Musculoskeletal

Pathology
Alemwosen T(MD,pathology)
 Bone
Structure of Bones
Bone is characterised by its hard matrix
matrix consists of two components, matrix proteins
and mineral
The main structural protein in bone matrix is
type I collagen
Most of the mineral deposited in bone is in the
form of a calcium phosphate complex known as
hydroxyapatite
 Inorganic elements- calcium hydroxyapatite(65%)
Store house of 99% of bodys calcium, 85% of bodys
phosphorus and 65% of bodys sodium and magnesium
Organic elements (35%) - Cells and proteins of the
matrix
Cells of the bone
Bone forming cells - Osteoprogenitor cells,
osteoblasts and osteocytes
Bone resorbing cells - Osteoclasts, monocyte
origin
 Osteoclasts - the bone-resorbing cells, are mono
or multinucleated cells
Involved in bone remodelling
The osteoblast family consists of:
Osteoblasts- bone forming cells
Osteocytes - form an interconnecting network
throughout bone matrix
 CELLS of BONE
OSTEOPROGENITOR (STEM)(TGF)
OSTEOBLASTS (surface of spicule)
under control of calcitonin to take blood calcium and put it into
bone
OSTEOCYTES - are osteoblasts which are now completely
surrounded by bone)
OSTEOCLASTS (macrophage lineage)
under control of PTH to chew up the calcium of bone and put it
into blood
Proteins
Type 1 collagen- 90%
Noncollagenous proteins-adhesion proteins, ca-binding
proteins, enzymes, cytokines ,growth factors..
 During development, bone is formed either
directly in connective tissue, as in the skull
(intramembranous ossification) or
on pre-existing cartilage, as in the limb bones
(endochondral ossification)
Epiphysis
from subarticular plate to epiphyseal cartilage
Metaphysis
Area between epiphyseal plate to the area where bone
develops its funnel or flute shape
Diaphysis
Body of bone, between metaphyses
Congenital and hereditary diseases of bone
1. Defects in nuclear proteins and transcription
factors
2. Defects in hormones and signal transduction
pathways
3. Defects in extracellular structural proteins
4. Defects in metabolic pathways
 Malformations and diseases caused by defects in
nuclear proteins and transcription factors
Uncommon
Failure of development of a bone (e.g. Absence of phalanx, rib or clavicle)
Formations of extra bones (e.g. Supernumerary digits (polydactyly) or ribs)
Fusion of adjacent digits (syndactyly)
Development of long spider like digits(Arachinodactyly)
Craniorachischisis -failure of closure of the vertebral column and skull
meningomyelocele or meningoencephalocele
Meningomyeleocele
CONGENITAL AND HEREDITARY DISEASES OF BONE
Achondroplasia
caused by defects in hormones and signal
transduction mechanisms
inherited disorder characterized by impaired
maturation of cartilage in the developing growth
plate
a major cause of dwarfism
majority of cases of achondroplasia are caused by
dominant mutations involving the gene coding for
fibroblast growth factor receptor 3
 Achondroplasia affects all bones that are formed
from cartilage
The skeletal abnormalities are not associated with
changes in longevity, intelligence or reproductive
status
An autosomal dominant condition (but often a new
mutation)
The patient has a head and trunk of normal size,
and disproportionately short but well-muscled
arms and legs
The face usually has a large forehead, prominent
supraorbital ridges, and deepset root of the nose
 Thanatophoria, dwarf (lethal)
micromelic shortening of the limbs
frontal bossing with relative macrocephaly,
a small chest cavity, and
a bell-shaped abdomen
underdeveloped thoracic cavity leads to
respiratory insufficiency, and the patients
frequently die at birth or soon after
thanatophoric dwarf
Osteogenesis Imperfecta
Aka "brittle bone disease,"
a group of hereditary conditions characterized by
abnormal development of type I collagen
Type I collagen is present in many different tissues,
including skin, joints, and eyes, and it is a major
component of normal osteoid
Several different genetic defects have been shown
to interfere with the normal synthesis of type I
collagen
 Four major forms of OI have been identified; the
most common variants are inherited as
autosomal dominant disorders
Whatever the subtype, OI is characterized by the
presence of multiple bone fractures
In the more severe forms of the disease, bone
fragility causes multiple fractures and fetal
demise in utero or shortly after birth
 Subtype Inheritance Collagen defect Major C/F
Postnatal Autosomal dominant Decreased synthesis Compatible
fracture, blue pro1(1) Normal stature,
OI I sclerae skeletal fragility, DI,
hearing
impairment,joint
laxity,blue sclera
Perinatal lethal Most are autosomal Abnormal short pro- Death in utero or
recessive ; some are 1(1) chain; within days of birth
OI II autosomal dominant Unstable triple helix Skeletal deformity with
excessive fragility &
? New mutations Abnormal or
multiple fractures.
insufficient pro-2(1) Blue scera

