Effects of bisphosphonates on the inflammatory processes of activated macrophages

All bisphosphonates are similar in terms of their inhibitory effects on bon e resorption, but seems to have different effects on inflammatory precesses . For example, clodronate and tiludronate have anti-inflammatory and antiar thritic activity in animals, while aminobisphosphonates exacerbate experime ntal arthritis in mice. Further, aminobisphosphonate induce acute phase res ponse in patients, while non-aminobisphosphonates do not. During the last f ew years, we have explored the effects of various bisphosphonates on the in flammatory processes in activated macrophages in vitro. Clodronate and tiludronate can inhibit proinflammatory cytokine and nitric oxide (NO) secretion from macrophages. In contrast, alendronate and ibandro nate enhances the secretion of IL- 1 beta and IL-6. The intracellular deliv ery, and, consequently, the effects of bisphosphonates on inflammatory resp onses in macrophages are considerably increased by the encapsulation of the drugs in liposomes. Clodronate and tiludronate are metabolised to an ATP-analogue by mammalian cells, while aminobisphosphonates (alendronate, ibandronate) are not. The l iposome-encapsulated ATP-analogue of clodronate (AppCCl(2)p) exerts similar effects as clodronate itself on proinflammatory cytokine and NO secretion from macrophages. In macrophages,the production of cytokines and NO is regu lated by transcription factors, such as nuclear factor KB (NF-KB). In accor dance with the effects on cytokine and NO secretion, clodronate and AppCCl( 2)p inhibit the nuclear localization of NF-kappa B in activated macrophages , while alendronate enhances it. The data thus strongly suggest that bisphosphonates can be grouped into tho se that are metabolised by macrophages and that are capable of inhibiting i nflammatory responses in macrophages, thus having potential anti-inflammato ry action, and those that are not metabolised and are not anti-inflammatory .