Advances in bone biology and new treatments for bone loss.
Recent advances in bone biology have led to a more detailed understanding of bone remodeling which is a process that leads to resorption of old bone and replacement by formation of new bone. The most important discoveries in this process of bone remodeling were those of the RANK Ligand/RANK/OPG system which is now recognized the dominant pathway regulating bone resorption. RANK Ligand (RANKL) is a cytokine belonging to the tumor necrosis factor family and is expressed by osteoblasts; it binds to membrane bound receptor RANK on osteoclasts and promotes differentiation of marrow cells through various stages to multinucleated osteoclasts which resorb bone. Several hormones such as parathyroid hormone, calcitriol and prostaglandins stimulate RANK Ligand expression by osteoblasts. Osteoblasts also secrete osteoprotegerin (OPG) which is a soluble receptor that is a potent antagonist of osteoclast formation by binding and inactivating RANKL and OPG is therefore an important regulator of bone resorption. OPG is stimulated by estrogen. OPG has been genetically engineered and in human subjects is a potent inhibitor of bone resorption. Another method for preventing bone resorption is to develope antibodies against RANKL and this has been shown to be a successful strategy. A single subcutaneous injection of this antibody (Denosumab) every 6 months proved to be a potent inhibitor of bone resorption and clinical fracture trials using this agent are now underway. These are novel developments that have risen from basic research in bone biology and other discoveries in the bone remodeling process can be expected to lead to further treatment options for various bone diseases.
Gallagher
J Chris
JC
Bone Metabolism Unit, Creighton University School Medicine, Omaha, NE 68131, USA. jcg@creighton.edu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000069448:Denosumab; D006801:Humans; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology*; D053244:Osteoprotegerin / Q000502:physiology; D053245:RANK Ligand / Q000276:immunology / Q000502:physiology / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053244:Osteoprotegerin; D053245:RANK Ligand; D000069448:Denosumab