Denosumab and bisphosphonates: Different mechanisms of action and effects

• Published in: Bone (New York, N.Y.) Vol. 48; no. 4; pp. 677 - 692
• Main Authors: Baron, Roland, Ferrari, Serge, Russell, R. Graham G
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01-04-2011
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Biological and medical sciences; Bone Density Conservation Agents - pharmacokinetics; Bone Density Conservation Agents - pharmacology; Bone Density Conservation Agents - therapeutic use; Bones, joints and connective tissue. Antiinflammatory agents; Clinical Trials as Topic; Denosumab; Diphosphonates - pharmacokinetics; Diphosphonates - pharmacology; Diphosphonates - therapeutic use; Disease Models, Animal; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Orthopedics; Osteoclasts - drug effects; Osteoporosis - drug therapy; Osteoporosis. Osteomalacia. Paget disease; Pharmacology. Drug treatments; RANK Ligand - pharmacokinetics; RANK Ligand - pharmacology; RANK Ligand - therapeutic use; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Osteoporosis; RANK ligand; Osteoclast; Denosumab; Bisphosphonates; Immunomodulator; Antiosteoporotic; Antiosteoclastic agent; Receptor activator Nfkb ligand; Morphology; Diseases of the osteoarticular system; Mechanism of action
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2010.11.020

Abstract To treat systemic bone loss as in osteoporosis and/or focal osteolysis as in rheumatoid arthritis or periodontal disease, most approaches target the osteoclasts, the cells that resorb bone. Bisphosphonates are currently the most widely used antiresorptive therapies. They act by binding the mineral component of bone and interfere with the action of osteoclasts. The nitrogen-containing bisphosphonates, such as alendronate, act as inhibitors of farnesyl-pyrophosphate synthase, which leads to inhibition of the prenylation of many intracellular signaling proteins. The discovery of RANKL and the essential role of RANK signaling in osteoclast differentiation, activity and survival have led to the development of denosumab, a fully human monoclonal antibody. Denosumab acts by binding to and inhibiting RANKL, leading to the loss of osteoclasts from bone surfaces. In phase 3 clinical studies, denosumab was shown to significantly reduce vertebral, nonvertebral and hip fractures compared with placebo and increase areal BMD compared with alendronate. In this review, we suggest that the key pharmacological differences between denosumab and the bisphosphonates reside in the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions.