Use of Physical Forces in Bone Healing

Fred R. T. Nelson, MD, Carl T. Brighton, MD, PhD, James Ryaby, PhD, Bruce J. Simon, PhD,
Jason H. Nielson, MD, Dean G. Lorich, MD, Mark Bolander, MD, PhD, and John Seelig, MD

Abstract
During the past two decades, a number of physical modalities have been approved
for the management of nonunions and delayed unions. Implantable direct current
stimulation is effective in managing established nonunions of the extremities and
as an adjuvant in achieving spinal fusion. Pulsed electromagnetic fields and capacitive coupling induce fields through the soft tissue, resulting in low-magnitude voltage and currents at the fracture site. Pulsed electromagnetic fields may be as effective as surgery in managing extremity nonunions. Capacitive coupling appears
to be effective both in extremity nonunions and lumbar fusions. Low-intensity ultrasound has been used to speed normal fracture healing and manage delayed unions.
It has recently been approved for the management of nonunions. Despite the different mechanisms for stimulating bone healing, all signals result in increased intracellular calcium, thereby leading to bone formation.
J Am Acad Orthop Surg 2003;11:344-354

Nonunion has been defined as no

demonstrated change in healing on
serial radiographs over a 3-month period.1 Delayed union is defined as a
speed of fracture healing that is slower than anticipated, with no implied
expectancy of either eventual healing
or eventual nonunion. Of approximately 6 million extremity fractures
that occur annually in the United
States,2,3 between 5% and 10% result
in either nonunion or delayed
union.3 Assuming an average cost in
lost wages and additional medical
treatment for each of these cases of
$10,000, the annual economic loss is
$3 to $6 billion. In an attempt to minimize problems with fracture healing,
improved methods of internal and external fracture immobilization have
been combined with appropriately
timed early transmission of physiologic forces across the fracture sites.4
Additionally, a number of adjunctive
treatment options to stimulate normal
fracture healing, delayed unions, and
nonunions have been developed.5

344

These options include direct current

(DC), pulsed electromagnetic fields
(PEMFs), capacitive couplings, and
ultrasound.
Over the past two decades, an estimated 400,000 fracture nonunions,
delayed unions, and fusions have
been managed by physical fields. In
January 2000, the Society for Physical Regulation in Biology and Medicine sponsored a symposium to review the clinical applications and
mechanisms of action for these various modalities. The core material
from that symposium has been organized into a format to help clinicians
become more effective in and
knowledgeable about application of
these physical signals. Physicians
should be familiar with commonly
used terms and their definitions (Table 1) and appreciate the history of
the clinical use of these physical
forces. A thorough understanding of
the mechanisms of action, indications for use, and clinical outcomes
of commonly used devices that gen-

erate physical forces to influence

fracture healing is necessary for
their optimal clinical application
(Table 2).

Dr. Nelson is Director of Resident Education, Henry Ford Hospital, Detroit, MI. Dr. Brighton is Paul
B. Magnuson Professor Emeritus of Bone and Joint
Surgery, Department of Orthopaedic Surgery,
University of Pennsylvania, Philadelphia, PA. Dr.
Ryaby is Senior Vice President, OrthoLogic,
Tempe, AZ. Dr. Simon is Director of Research,
EBI, Parsippany, NJ. Dr. Nielson is Chief Resident, Department of Orthopaedic Surgery, Jacoby Medical Center, Bronx, NY. Dr. Lorich is Associate Director, Orthopaedic Trauma Surgery,
Hospitals for Special Surgery, New York, NY. Dr.
Bolander is Professor of Surgery, Mayo Clinic,
Rochester, MN. Dr. Seelig is Doctor of Neurosurgery, San Diego, CA.
None of the following authors or the departments
with which they are affiliated has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Nelson,
Dr. Nielson, Dr. Lorich, and Dr. Seelig. Dr.
Brighton or the department with which he is affiliated has received research or institutional support from Biolectron. Dr. Brighton or the department with which he is affiliated has received
royalties from Biolectron. Dr. Brighton or the department with which he is affiliated serves as a
consultant to or is an employee of Biolectron. Dr.
Ryaby or the department with which he is affiliated serves as a consultant to or is an employee
of OrthoLogic. Dr. Simon or the department with
which he is affiliated has stock or stock options
held in Biomet. Dr. Bolander or the department
with which he is affiliated has received research or
institutional support from Simth & Nephew and
Exogen.
Reprint requests: Dr. Nelson, K-12, 2799 W.
Grand Boulevard, Detroit, MI 48202.
Copyright 2003 by the American Academy of
Orthopaedic Surgeons.

