Metabolic Bone Disease

Question 1

What is the function of osteoblasts?

Answer 1

Synthesize organic components of bone

Question 2

Mineralization is a _____ process

Answer 2

passive

Question 3

Which cells account for 90% of bone tissue cells and are responsible for mechano-transduction in bone tissue?

Answer 3

Osteocytes

Question 4

What is the function of osteoclasts?

Answer 4

Multi-nucleated giant cells that degrade bone matrix

Question 5

Which type of bone (compact or trabecular) is more actively remodeled?

Answer 5

Trabecular

Question 6

What type of remodeling is associated with each type of bone (Trabecular and Compact)

Answer 6

Trabecular: Cancellous remodeling

Compact: Cortical remodeling

Question 7

What are the differences between cancellous and cortical remodeling?

Answer 7

• Cancellous remodeling (Trabecular)
  
  • 12 BRUs/minute (25% turnover rate)
  • Higher surface to volume ratio
  • Complete remodeling takes 4-6 months
  • Osteoid laid down in discrete layers 3μm thick
  • Lamellae deposited in curved sheets that follow contour of the trabeculae
• Cortical remodeling (Compact)
  
  • 3 BRUs/minute (2-3% turnover rate)
  • Accounts for 20% of turnover
  • Remodeling cycle takes 4-6 months
  • Osteoblasts plus blood vessels follow osteoclasts through hollowed out tunnel
  • Concentric lamellae laid down

Question 8

How do PTH and 1,25(OH)D affect bone remodeling?

Answer 8

PTH and 1,25(OH)D are potent activators of osteoclast activity

Question 9

How does the composition of bone contribute to its stability?

Answer 9

Bone is made up of a mixture of materials good at resisting tensile loads (protein) with materials good at resisting compression (mineral)

Question 10

What is the primary protein component of the bone matrix?

Answer 10

Type I Collagen

Question 11

What does the Mechanostat tell us about the properties of bone? How does this information contribute to our understanding of bone loss in the elderly?

Answer 11

• Bone mass is stable within a narrow range of strain
• Bone formation occurs in response to overloading and bone loss occurs in response to underloading

Decreased sensitivity to mechanical loading is a key mechanism by which bone is lost in older adults

Question 12

Describe the hierarchical structure of bone from smallest components to largest

Answer 12

Collagen molecule → Collagen fibril → Collagen Fibers → Osteocyte lacuna (lamella) → Haversian canals (Osteons)

Question 13

Why do bones have fairly high resistance to cracks?

Answer 13

The interfaces between lamellae and osteons (cement lines) can absorb/dissipate force

Question 14

How are the functions of cortical and trabecular bone different?

Answer 14

Cortical: Fulfills mainly mechanical and protective function

Trabecular: Fulfills mainly metabolic function

Question 15

What is the WHO definition of osteoporosis?

Answer 15

• Compromised bone strength
• Increased Risk of fracture

Question 16

What is the gender preference in osteoporosis?

Answer 16

80% of cases are women - greater incidence than breast cancer

Question 17

Bone strength reflects the integration of ________ and _______

Answer 17

Bone density; Bone quality

Question 18

How are osteoporosis and BMD related?

Why is BMD necessary for osteoporosis diagnosis?

Answer 18

Low BMD density is a risk factor for fracture; A low trauma fracture partially due to low BMD is considered “established osteoporosis”

Most low trauma fractures occur in people who do not have osteoporosis

Question 19

What are differences of in vivo loading of long bones and vertebrae?

Answer 19

Long bones are slightly curved and loaded primarily by bending

Vertebrae are loaded primarily in compression and torsion

Question 20

What are some common risk factors for fracture of bone? Which is the most powerful predictor?

Answer 20

• Past fracture (Most powerful predictor)
• Sex (Females > Males)
• Age
• Glucocorticoid use (>7.5 mg/day)
• BMD (more than 1 SD change)

Question 21

What are the differences between the FRAX and Garvan risk factor calculators?

Answer 21

FRAX: past fracture, glucocorticoids, hip function, rheumatoid arthritis, smoking, alcohol

Garvan: Past fracture (graded); Falls (graded)

Question 22

What causes the differences between men and women for risk of fracture?

Answer 22

• Male bones grow larger than female bones
• Women have a period of rapid bone loss peri-menopausally
• In trabecular one, female loss tends to be patchier than males

Question 23

What is the most important differential diagnosis to osteoporosis? How is it different than osteoporosis?

