Pharm affecting bone mineral homeostasis: Cook

Question 1

Compare and contrast the mechanisms of action of
calcitonin, calcitriol and parathyroid hormone and manner in which they modify endogenous systems of calcium
regulation.

Answer 1

Calcitonin- opposes the effects of PTH by inhibiting bone resorption and promoting Ca and PO4 loss in urine.
MOA:
• Binds to plasma membrane receptor
• Decreases ruffled border surface area on
osteoclasts
• Not a global inhibitor of PTH
• Has direct renal effects

Calcitriol (active Vit. D)- promotes uptake of Ca and PO4 from the intestine (Ca from duodenum only), stimulates bone turnover (resorp/building), and inhibits losses of both Ca and PO4.
MOA:
• Stimulates Ca2+ and phosphate absorption in the
small intestine
• Induces synthesis of calbindin (family of Ca2+
binding proteins)
• Binds to transcription factor to increase mRNA,
protein synthesis
• Has additional effects to increase uptake of Ca2+
from intestine

PTH- stimulates activation of Vit. D, promotes resorption of bone AND building of bone, and inhibits loss of Ca in urine while promoting loss of PO4 in urine so there will be more free (uncomplexed) plasma Ca. 
MOA: 
• Binds to plasma membrane receptor
• Activates adenylate cyclase
• Increases [cyclic AMP]
• cAMP activates protein kinases
• Action results in increased urinary cAMP, a test
for parathyroid gland function.

Question 2

Discuss the mechanism of action, therapeutic role and severe limitations of bisphosphonates use in the treatment of osteoporosis.

Answer 2

Analogs of Sodium pyrophosphate
-non hydrolyzable pyrophosphates
MOA: kill osteoclasts
All Rx end in “dronate”
• etidronate (Didronel), alendronate (Fosamax),
risedronate (Actonel)- 10,000x more potent than 1st gens. used in Paget’s disease
• alendronate (Fosamax) used for osteoporosis
• All are absorbed very poorly in the intestine
• Must be taken after an overnight fast with a full
glass of water. No food for 30 minutes.
• Now have weekly dosage form.

Also great for pts. w metastatic bone mass loss

Serious complications of bisphosphonates therapy:
::Osteonecrosis of the Jaw
::Fractures of strongest part of femur bc bone is brittle due to lack of resorption
Therefore recommended that pt not take bisphosphonates for more than 5yrs

Question 3

Define the term calcimimetics and explain how such entities produce their respective mechanism of action.

Answer 3

Calcium Sensor Receptor Mimetics bind to the Calcium Sensor Receptor (CaSR)

Cinacalcet (Sensipar) is FDA approved for
hyperparathyroidism in patients with parathyroid
carcinoma.
Cinacalcet binds allosterically to CaSR and allows
PTH suppression at lower [Ca2+]. Effectively lowers
circulating PTH.

Question 4

What is cinacalcet? What effect does it have on PTH levels?

Answer 4

It is a calcimimetic and an osteoporosis drug. It sensitizes the Ca-sensing receptor. This lowers levels of PTH b/c the PT gland thinks that there is more Ca circulating than there actually is.

*think: it “sets” the “cal”cium sensor lower

Question 5

What is Teriparatide and what are its funny effects on bone formation, considering what it is?

Answer 5

Teriparatide (hrPTH 1-34) is a exogenous, low dose PTH analog. It directly stimulates bone formation when administered in LOW doses, without stimulating bone resorption. Great for women w/ osteoporosis after bisphosphonate tx. It may also stimulate IGF-1.

Question 6

What are SERMs and what are their benefit?

Answer 6

Selective Estrogen Receptor Modulators (SERMs) carry the beneficial effects of estrogen w/o stimulating breast cancer and DVT (due to production of clotting factors).

*not widely used due to expense. Used for pts recovering from or fighting BC

Ex:
Raloxifene

Question 7

What is Denosumab?

Answer 7

Mab to RANKL. Blocks stimulation of osteoclasts, decreases osteoporosis in pts w/ breast or prostate cancer.

Question 8

List the calcitriol analogs.

Answer 8

Calcipotriol
Dihydrotachysterol (effective in high doses for osteoporosos)
Paracalcitol (reduces PTH secretion)
22-Oxacalcitriol suppresses PTH gene expression

Question 9

Strontium ranelate. What’s it used for?

Answer 9

• Used in Europe for osteoporosis
• Blocks differentiation of osteoclasts and
promotes apoptosis
• Also promotes bone formation
• Increases bone mineral density and
decreases fractures

Question 10

What does Fluoride have to do with bone mineral density?

Answer 10

Potential agent in preventing osteoporosis
• Toxicity: osteosclerosis (hydroxyapatite replaced by
fluoroapatite), mottled enamel (fluorosis)