Bisphosphonates: an overview with special reference to alendronate.
Bisphosphonates, analogues of pyrophosphate, are potent inhibitors of osteoclast-mediated bone resorption. They are used in the treatment of Paget's disease of bone, hypercalcaemia and osteolytic bone disease of malignancy, primary and secondary hyperparathyroidism, and in osteoporosis. Bisphosphonate treatment causes an early reduction in bone resorption followed by a later reduction in bone formation. The early inhibition of bone resorption induces a reduction in serum calcium which leads to increased parathyroid hormone (PTH), and subsequently an increase in 1,25-dihydroxyvitamin D. The secondary hyperparathyroidism of bisphosphonate treatment also leads to urinary calcium conservation and phosphaturia, and a reduction in serum phosphate. The increase in the PTH following bisphosphonate therapy is a response to the change in serum calcium and can occur even when there is hypercalcaemia, and this can cause confusion in the interpretation of PTH results. The hypocalcaemic response to bisphosphonates is occasionally severe, especially in patients with hypoparathyroidism. The recent elucidation of bisphosphonate action at the cellular level on the mevalonate pathway has led to interest in its effects on lipoprotein metabolism, which may prove to be of clinical significance. Newer and more potent bisphosphonates are currently undergoing clinical trials in malignant bone disease and osteoporosis, and will lead to further advances in the optimal management of these conditions.