PMID- 31073924 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20220331 IS - 1179-1969 (Electronic) IS - 1170-229X (Print) IS - 1170-229X (Linking) VI - 36 IP - Suppl 1 DP - 2019 Apr TI - Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. PG - 65-99 LID - 10.1007/s40266-019-00662-z [doi] AB - 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((R))) 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 serious or severe AEs was found with diacerein versus placebo. CONCLUSIONS: GS and CS can be considered safe treatments for patients with OA. All eligible studies on ASU included in our analysis used the proprietary product Piascledine((R)) and allowed other anti-OA medications; thus, the safety of ASU must be confirmed in future studies without concomitant anti-OA medications. Given the safety concerns with diacerein, its usefulness in patients with OA should be assessed, taking into account individual patient characteristics. FAU - Honvo, Germain AU - Honvo G AUID- ORCID: 0000-0002-6992-6712 AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. germain.honvo@uliege.be. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. germain.honvo@uliege.be. FAU - Reginster, Jean-Yves AU - Reginster JY AUID- ORCID: 0000-0001-6290-752X AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. AD - Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia. FAU - Rabenda, Veronique AU - Rabenda V AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. FAU - Geerinck, Anton AU - Geerinck A AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. FAU - Mkinsi, Ouafa AU - Mkinsi O AD - Rheumatology Department, IBN ROCHD University Hospital, Casablanca, Morocco. FAU - Charles, Alexia AU - Charles A AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. FAU - Rizzoli, Rene AU - Rizzoli R AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. AD - Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. FAU - Cooper, Cyrus AU - Cooper C AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK. AD - National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK. FAU - Avouac, Bernard AU - Avouac B AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. FAU - Bruyere, Olivier AU - Bruyere O AUID- ORCID: 0000-0003-4269-9393 AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. LA - eng GR - MC_U147585819/MRC_/Medical Research Council/United Kingdom GR - MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom GR - G0400491/MRC_/Medical Research Council/United Kingdom GR - MC_U147585824/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 0 (Anthraquinones) RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Delayed-Action Preparations) RN - 0 (Drug Combinations) RN - 0 (Phytosterols) RN - 0 (Plant Extracts) RN - 0 (piascledine) RN - 1406-18-4 (Vitamin E) RN - 4HU6J11EL5 (diacerein) SB - IM MH - Anthraquinones/administration & dosage/*adverse effects/therapeutic use MH - Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/*adverse effects MH - Delayed-Action Preparations MH - Drug Combinations MH - Drug-Related Side Effects and Adverse Reactions/epidemiology/*etiology MH - Humans MH - Osteoarthritis/*drug therapy MH - Phytosterols/administration & dosage/*adverse effects/therapeutic use MH - Plant Extracts/administration & dosage/*adverse effects/therapeutic use MH - Randomized Controlled Trials as Topic MH - Treatment Outcome MH - Vitamin E/administration & dosage/*adverse effects/therapeutic use PMC - PMC6509099 COIS- O Bruyere has received grants from Biophytis, IBSA, MEDA, Servier, SMB, and Theramex, outside the submitted work. C. Cooper has received personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB, outside of the submitted work. J-Y. Reginster has received grants from IBSA-Genevrier, Mylan, CNIEL, and Radius Health (through their institution); consulting fees from IBSA-Genevrier, Mylan, CNIEL, Radius Health, and Pierre Fabre; fees for participation in review activities from IBSA-Genevrier, MYLAN, CNIEL, Radius Health, and Teva; payment for lectures from AgNovos, CERIN, CNIEL, Dairy Research Council (DRC), Echolight, IBSA-Genevrier, Mylan, Pfizer Consumer Health, Teva, and Theramex, outside of the submitted work. B. Avouac has received consulting fees from Novartis, BMS, Roche, Janssen Cilag, Expanscience, and IRIS and fees for participating in research activities from Sanofi, Amgen, Takeda, Allegan, Abbvie, Vertex, AstraZeneca, Ipsen, Leadiant, Otsuka, Jazz, Leo, and alexion, outside of the submitted work. G. Honvo, R. Rizzoli, O. Mkinsi, A. Geerinck, A. Charles and V. Rabenda have no conflicts of interest that are directly relevant to the content of this article. EDAT- 2019/05/11 06:00 MHDA- 2019/07/10 06:00 PMCR- 2019/05/09 CRDT- 2019/05/11 06:00 PHST- 2019/05/11 06:00 [entrez] PHST- 2019/05/11 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2019/05/09 00:00 [pmc-release] AID - 10.1007/s40266-019-00662-z [pii] AID - 662 [pii] AID - 10.1007/s40266-019-00662-z [doi] PST - ppublish SO - Drugs Aging. 2019 Apr;36(Suppl 1):65-99. doi: 10.1007/s40266-019-00662-z.