Musculoskeletal: Pathology - Bone remodelling, growth and development Flashcards
1
Q
Four cell types found in bone and their function
A
- Osteoprogenitor cells: pluripotent mesenchymal stem cells that differentiate into osteoblasts
- Osteoblasts: synthesise, transport and arrange matrix proteins, and initiate process of mineralisation; transform into osteocytes if surrounded by newly deposited matrix
- Osteocytes: control calcium and phosphate in microenvironment, also responsible for mechanotransduction (translate mechanical forces into biologic activity)
- Osteoclasts: bind to bone via integrins and form resorption (functions similarly to lysosome)
2
Q
What are the progenitor cells for osteoclasts?
A
Same haematopoietic progenitors as monocytes/macrophages
3
Q
Three factors which stimulate differentiation and maturation of osteoclasts
A
M-CSF
IL-1
TNF
4
Q
What is the lifespan of osteoclasts?
A
~2 weeks
5
Q
Which bones develop via intramembranous ossification?
A
Flat bones of face
Most bones of skull
Clavicles
6
Q
What is endochondral ossification?
A
Most common method of bone development, involves cartilage model which is then replaced by bone
7
Q
What is the underlying defect in osteogenesis imperfecta? What is the typical inheritance pattern?
A
Deficiency in type I collage
Autosomal dominant inheritance
8
Q
What pathology is caused by osteogenesis imperfecta?
A
Osteoporosis with marked cortical thinning and attenuation of trabeculae
9
Q
Which is the osteogenesis imperfecta subtypes are compatible with life and which result in death (usually during the perinatal period)?
A
Types I, III and IV compatible with survival
- Type III more severe disease with growth retardation, multiple fractures, and progressive kyphoscoliosis
Type II lethal in perinatal period due to excessive fragility
10
Q
What is osteoporosis? How is it classified?
A
Disorder characterised by porous bones with decreased bone mass
May be localised (e.g. disuse osteoporosis) or generalised (e.g. metabolic bone disease)
Generalised may be primary (postmenopausal, senile, or idiopathic) or secondary
11
Q
Give five examples of broad causes of secondary osteoporosis
A
- Endocrine disease (e.g. hyperparathyroidism)
- Neoplasia (e.g. multiple myeloma)
- Gastrointestinal disorders (e.g. malabsorption)
- Drugs (e.g. corticosteroids)
- Miscellaneous (e.g. osteogenesis imperfecta)
12
Q
What are the three determinants of peak bone mass?
A
Genetics
Physical activity
Nutrition
13
Q
What are four hormonal (menopausal) and four age-related factors contributing to the pathogenesis of osteoporosis?
A
Hormonal:
- Decreased oestrogen
- Increased IL-1, IL-6, TNF
- Increased RANK, RANKL expression
- Increased osteoclast activity
Age-related:
- Decreased osteoprogenitor replication/differentiation
- Decreased osteoblast activity
- Decreased matrix-bound growth factor activity
- Decreased physical activity
14
Q
Describe the typical clinical presentation of osteoporosis
A
Thoracolumbar vertebral fractures with progressive lumbar lordosis and kyphoscoliosis
Femoral neck and pelvic fractures (and their complications)
15
Q
How is osteoporosis usually diagnosed? What is the downside of using plain radiography?
A
With DEXA (dual-energy X-ray absorptiometry)
Plain radiographs are unable to reliably detect osteoporosis until 30-40% bone loss
16
Q
What are the three phases seen in Paget disease?
A
- Osteolytic stage
- Mixed osteoclastic-osteoblastic stage (ends with predominance of osteoblastic activity)
- Burnt-out quiescent osteosclerotic stage
17
Q
What is the pathology in Paget disease? What is the hallmark morphological feature?
A
There is gain in bone mass, but new bone is disordered and architecturally unsound
Hallmark morphological feature is mosaic pattern (haphazardly oriented units of lamellar bone)
18
Q
Describe the clinical presentation of Paget disease
A
Usually late adulthoods (>70yo)
Most cases are mild and asymptomatic
May present with pain due to microfractures or bony growth
Monostotic in 15%, polystotic in the remaining with axial skeleton or femur most commonly involved (in 80%)
19
Q
What is one of the important complications of Paget disease?
