Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis

Expert Opin Biol Ther. 2017 Jan;17(1):119-128. doi: 10.1080/14712598.2017.1263614. Epub 2016 Nov 30.


Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by focal pathologic bone resorption due to excessive activity of osteoclasts (OC). Receptor activator of nuclear factor kappa B ligand (RANKL) is essential for the proliferation, differentiation, and survival of OC. Denosumab (DMab) is a humanized monoclonal antibody that binds to RANKL with high affinity and blocks its subsequent association with its receptor RANK on the surface of OC precursors. Area covered: The authors review the molecular and cellular mechanisms underlying therapeutic applications of DMab, provide recent highlights on pharmacology, efficacy and safety of DMab, and discuss the potential of DMab as a novel therapeutic option for the treatment of rheumatoid arthritis. Expert opinion: Clinical results suggest that DMab is efficient both in systemic and articular bone loss in RA with limited side effects. Diminished bone erosion activity was also noted in RA patients on corticosteroids and bisphosphonates. Combination of DMab with an anti-TNF agent was not associated with increased infection rates. Collectively, these data indicate that DMab, in combination with methotrexate and possibly other conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs), is an effective, safe and cost-effective option for the treatment of RA.

Keywords: Denosumab; RANKL; osteoclast; rheumatoid arthritis.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / metabolism
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / metabolism
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism*
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / metabolism
  • Bone Resorption / drug therapy
  • Bone Resorption / metabolism
  • Carrier Proteins / administration & dosage
  • Carrier Proteins / metabolism
  • Denosumab / administration & dosage*
  • Denosumab / metabolism*
  • Drug Therapy, Combination
  • Humans
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • RANK Ligand / antagonists & inhibitors
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents
  • Bone Density Conservation Agents
  • Carrier Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFSF11 protein, human
  • Tumor Necrosis Factor-alpha
  • Denosumab