In vivo effects of bisphosphonates on the osteoclast mevalonate pathway

Estrogen deficiency is a leading cause of osteoporosis associated with incr eased osteoclastic bone resorption. In vitro studies indicate that the clin ically used nitrogen-containing bisphosphonates (N-BPs) such as alendronate (ALN), risedronate (RIS) and ibandronate (IBA) suppress bone resorption vi a inhibition of the mevalonate pathway enzyme farnesyl diphosphate (FPP) sy nthase in osteoclasts (Ocs). The object of this study was to test the hypot hesis that N-BPs inhibit the mevalonate pathway of Ocs in vivo. The mevalonate pathway enzyme hydroxymethyl-glutaryl-coenzyme A reductase ( HMGR), is modulated by feedback inhibition from downstream metabolites. We therefore evaluated the in vivo expression of HMGR in Ocs from animals trea ted with BP. The N-BPs, ALN, IBA and RIS, selectively suppressed HMGR expre ssion in up to 85% of rat tibia osteoclasts, after 48 hr treatment. Etidron ate and clodronate, bisphosphonates that do not inhibit FPP synthase, were without effect. Simvastatin treatment opposed ALN reduction of HMGR express ion, suggesting regulation by a metabolite(s) between mevalonate and FPP. T hese data provide the first in vivo evidence for N-BP effects on the mevalo nate pathway in osteoclasts, and strongly support the hypothesis that N-BPs act via this mechanism.