Journal
ARTHRITIS AND RHEUMATISM
Volume 60, Issue 5, Pages 1427-1437Publisher
WILEY-LISS
DOI: 10.1002/art.24445
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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 numher 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.
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