Unexpected Bone Formation Produced by RANKL Blockade

Trends Endocrinol Metab. 2017 Oct;28(10):695-704. doi: 10.1016/j.tem.2017.06.003. Epub 2017 Jul 19.


Denosumab (Dmab) is a humanized monoclonal antibody that blocks RANKL (receptor activator for nuclear factor κB ligand), thereby exerting a potent bone antiresorptive action. Dmab treatment leads to a dramatic and sustained increase in bone mass through mechanisms that are currently under debate. It is also a matter of controversy whether this potent action of Dmab could lead to intrabone dystrophic mineralization. Recent research has uncovered a possible anabolic role of Dmab involving RANKL-dependent reverse signaling in osteoblasts, and that bone marrow adipocytes can modulate osteoclastogenesis through the production of RANKL. We comment here on potential pathways which might account for the anabolic action of Dmab. The impact of this proposed mechanism needs to be addressed in further research.

Keywords: RANKL; antiresorptive; bone formation; denosumab; osteoporosis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Denosumab / pharmacology*
  • Humans
  • Incidental Findings
  • Osteoblasts / drug effects
  • Osteoblasts / physiology
  • Osteoclasts / drug effects
  • Osteoclasts / physiology
  • Osteogenesis / drug effects*
  • RANK Ligand / antagonists & inhibitors*
  • RANK Ligand / immunology


  • RANK Ligand
  • TNFSF11 protein, human
  • Denosumab