A 72-year-old woman sustains a low-energy hip fracture. DEXA scan shows T-score of −2.9 at the femoral neck. She is initiated on alendronate (bisphosphonate therapy). The primary mechanism of action of bisphosphonates is:

• A Inhibition of osteoblast differentiation via BMP pathway suppression
• B Direct stimulation of osteocalcin synthesis by osteoblasts
• C Competitive inhibition of RANKL binding to RANK receptor on osteoclast precursors
• D Inhibition of farnesyl pyrophosphate synthase in osteoclasts, disrupting their ruffled border and inducing apoptosis ✓

Explanation

Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate) inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway within osteoclasts, preventing prenylation of small GTPases (Ras, Rho) essential for osteoclast ruffled border formation, cytoskeletal organization, and survival — ultimately inducing osteoclast apoptosis. Non-nitrogen bisphosphonates (clodronate, etidronate) incorporate into non-hydrolyzable ATP analogues causing apoptosis by a different mechanism. Denosumab is the anti-RANKL monoclonal antibody. Teriparatide stimulates osteoblasts (anabolic agent). Long-term bisphosphonate use carries a risk of atypical subtrochanteric femoral fractures and osteonecrosis of the jaw.

Reference: Maheshwari Essential Orthopaedics, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.