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

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.