Objective

Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis.

Methods

Ovid Medline, Embase and CINAHL were searched between inception and June 2021 using MeSH terms and key words to identify studies examining the association between metformin use and outcome measures related to osteoarthritis. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. This systematic review is registered on PROSPERO (CRD42021261052 and CRD42021261060).

Results

Fifteen (10 pre-clinical and 5 human) studies were included. Most studies (10 pre-clinical and 3 human) assessed the effect of metformin using knee osteoarthritis models. In pre-clinical studies, metformin was assessed for the effect on structural outcomes (n = 10); immunomodulation (n = 5); pain (n = 4); and molecular pathways of its effect in osteoarthritis (n = 7). For human studies, metformin was evaluated for the effect on structural progression (n = 3); pain (n = 1); and immunomodulation (n = 1). Overall, pre-clinical studies consistently showed metformin having a chondroprotective, immunomodulatory and analgesic effect in osteoarthritis, predominantly mediated by adenosine monophosphate-activated protein kinase activation. Evidence from human studies, although limited, was consistent with findings in pre-clinical studies.

Conclusion

We found consistent evidence across pre-clinical and human studies to support a favourable effect of metformin on chondroprotection, immunomodulation and pain reduction in knee osteoarthritis. Further high-quality clinical trials are needed to confirm these findings as metformin could be a novel therapeutic drug for the treatment of osteoarthritis.

中文翻译：

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二甲双胍作为一种潜在的骨关节炎疾病缓解药物：对临床前和人体研究的系统评价

客观的

骨关节炎会导致严重的疼痛和残疾，但尚无批准的疾病缓解药物。我们系统地回顾了临床前和人体研究的证据，以证明二甲双胍在骨关节炎中具有潜在的疾病缓解作用。

方法

Ovid Medline、Embase 和 CINAHL 在成立至 2021 年 6 月期间使用 MeSH 术语和关键词进行搜索，以确定检查二甲双胍使用与骨关节炎相关结果测量之间关联的研究。两名评价者进行偏倚风险评估，3 名评价者独立提取数据。进行了定性证据综合。该系统评价已在 PROSPERO 上注册（CRD42021261052 和 CRD42021261060）。

结果

包括 15 项（10 项临床前和 5 项人类）研究。大多数研究（10 项临床前研究和 3 项人类研究）使用膝骨关节炎模型评估了二甲双胍的作用。在临床前研究中，评估了二甲双胍对结构结果的影响 (n = 10)；免疫调节（n = 5）；疼痛（n = 4）；及其对骨关节炎影响的分子途径 (n = 7)。对于人体研究，评估了二甲双胍对结构进展的影响 (n = 3)；疼痛（n = 1）；和免疫调节 (n = 1)。总的来说，临床前研究一致表明二甲双胍在骨关节炎中具有软骨保护、免疫调节和镇痛作用，主要由腺苷一磷酸激活蛋白激酶激活介导。来自人体研究的证据虽然有限，但与临床前研究的结果一致。

结论

我们在临床前和人体研究中发现了一致的证据，支持二甲双胍对软骨保护、免疫调节和膝骨关节炎疼痛减轻的有利作用。需要进一步的高质量临床试验来证实这些发现，因为二甲双胍可能成为治疗骨关节炎的新型治疗药物。