Answer 23

Osteomalacia - Quantity of bone is insufficient and architecture is impaired (matrix is under-mineralized and weak)

Question 24

How is osteomalacia seen on imaging?

Answer 24

• In normal bone, 2 sharp lines mark mineralization front (seen with tetracycline labeling)
  
  • Separation between the lines is a measure of how quickly new bone mineralizes
  • In osteomalacia, lines are smudged and there is increased osteoid volume (seen by staining)

Question 25

What becomes elevated in osteomalacia? Why?

Answer 25

PTH - mineral deficiency drives hyperparathyroidism Bone isoform of alkaline phosphatase - associated with osteoblast hyperactivity P1NP - Pro-peptide of type 1 collagen

Question 26

What two classes of drugs are used to reduce the risk of low trauma fracture? How does each work?

Answer 26

* Antiresorptives: work by limiting initiation of new BMUs (bone modeling units) * Since bone formation takes longer than bone resoprtion, inhibiting rate of process allows remodeling space to be filled * Anabolics (**Teriparatide**) = synthetic PTH analog * When given as a daily subcutaneous injection, action on osteoblasts is greater than action on osteoclasts

Question 27

What minerals in the diet can improve risk for fracture?

Answer 27

Vitamin D, Calcium, Phosphate

Question 28

What is the difference in calcium supplements of calcium carbonate vs. calcium citrate?

Answer 28

Calcium Carbonate is 40% elemental calcium wherease Calcium Citrate is only 21% elemental calcium - this affects how much should be taken

Question 29

How does estrogen serve as a treatment for osteoporosis?

Answer 29

Selective estrogen receptor modulators (SERMS): Synthetic estrogen with altered properties to enhance therapeutic benefit

Question 30

How are bisphosphonates (**Aledronate, Risedronate)** useful in preventing fracture? What do new forms do that overcome the problem of poor absorption?

Answer 30

Bisphosphonates inhibit the conversion of mevalonate to farnesyl → inhibition of protein farnesylation → leads to osteoclast apoptosis Old bisphosphonates were given orally and absorbed poorly; Newer forms are adminstered parenterally (**Zoledronic acid)**

Question 31

What is the function of Denosumab? What is a side effect?

Answer 31

Denosumab serves as a decoy receptor for RANKL * When RANKL binds the drug, it is unable to bind the endogenous receptor (RANK) → interruption of this interaction prevents osteoclast differentiation * Side Effect: Atypical femoral fractures

Question 32

What is the role of vitamin D in maintenance of stable calcium levels? How is it inactivated?

Answer 32

Vitamin D facilitates calcium absorption in the intestine, renal resorption of calcium, and increases bone remodeling Vitamin D is inactivated by 24-hydroxylation

Question 33

Describe the interaction between PTH and Vitamin D

Answer 33

1. When CaSR senses low calcium PTH is released 2. PTH stimulates the kidney to activate vitamin D (25 → 1,25) 3. Skeleton increases bone turnover

Question 34

What regulates phosphate excretion?

Answer 34

PTH and fibroblast growth factor 23 (FGF23)

Question 35

How does FGF23 reduce vitamin D?

Answer 35

FGF23 inhibits expression of 1-hydroxylase which reduces vitamin D activation FGF23 increases activity of 24-hydroxylase (increases vitamin D clearance)

Question 36

How does FGF23 reduce PTH and Phosphate?

Answer 36

FGF23 lowers phosphate through the urine Decreasing phosphate levels in the urine leads to decreased PTH secretion

Question 37

How is FGF23 associated with hypophosphatemic disorders? What are different ways this can occur?

Answer 37

Hypophosphatemic disorders occur due to accumulation of FGF23 * **Tumor induced osteomalacia** (tumors secrete FGF23) * **Autosomal dominant hypophosphatemic rickets** (FGF23 mutation) * **Autosomal recessive hypophosphatemic rickets** (FGF23 degredation is impaired) * **X-linked hypophosphatemic rickets**

Question 38

How can Osteomalacia lead to rickets?

Answer 38

Rickets is the consequence of osteomalacia before closure of the growth plates

Question 39

What is the mechanism of dysfunction in Paget's disease of bone? How does it present?

Answer 39

Unregulated bone turnover * Impaired biomechanical performance (woven bone) * Increased vascularity * Bone deformity (abnormal modeling and dysregulated remodeling)