{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:44:27Z","timestamp":1773758667087,"version":"3.50.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"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. Med."],"abstract":"<jats:p>Femoral head necrosis (FHN) is a progressive and disabling disorder caused by compromised blood supply to the femoral head. Current treatments primarily aim to slow progression. However, they often fail to reverse early-stage necrosis or reliably prevent disease advancement. Importantly, most approaches lack precise molecular targets for early intervention. Ozone therapy has emerged as a potential option because of its pleiotropic biological effects, such as modulating oxidative stress, improving microcirculation, and exerting anti-inflammatory activity. However, its mechanisms remain poorly understood. Clinical evidence is limited and inconsistent, and the absence of standardized protocols hinders evidence-based implementation. To address these gaps, this perspective proposes biomarkers as a translational bridge linking ozone-induced biological responses to FHN pathology. We further outline a dynamic, biomarker-guided framework through which ozone therapy can evolve from an empirical intervention into a mechanism-informed, personalized, and more standardized precision strategy. This approach offers a scientifically grounded pathway for advancing the clinical management of FHN.<\/jats:p>","DOI":"10.3389\/fmed.2026.1780893","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:20:42Z","timestamp":1773750042000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ozone therapy in femoral head necrosis: a perspective on biomarker-guided treatment rationalization and mechanistic exploration"],"prefix":"10.3389","volume":"13","author":[{"given":"Liang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]},{"name":"Department of Anesthesia and Perioperative Care, University of California, San Francisco","place":["San Francisco, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing-hua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, People\u2019s Hospital of Ordos Dongsheng District","place":["Ordos, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-ting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-mei","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mu-han","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-fan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Public Health, Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, The Second Affiliated Hospital of Inner Mongolia Medical University","place":["Hohhot, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang-liang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Xuanwu Hospital Capital Medical University, National Medical Center for Neurological Diseases, National Clinical Research Center for Geriatric Diseases","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1080\/10623320600904211","article-title":"Avascular necrosis of the femoral head: vascular hypotheses","volume":"13","author":"Kerachian","year":"2006","journal-title":"Endothelium"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e21.00176","DOI":"10.5435\/JAAOSGlobal-D-21-00176","article-title":"Osteonecrosis of the femoral head","volume":"6","author":"George","year":"2022","journal-title":"J Am Acad Orthop Surg Glob Res Rev"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s12020-011-9580-0","article-title":"Glucocorticoid-induced osteonecrosis","volume":"41","author":"Weinstein","year":"2012","journal-title":"Endocrine"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.gene.2018.05.091","article-title":"The pathogenesis of steroid-induced osteonecrosis of the femoral head: a systematic review of the literature","volume":"671","author":"Wang","year":"2018","journal-title":"Gene"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1007\/s00264-018-3977-9","article-title":"No differences in the efficacy among various core decompression modalities and non-operative treatment: a network meta-analysis","volume":"42","author":"Yoon","year":"2018","journal-title":"Int Orthop"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"28","DOI":"10.4103\/0019-5413.143911","article-title":"Management of femoral head osteonecrosis: current concepts","volume":"49","author":"Tripathy","year":"2015","journal-title":"Indian J Orthop"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/2045-9912-1-29","article-title":"Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress?","volume":"1","author":"Sagai","year":"2011","journal-title":"Med Gas Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"840623","DOI":"10.3389\/fphys.2022.840623","article-title":"Updated review on ozone therapy in pain medicine","volume":"13","author":"Hidalgo-Tall\u00f3n","year":"2022","journal-title":"Front Physiol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"365","DOI":"10.3233\/CH-180417","article-title":"Investigation of the effects of major ozone autohemotherapy application on erythrocyte deformability and aggregation","volume":"71","author":"Akbudak","year":"2019","journal-title":"Clin Hemorheol Microcirc"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.7150\/ijbs.41940","article-title":"Ozone therapy attenuates NF-\u03baB-mediated local inflammatory response and activation of Th17 cells in treatment for psoriasis","volume":"16","author":"Zeng","year":"2020","journal-title":"Int J Biol Sci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.3390\/ijms23052528","article-title":"Oxygen-ozone therapy for reducing pro-inflammatory cytokines serum levels in musculoskeletal and temporomandibular disorders: a comprehensive review","volume":"23","author":"de Sire","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref12","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":"de Lopes Jesus","year":"2017","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1302\/2058-5241.4.180036","article-title":"Osteonecrosis of the femoral head: pathophysiology and current concepts of treatment","volume":"4","author":"Petek","year":"2019","journal-title":"EFORT Open Rev"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"626","DOI":"10.21037\/atm.2019.11.22","article-title":"Bone turnover markers may predict the progression of osteonecrosis of the femoral head in aged males","volume":"7","author":"Shi","year":"2019","journal-title":"Ann Transl Med"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1186\/s13018-025-05897-8","article-title":"Elevated levels of \u03b2 C-terminal telopeptide of type 1 collagen and N-terminal mid-fragment of osteocalcin in patients with non-traumatic osteonecrosis of the femoral head","volume":"20","author":"Zhao","year":"2025","journal-title":"J Orthop Surg Res"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.cjtee.2019.09.003","article-title":"Low expression of vascular endothelial growth factor and high serum level of cyclic guanine monophosphate as the risk factors of femoral head osteonecrosis in alcohol-exposed Wistar rat","volume":"23","author":"Suyasa","year":"2020","journal-title":"Chin J Traumatol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"82","DOI":"10.2174\/157340310791162659","article-title":"The role of asymmetric Dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease","volume":"6","author":"Sibal","year":"2010","journal-title":"Curr Cardiol