Bisphosphonates: an overview with special reference to alendronate

Abstract

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 signi®cance. 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.

Systemic and local ibandronate enhance screw fixation

“…The nonamino-containing bisphosphonates are metabolised to non-hydrolyzable analogues of ATP and thus interfere with the cells' ATP-dependent intracellular enzymes. The end result for the mature osteoclasts seem to be impairment of function and apoptosis for both of these mechanisms, as well as a decrease in recruitment [3,20,25]. In addition, there is evidence suggesting that some bisphosphonates also may prevent osteocyte and osteoblast apoptosis [ 171.…”

Advances in understanding bone cancer pain

“…Bisphosphonates, used initially to treat malignancy- associated humoral hypercalcaemia, have shown promise at decreasing cancer-induced skeletal complications. The suggested mechanism of bisphosphonates' action is a direct inhibition of osteoclast and osteoclast precursor cell activation [Hiraga et al, 2001;Vasikaran, 2001;Neville-Webbe et al, 2002]. Recent reports have shown that bisphosphonate treatment can significantly reduce the number of activated osteoclasts and osteolytic destruction of bone [Breuil et al, 1998;Boissier et al, 2000].…”

Estudo da osteoclastogênese e da remodelação óssea durante a formação e erupção de molares de ratos tratados com bisfosfonatos.

“…Nos bisfosfonatos, o átomo central de oxigênio do pirofosfato é substituído por um átomo de carbono, ao qual dois radicais fosfato são ligados . Essa estrutura confere aos bisfosfonatos, afinidade por hidroxiapatita e, conseqüentemente, à superfície mineral óssea (Vasikaran, 2001). Com a descoberta de que os bisfosfonatos, além de inibirem a dissolução e crescimento de cristais de mineral, apresentam efeitos celulares sobre osteoclastos, seu uso em patologias caracterizadas por perda de densidade óssea se tornou amplamente difundido (Russell et al, 1999 (Russell, 2006).…”

“…Após infusão endovenosa, é rapidamente eliminado do plasma e 40% são excretados pela urina, não sendo metabolizado no organismo. Como os demais bisfosfonatos, liga-se rapidamente à hidroxiapatita do osso, e sua meia-vida de eliminação estimada é de 12 anos (Vasikaran, 2001). O alendronato liga-se a superfícies ósseas durante o processo de reabsorção.…”

“…O etidronato, bisfosfonato não nitrogenado e de primeira geração, apresenta potência anti-reabsortiva quinhentas vezes menor que a do alendronato (Vasikaran, 2001). Além disso, seus mecanismos de ação sobre o tecido ósseo são diferentes.…”