Journal of the American Academy of Orthopaedic Surgeons

Fred R. T. Nelson, MD, et al

Table 1
Terms and Definitions
Term

Definition

Physical forces

Include any mechanical, electrical, or sonic force applied to an area of bone fracture healing. This is in distinction from biochemical osteoinductive therapies.
Involves an implanted cathode placed in the area of expected bone stimulation and a
battery-based anode placed subcutaneously. A constant 20-A direct current is delivered.
Use magnetic coils that receive a specific pulsed electrical current that results in a magnetic flux density 0.1 to 18 G in the form of a pulse train with a 15-Hz or sinusoidal
76-Hz frequency. A pulse train is a rapid sequence, typically of twenty 220-sec repeating spikes. A gauss (G) is a unit of electromagnetic flux. (The earths geomagnetic field
is approximately 0.6 G.)
Requires two surface electrodes placed on the skin across a fracture site. A 60-kHz sinusoidal wave signal is generated by a 9-V battery; this results in an internal field of 0.1
to 20 mV/cm and a current density of 300 A/cm2 that is not felt by the patient.

Direct electrical stimulation

Pulsed electromagnetic
fields (PEMFs)

Capacitive coupling

History of Development of
Physical Fields
In 1841, Hartshorne6 described a case
of fracture nonunion that was treated with shocks of electric fluid
passed daily through the space between the ends of the bone. Lente7
in 1850 described three cases of delayed unions or nonunions treated
with galvanic current. More than 100
years later, electrical stimulation of
bone regained clinical scientific prominence when Fukada and Yasuda8 described piezoelectric potentials

generated by mechanical stress on the

crystalline structure of bone. At the
same time, ultrasound began to show
promise as a method of stimulating
fracture healing. In 1953, Corradi
used continuous wave ultrasound to
stimulate fracture healing, producing
an increase in periosteal callus.9
A central hypothesis in the application of physical forces is that straingenerated electrical potentials may be
a regulatory signal for cellular processes of bone formation. The idea
that electrical fields might be important in the repair process was de-

scribed in the early 1960s by Bassett

and Becker.10 AFourier transform was
used to break down the electromagnetic signal into its major and minor
components to predict the biologically important rate of generation of
electric potentials in bone by mechanical stress.10 This was used as the basis for selecting one of the currently
used PEMFs. Additional knowledge
of the nature of endogenous electric
fields in biology led to the development of the direct electric fields now
in use.11 Subsequently there was further development of PEMFs as well

Table 2
Devices That Generate Physical Forces
Device

Wave Form

Tissue Electrical Field

Direct current
Pulsed electromagnetic
field
Capacitive coupling

20 A
4.5-mseclong bursts of twenty 220-sec
18-G pulses repeated at 15 Hz
60 kHz, 10 A (rms), 6 V peak to peak
delivered by 9-V battery
790-mG field of a burst of twenty-one
260-sec pulses with repetition rate of 15 Hz
76.6-Hz sinusoidal 40-T (400 mG) peak-topeak AC magnetic field superimposed on
20-T DC magnetic field
Sinusoidal

As delivered
1.5 mV/cm; 10 A/cm2

Pulsed electromagnetic
field, modified
Combined magnetic field

Ultrasound

0.1 to 20 mV/cm and

300 A/cm2 at 60 kHz
4 mV/cm peak to peak
Magnetic field effect, not
induced field
N/A

rms = root-mean-square

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345

Use of Physical Forces in Bone Healing

as combined (DC and AC) magnetic

fields.
Arabbit fibular fracture model was
used to define the dose-response
curve for capacitive coupling in fracture healing. An internal field of 220
mV with a current density of 250 A
was the most effective for induction
of healing.12 The effects of ultrasound
on fracture callus stimulation were
studied by numerous investigators
using a variety of animal models.9
Pilla et al13 found that brief periods
(20 min/day) of pulsed ultrasound (a
200-sec burst of 1.5-MHz sinusoidal
waves repeated at 1 kHz) at a low intensity (30 mW/cm2) accelerated the
recovery of torsional strength and
stiffness in a midshaft fibular osteotomy of the rabbit.
Although most human clinical
studies conducted during the development of these devices were retrospective, prospective controlled studies now exist. However, most of these
record only the presence or absence
of healing as an end point. Outcomes
such as return to work or specific activities have not been reported but are
important for assessing the role of
these devices compared with alternative techniques to stimulate fracture
repair. Revascularization, as in core
decompression for osteonecrosis of
the femoral head, and stimulation of
articular cartilage repair in osteoarthritis are potential new applications
for these methodologies that are currently under investigation.

Direct Current
Basic Science
In 1981, Brighton et al11 showed
that with direct electrical stimulation,
the pO2 is lowered and pH raised in
the vicinity of the cathode. A low
pO2 is favorable to bone formation;
Brighton et al11 found lower pO2 at
the bone-cartilage junction of the
growth plate and in newly formed
bone and cartilage in fracture callus.
Among the cellular mechanisms of

346

electric currentinduced osteogenesis

are increased proteoglycan and collagen synthesis14 (Table 3).

