Efficacy and safety of intra-articular mesenchymal stem cell-based therapies in knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

backgroundKnee osteoarthritis (OA) causes significant chronic pain and disability. Current non-operative treatments are largely symptom-modifying. While intra-articular mesenchymal stem cell (MSC) therapies are promising, randomized controlled trials (RCTs) report inconsistent results due to heterogeneity in cell sources, preparations, and techniques.

methodsWe searched PubMed, Scopus, Cochrane Library, and Google Scholar through December 10, 2025. Peer-reviewed RCTs evaluating intra-articular stem cell-based therapies for knee OA were included. Primary analyses compared MSCs versus controls across pain, function, structure, and safety. Subgroup and sensitivity analyses explored heterogeneity by preparation, source, comparator, follow-up, age, and injection guidance.

resultsTwenty-eight RCTs were included. MSC therapies significantly improved pain: ΔVAS (MD -1.67; p = 0.007), post-treatment VAS (MD -3.55; p = 0.01), and KOOS pain (MD 15.37; p = 0.03). Functional gains occurred in KOOS ADL (MD 12.84; p = 0.04), KOOS sports (MD 11.76; p < 0.001), and KOOS symptoms (MD 15.16; p = 0.02). WOMAC, KOOS quality of life, and Lequesne Index showed no significant differences. Benefits were more consistent with culture-expanded preparations, bone marrow sources, saline controls, and ultrasound guidance. ΔVAS remained significant after excluding short follow-up studies; ΔVAS and KOOS pain remained significant in older cohorts. MRI-based WORMS scores were non-significant, indicating no consistent structural benefit. Safety analyses revealed higher rates of injection-site pain (RR 2.04; p = 0.0005), joint swelling (RR 3.39; p = 0.0003), and other adverse events (RR 1.26; p = 0.01). Serious complications (e.g., infection) were uncommon and non-significant.

conclusionCurrent evidence suggests stem cell-based therapies serve a primarily symptom-modifying rather than structure-modifying role. Higher frequencies of local reactions must be weighed against symptomatic benefits. Larger, standardized trials are needed to identify optimal preparations and patient profiles for consistent clinical benefit. KEY POINTS: • Intra-articular stem cell-based therapies demonstrate modest improvements in pain outcomes in knee osteoarthritis compared with control injections across randomized controlled trials, although results vary across cell preparations, comparators, and study conditions. • Symptomatic and functional improvements were observed in several KOOS domains, particularly activities of daily living, sports, and symptoms, with benefits appearing more consistent in selected subgroups rather than uniformly across all stem cell interventions. • Structural changes on MRI (WORMS) were not significantly improved, suggesting that current evidence supports symptomatic relief rather than consistent disease-modifying effects on joint structure. • Stem cell injections were associated with increased local reactions such as injection-site pain and joint swelling, while serious complications remained uncommon, indicating a generally manageable but non-negligible safety profile.