Bone Abstracts

Bisphosphonates are widely used drugs in the fight against osteoclast-mediated bone loss, including osteoporosis and Paget’s disease of bone. The first generation of these potent drugs such as clodronate, a non nitrogen-containing bisphosphonate, has been shown to inhibit osteoclast formation and osteoclastic bone resorption both in vitro and in vivo as well as inducing apoptotic cell death. Recent interest has centred on the effects of more potent nitrogen-containing bisphosphonate zoledronate that appears 10,000-fold more potent. However, their clear dose-dependent anti-resorptive effects on murine osteoclasts as well as their effects on osteoclast formation have not been fully understood. In this study, the effects of different concentrations of zoledronate and clodronate on murine osteoclasts were examined. Mouse marrow cells were cultured with zoledronate and clodronate (1 nM-1 μM) on ivory discs for 8–9 days. Zoledronate was found to significantly reduce osteoclast number and resorption dose-dependently with a complete inhibition at concentrations above 1 μM. Peak effects occurred at 10 μM, where it had strong cytotoxic effect on all marrow-derived cells. Clodronate significantly inhibited osteoclast resorption in all concentration ranges tested, causing two fold and three fold decrease at (1 nM–1 μM) and 10 μM respectively. Clodronate also caused a six fold decrease in osteoclast number at 10 μM. These results suggest that zoledronate is a strong and potent inhibitor of murine osteoclast formation and resorption, as well as highlighting the differences in cytotoxicity and potency between different concentrations of individual bisphosphonates and between bisphosphonate groups. A clear understanding of these effects may have important implications for better clinical use of bisphosphonates in treatment of cancers.