Clinical Data
After the initial clinical demonstration of fracture healing in 1971 by
Friedenberg et al,57 Brighton et al22 in
1977 reported the use of DC by percutaneous wire placement for tibial
nonunions that had been present for
an average of 3.3 years. Treated with
a field of 10 to 20 A over 12 weeks,
39 of 57 nonunions healed. Based on
this study and animal models, 20 A
was determined to be the preferred
current. In 1981, Brighton et al11 reported on 178 nonunions managed
with 4 percutaneously inserted cathodes, each delivering a 20-A DC, resulting in 149 successful unions. Success rates were 83.3% for tibial
nonunions, 66.7% for clavicular
nonunions, and 61.5% for humeral
nonunions. The presence of a synovial-lined pseudarthrosis prevented
healing.
Current Indications
In 1979, the Food and Drug Administration (FDA) approved the use
of DC in established nonunions. (An

established nonunion is one that

shows no visible progressive signs of
healing. The FDAs original definition
stipulated no visible signs of healing
for at least 3 months after at least 9
months since injury.) Originally the
anode was placed on the skin, with
a battery pack worn at the waist. Implantable batteries acting as anodes
were later developed to deliver a consistent 20-A current. The cathode
now can be wrapped in a spiral and
shaped to match the area of interest.
In contrast with surface induction,
implanted DC stimulation eliminates
the problem of patient compliance
when used in conjunction with a surgical procedure for internal fixation
or bone grafting. Direct electrical
stimulation also has been approved
by the FDA for use in spinal fusion.
An open exposure is required, and the
battery/anode is removed 6 months
after implantation.

Pulsed Electromagnetic
Fields
Basic Science
The PEMF signal was developed
to induce electrical fields in bone sim-

Table 3
Physical Forces in Bone Healing: Mechanisms of Action
Device (Clinical Studies)

Mechanism*

Direct current11-14

O2,11,14 synthesis collagen and proteoglycan11

Cytokines12,13,21-25

Pulsed electromagnetic
field (PEMF)15-20
Capacitive
coupling26-28
Modified PEMF31,32
Combined magnetic
field15,34

Bone cell proliferation,29 activate voltage-gated

calcium channels, PGE2, cytosolic calcium,

activated calmodulin,26 mRNA TGF-30
Vascular ingrowth, osteoblast migration, matrix
calcification33
Ion transport across cell membranes and ion
dependent cell signaling in tissues,35-37

growth cytokines38-47
Ultrasound9,48-51

Influx and efflux of K+,52 cartilage bone Ca++,53

adenylate cyclase activity,54 TGF-,54 PGE2,55

aggrecan and vascularity,9 PDGF-AB56
* Increases, stimulates, or activates

Journal of the American Academy of Orthopaedic Surgeons

Fred R. T. Nelson, MD, et al

ilar in magnitude and time course to

the endogenous electrical fields produced in response to strain. These
fields are thought to underlie the ability of bone to respond to a changing
mechanical environment, as described by Wolffs law. The signal consists of 4.5-mseclong bursts of twenty 220-sec 18-G pulses repeated at
15 Hz. This results in a time-varying
extracellular and intracellular electrical field.
Research with PEMFs has focused
on regulation of messenger RNA
(mRNA) and protein synthesis of the
transforming growth factor-beta
(TGF-)/bone morphogenetic protein
(BMP) gene family because these cytokines have been shown to modulate cellular activity of osteochondral
progenitor cells, chondrocytes, and
osteoblasts. In many animal studies
and recently in human clinical trials,
TGF-, BMP-2, and BMP-7 have been
shown to enhance fracture repair. In
an endochondral ossification model
using demineralized bone matrixinduced osteogenesis, PEMF treatment
caused an increase in chondrogenesis concomitant with an up-regulation
of TGF-.23 A several-fold increase in
BMP-2 and BMP-4 mRNA occurred
in chick calvarial osteoblasts in vivo
after 15 days of stimulation with this
same signal.58 In a rat calvarial osteoblast culture, 1 hour of stimulation resulted in a threefold increase in
BMP-2 mRNA and a sixfold increase
in BMP-4 mRNA.59
Two recent studies describe the effects of PEMF on TGF production.25,60 In one,25 confluent cultures
of MG63 human osteoblast-like cells
were stimulated for 8 hours a day for
4 days and showed a significant (P <
0.05) increase in TGF levels in stimulated versus control cells after 1 and
2 days of stimulation. PEMF enhances differentiation of MG63 cells, as evidenced by decreased proliferation
and increased alkaline phosphatase
activity and osteocalcin and collagen
production. These results support
earlier observations in the endochon-

