Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid metabolites as therapeutic agents for BRONJ.