Objective To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. Design Systematic review and meta-analysis of randomised trials. Data sources Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. Eligibility criteria for study selection Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. Main outcome measures The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was −0.37 SMD. Serious adverse events were analysed as relative risks. Methods Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. Results 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger’s tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD −0.08, 95% confidence interval −0.15 to −0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of −2.0 mm (95% confidence interval −3.8 to −0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). Conclusion Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. Systematic review registration PROSPERO CRD42021236894. The guarantor (BRdC) is willing to examine all requests for the full dataset after a period of two years from the date of this publication. The corresponding author should be contacted at bruno.dacosta@utoronto.ca

中文翻译：

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膝关节骨性关节炎的粘性补充剂：系统评价和荟萃分析

目的评价粘液补充剂治疗膝骨关节炎患者疼痛和功能的有效性和安全性。设计 随机试验的系统评价和荟萃分析。数据来源 从成立到 2021 年 9 月 11 日，对 Medline、Embase 和 Cochrane 对照试验中央注册库 (CENTRAL) 数据库进行了搜索。未发表的试验是从灰色文献和试验注册库中确定的。研究选择的资格标准 比较粘性补充剂与安慰剂或无干预治疗膝骨关节炎的随机试验。主要结果测量 预设的主要结果是疼痛强度。次要结局是功能和严重不良事件。疼痛和功能被分析为标准化平均差 (SMD)。预先指定的最小临床重要性组间差异为 -0.37 SMD。严重不良事件被分析为相对风险。方法 两名评价员独立提取相关数据并使用 Cochrane 偏倚风险工具评估试验的偏倚风险。预定义的主要分析仅基于每组≥100 名参与者的大型安慰剂对照试验。总结结果是通过随机效应荟萃分析模型获得的。还进行了随机效应模型下的累积荟萃分析和试验序贯分析。结果 169 项试验提供了 21 163 名随机参与者的数据。在疼痛和功能方面观察到小型研究效果和发表偏倚的证据（Egger 检验，P<0.001 和不对称漏斗图）。二十四大，疼痛的主要分析中包括的安慰剂对照试验（8997 名随机参与者）表明，与安慰剂相比，粘性补充剂与疼痛强度的小幅降低有关（SMD -0.08，95% 置信区间 -0.15 至 -0.02），下限95% 的置信区间，不包括组间最小的临床重要差异。这种效应对应于 100 mm 视觉模拟量表上 -2.0 mm 的疼痛评分差异（95% 置信区间 -3.8 至 -0.5 mm）。对疼痛的试验序贯分析表明，自 2009 年以来，已经有确凿的证据表明粘液补充剂和安慰剂之间的临床等效性。函数也得到了类似的结论。基于对 6462 名随机参与者进行的 15 项大型安慰剂对照试验，与安慰剂相比，粘液补充剂的严重不良事件风险具有统计学意义（相对风险为 1.49，95% 置信区间为 1.12 至 1.98）。结论 强有力的确凿证据表明，与安慰剂相比，粘胶补充剂导致膝关节骨关节炎疼痛略有减轻，但差异小于组间最小的临床重要性差异。强有力的结论性证据表明，与安慰剂相比，补充粘液补充剂也与严重不良事件的风险增加有关。该研究结果不支持广泛使用粘性补充剂治疗膝关节骨性关节炎。系统评价注册 PROSPERO CRD42021236894。担保人 (BRdC) 愿意在本出版物发布之日起两年后审查所有对完整数据集的请求。通讯作者应通过 bruno.dacosta@utoronto.ca 联系