The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism ofaction of nitrogen-containing bisphosphonates

Bisphosphonates, synthetic compounds used in the treatment of skeletal diso rders, suppress osteoclast-mediated bone resorption by a yet unidentified m echanism. Previous studies showed that some bisphosphonates can inhibit enz ymes of the mevalonate pathway, and nitrogen-containing bisphosphonates inh ibit protein prenylation in mouse macrophages, In the present study, we exa mined the involvement of the mevalonate pathway in basal and bisphosphonate -inhibited osteoclastic resorption in fetal mouse long bone explants, an ex perimental model representative of the in vivo action of bisphosphonates. M evastatin inhibited bone resorption at concentrations similar to those of t he potent bisphosphonate ibandronate, This effect could be totally reversed by the addition of mevalnate and geranylgeraniol but not farnesol, The fir st two intermediates but not the latter could also stimulate basal bone res orption, The inhibitory effect of ibandronate on bone resorption could be t otally reversed by the addition of geranylgeraniol and to a small extent on ly by mevalonate and farnesol, indicating that the bisphosphonate acts at a level of the mevalonate pathway different from that of mevastatin, Histolo gic sections of ibandronate-treated bone explants showed further rescue of functioning osteoclasts during concomitant treatment with geranylgeraniol, Finally, the reversibility of bisphosphonate inhibited osteoclastic resorpt ion by geranylgeraniol was also demonstrated for the potent nitrogen-contai ning bisphosphonates alendronate, olpadronate, and risedronate but not for the non-nitrogen-containing bisphosphonates clodronate and etidronate. Thes e studies demonstrate that protein geranylgeranylation but not farnesylatio n is important for osteoclast-mediated bone resorption and that nitrogen-co ntaining bisphosphonates exert their antiresorptive action probably by affe cting enzymes of the mevalonate pathway involved in the generation of geran ylgeranyl pyrophosphate.