Kim Albert S, Taylor Victoria E, Castro-Martinez Ariel, Dhakal Suraj, Zamerli Amjad, Mohanty Sindhu T, Xiao Ya, Simic Marija K, Pantalone Alyssa, Chu Julian, Cheng Tegan L, Croucher Peter I, Center Jacqueline R, Girgis Christian M, McDonald Michelle M
Cancer Ecosystems Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Faculty of Medicine and Health, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2010, Australia.
J Bone Miner Res. 2025 Mar 15;40(3):413-427. doi: 10.1093/jbmr/zjaf008.
Rebound bone loss following denosumab discontinuation is an important barrier in the effective long-term treatment of skeletal disorders. This is driven by increased osteoclastic bone resorption following the offset of RANKL inhibition, and sequential osteoclast-directed therapy has been utilized to mitigate this. However, current sequential treatment strategies intervene following the offset of RANKL inhibition and this approach fails to consistently prevent bone loss. Our previous work, using a mouse model of denosumab discontinuation, has shown that the processes that drive the rebound phenomenon occur earlier than when bone loss is detected, namely a rise and overshoot in serum tartrate-resistant acid phosphatase (TRAP). We identified that these changes in serum TRAP may provide an earlier window of opportunity to intervene with sequential therapy following RANKL inhibition withdrawal. Here, we show that early treatment with zoledronate (10 mg/kg, 3 wk following the last dose of OPG:Fc), preceding the rise and overshoot in serum TRAP, effectively mitigates rebound bone density loss through preventing the overshoot in serum TRAP. Further, we show that multiple doses of zoledronate (early treatment and during anticipated BMD loss) is superior in consolidating bone density gains made with RANKL inhibition and preventing rebound BMD loss as measured by DXA. Importantly, we demonstrate the efficacy of early and multi-dose zoledronate strategy in preventing bone loss in both growing and skeletally mature mice. MicroCT analysis showed improved trabecular bone structure in both the femur and lumbar vertebrae with zoledronate treatment compared with control. These increases in bone mass translated to increased fracture resistance in skeletally mature mice. This work provides a novel approach of early and multi-dose sequential treatment strategy following withdrawal of RANKL inhibition, contributing valuable insight into the clinical management of patients who discontinue denosumab therapy.
停用狄诺塞麦后出现的反弹性骨质流失是骨骼疾病有效长期治疗中的一个重要障碍。这是由RANKL抑制作用消失后破骨细胞骨吸收增加所驱动的，并且已经采用序贯破骨细胞靶向治疗来减轻这种情况。然而，目前的序贯治疗策略是在RANKL抑制作用消失后才进行干预，这种方法并不能始终如一地预防骨质流失。我们之前使用狄诺塞麦停药小鼠模型的研究表明，驱动反弹现象的过程比检测到骨质流失时更早发生，即血清抗酒石酸酸性磷酸酶（TRAP）升高并超过正常水平。我们发现血清TRAP的这些变化可能为在停用RANKL抑制后进行序贯治疗提供更早的干预时机。在此，我们表明，在血清TRAP升高并超过正常水平之前，用唑来膦酸（10mg/kg，在最后一剂OPG:Fc后3周）进行早期治疗，通过防止血清TRAP超过正常水平，有效地减轻了反弹性骨密度损失。此外，我们表明，多剂量的唑来膦酸（早期治疗以及在预期骨密度损失期间）在巩固RANKL抑制所带来的骨密度增加以及通过双能X线吸收法（DXA）测量预防反弹性骨密度损失方面更具优势。重要的是，我们证明了早期和多剂量唑来膦酸策略在预防生长中的小鼠和骨骼成熟小鼠骨质流失方面的有效性。显微CT分析显示，与对照组相比，唑来膦酸治疗使股骨和腰椎的小梁骨结构得到改善。这些骨量增加转化为骨骼成熟小鼠抗骨折能力的增强。这项工作提供了一种在停用RANKL抑制后进行早期和多剂量序贯治疗策略的新方法，为停用狄诺塞麦治疗的患者的临床管理提供了有价值的见解。
