Effects of tiludronate and ibandronate on the secretion of proinflammatory cytokines and nitric oxide from macrophages in vitro

Bisphosphonates inhibit osteoclastic bone resorption and are used for the treatment of bone diseases. Some bisphosphonates, such as clodronate and tiludronate, can be incorporated into non-hydrolysable ATP analogues in cells, whereas the more potent anti-resorptive aminoalkylbisphosphonates are not metabolised. Furthermore, clodronate inhibits proinflammatory cytokine and nitric oxide (NO) secretion from activated macrophages in vitro and has anti-inflammatory properties in vivo, especially when delivered into cells by liposomes. By contrast, aminobisphosphonates can induce an acute phase response and fever in vivo, which appears to involve the induction of cytokine secretion. In this study we examined the effect of liposomemediated intracellular delivery of one aminobisphosphonate, ibandronate, and one metabolizable bisphosphonate, tiludronate, on the secretion of inflammatory mediators. The intracellular uptake of bisphosphonates by macrophages was enhanced by a factor of 20–200 by using liposomes. Tiludronate dose-dependently inhibited both cytokine and NO secretion from activated macrophages, and liposomal tiludronate was more potent than the free drug. By contrast, ibandronate enhanced LPS-induced secretion of IL-1β and IL-6 but did not affect TNFα or NO secretion at non-cytotoxic concentrations. The present results, together with our previous studies, strongly suggest that bisphosphonates can be grouped into those that are metabolised by cells and that are capable of inhibiting cytokine and NO secretion from macrophages, thus having potential anti-inflammatory properties, and those that are not metabolised but can actually enhance the production of cytokines following macrophage activation.