Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment
Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment
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DOI：
10.1002/jbmr.3735
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发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Grauer, Andreas
中科院分区：
文献类型：
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作者：
Chavassieux, Pascale;Chapurlat, Roland;Grauer, Andreas
硬化素是一种由骨细胞产生的蛋白质，它抑制骨形成。在多种动物模型中，注射硬化素抗体可导致骨形成增加。Romosozumab是一种人源化的硬化素抗体，对骨骼具有双重作用，瞬时增加骨形成的血清生化标志物和降低骨吸收的血清标志物，导致人类骨密度增加和骨折风险降低。我们的目的是评价罗莫佐单抗对骨组织的影响。在多中心、国际、随机、双盲、安慰剂对照的绝经后骨质疏松症妇女骨折研究(FRAME)中，107名绝经后骨质疏松症妇女的子组在治疗2(n=34)或12(n=73)个月后接受过渡骨活组织检查，每月服用一次210毫克的罗莫佐单抗或安慰剂，以评估组织形态计量学和基于微计算机断层扫描的微建筑终点。2个月后，与四重荧光标记或安慰剂后评估的基线值相比，动态形成参数显著增加(P<；0.05至P<；0.001)(中位数MS/BS：罗莫佐单抗1.51%和5.64%；安慰剂在基线和2个月分别为1.60%和2.31%)与松质骨吸收参数显著降低(中位数ES/BS：安慰剂3.4%，罗莫佐单抗1.8%；P=0.022)和皮质内(ES/BS中位数：安慰剂6.3%，罗莫佐单抗1.6%；P=0.003)。在12个月时，与安慰剂组相比，罗莫佐单抗组的松质骨形成显著减少(P<；0.05至P<；0.001)，而在第2个月出现的吸收终点的较低值持续存在(P<；0.001)，表明骨转换减少(P=0.006)。骨膜和皮质骨无明显变化。这导致12个月时骨量和骨小梁厚度增加，骨小梁连通性改善，皮质孔隙度没有明显改变。总而言之，罗莫佐单抗早期和短暂地增加了骨形成，但骨吸收持续减少。抗吸收作用最终导致骨转换率降低。这种效应导致了骨量的显著增加和微结构的改善。(C)2019年美国骨与矿物研究学会。
Sclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized sclerostin antibody, has a dual effect on bone, transiently increasing serum biochemical markers of bone formation and decreasing serum markers of bone resorption, leading to increased BMD and reduction in fracture risk in humans. We aimed to evaluate the effects of romosozumab on bone tissue. In a subset of 107 postmenopausal women with osteoporosis in the multicenter, international, randomized, double-blind, placebo-controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), transiliac bone biopsies were performed either after 2 (n = 34) or 12 (n = 73) months of treatment with 210 mg once monthly of romosozumab or placebo to evaluate histomorphometry and microcomputed tomography-based microarchitectural endpoints. After 2 months, compared with either baseline values assessed after a quadruple fluorochrome labeling or placebo, significant increases (P < 0.05 to P < 0.001) in dynamic parameters of formation (median MS/BS: romosozumab 1.51% and 5.64%; placebo 1.60% and 2.31% at baseline and month 2, respectively) were associated with a significant decrease compared with placebo in parameters of resorption in cancellous (median ES/BS: placebo 3.4%, romosozumab 1.8%; P = 0.022) and endocortical (median ES/BS: placebo 6.3%, romosozumab 1.6%; P = 0.003) bone. At 12 months, cancellous bone formation was significantly lower (P < 0.05 to P < 0.001) in romosozumab versus placebo and the lower values for resorption endpoints seen at month 2 persisted (P < 0.001), signaling a decrease in bone turnover (P = 0.006). No significant change was observed in periosteal and endocortical bone. This resulted in an increase in bone mass and trabecular thickness with improved trabecular connectivity, without significant modification of cortical porosity at month 12. In conclusion, romosozumab produced an early and transient increase in bone formation, but a persistent decrease in bone resorption. Antiresorptive action eventually resulted in decreased bone turnover. This effect resulted in significant increases in bone mass and improved microarchitecture. (c) 2019 American Society for Bone and Mineral Research.