Author Reply To “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 would like to thank Centeno et al.1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar for their comments and respond to these accordingly. Improperly Grouping Vastly Heterogeneous Treatments Because there is no gold standard for the preparation of mesenchymal stromal cells (MSCs), the MSCs used in each study are inevitably different in terms of stem cell type, autologous or allograft MSCs, MSC dosage, and/or MSC volume and count. Therefore, the heterogeneity of the MSCs is inherent to this type of meta-analysis.2Kim S.H. Djaja Y.P. Park Y.B. Park J.G. Ko Y.B. Ha C.W. Intra-articular injection of culture-expanded mesenchymal stem cells without adjuvant surgery in knee osteoarthritis: A systematic review and meta-analysis.Am J Sports Med. 2019; (363546519892278)Google Scholar,3Kim S.H. Ha C.W. Park Y.B. Nam E. Lee J.E. Lee H.J. Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: A meta-analysis of randomized controlled trials.Arch Orthop Trauma Surg. 2019; 139: 971-980Crossref PubMed Scopus (43) Google Scholar Similarly, this phenomenon has occurred in meta-analyses focused on other biological therapies such as platelet-rich plasma.4Tan J. Chen H. Zhao L. Huang W. Platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: A meta-analysis of 26 randomized controlled trials.Arthroscopy. 2021; 37: 309-325Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,5Belk J.W. Kraeutler M.J. Houck D.A. Goodrich J.A. Dragoo J.L. McCarty E.C. Platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.Am J Sports Med. 2021; 49: 249-260Crossref PubMed Scopus (45) Google Scholar As we previously described in the limitations section in our meta-analysis,6Dai 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.Arthroscopy. 2021; 37: 340-358Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar we acknowledge that our systematic review and meta-analysis were limited by the included randomized controlled trials (RCTs), which were inherently heterogeneous owing to different MSC preparation strategies. Misclassifying Therapeutic Comparison Groups as True Placebo Comparators (Normal Saline Solution) First, as far as we know, among the various studies focused on intra-articular injections for osteoarthritis, there is no study that defines normal saline solution as a “true placebo comparator.” In contrast, Plasma-Lyte A (Baxter), a balanced isotonic crystalloid,7Young J.B. Utter G.H. Schermer C.R. et al.Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: A randomized trial.Ann Surg. 2014; 259: 255-262Crossref PubMed Scopus (140) Google Scholar contains physiological sodium (140 mEq/L), chloride (98 mEq/L), potassium (5 mEq/L), magnesium (3 mEq/L), and bicarbonate precursors (acetate, 27 mEq/L, and gluconate, 23 mEq/L), with pH 7.4, and is used as a source of water and as an electrolyte agent.7Young J.B. Utter G.H. Schermer C.R. et al.Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: A randomized trial.Ann Surg. 2014; 259: 255-262Crossref PubMed Scopus (140) Google Scholar Because it does not contain any biologically active substances, it was considered a placebo by the authors. In addition, we wonder how Centeno et al.1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar concluded that the cell culture media contained exosomes, because we have carefully checked the study by Kuah et al.8Kuah D. Sivell S. Longworth T. et al.Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: A randomized double-blind placebo-controlled single ascending dose study.J Transl Med. 2018; 16: 49Crossref PubMed Scopus (31) Google Scholar and found no statement that the cell culture media contained exosomes. Furthermore, we have also searched the study regarding the cell culture media and found that they contained buffering systems, inorganic salt, amino acids, proteins and peptides, fatty acids and lipids, vitamins, trace elements, antibiotics, and serum, without exosomes.9Freshney R.I. Basic principles of cell culture.in: Vunjak-Novakovic G. Freshney R.I. Culture of cells for tissue engineering. John Wiley & Sons, Inc., Hoboken, NJ2006: 3-21Crossref Scopus (35) Google Scholar Therefore, in the aforementioned study, the authors also considered the cell culture media as a placebo. Furthermore, even if we adopt the definition of Centeno et al.1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar of a true placebo comparator, that is, normal saline solution, and compare MSCs with normal saline solution (a total of 4 studies used normal saline solution as a control group: Shapiro et al.,10Shapiro S.A. Arthurs J.R. Heckman M.G. et al.Quantitative T2 MRI mapping and 12-month follow-up in a randomized, blinded, placebo controlled trial of bone marrow aspiration and concentration for osteoarthritis of the knees.Cartilage. 2019; 10: 432-443Crossref PubMed Scopus (28) Google Scholar Lee et al.,11Lee W.S. Kim H.J. Kim K.I. Kim G.B. Jin W. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: A phase IIb, randomized, placebo-controlled clinical trial.Stem Cells Transl Med. 2019; 8: 504-511Crossref PubMed Scopus (94) Google Scholar Khalifeh Soltani et al.,12Khalifeh Soltani S. Forogh B. Ahmadbeigi N. et al.Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: A pilot study.Cytotherapy. 2019; 21: 54-63Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and Emadedin et al.13Emadedin M. Labibzadeh N. Liastani M.G. et al.Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: A randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.Cytotherapy. 