Osteoporosis Pharmacology

Question 1

available as oral and parenteral formulations

• oral forms used to treat:

– to treat mild hypocalcemia

– as dietary supplements in adolescents, elderly and postmenopausal women

– taking too much can cause hypercalcemia, GI disturbances (e.g., constipation), CNS effects (e.g., lethargy) and renal dysfunction (e.g., polyuria, kidney stones)

• parenteral calcium salts are given to r_apidly increase calcium levels_ in patients with severe hypocalcemia

Answer 1

bisphosphonates-Alendronate

MOA: structural analogs of pyrophosphate, a normal constituent of bone,

Drugs of first choice…

 postmenopausal osteoporosis

 osteoporosis in men

 glucocorticoid‐ induced osteoporosis

 Paget disease of bone

 hypercalcemia of malignancy

toxicities: generally safe, but serious side effects can occur including

 esophagitis +/- ulceration, minimized by taking medication with 8 oz of water upon waking and waiting 30 min before any other liquid or food

 ocular inflammation

 osteonecrosis of the jaw

 atypical femur fractures

 atrial fibrillation

others: others: risedronate (PO), ibandronate (PO, IV), tiludronate (PO), zolendronic acid (IV, typically once/year)

zolendronic acid

(IV) has been associated most commonly with osteonocrosis of the jaw

(ONJ), often occurring after tooth extraction or some other dental procedure in cancer patients), also causes dose‐dependent kidney damage and rarely atrial fibrillation

Question 2

raloxifene-selective estrogen receptor modulator (SERM)

blocks estrogen effects in breast and uterus, and agonist at bone

due to its estrogen agonist effects on bone, used to prevent and treat postmenopausal osteoporosis

due to its antiestrogen effects in the breast, used to reduce the risk for development of (but not treat) estrogen‐ dependent breast cancer

toxicities: deep venous thrombosis, pulmonary embolism and stroke

SERM tamoxifen is generally not used to treat osteoporosis

Answer 2

teriparatide (PTH 1‐34)

endogenous PTH that retain activity of full length PTH

the only drug for osteoporosis that increases bone formation…

given continously= bone resorption by osteoclast is predominant

given as daily pulsed therapy, osteoblast responses predominant

Question 3

denosumab-monoclonal antibody that is a first‐in‐class RANKL inhibitor

decreases the formation and function of osteoclasts–>decrease bone resorption with increase bone mass density

treat osteoporosis in postmenpausal women at high risk fractures

should be taken with calcium and vitamin D

higher dose for the prevention of skeletal-related events in patients with metastases from solid tumor

Question 4

Treatment of Osteoporosis in Men

a major risk factor is hypogonadism, so testosterone replacement is an important part of therapy

• other contributors in men include glucocorticoids and androgen‐deprivation therapy for prostate cancer
• men generally respond to the drugs similar to women – bisphosphonates are the agent of choice – denosumab is an alternative

Answer 4

Drugs for Hypercalcemia

• furosemide… via action in TAL
• glucocorticoids… reduce intestinal absorption of Ca2+
• gallium nitrate… prevents bone resorption, used to treat hypercalcemia of malignancy, highly nephrotoxic
• bisphosphonates… approved for use to treat hypercalcemia of malignancy
• inorganic phosphates… IV use is life‐threatening and limited to patients with severe hypercalcemia; oral is milder and OK provided patients do not have renal impairment or already elevated phosphate levels
• edetate disodium… EDTA is a calcium chelating agent, can be dangerous since it can cause profound hypocalcemia with tetany, convulsion, dysrhythmias –> death

Question 5

cinacalcet-“calcimimetic” drug

binds to the calcium‐sensing receptors on the parathyroid gland…

increase their sensitivity to extracellular calcium, decrease PTH secretion

clinical application

 primary hyperparathyroidism (parathyroid carcinoma)

 secondary hyperparathyroidism due to CKD

Question 6

• acetaminophen for noninflammatory OA
• NSAIDs if inflammatory OA or acetaminophen inadequate for pain in non‐inflammatory OA
• Topical NSAIDs or capsaicin – 1% diclofenec gel is topical NSAID widely used for pain relief
• Resistant pain therapy includes:
• opioid analgesics
• intra‐articular hyaluronans
• glucosamine and chondroitin compounds (~safe even if lack of evidence of benefit)

Question 7

Osteomyelitis Treatment

• Antibiotic treatment should be based on the identification of pathogens from bone cultures at the time of bone biopsy or debridement
• Effective oral antibiotics include:

– clindamycin: MOA: Blocks peptide transfer (translocation) at 50S ribosomal subunit. Bacteriostatic. for: Anaerobic infections, Also effective against invasive group A streptococcal infection, adverse effects: (C difficile overgrowth)

– rifampin MOA: Inhibit DNA-dependent RNA polymerase, for: Mycobacterium tuberculosis; Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H influenzae type b

– trimethoprim‐sulfamethoxazole MOA: Inhibit dihydropteroate synthase, thus inhibiting folate synthesis. for: Gram ⊕ , gram ⊝ , Nocardia. TMP-SMX for simple UTI.

– fluoroquinolone MOA: Inhibit prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. Bactericidal. Must not be taken with antacids. for: Gram ⊝ rods of urinary and GI tracts (including Pseudomonas), some gram ⊕ organisms, otitis externa.

Question 8

inhibits osteoclasts to decrease bone resorption and inhibits renal tubular resorption of calcium to increase calcium excretion

this is a treatment for established osteoporosis, but not prevention.

also used in paget disease

it can treat hypercalcemia, but not preferred agent

intranasal spray, SC, IM