Sustained anti-osteoporotic action of risedronate compared to anti-RANKL antibody following discontinuation in ovariectomized mice

Bisphosphonates and the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab are effective anti-resorptive drugs commonly prescribed for osteoporosis. Both drugs may, however, have intolerable side effects; so, it is critical to examine their residual efficacy such as maintenance of bone mass following cessation. Therefore, we compared the changes in bone histology following discontinuation of the aminobisphosphonate risedronate and anti-RANKL antibody in ovariectomized (OVX) mice. Twelve-week-old female C57BL/6 N mice were OVX or sham operated. Four weeks after surgery, mice were treated with vehicle, a single injection of anti-RANKL antibody (5 mg/kg), or risedronate (5 μg/kg/day, s.c.) for 4 weeks (the treatment period), followed by vehicle treatment for an additional 4 weeks (discontinuation period). The lumbar spine and proximal tibia were evaluated by micro-computed tomography. In addition, the lumbar spine, proximal tibia, and the femoral shaft were examined by bone histomorphometry. After 4 weeks of discontinuation, OVX mice initially treated with the anti-RANKL antibody exhibited a trend of bone loss associated with increased turnover in both trabecular and cortical bones, although the difference was not significant. By contrast, OVX mice treated with risedronate exhibited maintained or even increased bone mass and suppressed bone turnover. Patients discontinuing denosumab should be carefully monitored for recurrent osteoporosis symptoms, and a replacement drug should be considered.