neous mutations are also common. Two defects are re-
///t
s
tps : s
tps :
quired for the development of facioscapulohumeral
hhtttp hhtttp
which is located on chromosome X (Xp21 gene),13 muscular dystrophy: (1) a deletion of D4Z4 repeats at
which explains why predominantly male patients are the subtelomeric region 4q35, and (2) a “toxic gain of
affected, whereas females are carriers and have milder function” of a putative gene called DUX4.21 The dis-
symptomatology. However, only two thirds of cases are ease affects teenagers, who have weakness of the facial
inherited (in recessive pattern) and one third are new, muscles and the shoulder girdle.
“sporadic” mutations. Clinically, the disease becomes Limb-girdle muscular dystrophy also occurs in both
k eers
rs evident when progressive proximal muscle weakness is
k
seen when a child begins to walk. A positive Gowers
eers
r s sexes. Autosomal recessive, autosomal dominant, and
ook ook
X-linked types of inheritance have been identified, with
b oo b o
sign is characteristic of the disease and describes the
o b o oo
the recessive form being more common and having an
o
/
e e
/ eb e/ / e b
way that a child helps himself or herself arise by
e
“climbing” with the hands up to the legs to stand up-
e ee/ e
/ e b
earlier age of onset. The etiology is defective proteins
participating in the formation of a dystrophin-
// t/.tm
right. Walking aids are required by age 10 years,
. m
whereas most patients are wheelchair dependent by age
: t . m
. m
glycoprotein complex. Both upper arms and legs are af-
: / / / t
ss : /
12 years. Pseudohypertrophy of the calf and deltoid
ss /
fected. Muscle weakness is proximal and slowly pro-
:
hhtttp hhtttp
gressive. Death from the disease is quite unusual and is
tp
muscles is an early typical sign that progresses to mus-
cle wasting and the replacement of the necrotic muscle
fibers by adipose and connective tissue.
tp
associated with cardiopulmonary complications.22
Oculopharyngeal muscular dystrophy is a trinucle-
otide repeat disorder associated with expansion of
Becker muscular dystrophy is a variant of DMD (GCN)10 to (GCN)11-17 at the 5' end of the coding re-
with less severe clinical manifestations and a greater
gion for poly(A)-binding protein nuclear 1 (PABPN1).23
rrss rrss
longevity. Like DMD, it is caused by a mutation in the
The pattern of inheritance is autosomal dominant, and
o ke
ke
dystrophin gene, which is inherited with an X-linked
o k
recessive pattern; but in Becker muscular dystrophy a e
k e the age of onset is between the fifth and sixth decades
oo
e bboo o e b o o o
partially functional form of dystrophin is produced, in
b e b o
of life. Patients present with weakness of the extraocu-
b o
lar muscles, blepharoptosis, and dysphagia. Proximal
/
e / e produced.14
m ee/ e
contrast with DMD where no functional dystrophin is
/ m ee/ / e
limb and facial weakness can be found during the later
t . . m . m
stages of the disease.
t .
s : /
: /
Congenital muscular dystrophy is an autosomal re-
/ / t
cessive disease present at birth. Mutations in genes en-
s : /
: /
/ / t
hhtttp
tp s
coding laminin-a2 chain, glycosyltransferase-like pro-
tein (known as LARGE), fukutin, and fukutin-related
hhtttp
tp s
Myasthenias and Myasthenic Syndromes
Myasthenia gravis is an autoimmune neuromuscular
disease caused by antibodies against the nicotinic ace-
protein have been reported as possible etiologic fac-
tors.15,16 The disease is associated with muscle weakness tylcholine receptors at the postsynaptic neuromuscular
and joint deformities that progress slowly. Severe brain junction. Specific HLA types (B8 and DR3) have been
malformations (lissencephaly and hydrocephalus) and found to be associated with the development of myas-
k eers
rs effects in other organ systems may be present.
Emery-Dreifuss muscular dystrophy (EDMD) is
k e r
e s
r s
thenia gravis. T-helper cells are first activated by bind-
ing of the T cell receptor to the epitope, which is the
bboooo k o o o
characterized by joint contractures of the elbows, the
b o k b o oo
acetylcholine receptor antigenic peptide fragment.
o
/
e e
/ e e e
/ e b
ankles, and the neck; progressive muscle wasting and
/
weakness of the upper arms and the lower legs; and se-
e e / e
/ e b
T cells stimulate B cells to convert into plasma cells,
which produce the antibodies against acetylcholine re-
e
: / / / .
t m m
vere cardiac problems caused by the absence of a trans-
t . : / / t
/ .
t m
. m
ceptors. Patients with thymoma or other abnormalities
of the thymus are predisposed to the disease.24 Al-
t p ss : /
membrane protein of the inner nuclear membrane
named emerin.17 Mutations in the genes EMD, LMNA,
p ss : /
though the exact mechanism is not clarified, a possible
t p p
t
hht t
SYNE1, SYNE2, and FHL1 are responsible for the dif-
ferent types of the disease (EDMD1-6).16,18,19 Another
classification is based on the pattern of inheritance,
t
hht t
hypothesis is that the thymus has an important role in
the development of T cells and the selection of the T
cell receptor, and thus it is potentially associated with
which may be X-linked, autosomal dominant, or auto- myasthenia gravis.
somal recessive. Another form of myasthenia gravis is caused by an-
k eers
rs Distal muscular dystrophy is a non–life-threatening
form of dystrophies with slow progression and a rela-
k eers
r s
tibodies against muscle-specific kinase protein, a neces-
sary substance for the formation of a neuromuscular
b ooook b ook
tively late age onset, which varies from 20 to 60 years.
oo
A mutation in the DYSF gene at the 2p13.3-p13.1 lo-
b oooo
junction. Antibodies against muscle-specific kinase in-
duce a decrease in the patency of the neuromuscular
/
e e
/ eb / e
/e b
cum is found to be responsible for this form of muscu-
ee ee/e/e b
junction.24,25 Myasthenia gravis is also associated with
/ t
///t m
lar dystrophy. Miyoshi myopathy, which is found in Ja-
. . m
pan, is related to a mutation of the DYSF gene at the
: : / t.
///t m
other autoimmune diseases, including rheumatoid arthri-
.m
tis, lupus, Hashimoto thyroiditis, and Graves disease.
s
tps : s
tps :
240
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Fatigability is the typical symptom of myasthenia There is a wide spectrum of clinical features related
k eers
rs ke rrss
gravis. Facial muscles are primarily affected, leading to
e
to CMT disease. The foot is usually affected first, with
b ooook b o ook
blepharoptosis and diplopia. Dysphagia, dysarthria,
o
and difficulties in breathing may also occur. The Myas-
drop foot as the initial symptom. Muscle wasting of the
o oo
o
lower leg, “stork leg” deformity, pes cavus (high arched
b
/
ee/e b / e e b
thenia Gravis Foundation of America has proposed a
ee /
clinical classification that includes five different classes / e e b
foot), and claw toes are common findings. Weakness of
ee /
the upper extremities, particularly the hands and the
t . m
.m
of increasing severity, with class V being characterized
: / ///t : / t
///t. m
. m
forearms, can be found at later stages of the disease.
s
tps :
by a paralysis of the respirating muscles that necessi-
s
tps :
Neuropathic pain, spasmodic muscular contractions,
hhtttp hhtttp
tates intubation and assisted ventilation to sustain and a loss of touch sensation may occur. Scoliosis and
life.26 hip and foot deformities are common findings.
Ocular myasthenia gravis is a form of myasthenia The characteristics of Guillain-Barré syndrome and
gravis limited to the muscles of the eye. Seventy-five CMT disease are summarized in Table 3.
percent of new myasthenia gravis cases present with oc-
ular involvement (diplopia, blepharoptosis) as the ini- Congenital Structural Myopathies
k rs
rs
tial manifestation.27 However, in almost 80% of these
ee k eers
r s A summary of the congenital structural myopathies is
ook ook
cases, ocular myasthenia gravis will progress to a gen-
b oo eralized disease.
b oo o oo
provided in Table 4. Bethlem myopathy is a rare
o
congenital myopathy with an autosomal dominant pat-
b
/
e e
/ eb Neuropathic Disorders
e/
e e
/ e b ee/ e
/ e b
tern of inheritance. Mutation in one of the three genes
coding for type VI collagen (COL6A1, COL6A2, and
: // t/.tm
. m
Guillain-Barré syndrome is an acute inflammatory de-
t . m
. m
COL6A3) is responsible for this type of muscular dys-
: / / / t
ss : /
myelinating neuropathy that is characterized by sym-
: /
trophy.36 Although the disease occurs during infancy,
ss
hhtttp
tp hhtttp
tp
metric weakness of the lower limbs that progresses in Bethlem myopathy progresses very slowly. Weakness of
an ascending fashion with or without accompanying the proximal muscle groups of the lower extremities
sensory deficits. The disease may also affect the cranial may cause walking difficulties and a positive Gowers
nerves and the respiratory muscles, requiring ventilator sign. Contractures of the fingers and the toes are typi-
assistance. cal findings for the disease, and tiptoe walking may
The etiology is related to an autoimmune response occur due to these contractures. The ongoing muscle
k errss
against gangliosides. Myelin is therefore damaged, re-
e k e rrss
e
cell death may cause an elevation of serum creatine ki-
bboooo k
sulting in nerve conduction block, muscle paralysis,
b o o o
and sensory and autonomic dysfunction. Several infec-
o k nase (CK).
b o oo
Centronuclear myopathies comprise a group of myo-
o
/
e e
/ e ee e
/ e b
tious agents have been identified to trigger this immune
/
reaction; the most common are Campylobacter jejuni,
ee e
/ e b
pathies characterized by abnormal location of nuclei in
/
muscle cells. Myotubular myopathy (MTM) is the most
t . m
. m
cytomegalovirus, and influenza viruses.28,29
t . m.m
common representative of this group of congenital
s : /
: /
/ / t
Acute inflammatory demyelinating polyneuropathy
: / /
/ / t
myopathies. Several patterns of inheritance have been
s :
hhtttp
tp s
is the most common form of Guillain-Barré syndrome.
However, five other subtypes exist. Miller Fisher syn-
drome is characterized by a triad of ophthalmoplegia, hhtttp
tp s
identified. X-linked recessive MTM is the most com-
monly diagnosed. It is caused by mutations of the
MTM1 gene at the locum Xq28 of chromosome X,
ataxia, and areflexia.30 In Chinese paralytic syndrome, which encodes for a protein named myotubularin.37
the nodes of Ranvier and the axoplasm of peripheral This is a lipid phosphatase responsible for cellular
nerves are affected. The disease is endemic to China transport and signaling. Non–X-linked myotubular
k eerss
and Mexico and has a fast recovery.31 In acute motor
r k
sensory axonal neuropathy, the axoplasm of the periph-
e r
e s
r s myopathies are rare. An autosomal recessive type is
caused by a mutation of the gene BIN1, whereas the
bboooo k o o o k
eral nerves is affected, but recovery is very slow. Acute
b o b o oo
dominant type is related to a gene named dynamin 2
o
/
e e
/ e e / e
/ e b
panautonomic neuropathy is associated with high mor-
tality rate due to cardiovascular problems.32 Autonomic
e e / e
/ e b
(DNM2) that is located on chromosome 19.38
The clinical image is typical as for most myopathies.
e
: / / / .
t m m
dysfunction occurs and sweating, photophobia, nausea,
t .
dysphagia, and constipation alternating with diarrhea
: / / / .
t m m
The neonates in the congenital type present with de-
t .
creased muscle tone and significant delays in the devel-
t p ss
p : /
are the most common symptoms. Bickerstaff brainstem
ss : /
opmental milestones. Affected individuals usually re-
t p p
t
hht t
encephalitis is characterized by opthalmoplegia, ataxia,
and hypereflexia.33 Although the onset of the disease is
intense, prognosis is usually good.
t
hht t
main nonambulatory. Other clinical features include
pulmonary complications as a result of weakness of the
respiratory muscles, and the development of specific
Charcot-Marie-Tooth (CMT) disease is the most morphologic characteristics, such as bell-shaped tho-
