4/10 Ca Pharma - Wondisford

Question 1

bone remodeling cycle

Answer 1

Question 2

meds for bone disorders

three categories and types within

Answer 2

1. nutritional

• calcium
• vitamin D

2. inhibitors of bone resorption (anti-catabolics)

• bisphosphonates
• estrogen, testosterone
• SERMs (selective estrogen receptor modulators)
• denosumab

3. stimulators of bone formation (anabolics)

• recombo parathyroid hormone (PTH 1-34)

Question 3

actions of calcium and vitamin D

Answer 3

CALCIUM (ex. CaCO3, Ca citrate, CaPO4)

• reduces PTH → block on osteoclasts → decr bone resorption
• incr Ca → incr mineralization (via osteocytes)

VITAMIN D

• activates osteoclasts → incr bone resorption
• incr vitamin D → incr mineralization (via osteocytes)

Question 4

bisphosphonates

Answer 4

anti-resorptive agents → block osteoclasts

recall: only agent that BUILDS bone is PTH (IN NORMAL AMT…excess? resorption)

mech: bind to bone surface at remodeling sites, where ingested by osteoclasts → cell death via two mechs:

1. non-N-containing BPs (ex. etidronate)
   
   • incorporated into ATP producting cytotoxic analog
2. N-containing BPs (ex. alendronate, zoledronic acid)
   
   • inhibit osteoclast mevalonate pathway → blocks prenylation of key reg proteins

tx: first line for osteoporosis and malignant hypercalcemia

contraindications:

• hypoCa
• swallowing disorders, inability to remain upright after oral
• significant renal insuff

side effects:

• upper GI disturbances (oral)
• flu like sx (IV)
• MSK pain
• rare: iritis, osteonecrosis of jaw, atypical femoral fractures

Question 5

estrogen/testosterone

Answer 5

estrogen = major hormonal determinant of bone mass conservation in women and men

• estrogen receptor has alpha and beta forms
  
  • alpha mediates most of the action on bone
• major action : reduce bone resorption via blockade of osteoclast devpt
• men?* aromatization of testosterone → estrogen
• major regulator of bone mass

Question 6

SERMs

Answer 6

selective estrogen receptor modulators

• tamoxifen
• raloxifene → incr OPG production (hi OPG/RANKL ratio)

mech: mimic estrogen action in some tissues, oppose estrogen action in others

Question 7

denosmab

Answer 7

mech: binds RANKL → inhibits osteoclast formation, activity, survival

Question 8

PTH 1-34

Answer 8

activates osteoblasts

tx: severe osteoporosis

contraindications:

• hx of skeletal malignancy or radiation
• preexisting hyperCa
• unexplained elev alkphos
• Paget’s disease

issues: subcut admin, expensive, osteosarcoma?

Question 9

secondary hyperparathyroidism

mechanisms in renal failure

clinical consequences

pathology

Answer 9

mechanisms:

1. hypocalcemia
2. hyperphosphatemia
3. decr 1,24(OH)2 D levels

leads to: weakness, bone pain, fractures, avascular hip necrosis

aka renal osteodystrophy → kidneys don’t make 1,25OHD

Question 10

meds for secondary hyperparathyroidism

(renal osteodystrophy)

Answer 10

• vit D analogs (calcitriol, paracalcitol, doxercaliferol)
  
  • directly decr PTH secretion
  • indicated for chronic kidney disease
• “calcimimetics” (cinacalcet)
  
  • positive allosteric activator of CaSR → directly decr PTH secretion
  • contraindication: hypocalcemia
  • adjust dose with hep failure
• phosphate binders (drop PO4 abs in gut)