REVIEW
Role of Collagen Derivatives in Osteoarthritis
and Cartilage Repair: A Systematic Scoping Review
With Evidence Mapping
Germain Honvo .Laetitia Lengele´.Alexia Charles. Jean-Yves Reginster.Olivier Bruye`re
Received: August 18, 2020 / Accepted: September 23, 2020 / Published online: October 17, 2020 The Author(s) 2020
ABSTRACT
Introduction: There is currently no disease-modifying drug for osteoarthritis (OA), and some safety concerns have been identified about the leading traditional drugs. Therefore, research efforts have focused on alternatives such as supplementation with collagen deriva-tives. The objective of this scoping review is to examine the extent, range, and nature of research, and to summarize and disseminate research findings on the effects of collagen
derivatives in OA and cartilage repair. The pur-pose is to identify gaps in the current body of evidence in order to further help progress research in this setting.
Methods: The databases Medline, Scopus, CENTRAL, TOXLINE, and CDSR were compre-hensively searched from inception to search date. After studies selection against eligibility criteria, following recommended methods, data were charted from the retrieved articles and these were subsequently synthesized. Numerical and graphical descriptive statistical methods were used to show trends in publications and geographical distribution of studies.
Results: The systematic literature search iden-tified a total of 10,834 records. Forty-one pub-lished studies were ultimately included in the review, 16 of which were preclinical studies and 25 were clinical studies (including four system-atic reviews/meta-analyses). Collagen hydro-lysate (CH) and undenatured collagen (UC) were the two types of collagen derivatives studied, with a total of 28 individual studies on CH and nine on UC. More than a third of studies originated from Asia, and most of them have been published after 2008. Oral forms of collagen derivatives were mainly studied; three in vivo preclinical studies and three clinical trials investigated intra-articularly injected CH. In most of the clinical trials, treatment dura-tions varied between 3 and 6 months, with the shortest being 1.4 months and the longest 11 months. All in vivo preclinical studies and Digital Features To view digital features for this article
go tohttps://doi.org/10.6084/m9.figshare.12987830. Electronic Supplementary Material The online version of this article (
https://doi.org/10.1007/s40744-020-00240-5) contains supplementary material, which is
available to authorized users.
G. Honvo (&) L. Lengele´ A. Charles J.-Y. Reginster O. Bruye`re
Division of Public Health, Epidemiology and Health Economics, University of Lie`ge, Lie`ge, Belgium e-mail: germain.honvo@uliege.be
G. Honvo L. Lengele´ A. Charles J.-Y. Reginster O. Bruye`re
World Health Organization (WHO) Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, University of Lie`ge, Lie`ge, Belgium
J.-Y. Reginster
Chair for Biomarkers Research, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
clinical trials, regardless of their quality, con-cluded on beneficial effects of collagen deriva-tives in OA and cartilage repair, whether used as nutritional supplement or delivered intra-artic-ularly, and whatever the manufacturers of the products, the doses and the outcomes consid-ered in each study.
Conclusions: Although current evidence shows some potential for the use of CH and UC as an option for management of patients with OA, there is still room for progress in terms of lab-oratory and clinical research before any defini-tive conclusion can be made. Harmonization of outcomes in preclinical studies and longer ran-domized placebo-controlled trials in larger populations with the use of recommended and validated endpoints are warranted before colla-gen derivatives can be recommended by large scientific societies.
Keywords: Osteoarthritis; Cartilage repair; Collagen derivatives; Collagen hydrolysate; Undenatured collagen; Scoping review; Evidence mapping
Key Summary Points
Why carry out this study?
There are currently no disease-modifying drugs for osteoarthritis (OA) and some safety concerns have been reported regarding the traditional leading anti-OA medications such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs).
As an alternative to traditional strategies, there is growing interest in
supplementation with collagen
derivatives; however, previous literature reviews show that little clinical evidence is available to support their therapeutic benefit for OA patients.
Early clarification of what is currently known about the effects of collagen derivatives in OA and cartilage repair, from preclinical research to real-life studies, appears essential to avoid any unnecessary continuing controversies. What was learned from the study?
This scoping review shows that there is relatively little evidence, both from preclinical and clinical research, on the usefulness of collagen derivatives in OA and cartilage repair; collagen hydrolysate (CH) and undenatured collagen (UC) are the two types of collagen derivatives studied so far, mainly as oral supplements. All in vivo preclinical studies and clinical trials, regardless of their quality,
concluded on beneficial effects of collagen derivatives in OA and cartilage repair, whether used as nutritional supplement (oral CH or UC) or delivered intra-articularly (intra-articular CH). However, three of the four in vitro studies available, all on CH, concluded that CHs from different sources and of different
molecular weights were either ineffective or even detrimental to OA cartilage. Gaps in the current research include: Limited number of in vitro studies; lack of harmonization of endpoints in preclinical studies; lack of long-term and large-scale randomized, placebo-controlled trials; lack of studies involving patients with hip or hand OA; lack of clinical studies investigating radiological changes in OA patients after supplementation with collagen derivatives.
