RANKL inhibition for the management of patients with benign metabolic bone disorders.
The receptor activator of NF-kappaB ligand (RANKL) is a member of the TNF receptor superfamily, essential for osteoclastogenesis. It binds to its receptor activator of NF-kappaB on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, while it activates mature osteoclasts and inhibits their apoptosis. The effects of RANKL are counteracted by osteoprotegerin (OPG), a neutralizing decoy receptor. Derangement of the balance in RANKL/OPG action is implicated in the pathophysiology of metabolic bone diseases, including osteoporosis. Current therapies used to prevent or treat metabolic bone diseases are thought to act, at least in part, through modification of the RANKL/OPG dipole. The idea of using a molecule that could specifically bind and neutralize RANKL to decrease bone resorption and subsequent bone loss is appealing. Recombinant OPG was initially tested. Denosumab, a fully human monoclonal antibody against RANKL, is a promising antiresorptive agent under investigation. It rapidly decreases bone turnover markers resulting in a significant increase in bone mineral density and reduction in fracture risk. However, because receptor activator of NF-kappaB activation by RANKL is also essential for T-cell growth and dendritic-cell function, inhibition of its action could simultaneously affect the immune system, leading to susceptibility in infections or malignancies.
Anastasilakis
Athanasios D
AD
Department of Endocrinology, 424 Military Hospital, Thessaloniki, Greece.
Toulis
Konstantinos A
KA
Polyzos
Stergios A
SA
Terpos
Evangelos
E
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D000069448:Denosumab; D006801:Humans; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D053245:RANK Ligand / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D053244:Osteoprotegerin; D053245:RANK Ligand; D011994:Recombinant Proteins; C505688:TNFSF11 protein, human; D000069448:Denosumab