Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption, but also accelerates bone formation. We examined whether bone formation is coupled with bone resorption in OPG-deficient (OPG(-/-)) mice using risedronate, an inhibitor of bone resorption. Histomorphometric analysis showed that bone formation-related parameters (e.g. mineral apposition rate and osteoblast surface/bone surface) in OPG(-/-) mice sharply decreased with suppression of bone resorption by daily injection of risedronate for 30 d. OPG(-/-) mice exhibited high serum alkaline phosphatase activity and osteocalcin concentration, both of which were decreased to the levels in wildtype mice by the risedronate injection. Serum levels of RANKL were markedly elevated in OPG(-/-) mice, but were unaffected by risedronate. The ectopic bone formation induced by bone morphogenetic protein-2 implantation into OPG(-/-) mice was not accelerated even with a high turnover rate of bone, but attenuation of mineral density from the ectopic bone was more pronounced than that in wild-type mice. These results suggest that bone formation is coupled with bone resorption at local sites in OPG(-/-) mice, and that serum RANKL levels do not reflect this coupling.