Efficacy of Chondroitin Sulfate in Patients with Knee Osteoarthritis: A Comprehensive Meta-Analysis Exploring Inconsistencies in Randomized, Placebo-Controlled Trials

Osteoarthritis (OA) is the most prevalent musculoskeletal disease in Western populations. It is recognized as an important cause of pain, loss of function and disability and is a major public health problem [1, 2] associated with a substantial and ever-growing burden on society [3, 4]. As life expectancy increases, OA is expected to become the fourth leading cause of disability by the year 2020 [5]. Despite the nearly concurrent publication of international evidence-based OA management guidelines, there are important differences in the interpretation of the evidence, and agreement is lacking concerning the different treatment modalities [6‐10]. This reality is particularly evident for the drug class of symptomatic slow-acting drugs in OA (SYSADOAs) [11, 12]. Discrepancies between the guidelines were related to the heterogeneity of the expert panels involved, geographical differences in the availability of pharmacotherapies and heterogeneity of the studies included [11]. For glucosamine sulfate (GS) and chondroitin sulfate (CS), the evidence for a beneficial effect on symptomatic knee OA is primarily supported by studies of uneven quality performed over > 25 years and, in most cases, supported by the pharmaceutical industry [13]. For GS, it was recently demonstrated that most of the heterogeneity in trials is explained by the brand and that whereas large inconsistency between trials was found, low risk of bias trials using one single pharmaceutical-grade product reveal a small but significant effect size (ES) [14]. The objective of this study was to conduct, for the first time, a similar assessment of the symptomatic effects of CS and to explore the potential determinants of the discrepancy between the results of studies investigating pain and function in knee OA by conducting a systematic review and stratified meta-analysis of available randomized placebo-controlled trials (RCTs).

The protocol of this meta-analysis has been published in the PROSPERO database under registration no. CRD42018087103. The systematic review and meta-analysis were performed following the recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions [15]. The findings are reported in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [16]. The Cochrane online platform Covidence was used to manage the review process. This article does not contain any studies with human participants or animals performed by any of the authors.

The objective of this meta-analysis was to determine whether oral CS is effective in alleviating pain and improving functional status in patients with knee OA and to identify the factors that explain heterogeneity in clinical trial results. Overall, this new meta-analysis showed that CS provides moderate pain benefit (SMD: − 0.63; 95% CI: − 0.91, − 0.35) and has a large effect on function (SMD: − 0.8 2; 95% CI: − 1.31, − 0.33), however with substantial inconsistency (I² = 94% and 95%, respectively). This large inconsistency decreased our confidence in such evidence, which was then graded as “low” [45]. Similar results were reported by the latest Cochrane review on CS in OA, which, however, concluded that the observed effects were clinically meaningful [46]. Investigating the causes of the heterogeneity, as recommended by Glasziou and Sanders [22], our sensitivity analyses on studies without any high risk of bias upgraded our confidence to “moderate” for pain (SMD: − 0.18; 95% CI: − 0.25, − 0.12; I² = 71%) and to “high” for the LI (SMD: − 0.28; 95% CI: − 0.39, − 0.18; I² = 44%, p = 0.10). This improved quality of the evidence was associated with decreased but statistically significant effect sizes, as reported by McAlindon et al. [47], who found that the aggregated effect size of CS was diminished when only high-quality trials were considered.

In contrast to our findings and those of some other meta-analyses on CS [46‐49], two meta-analyses concluded that the benefit of CS was minimal or non-existent [50, 51]. However, rather than any real differences in the combined treatment effect estimates, the conflicting conclusions reached by the authors of these meta-analyses were primarily because of the various results obtained when attempting to explain the observed heterogeneity in the overall effects [50] and the sample size restrictions in the study selection [51]. Additionally, in one of these meta-analyses, placebo-controlled and non-placebo-controlled studies were included and analyzed together, and some of the included studies did investigate intramuscular CS [50].

Although subgroup and sensitivity analyses are of an exploratory nature, they help to understand the reasons for the treatment effect variations across studies [15]. In the current meta-analysis, these exploratory analyses provide evidence that the effects of CS on pain and functional status are not the same, based on brand. In fact, after stratifying the analyses according to the compound’s manufacturer in studies with a low risk of attrition bias, we found greater effects in the subset of studies conducted with the pharmaceutical-grade CS of IBSA origin (SMD for pain: − 0.25; 95% CI: − 0.34, − 0.16) but lower and non-statistically significant effects (SMD for pain: − 0.08; 95% CI: − 0.19, + 0.02) when the preparations from the other manufacturers were used (p value for interaction = 0.02). Previous meta-analyses investigating inconsistency in trials on GS found similar results to those obtained in this meta-analysis [14, 52].

Differences in the treatment effects, according to brand, may be explained by differences in the quality of the compounds. Indeed, as reported by Volpi [37], these quality differences result in different therapeutic activity in the CS preparations. Pharmaceutical-grade CS preparations have been found to be of high and standardized purity and properties, contrary to the non-pharmaceutical-grade preparations [53, 54], which explains the position of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) regarding glucosamine and chondroitin (i.e., recommending only the patented pharmaceutical-grade preparations of crystalline GS and CS to ensure a clinical benefit in patients with OA) [9, 54]. Contrary to the ESCEO, some other clinical guidelines such as those of the Osteoarthritis Research Society International (OARSI) [7] and the American College of Rheumatology [8] did not make the same recommendation, primarily because they did not make any distinction in terms of quality of GS and CS.

Exploring heterogeneity, our analyses showed that the effect of CS was positive at 3 months and continued until 4–12 months of treatment, but not beyond. Such results may be misleading in terms of the long-term effect of CS. Of the three studies that contributed to the analysis in that subgroup, one used a non-pharmaceutical-grade CS (Table 1), and in the two others (which used CS of IBSA origin), the primary end point was the joint space width (JSW), and the Michel et al. study [55] included many patients without baseline pain. Therefore, these data are not sufficient to make a conclusion regarding the long-term symptomatic effects of CS. However, investigating the effect of CS on joint space narrowing, it was shown in a meta-analysis of RCTs that CS reduced the rate of decline of JSW of patients with knee OA over a 2-year treatment period [56].

The comparison of the CS effect according to the concomitant use of oral NSAIDs did not show any statistically significant difference between the subsets of studies that allowed NSAIDs and the others for both pain and the LI. However, our analyses showed a better effect of CS on pain when no concomitant NSAIDs were permitted. This finding might suggest that the intrinsic effect of CS is mitigated by the concomitant use of NSAIDs during RCTs. In this meta-analysis, half of the included studies allowed concomitant NSAIDs (Table 1).

Our analyses showed that doses of CS ranging from 800 mg to 2000 mg were effective on both pain and the LI, with a tendency for a better effect with the doses ranging from 1000 to 2000 mg/day.

Finally, investigating the sources of the remaining heterogeneity in various subgroups in studies without any high risk of bias, we found strong correlations between the treatment effects and study size, suggesting true heterogeneity due to study size [24]. This result might suggest that the smallest studies included (more) patients with more severe disease than the others. Indeed, it has been reported that the size of the treatment effect in clinical trials could be increased by selecting high-risk patients [57], given that patients with more severe disease seem to be more likely to demonstrate beneficial treatment effects than other patients [58]. However, we were unable to show a correlation between the mean baseline VAS scores and mean ES (SMD). For the studies included in this meta-analysis, in which a 0–100-mm visual analog scale (VAS) was used for pain measurement, various levels of pain at baseline were considered for patient inclusion; however, the mean baseline values were relatively close. Beyond the variations in the minimum level of pain required for inclusion, it is likely that patients with various levels of pain would have been included in each single study (SD varied from 13 to 17 mm VAS across most of the studies), which might have led to a likely within-study treatment effect variation and then to between-study heterogeneity [22].

Compared with the ES reported for opioid analgesics, oral NSAIDs or intra-articular hyaluronic acid for which the same inconsistency issue was reported [59‐61], CS appears to be a good treatment option for patients with OA, considering its superior safety profile [46]. Long-term trials assessing the symptomatic effects of oral CS are warranted. To obtain better results on the intrinsic benefit of CS over placebo, concomitant anti-OA medications (NSAIDs and others) should not be allowed during the trials, in accordance with the guidelines from the European Medicines Agency [62].

Some limitations are present in this meta-analysis, including the few studies on oral CS in OA, and particularly the number of studies that reported data on the LI, which limits any comparison of the effects of CS on pain and functional status. Another limitation to this meta-analysis is the fact that only the LI was considered as a measure of functional status. Indeed, at the stage of the protocol, pain, physical function and the LI were considered as co-primary outcomes. However, during the screening of individual studies, we realized that only a few studies assessed physical function using a specifically dedicated tool (5 studies used the WOMAC function questionnaire and 1 used another tool). Since the LI (including parameters on pain or discomfort, maximum distance walked and activities of daily living) and the WOMAC function index (including only questions assessing the degree of difficulty while performing various activities of daily living) do not really measure the same things, it would not have been adequate to combine data on function measured by these two different tools in a meta-analysis, as has been done for pain. Therefore, we decided to limit our outcomes of interest in this meta-analysis to pain and LI, using the LI as a measure of functional status.

Overall, oral CS is superior to placebo in the management of OA, with a moderate benefit for pain and a large effect on functional status measured by the LI, however with a high level of inconsistency. Our analyses showed that risk of bias, brand of CS and study size are the factors that explain the inconsistency in clinical trial results. Specifically, this meta-analysis demonstrated the following results.