Intra-articular (IA) oxygen-ozone (O₂O₃) has recently grown as a novel therapeutic option in knee osteoarthritis (KOA) and few studies in literature explored its safety and impact on pain and functional status in these patients. The aim of this study was to assess the effectiveness and safety of IA O₂O₃ compared to ialuronic acid (HA) in terms of pain, knee function, and health-related quality of life in patients affected by KOA over 31 weeks.

In this randomized, single-blind, controlled study patients aged≥60 years affected by KOA have been enrolled and randomly allocated to receive 4 IA knee injections once per week for 4 consecutive weeks of O₂O₃ or HA (T0–T3) and a follow-up visit 4 weeks after the fourth injection (T4). Patients having a Visual Analogue Scale (VAS)≥4 at 6 months follow-up visit (T5) underwent a second treatment cycle (T5–T8) and a 1-month follow-up visit (T9). All adverse events occurred, VAS, Oxford Knee Questionnaire, 12-Item Short Form Health Survey, and European Quality of Life-5 dimensions scores have been assessed.

Forty-six patients (mean aged 70.8±2.4 years) were enrolled and randomly allocated to O₂O₃ (n=23) or HA treatment group (n=23). Nineteen patients reported a VAS≥4 at T5, undergoing a second treatment cycle: 10 in O₂O₃ group and 9 in HA group. There were no significant differences in adverse events occurrence between the two groups. VAS scores showed a statistically significant reduction (P<0.013) compared to baseline during both treatment cycles in both groups. At both follow-up visits (T4 and T9) the VAS score was significantly lower in the HA group compared to O₂O₃ group (P<0.013).

IA O₂O₃ therapy could be comparable to IA HA in terms of safety profile and effectiveness in reducing pain in patients with KOA, even on a multiple injection cycles and long term follow-up.