1. Bone

2. Bone Organic matrix( 35%)- cells & proteinaceous osteoid
Inorganic elements( 65%)-calcium hydroxyapatite, 99% of body’s ca- 85% of P- 65% of Na and Mg
Remodeling: constant breakdown & renewal which the net effects may be bone maintenance, bone loss or bone deposition

3. Bone diseases Congenital diseases Acquired diseases Fractures
Osteonecrosis
Osteomyelitis
Tumors

4. Congenital diseases of bone

5. Developmental anomalies
localized problems in migration of mesenchymal cells & formation of condensations, dysostoses
Isolated sporadic lesion or a component of a complex syndrome
More common lesions
Aplasia- congenital absence of a digit or rib
Formation of extra bones- supernumerary digits or ribs
Abnormal fusion of bones- premature closure of cranial sutures or congenital fusion of ribs

6. Mutations
Interfere with bone or cartilage formation, growth, and/or maintenance of normal matrix components
More diffuse defects
Dysplasia osteodysplasia, chondrodysplasia

7. Other genetic metabolic disorders
Not usually thought of as primary skeletal diseases, eg; mucopolysaccharidoses like Hurler syn

8. Osteogenesis imperfecta (brittle bone disease)

9. Osteogenesis imperfecta (brittle bone disease)
A group of hereditary disorders caused by defective synthesis of type I collagen
Gene mutations in coding sequences for α1 or α2 chains, quality or quantity( premature degradation, dominant negative mutation )
Most, AD
Extraskeletal manifestations: skin, joints, eyes….

10. OI Too little bone, extreme skeletal fragility
Four major subtypes, extremely broad range of clinical outcome
Type I- normal lifespan, fractures during childhood, blue sclera, hearing loss, small misshapen teeth
Type II-fatal

11. Achondroplasia

12. Achondroplasia Activating Point mutation in FGF receptor3
Activation of receptor
Inhibits chondrocyte proliferation
Impaired long bone growth

13. Achondroplasia AD Spontaneous mutation( many cases )
Affected individuals are typically heterozygotes
Homozygotes die soon after birth because of abnormalities in chest development & respiratory failure

14. Clinical findings Most common form of dwarfism
Affects all bones that form from a cartilaginous framework
Most conspicuous changes: marked disporportionate shortening of proximal extremities, bowing of the legs, lordotic posture
Cartilage growth plate: disorganized & hypoplastic

15. Osteopetrosis

16. Osteopetrosis
A group of rare genetic disorders characterized by reduced osteoclast-mediated bone resorption, defective bone remodeling
Several variants, most common: 1- AD adult form with mild clinical manifestations 2- AR infantile with a severe/ lethal phenotype

17. Osteopetrosis Causing defects Those that disturb osteoclast function
Those that interfere with osteoclast formation & differentiation

18. osteoclast dysfunction
Bone resorption through osteocalsts: decalcification by proton pump and degrading enzymes also activation of mediators
Nature of osteoclast dysfunction unknown in many cases
Carbonic anhydrase II deficiency results in reduced bone demineralization( required for osteoclast H+ excretion)
Proton pump deficiency
Chloride channel defect

19. Clinical findings Fractures Cranial nerve problems
Recurrent infections( diminished hematopoiesis )
Hepatosplenomegaly
Bone marrow transplant

20. Acquired diseases of bone development
Nutritional deficiencies( vit c, vit d)
Primary & secondary hyperparathyroidism
Osteoporesis
Paget disease
Rickets & osteomalacia

21. Osteoporosis
Increased porosity of skeleton resulting from reduced bone mass, increase in bone fragility & fx
Localized to a bone or region or generalized
Most common forms: senile, postmenopausal
Bone loss generally occurs in areas containing abundant cancelloues bone so more pronounced in spine & femoral neck

