高剂量罗莫佐单抗促进了非人灵长类动物中填充有脱矿骨基质的临界尺寸尺骨缺损的骨再生。

High-dose romosozumab promoted bone regeneration of critical-size ulnar defect filled with demineralized bone matrix in nonhuman primates.

作者信息

Li Xiaodong, Asuncion Frank, Ominsky Michael, Niu Qing-Tian, Akesson Kristina E, Wang Jeffrey, Lieberman Jay, Ke Hua Zhu

机构信息

Amgen Inc., Thousand Oaks, CA, USA.

Orthopedics, Department of Clinical Sciences, Lund University, Malmö, Sweden.

出版信息

J Orthop Translat. 2025 Jul 10;54:1-7. doi: 10.1016/j.jot.2025.06.019. eCollection 2025 Sep.

DOI:10.1016/j.jot.2025.06.019

PMID:40809811

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12343352/

Abstract

BACKGROUND

Large bone defects are challenging to manage clinically and usually require treatment with bone graft or bone graft substitute. This study evaluated the effect of romosozumab, a sclerostin antibody, in combination with demineralized bone matrix (DBM) on bone regeneration in a critical-size ulnar defect model in nonhuman primates.

METHODS

In cynomolgus monkeys (N = 22, male, 10-12 years old), a full-cortex bone defect (0.5 cm long) was created in the left ulnar shaft and filled with DBM. Animals were randomized to receive vehicle (n = 10) or romosozumab (n = 12; 30 mg/kg) subcutaneously, every 2 weeks for 28 weeks. Radiographs of the left ulna were taken every 2 weeks for 28 weeks to monitor bone regeneration response. Ulnae were excised and analyzed by ex-vivo x-ray and micro-computed tomography (micro-CT) to evaluate bone repair, and lumbar vertebrae were excised for bone histomorphometric analysis to evaluate the systemic anabolic response.

RESULTS

In-vivo and ex-vivo x-ray images of surgical ulnae demonstrated that the critical-size ulnar defect fully bridged in 3 romosozumab-treated monkeys at week 28 but not in any vehicle-treated monkey. Micro-CT analysis demonstrated that average new bone volume and new bone area within the defect region were 118 % and 105 % greater, respectively, with romosozumab versus vehicle. Trabecular bone volume per tissue volume and trabecular thickness of lumbar vertebral body were 72 % and 92 % greater, and eroded surface was significantly lower with romosozumab versus vehicle.

CONCLUSION

High-dose romosozumab in combination with DBM improved bone regeneration in a critical-size ulnar defect model and increased bone mass in non-surgical bone in nonhuman primates.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE

Clinical management of large bone defect is complex and challenging. More effective management is needed. This paper reports the first nonhuman primate study that evaluated high-dose romosozumab in combination with demineralized bone matrix in a critical-size defect model and provides perspective for the future research evaluating the combination of romosozumab and bone graft or bone graft substitutes in various relevant clinical conditions.

摘要

背景

大型骨缺损的临床处理具有挑战性，通常需要采用骨移植或骨移植替代物进行治疗。本研究评估了硬化素抗体罗莫单抗与脱矿骨基质（DBM）联合应用对非人类灵长类动物临界尺寸尺骨缺损模型中骨再生的影响。

方法

在食蟹猴（N = 22，雄性，10 - 12岁）中，于左侧尺骨干制造一个全皮质骨缺损（长0.5 cm），并用DBM填充。将动物随机分为两组，分别皮下注射赋形剂（n = 10）或罗莫单抗（n = 12；30 mg/kg），每2周注射一次，共注射28周。在28周内每2周拍摄一次左侧尺骨的X线片，以监测骨再生反应。切除尺骨并通过离体X线和显微计算机断层扫描（micro-CT）进行分析，以评估骨修复情况，同时切除腰椎进行骨组织形态计量学分析，以评估全身合成代谢反应。

结果

手术侧尺骨的体内和离体X线图像显示，在第28周时，3只接受罗莫单抗治疗的猴子的临界尺寸尺骨缺损完全桥接，而接受赋形剂治疗的猴子均未出现这种情况。Micro-CT分析表明，与赋形剂相比，罗莫单抗治疗组缺损区域内的平均新骨体积和新骨面积分别增加了118%和105%。罗莫单抗治疗组腰椎椎体的每组织体积小梁骨体积和小梁厚度分别增加了72%和92%，侵蚀表面明显低于赋形剂治疗组。