common hereditary neurologic disorder. It comprises a rax, scoliosis, oblong face, high arched palates, and
k e rs
clinically heterogeneous group of peripheral nervous
rs
system disorders. CMT is caused by mutations that af-
e k eers
r s
long digits. The prognosis is poor, and affected individ-
uals usually die in their early 50s as a result of cardiac
b ooook b oook
fect the myelin sheath or the nerve axon. Duplication
o
of a region in 17p12 locum, which regulates the gene
or pulmonary conditions.
b oooo
Nemaline myopathy (NEM), also known as nema-
/
e e
/ eb ee/ e
/e b
PMP22, is found in 80% of the cases.34 Mutations of
/e/e b
line rod myopathy, is a congenital genetically heteroge-
ee
/ t
///t m
the gene MFN2 induce mitochondrial dysfunction that
. . m
subsequently affects neuromuscular synapses.35
: / t.
///t m
neous neuromuscular disorder. The abnormal thread-
.m
like rods in the muscle cells, which are also called
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 3
keerrss
b ooook and Charcot-Marie-Tooth Disease
b ook
Characteristics of the Two Most Common Neuropathic Disorders: Gullain-Barré Syndrome
o o b o oo
o
/
ee/e b Muscle Disorder
e
Etiology
e/ e
/ e b ee/ e
/ e b
Clinical Findings
Guillain-Barré syndrome
: / t
///t. m
.m
Acute inflammatory demyelinating
: / t
///t. m
. m
Symmetric weakness of the lower limbs
s
tps : s
tps :
hhtttp hhtttp
neuropathy Progression in an ascending fashion with or
Campylobacter jejuni, cytomegalovirus, and without accompanying sensory deficits
influenza viruses The disease may also affect the cranial nerves
and respiratory muscles, requiring ventilator
assistance.
Charcot-Marie-Tooth (CMT) Mutations that affect myelin sheath or Foot usually affected first (drop foot)
k eers
rs
disease nerve axon
k eers
r s
Duplication of a region in 17p12 locum, which
Muscle wasting of the lower leg, stork leg
deformity, pes cavus, and claw toes
ook ook
regulates the gene PMP22 Weakness of the upper extremities and
b oo b o
Mutations of the gene MFN2 induce
o b o oo
especially of the hands and forearms at later
o
/
e e
/ eb ee e
/ e b
mitochondrial dysfunction
/ e / e
/ e b
stages of the disease
Neuropathic pain
e
: // t/.tm
. m : / / t
/ .
t m
Spasmodic muscular contractions
. m
Loss of touch sensation
ss : / ss : / Scoliosis and hip and foot deformities common
hhtttp
tp hhtttp
tp
nemaline bodies, are characteristic pathology findings nisms include instability of the channels, decreased per-
for the disease. Several genetic mutations have been meability to chloride ions, and therefore prolonged
rrss rrss
identified and are responsible for the various clinical muscle contractions. Another reported etiology is a de-
o ke
ke forms of this entity. Six main types (NEM1-6) have
o k e
k e fective endoplasmic retinaculum, which fails to trans-
oo
e bboo o been described, comprising a wide variety of clinical
e b o o
manifestations regarding the severity and age of on-
b o port the channel to the cellular surface, deteriorating
e b o o
also its function. The etiology and the clinical findings
b
/
e / e m ee/ / e
set.39 Nemaline disease usually affects proximal muscle
groups as well as bulbar and trunk muscles. Neonates / / e
of common channelopathies is summarized in Table 5.
m ee
Two major forms of myotonia congenita exist:
t . . m t . .m
s : /
: /
/ / t
are hypotonic, and developmental stages are delayed.
/ / / t
Thomsen disease, which is inherited through an auto-
s : : /
hhtttp
tp s
Scoliosis occurs at an early age and progresses rapidly
during puberty. Respiratory problems are present in all
six types of the disease and in severe cases may be life tp s
somal dominant pattern, and Becker disease, which is
hhtttp
inherited in an autosomal recessive pattern. These two
forms differ mainly in the age of onset (early childhood
threatening. for Thomsen disease and late childhood in Becker dis-
ZASP-related myofibril myopathy (zaspopathy) is a ease), and severity of muscle weakness (Becker disease
relatively novel type of progressive muscular dystrophy. may cause permanent muscle weakness, stiffness, and
k eers
rs
It is caused by an A165V mutation in the ZASP gene,
which is located at chromosome 10 and is responsible
k e r
e s
r s
pain).41
The clinical image may vary. Early symptoms usually
bboooo k b o o
for encoding of the Z-disk-associated protein.40 The
o
pattern of inheritance is autosomal dominant. Zaspop-o k b o oo
include frequent falls, muscle stiffness that is improved
o
after several joint motion repetitions (warm-up effect)
/
e e
/ e ee/ e
/ e b
athy induces a disintegration of the Z-disk of the myo-
/ e
/ e b
and difficulties in swallowing, which may be compli-
ee
/ / t .
t m
fibrils in the muscle cells, decreasing their contractility.
. m
Patients with this form of myofibrillar myopathy have
: / / / t t m
cated with aspiration pneumonia. Permanent muscle
. . m
stiffness may cause the development of chronic joint
: /
t p ss
p : /
a more distal than proximal muscle phenotype. Both
ss : /
problems, gait disturbances, and injuries after a fall.
t p p
t
hht
are usually affected. t
anterior and posterior compartments of the lower leg
t
hht tParamyotonia congenita (von Eulenburg disease) is a
rare congenital neuromuscular disorder with an inci-
dence of 1 case per 350,000 people that is inherited
Myotonias/Channelopathies with an autosomal dominant pattern. The disease is
Myotonia congenita is a congenital neuromuscular also known as paradoxical myotonia because in con-
k eers
rs
channelopathy with an incidence of approximately
1 case per 100,000 people. More than 80 different mu-
k eers
r s
trast with myotonia congenita, muscle stiffness and
weakness become worse with exercise.
b ooook b ook
tations have been reported as responsible for the devel-
oo
opment of various subtypes of the disease. Most com-
b oooo
The etiology of paramyotonia congenita is multifac-
torial. Mutations in the gene SCN4A that interfere with
/
e e
/ eb ee/ e
/
mon is a mutation in the chloride channel gene
e b /e/e b
the inactivation speed of the sodium channel have been
ee
/ t
///t m
CLCN1, which is responsible for the formation of the
. . m
chloride ion channels.41 The pathophysiologic mecha-
: : / t.
///t m
reported.42 An increase in cellular excitability is found
.m
as a result of a prolonged inward current and the pres-
s
tps : s
tps :
242
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
Table 4
rs keerrss
b ooookCongenital Structural Myopathies
b o ook
o b o oo
o
/
ee/ e
/ e b ee/ e
Clinical Findings
/ e b
Bethlem myopathy
: / ///t. m
Autosomal dominant inheritance
t .m
Mutation in one of the three genes coding
: / t
///t. m
Early onset
. m
Very slow progression
s : s
for type VI collagen (ie, COL6A1, COL6A2,
tps tps :
Weakness of the proximal muscle groups of the lower
hhtttp hhtttp
and COL6A3) extremities
Walking difficulties
Positive Gowers sign (climbing up the thighs with
the hands)
Contractures of the fingers and the toes
Tiptoe walking
k eerss
Myotubular myopathy
r
(MTM)
X-linked recessive
k eers
r s
Mutations of the MTM1 gene at the locum
Neonates with decreased muscle tone and significant
delays in developmental milestones
b ooook b ooook
Xq28 of chromosome X (encoding protein
o
Patients nonambulatory
b oo
o
/
e e
/ eb myotubularin)
e/
e e
/ e b
Autosomal recessive type mutation of the
/ e
/ e b
Weakness of the respiratory muscles
Development of specific morphologic characteristics:
ee
gene BIN1
: // t/.tm
. m
Autosomal dominant type gene named
: / / t
/ t m
bell-shaped thorax, scoliosis, oblong face, high arched
. . m
palates, long digits
s : /
dynamin 2 (DNM2) located on
s ss : /
No good prognosis
hhtttp
tp hhtttp
tp
chromosome 19 Patients die in their early 50s
Nemaline myopathy Nemaline bodies: abnormal thread-like rods Six main types (NEM1-6)
(NEM) in the muscle cells Wide variety of clinical manifestations regarding the
severity and age of onset
Proximal muscle groups as well as bulbar and trunk
muscles affected
keerrss k e rrss
e
Neonates are hypotonic, and developmental stages
are delayed
bboooo k b o o
o o k b o oo
Scoliosis occurs at early age and progresses rapidly.
o
/
e e
/ e
ZASP-related myofibril Autosomal dominant
myopathy
e / e
/ e b
A165V mutation in the ZASP gene located
e e / e
/ e b
Both anterior and posterior compartments of the
lower leg are usually affected
e
t . m
at chromosome 10
. m t m
More distal than proximal muscle phenotype
. .m
s : : /
/ t
Encoding of the Z-disk-associated protein
/ / s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
ence of a window current because of modifications of sodes of muscle paralysis can be focal or generalized.
channel sensitivity to action potentials. There is a predilection in proximal muscle groups, but
Clinically, muscle stiffness and weakness are much facial and respiratory muscles are not affected.
k e rs
rs
worse with exercise and sometimes induced by cold
e k e r
e s
r s
bboooo k
temperatures. The symptoms are typically present
b o o
o o
within the first decade of life. The face and the upperk b o oo
Metabolic Myopathies–Mitochondriopathies
o
Glycogen storage diseases (GSDs) include a large group
/
e e
/ e extremities are primarily affected.
ee/ e
/ e b
Hyperkalemic periodic paralysis (HyperPP) and hy-
ee/ e
/ e b
of pathologies that are associated with defective glyco-
: / / t
/ .
t m
. m
pokalemic (HypoPP) periodic paralysis are rare chan-
: / / t
/ t m
gen metabolism.44 The reported incidence of GSDs var-
. . m
ies between 1 per 20,000 and 1 per 43,000 cases. Both
t p ss
p : /
nelopathies characterized by muscle weakness that are
ss : /
genetic and acquired pathogenetic mechanisms have
t p p
t
hht t
related to high or low serum potassium levels, respec-
tively. Nine common mutations of the SCN4A gene
have been described as the cause of almost 60% of Hy-
t
hht t
been found. The different types of GSDs, causative en-
zymatic defects, and main clinical symptomatology are
summarized in Table 6.
perPP cases, but a broad genetic heterogeneity exists
for at least 20% of the cases. HypoPP is related to mu- Fibromyalgia
k eers
tations of both SCN4A and CaCNA1S genes.43 Clini-
rs k e
cally, there is substantial overlap of these two condi-
ers
r s
Fibromyalgia is a systematic disorder of the central ner-
vous system that is associated with pain, mental impair-
b ooook b oook
tions. HyperPP has an earlier age of onset (about the
o
first decade of life), and the episodes of paralysis are
b ooo
ment, and other neurologic symptoms as a result of
o
central sensitization. The incidence of fibromyalgia is
/
e e
/ eb ee/ e
/e b
comparatively of shorter duration and usually do not
/e/e b
high, ranging between 2% and 4% of the population
ee
/ t
///t m
exceed 4 hours. HypoPP’s clinical manifestations are
. . m
apparent in the first or second decade of life. The epi-
: / t.
///t m
and showing a significant predilection to the female
.m
sex. The etiology is multifactorial: genetic factors, do-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 5
keerrss
b ooook b ook
Etiology and Clinical Findings of Most Common Channelopathies
o o b o oo
o
/
ee/ e
/ e b ee/ e
Clinical Findings
/ e b
Myotonia congenita
: / ///t. m
Over 80 different mutations
t .m
Most common mutation in gene CLCN1
: / t
///t. m
Frequent falls
. m
Muscle stiffness improved after several joint motion
s :
Decreased permeability to chloride ions =
tps s
tps : repetitions (warm-up effect)
hhtttp hhtttp
prolonged muscle contractions Difficulties in swallowing
Defective endoplasmic retinaculum Chronic joint problems, gait disturbances
Paramyotonia Autosomal dominant Symptoms within the first decade of life
congenita (von Mutations in the gene SCN4A that interfere Muscle stiffness and weakness
Eulenburg disease with inactivation speed of sodium channel Worsens with exercise and induced by cold
temperatures
k eers
rs k eers
r s Face and upper extremities affected
b ooook Hyperkalemic periodic