A
Risk of benign and malignant bony tumour transformation
20
Q
Describe the three stages of fracture healing
A
- Procallus formation:
- Immediately after fracture, rupture of blood vessels results in haematoma formation
- Fibrin mesh of haematoma seals off fracture site and creates framework for inflammatory cells, fibroblasts and new capillaries
- Release of cytokines (including PDGF, TGF-B, FGF, interleukins) from platelets and inflammatory cells results in activation of osteoprogenitor cells, and stimulated of osteoclastic/osteoblastic activity
- By end of first week, haematoma is organised, adjacent tissue is being modulated for fracture matrix production, and fractured ends of bone are being remodelled (PROCALLUS is formed) - Fibrocartilaginous callus formation:
- Activated osteoprogenitor cells deposit trabeculae of woven bone
- In some cases, activated mesenchymal cells around the fracture line differentiate into chondroblasts and produce fibrocartilage and hyaline cartilage
- Repair tissue reaches maximal girth at the end of the second or third week, resulting in stabilisation of fracture site - Bony callus formation:
- Cartilage along fracture line undergoes endochondral ossification and fractured ends become bridged by bony callus
- Bony callus becomes stiffer and stronger as it is mineralised
- Matures and is subject to weight-bearing forces: portions not physically stressed are resorbed, and callus decreases in size until shape and outline of fractured bone is re-established
- Medullary cavity is also restored
21
Q
Five reasons why fracture healing may be imperfect
A
- Displaced/comminuted fractures
- Inadequate immobilisation -> delayed union, nonunion
- Infection
- Foreign body
- Systemic illness (e.g. osteoporosis, osteomalacia)
22
Q
Where in the bone can avascular necrosis occur, and how does this change the presentation?
A
Can occur in medullary cavity of metaphysis/diaphysis, or in subchondral regions of epiphysis
In medullary cavity:
- Involves cancellous bone and marrow (cortex not affected due to dual blood supply)
- Asymptomatic unless large
- Stable
Subchondral:
- Triangular/wedge-shaped infarct (with subchondral plate at base)
- Articular cartilage remains viable (obtains nutrition from synovial fluid)
- Produces chronic pain (initially with activity only, then constant)
- May collapse and cause severe secondary osteoarthritis
23
Q
Describe seven mechanisms of avascular necrosis, giving specific examples where relevant
A
- Vascular interruption (e.g. fracture)
- Thromboembolism (e.g. decompression sickness)
- Vessel injury (e.g. vasculitis, radiation therapy, connective tissue disorders)
- Vascular compression (e.g. corticosteroids, tumours)
- Venous hypertension
- Infection
- Metabolic (e.g. chronic pancreatitis)
24
Q
What are the three methods of spread of bacteria in pyogenic osteomyelitis? Which of these is most common in children?
A
- Haematogenous
- Extension from contiguous site
- Direct implantation
25
What bones are most commonly affected in pyogenic osteomyelitis in children?
Long bones
26
What are the most common settings in which adults develop pyogenic osteomyelitis?
As complication of open fracture, surgical procedures, and diabetic foot infection
27
What is the most common pathogen that causes pyogenic osteomyelitis and how frequently is it isolated?
Staphylococcus aureus (80-90%)
28
What virulence factor of Staphylococcus aureus makes it adept at infecting bone?
Expresses receptors for bone matrix components which increases adherence
29
What organisms are more frequently isolated in osteomyelitis in the setting of genitourinary infection and IVDU?
E. coli
Pseudomonas aeruginosa
Klebsiella
30
What organisms are found in the setting of osteomyelitis secondary to direct spread/inoculation (i.e. in open fractures or surgery)?
Usually mixed bacterial infection
31
Which two organisms commonly cause osteomyelitis in neonates?
Haemophilus influenzae
Streptococcus agalactiae (group B strep)
32
What causative organism may be found in osteomyelitis in the setting of sickle cell?
Salmonella
33
In what % of cases of pyogenic osteomyelitis is no organism isolated?
