Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, China.
Acta Pharmacol Sin. 2012 Jul;33(7):924-34. doi: 10.1038/aps.2012.28. Epub 2012 May 21.
To investigate whether the stage of osteoarthritis (OA) progression influenced the efficacy of the third-generation bisphosphonate zoledronic acid in a rat medial meniscal tear model.
Medial meniscal tear (MMT) was surgically induced in adult male Sprague Dawley rats. Zoledronic acid (ZOL, 100 μg/kg, sc, twice a week) was administered starting immediately, early (from 4 weeks) or late (from 8 weeks) after OA induction. The degeneration of articular cartilage was evaluated with toluidine blue O staining. Subchondral bone remodeling was evaluated with X-ray micro-CT scanning. Joint pain was measured with respect to weight-bearing asymmetry. Calcitonin gene-related peptide (CGRP) expression in dorsal root ganglia (DRGs) was examined using immunofluorescence analysis. The afferent neurons in DRGs innervating the joint were identified by retrograde labeling with fluorogold.
Progressive cartilage loss was observed during 12 weeks after OA induction. Subchondral bone remodeling manifested as increased bone resorption at early stage (4 weeks), but as increased bone accretion at advanced stages (8 weeks). Immediately and early ZOL administration significantly improved subchondral microstructural parameters, attenuated cartilage degeneration, reduced weight-bearing asymmetry and CGRP expression, whereas the late ZOL administration had no significant effects.
The stage of OA progression influences the efficacy of ZOL in treating joint degeneration and pain. To obtain the maximum efficacy, bisphosphonate treatment should be initiated in rat with early stages of OA pathogenesis.
研究骨关节炎（OA）进展阶段是否会影响第三代双膦酸盐唑来膦酸在大鼠内侧半月板撕裂模型中的疗效。
通过手术诱导成年雄性 Sprague Dawley 大鼠内侧半月板撕裂（MMT）。唑来膦酸（ZOL，100 μg/kg，sc，每周两次）在 OA 诱导后立即、早期（4 周时）或晚期（8 周时）开始给药。用甲苯胺蓝 O 染色评估关节软骨退变。用 X 射线微 CT 扫描评估软骨下骨重塑。根据体重分布不对称性测量关节痛。通过免疫荧光分析检查背根神经节（DRG）中降钙素基因相关肽（CGRP）的表达。用荧光金逆行标记鉴定支配关节的 DRG 中的传入神经元。
OA 诱导后 12 周内观察到进行性软骨丢失。软骨下骨重塑表现为早期（4 周）骨吸收增加，但晚期（8 周）骨增生增加。立即和早期 ZOL 给药显著改善了软骨下微结构参数，减轻了软骨退变，减轻了体重分布不对称性和 CGRP 表达，而晚期 ZOL 给药则没有显著效果。
OA 进展阶段影响 ZOL 治疗关节退变和疼痛的疗效。为了获得最大疗效，应在 OA 发病早期开始双膦酸盐治疗。
