CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

Abstract

In the Beginning Stem cell-based therapies are a relatively new treatment for a variety of medical conditions; however, the concept is an old one, now in its sixth decade [6, 75], and the idea that cells might self-renew (a basic premise for stem-cell research) can be traced back to the 19th century [28]. In 1869, Goujon [28] demonstrated there was de novo ectopic bone and marrow generation after bone marrow transplantation in heterotopic anatomic sites. But it was not until 1968 that Tavassoli and Crosby [75] established the inherent osteogenic potential of bone marrow cells. Subsequently, several types of stem cells were described based on their source: embryonic, fetal, infant, and adult stem cells, but because of various legal, ethical, physiologic, and immunologic concerns, the embryonic and fetal types of cells have limited clinical applications [4]. Mesenchymal stem cells (MSCs) have been the preferred source for stem cell-based therapy because they can be obtained from many sources, including bone, tendon, skin, adipose tissue, the umbilical cord, blood, and amnion, and because they can differentiate in many different tissues, including muscles, bones, fat, and cartilage [59, 71]. The current concept of MSCs, a term first coined by Caplan [8], was discovered by Friedenstein [1], who demonstrated the multipotent nature of adult non-hematopoietic bone marrow cells, which had the ability to differentiate into osteoblasts, chondrocytes, and adipocytes [1, 8]. The in vitro chondrogenic potential of MSCs was demonstrated in 1998 [4, 57]. Subsequently, a case series of patients with knee osteoarthritis (OA) with histologic and arthroscopic evidence of cartilage regeneration was reported in 2002 [82]. To our knowledge, 23 original studies (excluding case reports) and 15 systematic reviews (with or without meta-analyses) have reported the outcomes of stem cell-based therapy in patients with knee OA. This topic has garnered tremendous attention, both among patients and researchers; currently more than 3000 trials regarding stem cell-based therapy in people with musculoskeletal diseases are underway [4]. Given the increasing number of patients with knee OA, it is essential that orthopaedic surgeons who treat this condition understand the current rationale for the clinical use of stem cell-based therapies, as well as the current state of knowledge in terms of its efficacy, safety, and associated regulations. The Argument Knee OA affects an increasingly large proportion of the population. It not only causes pain and functional limitations, but also imposes tremendous financial burdens both on patients and on healthcare systems [61, 62]. Inconsistent symptomatic relief with nonoperative treatment and the invasiveness of surgical treatment have prompted researchers to seek innovative non-surgical treatment options for knee OA. This has led to the exploration of self-renewal and the multi-lineage differentiation potential of stem cell-based therapies for regenerating cartilage in patients with knee OA [10, 26, 36, 47, 56]. These treatments now are being aggressively promoted in advertisements that suggest they are a non-invasive treatment that can reverse the disease and help the patient to avoid joint surgery. A regulatory framework we can only characterize as deficient allows unsubstantiated claims to persist in much of the world [39]. Nonetheless, keen interest from patients and the ability of providers to command cash remuneration (as many insurers do not pay for these treatments) has led to a rise in the number of stem cell clinics globally [79]. Although providers and researchers have questioned the appropriateness of wide use of these treatments based on the current evidence [32, 39, 66, 79], in fact, several prospective trials with a comparison group (Table 1) and prospective and retrospective studies without a comparison group (Table 2) have shown favorable results for the clinical use of stem cell therapy. However, varying levels of evidence and the potential drawbacks of current studies make it difficult for clinicians to be certain whether stem cell-based therapies are appropriate for widespread use [32]; questions about cost-effectiveness [14] and safety concerns [5, 49, 54] also have been raised.Table 1.: Summary of the studies comparing outcomes of various MSCs with control groupTable 1-A.: Summary of the studies comparing outcomes of various MSCs with control groupTable 2.: Clinical outcomes of studies in which outcomes of MSCs were not compared with a control groupTable 2-A.: Clinical outcomes of studies in which outcomes of MSCs were not compared with a control groupEssential Elements We sought to identify all original, prospective (randomized and non-randomized) and retrospective studies as well as systematic reviews with or a without meta-analysis related to stem cell-based therapy to treat knee OA. We excluded animal studies, in vitro and cadaveric studies, case reports, and descriptive reviews. We searched the terms “mesenchymal stem cells,” “mesenchymal stromal cells,” “osteoarthritis,” and “knee,” in PubMed and Google Scholar, which yielded 