Summary

A systematic review and metanalysis of randomized controlled trials to assess the efficacy and safety of mesenchymal stromal cell therapy for treating knee osteoarthritis or chondral lesions. The searches retrieved 5,942 references with 20 complete studies for data extraction. Metanalysis was performed. The risk of bias, heterogeneity and certainty of evidence were assessed.

Abstract

Introduction

Chondral lesion and osteoarthritis are associated with great morbidity and economic burden. Almost all patients present some level of disability and impairment in quality of life. Mesenchymal stromal cells (MSCs) has been gaining ground due to their intrinsic role in the repair and regeneration of joint tissues thanks to their plasticity, multipotency, immunomodulatory capacity and paracrine signaling.

Objective

To assess the efficacy and safety of MSC therapy for treating knee osteoarthritis or chondral lesions.

Methods

A systematic review and metanalysis of randomized controlled trials (RCTs) following the PRISMA 2020 statement. The protocol was prospectively registered at PROSPERO. Were included only parallel RCTs, whose participants were patients with symptomatic or asymptomatic knee osteoarthritis (primary or secondary) or chondral lesions, at any stage.
We considered RCTs specifically comparing stem cell therapy (autologous or allogeneic, combined or not with biocompatible materials) with any other therapy. Studies that assessed stem cell therapy combined with other technique were considered only if the same technique was also administered in the control group.
For assessing efficacy and safety, we considered the following outcomes: pain, physical function and participants experiencing serious adverse events as primary outcomes; health-related quality of life, participants experiencing any adverse effects, and need for second-look intervention as secondary outcomes. We assessed all outcomes at any time point. However, we only pooled similar time points together in short or long term (more than three months).
A broad search of the literature was performed using electronic and hand search. There was no restriction regarding date, language or status of publication. Sensitive search strategies were developed for the following databases: CENTRAL; BASE; LILACS; MEDLINE; Peter; SPORTDiscus; ClinicalTrials.gov; Open Grey.

Results

The selection process was carried out in two stages by two independent reviewers. The searches retrieved 5,942 references (457 duplicates). The reading of 5.485 titles and abstracts resulted in the exclusion of 5383. After reading the full text of the 102 remaining references (second step), 4 were excluded, 98 references were included: 20 complete studies and 57 ongoing. Data extraction was performed using a pre-established protocol. Any disagreement was resolved with a third reviewer.
Risk of bias (RoB) was assessed using Cochrane RoB table. Domains 3,4 and 5 were assessed in an outcome-level. The remaining domains were assessed at study-level.
For heterogeneity assessment, were considered methodological and clinical diversity. Statistical heterogeneity was considered by means of a Chi² and I² test (>50% indicating high inconsistency). Subgroup analysis were planned to explore reasons for heterogeneity.
Risk ratios and mean differences were calculated for dichotomous and continuous variables, respectively. Random-effects meta-analysis were performed considering heterogeneity and availability of data using Review Manager.
The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for each comparison and considering all primary outcomes, using GRADEpro GDT software.

Conclusion

MSC therapies have not been fully optimized, requiring standardization of methods and better definition of efficacy and safety in in well-designed studies.