{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T06:52:36Z","timestamp":1781679156992,"version":"3.54.5"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pain Res."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>As a gradual degenerative illness, knee osteoarthritis (KOA) is characterized by high rates of impairment and prevalence. Patients\u2019 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 16 randomized controlled trial (RCT) studies (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091,172) 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\u2009=\u2009\u2212\u20090.63, 95% CI (\u22121.17, \u22120.10),\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;lt;\u20090.01]; at 2 months, WOMAC pain[SMD\u2009=\u2009\u2212\u20091.39, 95% CI (\u22121.96, \u22120.81),\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;lt;\u20090.01], WOMAC function [SMD\u2009=\u2009\u2212\u20091.27, 95% CI (\u22122.06, \u22120.49),\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;lt;\u20090.01], and VAS[SMD\u2009=\u2009\u2212\u20091.25, 95% CI (\u22122.10, \u22120.40),\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;lt;\u20090.01] 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Intra-articular ozone therapies are effective in alleviating pain and improving joint function in patients with knee osteoarthritis in the short term (1\u20132 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>identifier CRD420251169941.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpain.2026.1843756","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:57:02Z","timestamp":1781675822000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The time-effect relationship of intra-articular ozone injection for knee osteoarthritis: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"7","author":[{"given":"Fengjiao","family":"Chen","sequence":"first","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Tao","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoxi","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]},{"name":"School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"212","DOI":"10.5312\/wjo.v13.i3.212","article-title":"Conservative treatment of knee osteoarthritis: a review of the literature","volume":"13","author":"Lim","year":"2022","journal-title":"World J Orthop"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.3390\/cells14231899","article-title":"Conservative management of focal chondral lesions of the knee and ankle: current concepts","volume":"14","author":"Migliorini","year":"2025","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1302\/2058-5241.6.210026","article-title":"Injections in the osteoarthritic knee: a review of current treatment options","volume":"6","author":"Fusco","year":"2021","journal-title":"EFORT Open Rev"},{"key":"B5","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.arthro.2019.05.043","article-title":"Oxygen-ozone therapy for the treatment of knee osteoarthritis: a systematic review of randomized controlled trials","volume":"36","author":"Sconza","year":"2020","journal-title":"Arthroscopy"},{"key":"B6","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1093\/bmb\/ldz028","article-title":"The temporal effect of intra-articular ozone injections on pain in knee osteoarthritis","volume":"132","author":"Oliviero","year":"2019","journal-title":"Br Med Bull"},{"key":"B7","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1002\/pmrj.12088","article-title":"Short-term therapeutic effects of ozone in the management of pain in knee osteoarthritis: a meta-analysis","volume":"11","author":"Arias-V\u00e1zquez","year":"2019","journal-title":"PM&R"},{"key":"B8","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Br Med J"},{"key":"B9","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/2046-4053-3-37","article-title":"Evaluation of the cochrane collaboration\u2019s tool for assessing the risk of bias in randomized trials: focus groups, online survey, proposed recommendations and their implementation","volume":"3","author":"Savovi\u0107","year":"2014","journal-title":"Syst Rev"},{"key":"B10","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021)","author":"Higgins","year":"2021"},{"key":"B11","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 (updated August 2024)","author":"Higgins","year":"2024"},{"key":"B12","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s42358-025-00443-w","article-title":"Efficacy of two doses of intra-articular ozone therapy for pain and functional mobility in knee osteoarthritis: a double-blind randomized trial","volume":"65","author":"Arjmanddoust","year":"2025","journal-title":"Adv Rheumatol"},{"key":"B13","first-page":"621","article-title":"Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis","volume":"30","author":"Giombini","year":"2016","journal-title":"J Biol Regul Homeost Agents"},{"key":"B14","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1177\/10538127251358732","article-title":"Intra-articular injections of oxygen-ozone versus hyaluronic acid for the treatment of knee osteoarthritis: a randomized controlled trial","volume":"39","author":"Sconza","year":"2026","journal-title":"J Back Musculoskelet Rehabil"},{"key":"B15","doi-asserted-by":"publisher","first-page":"8788","DOI":"10.3390\/ijms24108788","article-title":"Ozone