Chenhui Wang ¹ Mengwei Yan ² Yuru Li ³ Lei Han ³ Hongqian Wang ³ Shufeng Jia ³ Xingchen Liu ⁴ Yang Liu ¹ Fan Wu ¹ Baoguo Wang ^1*

• ¹ Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
• ² Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China
• ³ Taikang Yanyuan Continuing Care Retirement Community, Beijing, China
• ⁴ Harbin Medical University, Harbin, Heilongjiang, China

Objective: Knee osteoarthritis (KOA) is a degenerative joint condition, leading to disability and diminished quality of life. Molecular hydrogen has been proven to have antioxidant and anti-inflammatory properties, but few studies have investigated its effects on osteoarthritis. Our study aims to assess the therapeutic potential of hydrogen-oxygen mixture (H2-O2) inhalation for KOA. Methods: In this randomized controlled trial, eligible elderly KOA patients were randomly assigned to either Group H or Group C. Both groups participated in a 12-week home-based exercise (HBE) program, which included knee-joint exercises and health education. Group H additionally received H2-O2 inhalation for 60 minutes per day over 2 weeks, while Group C did not. The primary outcome was measured using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included inflammation levels (hs-CRP, NLR, PLR, LMR), Chair Stand Test (CST), Timed Up and Go (TUG), 36-item short-form health survey (SF-36), Exercise Adherence Rating Scale (EARS), and adverse events. Results: A total of 121 subjects were enrolled, with an average age of 81.2 years, and 80.2% were female. The between-group mean difference in the WOMAC total score was −5.2 (95% CI -12.1 to 1.7, P=0.140) at week 12, with Group H showing an improvement of -22.9 (95% CI −26.3 to −19.6, P<0.001) and Group C showing an improvement of -19.4 (95% CI −22.7 to −16.0, P<0.001) compared to baseline, revealing a significant group × time interaction (F(3, 356.034)=14.425, P<0.001). No significant differences were observed between both groups at week 12 in CST, TUG, SF-36 scores, EARS scores, or the incidence of adverse events. Conclusion: Although clinical significance was not achieved, H2-O2 inhalation alleviated KOA symptoms and enhanced functional activity in elderly patients undergoing the HBE program during the initial two weeks. However, its sustained effects on improving KOA symptoms were not observed.