paralysis (HyperPP)
b oook
Nine common mutations of the SCN4A gene
o o oo
Age at onset in the first decade of life
o
Episodes of paralysis of short duration (usually do
b
/
e e
/ eb Hypokalemic periodic
e/
e e
/ e b
Mutations of SCN4A and CaCNA1S genes
ee e
/ e b
not exceed 4 hours)
/
Age at onset in the first or second decade of life
paralysis (HypoPP)
: // t/.tm
. m : t . m
. m
Episodes of muscle paralysis (focal or generalized)
/ / / t
ss : / ss : /
Predilection in proximal muscle groups
hhtttp hhtttp
Facial and respiratory muscles not affected
tp tp
Table 6
Types of Glycogen Storage Diseases
keerrss Type Defective Enzyme

k e rrss
e
Symptomatology
bboooo k I (von Gierke disease)

o o o k
Glucose-6-phosphatase
b o b o oo
Growth failure, lactic acidosis, hyperuricemia
o
/
e e
/ e II (Pompe disease)
/ e e
Acid maltase
ee / b / e e b
Muscle weakness, heart failure, death by age 2
ee /
years (infantile variant)
t . m
. m t . m.m
III (Cori disease or Forbes)
s : /
: /
/ / t
Glycogen debrancher
s : /
: /
/ / t
Myopathy
IV (Andersen disease)
V (McArdle disease)
hhtttp
tp s Glycogen branching enzyme
hhtttp
Muscle glycogen phosphorylase
tp s Failure to thrive, death at age 5 years
Exercise-induced cramps, rhabdomyolysis, renal
failure by myoglobinuria
VI (Hers disease) Liver glycogen phosphorylase Exercise-induced muscle cramps and weakness,
growth retardation, hemolytic anemia
VII (Tarui disease) Muscle phosphofructokinase
k eers
rs VIII (now classified with VI; has
k e r
e s
r s
bboooo k been described as X-linked
recessive)
b o o
o o k b o oo
o
/
e e
/ e IX
/ e e b
Phosphorylase kinase
ee / / e e b
Delayed motor development, growth
ee
retardation
/
X (Considered a distinct condition;
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
now classified with VI)
t p ss
p : / t p ss
p : /
t
hht t
XI (Fanconi-Bickel syndrome)
XII (Red cell aldolase deficiency)
Glucose transporter
Aldolase A t
hht t Exercise intolerance, cramps
XIII β-enolase Exercise intolerance, cramps; increasing intensity
of myalgias over decades; serum creatine
kinase: episodic elevations; reduced with rest
k eers
rs 0 Glycogen synthase
k eers
r s Occasional muscle cramping
b ooook b oook
o b oooo
/
e e
/ eb /
pamine dysfunction, abnormal serotonin metabolism
ee e
/e b /e/e b
ders have been correlated with the development of fi-
ee
/ t
///t m
and/or growth hormone secretion, and psychological
. . m
factors have been reported. Several stress-related disor-
: / t.
///t m
bromyalgia, such as chronic fatigue syndrome, irritable
.m
bowel syndrome, and posttraumatic stress disorder.45,46
:
s
tps : s
tps :
244
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
The research on the pathophysiology of fibromyalgia compromise blood supply and further damage muscle
k eers
rs ke rr
has highlighted several potential pathways. The concept
e ss cells, leading to an abundant release of potassium and
b ooook b o ook
of heightened sensitivity of nociceptive systems indicates
o
that patients demonstrate an overreaction to repetitive
phosphate ions, myoglobulin, CK, and uric acid, which
o oo
o
can compromise renal function and activate the coagu-
b
/
ee/e b / e e b
stimuli in the absence of an exercise-related analgesic re-
ee /
sponse. Other authors have shown that patients with fi- / e e b
lation system, which leads to disseminated intravascu-
ee /
lar coagulation and potentially fatal arrhythmias.49
t . m
.m
bromyalgia have hyperactivity of the sympathetic ner-
: / ///t : / t
///t. m
. m
Clinical manifestations of rhabdomyolysis include
s
tps :
vous system and lowered adrenal response to physical or
s
tps :
muscle pain, weakness, swelling, and tenderness, al-
hhtttp hhtttp
mental stimuli. Increased levels of substance P in the ce- though “silent” cases without any muscle symptoms
rebrospinal fluid of patients with fibromyalgia is re- may exist. In more severe cases, symptomatology of hy-
ported to be the most reproducible laboratory finding. povolemic shock may be induced from the massive
Studies using magnetic resonance spectroscopy have transfer of intravascular fluid into muscle tissue. Ab-
shown increased glutamate/glutamine compounds in pa- normalities in serum electrolytes may also cause some
tients with fibromyalgia and increased levels of pain in- constitutional symptoms, such as nausea or vomiting,
k rs
rs r
tensity, greater fatigue, and more symptoms of depres-
ee k ee s
r s whereas in more severe disturbances such as confusion,
ook ook
sion.47 Reduced dopamine synthesis in the brain stem arrhythmias, or even coma can develop. A concentra-
b oo b o
and the limbic cortex has been found in studies with pos-
o b o oo
tion of myoglobulin in the kidneys may cause acute
o
/
e e
/ eb itron emission tomography.48
e/
e e
/ e b
Clinically, patients complain of widespread pain last-
ee e
/ e b
kidney injury, decreased urine production, and tea-
/
colored urine within the first 24 hours of muscle dam-
: // t/.tm
. m
ing more than 3 months that affects both proximal and
t . m
. m
age. The development of compartment syndrome is an-
: / / / t
ss /
distal muscle groups of the upper and lower extremi-
: ss : /
other potential complication caused by acute muscle
hhtttp hhtttp
ties. Moreover, the American College of Rheumatology swelling and is clinically manifested as pain and hypo-
tp
has described 18 designated points of increased tender-
ness and has recommended that fibromyalgia should be tp
esthesia of the affected compartment. Prognosis is de-
pendent mainly on the underlying etiology, the severity
considered when a patient has referred pain at 11 or of muscle injury, and the magnitude of complications.
more of these points. The mortality rate is reported to reach 20% for those
who develop acute kidney injury and 60% for those
k errss
Rhabdomyolysis
e k e rrss
e
with established renal impairment.52
bboooo k
Rhabdomyolysis is a clinical condition associated with
b o o o k
severe damage to skeletal muscles. It refers to the sys-
o Paraneoplasmic Myopathy
b o oo
o
/
e e
/ e ee e
/ e b
tematic consequences caused by the release of the
/
breakdown products of damaged muscle cells into the
ee e
/ e b
Lambert-Eaton myasthenic syndrome is caused by an
/
autoimmune reaction against presynaptic voltage gated
t . m
. m
bloodstream.49 The incidence of rhabdomyolysis is un-
t . m.m
calcium channels on the presynaptic nerve terminal.
s : /
: /
/ / t
clear. However, it is reported that approximately 85%
: / /
/ / t
These calcium channels are also found in the auto-
s :
hhtttp
tp s
of cases with major trauma will develop rhabdomyoly-
sis, and one fifth to one half of them will eventually end
up with acute kidney injury. hhtttp
tp s
nomic nervous system and the cerebellum, and this may
explain the autonomic symptoms and coordination
problems.
The etiology of rhabdomyolysis is multifactorial. Lambert-Eaton myasthenic syndrome is often con-
Any condition that may cause severe damage to the sidered a type of paraneoplasmic myopathy; several
striated muscles can possibly lead to rhabdomyolysis, types of malignant diseases and especially small cell
k eerss
including mechanical, biochemical, metabolic, and in-
r k e
fectious diseases, and pharmaceutical factors50,51 (Ta- r
e s
r s lung cancer are found in 50% to 70% of the cases.
Other autoimmune diseases, such as hypothyroidism or
bboooo k o o o k
ble 7). Genetic predisposition has also been reported in
b o b o oo
diabetes mellitus type I, may coexist, whereas an asso-
o
/
e e
/ e e / / e b
terms of inherited enzyme deficiencies (polymorphisms
e
or mutations in genes encoding various cytochrome
e e / e
/ e b
ciation with HLA DR3-B8 has also been reported.53
The clinical image involves a marked decrease of
e
: / / / .
t m m
P450 isoenzymes, coenzyme Q, myophosphorlyase,
t .
CPT2, and myoadenylate deaminase) that are associ-
: / / / .
t m m
proximal muscle strength, especially of the lower ex-
t .
tremities. Ocular and respiratory muscle involvement
t p ss
p : /
ated with recurrent episodes of rhabdomyolysis.49
t p ss : /
can be found in advanced stages. Bulbar muscles are
p
t
hht t
The pathophysiology consists of the initial muscle
cell damage, including the accumulation of sodium ions
from the bloodstream that consequently cause osmotic
t
hht t
rarely affected. Autonomic nervous system involvement
is usually expressed with blood pressure disorders, con-
stipation, sweating, and blurred vision.
intracellular swelling and disruption. The concentration
of calcium ions is elevated and leads to continuous
k e s
muscle contraction and inappropriate consumption of
rrs e
ATP that enter into a vicious cycle of uncontrolled ATP
e k ers
r s Approach to Diagnostic/Genetic Counseling
b ooook b oook
depletion-calcium ion influx. There is also an inflam-
o
matory response produced by neutrophil granulocytes,
b ooo
The evaluation of a patient presenting with muscle
o
weakness and/or pain is complex, but a systematic ap-
/
e e
/ eb ee/ e
/e b
which contributes to the swelling of muscle tissue and
/e/e b
proach can facilitate a differential diagnosis. Determin-
ee
/ t
///t m
release of reactive oxygen radicals. Swelling and a po-
. . m
tential development of compartment syndrome may
: / t.
///t m
ing the etiology of symptoms and localizing the ana-
.m
tomic site of the lesion within the neuromuscular
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs
Table 7
keerrss
b ooook Etiologic Factors of Rhabdomyolysis
b o ook
o b o oo
o
/
ee/e b Pathophysiologic
Mechanism
ee/ e
/ e b
Cause of Muscle Damage
ee/ e
/ e b
Crush injury
: / t
///t. m
.m
Blast injury
: / t
///t. m
. m
s
tps : Crush syndrome
s
tps :
hhtttp hhtttp
Motor vehicle injuries
Consistent limb pressure in a fixed position (after alcohol intoxication, prolonged surgery
and/or stroke)
Exertion Extreme physical exercise
Tetanus
Seizures
k eers
rs Impaired blood supply Embolism
k eers
r s
b ooook Thrombosis
ooook o oo
o
Prolonged arterial clamping (resuscitation from trauma or during vascular surgery)
b b
/
e e
/ eb Metabolic abnormalities
e/
e
Hypokalemia e
/
Hypernatremia
e b ee/ e
/ e b
: // t . m
. m
Hypocalcemia
/ t : / / t
/ .
t m
. m
ss : /
Hypophosphatemia
ss : /
hhtttp hhtttp
Hyperglycemia – hyperosmolar state – ketoacidosis
Infection
tp Hypothyroidism
Influenza A and B
tp
Salmonella
Epstein-Barr virus Legionella pneumophila
Coxsackie virus Lyme myositis
HIV Fungal
rrss rrss
Herpes viruses Trichinosis
o ke
ke
Cytomegalovirus
o k e
k e
Toxoplasmosis
oo
e bboo o Inflammatory diseases Dermatomyositis
Polymyositis
e b o
b o o e b o
b o
/
e / e Drugs and toxins Drugs
m ee/ / e Toxic agents
m ee/ / e
t .
Statins
. m Heavy metals
t . .m
s : /
: /
/ / t
Fibrates
Diuretics
s : /
: /
Insect bites
/
Haff disease/ t