therapy versus hyaluronic acid injections for pain relief in patients with knee osteoarthritis: preliminary findings on molecular and clinical outcomes from a randomized controlled trial","volume":"24","author":"Sconza","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12891-021-04017-x","article-title":"The comparison effects of intra-articular injection of platelet rich plasma (PRP), plasma rich in growth factor (PRGF), hyaluronic acid (HA), and ozone in knee osteoarthritis; a one year randomized clinical trial","volume":"22","author":"Raeissadat","year":"2021","journal-title":"BMC Musculoskelet Disord"},{"key":"B17","doi-asserted-by":"publisher","first-page":"111","DOI":"10.2147\/JPR.S142755","article-title":"Intra-articular ozone or hyaluronic acid injection: which one is superior in patients with knee osteoarthritis? A 6-month randomized clinical trial","volume":"11","author":"Raeissadat","year":"2018","journal-title":"J Pain Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1007\/s10067-018-4147-6","article-title":"The effects of ultrasound-guided corticosteroid injection compared to oxygen\u2013ozone (O2\u2013O3) injection in patients with knee osteoarthritis: a randomized controlled trial","volume":"37","author":"Babaei-Ghazani","year":"2018","journal-title":"Clin Rheumatol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e27585","DOI":"10.5812\/aapm.27585","article-title":"The effects of prolotherapy with hypertonic dextrose versus prolozone (intraarticular ozone) in patients with knee osteoarthritis","volume":"5","author":"Hashemi","year":"2015","journal-title":"Anesth Pain Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.jbmt.2024.03.066","article-title":"The effect of intra-articular ozone injection combined with home-based exercise on pain and function in daily living activities of patients with mild to moderate knee osteoarthritis, a randomized double-blinded controlled clinical trial","volume":"38","author":"Nazarieh","year":"2024","journal-title":"J Bodyw Mov Ther"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e0179185","DOI":"10.1371\/journal.pone.0179185","article-title":"Comparison between intra-articular ozone and placebo in the treatment of knee osteoarthritis: a randomized, double-blinded, placebo-controlled study","volume":"12","author":"Lopes de Jesus","year":"2017","journal-title":"PLoS One"},{"key":"B22","year":"2025"},{"key":"B23","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.ejr.2018.07.005","article-title":"Therapeutic efficacy of intra-articular injection of platelet\u2013rich plasma and ozone therapy in patients with primary knee osteoarthritis","volume":"41","author":"Gaballa","year":"2019","journal-title":"Egypt Rheumatol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1007\/s00167-016-4110-5","article-title":"Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options","volume":"25","author":"Duymu\u015f","year":"2017","journal-title":"Knee Surg Sports Traumatol Arthrosc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.3233\/BMR-240023","article-title":"The efficacy of ultrasonography-guided oxygen-ozone therapy versus corticosteroids in patients with knee osteoarthritis: a multicenter randomized controlled trial","volume":"37","author":"Aslan","year":"2024","journal-title":"J Back Musculoskelet Rehabil"},{"key":"B26","first-page":"471","article-title":"Treatment of middle-aged and aged patients with knee osteoarthritis of yang-deficiency induced cold-damp syndrome by ozone combined Chinese materia medica: a clinical research","volume":"33","author":"Li","year":"2013","journal-title":"Chin J Integr Trad Western Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e74140","DOI":"10.5812\/mejrh.74140","article-title":"Mid-term effectiveness of ozone (O2-O3) compared to platelet-rich plasma (PRP) in the management of knee osteoarthritis: a randomized parallel controlled trial","volume":"6","author":"Fern\u00e1ndez-Cuadros","year":"2019","journal-title":"Middle East J Rehabil Health Stud"},{"key":"B28","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3390\/biom11030356","article-title":"Oxygen-ozone therapy in the rehabilitation field: state of the art on mechanisms of action, safety and effectiveness in patients with musculoskeletal disorders","volume":"11","author":"de Sire","year":"2021","journal-title":"Biomolecules"},{"key":"B29","doi-asserted-by":"publisher","first-page":"232","DOI":"10.21767\/2049-5471.100057","article-title":"Could ozone be used as a feasible future treatment in osteoarthritis of the knee?","volume":"13","author":"Fern\u00e1ndez-Cuadros","year":"2016","journal-title":"Divers Equal Health Care"}],"container-title":["Frontiers in Pain Research"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1843756\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:57:03Z","timestamp":1781675823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1843756\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":29,"alternative-id":["10.3389\/fpain.2026.1843756"],"URL":"https:\/\/doi.org\/10.3389\/fpain.2026.1843756","relation":{},"ISSN":["2673-561X"],"issn-type":[{"value":"2673-561X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1843756"}}