DIGITAL FEATURES
This article is published with digital features, including a summary slide, to facilitate under-standing of the article. To view digital features for this article go to https://doi.org/10.6084/ m9.figshare.12987830.
INTRODUCTION
Osteoarthritis (OA) is the most common joint disease and a major public health issue of the current century [1]. Due to growing life expec-tancy, particularly in the developed countries, its global prevalence is rapidly increasing [1,2], making it a disease associated with an extremely high economic burden [2–4]. OA commonly affects the weight-bearing joints and consider-ably impairs the quality of life of millions of people due to chronic pain and functional limitations [5, 6], thus contributing to increase pace of aging, which may ultimately result in premature mortality in the affected people [7].
In the absence of disease-modifying drugs, current strategies for managing OA have relied on a combination of pharmacological and/or non-pharmacological treatments, with the aim of reducing the pain and improving physical function in patients [8, 9]. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) have been among the most used pharmacological treatments so far [10]. For years, paracetamol has been recommended as the first-line therapy [11, 12] despite its low effectiveness to reduce pain in OA [13]. How-ever, recent reports have suggested that this drug is not as safe as it was thought [14] and, consequently, recent guidelines have down-graded the use of paracetamol in OA [8, 9]. Likewise, safety concerns associated with the use of NSAIDs have limited recommendations for OA patients, particularly for those with comorbidities [15, 16]. To find alternatives to these drugs, research efforts have focused, since several years now, on medications that would reduce the symptoms of the disease and also be capable of repairing or at least slowing the degradation of articular cartilage. These treat-ments, known as symptomatic slow action drugs for osteoarthritis (SYSADOAs) are gener-ally considered safe and well tolerated by patients. Currently, glucosamine sulfate (GS) and chondroitin sulfate (CS) are the most used SYSADOAs [17,18], but collagen derivatives are also gaining increasing consideration, mainly as nutritional supplements [19–21].
As OA is a disease characterized by the pro-gressive destruction of articular cartilage, a major component of which is collagen, it has been postulated that supplementation with collagen hydrolysates may induce the synthesis of cartilage matrix, by stimulating the chon-drocytes [19], after intestinal absorption and accumulation in articular cartilage through blood circulation. In fact, experimental studies have demonstrated that peptides from orally administrated collagen hydrolysates accumu-lated in cartilage tissue a few hours after administration [22–24]. Investigating the effi-cacy of exogenous administration of collagen derivatives in treating OA in animal models, recent preclinical studies have reported promising results [25, 26], suggesting some potential for cartilage repair in OA patients. These kinds of results have prompted research-ers to evaluate the ability of supplementation with collagen derivatives to relieve OA symp-toms in humans.
However, previous literature reviews show that little clinical evidence is available to sup-port the therapeutic benefit of collagen deriva-tives in OA patients [27–29] and furthermore, a systematic literature review with meta-analysis found serious limitations in the methodological quality of these studies [27]. Additionally, almost all of the randomized placebo-controlled trials available on collagen derivatives in OA are on food ingredients or nutraceuticals, rather than pharmaceutical-grade products [30]. Using data from these clinical trials, the latest meta-analysis found that collagen supplementation had significant positive effect on some (i.e., stiffness) but not the other (i.e., pain and functional limitation) OA symptoms [31]. This lack of strong clinical evidence on the useful-ness of collagen derivatives for patients with OA may justify the fact that they are not currently recommended by the leading scientific societies on OA [8, 9, 32], although largely used by OA patients.
Lessons learned from GS and CS, which have been used for more than two decades as phar-maceutical-grade products and nutraceuticals, should serve for the development and clinical assessment of collagen derivative supplements as adequate alternative options for OA. In fact,
despite the wide use of these treatments, con-troversies have surrounded their beneficial effects for patients with OA until currently, due to inconsistent reports from clinical trials [33, 34]. Ultimately, meta-analyses with sub-group and sensitivity analyses have shown that most of the heterogeneity in results from clini-cal trials on GS and CS was explained by brand and risk of bias [35, 36]. Therefore, early clari-fication of what is currently known about the effects of collagen derivatives on cartilage repair from preclinical research, and on their thera-peutic role in human OA patients appears essential. This might help avoiding unnecessary continuing controversies by helping further designing preclinical research to better clarify the role of collagen derivatives in cartilage repair, in the case of insufficient evidence; as well, it might help better designing future clinical trials, with food-grade or pharmaceuti-cal-grade products manufactured using Good Manufacturing Practice.
