New England Musculoskeletal Institute, Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA.
J Bone Joint Surg Am. 2013 Apr 17;95(8):694-701. doi: 10.2106/JBJS.L.00285.
Systemic administration of sclerostin neutralizing antibody has led to increased bone formation in animal models of osteoporosis. The purpose of this study was to determine if systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats.
Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The sclerostin antibody (Scl-Ab) treatment groups included the continuous Scl-Ab group (twenty-one animals), the early Scl-Ab group (fifteen animals), and the delayed Scl-Ab group (fifteen animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0 through 12; weeks 0 through 2; and weeks 2 through 4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at zero, two, six, and twelve weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for twelve weeks (fifteen rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis.
In the primary study, four of fifteen defects in the continuous (zero to twelve-week) Scl-Ab group, three of fifteen defects in the early (zero to two-week) Scl-Ab group, and four of fifteen defects in the delayed (two to four-week) Scl-Ab group healed at twelve weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for twelve weeks demonstrated a significant increase in new bone formation (p < 0.05) compared with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls.
Administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by twelve weeks.
系统性给予硬骨素中和抗体可增加骨质疏松动物模型的骨形成。本研究的目的是确定系统性给予硬骨素中和抗体是否可增加大鼠临界尺寸股骨缺损的愈合反应。
在 Lewis 大鼠中建立临界尺寸股骨缺损，并将大鼠随机分为 4 组。硬骨素抗体（Scl-Ab）治疗组包括连续 Scl-Ab 组（21 只动物）、早期 Scl-Ab 组（15 只动物）和延迟 Scl-Ab 组（15 只动物），它们分别在第 0 至 12 周、第 0 至 2 周和第 2 至 4 周每周接受 2 次 25mg/kg 的 Scl-Ab 治疗；对照组 21 只动物在第 0 至 12 周接受载体治疗。在随后的研究中，在接受载体或硬骨素中和抗体治疗 12 周的大鼠中，于术后 0、2、6 和 12 周测量骨转换标志物（每组 15 只大鼠）。通过 X 线摄影、微计算机断层扫描、生物力学测试以及组织学和组织形态计量学分析评估形成的骨质量。
在主要研究中，连续（0 至 12 周）Scl-Ab 组 15 个缺损中有 4 个、早期（0 至 2 周）Scl-Ab 组 15 个缺损中有 3 个和延迟（2 至 4 周）Scl-Ab 组 15 个缺损中有 4 个在 12 周时愈合，而对照组无一例缺损愈合。在这两项研究中，硬骨素抗体治疗 12 周与对照组相比，新骨形成明显增加（p < 0.05）。三组治疗组在缺损愈合率和形成的新骨质量方面无显著差异。与对照组相比，连续 Scl-Ab 组动物的血清骨形成标志物明显升高（p < 0.05）。
给予硬骨素中和抗体可增加骨形成，导致一小部分大鼠的股骨缺损完全愈合，但大多数动物在 12 周时未愈合缺损。