Vol 11, No 5, September/October 2003

dral bone model that PEMF stimulation increases chondrogenesis by

enhancing differentiation of osteochondral precursor cells into a chondrogenic lineage without affecting
proliferation.24 In a second study,60
nonunion cells derived from patients
undergoing surgery were successfully cultured, and PEMF stimulation of
these cells resulted in significant (P
< 0.05) increases in TGF- production
compared with nonstimulated control cells.16 Cells derived from hypertrophic nonunion tissue were more
responsive than cells derived from
atrophic tissue, a result that supports
the clinical observation that patients
with hypertrophic nonunions respond more favorably to electromagnetic stimulation than do patients
with atrophic nonunions.

Clinical Data
More than 250 published basic research and clinical investigations
have evaluated the efficacy of PEMF
stimulation.21 In 1990, Sharrard reported a double-blind trial of delayed
unions in 45 tibial shaft fractures
managed by plaster cast, with active
PEMF units (n = 20) or identical dummy control units (n = 25) for a period
of 12 weeks.19 Nine of 20 fractures
(45%) in the active group healed,
compared with 3 of 25 fractures (12%)
in the control group (P < 0.01).19 Bassett et al61 reported on a series of 127
diaphyseal tibia nonunions treated
with PEMFs that yielded an overall
success rate of 87%. A year later, Bassett et al62 reported the results of
PEMF treatment with surgery and
bone grafting in 83 nonunions with
wide fracture gaps, synovial pseudarthrosis, and malalignment. These patients achieved an 87% success rate.
In a broad literature review comparing PEMF treatment of nonunions
with surgical therapy, Gossling et
al16 noted that 81% of reported cases
healed with PEMF versus 82% with
surgery. Also, the success of surgical
treatment for infected nonunions was
69%, whereas 81% of the PEMF-

treated group healed.16 In open fractures, surgical healing exceeded

PEMF (89% and 78%, respectively),
but in closed injuries, PEMFmanaged fractures healed more frequently than did surgically treated
fractures (85% and 79%, respectively). This study indicates the efficacy
of PEMF treatment to be comparable
to that of surgical intervention for
fracture nonunion.
PEMF treatment has applications
in the upper extremity, as well. Frykman et al17 reported that 35 of 44
scaphoid nonunions (80%) were managed successfully by PEMFs with cast
immobilization. However, in a continuation of that study published 6
years later, the overall success rate
had decreased to 69% because of
breakdown of some of the fractures
originally reported as unions. Proximal pole fractures healed in 50%.63
The daily dosage of PEMF treatment is important in the healing process. A dose-response study demonstrated that an increase in daily
treatment time correlates with a reduction in the time to healing of nonunion fractures.18 Patients treated for
10 hours per day healed an average
of 76 days earlier than did those treated fewer than 3 hours per day.

Current Indications
PEMF treatment is recommended
as an adjunct to standard fracture
management. Indications for use include nonunions, failed fusions, and
congenital pseudarthrosis. Recently,
the definition of a nonunion has been
modified to failure to exhibit visibly
progressive signs of healing.64 This
definition thus permits all forms of
electrical stimulation intervention to
take place earlier in the treatment
than previously and removes controversy regarding when a delayed
union may be considered a nonunion.
Generally, a fracture gap >5 mm,
suspected or documented synovial
pseudarthrosis, and severe devascularization are contraindications for
the use of PEMFs. Patients typically

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Use of Physical Forces in Bone Healing

are treated for 3 to 9 months depending on fracture location, severity, and

time from injury. Some difficult fractures may require management for
longer periods. The fracture should
progress to healing within 3 to 6
months. If surgery is needed, some
patients choose to continue use of the
stimulator to enhance healing after
surgery.

coupling is different from inductive

coupling of a combined DC and
pulsed electromagnetic field, there
appears to be a common pathway.65
In addition, Zhuang et al30 demonstrated that an appropriate capacitively coupled electrical field increased levels of mRNA for TGF-1
in osteoblastic cells by a mechanism
involving the calcium/calmodulin
pathway.

