Bisphosphonates

Bisphosphonates are synthetic, nonhydrolysable analogues of pyrophosphate in which the central oxygen atom of the -P-O-P- structure is replaced with a carbon atom to give the -P-C-P- group.

Actions. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone-resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate) inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts. They also bind strongly to hydrox-yapatite crystals and, in high doses, can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive efficacy. There is wide variation between these compounds in terms of their capacity to inhibit resorption relative to that of inhibiting mineralisation. Etidronate, for instance, must be administered cyclically to prevent déminéralisation whereas alendronate, more recently available, does not appear to interfere with mineralisation at antiresorptive doses and can be used continously.

Pharmacokinetics. Bisphosphonates are poorly absorbed after oral ingestion. Absorption is further impaired by food, drinks and drugs containing calcium, magnesium, iron or aluminium salts. A proportion of bisphosphonate that is absorbed is rapidly incorporated into bone; the remaining fraction is excreted unchanged by the kidneys. Once incorporated into the skeleton, bisphosphonates are released only when the bone is resorbed during turnover. They may be given orally or i.v.

Uses. Three bisphosphonates (alendronate, etidronate, risedronate) are currently licensed in the UK for the treatment of osteoporosis (zoledronate is also effective), and the others are used in Paget's disease of bone, and hypercalcaemia due to cancer (Pamidronate, clodronate, zoledronate). Bisphosphonates may also provide benefit for neoplastic disease that has spread to bone; evidence indicates that clodronate by mouth and Pamidronate i.v. are effective in the secondary prevention of bone metastases due to multiple myeloma and breast cancer.

Adverse effects include gastrointestinal disturbances, with oesophageal irritation being a particular problem with alendronate. This should be given at least 30 minutes before food, with the patient remaining erect during this period. Alendronate can be taken weekly (70 mg) instead of daily (10 mg). Disturbances of calcium and mineral metabolism (e.g. vitamin D deficiency, parathyroid hormone dysfunction) should be corrected before starting a bisphosphonate. Increased bone pain (as well as relief), fractures (high dose, prolonged use only) can occur due to déminéralisation of bone.

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