Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL

Arthritis Rheum. 2009 May;60(5):1427-37. doi: 10.1002/art.24445.


Objective: RANKL has been implicated in the pathogenesis of glucocorticoid-induced osteoporosis. This study was undertaken to evaluate the efficacy of denosumab, a neutralizing monoclonal antibody against human RANKL (hRANKL), in a murine model of glucocorticoid-induced osteoporosis.

Methods: Eight-month-old male homozygous hRANKL-knockin mice expressing a chimeric RANKL protein with a humanized exon 5 received 2.1 mg/kg of prednisolone or placebo daily over 4 weeks via subcutaneous slow-release pellets and were additionally treated with phosphate buffered saline or denosumab (10 mg/kg subcutaneously twice weekly). Two groups of wild-type mice were also treated with either prednisolone or vehicle.

Results: The 4-week prednisolone treatment induced loss of vertebral and femoral volumetric bone mineral density in the hRANKL-knockin mice. Glucocorticoid-induced bone loss was associated with suppressed vertebral bone formation and increased bone resorption, as evidenced by increases in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, TRAP-5b protein in bone extracts, serum levels of TRAP-5b, and urinary excretion of deoxypyridinoline. Denosumab prevented prednisolone-induced bone loss by a pronounced antiresorptive effect. Biomechanical compression tests of lumbar vertebrae revealed a detrimental effect of prednisolone on bone strength that was prevented by denosumab.

Conclusion: Our findings indicate that RANKL inhibition by denosumab prevents glucocorticoid-induced loss of bone mass and strength in hRANKL-knockin mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / analysis
  • Amino Acids / urine
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Bone Density / drug effects
  • Bone Resorption / drug therapy
  • Denosumab
  • Gene Knock-In Techniques
  • Glucocorticoids* / adverse effects
  • Male
  • Mice
  • Osteoporosis / chemically induced*
  • Osteoporosis / prevention & control*
  • Prednisolone
  • RANK Ligand / antagonists & inhibitors*
  • RANK Ligand / physiology
  • RANK Ligand / therapeutic use


  • Amino Acids
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Glucocorticoids
  • RANK Ligand
  • Denosumab
  • deoxypyridinoline
  • Prednisolone
  • Acid Phosphatase