Osteoarthritis (OA) is a degenerative joint disease affecting millions, imposing a significant economic burden. Current treatments offer short-term pain and inflammation control, but a disease-modifying OA drug remains elusive. Mesenchymal stem cells (MSCs) have shown promise in treating chronic diseases, including OA, by potentially inhibiting inflammation and supporting chondrocytes. Autologous cellular injections are widely used in orthopedics, but rigorous clinical trial data comparing their efficacy to corticosteroid injections (CSI) are limited. This study aimed to determine the safety and efficacy of three different types of cell injections compared to CSI in patients with knee OA, hypothesizing that cell therapies would be superior to corticosteroids at 1 year.

The literature contains limited data from well-designed randomized controlled trials comparing various cellular injections for knee OA. While in vitro studies and smaller trials suggest potential benefits of MSCs, large-scale, robust clinical trials are lacking. The heterogeneity among autologous and allogeneic cell products raises concerns about the consistency and efficacy of these therapies. Existing literature primarily relies on laboratory data, focusing on factors like MSC counts or secretory factors, while human clinical research hasn't consistently shown superiority of cellular treatments over corticosteroids. Meta-analyses show varying results, adding to the ongoing debate.

This multicenter, single-blinded, randomized, controlled clinical trial enrolled 480 patients with knee OA (Kellgren-Lawrence grades II-IV). Participants were randomized into four cohorts (three treatment arms and a control arm): autologous bone marrow aspirate concentrate (BMAC), autologous stromal vascular fraction (SVF), allogeneic human umbilical cord tissue-derived mesenchymal stromal cells (UCT), and corticosteroid injection (CSI). The co-primary endpoints were changes in visual analog scale (VAS) pain score and Knee injury and Osteoarthritis Outcome Score (KOOS) pain score from baseline to 12 months. Secondary outcomes included EQ-5D, PROMIS-29, and MRI scores. Safety was assessed by monitoring adverse events (AEs). Statistical analyses included repeated-measures analysis of change scores, sensitivity analyses, and subgroup analyses based on age, sex, ethnicity, and Kellgren-Lawrence grade. Single-cell RNA sequencing was performed on a subset of samples to evaluate cellular heterogeneity and diversity.

At 1 year post-injection, no significant differences were found between the three cell therapy groups and the CSI control group in either VAS pain scores or KOOS pain scores. While all treatments exceeded the minimally clinically important difference, no group demonstrated superior pain relief or improved function compared to CSI. MRI scores showed no significant changes from baseline in any group. There were no procedure-related serious adverse events. Subgroup analyses revealed significant interactions between treatment group and age, and treatment group and sex for VAS pain scores, but not for KOOS pain scores. Secondary outcome measures (EQ-5D, PROMIS-29 domains except Physical Function) also showed no significant differences between groups. Single-cell RNA sequencing revealed distinct cell subpopulations within autologous cell sources and a uniform MSC phenotype in the UCT group.

This large, well-designed trial failed to demonstrate the superiority of any of the three cell therapies over CSI for knee OA at 1 year. These findings challenge the prevailing assumption of superior efficacy of cell therapies compared to CSI. The lack of significant improvement across all groups raises questions about the therapeutic mechanisms of action of these cellular injections in the context of a chronic disease like knee OA. The significant interactions of treatment group with age and sex on VAS pain scores suggest potential for personalized approaches based on patient characteristics, warranting future investigation. While the study confirmed the safety and tolerability of the interventions, the absence of a clear benefit over CSI needs to be carefully considered in clinical practice.

This study demonstrates that at 1 year post-injection, none of the three investigated cell therapies were superior to corticosteroid injection for the treatment of knee OA. The findings highlight the need for further research into the optimal treatment strategies for knee OA, considering patient-specific factors and longer-term outcomes. Future research could investigate different cell types, cell preparation methods, or combinations of therapies, and might benefit from focusing on different patient subgroups or employing longer follow-up periods.

While the study is large and well-designed, limitations exist. The relatively short 1-year follow-up might not adequately capture the long-term effects of the interventions. The small number of patients in certain racial subgroups limited meaningful subgroup analysis. The nature of the blinding, which allowed the investigators to be unblinded, could have introduced subtle bias, even if patients remained blinded. The possibility of placebo effects from both the sham procedures and injections in general remains a consideration.