Capacitive Coupling

Clinical Data
In a prospective, nonrandomized
multicenter study comparing patients
with 17 recalcitrant nonunions (who
had undergone prior surgery or electrical stimulation) with 5 who had
routine nonunions (no previous treatment), Brighton and Pollack1 reported a mean healing rate of 77.3% with
capacitive coupling after a mean of
22.5 weeks. Brighton et al66 used logistic regression analysis in a retrospective study of the healing rate of
271 tibial nonunions treated by DC,
capacitive coupling, or bone graft.
The authors identified seven risk factors that adversely affected the healing rate of nonunions managed with
capacitive coupling: duration of nonunion, prior bone graft surgery, prior electrical stimulation, open fracture, osteomyelitis, comminuted or
oblique fracture, and atrophic nonunion. With no or one risk factor
present, there were no significant differences among the three treatment
methods (96% to 99%). With the presence of two to five risk factors, capacitive coupling yielded poorer results
in managing atrophic nonunion; otherwise, results were similar regardless of treatment modality. With six
or seven risk factors, all three forms
of treatment provided poor results.
Unfortunately, this study did not
evaluate smoking as a possible risk
factor.
Scott and King27 reported the results of a small, prospective doubleblind study using capacitive coupling
in the management of established
nonunions. They found a statistical-

Basic Science
Use of capacitive coupling for fracture healing stimulation involves the
application of two surface electrodes
placed on the skin with the fracture
between the electrodes. The induced
field is driven by an oscillating electric current, as opposed to the electromagnetic field induction of PEMF.
In an in vitro rat calvarial bone cell
model, Brighton et al29 found that
field strength was the dominant factor affecting bone cell proliferative response to a capacitive coupled field.
Field strengths calculated at 0.1 to 20
mV/cm (60 kHz and 300 A/cm2),
with various pulse configurations as
well as continuous signals, are effective in stimulating bone cell proliferation.29 The clinical effect of electrically induced osteogenesis is easily
recognized. However, the basic physiology of how electrical signals stimulate bone is more difficult to demonstrate in the laboratory. Using
various metabolic inhibitors, Lorich
et al26 showed that signal transduction in capacitive coupling stimulation activated voltage-gated calcium
channels, leading to increases in prostaglandin E2 (PGE2), cytosolic calcium, and activated calmodulin. This
is in contrast to signal transduction
of indirect coupling and combined
magnetic fields (CMFs), in which the
cytolsolic calcium is secondary to release of calcium from intracellular
stores. This leads to an increase in activated calmodulin. Although the initial signal transduction of capacitive

348

ly significant association between the

use of capacitive coupling and eventual union. Six of the 10 nonunions
in the actively managed group
healed, compared with none of the 11
in the placebo group (P = 0.004). There
also have been two double-blind prospective lumbar fusion studies using
capacitive coupling. Goodwin et al28
studied 179 patients randomized into
groups assigned active or nonactive
coils after lumbar fusion. The authors
reported a statistically significant (P
= 0.0043) increased rate of fusion in
the active group (84.7%) compared
with the placebo group (64.9%). Posterolateral bone graft combined with
concurrent instrumentation of the affected levels had a higher rate of fusion than did graft without instrumentation. Within the instrumented
group, stimulated patients showed
higher fusion rates than did the placebo control subjects.

Current Indications
Capacitive coupling is indicated
for nonunions of long bones and the
scaphoid and as an adjunct treatment
in spinal fusions. In applying capacitive coupling, cast immobilization
typically is used. Two small windows
are cut out for the application of the
electrodes, which are positioned
across the approximate site of the
fracture and moistened before application. When the pads dry, the monitor detects the loss of contact and sets
off an alarm, indicating that the pads
need to be remoistened. Currently
available electrodes last up to 1 week
without requiring reapplication of
gel. The pads are worn 24 hours a day
and are changed weekly, or more often as required for hygiene. The device uses a 9-V battery that should be
replaced daily. Skin reaction is usually mild. If necessary, electrodes can
be moved to a new skin site. Treatment is discontinued if there is severe
skin reaction. Serial anteroposterior,
lateral, and oblique radiographs are
used to monitor progression of healing, as in normal fracture manage-

Journal of the American Academy of Orthopaedic Surgeons

Fred R. T. Nelson, MD, et al

ment. Device usage is typically 25

weeks and is discontinued when the
fracture heals or after 3 months of no
progression in healing.

Pulsed Electromagnetic
Field, Modified
Basic Science
A modified PEMF was developed
to reduce energy requirements. It delivers an average 790-mG field of a
burst of twenty-one 260-sec pulses
repeated at 15 Hz. The devices are
horseshoe-shaped, flattened solenoids; some use a saddle-shaped coil.
There are several suggested mechanisms of action. Using the original
PEMF signal (also with a repetition
rate of 15 Hz), Yen-Patton et al33
showed that this modified PEMF increased the number of vessels, or
sprouting, in endothelial tissue by
a factor of 10 to 15. The neovascularization occurs in vitro after 5 to 8
hours of stimulation. The authors also
noted increased migration of osteoblasts and an enhanced mineralization of new fibrocartilage.33 A different field was developed for the spine,
delivered by dual coils that encompass the entire lumbar area. This is a
160-mG field of ninety-nine 260-sec
pulses.
Clinical Data
Amulticenter open trial of the modified PEMF device was conducted
with 139 patients who had one or more
fractures that had not healed for at
least 9 months (some >5 years).31 The
lengthy time of nonunion served as
the baseline because spontaneous fracture healing was unlikely to occur. The
only intervention applied was the addition of PEMF therapy prescribed for
8 hours a day for at least 90 days. Fracture healing was judged by four criteria: cortical bone bridging and absence of motion on stress radiographs,
no or minimal pain, no or minimal
edema, and no need for casting. On
completion of the course of treatment,