28. Paget disease ( osteitis deformans)

29. Paget disease
Gain in bone mass but newly formed bone is disordered & lacks strength
Repetitive episodes of regional osteoclastic activity & bone resorption- followed by exuberant bone formation- finally by exhaustion of cellular activity
Osteolytic stage, mixed osteoclastic- osteoblastic stage, osteosclerotic stage
Age: mid adulthood
Marked variation in prevalence in different populations

30. Morphology Lytic phase- numerous & large osteoclasts
Mixed phase- prominent osteoblasts, marrow replaced by loose connective tissue
Mosaic pattern( pathogonomic histologic feature )

31. Pathogenesis
Paramyxovirus infection IL-1 secretion from infected cells, M-CSF activate osteoclasts
Other suggested mechanism: intrinsic hyperresponsiveness of osteoclasts to activating agents as, vitD & RANK ligand.

32. Clinical course
Monostotic 15% ( tibia, ilium, femur, skull, vertebra, humerus )
Polyostotic ( pelvis, spine, skull ) axial skeleton or proximal femur , 80% of cases
Ribs, fibula & small bones of hands & feet : unusual
Most cases are mild & discovered incidentally
Elevation in serum ALKP & increased urinary excretion of hydroxyproline

33. Manifestations Warmth of overlying skin & subcutis
In extensive polyostotic disease high output congestive heart failure
In proliferative phase of skull disease, nerve impigment headache & visual and auditory disturbances
Back pain with vertebral lesions, fx & nerve root compression
Deformity of long bones of leg
Sarcoma in 1% of patients parallel to lesions except vertebra

35. Rickets & Osteomalacia
Defective bone mineralization

36. Hyperparathyroidism

37. PTH Osteoclast activation( increased RANKL production by osteoblasts )
Increased resorption of ca by renal tubules
Increased urinary excretion of phosphate
Increased synthesis of 1,25(OH)2 vitD by kidneys
Net result: elevation in serum ca, inhibiting PTH

38. Hyperparathyroidism
Significant skeletal changes related to unabated osteoclast activity
Entire skeleton is affected, some sites may be more severely affected
PTH is directly responsible for bone changes in primary but additional influences contribute in secondary
Inadequate 1,25(OH)2 vitD synthesis in chronic renal failure

39. Hallmark: Increased osteoclastic activity & bone resorption

40. Brown tumor
Osteitis fibrosa cystica

41. Fractures

42. Healing Blood coagulum
recruit inflammatory cells, fibroblast & endothelium
Release of cytokines from plts & inflammatory cells
Activate bone progenitor cells
Soft tissue callus, within a week
Deposition of woven bone
Chondroblasts
Early repair process peak within 2-3 wks
Bony callus
Weight bearing leads to resorption of callus from nonstressed sites

43. Disrupting factors Displaced & comminuted fractures
Inadequate immobilization nl constiuents do not form
Too much motion along fx gap
Infection
Inadequate levels of ca or p, vit deficiencies, systemic infection, diabetes, vascular insufficiency

44. Osteonecrosis ( avascular necrosis)

45. Mechanisms Vascular compression or disruption Steroid administration
Thromboembolic disease
Primary vessel disease (eg; vasculitis )

46. Osteonecrosis Cortex, usually not affected Subchondral infarcts
Medullary infarcts

47. Osteomyelitis
Pyogenic
tuberculous

48. Pyogenic osteomyelitis
Routes
Organisms: staph aureus, E-coli and strep group B, salmonella, mixed bacterial infections
No organism isolated, 50% of cases
Associated suppurative arthritis in infants
Sequestrum
Involucrum
Subperiosteal abscess and draining sinus
After the 1st week of infection chronic inflammatory cell become numerous
¼ of cases do not resolve and persist as chronic infection

50. Complications of chronic OM
Acute flare ups
Pathologic fx
Secondary amyloidosis
Endocarditis
Sepsis
SCC
Osteosarcoma, rarely

51. Tuberculous OM 1-3% of pulmonary infections
Usually reach the bone through blood stream( long bones & vertebra) , although direct spread may be
Solitary
Pott disease, vertebral deformity & collapse with secondary neurologic deficit, soft tissue abscess( psoas muscle ), common