hhtttp
tp s Neuroleptics
Neuromuscular blocking
agents hhtttp
tp s
Selective serotonin
reuptake inhibitor
Amphetamines, cocaine,
k eers
rs
heroin, lysergic acid
diethylamide (LSD)
k e r
e s
r s
bboooo k Body temperature Hyperthermia
b o o
o o k b o oo
o
/
e e
/ e Genetic predisposition
Hypothermia
Glycolysis
ee/ e
/ e b Lipid metabolism
ee/ e
/ e b Mitochondrial
: / / / .
t m m
Phosphofructokinase
t .
Glucogen storage diseases
Carnitine
/ / t
/ .
t m
. m
palmitoyltransferase I
:
Succinate dehydrogenase
Cytochrome c oxidase
t p ss
p : / VIII, IX, X, XI
ss
and II
t p p : / Coenzyme Q10
t
hht t t t
Acyl coenzyme A
hhtdehydrogenase
Thiolase
system is of paramount importance. The patient’s his- quired to identify pathologies from the central and pe-
tory and physical examination have a major role in dis- ripheral nervous systems. The distribution of weakness
k eers
rs tinguishing motor impairment caused by muscle asthe-
k eers
r s is a useful guide to differential diagnosis. An algorithm
ook ook
nia from that secondary to other etiologies. showing the steps of the diagnostic procedure based on
b oo oo
Information regarding the age of onset, sex, coexisting
b b oooo
the pattern of muscle weakness is presented in Figure 1.
/
e e
/ eb ee/ e
/e b
metabolic and rheumatic diseases, endocrinopathies,
medication history, and alcohol and substance abuse
ee/e/e b
Laboratory studies should include serum, urine, and
cerebrospinal fluid examination and immune tests. In-
t . m
. m
are significant. A detailed neurologic examination is re-
: / ///t : / t.
///t m
.m
creased concentrations of muscle enzymes, such as CK,
s
tps : s
tps :
246
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e Figure 1
ee/ e
/ e b ee/ e
/ e b
Algorithm for differential diagnosis of objective muscle weakness based on its pattern and distribution.
t . m m t . m m
(Courtesy of Marc L. Miller: Approach to the patient with muscle weakness. UpToDate May 2012.
. .
s : /
: / / t s : / / / t
http://www.uptodate.com/contents/approach-to-the-patient-with-muscle-weakness.)
/ : /
hhtttp
tp s
lactate dehydrogenase, aldolase, and transaminases (se- hhtttp
tp s
In Lambert-Eaton myasthenic syndrome, EMG may
rum glutamic oxaloacetic transaminase, serum glutamic demonstrate a myopathic pattern as a result of neuro-
pyruvic transaminase) in serum are highly indicative of muscular block. EMG should be combined with mea-
the presence of muscle disease. Specific serologic tests surement of the amplitude of a compound muscle ac-
eers
may reveal inflammatory myopathies or a background
rs
of connective tissue disease. Anti-histidyl-t-RNA syn-
k k e r
e s
r s
tion potential evoked by nerve stimulation before and
after exercise.54
bboooo k b o o
o k
thetase (anti-Jo-1) antigens are specific for myositides,
o
whereas antinuclear antibodies (anti-Sm, anti-Ro, anti-
b o oo
Muscle biopsy is often necessary to confirm the diag-
o
nosis and determine the type of myopathy. Special stains
/
e e
/ e / e
/ e b
La, and anti-RNP) can be found in several rheumatic dis-
ee ee/ e
/ e b
have been used to reveal specific enzyme deficiencies
eases.
/ / t
/ .
t m
. m
Electrophysiologic studies, including nerve conduc-
: : / / t
/ .
t m
and/or the accumulation of glycogen or lipid in glycogen
. m
or lipid storage myopathies, respectively. Electron micro-
ss : /
tion velocity studies and EMG, are helpful in localizing
t p p t p ss
p : /
scopic examination is helpful to identify specific forms
t
hht t
the site of the lesion in the peripheral nerve pathway,
the neuromuscular junction, or within the muscle. It is
generally difficult to make distinctions between heredi-
t
hht t
of myopathy (for example, IBM).
Genetic testing has been a significant tool for the di-
agnosis and the classification of cases with inherited
tary and acquired myopathies using EMG. The motor myopathies and muscle dystrophies.55,56 However, ge-
unit potentials are low and spiky. The pattern of re- netic heterogeneity and conventional molecular meth-
k e rs
rs e
with muscle contraction. In muscular dystrophies, large
e k ers
cruitment typically becomes full with just a small firing
r s
ods make the genetic assessment of most inherited
myopathies a copious procedure. Algorithms aimed at
b ooook b ook
motor units on a background of small spiky units can
oo
be seen because of the presence of muscle fibers of vari-
b oooo
reducing the number of genes qualified for possible mo-
lecular genetic testing have been proposed based on
/
e e
/ eb / e
/e b
able diameter. In inflammatory muscle diseases (der-
ee ee/e/e b
morphologic and clinical criteria (Figure 2).
/ t
///t m
matomyositis, polymyositis), and nonspecific fibrilla-
. . m
tions may be seen because of muscle fiber degeneration.
: : / t.
///t m
Next-generation sequencing has been shown to be
.m
an efficient and effective method to facilitate diagnosis.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss Figure 2
e rrss
Flowchart algorithm for diagnostic purposes aimed at reducing the number of genes qualified for possible
e
molecular genetic testing, using clinical data as the starting point. (Adapted from Udd B: 165th ENMC Interna-
k
bboooo k 2009;19[6]:429-438.)
b o o
o o k b o oo
tional Workshop: Distal myopathies, 6-8th February 2009, Naarden, The Netherlands. Neuromuscul Disord
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m
DNA is first broken into a library of small fragments.
t . m.m
thies, myotonias, channelopathies, mitochondriopa-
: / /
/ / t
These fragments are then attached to oligonucleotide
s : s : /
: /
/ / t
thies, and paraneoplasmic myopathies.
hhtttp
tp s
adapters that facilitate the biochemistry necessary for
the sequencing reaction. Genetic content among sam-
ples and germline and somatic variants of interest can hhtttp
tp s
Overall, the differential diagnosis of muscle disor-
ders is a complex procedure. A systematic approach to
these cases, which should follow a detailed history and
be identified; single nucleotide polymorphisms, inser- clinical examination and orthological utilization of ev-
tions and deletions (indels), copy number variants, and ery new imaging and laboratory tool needed, will facil-
other structural variations may be found using this new itate accurate diagnosis and treatment.
k eers
rs technology. Next-generation sequencing and DNA mul-
k
tiplexing can be used to retrieve pathogenic mutations
e r
e s
r s
bboooo k o o o
in cases with heterogeneous neuromuscular disorders.55
b o k Key Study Points
b o oo
o
/
e e
/ e e e
/ b
Other researchers have used whole genome or whole
/ e
exome sequencing (ES) for the genetic diagnosis of
e •
ee/ e
/ e b
Abnormal accumulation of pathogenic proteins
: / / / .
t m m
given monogenic muscle diseases.57 However, these two
t .
methods have several disadvantages for routine molec-
: / / t
/ .
t m
. m
(amyloid-β, phosphorylated tau protein, and
t p ss : /
ular diagnosis, including coverage, variant analysis, val-
p t p ss
p : /
others) may have a causative effect in immune
t
hht t
idation, and price. The major drawback is that the
whole exome sequencing capture library could not be
customized and should be updated to incorporate novel
t
hht •t system deregulation.
The absence of protein dystrophin is responsible
for DMD. Its production is regulated by a gene
genes. located at chromosome X (Xp21 gene). How-
ever, one third of cases comprises new sporadic
k eers
rs Summary
k eers
r s •
mutations.
Specific HLA types (B8 and DR3) have been
b ooook b oook
o
Muscle disorders include a wide spectrum of pathologic
b oooo
found to be associated with the development of
/
e e
/ eb ee/ e
/e b
entities, ranging from inflammatory myopathies, mus-
e /e/e b
myasthenia gravis. Antibodies against muscle
specific kinase induce a decrease in patency of
e
/ t
///t m
cular dystrophies, and different types of myasthenic
. . m
syndromes to neuropathic disorders, structural myopa-
: : / t.
///t m
the neuromuscular junction.
.m
s
tps : s
tps :
248
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
tis: Conformational multifactorial ageing-related degen-
k eerss
r keerrss erative muscle disease associated with proteasomal and
ook ook
lysosomal inhibition, endoplasmic reticulum stress, and
b oo
1.
b o
Lieber RL, Fridén J: Clinical significance of skeletal
o o oo
accumulation of amyloid-β42 oligomers and phospho-
b o
/
ee/e b 140-151.
ee/ / e b
muscle architecture. Clin Orthop Relat Res 2001;383:
e ee/ e
/ e b
rylated tau. Presse Med 2011;40(4, pt 2):e219-e235.
This review article presents the newest research ad-
2.
/ t
///t. m
.m
Galpin AJ, Raue U, Jemiolo B, et al: Human skeletal
: : / t . m
. m
vances for better understanding the pathogenesis of spo-
///t
radic inclusion body myositis.
s
tps :
muscle fiber type specific protein content. Anal Biochem
s
tps :
hhtttp hhtttp
2012;425(2):175-182. 11. Haubenberger D, Bittner RE, Rauch-Shorny S, et al: In-
The authors present a reliable method for human skeletal clusion body myopathy and Paget disease is linked to a
muscle fiber type specific protein analysis. They show that novel mutation in the VCP gene. Neurology 2005;65(8):
particular proteins exist in a hierarchal fashion through- 1304-1305.
out the continuum of skeletal muscle fiber types.
k e
3.
ers
rs k e
Pette D, Staron RS: Myosin isoforms, muscle fiber
ers
r s
12. Sahenk Z, Mendell JR: The muscular dystrophies: Dis-
tinct pathogenic mechanisms invite novel therapeutic
b ooook 500-509.
b oook
types, and transitions. Microsc Res Tech 2000;50(6):
o b o oo
approaches. Curr Rheumatol Rep 2011;13(3):199-207.
o
/
e e
/ eb 4.
e/
e e
/ e b
Stark H, Schilling N: A novel method of studying fasci-
e / e
/ e b
A splicing disorder related to RNA toxicity is the com-
mon mechanism for facioscapulohumeral muscular dys-
e
t . m
. m
cle architecture in relaxed and contracted muscles.
: // / t : / / t
/ t m
trophy and myotonic dystrophies.
. . m
ss : /
J Biomech 2010;43(15):2897-2903.
ss
13.
: /Velázquez-Wong AC, Hernández-Huerta C, Márquez-
hhtttp
tp hhtttp
tp
The authors describe muscle architecture in more detail Calixto A, et al: Identification of duchenne muscular
and compare relaxed and contracted states. dystrophy female carriers by fluorescence in situ hybrid-
ization and RT-PCR. Genet Test 2008;12(2):221-223.
5. Rana M, Wakeling JM: In-vivo determination of 3D
muscle architecture of human muscle using free hand ul- 14. Magri F, Del Bo R, D’Angelo MG, et al: Clinical and mo-
trasound. J Biomech 2011;44(11):2129-2135. lecular characterization of a cohort of patients with novel
keerrss k e rrss
The authors developed and validated methods to deter-
e
nucleotide alterations of the dystrophin gene detected by
bboooo k sions using ultrasound.

