Bustamante-Gomez Cecile, Fu Qiang, Goellner Joseph J, Thostenson Jeff D, Reyes-Pardo Humberto, O'Brien Charles A
Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Bone. 2025 Jun 16;199:117567. doi: 10.1016/j.bone.2025.117567.
Histological analyses suggest that sclerostin inhibition increases bone mass primarily by stimulating modeling-based bone formation. However, clinical studies show that anti-resorptive therapies, which inhibit bone remodeling, blunt the anabolic effect of the anti-sclerostin antibody romosozumab. Moreover, suppressing remodeling inhibits bone formation in Sost-deficient mice. These latter studies suggest that bone remodeling is required for the full anabolic effect of sclerostin suppression. To address this, we suppressed bone remodeling in mice using the anti-RANKL antibody denosumab and then administered romosozumab, along with continued denosumab. Controls received either vehicle, denosumab alone, or romosozumab alone. The romosozumab-induced increase in bone was not blunted by denosumab. Similarly, the romosozumab-induced increases in osteoblast number and bone formation were not altered by denosumab. The anabolic effect of romosozumab was also not altered in a mouse model of rebound resorption caused by denosumab discontinuation. Nonetheless, denosumab reduced bone formation in Sost-deficient mice. These results demonstrate a striking difference in the dependence on bone remodeling for the anabolic effects of sclerostin suppression versus genetic inactivation of Sost and suggest distinct mechanisms drive osteoblast production in the two conditions. In addition, they suggest that the blunted response to romosozumab in clinical studies is not due to suppressed remodeling.
组织学分析表明，抑制硬化蛋白主要通过刺激基于塑形的骨形成来增加骨量。然而，临床研究表明，抑制骨重塑的抗吸收疗法会削弱抗硬化蛋白抗体罗莫单抗的合成代谢作用。此外，抑制重塑会抑制Sost基因缺陷小鼠的骨形成。这些后期研究表明，骨重塑是硬化蛋白抑制发挥完全合成代谢作用所必需的。为了解决这个问题，我们使用抗RANKL抗体地诺单抗抑制小鼠的骨重塑，然后给予罗莫单抗，并持续使用地诺单抗。对照组分别接受赋形剂、单独使用地诺单抗或单独使用罗莫单抗。地诺单抗并未削弱罗莫单抗诱导的骨量增加。同样，地诺单抗也未改变罗莫单抗诱导的成骨细胞数量增加和骨形成。在因停用 地诺单抗导致的反弹吸收小鼠模型中，罗莫单抗的合成代谢作用也未改变。尽管如此，地诺单抗减少了Sost基因缺陷小鼠的骨形成。这些结果表明，在硬化蛋白抑制的合成代谢作用对骨重塑的依赖性与Sost基因失活之间存在显著差异，并提示在这两种情况下驱动成骨细胞生成的机制不同。此外，这些结果表明临床研究中对罗莫单抗反应减弱并非由于重塑受到抑制。