50%
34
Five complications of pyogenic osteomyelitis
1. Sequestrum: necrosis of bone segment
2. Draining sinus: occurs in setting of rupture of periosteum and formation of soft tissue abscess
3. Septic arthritis: in infants (uncommon complication in adults)
4. Involucrum: subperiosteal new bone that encloses infected bone
5. Chronic osteomyelitis: may in turn leads to pathologic fracture, secondary amyloidosis, endocarditis, sepsis, sarcoma, SCC of sinus tract
35
Describe two morphological variants of osteomyelitis
1. Brodie abscess: small intraosseous abscess that frequently involves the cortex and is walled off by reactive bone
2. Sclerosing osteomyelitis of Garré: sclerotic focus of continuing new bone formation, typically in jaw
36
Describe the six classes of primary bone tumours, including their relative % incidence
1. Haematopoietic (40%)
2. Chondrogenic (20%)
3. Osteogenic (19%)
4. Fibrogenic
5. Unknown origin (10%)
5. Neuroectodermal
37
Two malignant haematopoietic primary bone tumours
1. Myeloma
2. Malignant lymphoma
38
Four benign chondrogenic primary bone tumours
1. Osteochondroma
2. Chondroma (hyaline cartilage tumour)
3. Chondroblastoma (rare)
4. Chrondromyxoid fibroma
39
One malignant chondrogenic primary bone tumour
1. Chondrosarcoma
40
Two benign osteogenic primary bone tumours
1. Osteoid osteoma
2. Osteoblastoma
41
One malignant osteogenic primary bone tumour
1. Osteosarcoma
42
One benign and one malignant fibrogenic primary bone tumour
Benign: fibroma
Malignant: fibrosarcoma
43
Three benign primary bone tumours of unknown origin
1. Giant-cell tumour (contains mononuclear cells)
2. Unicameral bone cyst
3. Aneurysmal bone cyst
44
What is the most common benign bone tumour?
Osteochondroma (also called exostosis)
45
Describe the typical clinical presentation of an osteochondroma
Sessile/mushroom-shaped benign tumour which is slow-growing and often an incidental finding
Usually stops growing at time of growth plate closure
46
Where do chondroblastomas typically occur?
Around the knee
47
Do chondroblastomas metastasise?
Yes, can produce pulmonary metastases in response to pathologic fracture or repeated curettage
48
Which benign tumour can be mistaken for sarcoma?
Chondromyxoid fibroma
49
What is chondrosarcoma? In what part of the skeleton does it typically arise?
Malignant chondrogenic tumour composed of malignant hyaline and myxoid cartilage
Commonly arises in central skeleton (rarely in extremities)
50
Differentiate between osteoid osteoma and osteoblastoma
Histologically identical
Osteoid osteoma <2cm in greatest dimension, with nocturnal pain that responds to aspirin
Osteoblastoma >2cm in greatest dimension, pain does not respond to aspirin
51
Where do osteoid osteomas typically arise? In which age group are they most common?
In the appendicular skeleton and posterior spine
Usually occur in teens and 20s
52
Where do osteoblastomas typically arise?
More frequent spine involvement compared with osteoid osteomas
53
What is the most common primary malignant bone tumour (excluding haematopoietic malignancies)?
Osteosarcoma
54
Describe the bimodal distribution of osteosarcoma
Mostly in young people <20yo
Some cases in the elderly with predisposing conditions (e.g. Paget disease)
55
What is a possible complication of fracture nonunion?
Cystic degeneration of central callus with formation of pseudoarthrosis (false joint, may be lined by synovial-like cells)
56
Where do osteosarcomas typically arise?
In long bone metaphyseal regions, with 50% occurring around the knee
57
One type of malignant neuroectodermal primary bone tumour
Ewing sarcoma
58
What is Ewing sarcoma? In what age group does it typically occur, and where do they usually arise?
Primary malignant small round-cell tumour of bone and soft tissue
Typically in children and young people <20yo
Usually arise in diaphysis of long tubular bones (femur, pelvis)
59
Three pathways of spread of bony metastases
1. Direct extension
2. Haematogenous
3. Intraspinal seeding via Batson plexus of veins
60
What are the most common sources of bony metastases in adults?
>75% from prostate, breast, kidney and lung cancers
61
What are the most common sources of bony metastases in children?
Neuroblastoma, Wilms tumour, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma
62
Which two primary malignancies may produce solitary bony metastases?