b o o
o o k
mine in vivo muscle fascicle orientations in three dimen- direct sequencing. BMC Med Genet 2011;12:37.
b o oo
o
The authors analyzed a sample of patients carrying
/
e e
/ e 6.
ee/ e
/ e b
Hak AE, de Paepe B, de Bleecker JL, Tak P-P, de Vis-
/ e e b
point mutations or complex rearrangements in the
ee /
DMD gene. They report a phenotypic correlation in
. m m
ser M: Dermatomyositis and polymyositis: New treat-
t . t . m.m
dystrophinopatic patients, which helps to understand
: / / / t
ment targets on the horizon. Neth J Med 2011;69(10):
s : / s : / /
/ / t
the premessenger RNA maturation defects and dystro-
:
410-421.
hhtttp
tp s
The authors support that there is an immune mediated
inflammation involved with the development of idio- hhtttp
tp s phin functional domains. The authors believe that these
data could direct new therapeutic approaches relying on
a more precise definition of the genetic defects.
pathic inflammatory myopathies. Results from the use
of blockers of the lymphotoxin signaling pathway are 15. Jimenez-Mallebrera C, Brown SC, Sewry CA, Muntoni
awaited. The authors suggest that anti-B cell therapy F: Congenital muscular dystrophy: Molecular and cellu-
k eers
r
may be a valuable therapeutic option for the treatment
s
of refractory idiopathic inflammatory myopathies.
k e r
e s
r s
lar aspects. Cell Mol Life Sci 2005;62(7-8):809-823.
bboooo k
7.
o o
o o k
Dalakas MC, Hohlfeld R: Polymyositis and dermatomy-
b
16.
b o oo
Bertini E, D’Amico A, Gualandi F, Petrini S: Congenital
o
muscular dystrophies: A brief review. Semin Pediatr
/
e e
/ e ositis. Lancet 2003;362(9388):971-982.
ee/ e
/ e b ee/ e
/ e b
Neurol 2011;18(4):277-288.
8.
/ t . m
. m
Mimori T, Nakashima R, Hosono Y: Interstitial lung
: / / t : / / t .
t m
The authors provide a clinical description of the most
. m
important forms of CMD. Particular attention is paid to
/
t p p : /
disease in myositis: Clinical subsets, biomarkers, and
ss
treatment. Curr Rheumatol Rep 2012;14(3):264-274.
t p ss
p : /
the main keys for a diagnostic approach, highlighting
t
hht t
Interstitial lung disease is found in nearly one half of
myositis patients. Autoantibodies as well as imaging and
t
hht t
the requirement for concurrence of expertise in multiple
specialties (neurology, morphology, genetics, and neuro-
radiology). Molecular diagnosis is significant for
histopathological studies are useful for the classification phenotype-genotype correlations, genetic counseling,
of interstitial lung disease in myositis and provide useful and prognosis. Level of evidence: IV.
information for predicting prognosis and determining
k eers
rstreatment.
k eers
r s 17. Muchir A, Worman HJ: Emery-Dreifuss muscular dys-
trophy. Curr Neurol Neurosci Rep 2007;7(1):78-83.
b ooook9.
b ook
Garlepp MJ, Mastaglia FL: Inclusion body myositis:
oo
New insights into pathogenesis. Curr Opin Rheumatol
b oooo
/
e e
/ eb 2008;20(6):662-668.
ee/ e
/e b 18.
e /e/e b
Zhang Q, Bethmann C, Worth NF, et al: Nesprin-1 and
-2 are involved in the pathogenesis of Emery Dreifuss
e
10.
/ t
///t. m
. m
Askanas V, Engel WK: Sporadic inclusion-body myosi-
: : / t
///t m
muscular dystrophy and are critical for nuclear envelope
. .m
integrity. Hum Mol Genet 2007;16(23):2816-2833.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
19. Gueneau L, Bertrand AT, Jais JP, et al: Mutations of the 29. Drenthen J, Yuki N, Meulstee J, et al: Guillain-Barré
k eers
rs rr
FHL1 gene cause Emery-Dreifuss muscular dystrophy.
kee ss syndrome subtypes related to Campylobacter infection.
ook ook
Am J Hum Genet 2009;85(3):338-353. J Neurol Neurosurg Psychiatry 2011;82(3):300-305.
b oo b o o b o oo
o
The authors report that Campylobacter jejuni infections
/
ee/e b 20.
/ e e b
Guglieri M, Magri F, Comi GP: Molecular etiopatho-
ee /
genesis of limb girdle muscular and congenital muscular
ee/ e
/ e b
are strongly but not exclusively associated with axonal
Guillain-Barré syndrome.
: /
Acta 2005;361(1-2):54-79. t
///t. mm
dystrophies: Boundaries and contiguities. Clin Chim
. :
30.
/ t
///t. m
. m
Roberts T, Shah A, Graham JG, McQueen IN: The
s
tps : s
tps :
hhtttp hhtttp
Miller Fischer syndrome following campylobacter enter-
21. Tawil R, Van Der Maarel SM: Facioscapulohumeral itis: A report of two cases. J Neurol Neurosurg Psychi-
muscular dystrophy. Muscle Nerve 2006;34(1):1-15. atry 1987;50(11):1557-1558.
22. Mathews KD, Moore SA: Limb-girdle muscular dystro- 31. Tang XF, Zhang XJ: Guillain-Barré syndrome or “new”
phy. Curr Neurol Neurosci Rep 2003;3(1):78-85. Chinese paralytic syndrome in northern China? Electro-
k eers
rs 23.
k eers
r
Hino H, Araki K, Uyama E, et al: Myopathy phenotypes
encephalogr Clin Neurophysiol 1996;101(2):105-109.
b ooook o ook
in transgenic mice expressing mutated PABPN1 as a
b o
32.
b oo
Akbayram S, Doğan M, Akgün C, et al: Clinical fea-
o o
tures and prognosis with Guillain-Barré syndrome. Ann
/
e e
/ eb Mol Genet 2004;13(2):181-190.
e/
e e
/ e b
model of oculopharyngeal muscular dystrophy. Hum
ee/ e
/ e b
Indian Acad Neurol 2011;14(2):98-102.
24.
: // t/.tm
. m
Spillane J, Beeson DJ, Kullmann DM: Myasthenia and
: / / t
/ .
t m
The authors showed that Guillain-Barré syndrome is not
. m
uncommon in children younger than 2 years of age, and
ss : /
related disorders of the neuromuscular junction. J Neu-
ss : /
cerebrospinal fluid protein level might be found high in
hhtttp
tp hhtttp
tp
the first week of the disease in about 50% of the pa-
rol Neurosurg Psychiatry 2010;81(8):850-857.
tients, with a higher rate of morbidity and mortality in
This review article focuses on recent advances in the di- patients with axonal involvement than in those with
agnosis and the treatment of disorders of the neuromus- acute inflammatory demyelinating polyradiculoneurop-
cular junction. athy.
keerrss 25. Masuda T, Motomura M, Utsugisawa K, et al: Antibod-
k e rrss
e
ies against the main immunogenic region of the acetyl-
33. Nagashima T, Koga M, Odaka M, Hirata K, Yuki N:
Continuous spectrum of pharyngeal-cervical-brachial
bboooo k b o o
o k
choline receptor correlate with disease severity in myas-
o
thenia gravis. J Neurol Neurosurg Psychiatry 2012; 64(10):1519-1523.
b o oo
variant of Guillain-Barré syndrome. Arch Neurol 2007;
o
/
e e
/ e 83(9):935-940.
ee/ e
/ e b 34.
ee/ e
/ e b
Choi B-O, Kim NK, Park SW, et al: Inheritance of
t m
The authors suggest that the main immunogenic region
. . m t . m.m
s : /
: /
/ / t
antibodies assay may be useful for predicting myasthe-
nia gravis symptom severity, especially for discriminat-
s : /
: /
Charcot-Marie-Tooth disease 1A with rare nonrecurrent
/ / t
genomic rearrangement. Neurogenetics 2011;12(1):
gravis.
hhtttp
tp s
ing between ocular and generalized types of myasthenia
hhtttp
tp s 51-58.
The authors reported an Alu-Alu-mediated rearrange-
ment with the FoSTeS by the MMBIR and a two-step re-
26. Jaretzki A III, Barohn RJ, Ernstoff RM, et al: Myasthe- arrangement of the replication based FoSTeS/MMBIR
nia gravis: Recommendations for clinical research stan- and meiosis-based recombination that are associated
dards. Task Force of the Medical Scientific Advisory with CMT disease 1A peripheral neuropathy.
k eers
rs Board of the Myasthenia Gravis Foundation of Amer-
ica. Neurology 2000;55(1):16-23.
k e r
e s
r s 35. Feely SM, Laura M, Siskind CE, et al: MFN2 mutations
bboooo k b o o
o o k b o oo
cause severe phenotypes in most patients with CMT2A.
o
Neurology 2011;76(20):1690-1696.
/
e e
/ e
27.
e e
/ e b
Wu X, Tuzun E, Li J, et al: Ocular and generalized my-
/
asthenia gravis induced by human acetylcholine recep-
e e / e
/ e b
The authors report that MFN2 mutations are found par-
e
: / / / .
t m
tor γ subunit immunization. Muscle Nerve 2012;45(2):
t . m : / / t t m
ticularly likely to cause severe neuropathy that may be
. . m
primarily motor or motor accompanied by prominent
/
209-216.
t p ss : /
The authors present their findings indicating that ocular
p t p ss
p : /
proprioception loss.
t
hht t
myasthenia gravis may be induced by immunity to the
acetylcholine receptor γ subunit. t
hht t
36. Briñas L, Richard P, Quijano-Roy S, et al: Early onset
collagen VI myopathies: Genetic and clinical correla-
tions. Ann Neurol 2010;68(4):511-520.
28. Mossberg N, Nordin M, Movitz C, et al: The recurrent
Quantitative reverse transcription-polymerase chain re-
Guillain-Barré syndrome: A long-term population-based
action is a helpful tool for the identification of some
k eers
rs study. Acta Neurol Scand 2012;126(3):154-161.
k
The authors conclude that episodes of recurrent
eers
r s mutation-bearing genes. The clinical classification pro-
posed by the authors allows genotype-phenotype rela-
b ooook oook
Guillain-Barré syndrome are shorter than in monopha-
b o b oooo
tionships to be explored.
/
e e
/ eb e / /e b
sic Guillain-Barré syndrome. However, no immunologic
e
predisposing factors for recurrence beyond the previ-
e
37.
e /e/e b
Tsai T-C, Horinouchi H, Noguchi S, et al: Characteriza-
e
/
burst could be identified.
: t
///t m
ously demonstrated relationship to a weaker respiratory
. . m : / t.
///t m
tion of MTM1 mutations in 31 Japanese families with
.m
myotubular myopathy, including a patient carrying
s
tps : s
tps :
250
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
240 kb deletion in Xq28 without male hypogenitalism. pathophysiology to therapy. Nat Rev Rheumatol 2011;
k eers
rsNeuromuscul Disord 2005;15(3):245-252.
keerrss 7(9):518-527.
b ooook
38.
b o ook
o
Romero NB: Centronuclear myopathies: A widening
o oo
The authors review the pathophysiologic mechanism re-
o
lated to fibromyalgia and present potential pharmaco-
b
/
ee/e b ee/ e
/ e b
concept. Neuromuscul Disord 2010;20(4):223-228.
The authors present particular histopathologic abnor-
e / e
/ e b
logical treatments, including monoamine modulators,
calcium channel modulators, and γ-aminobutyric acid
e
t
///t. m
.m
malities associated with specific mutations that are help-
: / : / ///t. m
. m
modulators.
t
s
tps :
ful for distinguishing between nuclear centralization and
s
tps :
hhtttp hhtttp
nuclear internalization. 47. Valdés M, Collado A, Bargalló N, et al: Increased
glutamate/glutamine compounds in the brains of pa-
39. Olivé M, Goldfarb LG, Lee H-S, et al: Nemaline myo- tients with fibromyalgia: A magnetic resonance spec-
pathy type 6: Clinical and myopathological features. troscopy study. Arthritis Rheum 2010;62(6):1829-1836.
Muscle Nerve 2010;42(6):901-907. The distinctive metabolic features described in the right
amygdala of patients with fibromyalgia suggest the pres-
The authors present a unique subtype NEM6, which is
k eers
rsously reported NEM6 pedigrees.
k eers
r s
phenotypically similar and probably allelic to two previ-
ence of neural dysfunction in emotional processing.
b ooook b ooook 48.
b o oo
Wood PB, Schweinhardt P, Jaeger E, et al: Fibromyalgia
o
patients show an abnormal dopamine response to pain.
/
e e
/ eb 40.
e/ e
/ e b
Selcen D, Engel AG: Mutations in ZASP define a novel
form of muscular dystrophy in humans. Ann Neurol
e ee/ e
/ e b
Eur J Neurosci 2007;25(12):3576-3582.
2005;57(2):269-276.
: // t/.tm
. m 49.
: / / t . m
. m
Parekh R, Care DA, Tainter CR: Rhabdomyolysis: Ad-
/ t
41.
ss : /
Ulzi G, Lecchi M, Sansone V, et al: Myotonia congen-
ss : /
vances in diagnosis and treatment. Emerg Med Pract
hhtttp hhtttp
2012;14(3):1-15.
tp
ita: Novel mutations in CLCN1 gene and functional
characterizations in Italian patients. J Neurol Sci 2012;
318(1-2):65-71.
tp This review article examines the current evidence on
symptoms and diagnostic methods as well as standard
first-line treatments of rhabdomyolysis.
The authors present 12 novel mutations in CLCN1 that
may contribute to genotype-phenotype correlations of
myotonia congenita. 50. Dalakas MC: Toxic and drug-induced myopathies.
keerrss k e rrss
e
J Neurol Neurosurg Psychiatry 2009;80(8):832-838.
bboooo k
42.
b o o o
tation in SCN4A causes severe myotonia and school-
o k
Yoshinaga H, Sakoda S, Good J-M, et al: A novel mu-
51.
b o oo
Valiyil R, Christopher-Stine L: Drug-related myopathies
o
/
e e
/ e 2):15-19.
ee e
/ e b
age-onset paralytic episodes. J Neurol Sci 2012;315(1-
/ e / e
/ e b
of which the clinician should be aware. Curr Rheumatol
Rep 2010;12(3):213-220.
e
t . m
. m
The authors discuss the novel mutation of the skeletal
. m m
Drug-related myopathies are potentially reversible in
t .
: / /
/ / t
muscle sodium channel (SCN4A), pI693L, which is re-
s : s : /
: /
/ / t
their early stages. It is important to be able to recognize
hhtttp s
sponsible for HypoPP and is correlated with a severe
tp
clinical form of paramyotonia congenita.
hhtttp
tp s toxic myopathies and discontinue therapy early before
muscle damage becomes irreversible.
43. Matthews E, Portaro S, Ke Q, et al: Acetazolamide effi- 52. Splendiani G, Mazzarella V, Cipriani S, Pollicita S,
cacy in hypokalemic periodic paralysis and the predictive Rodio F, Casciani CU: Dialytic treatment of
rhabdomyolysis-induced acute renal failure: Our experi-
role of genotype. Neurology 2011;77(22):1960-1964.
ence. Ren Fail 2001;23(2):183-191.
k eers
rs k e r
The authors showed that only half of the genotyped pa-
e
tients with HypoPP respond to acetazolamide, and that s
r s
bboooo k response.
b o o
o k
there is a correlation between genotype and treatment
o
53. Takamori M: Lambert-Eaton myasthenic syndrome:
b o oo
Search for alternative autoimmune targets and possible
o
/
e e
/ e 44.
ee/ e
/ e b
Shin YS: Glycogen storage disease: Clinical, biochemi-
e e
/ e b
compensatory mechanisms based on presynaptic cal-
/
cium homeostasis. J Neuroimmunol 2008;201-202:
e
: / / t
/ .
t m
. m
cal, and molecular heterogeneity. Semin Pediatr Neurol
145-152.
: / / t
/ .
t m
. m
2006;13(2):115-120.
t p ss
p : / 54.
t p ss
p : /
Meriggioli MN, Sanders DB: Advances in the diagnosis
45. t
hht t
Clauw DJ, Arnold LM, McCarberg BH; FibroCollabo-
rative: The science of fibromyalgia. Mayo Clin Proc
t
hht t of neuromuscular junction disorders. Am J Phys Med
Rehabil 2005;84(8):627-638.
2011;86(9):907-911. 55. Laing NG: Genetics of neuromuscular disorders. Crit
The authors present new concepts regarding fibromyal- Rev Clin Lab Sci 2012;49(2):33-48.
gia and highlight the fact that the condition remains un-
k eers
rs k eers
r s
diagnosed in 75% of patients. There is ongoing research
to determine the role of analogous central nervous sys-
The authors discuss the significant role of NGS in caus-
ative genes for the different types of neuromuscular dis-
b ooook oook
tem factors in the other cardinal symptoms of fibro-
b o ooo
orders. However, NGS is not good at identifying repeat
o
expansions or copy number variations.
b
/
e e
/ eb nitive dysfunction.
ee/ e
/e b
myalgia, such as fatigue, nonrestorative sleep, and cog-
ee/e/e b
46.
/ t
///t. m
. m
Schmidt-Wilcke T, Clauw DJ: Fibromyalgia: From
: : / t.
///t m
.m
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
56. Guglieri M, Bushby K: How to go about diagnosing and The authors present ES as a diagnostic alternative for
k eers
rs rrss
managing the limb-girdle muscular dystrophies. Neurol
kee
genetically heterogeneous disorders. They found that ES
ook ook
India 2008;56(3):271-280. is a rapid and first-tier method to screen for mutations,
b oo b o o b o oo
although its application requires the disclosure of the
o
/
ee/e b 57.
e e
/ e b
Dias C, Sincan M, Cherukuri PF, et al: An analysis of
/
exome sequencing for diagnostic testing of the genes as-
e e e
/ e b
extent of coverage for each targeted gene. Therefore,
/
supplementation with second-tier Sanger sequencing for
e
: / ///t
Hum Mutat 2012;33(4):614-626.. m
.m
sociated with muscle disease and spastic paraplegia.
t : / t
///t. m
. m
full coverage is required.
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb e/
e e
/ e b ee/ e
/ e b
: // t/.tm
. m : / / t
/ .
t m
. m
ss : / ss : /
hhtttp
tp hhtttp
tp
keerrss k e rrss
e
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
t . m
. m t . m.m
s : /
: /
/ / t s : /
: /
/ / t
hhtttp
tp s hhtttp
tp s
k eers
rs k e r
e s
r s
bboooo k b o o
o o k b o oo
o
/
e e
/ e ee/ e
/ e b ee/ e
/ e b
: / / t
/ .
t m
. m : / / t
/ .
t m
. m
t p ss
p : / t p ss
p : /
t
hht t t
hht t
k eers
rs k eers
r s
b ooook b oook
o b oooo
/
e e
/ eb ee/ e
/e b ee/e/e b
: / t
///t. m
. m : / t.
///t m
.m
s
tps : s
tps :
252
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 21
e rs
rs e rrss
oo
kNerve
ook e Disorders o k
ook
o
e o oo
o
/e/ebb Jeffrey A. Rihn, MD
e / e
/ b
e b
Jeremy Simon, MD
e / e
/
Melissa M. Guanche, MD b
e b
e t
///t. m
.m e t
///t. m
. m e
s: /
: s : /
:
tps
hhtttp tps
hhtttp
signals. Motor neurons transmit information from the
Introduction central nervous system to the skeletal muscle and
k eerss
The topic of nerve disorders is extensive and encom-
r k eer
passes a wide range of pathologies and diagnoses. Dis-s
r s
smooth muscle of the viscera. Sensory neurons transmit
the information from internal and external stimuli to
b ooook b oook
orders of the nervous system are commonly encoun-
o b o oo
the central nervous system. The neuron has three main
o
components: the cell body, the axon, and the dendrites.
/
e e
/ eb e/ e
/ e b
tered in the clinical setting across all orthopaedic
subspecialties. The diagnosis of such disorders can be
e ee/ e
/ e b
The dendrites receive information from other neuronal
: // t/.tm
challenging because many of the causes have similar
. m
symptoms and presentation. A thorough history and
: / / t
/ .
t m
axons or external stimuli, the cell body processes the
. m
signal, and the axon transmits the signal to other neu-
ss : / s : /
rons or end organs (skeletal muscle) through chemical
s
hhtttp hhtttp
physical examination, appropriate imaging studies,
tp
electrodiagnostic studies, and laboratory work can all
be helpful in reaching a diagnosis. Treatment options
vary widely according to the diagnosis. Some forms of
tp
or electrical synapses.
Myelin is a lipid-rich material produced by glial cells
(oligodendrocytes in the central nervous system and
neuropathy, such as Charcot-Marie-Tooth (CMT) dis- Schwann cells in the peripheral nervous system) that
ease and amyotrophic lateral sclerosis (ALS), are pro- surrounds axons, facilitates the rapid propagation of
the electric signal, and provides structural and meta-
k errss
gressive, with treatment focusing on preserving func-
e k
tion where possible and providing symptomatic relief.
e rrss
e
bolic support of the neuron.1 Regularly spaced inter-
bboooo k b o o
o o
Other forms of neuropathy, such as carpal tunnel syn-
k ruptions in the myelin sheath, called the nodes of Ran-
b o oo
o
vier, expose sodium-gated channels of the axonal
/
e e
/ e e / / e b
drome, are amenable to surgical treatment. The pur-
e
pose of this chapter is to provide an overview of the ba-
e ee/ e
/ e b
membrane that allow for salutatory conduction of ac-
tion potentials down the axon. The clinical effects of
t . m
sic anatomy of the nervous system and the evaluation
. m t . m.m
numerous disorders of the nervous system, including
s : /
: /
/ / t
and management of common nerve disorders that are
: / /
/ / t
multiple sclerosis and Guillain-Barré syndrome, are the
s :
tp s
encountered in orthopaedic practice.
hhtttp hhtttp s
result of axonal demyelination. Not all axons in the
tp
nervous system are myelinated.
Anatomy of the Nervous System Spinal Cord

