Bone Pathology

Question 1

Basic Structure and Function of Bone

Answer 1

Question 2

Cellular Components of Bone: Osteoblasts

Answer 2

Question 3

Cellular Components of Bone: Osteoclasts

Answer 3

Question 4

Woven or Lamellar?

Answer 4

Question 5

Explain Endochondral Ossification

Answer 5

Question 6

Explain Endochondral Ossification: Primary Spongiosia

Answer 6

Question 7

Explain Itramembranous ossification

Answer 7

• flat bones
• formed direct from osteoblasts
  
  • no cartilage anlagen
• enlargement- new bone on pre-exsisting surface

Question 8

Roles of GH, T3, PTHrP, Int, SOX9, RUNX2, and FGF3

Answer 8

Question 9

Remodeling

Answer 9

• constant turnover of bone; tightly regulated process
• ~10% of skeleton is replaced annually
• takes place at BMU
  
  • coupled osteoblast and osteoclast activity on bone surface
  • orderly sequence of osteoclast attachment, resorption, osteoblast attachment and proliferation, and matrix synthesis
• Regulated by cell-cell interaction and cytokines

Question 10

Cytokines in remodeling

Answer 10

RANK- osteoclast precursor

RANKL- osteoblasts

OPG- “decoy” receptor; bind RANKL and prevent interaction with RANK

RANK-RANKL activate NF-kB

M-CSF produced by osteoblasts; stimulates tyrosine kinase cascade leading to osteoclast differentiation

Question 11

Explain this and balance of remodeling

Answer 11

Bone formation and remodeling modulated by connection between RANK and WNT pathways

factors affecting balance: hormones, vit D, cytokines, growth factors

paracrine crosstalk between osteoclasts and osteoblasts: as bone is broken down substances are released that stimulate osteoblasts

peak bone mass achieved in early adulthood: by 4th decade resorption exceeds formation and steady decline in skeletal mass

Question 12

Achondroplasia

Answer 12

most common skeletal dysplasia

autosomal dominant

retarded cartilage growth

shortened proximal extremities

enlarged head with bulging forehead

gain of function mutations in FGFR3

normally FGFR3 inhibits endochondral growth

constitutive activation = surpassed growth

approx. 90% are new mutation: almost all in paternal allele

Question 13

Osteogenesis Imperfecta (OI)

Answer 13

Deficiencies in synthesis of type I collagen - osteoid

most common inherited disorder of connective tissue

bone and other tissue rich in collagen: joints, eyes, ears, skin, teeth

autosomal dominant mutations in a1 and a2 chains of type I collagen: effective assembly of collagen polypeptides

too little bone > extreme skeletal fragility

blue sclerae > decreased collagen (think sclerae)

hearing loss > impaired conduction

dental abnormalities > deficient dentin

Question 14

Types of osteogenesis imperfect

Answer 14

Question 15

Osteopetrosis

Answer 15

• AKA marble bone disease or Albers-Schonberd disease
• reduced bone resorption and diffuse, symmetric skeletal sclerosis
• Imparied formation or function of osteoclasts
• mutations interfere with acidification of osteoclast resorption pit
  
  • i.e. CA2 required to generate protons from CO2 and H2O
  • Lack of CA2 prevents acidification of resorption pit: prevents osteoclast activity
• lack medullary canal
• ends long bones are misshapen: Erlenmeyer flask deformity
• small neural foramina compress nerves
• primary spongiosia persists
• no room for marrow elements
• woven bone remains because mature trabecular cannot form