Progressive Autosomal Altered structure of Compatible with survival

GR, s, blue sclera which
deforming dominant(75%) pro-peptides of pro- become white,
OI III Autosomal 2(1) deformities,hearing
recessive(25%) Impaired triple helix impairment,dentinogenesi
formation s imperfecta

Postnatal Autosomal dominant Short pro-2(1) chain Compaible with

fractures, Unstable triple helix survival; moderate
OI IV normal scerae skeletal
fragility,short
Osteogenesis Imperfecta
Osteogenesis Imperfecta
Other features
Hearing loss
Blue sclera
Dental imperfections
Osteopetrosis
"marble bone disease
encompasses a group of uncommon hereditary
disorders caused by deficient osteoclastic activity
Both autosomal recessive and autosomal
dominant variants have been recognized
Defective osteoclastic activity in these patients
results in the deposition of abnormally thickened,
heavily mineralized, abnormally brittle bone
 Fracture like a piece of chalk
In addition to an increased incidence of
fractures, patients with osteopetrosis also suffer
from anemia, thrombocytopenia
Increased susceptibility to infections caused by a
dramatic decrease in the amount of marrow
space available for hematopoiesis
Abnormally thickened bone may also compress
nerve roots, accounting for a high frequency of
cranial nerve palsies in these patients
OSTEOPOROSIS AND ACQUIRED METABOLIC
DISEASES
Osteoporosis
is a disease in which there is a reduction in bone
mass in the presence of normal mineralisation
is diagnosed by radiological assessment of bone
mineral density
Clinically, osteoporosis may present as a fragility
fracture, loss of height, or stooping deformity
(kyphosis or 'dowager's hump') due to wedge
fractures of the vertebral bodies
The most common forms are senile
and postmenopausal osteoporosis
Categories of generalized osteoporosis(read about specific mechanisms)

PRIMARY SECONDARY
Postmenopausal Endocrine disorders
Senile e.g Hyperparathyroidism
Drugs
Idiopathic e.g. corticosteroids
Neoplasia
e.g. Multiple myeloma
Miscellaneous
e.g. Immobilization
Gastrointestinal
e.g. Malnutrition
 Characterized by increased porosity of the
skeleton
often results from a combination of age-related
bone loss and additional bone loss from another
cause; by far the most common such cause is
post-menopausal estrogen withdrawal
Pathogenesis
caused by a loss of coupling in the bone
remodelling process
 This can be due to
increased bone resorption,
decreased bone formation, or
Both
The loss of coupling results in a net loss of
bone volume
In contrast to osteomalacia , mineralisation of
bone is normal
 Osteoporosis is commoner in females than males
and is less common in blacks
Complications
The major complications of osteoporosis are:
skeletal deformity
bone pain (usually due to compression fracture)
fracture
The commonest clinical feature of osteoporosis is
the progressive loss of height that occurs with age
Diseases caused by osteoclast dysfunction
Paget disease (Osteitis deformans)
Characterized by episodes of localized, frenzied osteoclastic
activity and bone resorption, followed by exuberant bone
formation
Collage of matrix madness
Usually begins during mid-adult life and increases steadily
after that time
 There are three phases in the development of Paget disease:
An initial osteolytic stage
A mixed osteoclastic-osteoblastic stage with dominance of
osteoblastic activity
A burnt-out quiescent osteosclerotic stage
 Stage 1

Diagramatic representation
of Paget Disease showing Stage 2
The three phases in the
Evolution of the disease

Stage 3
Morphology
A solitary lesion (monostotic) or may be multifocal
(polyostotic)

