A 55-year-old postmenopausal woman has a DXA T-score of −2.8 at the lumbar spine. She sustains a low-energy vertebral compression fracture. She is started on alendronate. What is the mechanism of action of bisphosphonates in osteoporosis?
- A Stimulation of osteoblast differentiation via Wnt/β-catenin signalling, increasing bone formation
- B Inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and inducing osteoclast apoptosis ✓
- C Competitive inhibition of RANKL, preventing osteoclast maturation and activation
- D Activation of parathyroid hormone receptor type 1, stimulating osteoblastic bone formation
Correct answer: B. Inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and inducing osteoclast apoptosis
Explanation
Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate) inhibit farnesyl pyrophosphate (FPP) synthase in the intracellular mevalonate pathway. This blocks prenylation of small GTPases (Ras, Rho, Rac) essential for osteoclast ruffled border formation, cytoskeletal organisation, and survival, leading to osteoclast apoptosis and reduced bone resorption. Denosumab (anti-RANKL monoclonal antibody) works via option C. Romosozumab/teriparatide work via Wnt and PTH-receptor pathways respectively.
Reference: Maheshwari Essential Orthopaedics, 6th ed.
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Written and medically reviewed by the StethoPrep medical team.