9.6 Bone Metabolism Drugs
Bone metabolism pharmacology targets osteoporosis, Paget's disease, and hypercalcemia through agents that modulate osteoclast and osteoblast activity.
Bisphosphonates
Mechanism & Clinical Use
Pyrophosphate analogs that bind hydroxyapatite in bone. Inhibit osteoclast activity (induce apoptosis, inhibit farnesyl pyrophosphate synthase). Decrease bone resorption.
Agents:
- • Alendronate: Oral daily/weekly; osteoporosis
- • Risedronate: Oral; osteoporosis, Paget's disease
- • Ibandronate: Oral monthly or IV quarterly
- • Zoledronic acid: IV yearly; most potent; hypercalcemia of malignancy
Administration (Oral):
- • Take on empty stomach with water
- • Remain upright 30-60 min (prevent esophagitis)
- • No food/drink for 30 min
Adverse Effects:
- • Esophagitis, GI upset (oral forms)
- • Osteonecrosis of jaw (rare; dental procedures)
- • Atypical femoral fractures (long-term use)
- • Hypocalcemia, flu-like symptoms (IV)
RANKL Inhibitor
Denosumab
Monoclonal antibody against RANKL (receptor activator of NF-κB ligand). Prevents RANK-RANKL interaction, inhibiting osteoclast formation/activation. More potent than bisphosphonates.
Indications:
- • Osteoporosis (subcutaneous every 6 months)
- • Bone metastases, giant cell tumor
- • Alternative if bisphosphonates not tolerated
Adverse Effects:
- • Hypocalcemia (give Ca²⁺ and vitamin D supplements)
- • Osteonecrosis of jaw
- • Atypical femoral fractures
- • Serious infections (skin, GI, urinary)
- ⚠️ Rapid bone loss if discontinued (rebound effect)
Anabolic Agents
Teriparatide
Recombinant PTH (1-34 fragment). Intermittent dosing stimulates osteoblasts → bone formation. (Note: Continuous PTH causes bone resorption via RANKL.)
- • Severe osteoporosis, high fracture risk
- • Daily subcutaneous injection (up to 2 years)
- ⚠️ Osteosarcoma (animal studies); contraindicated in Paget's, prior radiation
Abaloparatide
PTH-related peptide analog. Similar to teriparatide but more selective for anabolic pathways.
- • Postmenopausal osteoporosis
- • Daily subcutaneous (up to 18 months)
- • Similar warnings to teriparatide
Romosozumab
Monoclonal antibody against sclerostin (SOST protein). Dual effect: ↑ bone formation (↑ osteoblasts), ↓ bone resorption (↓ osteoclasts).
- • Postmenopausal osteoporosis, high fracture risk
- • Monthly subcutaneous for 12 months
- ⚠️ Cardiovascular risk (MI, stroke); contraindicated in recent MI/stroke
Calcium & Vitamin D
Calcium Supplements
- • Calcium carbonate: 40% elemental Ca; take with food (needs acid)
- • Calcium citrate: 21% elemental Ca; better absorption; can take without food
- • Adjunct to all osteoporosis therapies
- Target 1000-1200 mg/day; adverse: constipation, kidney stones
Vitamin D
- • Cholecalciferol (D3): Supplementation, deficiency
- • Ergocalciferol (D2): Alternative form
- • Calcitriol (1,25-(OH)₂D₃): Active form; hypoparathyroidism, CKD
- • Essential for calcium absorption
- Target 800-1000 IU/day; toxicity: hypercalcemia, kidney stones
Calcitonin
Hormone from thyroid C-cells. Inhibits osteoclast activity, ↓ bone resorption, ↓ serum calcium. Less effective than bisphosphonates.
Indications:
- • Paget's disease (salmon calcitonin)
- • Hypercalcemia (acute management)
- • Osteoporosis (nasal spray; less used now)
Adverse Effects:
- • Nausea, flushing (salmon calcitonin)
- • Nasal irritation (intranasal)
- • Possible cancer risk (long-term)
- • Tachyphylaxis (decreased response over time)