Risk of bias and brand explain the observed inconsistency in trials on glucosamine for osteoarthritis:a meta-analysis of placebo-controlled trials

Abstract

Purpose: the aim of this study was to determine whether study sponsor, chemical formulation, brand of glucosamine, and/or risk of bias explain observed inconsistencies in trial findings of glucosamine’s efficacy for treating pain in osteoarthritis (OA) clinical trials. Furthermore, we determined the effect of glucosamine on pain in OA and how the aforementioned factors play a role in regards to the efficacy of the preparation on pain in OA. Methods: A systematic review and stratified meta-analysis of randomized placebo-controlled trials (RCTs) were conducted. Inclusion criteria consisted of RCTs testing glucosamine compounds vs. placebo in humans with combined treatment regimens as an exclusion criterion (i.e. glucosamine combined with other intervention vs. placebo). Random effects models were applied with inconsistency (I-squared) and heterogeneity (Tau-squared) using Review Manager and SAS, respectively. The major outcome measure was reduction of pain. Selecting outcome-measuring scale for data extraction was done after a predefined verified hierarchy of pain scales; the standardized mean difference (SMD and [95%CI]) served as effect size. Results: The inclusion criteria yielded 25 trials (3,458 patients). Compared with a placebo, glucosamine reduced pain (SMD = -0.51 [-0.72 to -0.30]), although expected high level of between-trial inconsistency was observed (I-sq=88%). The single most important explanation (i.e., covariate) was brand (reducing heterogeneity by 41%, p=(0.00032): Twelve trials (1,437) using the Rottapharm|Madaus product apparently resulted in significant pain reduction (-1.05 [-1.43 to -0.68],), with a large amount of inconsistency(I-sq=92%); whereas 13 trials (1,963 patients) using non-Rottapharm|Madaus products consistently failed to show a reduction in pain when compared with placebo (-0.11 [-0.46 to 0.24], I-sq=10%) - Tau-sq reduced from 0.601 to 0.359 (p<0.001). The second most important explanation was overall risk of bias (reducing Tau-sq by 32%). Conclusions: Trials using the Rottapharm|Madaus glucosamine product had a superior outcome on pain in OA compared to other preparations of glucosamine, though Rottapharm|Madaus trial showed large inconsistency in their results and therefore confidence in the results in limited. We did not find an effect of other brands of glucosamine. Most of the observed heterogeneity in trials on glucosamine for (OA) can be explained by brand and risk of bias.Tabled 1Stratified meta-analysisVariableTrialsEffect size95%CItau-squaredp-value for interactionAll trials25−0.58(−0.90 to −0.26)0.601Label:0.3590.00032Other label13−0.11(−0.46 to 0.24)Rottapharm|Madaus12−1.05(−1.43 to −0.68)Chemical structure:0.54670.082HCl40.03(−0.72 to 0.77)SO421-0.7(−1.04 to −0.36)Risk of bias (overall)0.40790.004Low RoB8−0.09(−0.54 to 0.36)Unclear RoB7−0.39(−0.90 to 0.12)High RoB10−1.14(−1.59 to −0.69)Industry funding0.54990.0767Yes14−0.83(−0.41 to 1.24)No11−0.26(−0.73 to 0.20) Open table in a new tab