The discovery of receptor activator of nuclear factor-kappaB ligand (RANKL) elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Osteoprotegerin (OPG), a soluble decoy receptor of RANKL, inhibits both differentiation and function of osteoclasts. OPG-deficient (OPG-/-) mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. Deficiency of OPG in human has been shown to result in juvenile Paget's disease. Blood alkaline phosphatase activity of OPG-/- mice was about four times as high as that of wild-type mice. These results suggest that osteoclastic bone resorption coincidentally induces osteoblastic bone formation by an unknown factor (called coupling factor). Collagen sponge disks containing bone morphogenetic protein-2 (rhBMP-2) were implanted into the dorsal muscle pouches in OPG-/- mice and wild-type mice, and bone mineral density (BMD) of the collagen sponge disks was determined every week for 3 weeks. No significant difference in BMD of the disc was observed between OPG-/- mice and wild-type mice. These results suggest that bone formation is accurately coupled with bone resorption at local sites in OPG-/- mice.