Bisphosphonates

Bisphosphonates are synthetic analogues of pyrophosphate that bind avidly to hydroxyapatite in bone mineral and are taken up by osteoclasts during bone resorption, where nitrogen-containing bisphosphonates (alendronate, zoledronate, risedronate) inhibit farnesyl diphosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and survival. They are approved for osteoporosis, Paget's disease, hypercalcaemia of malignancy, and bone metastases, where they significantly reduce fracture risk and skeletal-related events. Observational and secondary-analysis data suggest broader aging-relevant effects: zoledronate (intravenous, annual) was associated with reduced all-cause mortality in a randomised trial in patients with recent hip fracture (HORIZON Recurrent Fracture Trial; Lyles et al., 2007, NEJM) and in observational cohorts, and bisphosphonate use has been associated with reduced breast, colorectal, and possibly other cancers in several epidemiological studies, though residual confounding cannot be excluded. Geroscience interest centres on possible senolytic-adjacent effects — bisphosphonates deplete osteoclast progenitors and may selectively reduce calcification-associated senescent cell burden — but these mechanisms are hypothetical in humans. Side effects include oesophageal irritation, osteonecrosis of the jaw (rare, mainly with high-dose intravenous use), and atypical femoral fractures with prolonged therapy.