Although any bone may be affected, the spine, skull, and

pelvic bones are especially common sites of involvement
 Because the bone formation occurs in an erratic pattern,
areas of new bone are juxtaposed in a random mosaic
pattern, giving the appearance of a jigsaw puzzle
Clinical features
Usually asymptomatic , incidental radiographic findings
Pain localized to the affected bone-most common
Headache, enlargement of the head, Visual disturbances, and
deafness
All caused by deformity of the bones of the skull and impingement on
cranial nerves
Back pain, kyphosis
High-output congestive heart failure
Transverse fractures of long bones (chalkstick fracture)
In about 1% of the cases osteosarcoma develops
Rickets and osteomalacia
characterized by deficient mineralisation of the organic
matrix of the skeleton
Rickets is the name given to osteomalacia affecting the
growing skeleton of children
Causes of osteomalacia, or rickets, include:
dietary deficiency of vitamin D
deficiency of vitamin D metabolites
intestinal malabsorption
renal disease
Malabsorption of calcium and phosphate from the
intestine is the commonest cause of osteomalacia in
adults
Diagnosis
The characteristic clinical deformities of rickets
include:
bowing of the long bones of the leg
pronounced swelling at the costochondral junctions
flattening or 'bossing' of the skull
Inadequate mineralisation of bone reduces its
normal strength and allows deformities to
develop
 When the levels of vitamin D metabolites are low, calcification
cannot occur and cartilaginous proliferation continues
This accounts for the enlargement of long bones and the ribs
at growth plates
Other features
craniotabes
frontal bossing and a squared appearance to the head
rachitic rosary."
pigeon breast deformity
Harrison's groove
Diagnosis
The characteristic clinical deformities of rickets include:
Bowing of the long bones of the leg
Pronounced swelling at the costochondral junctions
Flattening or 'bossing' of the skull
 When the levels of vitamin D metabolites are
low, calcification cannot occur and
cartilagenous proliferation continues
This accounts for the enlargement of long
bones and the ribs at growth plates
characteristic pathological feature in adults
with osteomalacia is spontaneous incomplete
fractures
Bone Diseases Associated With
Hyperparathyroidism
Dicussed on endocrinology
OSTEOMYELITIS
Inflammation of bone and marrow cavity
caused by an infectious organism
offending organisms reach the bone by one of
three routes:
1. hematogenous dissemination,
2. direct extension from a focus of acute infection in the
adjacent joint or soft tissue, or
3. traumatic implantation after compound fractures or
orthopedic surgical procedures
 In most patients, osteomyelitis is hematogenous in
origin
In many cases the infection arises in a previously
healthy individual
other cases are associated with a more obvious
source of infection
Staphylococcus aureus is the most common
causative organism
Other common pathogens include pneumococci
and gram-negative rods,Escherichia coli and group
B streptococci
 Salmonella is an especially common pathogen
responsible for osteomyelitis occurring in
patients with sickle cell disease
Mixed bacterial infections, including anaerobes,
are responsible for many cases of osteomyelitis
developing after bone trauma
MORPHOLOGY
intense, neutrophilic inflammatory infiltrate at
the site of bacterial invasion
 The location of infection varies with age
In children, metaphyses of long bones are typically involved
In adults, hematogenous osteomyelitis primarily affects
vertebral bodies that remain quite vascular
In infants, the existence of loose periosteal attachments and
connections between the vessels in the metaphysis and
epiphysis allows the infection to spread to the epiphysis and
joint capsule
The involved bone becomes necrotic
In long bones, the infection spreads through the cortical
bone and may reach the periosteum, sometimes creating
a subperiosteal abscess
From the subperiosteal area, the infection may spread into
adjacent soft tissues to create draining sinuses
Chronic osteomyelitis
develops as a sequel of acute infection
Over time, an influx of chronic inflammatory cells into
the focus of osteomyelitis initiates a repair reaction
(osteoclast activation, fibroblastic proliferation, and
new bone formation)
Residual necrotic bone, termed the sequestrum, may
be resorbed by osteoclastic activity
Larger sequestra are eventually surrounded by a rim
of reactive bone, termed the involucrum
 When a well-defined rim of sclerotic bone
surrounds a residual abscess, the lesion is
sometimes designated a Brodie abscess
Chronic osteomyelitis may be complicated by
the development of draining sinuses and
