Metabolic Bone Disease Flashcards
What is the function of osteoblasts?
Synthesize organic components of bone
Mineralization is a _____ process
passive
Which cells account for 90% of bone tissue cells and are responsible for mechano-transduction in bone tissue?
Osteocytes
What is the function of osteoclasts?
Multi-nucleated giant cells that degrade bone matrix
Which type of bone (compact or trabecular) is more actively remodeled?
Trabecular
What type of remodeling is associated with each type of bone (Trabecular and Compact)
Trabecular: Cancellous remodeling
Compact: Cortical remodeling
What are the differences between cancellous and cortical remodeling?
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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
How do PTH and 1,25(OH)D affect bone remodeling?
PTH and 1,25(OH)D are potent activators of osteoclast activity
How does the composition of bone contribute to its stability?
Bone is made up of a mixture of materials good at resisting tensile loads (protein) with materials good at resisting compression (mineral)
What is the primary protein component of the bone matrix?
Type I Collagen
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?
- 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
Describe the hierarchical structure of bone from smallest components to largest
Collagen molecule → Collagen fibril → Collagen Fibers → Osteocyte lacuna (lamella) → Haversian canals (Osteons)
Why do bones have fairly high resistance to cracks?
The interfaces between lamellae and osteons (cement lines) can absorb/dissipate force
How are the functions of cortical and trabecular bone different?
Cortical: Fulfills mainly mechanical and protective function
Trabecular: Fulfills mainly metabolic function
What is the WHO definition of osteoporosis?
- Compromised bone strength
- Increased Risk of fracture
What is the gender preference in osteoporosis?
80% of cases are women - greater incidence than breast cancer
Bone strength reflects the integration of ________ and _______
Bone density; Bone quality
How are osteoporosis and BMD related?
Why is BMD necessary for osteoporosis diagnosis?
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
What are differences of in vivo loading of long bones and vertebrae?
Long bones are slightly curved and loaded primarily by bending
Vertebrae are loaded primarily in compression and torsion
What are some common risk factors for fracture of bone? Which is the most powerful predictor?
- Past fracture (Most powerful predictor)
- Sex (Females > Males)
- Age
- Glucocorticoid use (>7.5 mg/day)
- BMD (more than 1 SD change)
What are the differences between the FRAX and Garvan risk factor calculators?
FRAX: past fracture, glucocorticoids, hip function, rheumatoid arthritis, smoking, alcohol
Garvan: Past fracture (graded); Falls (graded)
What causes the differences between men and women for risk of fracture?
- 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
What is the most important differential diagnosis to osteoporosis? How is it different than osteoporosis?
Osteomalacia - Quantity of bone is insufficient and architecture is impaired (matrix is under-mineralized and weak)
How is osteomalacia seen on imaging?
- 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)
What becomes elevated in osteomalacia? Why?
PTH - mineral deficiency drives hyperparathyroidism
Bone isoform of alkaline phosphatase - associated with osteoblast hyperactivity
P1NP - Pro-peptide of type 1 collagen
What two classes of drugs are used to reduce the risk of low trauma fracture? How does each work?
- 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
What minerals in the diet can improve risk for fracture?
Vitamin D, Calcium, Phosphate
What is the difference in calcium supplements of calcium carbonate vs. calcium citrate?
Calcium Carbonate is 40% elemental calcium wherease Calcium Citrate is only 21% elemental calcium - this affects how much should be taken
How does estrogen serve as a treatment for osteoporosis?
Selective estrogen receptor modulators (SERMS): Synthetic estrogen with altered properties to enhance therapeutic benefit
How are bisphosphonates (Aledronate, Risedronate) useful in preventing fracture? What do new forms do that overcome the problem of poor absorption?
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)
What is the function of Denosumab?
What is a side effect?
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
What is the role of vitamin D in maintenance of stable calcium levels? How is it inactivated?
Vitamin D facilitates calcium absorption in the intestine, renal resorption of calcium, and increases bone remodeling
Vitamin D is inactivated by 24-hydroxylation
Describe the interaction between PTH and Vitamin D
- When CaSR senses low calcium PTH is released
- PTH stimulates the kidney to activate vitamin D (25 → 1,25)
- Skeleton increases bone turnover
What regulates phosphate excretion?
PTH and fibroblast growth factor 23 (FGF23)
How does FGF23 reduce vitamin D?
FGF23 inhibits expression of 1-hydroxylase which reduces vitamin D activation
FGF23 increases activity of 24-hydroxylase (increases vitamin D clearance)
How does FGF23 reduce PTH and Phosphate?
FGF23 lowers phosphate through the urine
Decreasing phosphate levels in the urine leads to decreased PTH secretion
How is FGF23 associated with hypophosphatemic disorders? What are different ways this can occur?
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
How can Osteomalacia lead to rickets?
Rickets is the consequence of osteomalacia before closure of the growth plates
What is the mechanism of dysfunction in Paget’s disease of bone?
How does it present?
Unregulated bone turnover
- Impaired biomechanical performance (woven bone)
- Increased vascularity
- Bone deformity (abnormal modeling and dysregulated remodeling)