52. End of first session

53. Bone tumors
Primary
metastatic

54. General considerations
Classification: cell of origin and apparent pattern of differentation
Osteosarcoma: the most common primary bone cancer then CSA and EWS
Osteochondroma & fibrous cortical defect: frequent
Most bone tumors occur during first several decades and have a propensity to originate in long bones of extremities
Specific tumor types target certain age groups & anatomic sites, OSA , CSA

55. General considerations
Most bone tumors arise without any prior known cause but
Genetic syndromes( Li-Fraumeni & retinoblastoma syndromes ), bone infarcts, chronic osteomyelitis, paget dis, radiation and metal orthopedic devices are associated with OSA
Clinical presentations

57. Major tumor types Abnormal development Benign neoplasm
Malignant neoplasm
Neoplasms of uncertain potential

58. Bone- forming tumors
Osteoma
Osteoid osteoma
osteosarcoma

59. Osteoma
Many cases are developmental aberrations or reactive growths rather than true neoplasms
Most common in head & neck including paranasal sinuses
Middle age
Solitary
Localized, slowly growing hard exophytic masses on bone surface
Multiple lesions are a feature of Gardner syn

60. Osteoid osteoma & Osteoblastoma
Age: teenage & 20s
Male predilection
Distinguished by size, site of origin, radiographic appearance

61. Clinical presentation
Site
Size
Tumor
Localized pain
Responsive to aspirin
Proximal femur & tibia
Less than 2 cm
Osteoid osteoma
Pain ,Not responsive to aspirin
Vertebral column
larger
Osteoblastoma

63. Osteosarcoma
Age- 75% younger than 20, a second peak in elderly usually with other conditions including Paget dis, bone infarct, prior irradiation
Male>female
Location: most tumors arise in metaphysis of long bones of extremities 60% around the knee, 15% around the hip, 10% at shoulder, 8% jaw
Subtypes- the most common type: primary, solitary, intramedullary and poorly differentiated

66. Pathogenesis RB gene mutations occur in 60-70% of sporadic tumors
Patients with hereditary retinoblastomas have a thousandfold greater risk of developing OSA
Many OSA develop at sites of greatest bone growth

67. Clinical features Typical presentation: painful enlarging mass X-ray
Hematogenous spread, 10-20% of patients have demonstrable pulmonary metastasis at time of DX
Long-term survival: 60-70%
Secondary OSA, highly aggressive that do not respond well to therapy

68. Cartilage forming tumors
Osteochondroma
Chondroma
chondrosarcoma

69. Osteochondroma( Exostose )
Age- late adolescent & early adulthood but multiple become apparent during childhood
Inactivation of both copies of EXT gene in chondrocytes is implicated in both sporadic and hereditary
EXT gene- a tumor suppressor gene encoding glycosyltransferases essential for polymerization of heparin sulfate

70. Osteochondroma
Location- bones of endochondral origin arising at metaphysis near the growth plate of long tubular bones
Occasionally develop from bones of pelvis, scapula and ribs( sessile )
Short tubular bones of hands and feet: rare
Clinical presentation

72. Chondroma Enchondroma, juxtacortical chondroma Age- 20-50 yrs old
Location- solitary at metaphysis of tubular bones esp short tubular bones
Ollier disease -multiple chondromas preferentially involving one side of the body
Maffucci syndrome- multiple chondromas and benign soft tissue angiomas

73. Clinical features
Incidental findings
X-ray
Malignant transformation

74. Chondrosarcoma Age- 40 or older Male>female
Subclassification: intramedullary, juxtacortical
Variants: conventional, myxoid, dedifferentiated, clear-cell, mesenchymal.
Dediferentiation occur in about 10% of low-grade CSA

