title: Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL.
abstract: 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.
  
  
  CONCLUSIONS
  Our findings indicate that RANKL inhibition by denosumab prevents glucocorticoid-induced loss of bone mass and strength in hRANKL-knockin mice.
authors.affiliation: Department of Medicine III, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany. lorenz.hofbauer@uniklinikum-dresden.de
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Ute
authors.initials: U
authors.lastname: Zeitz
authors.forename: Michael
authors.initials: M
authors.lastname: Schoppet
authors.forename: Monika
authors.initials: M
authors.lastname: Skalicky
authors.forename: Christiane
authors.initials: C
authors.lastname: Schüler
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000596:Amino Acids / Q000652:urine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D000069448:Denosumab; D055879:Gene Knock-In Techniques; D005938:Glucocorticoids / Q000009:adverse effects; D008297:Male; D051379:Mice; D010024:Osteoporosis / Q000139:chemically induced* / Q000517:prevention & control*; D011239:Prednisolone; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology / Q000627:therapeutic use
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D053245:RANK Ligand; D000069448:Denosumab; C036020:deoxypyridinoline; D011239:Prednisolone; D000135:Acid Phosphatase