Rev"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/rheumatology\/ken462","article-title":"Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway","volume":"48","author":"Okazaki","year":"2009","journal-title":"Rheumatology (Oxford)"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.taap.2012.12.001","article-title":"NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells","volume":"267","author":"Pecorelli","year":"2013","journal-title":"Toxicol Appl Pharmacol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"212","DOI":"10.4103\/2045-9912.215752","article-title":"Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility","volume":"7","author":"Smith","year":"2017","journal-title":"Med Gas Res"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s00011-009-0001-2","article-title":"Preconditioning with ozone\/oxygen mixture induces reversion of some indicators of oxidative stress and prevents organic damage in rats with fecal peritonitis","volume":"58","author":"Rodr\u00edguez","year":"2009","journal-title":"Inflamm Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxidative Med Cell Longev"},{"key":"ref23","first-page":"E43","article-title":"Treatment of femoral head osteonecrosis with ozone therapy: pilot trial of a new therapeutic approach","volume":"25","author":"An","year":"2022","journal-title":"Pain Physician"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1002\/jor.24400","article-title":"Serum biomarkers related to glucocorticoid-induced osteonecrosis of the femoral head: a prospective nested case-control study","volume":"37","author":"Wang","year":"2019","journal-title":"J Orthop Res"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"13207","DOI":"10.1038\/s41598-024-63837-8","article-title":"Integrated proteomics and metabolomics analysis of sclerosis-related proteins and femoral head necrosis following internal fixation of femoral neck fractures","volume":"14","author":"Liu","year":"2024","journal-title":"Sci Rep"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"5155","DOI":"10.1007\/s00216-024-05453-z","article-title":"In situ metabolomic analysis of osteonecrosis of the femoral head (ONFH) using MALDI MSI","volume":"416","author":"Li","year":"2024","journal-title":"Anal Bioanal Chem"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1002\/jor.23129","article-title":"Unique plasma metabolomic signature of osteonecrosis of the femoral head","volume":"34","author":"Liu","year":"2016","journal-title":"J Orthop Res"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1419742","DOI":"10.3389\/fendo.2024.1419742","article-title":"Identification of candidate genes and chemicals associated with osteonecrosis of femoral head by multiomics studies and chemical-gene interaction analysis","volume":"15","author":"Lu","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1002\/sim.2929","article-title":"Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond","volume":"27","author":"Pencina","year":"2008","journal-title":"Stat Med"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41591-018-0300-7","article-title":"High-performance medicine: the convergence of human and artificial intelligence","volume":"25","author":"Topol","year":"2019","journal-title":"Nat Med"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e0149803","DOI":"10.1371\/journal.pone.0149803","article-title":"Biomarker-guided adaptive trial designs in phase II and phase III: a methodological review","volume":"11","author":"Antoniou","year":"2016","journal-title":"PLoS One"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1080\/10543406.2025.2489291","article-title":"Biomarker-guided adaptive enrichment design with threshold detection for clinical trials with time-to-event outcome","volume":"35","author":"Hua","year":"2025","journal-title":"J Biopharm Stat"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1038\/bjc.2014.156","article-title":"Adaptive designs for clinical trials assessing biomarker-guided treatment strategies","volume":"110","author":"Wason","year":"2014","journal-title":"Br J Cancer"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.21037\/atm-21-6027","article-title":"Challenges and opportunities in biomarker-driven trials: adaptive randomization","volume":"10","author":"Park","year":"2022","journal-title":"Ann Transl Med"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"6501046","DOI":"10.1155\/2017\/6501046","article-title":"Measurement and clinical significance of biomarkers of oxidative stress in humans","volume":"2017","author":"Marrocco","year":"2017","journal-title":"Oxidative Med Cell Longev"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2585","DOI":"10.1021\/acs.jproteome.0c00035","article-title":"Optimization of synovial fluid collection and processing for NMR metabolomics and LC-MS\/MS proteomics","volume":"19","author":"Anderson","year":"2020","journal-title":"J Proteome Res"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.3390\/biomedicines12071496","article-title":"Navigating challenges and opportunities in multi-omics integration for personalized healthcare","volume":"12","author":"Mohr","year":"2024","journal-title":"Biomedicine"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13059-017-1215-1","article-title":"Multi-omics approaches to disease","volume":"18","author":"Hasin","year":"2017","journal-title":"Genome Biol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3389\/fmolb.2015.00044","article-title":"Longitudinal omics modeling and integration in clinical metabonomics research: challenges in childhood metabolic health research","volume":"2","author":"Sperisen","year":"2015","journal-title":"Front Mol Biosci"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.2106\/JBJS.19.01271","article-title":"Nontraumatic osteonecrosis of the femoral head: where do we stand today?: a 5-year update","volume":"102","author":"Mont","year":"2020","journal-title":"J Bone Joint Surg Am"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"052006","DOI":"10.1088\/1748-605X\/ad6dc6","article-title":"Exploring of exosomes in pathogenesis, diagnosis and therapeutic of osteonecrosis of the femoral head: the mechanisms and signaling pathways","volume":"19","author":"Chen","year":"2024","journal-title":"Biomed Mater"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1186\/s12911-024-02722-w","article-title":"Prediction of femoral head collapse in osteonecrosis using deep learning segmentation and radiomics texture analysis of MRI","volume":"24","author":"Gao","year":"2024","journal-title":"BMC Med Inform Decis Mak"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e7586","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials","volume":"346","author":"Chan","year":"2013","journal-title":"BMJ"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"2973","DOI":"10.1002\/sim.5403","article-title":"Biomarkers and surrogate endpoints in clinical trials","volume":"31","author":"Fleming","year":"2012","journal-title":"Stat Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1780893\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:20:44Z","timestamp":1773750044000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1780893\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":44,"alternative-id":["10.3389\/fmed.2026.1780893"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1780893","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,17]]},"article-number":"1780893"}}