Ozone and Hyaluronic Acid, Alone and in Combination: Exploring Temporal Dynamics and Synergies in Intraarticular Therapy for Knee Osteoarthritis.

Background: Knee Osteoarthritis (KOA) is the most common chronic joint disease in old age. Treatment for KOA focuses on symptom relief and improvement of function. Intraarticular hyaluronic acid (HA) is a well-documented treatment for KOA; it provides pain relief and enhances joint function by increasing lubrication and synovial fluid viscosity. Recently, there has been a growing interest toward the medical effects of oxygen-ozone (O3) treatment, especially for musculoskeletal disorders.

Objective: We investigated whether a combination of intraarticular O3 and HA could reduce pain and improve functional and clinical outcomes compared with the same treatments administered separately in patients with KOA.

Study design: This is a retrospective, comparative, observational study approved by the institutional review board of the "Sapienza" University of Rome [RS 6599/2021].

Setting: Physical Medicine and Rehabilitation Unit of Sant'Andrea University Hospital, Rome, Italian Republic.

Methods: A total of 106 patients with KOA were examined. Of these, 84 patients met the eligibility criteria and were divided into one of 3 treatment groups: intraarticular O3 therapy (n = 28), intraarticular HA injections (n = 26), or a combination of both (n = 30). Outcome measures were assessed using the Numeric Rating Scale (NRS-11) for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for functional disability, Knee Society Scores (KSS) for knee assessment, and the 12-item Short-Form Health Survey (SF-12) for quality of life.

Results: Significant differences occured between groups at various evaluation points. At the end of treatment (T1), O3 alone and O3 combined with HA showed superior pain relief compared to HA alone; HA alone and O3 combined with HA demonstrated better stiffness alleviation compared to O3 alone. The combination therapy showed advantages in the WOMAC physical function score, total WOMAC score, KSS knee score, KSS functional score, 12-item Physical Component Summary (PCS-12) score and 12-item Mental Component Summary (MCS-12) score compared to O3 alone and HA alone treatments (P < 0.05). At the one-month follow-up (T2), O3 combined with HA showed significant differences in NRS-11 and WOMAC physical function scores compared to O3 alone (P = 0.026 and P = 0.011, respectively). The KSS knee score, KSS functional score, PCS-12 score, and MCS-12 score all showed differences between the O3 combined with HA and both the O3 and HA alone groups (P < 0.05). At the 3-month follow-up (T3), HA alone demonstrated superiority in the WOMAC pain and physical function scores over O3 alone (P < 0.001 and P = 0.023, respectively). Compared to O3 alone, O3 combined with HA showed advantages in WOMAC stiffness, WOMAC physical function, and total WOMAC scores, as well as the KSS knee score, KSS functional score, PCS-12 score, and MCS-12 score (P < 0.05).At the 6-month follow-up (T4), significant differences favored HA in the WOMAC pain, physical function, and total WOMAC scores compared to O3 (P = 0.039, P = 0.029, and P = 0.034, respectively). O3 combined with HA demonstrated advantages in total WOMAC and KSS knee score compared to O3 (P = 0.034 and P = 0.004, respectively). Within each group, all outcome measures exhibited statistically significant improvements at every follow-up (P < 0.05).

Limitations: A limited number of patients were retrospectively recruited.

Conclusions: Our study suggests that intraarticular O3 therapy and HA, alone or combined, provide distinct and complementary benefits for knee osteoarthritis. O3 therapy offers immediate pain relief, while HA contributes to sustained improvements in pain and function. The combination demonstrates a synergistic effect, enhancing joint functionality and quality of life.