Diphosphonates

Diphosphonates, more commonly called bisphosphonates, are a class of antiresorptive medicines. They feature a central carbon atom bound to two phosphonate groups, forming a stable P-C-P backbone that resists hydrolysis. After administration they become incorporated into bone and are gradually released during remodeling. The class comprises nitrogen-containing and non-nitrogen-containing agents.

They inhibit osteoclast-mediated bone resorption. Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast function and triggering apoptosis. Non-nitrogen-containing bisphosphonates are metabolized to toxic ATP analogs that disrupt osteoclasts. The overall effect is reduced bone turnover and preservation or improvement of bone density.

They are used to treat osteoporosis and other conditions with excessive bone resorption, such as Paget disease, hypercalcemia of malignancy, and bone metastases or multiple myeloma. They lower fracture risk and help manage calcium levels but do not cure the underlying disease.

Administration is oral (with various dosing schedules) or by intravenous infusion, with bioavailability limited for oral forms. Renal function and calcium status should be monitored; patients are advised to ensure adequate calcium and vitamin D intake. Common side effects include gastrointestinal irritation with oral forms and flu-like reactions after infusions. Rare but serious risks include osteonecrosis of the jaw and atypical femoral fractures, especially with long-term use or in predisposed individuals. They should be avoided in significant hypocalcemia or severe renal impairment.

Common agents include alendronate, risedronate, ibandronate, and zoledronic acid; older drugs such as etidronate and pamidronate are also used.