Vol 11, No 5, September/October 2003

patients who wore the device for at

least 3 hours a day for a minimum of
90 days had a significantly (P < 0.05)
better healing rate than did patients
who complied to a lesser degree with
the treatment regimen (80% versus
19.2%). There was no significant difference in fracture healing rate for the
average wear times of 3 to 6 hours, 6
to 9 hours, and >9 hours. Healing occurred in the presence of fracture gaps
6 mm whether the patient was a
smoker or had comminution, an open
fracture, prior infection, or multiple
surgical procedures. Long-term followup 4 years later revealed essentially
the same healing rate with no longterm adverse effects.
Mooney32 reported the results of
a prospective, multicenter, randomized, placebo-controlled clinical trial
of PEMF stimulation for lumbar spine
fusion. One hundred ninety-five patients underwent interbody fusion (anterior and posterior approaches). (Interbody fusions are easier to evaluate
than posterolateral fusions.) Spine fixation was by hook and rod, predating the use of pedicle screws. Patients
were prescribed the device for a total of 8 hours a day for a minimum
of 90 days or until healed. An analysis of usage versus fusion success
demonstrated that a dosage of only
4 hours a day for 90 days was enough
to significantly (P = 0.005) increase fusion rates. Consistent use at this level resulted in an overall fusion rate
of 92% in the PEMF group compared
with 64.9% in the placebo group. In
a second phase of this study, 126 patients with a failed fusion who were
at least 9 months from prior surgery
were given an active device to use for
8 hours a day for at least 90 days. No
additional surgery was done. The
study included both interbody and
posterolateral fusions at one or more
levels. Of patients who wore the device for at least 2 hours, 67% achieved
solid fusion.32 In a historical cohort
study of 42 patients treated with PEMF
stimulation and 19 nonstimulated patients, Marks67 found that the rate of

fusion enhancement (97.6% and 52.6%,

respectively) was statistically significant (P < 0.001).

Current Indications
The use of modified PEMF devices is indicated for fracture nonunions
that demonstrate no radiographic evidence of progression of bony healing. The recommended dose is 3
hours of daily usage until healing occurs, typically 3 to 6 months. Use of
the Spinal-Stim (Orthofix, McKinney,
TX) is indicated as an adjunct to spinal fusion surgery to increase the
probability of fusion success and as
a nonsurgical treatment to salvage a
failed spinal fusion. The recommended dose is at least 2 hours a day until
the patient is healed, typically 3 to 9
months.

Combined Magnetic Fields

Basic Science
The scientific basis of CMFs is
predicated on theoretic physics confirmed by experimental demonstrations that combinations of dynamic
and static magnetic fields affect ion
transport across cell membranes and
affect ion-dependent cell signaling
in tissues.35-37 Specifically, combined
AC and DC magnetic fields are predicted to couple to calcium-dependent and magnesium-dependent
cellular signaling processes in tissues.
Cellular studies of CMFs have addressed effects on both signal transduction pathways and growth factor
production. The resulting working
model from the studies of Fitzsimmons and colleagues38-40 is the
proposal that short-duration CMF
stimulus of 30 minutes activates secretion of growth factors (eg, insulinlike growth factor-II [IGF-II]). The
clinical benefit on bone repair is the
result of this up-regulation of growth
factor production, with the short-term
(30-minute) CMF stimulus acting as
a triggering mechanism that couples

349

Use of Physical Forces in Bone Healing

to the normal molecular regulation of

bone repair mediated by growth factors. The studies underlying this
working model have shown effects of
CMFs on calcium ion transport38 and
cell proliferation.39 In 1995, Fitzsimmons and colleagues40,41 reported
IGF-II release and increased IGF-II receptor expression in osteoblasts. Effects of CMFs on IGF-I and IGF-II in
rat fracture callus were reported by
Ryaby et al.42 Recent studies have
shown effects of CMFs on experimental fracture healing43,44 and on osteopenic animal models,45,46 possibly
mediated by attenuation of tumor necrosis factor dependent signaling
in osteoblasts.47 However provocative, the role of growth factors in
transduction of CMFs in cells and tissues, and the link to the observed clinical benefit of CMFs, require further
investigation.

