Bone Pharmacology Flashcards
(27 cards)
What 3 proteins are up-regulated by vitamin D to enhance Ca2+ absorption?
- TRPV6 - actively pulls in Ca2+ from the gut lumen
- Calbindin - intracellular storage/transport
- PMCA - actively pumps Ca2+ across the basolateral cell membrane into the blood
Treatment of hypercalcemia - 3 prong approach
- Increase urinary calcium excretion
- Inhibit bone resorption
- Decrease intestinal absorption of Ca2+
Treatment for hypercalcemia of malignancy
Bisphosphonates are the mainstay; IV infusion inhibits osteoclastic bone resorption, resolving hypercalcemia over 24-72 hours and lasting several weeks
Agents to increase urinary calcium excretion in hypercalcemia
Loop diuretics
Agents to inhibit bone resorption in hypercalcemia
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
Agents to decrease intestinal calcium absorption in hypercalcemia
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
Acute calcium replacement - Indications & Treatment
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)
Calcium RDAs
Adolescents - 1,300mg
Adults 19-50, including pregnant/lactating women and men 51-70 - 1,000mg
Women > 50 and men > 70 - 1,200mg
Oral calcium supplementation - Adverse effects
Usually well tolerated up to 2,500 mg/day
May cause GI upset - constipation, bloating, nausea (Calcium Carbonate > Calcium Citrate)
Vitamin D RDAs & Adverse Effects
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
Effects of estrogen on Ca2+
Agonists at ER receptors on osteoblasts up-regulates production of osteoprotegerin (OPG), decreasing number and activity of osteoclasts
Osteoprotegerin (OPG)
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
Effects of glucocorticoids on Ca2+
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
Dietary Sources of Vitamin D
Cholecalciferol (Animal D3)
Ergocalciferol (Plant D2) - less completely absorbed
Calcifediol
25-OH-D3
Does not require hepatic 25-hydroxylation; most useful in patients with hepatic disease
Calcitriol
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)
Dihydrotachysterol
Functionally equivalent to 1-alpha-OH-D3
Requires hepatic 25-hydroxylation to become active
Used as an alternative to Calcitriol
Bisphosphonates - Mechanism
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
Bisphosphonates - Agents
Alendronate / Risedronate - Once-weekly dosing (oral)
Zoledronate - Once yearly dosing (IV)
Bisphosphonates - Adverse Effects
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
Roloxifine - Mechanism & Use
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
Advantages of SERMs vs. Estrogen
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
Recommendations for use of estrogen in osteoporosis management
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
Teriparatide - Mechanism, Use, Adverse Effects
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
