Bisphosphonates in development for metabolic bone disease

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Abstract
Bisphosphonates are analogues of endogenous pyrophosphate and exhibit profound effects on bone metabolism. These compounds have been shown to inhibit the recruitment and/or activity of osteoclasts (bone-resorbing cells) and to increase bone mass by reducing both the activation frequency of new bone remodelling units and the depth to which osteoclasts resorb bone. In animal studies, several bisphosphonates (etidronate, tiludronate, pamidronate, and cimadronate (YM-175) have also produced beneficial biomechanical effects on bone (increases in bone strength, stiffness and fracture load) in conjunction with increases in bone mass. Because of the bisphosphonates' high affinity for bone, very few soft-tissue effects or toxicities are observed. Bisphosphonates have shown clinical efficacy in metabolic bone diseases such as Paget's disease, metastatic hypercalcaemia and postmenopausal osteoporosis, and their use is under investigation in other diseases of abnormal bone turnover such as glucocorticoid-induced osteoporosis, hyperthyroidism, hyperparathyroidism and rheumatoid arthritis. Future work with these important therapeutic agents will optimise desired effects and identify and minimise adverse effects.