Question 16

Severe Infantile form of osteopetrosis

Answer 16

Autosomal recessive

evident in utero or soon after birth

fracture, anemia, hydrocephaly

death early

repeated infections du etc leukopenia

Question 17

Mild Adult form of Osteopetrosis

Answer 17

Repeated fractures

mild cranial nerve deficits

anemia

*kaplan- carbonic anhydrase deficiency

Question 18

Acquired Disorder: Osteoporosis

Answer 18

osteopenia (decreased bone mass)

osteopenia severe enough to significantly increase risk of fracture

bone mass >2.5 STDs below mean peak bone mass

localized and generalized

senile and postmenoposal most common

normal bone but decreased in quantity (thin)

some bones more severely impacted

Senile- cortex thinned

post menopausal- trabecular plates perforated and thinned

clinical manifestations depend on involved bones

cant be reliably detected by x-rays

Question 19

Best screenings for osteoporosis

Answer 19

Quantitative CT and DEXA scans

Question 20

Osteoporosis: prevention and treatment

Answer 20

exercise, calcium, vitamin D, bisphophonates

Question 21

Paget Disease (osteitis deformans)

Answer 21

increased disorder bone (uncoupling of BMU)

usually begins in late adulthood

both environmental and genetic causes

Question 22

phases of Paget Disease

Answer 22

Initial osteolytic phase: osteoclast activity. with resorption pits: osteoclasts are giant with abundant nuclei

Mixed phase: osteoclasts persist, now with osteoblastic rimming; marrow replaced by loose connective tissue; osteoprogenitor cells and blood vessels

Sclerotic phase: mosaic pattern of lamellar bone; prominent cement lines; periosseous tissue replaced by normal marrow, thickened trabecular and soft, porous cortices.

Question 23

Stage of Paget?

Answer 23

Stage 3: sclerotic phase

Question 24

Clinical findings and treatment of Paget disease

Answer 24

variable

majority of patients asymptomatic; incidental radiographic finding

most symptoms are mild; readily created with calcitonin and bisphophonates

Question 25

Hyperparathyroidsim

Answer 25

**osteoclast activation -** increased bone resorption and calcium mobilization; due to increased RANKL expression. on osteoblasts **increased calcium resorption** by renal tubules **increased urinary excretion of phosphates** **increased synthesis of active vitamin D** by kidneys; calcium absorption from the gut; induces RANKL on osteoblasts thus mobilizing bone calcium

Question 26

Hyperparathyroidism associated disorders

Answer 26

Osteoporosis: generalized; phalanges, vertebrae, proximal femur **dissecting osteitis** - osteoclasts tunnel through trabecular; marrow spaces replaced by fibrovascular tissue **brown tumor**- bone loss leads to micro fractures and secondary hemorrhage; influx of macrophages and fibrous tissue; can undergo cystic degeneration **osteitis fibrosa cystica- hallmark of severe hyperparathyroidism;** increased bone cell activity; peritrabecular fibrosis; cystic brown tumors

Question 27

?

Answer 27

brown tumor and osteitis fibrous cystica caused by hyperparathyroidism

Question 28

Secondary response to hyperparathyroidism

Answer 28

**chronic hypocalcemia** compensatory overactivity of parathyroids, increased PTH **renal failure** most common cause; inadequate vitamin D sythesiss; affects Gi calcium absorption decreasing bone mass leads to more susceptible to fractures, bone deformation, and joint problems treatment: decreased PTH levels reverses bone changes

Question 29

Renal Osteodystrophy and mechanisms of skeletal deformities

Answer 29

skeletal changes in chronic renal disease **mechanisms of skeletal deformities with renal disease** * **tubular dysfunction-** renal tubular acidosis; low pH dissolves hydroxyapatite and demineralizes and osteomalacia * **generalized renal failure**- affects glomerular and tubular function; reduced phosphate excretion; chronic hyperphosphatemia; hypocalcemia; secondary hyperparathyroidism * **decreased production of secreted factors-** involves BMP-7, FGF23, Klotho; results in osteopenia and osteomalacia

Question 30

3 main types of Renal Osteodystrohpy

Answer 30

High turnover- increased bone resorption and formation low turnover (aplastic)- little osteoblastic and osteoclastic activity; osteomalacia less commonly mixed pattern

Question 31

Osteocnecrosis

Answer 31

infarction of bone and marrow medullary cavity or medulla and cortex usually due to fractures or steroids all cause vascular insufficiency by: mechanical injury; thromboembolism; external pressure, venous occlusion.