Thus, the objective of this scoping review is to examine the extent, range, and nature of research, and to summarize and disseminate research findings on the effects of collagen derivatives on cartilage and specifically on articular cartilage, as well as on the effects of these compounds as a symptomatic and/or chondroprotective treatment in OA patients. Our purpose is to identify research gaps in the available evidence and to progress research on this potentially promising therapeutic or adju-vant option for OA patients.
METHODS
This scoping review was conducted according to the guidance developed by the Joanna Briggs Institute (JBI), which was first published in 2015 [37] and updated in 2017. We also followed recommendations by Arksey and O’Malley [38] and those by Levac, Colquhoun and O’Brien [39]. The Covidence online software was used to manage the entire review process, including screening of records based on title and abstracts, and full texts screening. The findings of this research were reported according to the Pre-ferred Reporting Items for Systematic reviews
and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [40]. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Protocol and Registration
The protocol of this scoping review was not registered in PROSPERO, as scoping reviews do not fall into the scope covered by this database. However, the protocol, dated February 29, 2020, is available from the authors to anyone who would like to have access to it.
Eligibility Criteria Inclusion Criteria
Pre-clinical studies (in vitro and in vivo labora-tory animal studies) on the effects of collagen derivatives on any type of cartilage, clinical studies (interventional studies), epidemiological non-interventional studies (observational stud-ies), and post-marketing surveillance studies assessing the symptomatic and/or chondropro-tective effects of collagen derivatives in patients with osteoarthritis were included in this scop-ing study, regardless of the study design. Studies on combination products (i.e., collagen deriva-tives combined with anti-OA medication) were also included, as were studies simultaneously involving patients with OA and patients with diseases other than OA. Finally, evidence syn-thesis studies, such as systematic literature reviews and meta-analyses, were considered for inclusion.
Exclusion Criteria
Clinical trials, epidemiological non-interven-tional studies, and post-marketing surveillance studies in veterinary medicine were excluded, as were studies on collagen as biomarker of OA or other diseases. We also excluded studies using collagen as a carrier for other therapies (e.g., stem cells or chondrocytes for transplantation), as well as studies using collagen as a scaffold for cartilage repair. Simple literature reviews (non-systematic reviews), letters, comments, and
editorials were not considered for inclusion in this scoping study. No date limitation was applied to the search, however articles in lan-guages other than English or French were excluded; this language restriction has been chosen because of time constraints for trans-lating articles from other languages, as no member of the research team has competences in languages such as Chinese, Japanese, or Russian, etc.
Information Sources and Search Strategies We comprehensively searched the following literature databases, with search strategies adapted to each database: Medline (Ovid), Sco-pus, Cochrane Central Register of Controlled Trials (Ovid CENTRAL), TOXLINE (ProQuest), and Cochrane Database of Systematic Reviews (Ovid CDSR). Each database was searched from inception to February 28, 2020.
The search strategies were constructed using combinations of words describing the popula-tion/disease of interest (‘‘osteoarthritis’’ or ‘‘car-tilage’’), the studied concept (‘‘collagen derivatives’’), and the context (‘‘treatment’’ [of osteoarthritis]; [cartilage] ‘‘repair’’ or ‘‘regenera-tion’’). Depending on the database, combina-tions of free vocabulary words and/or controlled terms were used. The detailed search strategies for all databases are shown in the appendix to this article (Electronic supplementary file 1), except that of the Cochrane Database of Sys-tematic Reviews, as the search of that database returned no result.
The reference list of systematic reviews that were included were hand-searched for addi-tional studies that would not have been found through databases search.
Electronic clinical trial registries such as ClinicalTrials.gov, the World Health Organisa-tion InternaOrganisa-tional Clinical Trial Registry plat-form (WHO ICTRP), the International Standard Randomised Controlled Trial Number (ISRCTN) registry and the European Union Clinical Trials Register, as well as the Clinical Trials Registry-India (CTRI) and the Chinese Clinical Trial Registry (ChiCTR) were also searched for
potential ongoing clinical trials on collagen derivatives in OA.
Selection of Sources of Evidence
Two reviewers (GH and LL) independently screened the titles and abstracts of the records to identify all potentially relevant studies. Once a selection decision was made by the two reviewers on all records, a consensus meeting was set up to solve disagreements. If the rele-vance of a study was unclear or if disagreements persisted based on the information in the abstract, the study was included for more information in the full text. After this step, the full texts of the selected studies were searched, and a new selection process was undertaken independently by the two reviewers (GH and LL), based on full article screening against the eligibility criteria. Studies that were selected by the two review authors were automatically included in the review. A consensus meeting was organized to make a final decision regard-ing studies for which the review authors took divergent selection decisions.
