Randomized Controlled Trial on the Combined Effect of Prolotherapy and Personalized Physical Activity on Knee Osteoarthritis Progression: Impact on IL-1β, MMP-3 Biomarkers and Clinical Outcomes

Abstract

Background Non-operative management of knee osteoarthritis (OA) remains a significant challenge, primarily focusing on pain relief, functional improvement, and inflammation reduction. Prolotherapy has been recognized as an effective treatment for joint and ligament pain, with evidence supporting its ability to improve outcomes in knee OA. Structured physical activity also offers benefits in terms of mobility and function, although its effects are less pronounced when used in isolation, without adjunctive therapy. In knee OA, inflammation is driven by biomarkers such as interleukin-1 beta (IL-1β) and matrix metalloproteinase-3 (MMP-3), which contribute to cartilage degradation. While evidence supporting treatments that improve both clinical and biochemical outcomes is limited, research on combined intervention therapies and physical activity, capable of impacting both clinical outcomes and biomarkers, remains inconclusive. Objective This study aimed to determine the effects of prolotherapy combined with personalized physical activity on (1) clinical outcomes, (VAS-assessed pain intensity, WOMAC-assessed functional status, and quality of life) and on (2) serum IL-1β and MMP-3 levels in patients with knee OA. Methods This randomized controlled trial employed a pretest–posttest nonequivalent control group design. A total of 74 outpatients with knee osteoarthritis (OA) who met the predefined inclusion criteria were recruited from the pain clinics of three hospitals affiliated with the Faculty of Medicine, Universitas Islam Indonesia. Participants underwent open-label randomization and were allocated to either the intervention or control arm. The intervention group received standardized prolotherapy combined with personalized physical activity. Clinical outcomes—functional status assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and health-related quality of life—as well as serum inflammatory biomarkers (interleukin-1 beta [IL-1β] and matrix metalloproteinase-3 [MMP-3]) were measured at baseline and following the intervention. Statistical analysis was conducted using paired t-tests to evaluate within-group changes and analysis of covariance (ANCOVA) to assess adjusted between-group effects. Results Participants receiving prolotherapy combined with personalized physical activity demonstrated statistically significant reductions in pain and functional impairment, improved quality of life, and significant decreases in IL-1β and MMP-3 levels compared with baseline and control outcomes, indicating simultaneous clinical and inflammatory modulation. Conclusion The combination of prolotherapy and personalized physical activity resulted in superior clinical improvement and meaningful reduction of inflammatory biomarkers associated with knee OA progression, supporting its potential as an integrative and mechanism-targeted therapeutic strategy

Bangladesh Journal of Medical Science Vol. 25 No. 04 October’26 Page: 1236-1246