Antiresorptive Agents (First-Line for Postmenopausal Osteoporosis):
- Bisphosphonates (Alendronate, Risedronate, Ibandronate, Zoledronic Acid):
- Mechanism: Inhibit osteoclast activity, reducing bone resorption. – Efficacy: Increase bone mineral density (BMD) and reduce fracture risk. – Administration: Oral (weekly/monthly) or IV (yearly for zoledronic acid). – Adverse Effects: Esophageal irritation (oral), atypical femoral fractures, osteonecrosis of the jaw (ONJ) with prolonged use. – Rationale: Cost-effective, generic availability, and strong evidence base (e.g., Fracture Intervention Trial for alendronate). –
- Denosumab (RANKL Inhibitor):
- Mechanism: Binds to RANKL, inhibiting osteoclast formation and function. – Efficacy: Superior to bisphosphonates in increasing BMD and reducing vertebral/hip fractures. – Administration: SC every 6 months. – Adverse Effects: ONJ, hypocalcemia, potential rebound fractures if discontinued abruptly. – Rationale: Preferred for high-risk patients (e.g., severe osteoporosis, glucocorticoid use). –
- Anabolic Agents (For Severe Osteoporosis or High Fracture Risk):
- Teriparatide/Abaloparatide (Parathyroid Hormone Analogues):
- Mechanism: Stimulate osteoblast activity, promoting bone formation. – Efficacy: Reduce vertebral/non-vertebral fractures; limited to 2 years due to potential osteosarcoma risk. – Administration: SC daily. – Rationale: Used when antiresorptives fail or for severe disease. –
- Romosozumab (sclerostin inhibitor):
- Mechanism: Inhibits sclerostin, promoting bone formation and reducing resorption. – Efficacy: Rapid BMD increase; reduces vertebral/clinical fractures. – Administration: SC monthly for 12 months. – Rationale: First-line for high-risk patients (e.g., recent fragility fractures).
- Odanacatib
- Mechanism: Cathepsin K inhibitor, selectively inhibits bone resorption without suppressing bone formation. – Efficacy: Demonstrated increased bone mineral density (BMD) and reduced fracture risk in phase 3 trials. – Safety Concerns: Increased risk of skin infections, morphometric vertebral fractures, and potential for atypical femoral fractures. Discontinued due to safety issues. – Rationale: Targets osteoclast activity specifically, preserving bone formation, but safety concerns halted development. –
- Blosozumab
- Mechanism: Monoclonal antibody against sclerostin, an anabolic agent that stimulates bone formation. – Efficacy: Phase 2 trials showed significant BMD increases and reduced fracture risk, but phase 3 trials were discontinued due to adverse events. – Safety Concerns: Increased risk of cardiovascular events, injection-site reactions, and potential for osteonecrosis of the jaw. – Rationale: Promising anabolic effects, but cardiovascular risks and other adverse events led to discontinuation. –
- Romosozumab
- Mechanism: Monoclonal antibody against sclerostin, dual anabolic/antiresorptive action. – Efficacy: Approved for postmenopausal osteoporosis; reduces fracture risk and increases BMD. – Safety Concerns: Increased risk of myocardial infarction, stroke, and hypocalcemia. Requires cardiovascular risk assessment before use. – Rationale: Dual action is beneficial, but cardiovascular risks necessitate careful patient selection. –
- Abaloparatide
- Mechanism: Parathyroid hormone-related protein (PTHrP) analog, anabolic agent that stimulates bone formation. – Efficacy: Reduces vertebral and non-vertebral fractures; increases BMD. – Safety Concerns: Increased risk of hypercalcemia, orthostatic hypotension, and potential for osteosarcoma (long-term use). – Rationale: Effective anabolic therapy, but hypercalcemia and orthostatic hypotension require monitoring. –
- Setrusumab (BPS804)
- Mechanism: Monoclonal antibody against sclerostin, anabolic agent. – Efficacy: Phase 2 trials showed significant BMD increases, but phase 3 trials are ongoing. – Safety Concerns: Potential for similar adverse events as other sclerostin inhibitors