Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies.
Osteoporosis and several other bone disorders occur when there is an imbalance between the resorption and formation components of bone remodeling activity. Therapies available for some of these conditions modulate the activity of osteoclasts and/or osteoblasts. The recent discoveries of receptor activator of NF-kappaB ligand (RANKL), an endogenous activator of osteoclastogenenesis and osteoclast activity and its inhibitor, osteoprotegerin (OPG) as pivotal regulatory factors in the pathogenesis of bone diseases like osteoporosis provide unique targets for therapeutic agents. In laboratory animals and now in humans, administering forms of OPG markedly inhibits osteoclast activity and improves bone strength, documenting that the strategy of inhibiting RANKL activity has therapeutic promise. A highly specific, fully human antibody against RANKL has been produced (denosumab) that in early studies in humans reduces bone turnover and improves bone density. Attributes of denosumab in these clinical studies include a very rapid onset of action, sustained effects for several months after a single injection, and good tolerability. These results provide the basis for studies evaluating the effectiveness of denosumab in several clinical conditions characterized by increased osteoclastic activity.
McClung
Michael R
MR
Oregon Osteoporosis Center, 5050 NE Hoyt Street, Suite 651, Portland, OR 97210, USA. mmcclung@orost.com
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human