Calcium and Bone Pharmacology Flashcards
What conditions are responsible for 90% of hypercalcemia?
1) Hyperparathyroidism – mild and prolonged
2) Malignancy – more severe, ≈20% of cancer patients (lung, breast, hematologic); most commonly caused by increased production of PTHrP
What are the 3 goals of hypercalcemia therapy?
1) Increase urinary calcium excretion
2) Diminish intestinal absorption of calcium
3) Inhibit accelerated bone resorption
What is the treatment of hypercalcemia?
- Treat underlying disease
- Avoid certain meds – Thiazides, vitamin D
- Curtail dietary intake Ca++ and Vitamin D
- ↑ Salt and water intake
What is the first line therapy for hypercalcemia?
- Bisphosphonates
What is the effect of bisphosphonates?
- Inhibition of accelerated bone resorption
- Nonhydrolyzable analogue of pyrophosphate that is resistant to phosphatases
How long is the effect of bisphosphonate?
Zoledronate (highly potent newer drug), and others – effect may last for months
What is the mechanism of action of bisphosphonates?
- Binds to bone matrix and undergoes endocytosis by osteoclasts (is absorbed into the bone)
- Intracellular release into the cytosol
- Inhibition of cell function; induction of apoptosis
What are the adverse effects of bisphosphonates?
- Hypocalcemia
- Acute phase reaction - transient flu-like syndrome (common)
- Potential nephrotoxicity
- Precipitation of calcium bisphosphonate
- Jaw necrosis (rare)
- mostly in oncology patients
- after oral surgery or infection (dental consult before beginning therapy)
What is the second line treatment for severe hypercalcemia?
Calcitonin
- endogenous peptide hormone , C cells of thyroid gland secrete in response to high calcium
How is calcitonin administered?
- Subcutaneous or intramuscular injection
- Salmon calcitonin is used due to potency
What is the mechanism of action of calcitonin?
- cell surface G-protein-coupled receptor on osteoclasts, ↓ bone resorption
- ↑ urinary calcium excretion
What is another use for calcitonin?
- Bone analgesic
How does resistance to calcitonin develop?
- Resistance from down regulation of receptors, and from antibody formation
In what population is hypocalcemia often seen?
- Hospitalized patients
- due to chronic/acute renal failure, vitamin D deficiency, Mg++ deficiency, acute pancreatitis, hypoparathyroidism
What is the treatment for mild/asymptomatic hypocalcemia?
- Oral calcium supplements (calcium carbonate)
- Goal is to increase intestinal calcium absorption
- Can use vitamin D to enhance absorption, active form (calcitriol) may be used
What is the treatment of severe hypocalcemia? (i.e. seizures, tetany)
- IV calcium
- Calcium gluconate (best), calcium chloride (more Ca+, more rapid but more irritating to veins)
What is the most common cause of hypercalcemia?
Hyperparathyroidsm
What are the common causes of hyperparathyroidism?
- Primary – parathyroid adenoma or hyperplasia, carcinoma (rare) – treat with parathyroidectomy
- Secondary – chronic renal failure, malabsorption syndromes (activation of parathyroids to low calcium)
- Tertiary – progression into autonomous hypersecretion of PTH associated with hypercalcemia (not significant)
What drug is used in secondary hyperparathyroidism in chronic kidney disease?
Calcimimetics => Cinacalcet Hydrochloride
What are the other indications of cinacalcet hydrochloride?
- Hypercalcemia in parathyroid carcinoma
- Primary hyperparathyroidism
What are the major side effects of cinacalcet?
hypocalcemia, nausea, vomiting
What is the mechanism of action of cinacalcet?
- Allosteric regulator of CaSR
- which decreases serum PTH
What are the major preventative measures against osteoporosis?
1) Optimize calcium and vitamin D intakes throughout life
2) Weigh bearing exercise
- increases bone mass (anabolic effect)
- Decreases falls (strength and balance)
3) Falls Prevention
What types of calcium supplements are available?
- Calcium carbonate (Tums) – highest Ca++ content (40%), absorption impaired with achlorhydria
- Calcium citrate (Citracal)– more bioavailable, lower Ca++ content (21%)
What are the side effects of calcium supplements?
- GI effects
- Decreased absorption of other minerals, drugs
- Milk-alkali syndrome
Adequate absorption of calcium requires what other supplement?
Vitamin D
What is the primary function of vitamin D?
↑ GI absorption of calcium via increased intestinal calcium transport
What occurs when there is inadequate vitamin D?
When vitamin D is inadequate => secondary hyperparathyroidsm
What are the primary vitamin D supplements?
- vitamin D2 (ergocalciferol) and D3 (cholecalciferal) - oral
- 1,25(OH)2D - calcitriol - fully active, more
What other patients should take vitamin D supplements?
- fat malabsorption
- fat soluble, toxicity (hypervitaminosis D)
What is the approach to osteoporosis therapy?
- Vitamin D
- Calcium
- Anti-resportive agents (i.e. *bisphosphonates, SERMS, Danosumab, calcitonin) block bone respiration
- Bone forming (anabolic) agents (i.e. PTH) increase bone formation
What is the first lien therapy for osteoporosis?
Bisphosphonates (Fosamax and other oral analogs)
What is the action of bisphosphonates?
- Antiresportive, inhibits osteoclasts
- Increases bone mineral density
- Decreases fractures
How can bisphosphonates administered?
- Orally => empty stomach and lots of water
- Injection => every 3 months (ibandronate) or yearly (zoledronate)
What are the adverse effects of bisphosphonates?
- GI irritation ( esophagus, stomach)
What drug is used in postmenopausal osteoporosis?
- Estrogen
What is the action of estrogen in osteoporosis?
- Antiresorptive, inhibits osteoclasts, reduced turnover, nuclear ER complex regulates OB gene expression
- ↑ BMD and ↓ fractures
- Used to treat menopausal symptoms
What risk is associated with estrogen use?
May ↑ risk of heart attacks, strokes, breast cancer, migraines, blood clots (WHI study)
What SERM (selective estrogen receptor modulator) is used for post menopausal osteoporosis?
Raloxifene
- Less effective for osteoporosis than other agents
- Does not help with menopausal symptoms
What is the action of Raloxifene?
Agonist (estrogenic) effects in bone, antagonist in breast and uterus
How is Raloxifene administered?
Easy to take orally
What is the action of calcitonin?
- Antiresorptive agent, inhibits osteoclasts (cell surface receptor on OC)
- Analgesic effect (helpful for bone pain)
What is the homeostatic role of PTH?
Homeostatic role – maintains blood calcium by withdrawal from bone stores, reduces bone mass
What is the THERAPEUTIC role of PTH?
Therapeutic role – intermittent PTH treatment BUILDS bone mass
What is teriparatide?
- PTH analog => first 34 amino acid of active PTH
What is the action of Teriparatide?
- Stimulates osteoblasts and new bone growth
- ↑ turnover, improves micro-architecture
- ↑ BMD and ↓ fractures
- Very effective, but very expensive
How is Teriparatide administered?
Daily subcutaneous injection (intermittent), short half life
What adverse side effects associated with Teriparatide?
- hypercalcemia
- hypercalciuria,
What is the indication of Teriparatide?
Use in patients with high risk of fracture
Should Terparatide be used with bisphosphonates?
Use with Bisphosphonates is controversial => likely should not use
