Kohler Rachel, Segvich Dyann M, Reul Olivia, Metzger Corinne E, Allen Matthew R, Wallace Joseph M
Weldon School of Biomedical Engineering, Purdue University, Indianapolis, IN, United States.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
Bone. 2025 May;194:117415. doi: 10.1016/j.bone.2025.117415. Epub 2025 Jan 28.
Comorbid diabetes and chronic kidney disease create a complex disease state with multi-faceted impacts on bone health, primarily reduced bone mass and tissue quality. To reduce fracture risk in this growing population, interventions are needed that target both bone mass and quality. Romosozumab (Romo) is an FDA-approved sclerostin inhibitor that has been shown to increase bone mass and strength in a murine model of combined diabetes and CKD (DKD), while Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone mechanical properties by increasing bone bound water content. We aimed to test whether combined RAL and Romo treatment could improve bone quality in our murine model of DKD more than either treatment alone. Using a previously established streptozotocin- and adenine-diet-induced model, male, C57BL/6J mice were randomly divided into four treatment groups and given daily subcutaneous injections of 100 μL vehicle (phosphorus buffered saline, PBS) or 0.5 mg/kg RAL. In addition, two groups were also given a weekly dose of Romo (10 mg/kg). Overall, Romo increased whole-bone strength and RAL improved tissue-level mechanical properties. Combined RAL-Romo treatment led to significantly higher cortical and trabecular bone mass compared to untreated controls. These morphological improvements created corresponding improvements in cortical bending strength and vertebral trabecular compression strength. These results suggest that combined RAL-Romo treatment provides both mass and quality improvements to DKD bone.
糖尿病和慢性肾脏病共存会导致一种复杂的疾病状态，对骨骼健康产生多方面影响，主要表现为骨量减少和组织质量下降。为降低这一不断增长的人群的骨折风险，需要采取针对骨量和质量的干预措施。罗莫单抗（Romo）是一种经美国食品药品监督管理局（FDA）批准的硬化蛋白抑制剂，已证实在糖尿病合并慢性肾脏病（DKD）的小鼠模型中可增加骨量和骨强度，而雷洛昔芬（RAL）是一种用于治疗骨质疏松症的轻度抗吸收药物，也已证实在通过增加骨结合水含量来提高骨力学性能。我们旨在测试联合使用RAL和Romo治疗是否比单独使用任何一种治疗方法能更好地改善我们的DKD小鼠模型的骨质量。利用先前建立的链脲佐菌素和腺嘌呤饮食诱导的模型，将雄性C57BL/6J小鼠随机分为四个治疗组，每天皮下注射100μL赋形剂（磷酸盐缓冲盐水，PBS）或0.5mg/kg RAL。此外，两组还每周给予一次Romo（10mg/kg）。总体而言，Romo提高了全骨强度，RAL改善了组织水平的力学性能。与未治疗的对照组相比，联合使用RAL-Romo治疗导致皮质骨和小梁骨量显著更高。这些形态学上的改善相应地提高了皮质骨弯曲强度和椎体小梁压缩强度。这些结果表明，联合使用RAL-Romo治疗可同时改善DKD小鼠的骨量和骨质量。
