Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, 2010, Australia.
J Bone Miner Res. 2024 May 2;39(4):484-497. doi: 10.1093/jbmr/zjae023.
Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.
停药后骨量反跳丢失是一个重要的临床挑战。目前预防这种情况的治疗策略未能抑制破骨细胞介导的骨吸收的增加和超过。在这项研究中，我们使用 denosumab 治疗和停药的小鼠模型来显示在 RANKL 抑制和停药期间破骨细胞形成和活性的时间变化。我们表明，在 RANKL 抑制停药后驱动破骨细胞形成和随后骨吸收的细胞过程先于骨丢失的反弹。此外，在当前临床实践中用于骨转换标志物之前，检测到血清 TRAP 和 RANKL 水平的升高。这些机制上的进展可能为在 denosumab 停药后进行序贯治疗提供更明确的干预机会窗口提供了深入的了解。