75. Clinical features Site- pelvis, shoulder and ribs X-ray
Direct correlation between grade and biologic behavior
5-year survival-Low-grade tumors: 80-90%
grade 3 tumors: 43%
Metastasis in grade 1 tumors:rare
grade 3 tumors: 70%
Size >10cm
Hematogenous spread, lung, skeleton

78. Fibrous and fibro-osseous tumors
Fibrous cortical defect & Nonossifying fibroma
Fibrous dysplasia

79. Fibrous cortical defect
30-50% of all children older than 2 yrs old
Developmental defects rather than true neoplasm
Mostly smaller<0.5cm and arise in metaphysis of distal femur or proximal tibia
Bilaterality or multiplicity: 50%
Asymptomatic and usually incidental findings
Most undergo spontaneous differentiation

81. Fibrous dysplasia Localized developmental arrest Clinical patterns:
Monostotic
Polyostotic
Polyostotic disease associated by café au lait skin pigmentation and endocrine abnormalities esp precocious puberty( McCune-Albright syn )
Rarely polyostotic disease can transform into osteosarcoma.

82. Monostotic FD 70% of cases Age- early adolescence
Most common sites: ribs, femur, tibia, jaw bones, calvaria & humerus
Asymptomatic & usually incidental findings
Can cause marked enlargement and distortion of bone

83. Polyostotic FD Majority of remaining cases Age- slighly earlier
Site- femur, skull, tibia, humerus
Craniofacial involvement- 50%, 100%

84. McCune-Albright syn 3% of cases
Sexual precocity, hyperthyroidism, GH secreting pituitary adenoma, primary adrenal hyperplasia.
The severity of manifestations depends on the number and cell types that harbor G-protein mutation
Bone lesions, often unilateral & skin lesions usually limited to the same side of the body.
Macules are classically large, dark to light brown and irregular.

86. Miscellaneous bone tumors
Ewing sarcoma
Primitive neuroectodermal tumor
Giant cell tumor of bone
Metastatic disease

87. Ewing Sarcoma and Primitive Neuroectodermal tumor
PNET- neural differentiation
EWS- undifferentiated
Age- most yrs %<20yrs
Translocation-95% of patients have t( 11;22 ) (q24;q12 ) or t(21;22)(q22;q12)
A chimeric protein which is an active transcription factor

88. Clinical features
Typical presentation: painful enlarging mass in diaphysis of long tubular bones( esp femur ) & pelvic flat bones
Systemic signs and symptoms in some
X-ray- onion skin pattern of periosteal reaction
5-yrs survival: 75%

90. Giant-Cell Tumor of Bone
Benign, locally aggressive
Age yrs
Location- epiphysis of long bones around the knee
X-ray- large purely lytic and eccentric lesion
Cortical destruction±
Recurrence: ½ of cases
Metastasis to lungs: 4%

92. Metastatic disease Pathways of spread -Direct extension
-Lymphatic or hematogenous
-Intraspinal
Origin
Adults- prostate, breast, kidney, lung
Children- Neuroblastoma, Wilm’s tumor, OSA, EWS, RMS

93. Metastasis site axial skeleton proximal femur humerus X-ray pure lytic
pure blastic
both

94. END OF SECOND SESSION

95. DISEASES OF THE JOINTS
Basic pathology

96. Degenerative joint disease
The most common type of joint disease .
Progressive erosion of articular cartilage.
Important cause of physical disability in olders.
Suffix itis is misleading.
Cartilage biochemical & metabolic changes result in it’s breakdown.

97. D.J.D
Primary:appears without apparent initiating cause as an aging process
Secondary:appears in younger
individuals having some predisposing conditions eg,trauma,underlying systemic disease,diabetes………

98. pathogenesis (↓collagen synthesis,↑collagen degradation)
Aging prevalence increases > 50
Mechanical stresses
Genetic factors
Chondrocytes play a primary role
(↓collagen synthesis,↑collagen degradation)
probably ↑apoptosis

99. Gross Granular articular surface,softer than nl Loss of cartilage
Ivory appearance of exposed bone
Subchondral cyst
Dislodged pieces of cartilage & bone into the joint(joint mice)

