The time-effect relationship of intra-articular ozone injection for knee osteoarthritis: a systematic review and...

As a gradual degenerative illness, knee osteoarthritis (KOA) is characterized by high rates of impairment and prevalence. Patients' quality of life is seriously jeopardized, and healthcare systems and social advancement are continuously burdened. Because it is minimally invasive, intra-articular injection treatment is frequently used to treat KOA. Among these, ozone therapy has drawn more and more clinical interest because of its ease of use, affordability, and observable symptom relief. Its scientific application in long-term management strategies is limited, nonetheless, because the exact length of its therapeutic benefits is still unknown.

This study is to integrate clinical data from various follow-up time points using systematic review and meta-analysis techniques in order to comprehensively assess the temporal efficacy of intra-articular ozone therapy in reducing symptoms among patients with KOA. In order to provide evidence-based support and decision-making references for phased and continuous clinical treatment planning, the goal is to elucidate the temporal aspects of persistent therapeutic effects.

Searches were conducted in PubMed, Embase, the Cochrane Library, Web of Science, and Scopus from the inception of each database up to December 3, 2025. Two reviewers independently extracted data using the Cochrane Risk of Bias Assessment Tool and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and assessed the quality of the evidence and the certainty of the evidence for each outcome measure. Outcomes included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC stiffness, WOMAC physical function, WOMAC Total, and Visual Analog Scale (VAS) pain. For combined outcomes, standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. Statistical analysis and graphing of included information were performed using Review Manager 5.4.1, Stata 15.0, and GRADEpro GDT.

A total of 16 randomized controlled trial (RCT) studies (n = 1,172) were included in this review. Meta-analysis results demonstrated that intra-articular ozone therapy exhibits a clear time-dependent effect on symptom improvement in patients with KOA. At short-term follow-up, the WOMAC total decreased at 1 month post-intervention [SMD = - 0.63, 95% CI (-1.17, -0.10), P < 0.01]; at 2 months, WOMAC pain[SMD = - 1.39, 95% CI (-1.96, -0.81), P < 0.01], WOMAC function [SMD = - 1.27, 95% CI (-2.06, -0.49), P < 0.01], and VAS[SMD = - 1.25, 95% CI (-2.10, -0.40), P < 0.01] all showed significant improvement. However, During the 3-month follow-up, no statistically significant differences were observed in any of the outcomes. At 6 and 12 months, compared with the control group, the ozone group showed statistically significantly worse scores in several outcomes, suggesting that ozone not only lacks sustained efficacy but may also be inferior to active control therapies in the long term.

Intra-articular ozone therapies are effective in alleviating pain and improving joint function in patients with knee osteoarthritis in the short term (1-2 months), with effects peaking at 2 months. By 3 months, the therapeutic effect diminishes, and by 6 or 12 months, the evidence of efficacy is very weak, whereas active comparators (such as hyaluronic acid) demonstrate superior therapeutic outcomes at these time points. These findings suggest that ozone therapy may serve as a short-term treatment option but also underscore the need for placebo-controlled long-term trials and studies on repeated dosing regimens before recommending repeat injections.

identifier CRD420251169941.