Table 3.

Synthesis of systematic reviews and/or meta-analyses on collagen derivatives for treatment of OA patients

First author (year)	Study type	Objective of the review	Databases searched	Model used for analyses	Number of studies included (on collagen)
De Silva (2011) [76]	Systematic review	To critically evaluate the evidence regarding complementary and alternative medicine (CAM) taken orally or applied topically (excluding glucosamine and chondroitin) in the treatment of OA	Allied and Complementary Medicine; EMBASE; Ovid MEDLINE; ACP Journal Club; CENTRAL; CDSR; DARE	Not applicable	1 study on collagen Moskowitz, 2000 (a simple literature review reporting results from an RCT)
García-Coronado (2019) [31]	Meta-analysis	To evaluate the effect of collagen-based supplements on OA symptoms through a meta-analysis of randomized controlled trials (RCTs)	PubMed-Medline, Scopus, and Google Scholar databases	Random effects model (using the DerSimonian–Laird method) and the generic inverse variance method	5 RCTs Benito-Ruiz, 2009 Kumar, 2015 Lugo, 2016 McAllindon, 2011 Schauss, 2012
Liu (2018) [28]	Systematic review and meta-analysis	To evaluate efficacy and safety of supplements compared with placebo in people with hand, hip or knee OA	MEDLINE, EMBASE, CENTRAL, Allied and Complementary Medicine and Cumulative Index to Nursing and Allied Health Literature	Random effects model	4 RCTs on collagen Benito-Ruiz, 2009 Kumar, 2015 Lugo, 2016 McAlindon, 2011
Van Vijven (2012) [27]	Systematic review and meta-analysis	To summarize the evidence from RCTs and quasi-RCTs that have examined the effectiveness of collagen derivatives for symptomatic and chondroprotective treatment in patients with OA	CENTRAL, PubMed, and EMBASE	Fixed effect model and random effects model	8 RCTs in qualitative synthesis, and 3 in quantitative analysis (CH vs. placebo, 6-month follow-up) Benito-Ruiz, 2009 McAlindon, 2011 Moskowitz, 2000

First author (year)	GRADE assessment of evidence (YES/NO)	Funding source or sponsor of the study	Authors’ conclusion	Aeras of uncertainty/future directions of research, as suggested by the authors
De Silva (2011) [76]	No	Funded by Arthritis Research UK (formerly the Arthritis Research Campaign)	This systematic review provides evidence on efficacy of a number of CAM therapies that were used in OA. The major limitation in reviewing the evidence is the paucity of randomized controlled trials in the area	Widening the evidence base, particularly for those compounds for which there is promising evidence, should be a priority for both researchers and funders
García-Coronado (2019) [31]	No	NA	The results of this meta-analysis showed that collagen is effective in improving OA symptoms by the decrease of both total WOMAC index and VAS score	Further longer clinical trials in larger populations are required in order to corroborate the potential beneficial effects of collagen supplementation in patients with symptomatic OA
Liu (2018) [28]	Yes	Funded by an NHMRC programme grant APP 1,091,302	The overall analysis including all trials showed that supplements provided moderate and clinically meaningful treatment effects on pain and function in patients with hand, hip or knee OA at short term, although the quality of evidence was very low. (…) Supplements had no clinically important effects on pain and function at medium-term and long-term follow-ups	Further large and robust RCTs with longer treatment duration are needed to confirm efficacy of supplements with large treatment effects at short term in the presence of limited study quality evidence (…). It is especially important to further evaluate safety of these supplements in the long run
Van Vijven (2012) [27]	Yes	No funding was obtained for this study	There is insufficient evidence to recommend the generalized use of collagen hydrolysate in daily practice for the treatment of patients with OA	More independent and high-quality studies are needed to establish the therapeutic effects of collagen derivatives and to confirm whether or not they are chondroprotective

CDSR Cochrane Database of Systematic Reviews, CENTRAL Cochrane Central Register of Controlled Trials, DARE Database of Abstracts of Reviews of Effects, GRADE Grading of Recommendations Assessment, Development and Evaluation, NA Information not available, RCT randomized controlled trial