665 articles. After removing 317 duplicate articles, we conducted an abstract review of 348 articles. We eliminated 119 studies that were not related to the review topic. Further, we excluded 142 animal studies, 10 case reports, and 39 descriptive reviews. Finally, we included randomized controlled trials (RCTs) (n = 9), systematic reviews (n = 9) and meta-analyses (n = 6), as well as prospective (n = 13) and retrospective observational studies (n = 1) with or without control groups, resulting in the inclusion of 38 studies in this review. We assessed the quality of evidence of the included studies with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) pro-Guideline Development Tool online application using GRADE criteria [31], which is an explicit framework for developing and presenting summaries of evidence. Based on this assessment, nine RCTs included in this review had low-quality evidence [30, 46, 48, 50, 52, 60, 80, 82, 85] and 14 observational studies had very low-quality evidence [3, 7, 16, 19, 25, 35, 40-42, 44, 45, 63, 65, 69]. The quality of evidence was downgraded for several reasons, most commonly the use of concomitant treatment or adjuvant treatment, small sample size, short follow-up duration, and publication bias. On the Science The differentiation potential and immune modulation are the two principal ways stem cell-based therapies are postulated to benefit patients with knee OA. MSCs differentiate during culturing as a function of their multipotency, specific surface antigen expression, and plastic adherence, which are believed to result in tissue regeneration. In addition, MSCs possess paracrine and immune-modulating effects through the release of growth factors and cytokines, resulting in reduced inflammation [9, 70, 84]. Because the pathophysiology of knee OA involves degenerative and inflammatory processes, tissue regeneration and modulation of the immune response by MSCs, as described above, were proposed as beneficial properties in these patients [70]. Moreover, MSCs can be isolated from a variety of sources, such as bone marrow, adipose tissue, umbilical cord, amniotic fluid, synovial tissue, peripheral blood, dental pulp, and skeletal muscles [59]. Bone marrow-derived MSCs and adipose tissue-derived MSCs have been used in most clinical studies. They are generated through a two-stage procedure involving the in vitro culture expansion of a particular cell type to produce a numerically enhanced, homogeneous cell lineage. This also involves a precise determination of the number of cells administered to the patient, which helps to ensure the procedure is reproducible [56]. In contrast, products such as bone marrow aspirate concentrate and adipose tissue stromal vascular fraction are obtained and prepared in a one-stage procedure without precise cell expansion by culturing. This results in a non-specific, heterogeneous cell mixture and only a small amount of MSCs available for clinical use. Because of extensive in vitro cell manipulation, bone marrow-derived MSCs and adipose tissue-derived MSCs are classified as an advanced-therapy medicinal product and are subject to more complex regulations than the adipose tissue stromal vascular fraction and bone marrow aspirate concentrate, which do not undergo substantial cell manipulation [22]. In addition, the process of obtaining MSCs in vitro and their expansion entails a waiting period and involves a higher treatment cost. Owing to an easier and faster preparation procedure and fewer regulations, bone marrow aspirate concentrate and adipose tissue stromal vascular fraction have increasingly been used in clinical practice. What We (Think) We Know Efficacy of MSCs in Knee OA We reviewed the clinical outcomes of studies that compared a patient group treated with MSCs against a control group (Table 1) as well as studies in which MSC outcomes were not compared with a control group (Table 2). Previous studies have evaluated the efficacy of MSCs using patient-reported outcome measures (PROMs) such as the pain VAS, WOMAC score, IKDC score, Knee injury and Osteoarthritis Outcome Score (KOOS), Knee Society Score (KSS), 36-Item Short Form (SF-36), Hospital for Special Surgery knee score, Patient Global Assessment, Short Arthritis Assessment Scale, Lysholm score, and Tegner activity scale (function) [3, 7, 16, 19, 25, 30, 35, 40-42, 44-46, 48, 50, 52, 60, 63, 65, 69, 80, 82, 85]. We evaluated whether the improvements in PROMs in the original studies exceeded minimum clinically important difference (MCID) values based on previously reported MCID of 19.9 points for the 100-point VAS pain score [77], 0.9 points for the 10-point pain VAS score [83], 9 points for the knee component, and 10 points for the function component of KSS [55], 27 points for the pain component and 20 points for the function component of 100-point WOMAC score [20], 0.7 for the pain component, function component and total WOMAC Likert scale score [2], 16.7 points for the IKDC score [29], 12 points for the pain component and 8 for activity of daily living component of KOOS [18], and 10 points for the SF-36 [21]. Among 10 studies involving a comparison with a control group, seven studies reported