2018; 20: 1238-1246Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), we still do not find a significant difference between MSCs and normal saline solution in pain relief (mean difference in visual analog scale [VAS] score for pain, –0.21; 95% confidence interval, –1.48 to 1.07; P = .75; I2 = 0%). Excluding at Least 1 Study That Met Inclusion Criteria Our search strategies reflected our research question, and although the study listed by Centeno et al.1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar in their letter was not included,14Centeno 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.J Transl Med. 2018; 16: 355Crossref PubMed Scopus (17) Google Scholar this omission does not reflect an incomplete search in the context of our research aims. We admit that no search is entirely exhaustive; however, we respectfully disagree with Centeno et al. that we have overlooked their study.14Centeno 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.J Transl Med. 2018; 16: 355Crossref PubMed Scopus (17) Google Scholar Rather, it was outside the scope of our reviews and was not identified using our research-specific, a priori search terms.6Dai 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.Arthroscopy. 2021; 37: 340-358Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar As such, we stand by our search strategies, which were aligned with our research questions and intended outcomes and were constructed according to Cochrane Library guidelines. Presenting Positive Results Reported in More Than Three-fourths of Reviewed Studies as Monolithically Negative Result First, we have carefully checked the Cochrane Handbook for Systematic Reviews of Interventions, version 6.1, and found that it did not mention that when three-fourths or more of the included studies were positive, the pooled results should be positive.15Higgins J.P. Thomas J. Chandler J. et al.Cochrane handbook for systematic reviews of interventions. Version 6.1. John Wiley & Sons, Hoboken, NJ2020Google Scholar In addition, to test the conjecture of Centeno et al.,1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar we have also searched other studies and found that in the previous meta-analysis by Rienzi et al.,16Rienzi L. Gracia C. Maggiulli R. et al.Oocyte, embryo and blastocyst cryopreservation in ART: Systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.Hum Reprod Update. 2017; 23: 139-155PubMed Google Scholar even if 67% of the included studies (Fig 3a in their study) or 100% of the included studies (Fig 2b in their study) were significantly positive, there were still no significant differences in the pooled results. Moreover, we have also checked our data and found that for the pre- to post-intervention change in the VAS pain score, 4 of 9 RCTs showed that MSCs had a significant positive result compared with control whereas the remaining 5 studies showed no significant difference between MSCs and control (Fig 3A in our study6Dai 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.Arthroscopy. 2021; 37: 340-358Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Similarly, for the pre- to post-intervention change in the Western Ontario and McMaster Universities Osteoarthritis Index total score, only 3 of 8 RCTs suggested that MSCs were significantly better than control whereas the remaining 5 RCTs did not find a significant difference between MSCs and control (Fig 4A in our study6Dai 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.Arthroscopy. 2021; 37: 340-358Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Therefore, fewer than half of the RCTs found that MSCs had a significant advantage over control for either the VAS pain score or Western Ontario and McMaster Universities Osteoarthritis Index total score, which is much different from the exaggerated statement in the letter by Centeno et al.1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar (“somehow managing to present positive results reported in more than three-fourths of the reviewed studies as a monolithically negative result”). Perhaps the writers of the letter1Centeno C. Burnham R. Rowan P. Le A. Malanga G. Freeman M. Regarding “Intra-articular mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis.”.Arthroscopy. 2021; 37: 1361-1362Abstract Full Text Full Text PDF Scopus (1) Google Scholar have clinically observed that MSCs had positive results in some of their patients and, therefore, they strongly believe that MSCs are effective for the treatment of osteoarthritis. However, a meta-analysis is a statistical analysis that combines the results of multiple scientific studies, with each study reporting measurements that are expected to have some degree of error.15Higgins J.P. Thomas J. Chandler J. et al.Cochrane handbook for systematic reviews of interventions. Version 6.1. John Wiley & Sons, Hoboken, NJ2020Google Scholar After a systematic literature search and pooling of the current evidence, not only was there no significant difference in VAS pain scores between MSCs and placebo but also the smallest treatment effect for the VAS pain score did not exceed the minimal clinically important difference. Additionally, there was no significant difference in the percentage of patients crossing the minimal clinically important difference threshold between the MSC and placebo groups for the VAS pain score, which further confirmed the results that MSC injections were not found to be superior to placebo.6Dai 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.Arthroscopy. 2021; 37: 340-358Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In summary, we fully acknowledge that our systematic review and meta-analysis were limited by the included RCTs, which were inherently heterogeneous owing to different MSC preparation strategies. A set of standards for the preparation of MSCs is required to improve the quality of future studies in this area. Furthermore, there is a need for high-quality RCTs with larger numbers of participants in the future. Download .pdf (.14 MB) Help with pdf files ICMJE author disclosure forms

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