The spinal cord is organized into tracts of axons that
At its most basic level, the nervous system is divided
carry information to and from the brain. It also contains
k ee s
into the central and peripheral nervous systems. The
rrs k e r
e
central nervous system consists of the brain and the spi- s
r sinterneurons that communicate signals to and from the
brain and the peripheral nerves and neurons that locally
bboooo k b o o
o o k
nal cord and functions to initiate, send, receive, and co-
ordinate signals that control bodily functions. The pe-
b o oo
control many of the body’s reflexes. When looking at a
o
/
e e
/ e ee/ e
/ e b
ripheral nervous system serves to transfer signals to and
e e
/ e b
cross section of the spinal cord, the peripheral white mat-
/
ter represents the myelinated axons of the motor and sen-
e
/ / t
/ t m
from the central nervous system. The basic functioning
. . m
unit of the nervous system is the neuron, a cell that
: : / / t
/ .
t m
. m
sory tracts, and the central gray matter represents the
ss : /
maintains an electrical gradient across its membrane
t p p t p ss : /
neuronal cell bodies and unmyelinated interneurons.2 In
general, motor information is carried from the brain
p
t
hht t
and transmits messages using depolarizing electrical
t
hht t
(motor cortex) down the spinal cord (efferent pathway),
and sensory information is carried from the periphery
(sensory receptors) up the spinal cord (afferent pathway).
Dr. Rihn or an immediate family member has received The corticospinal tracts (lateral and anterior) of the spi-
research or institutional support from DePuy and serves nal cord consist of axons of the upper motor neurons
k eerss
r k ee
ber of the North American Spine Society. Neither of thers
r s that originate largely in the contralateral motor cortex
of the brain.2 Through interneurons or direct synapse,
b ooookfollowing authors nor any immediate family member
b oook
o b oooo
these axons carry information to the lower motor neu-
rons, the cell bodies of which are housed in the anterior
/
e e
/ eb e / e
/e b
has received anything of value from or has stock or
stock options held in a commercial company or institu-
e ee/e/e b
or ventral horns of the spinal cord.3 The efferent axons
/ t
///t
chapter: Dr. Simon and Dr. Guanche.
: m
tion related directly or indirectly to the subject of this
. . m : / t.
///t m
of these lower motor neurons comprise the ventral root
.m
of the spinal cord that forms the spinal nerve.
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
k eers
rs k eers
r s
o
/
e e
/ eb Figure 1
e/
e e
/ e b
The cross-sectional anatomy of the spinal cord.
ACS = anterior corticospinal tract, ALS = antero-
lateral system, DC = dorsal column tracts, DH =
Figure 2
e / e
/ e b
The cross-sectional anatomy of a peripheral nerve
root. The box to the left depicts an unmyeli-
e
t . m
. m
dorsal (posterior) horn, DR = dorsal root, DRG =
: // / t : / / t
/ .
t m
nated fiber, and the box at the bottom depicts
. m
a myelinated fiber. (Reproduced from Lee SK,
ss /
dorsal root ganglion, LCS = lateral corticospinal
: ss : / Wolfe SW: Peripheral nerve injury and repair.
hhtttp hhtttp
trac, SN = spinal nerve, VH = ventral (anterior)
tp tp
J Am Acad Orthop Surg 2000;8[4]:243-252.)
horn, VR = ventral root.
The sensory tracts of the spinal cord are divided Nerve Injury and Healing
largely into the dorsal column tracts, which carry pro-
Peripheral nerve injury from direct compression and/or
rrss rrss
prioception and vibration information, and the antero-
trauma is frequently encountered in orthopaedics. The
o ke
ke o k
mation (spinothalamic tract).2 The axons of the dorsale
lateral system, which carry pain and temperature infor-
k e varying degrees of peripheral nerve injury have been

