Abstract
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.
Highlights
Osteoporosis is characterized by low bone mass and elevated risk of fragility fractures
We compared the effects of anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody (Ab) administration and cessation to risedronate administration and cessation on bone structure by micro-CT analysis of the lumbar spine (Fig. 2A) and proximal tibia (Fig. 3A)
The Ab group showed significantly higher Bone volume (BV)/tissue volume (TV) and Tb.N and lower Tb.Sp compared with the OVX group 4 weeks after single Ab administration
Summary
Osteoporosis is characterized by low bone mass and elevated risk of fragility fractures. Recent advances in the understanding of bone metabolism have led to the development of various anti-osteoporosis drugs. Bisphosphonates (BPs) are the most commonly used anti-resorptive drugs because they demonstrated efficacy for increasing bone mineral density (BMD) and reducing fracture risk (Liberman et al, 1995; Black et al, 1996; Harris et al, 1999). BPs are incorporated into bone and released during resorption by osteoclasts, leading to sustained suppression of bone remodeling. A fully human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), is another anti-resorptive drug with a distinct mechanism of action. Denosumab increases BMD and reduces the risk of fragility fractures by inhibiting the differentiation and activation of osteoclasts (Cummings et al, 2009)
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