Denosumab for the treatment of osteoporosis.
Being a connective tissue, bone can increase or decrease its mass through the process of remodeling. Using a discovery in the mid-1980s-that tumor necrosis factor (TNF) could dramatically increase formation of osteoclasts (the cells that break down bone)-researchers at Amgen (Thousand Oaks, CA) discovered a TNF-like molecule that regulated bone resorption. Elevations in the expression of this molecule, receptor activator of nuclear factor-κB ligand (RANKL), can cause excessive bone destruction. A blocking antibody to RANKL named denosumab inhibits osteoclast formation and bone degradation. In a large multicenter clinical trial, known as the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), the effects of denosumab were tested in 60- to 90-year-old women over 3 years. Statistically significant reductions in fracture risk at the vertebral column, hip, and nonvertebral sites were associated with increases in bone mineral density (BMD) and reciprocal decreases in markers of bone resorption. However, the FREEDOM trial did not test the most beneficial use of a resorption blocking drug-to target the rapid bone loss that occurs in late perimenopause and early postmenopause. One adverse effect from denosumab is cellulitis, and research in animals suggests that RANKL/RANK interaction is needed for Langerhans cell (LC) survival in the skin. Further mechanistic and clinical studies on the role of RANKL in the skin are needed.
Iqbal
Jameel
J
Mount Sinai School of Medicine, New York 10029, USA.
Sun
Li
L
Zaidi
Mone
M
D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology* / Q000528:radiation effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D002986:Clinical Trials as Topic; D000069448:Denosumab; D006801:Humans; D007801:Langerhans Cells / Q000187:drug effects / Q000502:physiology; D010006:Osteoblasts / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy*; D053245:RANK Ligand / Q000009:adverse effects / Q000187:drug effects / Q000494:pharmacology* / Q000502:physiology / Q000528:radiation effects / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D000069448:Denosumab