Question 32

?

Answer 32

Osteonecrosis: •Medullary infarcts – geographic•Cortex not affected•Collateral blood flow•**In subchondral infarcts – wedge shaped necrosis**•Overlying articular cartilage viable•Supplied by synovial fluid

Question 33

?

Answer 33

Osteonecrosis: •**Empty lacunae** surrounded by necrotic adipocytes•Healing response – osteoclasts resorb necrotic trabeculae•Remaining trabeculae act as scaffolding for new bone•With subchondral infarcts the pace of replacement is too slow•à Collapse of the necrotic bone and distortion, fracture, and sloughing of articular cartilage

Question 34

Osteonecrosis symptoms

Answer 34

•Symptoms depend on location & extent of infarction•**Subchondral – pain with activity initially**•Constant later•Collapse à severe secondary arthritis•**Medullary – small & clinically silent**•Exceptions Gaucher disease & sickle cell anemia

Question 35

Osteomyelitis

Answer 35

* Inflammation of bone & marrow•Secondary to infection * Pyogenic bacteria & mycobacteria most common * Infection through: hematogenous spread, extension from contiguous site, direct implantation * ***Staphylococcus aureus*** **80%-90% of culture positive cases**

Question 36

Infections pathogens of osteomyelitis

Answer 36

* **GU infections & IV drug users –** ***E. coli, Pseudomonas, Klebsiella***•**Neonates –** ***H. influenzae*** **and Group B strep** * **Sickle cell patients –** ***Salmonella*** * Mixed infections – direct spread/inoculation•50% - no organism isolated

Question 37

?

Answer 37

Osteomyelitis: * Acute – bacterial proliferation * **Neutrophils**•Necrosis of bone marrow * Subperiosteal abscess may form•Lifting of periosteum à impaired blood supply ànecrosis * Dead bone = sequestrum - surrounded by involucrum * Ruptured periosteum can drain to skin

Question 38

?

Answer 38

Osteomyelitis * After a week, chronic inflammatory cells release cytokines causing * Osteoclastic bone resorption * Ingrowth of fibrous tissue * Deposition of reactive bone * Involucrum – shell of living tissue around infected bone

Question 39

disease and treatment?

Answer 39

Osteomyelitis * May manifest as acute systemic illness or minimal subtle symptoms * Characteristic radiographic finding s•**Lytic bone destruction with surrounding sclerosis** * Tx: antibiotics & surgical drainage * Up to 25% persist as chronic infection * Causes•Delay in diagnosis•Extensive bone necrosis•Inadequate therapy•Weakened immune system•Spontaneous acute flare-ups * Complications: pathologic fracture, secondary amyloidosis, endocarditis, sepsis, malignancy

Question 40

Mycobacterial osteomyelitis

Answer 40

•1-3% of patients with TB have osseous involvement•Infection may persist for years•Localized pain, low grade fevers, chills, weight loss•Usually solitary•**Caseating granulomata**•Destructive & treatment resistant than pyogenic ## Footnote •**Pott disease – tubercular spondylitis**•Multiple vertebrae•Extends into soft tissue•Permanent compression fractures•Scoliosis or kyphosis•Neurologic defects due to spinal cord & nerve compression•Other complications•Arthritis, sinus tract, abscess, amyloidosis

Question 41

Skeletal Syphilis and types

Answer 41

* *Treponema pallidum* (spirochete)•Congenital syphilis – lesions appear around 5^th month of gestation•Areas of active endochondral ossification & periosteum * “Saber shin” – massive reactive periosteal bone deposition * Acquired syphilis – tertiary stage•Nose, palate, skull, extremities

Question 42

???

Answer 42

Skeletal syphilis