Kinetic reconstruction reveals time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys
Kinetic reconstruction reveals time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys
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DOI：
10.1016/j.bone.2017.04.005
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发表时间：
2017-08-01
期刊：
影响因子：
4.1
通讯作者：
Ominsky, Michael S.
中科院分区：
文献类型：
--
作者：
Boyce, Rogely Waite;Niu, Qing-Tian;Ominsky, Michael S.
Romosozumab是一种正在开发的用于治疗骨质疏松症的人源化单克隆sclerostin抗体，对骨具有独特的作用机制，可增加骨形成并减少骨吸收。对骨形成的影响是短暂的，会引起骨形成的快速增加，并随着持续治疗而减弱。虽然骨形成减弱，但骨矿物质密度（BMD）继续增加。为了探索可能有助于脊柱BMD进行性增加的潜在组织水平机制，我们使用动力学重建技术来检查romosozumab对给予romosozumab 10周和28周的成年食蟹猴椎体松质骨中建模和重塑单位的影响。10周的研究持续时间捕获了一段基于建模的高骨形成期，28周的研究持续时间是在长期治疗发生的松质骨中骨形成的自我调节或衰减之后。应用于动力学重建的连续荧光染料标记也用于评估早在3周时对成骨细胞功能的治疗效果，椎体松质骨中重塑和建模形成位点的动力学重建显示，在第3周，romosozumab使重塑位点中的矿物质沉积速率显著短暂增加，继续治疗无法维持。然而，在第10周和第28周，romosozumab治疗引起重塑形成部位的类骨质标记分数（成骨细胞效率的指数）持续改善，这是重塑包的最终壁厚度（W.Th）显著增加的主要原因。在第10周，重塑W.Th与建模包的最终W.Th相匹配。在第10周和第28周，romosozumab显著减少侵蚀表面（ES/BS）。在第28周，romosozumab还显著降低了吸收期（Rs.P）和最终吸收深度（Rs.De）。最终Rs.De的减少与W.Th的增加相结合，导致骨平衡（BB）在重塑单位水平上显著增加。治疗28周后对椎体骨膜和皮质内表面骨形成的评估显示，romosozumab显著增加了这些表面上的骨形成，这些表面在第28周时已经减弱，导致新骨膜和皮质内骨在第28周时显著增加。这些数据表明，多种因素可能有助于romosozumab治疗后脊柱BMD的增加。在治疗的早期阶段，增加的建模为基础的骨形成，增加W.Th在重建部位，减少重建空间继发于减少ES/BS在椎体松质骨，并增加骨膜和皮质内骨形成在椎体皮质有助于脊柱BMD的早期增加。在骨形成的自我调节之后，当基于建模的骨形成减弱时，继发于ES/BS降低的重塑空间减少以及继发于最终Rs.De降低和W.Th增加的正BB有助于长期治疗的脊柱BMD的逐渐增加。(C)2017年安进公司爱思唯尔公司出版
Romosozumab, a humanized monoclonal sclerostin antibody under development for the treatment of osteoporosis, has a unique mechanism of action on bone increasing bone formation and decreasing bone resorption. The effects on bone formation are transient, eliciting a rapid increase in bone formation that attenuates with continued treatment. Although bone formation attenuates, bone mineral density (BMD) continues to increase. To explore potential tissue-level mechanisms that could contribute to a progressive increase in spine BMD, we used kinetic reconstruction techniques to examine the effects of romosozumab on modeling and remodeling units in vertebral cancellous bone from adult cynomolgus monkeys administered romosozumab for 10 and 28 weeks.The 10-week study duration captured a period of high modeling-based bone formation, and the 28-week study duration followed the self-regulation or attenuation of bone formation in cancellous bone that occurs with longterm treatment. Sequential fluorochrome labels applied for the kinetic reconstruction were also used to evaluate treatment effects on osteoblast function as early as 3 weeks, and on bone formation and bone accrual in the vertebral cortex over 28 weeks.Kinetic reconstruction of remodeling and modeling formation sites in vertebral cancellous bone revealed that romosozumab effected significant transient increases in mineral apposition rate in remodeling sites at week 3 that was not sustained with continued treatment. However, romosozumab treatment caused sustained improvement in fractional labeling of osteoid, an index of osteoblast efficiency, at remodeling formative sites at both weeks 10 and 28 that was the major contributor to significant increases in final wall thickness (W.Th) of remodeling packets. Remodeling W.Th matched the final W.Th of modeling packets at week 10. At both weeks 10 and 28, romosozumab significantly decreased eroded surface (ES/BS). At week 28, romosozumab also significantly reduced resorption period (Rs.P) and final resorption depth (Rs.De). The reduced final Rs.De combined with the increased W.Th resulted in a significant increase in bone balance (BB) at the level of the remodeling unit. Assessment of bone formation on the vertebral periosteal and endocortical surfaces following 28 weeks of treatment revealed that romosozumab significantly increased bone formation on these surfaces, which had attenuated by week 28, resulting in significant increases in new periosteal and endocortical bone by week 28.These data suggest that multiple factors potentially contribute to the increase in spine BMD with romosozumab treatment. In the early period of treatment, increased modeling-based bone formation, increased W.Th at remodeling sites, a decrease in remodeling space secondary to decreased ES/BS in vertebral cancellous bone, and increased periosteal and endocortical bone formation in the vertebral cortex contribute to the early increase in spine BMD. Following the self-regulation of bone formation when modeling-based bone formation has attenuated, a decrease in remodeling space secondary to reduced ES/BS and a positive BB secondary to decreased final Rs.De and increased W.Th contribute to the progressive increase in spine BMD with long-term treatment. (C) 2017 Amgen Inc. Published by Elsevier Inc.