Bisphosphonates are stable analogues of pyrophosphate characterised by a P-C-P bond. Avariety of bisphosphonates has been synthesised, the potency of which depends on the length and structure of the side chain. Bisphosphonates have a strong affinity for bone apatite, both in vitro and in vivo, which is the basis for their clinical use. They are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis. The potency of bisphosphonates in inhibiting bone resorption varies greatly from compound to compound and ranges 10,000-fold in vitro, so that the doses used clinically also vary. The mechanism of action on osteoclasts includes inhibition of the proton vacuolar adenosine triphosphatase (ATPase) and alteration of the cytoskeleton and the ruffled border. Aminobisphosphonates also inhibit several steps of the mevalonate pathway, thereby modifying the isoprenylation of guanosine triphosphate binding proteins.
返回顶部