Kidney and thyroid cancers
63
Which parts of the skeleton are most commonly affected by bony metastases?
Axial skeleton, proximal femur, and humerus
64
Four primary malignancies which tend to produce osteolytic bony metastases
Kidney, lung, GIT, melanoma
65
Primary malignancy which tends to produce sclerotic bony metastases
Prostate
66
Describe the neurovascular supply of hyaline cartilage
Avascular
No lymphatic drainage
Not innervated
67
What are the three compositional elements of hyaline cartilage and what is the role of each?
1. Type 2 collagen for increased tensile strength
2. Water and proteoglycans for turgor, elasticity, and reduction in friction
3. Chondrocytes which synthesise and degrade matrix (secrete degradative enzymes and enzyme inhibitors)
68
What is osteoarthritis?
Condition characterised by chronic erosion of articular cartilage
69
What is the difference between primary and secondary osteoarthritis?
Primary:
- Aging phenomenon, with exponentially increasing prevalence over age 50yo
- Usually oligoarticular
Secondary:
- In setting of predisposing condition (e.g. previous injury, congenital developmental deformity, underlying systemic disease such as DM or obesity)
70
Describe the pathogenesis of osteoarthritis (three stages)
1. Chondrocyte injury:
- Contribution from aging and biochemical/genetic factors
2. Early osteoarthritis:
- Chondrocytes proliferate and secrete inflammatory mediators, collagens, proteoglycans and proteases
- Results in remodelling of cartilaginous matrix and secondary inflammatory changes in synovium and subchondral bone
3. Late osteoarthritis:
- Repetitive injury and chronic inflammation results in chondrocyte drop out, marked cartilage loss, and subchondral bony thickening with osteophyte formation
71
Describe the typical clinical presentation of osteoarthritis
Usually asymptomatic until age 50
After age 50:
- Deep achy pain worse with use
- Morning stiffness
- Crepitus
- Limited range of movement
- May get nerve root compression and radicular pain in setting of spinal foramina osteophytes
72
Which joints are most typically affected in osteoarthritis?
Hips
Knees
Lower lumbar and cervical vertebrae
PIPJ and DIPJ
First MCPJ and first TMTJ
73
What Heberden nodes?
Prominent osteophytes at DIPJ common in women with osteoarthritis
74
Which joints are more commonly affected in women vs men with osteoarthritis?
Women: knees, hands
Men: hips
75
Which joints are typically spared in osteoarthritis?
Shoulders
Elbows
Wrists
76
What is rheumatoid arthritis and how does it affect the joints?
Chronic systemic inflammatory disorder
In joints, produces nonsuppurative proliferative and inflammatory synovitis which often progresses to destruction of articular cartilage and ankylosis of joints
77
Describe the six histological features of rheumatoid arthritis
1. Infiltration of synovial stroma by lymphoid inflammatory infiltrate
2. Hypervascularity
3. Fibrin deposition on synovium and floating fibrin "rice bodies" in joint space
4. Accumulation of neutrophils in synovial fluid and superficial (but not deep) synovium
5. Osteoclastic activity producing erosions, subchondral cysts, and osteoporosis
6. Pannus formation
78
Describe the pathogenesis of rheumatoid arthritis
Involves exposure of genetically susceptible host to an arthritogenic antigen
Results in breakdown of self-tolerance with subsequent chronic inflammatory reaction
Continuing autoimmune reaction results in joint destruction, and is marked by CD4+ T cell activation and release of inflammatory mediators (especially TNF)
79
Nine inflammatory mediators implicated in the pathogenesis of rheumatoid arthritis
TNF
IFN-y
IL-17
IL-1
IL-6
IL-23
TGF-B
PGE2
NO
80
Which two antibodies together are sensitive and specific for rheumatoid arthritis?
Rheumatoid factor (autoantibodies to Fc portion of autologous IgG, usually IgM; present in 80% but not specific)
Anti-CCP
81
Which HLA locus is linked to rheumatoid arthritis?
HLA-DRB1
82
What are some possible candidates for the arthritogenic antigen that triggers rheumatoid arthritis?