Clinical Data
In a prospective, randomized pilot study of patients with acute, phase
1 Charcot neuroarthropathy, 10 control subjects and 11 patients treated
with CMFs were followed weekly
and treated until the difference in
temperature between the two feet
was less than 2C, foot volumes were
within 10% of each other, and fracture consolidation had occurred.68
Subsequently, 10 more patients were
added to the CMF-treatment group.
Results showed that the mean time
to consolidation in the control group
was 23.2 7.7 weeks. In contrast,
treatment with the CMF device decreased time to consolidation to 11.1
3.2 weeks (P < 0.001). There was no
statistically significant difference in
entry criteria between the control and
CMF groups.
The most recent application of
CMFs has been as an adjunctive stimulation device for spinal fusion.69 A
prospective, randomized, doubleblind, placebo-controlled trial was
conducted on primary uninstrumented lumbar spine fusion. Patients had
one- or two-level fusions (between L3

350

and S1) with either autograft alone or

in combination with allograft. The
CMF device configured for spinal fusion has a single posterior coil centered over the fusion site. Treatment
was applied for 30 minutes a day for
9 months. The primary end point was
assessment of fusion at 9 months,
based on radiographic evaluation by
a blinded panel consisting of the treating physician, a musculoskeletal radiologist, and a spine surgeon. This
panel evaluation differed from those
of other spinal fusion studies with
noninvasive bone growth stimulators
in that the treating surgeons assessment of fusion could be overruled by
the blinded panel. Of the 243 patients
enrolled, 201 were available for evaluation. Of the patients with active devices, 64% healed at 9 months; only
43% of placebo-device patients healed
(P = 0.003 by Fishers exact test).
Among female patients, 67% of those
with active devices achieved fusion
compared with 35% of those with
placebo devices (P = 0.001 by Fishers
exact test). Of the 201 patients,
repeated-measures analyses of fusion
outcomes showed a main effect of
treatment favoring the active treatment (P = 0.030) in a model with only
a main effect. In a model with main
effect and a time-by-treatment interaction, the time-by-treatment interaction was significant (P = 0.024), indicating acceleration of healing. The
investigators concluded that the adjunctive use of the CMF device for
noninstrumented fusions results in
higher fusion rates and in earlier fusions. This was the first randomized
clinical trial of noninstrumented primary posterolateral lumbar spine fusion with evaluation by a blinded, unbiased panel. The fusion rates in this
study were lower than those of other
noninstrumented studies reported in
the literature. The lower success rates
are thought to be because of the highrisk patient group (average age, 57
years) coupled with the use of noninstrumented technique with posterolateral fusion only.

Current Indications
Application of CMFs for 30 minutes a day has been shown to be effective for management of nonunions
and as adjunctive stimulation for primary spinal fusion. Future indications
for CMFs may include osteoarthritis
and neuroarthropathy, but adoption
of additional applications will require
increased knowledge of the tissuelevel mechanisms combined with welldesigned clinical trials.

Ultrasound
Basic Science
Azuma et al70 confirmed the increased efficiency of the 200-sec
burst (versus 100-sec and 400-sec
bursts) of 1.5-MHz sinusoidal waves
repeated at 1 kHz (versus 2 kHz) at
a low intensity of 30 mW/cm2. Additional animal data suggest that the
biology of fracture healing can be accelerated by the use of ultrasound but
that no specific stage of healing is
more sensitive than another.70 There
is a wide range of proposed mechanisms by which low-intensity ultrasound stimulates fracture healing.9
Minimal heating effect (well below
1C) may increase some enzymes,
such as matrix metalloproteinase 1
(interstitial collagenase), which are
exquisitely sensitive to small variations in temperature.71 Ultrasound
has been shown to change the rate of
influx and efflux of potassium ions,
increase calcium incorporation in
both differentiating cartilage and
bone cell cultures, and increase second messenger activity paralleled by
the modulation of adenylate cyclase
activity and TGF- synthesis in osteoblastic cells.52 In primary chondrocytes, the application of ultrasound
at 50 mW/cm2 increased release of
cellular calcium.53 Increased PGE2
production via the induction of
cyclooxygenase-2 mRNA occurs in
mouse osteoblasts in a manner similar to that which is effected by fluid
shear stress and tensile force stimu-

Journal of the American Academy of Orthopaedic Surgeons

Fred R. T. Nelson, MD, et al

li.55 Ultrasound has been shown to increase the expression of genes involved in the inflammation and
remodeling stages of fracture repair.
Low-intensity ultrasound stimulates
an up-regulation of aggrecan gene expression in cultured chondrocytes
and stimulates proteoglycan synthesis in rat chondrocytes by increasing
aggrecan gene expression.72 This
might explain the role of ultrasound
in augmenting endochondral ossification and thus increasing the mechanical strength and overall repair
of the fractured bone. Given the effect of low-intensity ultrasound on
hundreds of genes working in a complex biologic system to achieve the
healing response, it would likely be
misleading to overemphasize the impact of a single gene. Low-intensity
ultrasound treatment over a 10-day
period stimulated a greater degree of
vascularity in an osteotomized dog
ulna model of fracture healing.73 It is
generally believed that greater blood
flow serves as a principal factor in the
acceleration of fracture healing. Indeed, one of the main biologic goals
of the inflammatory response is to reestablish the blood supply to the injured area.