better clinical outcomes in the MSC group and three reported no difference at the final follow-up [30, 44, 82] (Table 1). However, clinical improvements exceeded MCID values in only four comparative studies [48, 50, 52, 60] (Table 1). By contrast, all 13 studies that lacked a control group reported improved clinical outcomes compared with pre-treatment PROM scores (Table 2), and of those, 12 found improvements larger than the MCID while only one did not [63]. It is important to note that lower-quality studies (such as those that lack control groups) tend to report increased estimates of treatment benefits compared with higher quality studies (such as those with control groups), and so this set of findings should be interpreted with great caution. The fact that only four of 10 comparative studies reported improvements greater than the MCID while 12 of 13 noncomparative studies did may be an example of lower-quality (and lower level-of-evidence) studies tending to report inflated estimates of treatment effect sizes. Finally, the baseline severity of knee OA and the post-treatment change in the patients in various studies we evaluated was inconsistently reported and was widely variable; this precluded us from providing a stratified summary of results based on disease severity. Although most of the original studies reported improvements in pain and function at the final follow-up examination, these studies had several limitations, in addition to the major one noted above (that studies without control groups tend to overestimate treatment benefits compared with studies with control groups). First, most of the studies had short-term follow-up periods (less than 24 months) and only two studies had a mid-term follow-up duration of 5 years or more [16, 65]. Second, 13 of 23 clinical studies did not have a control group, and one of 10 comparative studies was a non-randomized trial. Moreover, no studies compared MSC therapies with established surgical procedures such as TKA. Third, more than one-third of the studies had fewer than 10 patients; in light of expected high inter-patient variability, it is difficult to draw meaningful inferences from such small studies [11, 56, 67]. Fourth, the existing studies used multiple types of MSC preparations such as bone marrow-derived MSC, adipose tissue-derived MSC, bone marrow aspirate concentrate, and adipose tissue stromal vascular fraction; additionally, they used multiple delivery methods, which may have influenced the findings because of variations in the chondrogenic differentiation potential and immunomodulatory capacity of various types of cells and delivery methods [12, 37, 43, 88]. Fifth, there was variability and lack of standardization in dosing, as well as heterogeneity of the outcome variables and use of concomitant treatments such as high tibial osteotomy, hyaluronic acid, or platelet-rich plasma, eliminating the possibility of comparing several studies and making a general statement about the efficacy of MSC therapies [11, 32, 67]. Sixth, there was a high risk of assessment bias in currently available studies because of a lack of participant blinding [67]. Selective reporting of positive outcomes may also lead to publication bias. As a result of the above-mentioned shortcomings in the original studies we evaluated, we have serious concerns about the use of MSCs in patients with knee OA. Safety The multipotent nature of MSCs can be considered a double-edged sword because of oncogenicity after in vivo transplantation, which may lead to unpredictable and uncontrolled differentiation into multiple cell types [13]. Additionally, there have been concerns regarding the potential risks of an immunologic reaction and infection because of the serum used to culture MSCs. However, no studies evaluating MSCs for knee OA included in this review reported such complications [81]. One of the RCTs involving intra-articular MSCs analyzed the safety of MSCs as a primary outcome measure; it reported 10 minor adverse events in five of 18 patients [3]. All adverse events reported in that study (such as pain with an injection, knee swelling, and local warmth) were treatment-related and mild-to-moderate in severity, and none resulted further specific interventions or hospitalization. In another study, patients were divided into three dose-escalation cohorts and received a low-dose (1 x 107), medium-dose (5 x 107), or high-dose (1 x 108) intra-articular injection of MSCs [35]. Safety was reported in all three cohorts, with no major treatment-related adverse events during the 2-year study period. Similarly, 14 other studies demonstrated no major adverse events that were directly related to cell treatments in knee OA [7, 19, 25, 30, 44, 48, 50, 52, 60, 63, 65, 69, 80, 85]. Moreover, several systematic reviews and meta-analyses evaluating studies in which MSCs were administered both locally and systemically with a follow-up duration of up to 75 months found no adverse events in terms of oncogenesis, infection, or hypersensitive reactions [67, 68, 88]. We note also that most of the studies we considered are too small to assess safety for uncommon—but potentially important—side effects and harms [53]. In