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DEMS Unit 3 > Bone Pharmacology > Flashcards

Bone Pharmacology Flashcards

1
Q

What 3 proteins are up-regulated by vitamin D to enhance Ca2+ absorption?

A
  1. TRPV6 - actively pulls in Ca2+ from the gut lumen
  2. Calbindin - intracellular storage/transport
  3. PMCA - actively pumps Ca2+ across the basolateral cell membrane into the blood
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2
Q

Treatment of hypercalcemia - 3 prong approach

A
  1. Increase urinary calcium excretion
  2. Inhibit bone resorption
  3. Decrease intestinal absorption of Ca2+
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3
Q

Treatment for hypercalcemia of malignancy

A

Bisphosphonates are the mainstay; IV infusion inhibits osteoclastic bone resorption, resolving hypercalcemia over 24-72 hours and lasting several weeks

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4
Q

Agents to increase urinary calcium excretion in hypercalcemia

A

Loop diuretics

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5
Q

Agents to inhibit bone resorption in hypercalcemia

A

Bisphosphonates - IV infusion resolves hypercalcemia of malignancy over 24-72 hours; effect lasts several weeks

Calcitonin - rapidly reduces serum Ca2+ within 4-6 hours by decreasing Ca2+ mobilization from bone; ‘escape’ effect occurs within several days, however

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6
Q

Agents to decrease intestinal calcium absorption in hypercalcemia

A

Glucocorticoids - used for chronic hypercalcemia resulting from overproduction (granulomatous disease) or excess ingestion of Calcitriol; decrease Ca2+ absorption by down-regulating calcium binding proteins

Phosphates - administered orally for short-term hypercalcemic control, i.e. pre-surgery for hyperparathyroidism

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7
Q

Acute calcium replacement - Indications & Treatment

A

Severe hypocalcemic tetany (serum calcium < 7.5mg/dL) - treated with IV calcium gluconate (preferred) or IV Calcium chloride (less ideal, causes cutaneous burning sensation and peripheral dilation)

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8
Q

Calcium RDAs

A

Adolescents - 1,300mg

Adults 19-50, including pregnant/lactating women and men 51-70 - 1,000mg

Women > 50 and men > 70 - 1,200mg

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9
Q

Oral calcium supplementation - Adverse effects

A

Usually well tolerated up to 2,500 mg/day

May cause GI upset - constipation, bloating, nausea (Calcium Carbonate > Calcium Citrate)

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10
Q

Vitamin D RDAs & Adverse Effects

A

Adults up to 70 years old - 600 IU

Adults > 71 years old - 800 IU

Safe up to doses of 10,000 IU over several months; signs of toxicity are hypercalciuria and hypercalcemia

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11
Q

Effects of estrogen on Ca2+

A

Agonists at ER receptors on osteoblasts up-regulates production of osteoprotegerin (OPG), decreasing number and activity of osteoclasts

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12
Q

Osteoprotegerin (OPG)

A

OPG is expressed by osteoblasts in response to estrogen binding; it acts as a ‘decoy’ to bind RANKL on osteoblasts, preventing binding of RANKL to RANK and thereby preventing osteoblast activation

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13
Q

Effects of glucocorticoids on Ca2+

A

Glucocorticoids antagonize Vitamin D-mediated intestinal Ca2+ absorption; this lowers serum Ca2+ which in turn increases PTH to stimulate osteoclast activity

30-50% of patients on chronic glucocorticoids may develop osteoporotic bone fractures

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14
Q

Dietary Sources of Vitamin D

A

Cholecalciferol (Animal D3)

Ergocalciferol (Plant D2) - less completely absorbed

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15
Q

Calcifediol

A

25-OH-D3

Does not require hepatic 25-hydroxylation; most useful in patients with hepatic disease

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16
Q

Calcitriol

A

1,25(OH)2-D3

Most useful in patients with decreased synthesis of calcitriol due to chronic renal failure or type 1 vitamin D-dependent rickets (renal 1-hydroxylase deficiency)

17
Q

Dihydrotachysterol

A

Functionally equivalent to 1-alpha-OH-D3

Requires hepatic 25-hydroxylation to become active

Used as an alternative to Calcitriol

18
Q

Bisphosphonates - Mechanism

A

Binds to active sites of bone remodeling and has direct inhibitory effects on osteoclasts there by 1. increased osteoclast apoptosis and 2. inhibition of prenylation of proteins necessary for osteoclast function

19
Q

Bisphosphonates - Agents

A

Alendronate / Risedronate - Once-weekly dosing (oral)

Zoledronate - Once yearly dosing (IV)

20
Q

Bisphosphonates - Adverse Effects

A

GI effects - heartburn, abdominal pain, diarrhea

Esophagitis - reduced if taken following overnight fast, upright, with water, with nothing by mouth for 30-60 minutes

Bone/joint/muscle pain - Rare

21
Q

Roloxifine - Mechanism & Use

A

Selective Estrogen Receptor Modulator (SERM) - acts as estrogen agonist on bone and liver; inactive on uterus and antagonistic on breast

Second-line for prevention / treatment of osteoporosis in patients who cannot tolerate bisphosphonates, or in patients at risk of breast cancer

22
Q

Advantages of SERMs vs. Estrogen

A

Advantages of SERMs - Reduced risk of breast cancer and coronary events

Disadvantages of SERMs - Exacerbation of hot flahses, similar risk of thromboembolism due to agonist action at liver

23
Q

Recommendations for use of estrogen in osteoporosis management

A

Estrogen is not recommended as first-line treatment for osteoporosis due to increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism

Estrogen as menopausal hormone therapy should be limited to women with significant hot flashes who are not at risk for heart disease

24
Q

Teriparatide - Mechanism, Use, Adverse Effects

A

Synthetic PTH Fragment; administration paradoxically increases osteoblastic activity with increased bone formation

Use in osteoporosis as the only agent which actually stimulates bone formation

Adverse Effects - Nausea, headache, dizziness, muscle pain, hypercalcemia

25
Q

Calcitonin - Mechanism, Use, Adverse Effects

A

Inhibits osteoclastic bone resorption causing a modest increase in bone mass; approved for treatment of osteoporosis only

Adverse Effects: Nausea, hand swelling, urticaria, cramps, rhinitis, epistaxis

26
Q

Denosumab - Mechanism & Use

A

Humanized monoclonal antibody against RANKL on osteoblast; reduces RANK-mediated activation of osteoclasts

Used as alternative treatment of osteoporosis in patients with high fracture risk who are intolerant of or unresponsive to bisphosphonates; administered SC x 6 months

27
Q

Hydrochlorothiazide - Mechanism

A

Enhances PTH-mediated reabsorption of Ca2+ in the kidney; additionally, block of Na+ reabsorption may indirectly result in increased Ca2+ reabsorption

DEMS Unit 3 (7 decks)

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