INSERM UMR 1033, Université de Lyon, Lyon, France.
Amgen, Boulogne Billancourt, France.
J Bone Miner Res. 2019 Apr;34(4):626-631. doi: 10.1002/jbmr.3631. Epub 2019 Jan 2.
Denosumab, a RANKL inhibitor, reduced the risk of vertebral, hip, and nonvertebral fractures in the Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial of postmenopausal women with osteoporosis compared with placebo. Previous bone histomorphometric analysis in FREEDOM showed decreased bone resorption and turnover in cancellous bone after 2 and 3 years. The purpose of the present study was to evaluate the effects of denosumab compared with placebo in the cortical compartment from transiliac bone biopsies obtained during FREEDOM. A total of 112 specimens were evaluable for cortical histomorphometry, including 67 obtained at month 24 (37 placebo, 30 denosumab) and 45 at month 36 (25 placebo, 20 denosumab). Eroded surface, osteoclast surface, erosion depth, and wall thickness were measured on the endocortical surface. Cortical thickness and cortical porosity were also measured. Dynamic parameters of bone formation were assessed for endocortical, periosteal, and intracortical envelopes. Endocortical osteoclast surface, eroded surface, and mean and maximum erosion depth were significantly lower in the denosumab group versus placebo at months 24 and 36 (p < 0.0001 to p = 0.04). Endocortical wall thickness and intracortical measures (cortical porosity and cortical thickness) were not different between the two groups. Dynamic parameters were low with tetracycline labels in cortical bone observed in 13 (43%) and 10 (50%) of denosumab biopsies at months 24 and 36, respectively, reflecting a marked decrease in bone turnover. In conclusion, our data reveal the mechanism of action of denosumab on cortical bone: inhibition of osteoclastic resorption and reduced activation of new remodeling sites. In addition, reduced endocortical erosion depth with no change of wall thickness may contribute to increased bone strength by reducing the bone loss and fragility associated with deep resorption cavities and may likely contribute to the greater BMD gain with denosumab than with other antiresorptive agents. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
地舒单抗是一种 RANKL 抑制剂，与安慰剂相比，可降低绝经后骨质疏松症妇女 Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months（FREEDOM）试验中椎骨、髋骨和非椎骨骨折的风险。FREEDOM 中的先前骨组织形态计量学分析显示，在 2 年和 3 年后松质骨中的骨吸收和转换减少。本研究的目的是评估与安慰剂相比，地舒单抗在 FREEDOM 中获得的髂骨活检的皮质隔室中的作用。共有 112 个标本可用于皮质组织形态计量学评估，其中包括 24 个月时获得的 67 个标本（37 个安慰剂，30 个地舒单抗）和 36 个月时获得的 45 个标本（25 个安慰剂，20 个地舒单抗）。在皮质内表面测量侵蚀表面、破骨细胞表面、侵蚀深度和壁厚度。还测量了皮质厚度和皮质孔隙率。评估了骨形成的动态参数，包括皮质内、骨膜和皮质内包膜。与安慰剂相比，地舒单抗组在 24 个月和 36 个月时，骨内破骨细胞表面、侵蚀表面和平均及最大侵蚀深度均显著降低（p < 0.0001 至 p = 0.04）。两组之间的皮质内壁厚度和皮质内测量值（皮质孔隙率和皮质厚度）没有差异。在 24 个月和 36 个月时，分别有 13（43%）和 10（50%）个地舒单抗活检标本中用四环素标记观察到皮质骨中的动态参数较低，反映出骨转换明显减少。总之，我们的数据揭示了地舒单抗对皮质骨的作用机制：抑制破骨细胞吸收和减少新的重塑部位的激活。此外，骨内侵蚀深度降低而壁厚度不变可能通过减少与深部吸收腔相关的骨丢失和脆弱性来增加骨强度，并可能有助于地舒单抗比其他抗吸收剂获得更大的 BMD 增益。
