Nutritional Implications of Methotrexate in Osteoarthritis: A Systematic Review and Meta-Analysis

Introduction: Osteoarthritis (OA) is a prevalent degenerative joint condition with limited treatment options targeting disease modification. Methotrexate (MTX), widely used in rheumatoid arthritis for its anti-inflammatory properties, may offer similar benefits in OA. However, its effectiveness and nutritional implications in OA remain uncertain. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines, registered in PROSPERO (CRD42024592121). We searched PubMed, Web of Science, OVID, and Cochrane Central up to August 2024 for randomized controlled trials comparing MTX with placebo in OA patients. Risk of bias was assessed using the Cochrane RoB 2 tool, and data were synthesized using Review Manager (RevMan) 5.4. Results: Four trials involving 416 participants were included. MTX significantly reduced pain at 3 months (SMD = -0.33, p = 0.006) and 6 months (SMD = -0.53, p = 0.0004), and stiffness at 6 months (SMD = -0.48, p < 0.0001). No significant improvement in physical function was found in the primary analysis (SMD = -1.07, p = 0.09), but sensitivity analysis excluding one high-risk study showed a modest benefit (SMD = -0.34, p = 0.01). Adverse events were consistent with low-dose MTX use. No study reported folate levels, but folate supplementation is recommended to mitigate MTX-related nutritional risks. Discussion: MTX appears to offer symptom relief in OA and may enhance function in select patients. Nutritional monitoring, particularly folate status, should accompany MTX therapy. Conclusion: MTX shows promise as an adjunct therapy for OA. Larger, long-term trials incorporating nutritional parameters are warranted.