oo
e bboo o e b o o
column decussate via interneurons in the brainstem,
b o e b o
classified as neurapraxia, axonotmesis, and neurot-
b o
mesis.1-3,6 Neurapraxia represents the mildest form of
/
e / e m ee/ e
whereas the axons of the spinothalamic tract decussate
/
via interneurons in the spinal cord, approximately two
m ee/ / e
nerve injury, in which there is transient loss of nerve
t . . m t . m
function across the site of injury. Neurapraxia is typi-
.
s : : /
/ t
levels cranial to their entry.3 The cell bodies of the pri-
/ /
mary sensory neurons that contribute axons to both of
s : /
: /
/ / t
cally caused by a compression injury that results in fo-
glion (Figure 1).

hhtttp
tp s
these sensory tracts are housed in the dorsal root gan-
hhtttp
tp s
cal myelin damage but preservation of the axon.5 Re-
covery from this type of injury is typically complete by
6 to 8 weeks after the injury.6
Axonotmesis is defined by damage to the nerve fi-
Peripheral Nervous System bers (axons) but preservation of the supporting connec-
The peripheral nervous system is grossly divided into tive tissue structures of the nerve (endoneurium,
k eers
rs
the somatic (controls skeletal muscle) and autonomic
(controls visceral, smooth muscle function) nervous
k e r
e s
r s perineurium, and epineurium).6 This type of injury is
characterized by wallerian degeneration, or degenera-
bboooo k b o o
systems. A peripheral nerve consists of multiple neu-
o o k
ronal axons, or nerve fibers, bundled together and sur-
b o oo
tion of the portion of the axon distal to the injury. Re-
o
/
e e
/ e ee/ e
/ e b
rounded by connective tissue, a vascular supply, and
e / e
/ e b
covery from this type of injury is characterized by
spontaneous regeneration of the remaining axon along
e
/ / t .
t m
cellular components, including Schwann cells, fibro-
. m
blasts, and macrophages.4 The endoneurium is a layer
: / : / / t
/ .
t m
. m
the preserved pathway (intact neurolemma). Although
this process occurs slowly, at a rate of approximately 1
t p ss
p : /
of connective tissue that surrounds each axon and its
ss : /
mm per day, recovery of nerve function does occur.
t p p
t t
associated Schwann cells. The neurolemma, a thin layer
hht
between the myelin sheath and the endoneurium, is the
outermost layer of the Schwann cell.4 The axons are
t
hht t
Neurotmesis is the most severe type of nerve injury,
representing a complete transection of the nerve. This
type of injury results in complete loss of motor and sen-
bundled into fascicles contained within the perineu- sory function in the distribution of the involved nerve.
rium, which contributes significantly to the tensile In the absence of surgical repair, recovery of function
k eers
rs
strength of the nerve.5 The fascicles are bound together
k e
by the outer covering of the nerve, the epineurium. The
ers
r s
does not occur.6 Surgical repair of the nerve does in-
crease the chance of recovery; however, recovery even
b ooook b oook
epineurium is composed of connective tissue that func-
o
tions in protecting and supporting the fascicles.5 The
b ooo
with surgical repair is often incomplete. Early repair
o
may provide better results than delayed repair.7 For
/
e e
/ eb ee/ e
/e b
inner portion of the epineurium runs between the fasci-
/e/e b
larger nerves, a microsurgical approach with grouped
ee
/ t
///t
rounds the entire nerve5 (Figure 2).
: m
cles, and the outer portion forms a sheath that sur-
. . m / t.
///t m
fascicular repair, where an attempt is made to line up
.m
and repair the fascicles rather then just lining up the
:
s
tps : s
tps :
254
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 21: Nerve Disorders
k eers
rs keerrss
b ooook b o ook
o b o oo
o
/
ee/e b ee/ e
/ e b ee/ e
/ e b
: / t
///t. m
.m : / t
///t. m
. m
s
tps : s
tps :
hhtttp hhtttp
Figure 3 An EMG tracing depicting fibrillation potentials
seen as spontaneous (nonvoluntary) electrical
k eers
rs eers
r s
activity on the needle EMG. There are three dif-
ferent fibrillation potentials on the screen (A, B,
k
Figure 4 This EMG tracing demonstrates positive waves.
Like fibrillation potentials, these potentials are
ook ook
also spontaneous and a sign of denervation.
b oo
and C). The characteristics of fibrillations are
oo
their regularity, short duration (< 5 Hz), and low
b b o oo
They are also regularly firing, have a somewhat
o
/
e e
/ eb amplitude (< 1 mV).
e/
e e
/ e b ee/ e
/ e b
longer duration, and are characterized by an
initial downward (“positive”) deflection (arrow).
The clinical significance is the same as a
: // t/.tm
. m : / / t
/ .
t m
. m
fibrillation.
ss /
epineurium, may improve recovery, although this issue
: ss : /
hhtttp hhtttp
remains debatable.7 In smaller, more distal nerves, sim-
tp
ple repair of the epineurium has been shown to provide
similar results to grouped fascicular repair.8 tpparameters are used to determine abnormalities in the
F-wave response, but most commonly prolonged la-
tency.
Electrodiagnostics Electromyography
keerrss k e
Electrodiagnostics can be a useful tool in the evaluationrrss
e
This portion of the study involves placement of a nee-
dle into the muscle. The parameters assessed are resting
bboooo k b o o
o o k
of a patient with a suspected peripheral nerve disorder.
b o oo
membrane activity, recruitment, and motor unit analy-
o
/
e e
/ e e / / e b
The electrodiagnostic evaluation can assess and help lo-
e
calize abnormalities involving the anterior horn cell,
e ee/ e
/ e b
sis. A muscle at rest has little spontaneous electrical ac-
tivity. If an axonal lesion has occurred, characteristic
t . m
nerve root, plexus, peripheral nerve, neuromuscular
. m t . m m
findings of membrane instability called fibrillations and
.
s : /
: /
/ / t
junction, and muscle. The assessment is typically two-
: / /
/ / t
sharp waves will appear (Figures 3 and 4). The patient
s :
hhtttp
tp s
fold: a nerve conduction velocity study and needle elec-
tromyography (EMG). The timing of the study always
needs to be considered because nerve injuries may take hhtttp
tp s
will be asked to voluntarily contract the muscle, and
the recruitment pattern will then be assessed. If there is
a block in conduction or a significant axonal lesion, the
up to 3 weeks to be accurately assessed by electrodiag- normal number of motor units will not be activated,
nostics. and a pattern of decreased recruitment will be evident.
By recruiting the units by asking the patient to mini-
k ee s
Nerve Conduction Velocity Study
rrs
The nerve conduction velocity study involves generat-
k e r
e s
r s mally contract the muscle of interest, each unit’s size,
shape, and duration can be assessed. Abnormal appear-
bboooo k b o o
o o k
ing an electrical stimulus to a peripheral nerve and re-
b o oo
ances of these units may indicate a chronic process and
o
/
e e
/ e e / e
/ e b
cording the action potential. This is done for both the
sensory and the motor components of the nerve. Nor-
e e / e
/ e b
a pattern of reinnervation. These abnormal types of
motor units, with increased duration and multiple up
e
: / / t
/ .
t m
mal values are well described for amplitude, latency
. m
(time when depolarization begins), and conduction ve-
: / / t
/ .
t m
. m
and down deflections from the isoelectric baseline, indi-
cate incomplete remyelination and are referred to as
t p ss
p : /
locity.9 Aberrations in any of these parameters can be
t p ss : /
polyphasic motor units.
p
t
hht t
indicative of a problem with that nerve. Diffuse abnor-
malities are indicative of peripheral neuropathy. If the
abnormalities are in the distribution of a specific area
t
hht t The needle portion of the study is normally per-
formed in conjunction with the nerve conductions for a
complete study. It can help to more completely charac-
of the plexus, this indicates a plexopathy. Other studies terize the problem (axonal loss, chronicity versus acu-
that may be used in the nerve conduction workup for ity) and assess for disorders not able to be seen on the
k e rs
peripheral neuropathy are so-called late responses.
rs
These include the F-wave, which is a response gener-
e k eers
r s
nerve conduction velocity study, such as anterior horn
cell and myopathy. Typical needle EMG screening
b ooook b oook
ated in a motor nerve that will travel to the anterior
o
horn cell and fire back a response that is recorded at a
b ooo
involves five to six muscles with different nerve roots
o
and peripheral nerve supply. Abnormalities found in
/
e e
/ eb ee/ e
/e b
distal pickup. This motor-motor response is of lower
/e/e b
specific patterns are indicative of pathology involving
ee
/ t
///t m
amplitude (approximately 5% of the compound motor
. . m
action potential) and of longer latency. Several different
: / t.
///t m
that region. For example, abnormalities found in the
.m
deltoid (C5-6, axillary nerve), biceps (C5-6, musculocu-
:
s
tps : s
tps :
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp
hhtttp
k eers
rs keerrss Disorders Associated With Neuropathy
b ooook b o ook
o
Compression Neuropathy
b o oo
o
/
ee/e b ee/ e
/ e b e / e
/ e b
The most common forms of peripheral neuropathies
seen in orthopaedic practice are compression neuropa-
e
: / t
///t. m
.m / t
///t. m
thies. Compression may occur intraspinally (nerve root
. m
compression) or in the periphery and may lead to de-
:
s
tps : s
tps :
myelination, axonal loss, or both. Patients will often re-
hhtttp hhtttp
port sensory and/or motor deficits that will result in
dermatomal/myotomal patterns distal to the site of en-
trapment. Physical examination will often support the
symptom description, but in cases of severe pain or
communication barriers, the diagnosis may not be
k eers
rs k eers
r s
straightforward. In these cases, referral for electrodiag-
nostics may be critical in confirming or refuting the di-
b ooook b ooook agnosis.
b o oo
o
Common causes of intraspinal compression include
/
e e
/ eb Figure 5
e/
e e
/ e b
This tracing represents the compound motor ac-
tion potentials for a nerve below and above an
area of block. The first tracing (A1, top tracing)
ee/ e
/ e b
herniated nucleus pulposus or stenosis. Compression
secondary to epidural hematoma, abscess, lipomatosis,
: // t/.tm
. m
has a higher amplitude, and the duration of the
: / / t
/ .
t m
. m
or tumor may also occur. Entrapment and compression
ss /
response is short. The second tracing (A2, bot-
: s : /
neuropathies may occur in the upper and lower extrem-
s
hhtttp hhtttp
tom tracing) shows a lower amplitude, and du-
tp
ration is prolonged. This represents conduction
block and focal disruption of the myelin sheath.
tp
ities. These conditions often require surgical decom-
pression to prevent progression and, in many cases, to
allow for neural regeneration. A classic example in the
upper limb is carpal tunnel syndrome.12 The American
taneous nerve), pronator teres (C5-6, median nerve) Academy of Orthopaedic Surgeons (AAOS) clinical
and the cervical paraspinal nerves would indicate a C6 practice guidelines list early surgery without conserva-
keerrss radiculopathy.
k e rrss
e
tive treatment as an option in patients with axon loss,13
bboooo k Diagnosis
b o o
o o k thus highlighting the importance of categorization of
the median nerve injury.14
b o oo
o
/
e e
/ e / e e b
The type of injury may also be ascertained by which
ee /
parameters of the nerve conduction velocity study are
ee/ e
/ e b
In the lower limbs, common peroneal neuropathy
may occur with compression at the fibular head. It can
t . m
. m t . m.m
mimic a lumbar radiculopathy clinically and make for a
: /
: /
affected; if there is a decrease in amplitude across a spe-
/ / t
cific segment and enough time has been allowed for
s s : /
: /
/ / t
challenging diagnosis. Furthermore, common peroneal
hhtttp
tp s
wallerian degeneration, the pathology can be consid-
ered conduction block. Wallerian degeneration has
hhtttp
tp s
neuropathy may present atypically with involvement of
the superficial motor fibers and sparing of its sensory
fibers. Common peroneal neuropathy at the fibular
been reported to start at approximately 3 to 5 days fol-
lowing the appearance of an axonal lesion.10 A classic head is the most common mononeuropathy of the
example seen in orthopaedics would be an ulnar neu- lower limb. It can present atypically with selective in-
ropathy at the elbow (Figure 5). If a patient sustains an volvement of the superficial peroneal motor fibers and
k eers
rs injury at the cubital tunnel involving the ulnar nerve,
he or she may experience pain, numbness, and weak-
k e r
e s
r s sparing of the superficial peroneal sensory fibers.15
Compression of a peripheral nerve may lead to is-
bboooo k o o o k
ness in that distribution. If the electrodiagnostic study
b o b o oo
chemia secondary to disruption of the vasa nervorum,
o
/
e e
/ e e e
/ e b
is the day of injury, whether the lesion is predominantly
/
axonal or conduction block cannot be determined. It
e e e
/ e b
flattening/squeezing of the myelin, or crush injury to
/
the axons. Nerves may also be transected by projectiles
e
: / / / .
t m m
can take up to 3 weeks to find fibrillations in the most
t . : / / t
/ .
t m
. m
or severed with sharp objects. In these cases, regenera-
t p ss : /
distal muscles on the needle portion and for the distal
amplitudes to decrease in the nerve conduction velocity
p t p ss : /
tion is unlikely to occur, and referral for reconstruction
may be critical. Compression of the lower trunk of the
p
t
hht t
study.11 A repeat study would be recommended at
3 weeks from the onset of injury.
In general, slowing of conduction velocity, pro-
t
hht t
brachial plexus may occur via a Pancoast tumor from
growth at the apex of the lung.
Nerve conduction velocity studies in distal compres-
longed duration of the action potential, and prolonged sive neuropathy may reveal prolonged distal latency of
distal latency are indicative of a demyelinating process. the affected nerve, either sensory, motor, or both. Con-
k eers
rs After enough time has passed for wallerian degenera-
ee
tion, there will be a reduction in the proximal and dis-
k rs
r s duction velocity and duration may also be affected if
myelin dysfunction is present. Decreased amplitude of
b ooook b
indicates the condition is an axonal loss process.ook
tal compound muscle action potential amplitudes. This
oo b oooo
the distal response may reflect axonal damage. If the
amplitude is low above an area of compression but pre-
/
e e
/ eb / e
/e b
Table 1 shows the findings on nerve conduction ve-
ee ee/e/e b
served distally, this may indicate conduction block
nating nevropathies.
: / t
///t m
locity studies that are observed in axonal and demyeli-
. . m : / t.
///t m
across that segment. The needle EMG portion in the
.m
study of compression neuropathy can confirm axonal
s
tps : s
tps :
256
hhtttp
e t
///t. m
. m e t
///t. m
. m e
s : /
: s : /
:
tps
hhtttp tps
hhtttp
Chapter 21: Nerve Disorders
k eers
Table 1
rs keerrss
b ooook b ook
Common Findings on Nerve Conduction Velocity Studies
o o b o oo
o
/
ee/e b Nerve Injury Latency
ee/ e
/ e b Conduction Velocity Amplitudes
ee/ e
/ e b F-Wave Latency
Axonal
Demyelinating
Normal
: / t
///t
Prolonged. m
.m
Normal
Slow
: / ///t. m
Reduced
t . m
Normal or reduced
Normal
Absent or prolonged
s
tps : s
tps :
hhtttp
loss by the presence of fibrillations and/or sharp waves. hhtttp
Amyotrophic Lateral Sclerosis
The presence of polyphasia suggests that the lesion is Also known as Lou Gehrig disease, ALS is a rapidly
chronic and that a reinnervation process is occurring. A progressive neurodegenerative disease of the upper and
lower motor neurons that causes loss of voluntary mus-
k e s
decreased recruitment pattern may also be noted and
rrs e r
can be present in both conduction block as well as ax-
e k e s
r s cle control, respiratory failure, and ultimately death,
b ooook
onal lesions.
b ooook b o oo
typically within 3 to 5 years from the onset of symp-
o
toms. The disease typically presents in the fifth or sixth
/
e e
/ eb Neuropathies With a Genetic Basis
e/
e e
/ e b ee/ e
/ e b
decade of life and affects men more often than women.
Although most cases of ALS occur sporadically, genetic
CMT Disease
// t/.tm
. m
CMT disease refers to inherited peripheral neuropathy,
: : / / t
/ .
t m
. m
factors are thought to play a role in all cases of ALS,
ss : /
also referred to as hereditary motor and sensory neu-
s : /
and up to 10% of cases are attributed to inherited
s
hhtttp
tp hhtttp
tp
ropathy (HMSN). Since it was first described in late forms of the disease with familial history.20,21 Approxi-
1886, more than 50 genetic mutations have been found mately 20% of the familial cases of ALS are attributed
to cause various forms of CMT disease, with auto- to genetic mutations that affect the antioxidant enzyme
somal dominant, autosomal recessive, and X-linked in- superoxide dismutase 1 (SOD1).20,22 Pathologic transac-
heritance patterns. Although numerous forms of CMT tive response DNA binding protein, TDP-43, has re-
cently been implicated in sporadic ALS as well as famil-
rrss rrss
disease have been described with varying degrees of se-
ial forms of the disease that are not associated with a
o ke
ke o
vided into two groups based on nerve conduction ve- k e
verity and clinical presentation, it has been largely di-
k e SOD1 mutation.23 Pathologically, these deficits lead to
oo
e bboo olocity. CMT type 1 (HMSN I) is the result of
e b o
b o o e b
plasm of affected neurons.24o
the accumulation of abnormal protein within the cyto-
b o
/
e / e / / e
demyelination and has a nerve conduction velocity that
m ee
is slowed, whereas CMT type 2 (HMSN II) is the result
m ee/ / e
The diagnosis of ALS, particularly early in the dis-
t . . m t . .m
ease process, can be difficult, as other disease processes,
s : /
: /
/ / t
of axonal degeneration with a near-normal nerve con-
: / /
/ / t
including multiple sclerosis, stroke, and cervical spon-
s :
hhtttp
tp s
duction velocity.16 The classification of CMT disease
continues to be modified as more genetic information
becomes available. The two most common forms of
hhtttp
tp s
dylotic myeloradiculopathy, can mimic the early pre-
sentation of ALS. The hallmark of ALS is the involve-
ment of both upper and lower motor neurons. Upper
CMT disease are CMT1A and CMT1X.17 CMT1A has motor neuron findings include hyperreflexia, spasticity,
an autosomal dominant inheritance pattern and is ankle clonus, and positive Babinski and Hoffman signs.
caused by a mutation in the peripheral myelin protein Lower motor neuron findings include flaccid paralysis,
k e s
gene PMP-22 on chromosome 17 that is necessary for
rrs
appropriate myelin formation by Schwann cells.17,18
e k e r
e s
r s muscle atrophy, and fasciculations. The diagnosis of
ALS is suggested by these findings in the extremities
bboooo k
CMT1X is an X-linked form of CMT caused by a mu-
b o
tation in the gap junction protein β1 gene (GJB1),o
o o k b o oo
combined with dysarthria, dysphagia, and tongue atro-
o
/
e e
/ e ee/ e
/ e b
which is expressed in Schwann cells.19 These two forms
e / e
/ e b
phy and/or fasciculations attributable to cranial nerve
involvement. ALS is purely a disease of motor neurons
e
/ / t .

