Since bisphosphonates prevent bone loss in osteoporosis and rheumatoid arthritis, diseases in which the osteoclastogenic and inflammatory cytokine interleukin-6 plays a pathophysiologic role, we studied whether these drugs regulate the production of this cytokine by osteoblasts. Spontaneous and IL-1 + TNF-alpha stimulated IL-6 release was measured in supernatants of cultures of human osteoblastic osteosarcoma cells MG-63, pretreated for 4 hours with different doses of etidronate, clodronate or alendronate using a specific bioassay. Etidronate [from 10(-4) to 10(-8) M] or alendronate [from 10(-6) to 10(-11) M] inhibited in a dose-dependent manner the cytokine-induced IL-6 secretion [60+/-9.5% at 10(-5) M and 65+/-12% at 10(-7) M, respectively; p < 0.01]. Though significant, the inhibitory effect of clodronate was less [35+/-7% at 10(-5) M, p < 0.05]. These in vitro observations might have in vivo relevance in explaining at least in part the mechanisms by which bisphosphonates inhibit systemic and periarticular bone resorption.