EBV
Citrullinated proteins in smokers
83
Describe the clinical presentation of rheumatoid arthritis including typical joint involvement
Initial non-specific presentation with malaise, fatigue and generalised weakness
Over few weeks to months there is subsequent joint involvement
Typically symmetrical involvement with small joints first (progresses from MCPJ and PIPJ of hands to feet, wrists, ankles, elbows and knees)
Joints swollen, warm, painful, and worse on waking or with periods of inactivity
Destruction of tendons, ligaments and joint capsules produces characteristic deformities (e.g. swan neck, boutonnière)
May also present with rheumatoid nodules (cutaneous lesions)
84
Four radiologic hallmarks of rheumatoid arthritis
1. Joint effusions
2. Juxta-articular osteopenia
3. Erosions and narrowing of joint space
4. Loss of articular cartilage
85
What are the findings on synovial fluid aspirate in rheumatoid arthritis?
Not specific but shows inflammatory change with neutrophils, increased protein and decreased mucin
86
What is the usual source of bacteria in septic arthritis?
Haematogenous spread
Except in neonates where it may be due to spread from adjacent epiphyseal osteomyelitis
87
Five common causative organisms in bacterial septic arthritis
1. Gonococcus
2. Staphylococcus
3. Streptococcus
4. Haemophilus influenzae
5. Gram negative bacilli (e.g. E. coli, Salmonella, Pseudomonas)
88
What is a common causative organism of septic arthritis in children <2yo?
H. influenzae
89
What is a common causative organism of septic arthritis in older children and adults?
S. aureus
90
What is a common causative organism of septic arthritis in late adolescence and young adulthood?
Gonococcus
91
What is a common causative organism of septic arthritis in sickle cell?
Salmonella
92
Does gonococcal arthritis affect men and women equally?
No, more common in sexually active women
93
What is the most common pattern of joint involvement in non-gonococcal septic arthritis?
Usually single joint affected
In order of decreasing frequency: knee, hip, shoulder, elbow, wrist, sternoclavicular
94
Which joints are typically affected in tuberculous arthritis?
Weight-bearing joints (hips, knees, ankles)
95
Describe the typical presentation of Lyme arthritis
Occurs within few weeks to 2yrs of initial illness
Characterised by vomiting and migratory polyarthritis
96
Six causative organisms of viral septic arthritis
1. Alphavirus
2. Parvovirus B19
3. Rubella
4. EBV
5. HBV
6. HCV
97
What are the different possible causes of crystal arthropathies?
Endogenous or exogenous crystals
Endogenous includes monosodium urate (gout) and calcium pyrophosphate dihydrate (CPPD; pseudogout)
Exogenous includes talcum, silicone
98
Describe the typical clinical course of gout
Transient attacks of acute arthritis due to crystallisation of urates within and around joints
Leads to chronic gouty arthritis and formation of tophi (large crystal aggregates with surrounding inflammation)
Most with chronic gout will also develop urate nephropathy
99
Describe the possible causes of primary vs secondary gout
Primary:
- Due to urate overproduction: dietary, unknown enzyme defects (in 80-90%), known enzyme defects (rare; usually in HGPRT enzyme)
- Due to decreased uric acid excretion
Secondary:
- Due to urate overproduction: increased nucleic acid turnover (e.g. leukaemia), inborn errors of metabolism
- Due to decreased uric acid excretion (e.g. CKD)
100
Seven risk factors for gout
1. Hyperuricaemia (>6.8mg/dL)
2. Increasing age and duration of hyperuricaemia (20-30yrs of hyperuricaemia increases risk)
3. Genetics (including HGPRT enzyme deficits)
4. Excessive alcohol consumption
5. Obesity
6. Drugs (e.g. thiazides)
7. Lead toxicity
101
What joint is affected in ~50% of first presentations of acute gout?
Usually monoarticular
50% in first MTPJ
102
Which joints are most often affected in gout?
First MTPJ
90% experience acute attacks in insteps, ankles, heels, knees, wrists, fingers and elbows
103
Describe the pathogenesis of gout
104
What joints are typically affected in pseudogout?
May be monoarticular or polyarticular
Affects knees, wrists, elbows, shoulders, ankles
105
Three risk factors for pseudogout
1. Increasing age
2. Predisposing conditions (e.g. hyperparathyroidism, haemochromatosis)
3. Hereditary factors (e.g. ANKH mutation)
