Receptor activator of nuclear factor-kappa B ligand and osteoprotegerin: maintaining the balance to prevent bone loss (original) (raw)

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor B ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis. (Endocrine Reviews 29: 155-192, 2008) prostate cancer metastasis to bone J. RANKL and RANKL inhibition in animal models of multiple myeloma K. RANKL and RANKL inhibition in fracture and fracture repair IV. Role and Regulation of OPG/RANKL in the Human Skeleton A. Postmenopausal osteoporosis B. Men C. Glucocorticoid treatment D. Paget's disease of bone E. Rheumatoid arthritis V. Clinical Therapeutics Targeting the RANK/RANKL/OPG System A. Mechanism of action of denosumab B. Clinical studies of denosumab in postmenopausal women with osteoporosis