pathologic fractures
Other complications include septicemia, acute
bacterial arthritis, squamous cell carcinoma,
amyloidosis
Clinical feature
Initially causes systemic manifestations similar
to those seen in any other acute infection,
such as fever, malaise, and leukocytosis
local pain, swelling, and redness may occur in
some adults
Tuberculous Osteomyelitis
Hematogenously born
Rarely direct extension e.g. From the lung to the ribs or from the
tracheobronchial nodes to the vertebrae
Bone infection is usually solitary but can be multiple in HIV/AIDS
The spine ( esp. thoracic and lumbar ) is the most common site;
followed by the knees and hips
More destructive and resistant to control than Pyogenic cases
Spreads through large areas of medullary cavity and causes
extensive necrosis
 Pott disease in the spine, infection extends
through intervertebral discs to involve multiple
vertebrae & extends into soft tissues, forming
abscess( psoas abscess or cold abscess)
POTTs DISEASE
Clinical feature
Pain on motion
Swelling
Symptom complex of tuberculosis
Vertebral deformities (scoliosis , kyphosis)
Neurological deficits secondary to spinal cord and nerve
compression
 BONE TUMORS
Primary bone tumors are considerably less common
than are metastatic lesions
most common originating sites for bone metastases,
in descending order of frequency, are the
prostate,
breast,
lung,
kidney,
gastrointestinal tract, and
thyroid
 Metastases may be destructive (osteolytic) or associated
with reactive new bone formation (osteoblastic)
Most metastasis are osteolytic , some tumors e.g. prostate can
be osteoblastic
Some conditions are associated with increased risk of
bone tumors e.g. Paget disease of bone, chronic
osteomyelitis, and exposure to radiation
Few cases are associated with hereditary tumor
syndromes
Gardner syndrome (osteomas)
familial retinoblastoma (osteogenic sarcomas)
BONE TUMORS
Benign or malignant
Malignant- primary(de novo) or secondary
Risk factors- Paget diseases , radiation ,fibrous dysplasia,
hereditary (p53 and RB genes)
Can be
Bone forming
Cartilage forming
Others
Bone-Forming Tumors
characterized by the production of osteoid by
the tumor cells
Benign
osteoma
Osteoid Osteoma
Osteoblastoma
Malignant
Osteogenic sarcoma
Osteoma
benign lesions of bone that (may be developmental aberrations
or reactive growths)
commonly encountered in the head and neck, including the
paranasal sinuses
present as localized, usually solitary, hard, exophytic growths
attached to the surface of the bone
Histologically, osteomas are composed of a bland mixture of
woven and lamellar bone, which may be difficult to distinguish
from normal bone
Osteoma
Involve skull and facial bones as a bossolated, round mass
Usually solitary
Middle age adults
Multiple in Gardner syndrome
Slowly growing ,impinge on brain or eyes or bring cosmetic
problems
Doesnt transform in to osteosarcoma
Osteoid osteoma and Osteoblastoma
Identical histology but different size ,site and symptoms
Morphology
Gritty tan hemorrhagic tissue
Well circumscribed, trabeculae of woven bone lined by
osteoblasts, well vascularised, hemorrhagic stroma ,
surrounding marked reactive bone leaving the tumor as a
central nidus
Radiologic findings
well-circumscribed lesions, which usually involve the cortex
and rarely the medullary cavity of bone
Radiologic findings
well-circumscribed lesions, which usually
involve the cortex and rarely the medullary
cavity of bone
 Central hemorrhagic nidus
surrounded by dense rim of
sclerotic bone
Osteosarcoma (osteogenic sarcoma)
The most common primary malignant bone tumor
(exclusive of myeloma and lymphoma)
Malignant cells must produce osteoid
Peak in 2nd decade with gradual decrease thereafter
75% of cases are < 20yrs of age
M> F
Secondary osteosarcomas occur in an older age group
than do primary conventional osteosarcomas
Signs/Symptoms:
Pain and swelling
Pathologic fracture is uncommon
 Conventional osteosarcomas are aggressive lesions that
metastasize through the bloodstream early in their
course
The lungs are a common site of metastases
Anatomic Distribution:
60% arise around the knee
Metaphysis of long bones
 Characteristically destroys the cortex and frequently
extends inward into the marrow cavity and outward into
adjacent soft tissues
The tumor often elevates the periosteum to produce the
so-called Codman triangle on radiographs
The hallmark of osteosarcoma is the formation of osteoid
by malignant mesenchymal cells
 Microscopy Osteoblastic, chondroblastic,
fibroblastic, telangiectatic, small cell and giant cell
variants
The most common variant is that which arises in the
metaphysis of long bones
is primary, solitary, intramedullary and poorly
differentiated with production of bone matrix