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Regarding “Intra-articular Mesenchymal Stromal Cell Injections Are No Different From Placebo in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials”

      We read with anticipation the recently published review by Dai et al.,
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      “Intra-articular Mesenchymal Stromal Cell Injections Are No Different From Placebo in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.” We appreciated the authors’ efforts to compile a comprehensive review and meta-analysis of Level I studies, which contrast with prior reviews of mesenchymal stromal cell (MSC) injections that have included lower-quality research. We were disappointed to find a number of issues leading us to believe that the review fails to support the authors’ primary conclusion, including improperly grouping vastly heterogeneous treatments, misclassifying therapeutic comparison groups as true placebos, excluding at least 1 study that met the inclusion criteria, and somehow managing to present positive results reported in more than three-fourths of the reviewed studies as a monolithically negative result.
      Dai et al.
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      grouped together studies describing the use of culture-expanded bone marrow MSCs, culture-expanded adipose MSCs, stromal vascular fraction (SVF), culture-expanded placental MSCs, culture-expanded umbilical cord MSCs, and bone marrow concentrate (BMC) with platelet-poor plasma and analyzed them as if they were a uniform therapy with associated uniform efficacy. Outside of involving the use of some type of MSC, the therapies are vastly different and not comparable. The MSC types that Dai et al. considered a therapeutically homogeneous group show substantial disparities associated with therapeutic outcomes, including differentiation potential, inflammatory suppression, and cartilage repair characteristics.
      • Mohamed-Ahmed S.
      • Fristad I.
      • Lie S.A.
      • et al.
      Adipose-derived and bone marrow mesenchymal stem cells: A donor-matched comparison.
      ,
      • Xu L.
      • Liu Y.
      • Sun Y.
      • et al.
      Tissue source determines the differentiation potentials of mesenchymal stem cells: A comparative study of human mesenchymal stem cells from bone marrow and adipose tissue.
      Moreover, culture-expanded products contain a homogeneous population of cell types, whereas SVF and BMC contain a mixture of many different cell types.
      • Xu L.
      • Liu Y.
      • Sun Y.
      • et al.
      Tissue source determines the differentiation potentials of mesenchymal stem cells: A comparative study of human mesenchymal stem cells from bone marrow and adipose tissue.
      • Niemeyer P.
      • Kornacker M.
      • Mehlhorn A.
      • et al.
      Comparison of immunological properties of bone marrow stromal cells and adipose tissue-derived stem cells before and after osteogenic differentiation in vitro.
      • Liao H.T.
      • Chen C.T.
      Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells.
      As an example, SVF is hematopoietic stem cell poor whereas BMC is hematopoietic stem cell rich, a difference that potentially results in divergent efficacy rates. Grouping all MSC-based procedures together for meta-analysis as Dai et al. did is analogous to doing the same with shoulder arthroscopy, open shoulder repair, and shoulder joint replacement as homogeneous “surgical shoulder therapy.” The result is that the procedures with the higher efficacy rates are diluted by combining them with less efficacious procedures, undermining the results of the pooled analysis.
      The grouped studies also included quite different control groups, belying the claim in the title that MSCs were compared with placebo controls across all studies. The control groups that the authors included as “placebos” included normal saline solution, hyaluronic acid, conditioned media, plasma, Ringer lactate, and conservative care.
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      Indeed, only 4 of the 13 studies included for review used a true placebo comparator (normal saline solution), whereas 5 studies used hyaluronic acid, a common injection therapy for knee osteoarthritis, in their comparison group. Furthermore, 2 studies used uncommon therapies, including Plasma-Lyte A (serum, albumin, and dimethyl sulfoxide) (Baxter) and conditioned cell culture media, the latter of which contains exosomes and is already in use in early clinical trials as a knee osteoarthritis therapeutic agent.
      • Lu J.
      • Wang Q.Y.
      • Sheng J.G.
      Exosomes in the repair of bone defects: Next-generation therapeutic tools for the treatment of nonunion.
      ,
      • Li Z.
      • Wang Y.
      • Xiao K.
      • Xiang S.
      • Li Z.
      • Weng X.
      Emerging role of exosomes in the joint diseases.
      Collectively, the mixture of studies that used control groups with varying amounts of efficacy, rather than true placebo treatments, could have had only a single result: to bias the meta-analysis result toward the null. We are surprised the article by Dai et al.
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      passed the peer-review process given the improper inclusion of studies using non-placebo and potentially therapeutic comparison groups. Moreover, it is surprising that the authors did not include at least 1 positive randomized controlled trial that fits with the other included studies. A 2018 study by Centeno et al.
      • Centeno C.
      • Sheinkop M.
      • Dodson E.
      • et al.
      A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: A randomized controlled trial with 2 year follow-up.
      described the comparison of BMC to physical therapy using a crossover design. The comparison arm of the trial is equivalent to that in the study by Freitag et al.,
      • Freitag J.
      • Bates D.
      • Wickham J.
      • et al.
      Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial.
      which Dai et al. did include in their meta-analysis while inexplicably excluding the article by Centeno et al.
      In their title and conclusions, the authors overshadow the positive results of their meta-analysis.
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      When the 13 studies used for the pooled analysis are individually reviewed, 10 of the 13 indicated significant superiority of the various forms of MSCs used versus the diverse comparison groups. This fact is apparent on review of the multiple forest plots that Dai et al.
      • Dai W.
      • Leng X.
      • Wang J.
      • et al.
      Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.
      provided. We are left with the overwhelming impression that the results reported by Dai et al. in their systematic review and meta-analysis have little relation to the actual efficacy of MSC therapy for knee osteoarthritis.

      Supplementary Data

      References

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