addition, owing to marketing strategies by stem cell clinics and high-dollar investments in businesses involving stem cell-based therapies, concerns regarding the safety of MSCs may be under-reported or sometimes undisclosed [67, 68]. Although the available evidence suggests that MSCs seem relatively safe, the small sample sizes, short-term follow-up durations, and concerns about publication bias in the papers published to date cause us to conclude that the long-term safety of these treatments is, in fact, unknown. Disease-modifying Ability of Stem Cells A treatment modality for knee OA that can delay or reverse the progression of cartilage degeneration may be considered as disease-modifying. Notably, the ability of MSCs to alter the natural history of knee OA has been evaluated in 20 studies using MRI, second-look arthroscopy, and/or histologic assessment to report the status of cartilage after the application of MSCs [7, 19, 25, 30, 35, 40-42, 45, 46, 48, 50, 52, 60, 63, 65, 69, 80, 82, 85]. One RCT reported cartilage improvement at 12 months in the MSC group using quantitative T2 MRI mapping [80]. Another study demonstrated that Whole Organ Magnetic Resonance Imaging Score (WORMS) MRI scores were maintained only in the high-dose group and were worse than at baseline in the control and low-dose groups at 12 months [51]. Although another study demonstrated cartilage status improvements in the MSC group using an MRI evaluation at 12 months [85], several adjunctive procedures such as high tibial osteotomy and microfracture were performed as a part of the treatment. These other treatments introduce severe confounding in the form of co-treatment bias, and because of that, interpretation of findings about cartilage regeneration after MSC treatment is very challenging and sometimes impossible [32]. And not all studies have found cartilage regeneration. One RCT demonstrated no change in WORMS scores from baseline to the final follow-up evaluation in the MSC group [30]. Eight of these 20 studies used second-look arthroscopy and/or histology to analyze improvements in the cartilage status from baseline. Six of those eight studies demonstrated improved arthroscopic scores or International Cartilage Repair Society grades [35, 41, 42, 46, 65, 82]. In contrast, one study reported that all patients showed signs of severe OA (Osteoarthritis Research Society International Histologic Grade > 3) on histologic analysis, despite therapy [69]. Another study revealed that 76% had the repair rated as abnormal or severely abnormal by ICRS standards on second-look arthroscopic findings [45]. Taken together, the 20 studies that evaluated cartilage regeneration reported either inconclusive, negative, or difficult-to-interpret results, and they generally had small sample sizes with short durations of follow-up. Because of those limitations, we believe currently available studies do not generally support the claim that stem cell-based therapies consistently improve the natural history of the disease in patients with knee OA. Stem Cell Injection Versus Implantation The preferred method of MSCs administration has been a controversial topic. We found only six studies that evaluated the results of direct implantation of MSCs instead of an intra-articular injection. Among these six, four were non-comparative observational studies and all reported improvement in PROMs exceeding the MCID and better cartilage grading scores on MRI, second-look arthroscopy, or histology at final follow-up [40, 41, 45, 65]. Another observational study comparing the outcomes of MSC implantation with fibrin scaffold versus combined injection with MSC and platelet-rich plasma reported better clinical outcomes and arthroscopic cartilage grading score at 1 year follow-up in the implantation group [42]. Furthermore, the only RCT among these six studies reported better arthroscopic and histological cartilage grading scores in the cell-transplanted group than placebo at 10 months follow-up, although there was no difference in clinical outcomes in between the two groups [82]. Because of these important shortcomings in the available evidence as well as those described earlier, it is difficult make any conclusions regarding a preferred method of MSCs administration. Systematic Reviews We found 15 systematic reviews, with or without a meta-analysis, related to stem cell use for knee OA [11, 15, 17, 24, 32-34, 38, 66, 67, 72, 73, 86-88]. This is a surprisingly high number, considering that these reviews evaluated only 23 original studies on the topic (Table 3). We see the high ratio of systematic reviews to original research as a matter of concern; systematic reviews are read and cited disproportionately to original research papers, and meta-analyses should only be performed on a high-quality evidence base (ideally, meta-analyses should be limited to RCTs). In the absence of a strong evidence base, it is possible to be badly misled by study designs—such as systematic review and meta-analysis—when they seek to synthesize and pool results from lower-quality studies.Table 3.: Evidence from the systematic reviews/meta-analysis related to MSCs in knee OATable 3-A.: Evidence from the systematic