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 clodrona te and tiludronate, can be incorporated into non-hydrolysable ATP anal ogues in cells, whereas the more potent anti-resorptive aminoalkylbisp hosphonates are not metabolised. Furthermore, clodronate inhibits proi nflammatory cytokine and nitric oxide (NO) secretion from activated ma crophages in vitro and has antiinflammatory properties in vivo, especi ally when delivered into cells by liposomes. By contrast, aminobisphos phonates can induce an acute phase response and fever in vivo, which a ppears to involve the induction of cytokine secretion. In this study w e examined the effect of liposome-mediated intracellular delivery of o ne aminobisphosphonate, ibandronate, and one metabolizable bisphosphon ate, tiludronate, on the secretion of inflammatory mediators. The intr acellular uptake of bisphosphonates by macrophages was enhanced by a f actor of 20-200 by using liposomes. Tiludronate dose-dependently inhib ited both cytokine and NO secretion from activated macrophages, and li posomal tiludronate was more potent than the free drug. By contrast, i bandronate enhanced LPS-induced secretion of IL-1 beta and IL-6 but di d not affect TNF alpha or NO secretion at non-cytotoxic concentrations . The present results, together with our previous studies, strongly su ggest that bisphosphonates can be grouped into those that are metaboli sed by cells and that are capable of inhibiting cytokine and NO secret ion from macrophages, thus having potential anti-inflammatory properti es, and those that are not metabolised but can actually enhance the pr oduction of cytokines following macrophage activation. (C) 1998 Elsevi er Science Inc.