100. D.J.D

101. Microscopy Fibrilation & cracking of the matrix
Sloughing of full thickness of cartilage
Bone eburnation
Small fractures through the articulating bone
Joint mice(dislodged pieces of bone & cartilage)
Osteophytes
Minor changes in synovium as congestion ,fibrosis & scattered chronic inflammatory cells

102. Articular cartilage Fibrilation of the surface
Fissures (horizontal & vertical)

103. Cartilage cloning
Duplication of tidemark

104. Vascular penetration at base of cartilage
Cysts in the subchondral bone
Nonspecific synovitis

105. Clinical course Deep achy pain,worsens with use.
Involvement of one or a few joints
Commonly:hip,knee,lower lumbar &
cervical vertebra,interphalangeal
joints of finger(proximal & distal), first
carpometacarpal & tarsometatarsal
joints

106. Rheumatoid arthritis A Chronic systemic inflammatory disorder
May affect many tissues & organs
such as:skin,blood vessels,heart,lungs
& muscle. principally attack the joints.
Nonsuppurative proliferative synovitis that often
progress to destruction of cartilage & joint
ankylosis
Symmetric polyarticular arthritis
Most of them Chronic relapsing & remitting course
& eventually leads to severe joint destruction

107. Pathogenesis Genetic predisposition Strong association of HLA-DR1&DR4
Environmental factors ???
EBV,Borrelia,mycoplasma,parvovirus.?
Autoimmune reaction
ALTHOUGH INITIATING AGENT IS STILL
UNKNOWN

108. Morphology in the joints
Dense perivascular inflammatory infiltration as:lymphoid follicles,plasma cells& macrophages in the synovial stroma
Increased vascularity(vasodilation & angiogenesis)
Fibrin aggregates in synovium & floating in joint space as rice bodies
Osteoclast activity in underlying bone
Pannus formation

109. Synovium Protrusion of large & edematous villi into the joint
Variable color: yellowish , gray or brown

110. Infiltration of mononuclear inflammatory cells
Vascular proliferation

111. Nodular lymphocytosis with germinal centers
Plasma cell cuffing

112. Hypertrophy & hyperplasia of synovial cells
Synovial giant cells(Grimley-sokoloff GC)

113. Fibrin exudate
as loose bodies (rice bodies) or
attached by inflammatory stalk to synovium

114. Pannus A neoplasm-like growth of inflamed synovial tissue
leads to destruction of joint structures
Two types :
- vascular inflammatory type
- avascular fibrous type

115. pannus

116. Eventually Fibrous obliteration of the joint
Deformed joints with minimal or no range of motion

118. Gout
Recurrent episodes of acute arthritis, sometimes accompanied by large crystalline aggregates(tophi) & joint deformity
Elevated level of uric acid is an essential component

119. Types
Primary( 90% of cases )
- Unknown enzyme defect(85-90% of primary gout) mostly due to overproduction
- Known enzyme defect (partial ↓HGPRT)
Secondary( 10% of cases )
- ↑nucleic acid turnover(leukemias)
- CRF

120. Clinical features Evolution of gout 1-Asymptomatic hyperuricemia
2-Acute gouty arthritis
3-Intercritical gout
4-Chronic tophaceous gout(arthritis & soft tissue tophi)
Gouty nephropathy, renal tubule obstruction , renal stones , tophi

121. Major manifestations Acute arthritis
Chronic tophaceous arthritis(deposition on articular cartilage & joint capsule)
Persistant chronic inflammation eventually
fibrosis of the synovium & erosion of articular cartilage ± fusion of the joint
Gouty nephropathy : obstruction of renal tubules by UA crystals , UA renal stones , tophi in the interstitium , scarred & shrunken kidney & CRF