Lisa K. Cannada-Orthopaedic Knowledge Update 11-American Academy of Orthopaedic Surgeons (2014) PDF

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Lisa K. Cannada-Orthopaedic Knowledge Update 11-American Academy of Orthopaedic Surgeons (2014) PDF

Încărcat de

Drepturi de autor:

Formate disponibile

Orthopaedic

e bboo o Todd A. Milbrandt, MD

m ee/ / e mercial purpose.

bboooo k Lisa Claxton Moore, Managing Editor

b ooook Department of Orthopaedic Surgery

b ooook b ooook University

Department of Adult Joint Reconstruction GEORGE C. BABIS, MD, PHD

b oo Iowa City, Iowa

b ooook Omaha, Nebraska

b ooook University of Kentucky

MOHIT BHANDARI, MD, PHD, FRCSC

Professor and Academic Head MICHELLE S. CAIRD, MD

keerrss McMaster University

bboooo k Hamilton, Ontario, Canada

bboooo k CHRISTOPHER M. BONO, MD

RACHEL M. DEERING, MPH CYRIL B. FRANK, MD

KISHOR GANDHI, MD, MPH

keerrss Northwestern University Feinberg School

BRIAN T. FEELEY, MD ERIC GIZA, MD

b oo Department of Orthopaedic Surgery

b ooook KURT D. HANKENSON, DVM, MS, PHD

b ooook Columbia University

keerrss Baton Rouge, Louisiana

STEFANIE PEGGY KUHNEL, MD WILLIAM N. LEVINE, MD

b ooook University of Western Ontario

ISADOR H. LIEBERMAN, MD, MBA, FRCSC

keerrss Orlando Health Orthopedic Residency

ANTHONY C. LUKE, MD, MPH SAMIR MEHTA, MD

b ooook San Francisco, California

keerrss Associate Professor

bboooo k Chief, Sports Medicine and Shoulder Surgery

bboooo k Assistant Clinical Professor

b ooook MedStar Union Memorial Hospital

keerrss Professor of Orthopaedics

bboooo k BRAD PETRISOR, MSC, MD, FRCSC

Center VASILEIOS I. SAKELLARIOU, MD, PHD

b oo b oo Hospital for Special Surgery

b ooook Orthopedic Fellow

b ooook San Francisco, California

Spinal Deformity JEREMY SIMON, MD

keerrss Memphis, Tennessee

bboooo k MARA L. SCHENKER, MD

bboooo k ANDREW J. SCHOENFELD, MD

b ooook Department of Orthopaedic Surgery

bboooo k PETER TANG, MD, MPH

Department of Orthopaedic Surgery JENNIFER WEISS, MD

b ooook Seattle Children’s Hospital

keerrss media and multiple venues for education,

bboooo k including webinars, lectures, and even You

bboooo k other goal of this update was to ensure

American Academy of Orthopaedic Sur- I appeal to residents and young practitioners

b ooook SECTION EDITOR:

b ooook JONATHON K. SALAVA, MD

ANIMESH AGARWAL, MD . . . . . . . . . . . . . . . . 509 CHAPTER 46

k e e rrss KARL A. BERGMANN, MD . . . . . . . . . . . . . . . 659

bboooo k Mechanism Injuries

tive physicians after general surgeons, neurosurgeons,

b ooook of prescription drug abuse.28

keerrss physician’s personal morality. This conflict may poten-

son from tripping. Dr. Clarke pauses for a moment,

5. Pellegrino ED, Thomasma DC: The Virtues in Medical

kee s Instr Course Lect 2005;54:3-9.

r s Students. New York, NY, Norton & Company, 2009,