reviews/meta-analysis related to MSCs in knee OATable 3-B.: Evidence from the systematic reviews/meta-analysis related to MSCs in knee OANonetheless, nearly all systematic reviews concluded that evidence of the efficacy of intra-articular MSCs in terms of clinical outcomes and cartilage repair remains limited [11, 17, 24, 32-34, 38, 66, 67, 72, 73, 86, 87], an important warning that we agree with, particularly considering that there is only limited evidence for the use of different types of stem-cell injections in the treatment of knee OA when evaluating PROMs, pain, and radiographic, arthroscopic and histologic outcomes [67]. Knowledge Gaps and Unsupported Practices Regulatory Issues Regulations for the clinical use of stem cell products around the world vary by country. Even in the United States and European Union countries, which have strict regulations, businesses offering stem cells seem to be exploiting loopholes [22, 23, 79]. For instance, the United States FDA outlines a risk-based, three-tiered approach to the regulation of human cells, tissues, and cellular- and tissue-based products (Table 4) [27]. Because it is not necessary to seek premarketing authorization from the FDA for Category 2/361 products, the regulatory bar for such products is considered to be lower than for products requiring FDA approval [79]. This regulatory loophole has been exploited by businesses that falsely claim their products to be in Category 2 [23, 66, 78, 79]. This may have contributed to the growth in stem cell clinics in the United States. However, in developing countries such as India, China, Mexico, and Thailand, the regulatory framework is more permissive or unable to provide effective oversight [27, 64, 79]. Hence, there has been tremendous growth of stem cell clinics worldwide in recent years, offering and actively marketing MSCs for various musculoskeletal problems including knee OA.Table 4.: Three-tiered approach for regulation of HCT/Ps by the FDAA key reason for the growing popularity of businesses offering stem cell therapies worldwide is direct-to-consumer online marketing, especially on social media [58, 74, 76]. This under-regulated and market-driven clinical practice is problematic because marketers exaggerate the efficacy of treatments and do not adequately disclose associated risks, the possibility of failure, and potential costs [39]. We believe there is a need for stricter regulatory frameworks at the national level to contain misleading marketing practices and unsubstantiated claims in direct-to-consumer advertisements. Barriers and How to Overcome Them We believe the current evidence in terms of efficacy, safety, and disease-modifying potential does not support widespread clinical application of stem cell therapy for patients with knee OA. Future research should emphasize trial designs that limit bias, in particular blinded RCTs with adequate sample sizes. Based on the available evidence, it also is impossible to draw inferences about the duration of any putative improvements in clinical scores and cartilage appearance after stem cell therapy in patients with knee OA. Long-term studies with larger patient cohorts are needed to assess the effects of MSCs on cartilage regeneration in patients with knee OA. In addition, future studies should avoid using adjunctive procedures (co-treatments) so that the true potential of stem cell-based therapies for treating knee OA may be evaluated, without confounding by co-treatment bias. Furthermore, researchers should standardize (or at least compare objectively and consistently) the source, dose, preparation, and different means of administering MSCs. We would hope that the next round of clinical studies would evaluate the durability and quality of repaired cartilage tissue, and seek any associations between the extent of cartilage repair and observed clinical improvements. Finally, strict laws and regulations should be implemented at the national level to restrict businesses from selling unproven stem cell-based therapies, and from making unsubstantiated claims in advertisements and other promotional materials. Five-year Forecast We speculate that the clinical use of stem cell-based therapy for knee OA will continue to rise in the near future, mostly through stem cell clinics. Stricter regulations may be imposed on stem cell-based therapies in developed countries in the future; however, this might not occur in developing countries such as India, China, and Thailand. Moreover, considering the now-lucrative remuneration models for businesses and physicians involved in administering stem cell therapies in those countries, we expect a large increase in the number of stem cell clinics in the near future. Patients with knee OA who have not benefitted from other nonoperative treatment modalities and who do not want to undergo TKA may be particularly attracted to stem cell-based therapies. If the United States and the European Union adopt a more-restrictive regulatory posture, we wonder whether patients from those regions may increasingly be lured to developing nations (where the restrictions are likely to be less strict for the foreseeable future) under medical tourism arrangements.