Affiliation: Rheumatic Disease Unit, University of Alberta, 562 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2
Although bisphosphonates have found widespread use in disorders of bone metabolism, there has been no serious examination of published work describing their anti-inflammatory and immune modifying properties. Structurally as well as mechanistically, they have been divided into amino-and non-aminobisphosphonates. The former appear to form toxic ATP analogues within cells whilst the latter inhibit enzymes in the mevalonate pathway thereby leading to impaired prenylation of small GTPases regulating diverse cellular processes such as cell viability and proliferation. In vitro studies indicate that these agents impair the accessory function of antigen-presenting cells in T cell proliferation, proliferation of macrophage precursors, macrophage migration, and induce macrophage cytotoxicity / apoptosis. Their effects on cytokine generation in vitro are complex and dependent on the molecular class of bisphosphonate examined, the concentration employed, the cell type examined, and evaluation of cultured cells v ersus whole blood assays. In vivo, aminobisphosphonates induce generation of proinflammatory cytokines in the short term although chronic administration may suppress these cytokines. In animal models they ameliorate established antigen and adjuvant induced arthritis although they appear to be less effective in collagen induced arthritis. Liposomal formulations of non-aminobisphosphonates, especially clodronate, induce macrophage cytotoxicity and amelioration of synovitis associated with depletion of synovial lining cells. The limited clinical studies performed to date in patients with rheumatoid arthritis and ankylosing spondylitis, primarily evaluating pamidronate, do not allow firm conclusions but suggest that bisphosphonates exert a dose dependent anti-inflammatory effect in patients with chronic arthritis. Further studies employing the more potent third generation aminobisphosphonates are warranted.