123. Purine metabolism Complete lack of HGPRT: Lesch-Nyhan syndrome:
Synthesis of purine from nonpurine precursors : Denovo pathway
Synthesis of purine nucleotides from free purine bases : Salvage pathway
which are catalyzed by two transferases
HGPRT & APRT
Complete lack of HGPRT: Lesch-Nyhan syndrome:
↑↑↑excretion of UA , severe neurologic dis &MR

128. Acute suppurative arthritis
The most common cause is bacteria
Common pathogens:gonococci,staphylococci, streptococci, hemophilus.inf, gram neg rods.
Complement deficiency (C5,C6,C7): susceptible to gonococcal arthritis
In sickle cell disease : salmonella is important

129. Lyme disease Involves multiple organ systems
Typically affects large joints such as the knee , shoulder & elbow
Early lyme arthritis : synovium resembles early RA & oninoin-skin-like lesions
Late dis: extensive erosion of the cartilage in large joints

130. Diseases of skeletal muscle
Basic pathology

135. Skeletal muscle diseases
Neurogenic atrophy
Neuromuscular junction disorders(myasthenia gravis)
Primary diseases

136. Primary diseases Myopathy Muscular Dystrophy Congenital
-Ion channel myopathies
-Inborn errors of metabolism
-Mitochondrial myopathy
Toxic
Intrinsic exposure( thyroxine )
Extrinsic exposure( alcohol, drugs)
Muscular Dystrophy
X- linked
Autosomal
Myotonic dystrophy

137. Muscle atrophy Neurogenic atrophy Type 2 myofiber atrophy
The two most common causes:
Neurogenic atrophy
Type 2 myofiber atrophy
disuse atrophy,glucocorticoids,
endogenous hypercortisolism

138. Neurogenic atrophy Random atrophy of both fiber types
Angular atrophied fibers
Small & later large groups of atrophied fibers
Loss of checkerboard
pattern with reinnervation
(fiber type grouping)

139. Reinnervation

140. Werding-Hoffman disease
Markedly atrophic fibers with a rounded cotour
Large groups of atrophic fibers
Often scattered hyper
-trophic fibers

141. Type 2 myofiber atrophy Very nonspecific
Relatively common finding in a muscle BX
Most common causes:prolonged steroid therapy,disuse related to prolonged bed rest or joint diseases

142. Type 2 myofiber atrophy
angular & atrophic fibers similar to neurogenic atrophy
Absence of group atrophy
ATPase is essential for DX

143. Myasthenia gravis
Acquired autoimmune disorder of neuromuscular transmission
Any age
Peak age in female 2-3rd decade ,male later
F>M
Caused by anti-AchR which result in reduced number of AchR by two mechanisms:
*internalization & down-regulation of the receptor
* blockage of receptors

144. Clinical features Myasthenia gravis Weakness & fatigability of muscles
Cranial muscles,specially lids &extraocular muscles are early involvements(diplopia & ptosis)
Weakness increases during repeated use

145. X-linked muscular dystrophy
Defective gene product: dystrophin
Clinical features: progressive muscle weakness of proximal limb muscles(early) specially in lower extremity
Generalized weakness as the disease progresses
Other involvements:cardiomyopathy,mental impairment
Cause of death:mainly respiratory failure

147. Duchenne muscular dystrophy < 5Y/O
Muscular dystrophies
Dystrophin
Onset age
Clinical course
Duchenne muscular dystrophy
Absent
< 5Y/O
Wheelchair dependent by 12 y/o
Death at 20
Becker muscular dystrophy
Abnormal
5-15 Y/O
Walk beyond 15 y/o Most survive into 4thdecade

148. Duchenne’s muscular dystrophy
Marked variation in muscle fiber size
Fiber necrosis
Myophagia
Fiber regeneration
Endomysial fibrosis
Scattered large hyalinize hypereosinophilic fibers (hypercontracted)
Late stage:fiber loss & adipose tissue infiltration

149. Duchenne’s dystrophy carrier

151. Becker’s muscular dystrophy
Morphology
Similar to DMD
But fiber necrosis & regenerative changes much less conspicuous than Duchenne’s

155. THE END