Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis

Abstract

Background Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are an important drug class in the treatment armamentarium for osteoarthritis (OA). Objective We aimed to re-assess the safety of various SYSADOAs in a comprehensive meta-analysis of randomized placebo-controlled trials, using, as much as possible, data from full safety reports. Methods We performed a systematic review and random-effects meta-analyses of randomized, double-blind, placebo-controlled trials that assessed adverse events (AEs) with various SYSADOAs in patients with OA. The databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus were searched. The primary outcomes were overall severe and serious AEs, as well as AEs involving the following Medical Dictionary for Regulatory Activities (MedDRA) system organ classes (SOCs): gastrointestinal, cardiac, vascular, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue, renal and urinary system. Results Database searches initially identified 3815 records. After exclusions according to the selection criteria, 25 studies on various SYSADOAs were included in the qualitative synthesis, and 13 studies with adequate data were included in the meta-analyses. Next, from the studies previously excluded according to the protocol, 37 with mainly oral nonsteroidal anti-inflammatory drugs (NSAIDs) permitted as concomitant medication were included in a parallel qualitative synthesis, from which 18 studies on various SYSADOAs were included in parallel meta-analyses. This post hoc parallel inclusion was conducted because of the high number of studies allowing concomitant anti-OA medications. Indeed, primarily excluding studies with concomitant anti-OA medications was crucial for a meta-analysis on safety. The decision for parallel inclusion was made for the purpose of comparative analyses. Glucosamine sulfate (GS), chondroitin sulfate (CS) and avocado soybean unsaponifiables (ASU; Piascledine ® ) were not associated with increased odds for any type of AEs compared with placebo. Overall, with/without concomitant OA medication, diacerein was associated with significantly increased odds of total AEs (odds ratio [OR] 2.22; 95% confidence interval [CI] 1.58–3.13; I 2 = 52.8%), gastrointestinal disorders (OR 2.85; 95% CI 2.02–4.04; I 2 = 62.8%) and renal and urinary disorders (OR 3.42; 95% CI 2.36–4.96; I 2 = 17.0%) compared with placebo. In studies that allowed concomitant OA medications, diacerein was associated with significantly more dermatological disorders (OR 2.47; 95% CI 1.42–4.31; I 2 = 0%) and more dropouts due to AEs (OR 3.18; 95% CI 1.85–5.47; I 2 = 13.4%) than was placebo. No significant increase in s...

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis

“…Both glucosamine and CS can be considered as safe treatments for patients with OA. A recent systematic review and meta-analysis found no statistically significant increase in odds between glucosamine or CS, each compared with placebo, for any system organ class (SOC)-related disorders including: GI, cardiac, vascular, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue, and disorders of the renal and urinary systems [16]. In addition, no difference in odds for severe and serious AEs, and for withdrawals due to AEs was found for glucosamine or CS versus placebo.…”

“…Diacerein has a small beneficial effect on OA pain; however, the safety of diacerein has been called into question. In a meta-analysis, the odds of any AE with diacerein was more than twice that of placebo (odds ratio [OR] 2.22, 95% CI 1.58, 3.13) [16]. This was largely due to increased odds of GI AEs with diacerein versus placebo (OR 2.85, 95% CI 2.02, 4.04), of which diarrhea, abdominal pain, soft stools, and colitis were frequently reported, and a high increase in odds of renal and urinary disorders with diacerein (OR 3.42; 95% CI 2.36, 4.96), urine discoloration being the most reported effect.…”

Recommendations for the Reporting of Harms in Manuscripts on Clinical Trials Assessing Osteoarthritis Drugs: A Consensus Statement from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)

“…Recently, the ESCEO commissioned several systematic reviews and meta-analyses of randomized, placebo-controlled trials to reassess the safety of various anti-OA medications, including topical nonsteroidal anti-inflammatory drugs (NSAIDs), symptomatic slow-acting drugs for OA (SYSADOAs) and intra-articular hyaluronic acid (IAHA) [30][31][32]. For this purpose, the MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus databases were comprehensively searched.…”

“…The methodology and the outcomes of these systematic reviews have been extensively described in each manuscript. From the articles included in each systematic review, we collected information on how AE data were reported; details on how AE-related results were reported in each article retrieved from the systematic review processes can be found in the tables describing the characteristics of the included studies in each specific manuscript reporting the outcomes of these new meta-analyses (in this supplement) [30][31][32]. For the purpose of preparing the ESCEO recommendations for the reporting of harms in future manuscripts on trials on anti-OA medications, we summarized the ways in which harms-related data have been reported across the articles retrieved for these new ESCEO meta-analyses, and report here the common sub-standard harms reporting practices found in these prior manuscripts on RCTs on anti-OA drugs.…”

“…The articles selected for the ESCEO meta-analyses on the safety of some anti-OA medications [30][31][32] hide important divergence in the reporting of AEs, which we report here. As previously stated, these meta-analyses were aimed at assessing the AEs associated with the use of topical NSAIDs, SYS-ADOAs and IAHA for the management of OA.…”