The effectiveness and safety of methotrexate in the intervention of osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

The findings of this meta-analysis suggest that methotrexate is both safe and effective for treatment of pain and joint stiffness in patients with osteoarthritis. James W. Mold, MD, MPH

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Background:
Osteoarthritis (OA) is a prevalent chronic joint disorder among middle-aged and older adults, characterized by progressive cartilage degeneration, subchondral bone remodeling, and osteophyte formation, leading to joint pain, stiffness, dysfunction, and reduced quality of life. With the global aging population, OA imposes a growing socioeconomic burden, yet no disease-modifying therapy is currently available—particularly for moderate-to-severe stages. Emerging evidence implicates synovial inflammation as a central contributor to OA symptoms and progression, raising interest in methotrexate (MTX), a well-established, low-dose anti-inflammatory agent used safely in rheumatoid arthritis. Preliminary studies suggest MTX may alleviate OA-related pain, but findings from randomized controlled trials (RCTs) have been inconsistent and limited in number. Given recent new RCTs and the heterogeneity of existing outcomes, an updated systematic review and meta-analysis is urgently needed to clarify the efficacy and safety of MTX in OA and inform future clinical trial design.

Methods:
PubMed, ClinicalTrials, Web of Science, Cochrane Library and other databases were searched to find randomized controlled trials (RCT) of MTX treatment of OA. Methodological quality was assessed using the Cochrane "risk of bias" assessment tool, and the meta-analysis was conducted using Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, London, UK).

Results:
Fifteen RCTs involving 1591 participants were included in this review. The meta-analysis results showed that the ineffective rate in the experimental group was lower [RR: 0.40 (0.24, 0.67), P = .004]; the VAS in the experimental group was lower [WMD: −0.66 (−1.08, −0.24), P = .002]; the WOMAC score-stiffness in the experimental group was lower [WMD: −0.72 (−1.04, −0.41), P < .00001]; the WOMAC score-function in the experimental group was lower [WMD: −7.72 (−13.56, −1.87), P = .01]. The adverse events in the experimental group were not statistically significant compared with the control group [RR: 1.04 (0.77, 1.42), P = .78].

Conclusion:
MTX demonstrates potential in effectively alleviating pain, improving joint function, and slowing disease progression in patients with OA. Its safety profile is comparable to that of control treatments, making it a viable and reliable therapeutic option worthy of broader clinical application.

Author/s:

Wan, Lifei, Yang, Qianyue, Yang, Kailin, Zeng, Liuting, Sun, Lingyun