Clinical Data
The initial clinical trials for ultrasound were focused on reduction of
healing time. A randomized, doubleblind, placebo-controlled study of 67
closed or grade 1 open tibial fractures
using ultrasound treatment of 20 minutes a day at 30 mW/cm2 led to a significant (P < 0.01) 24% reduction in
the time of clinical healing (86 5.8
days in the active-treatment group
compared with 114 10.4 days in the
control group).48 Using both clinical
and radiographic criteria, a 38% decrease in the time to overall healing
was apparent. Twelve of 34 placebotreated patients (35%) developed delayed union, whereas only 2 of 33
ultrasound-treated patients (6%) had
delayed union (P < 0.01). In another
multicenter, prospective, randomized,

Vol 11, No 5, September/October 2003

double-blind, placebo-controlled clinical trial of 61 dorsally angulated fractures of the distal radius, the mean
time to union was significantly (P <
0.0001) reduced by 38% for ultrasound-treated patients (61 3 days)
compared with placebo-treated patients
(98 5 days).49 Ultrasound treatment
resulted in a significantly (P < 0.01)
smaller loss of reduction (20 6%) compared with placebo (43 8%).49 Other
successful clinical trials have demonstrated reduction of healing time with
ultrasound, including leg-lengthening
procedures.9 Ultrasound treatment of
nonunions resulted in an 85% healing rate in 385 nonunions, with a mean
healing time of 14 months.9
Ultrasound is not effective in all
settings requiring bone healing (ie,
tibial fractures stabilized with intramedullary fixation). Other clinical
studies have demonstrated enhanced
rate of fracture healing in smokers,
patients with diabetes, and patients
with renal insufficiency or who are using steroids.

Current Indications
In October 1994, low-intensity ultrasound was approved for the stimulation of healing of fresh fractures.
In February 2000, approval was extended to the treatment of established
nonunions. The device requires a daily 20-minute application of the ultrasound head on the skin through a window in the immobilization device. The
device is not portable; it must be attached to a wall power source while
in use. With the depth of penetration
at 3.5 cm, the device must be close to
the bone to be effective.

Clinical Management
In the management of nonunions
with physical fields, the degree of immobilization required for patient
comfort is usually similar to that for
gradual healing without stimulation.
Nonunions should be adequately stabilized and have good healing poten-

tial (adequate soft-tissue coverage

and evidence of a good blood supply). The presence of a synovial
pseudarthrosis (articular-like surface)
is a contraindication for all physical
stimulation devices. A fracture with
palpable motion is generally immobilized a joint above and below; however, some humeral, forearm, and leg
fractures may be more effectively immobilized in a fracture brace. Delayed
unions and nonunions that are malaligned require surgical correction before healing can occur. Weight bearing is determined by the same criteria
as those used for nonstimulated management of a slow-healing fracture.
If physical stimulation is to be used
after internal fixation and/or grafting
of a nonunion, postoperative management is generally the same as for
cases in which no external stimulation is used. The cost effectiveness of
any fracture stimulation device depends on knowing which fractures respond best, the requirements for fixation or grafting, and the patients
employment, personal, and social circumstances.

Summary
Physical stimulation in the form of
electrical fields and ultrasound is
important in orthopaedic applications, including for nonunions and
spinal fusions. The common effect of
these forces appears to be an increase in intracellular calcium by a
variety of cellular mechanisms. This
results in an increase in osteoblastic
function in cells capable of bone formation. In selected cases, the success
rate approximates that of surgical
procedures. Physical forces also can
be used to enhance open techniques
such as bone grafts for fracture healing, arthrodeses, and spinal fusions.
Outcomes such as return to specific
activities or work have not yet been
reported. This information will be
important to assess these devices
comparatively with alternative tech-

351

Use of Physical Forces in Bone Healing

niques of stimulating fracture repair.

Future research directions for electrical fields will include fractures at
risk, failed fusion, porous ingrowth,
osteoporosis, and revascularization

after core decompression for osteonecrosis of the femoral head.

Stimulation of articular cartilage
synthesis in osteoarthritis currently
is being investigated. Ultrasound is

being evaluated for stimulation of

fresh fractures in patients with comorbidities including older patient
age, diabetes, active smoking status,
vascular insufficiency, and obesity.

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