Ozone Therapy as a Redox-Modulating Strategy in Degenerative Musculoskeletal Diseases: A Clinical–Mechanistic Review

Background/Objectives: Degenerative musculoskeletal diseases represent a major cause of chronic pain and disability worldwide and are increasingly associated with dysregulated oxidative stress and impaired redox signaling. Conventional therapeutic strategies are often limited to symptomatic management, prompting interest in adjunctive approaches that target underlying biological mechanisms. Among these, medical ozone therapy has been proposed as a redox-modulating intervention in various musculoskeletal conditions. Methods: A narrative clinical–mechanistic review of the literature was conducted using PubMed/MEDLINE, Scopus, and Google Scholar to identify experimental and clinical studies examining oxidative stress, redox signaling, and the application of medical ozone therapy in degenerative musculoskeletal disorders. Preclinical models published between 2000 and 2025 and randomized controlled trials published between 2020 and 2025 were critically evaluated and synthesized qualitatively, with attention to biological plausibility, clinical outcomes, and methodological limitations. A PRISMA-style flow diagram was used to document study selection. Results: Evidence from experimental studies supports a role for controlled oxidative stimuli in activating adaptive cellular defense pathways, including redox-sensitive signaling mechanisms involved in inflammation and tissue homeostasis. Clinical studies across conditions such as intervertebral disc disease, knee osteoarthritis, and other degenerative or overuse-related disorders report short- to mid-term improvements in pain and function following ozone therapy. However, substantial heterogeneity in study design, treatment protocols, and outcome measures limits comparability. Critically, many trials report statistically significant differences that do not consistently exceed the minimal clinically important difference (MCID) for pain and disability indices, and no trial has validated the proposed Nrf2-mediated mechanism in human tissue at clinically administered doses. Conclusions: Current evidence suggests that ozone therapy may exert biologically plausible effects through hormetic redox modulation and may provide symptomatic benefit in selected patients with degenerative musculoskeletal diseases. Nonetheless, the lack of standardized protocols, high-quality long-term data, and mechanistic biomarker validation warrants cautious interpretation. Ozone therapy should be regarded as an investigational adjunct rather than a disease-modifying or standalone standard of care. Further rigorous clinical trials integrating mechanistic biomarkers, sham-controlled designs, and standardized methodologies are needed to clarify the therapeutic role and safety profile of ozone therapy in musculoskeletal medicine.