Data Charting Process and Data Items
Three reviewers (LL, AC, and GH) were involved in the data charting process. This consisted in charting key items of information relevant to the objective of the scoping review, from the primary research articles. One of the reviewers (LL) charted the data from preclinical studies, and the second reviewer (AC), from clinical studies. Then, the data charted from each cate-gory of research papers (preclinical and clinical) by the first two reviewers were cross-checked by the third reviewer (GH) while making the syn-thesis of studies, to detect and correct any mis-take in the extracted data. All the synthetized data were checked again by the three review authors before the submission of the manu-script for publication.
The data charting process was conducted using pre-designed forms. As the nature of key information may vary according to the types of studies [39], we designed specific data charting forms for preclinical and clinical studies. These
forms were pre-tested by the team before engaging in the formal data charting process.
We extracted, from each study, general information to identify the study, and more specific information on the study population, information on the type and characteristics of collagen derivative studied, information on the methodology of the study, and finally, the main result(s) and conclusion(s) of the study. More specifically, the following extraction fields were considered: Authors of the study (first author only), year of publication, name of the journal, country of origin of the study, objective/aim/ purpose of the study, study population, sample size, type and source of collagen, administration route, outcome(s) of interest, study design, brief description of the methodology of the study, duration of the study, outcomes measurement tools, key findings of the study, limitation(s) of the study according to the authors, conclu-sion(s) of authors, aeras of uncertainty and future direction of research (perspectives), as suggested by the authors.
In the case of missing important information in the published articles, the authors were contacted by e-mail to get the missing data. Because of time constraints, we defined a deadline of a week, after having sent the e-mail, for receiving missing data from authors, after which the missing data were considered as ‘‘unavailable data’’.
Critical Appraisal of Individual Sources of Evidence
As explained by Arksey and O’Malley [38], and further outlined in the guideline developed by the Joanna Briggs Institute for conducting scoping reviews [37], a formal assessment of the methodological quality or risk of bias of the included studies was not performed. Indeed, this is out of the scope of scoping reviews. Synthesis of Results
We created a PRISMA flow chart of study selec-tion to report the studies selecselec-tion process with the number of included and excluded studies at each step of the selection; specific numbers with
reasons of full texts exclusions were explicitly reported in the flow chart. The key information from each article, as described in the data items section, were reported in tables summarizing the main characteristics and findings of the included studies. Preclinical studies and clinical studies were described separately to ease understanding, given that these two kinds of research papers do not necessary report the same type of key information.
We used a narrative approach to report information from the included studies, in addition to the summary provided in tables, with no attempt to aggregate findings from various studies, as this is not the aim of a scoping review. We presented numerical and/or graphical syntheses of the extent, nature, and distribution of the different types of studies retrieved from our literature search, using methods of descriptive statistics. Where appro-priate, graphical representations were preferred to visualize various aspects related to the research activity on the effects of collagen derivatives on articular cartilage and OA, using the STATA and Microsoft Excel software. We used choropleth world maps (drawn using Microsoft Excel 2019) to show the geographical distribution of studies, trend graphs to visualize the trends in publications on collagen deriva-tives over time, and a bar diagram to depict the relative frequency of each specific type of study.
RESULTS
Literature SearchOur electronic databases search yielded 10,825 records, and nine additional records were iden-tified through manual search and clinical trials registries search. After duplicates were removed, 9405 records were screened based on title and abstracts. This primary screening led to 99 full texts that were assessed against the eligibility criteria. Ultimately, 48 studies were included in the scoping review. All the detailed review process and reasons for full-text exclusions with numbers of excluded full texts are shown in Fig.1.
Description of Evidence on Collagen Derivatives in OA and Cartilage Repair Types of Studies
A total of 41 studies have been published on collagen derivatives in OA and cartilage repair so far. Sixteen of these studies were preclinical in vitro and in vivo studies [25,26,41–54] and 25 were clinical studies (including clinical trials, observational studies, and systematic reviews/ meta-analyses) [27, 28, 31, 55–76]. Figure2
depicts the distribution of the studies by specific study type. The most published studies are clinical trials (15 publications), followed by in vivo preclinical studies (12 publications). There are currently four published in vitro studies on effects of collagen derivatives on cartilage, six observational studies, and four systematic reviews/meta-analyses that have
assessed the symptomatic effects of collagen derivatives in OA patients.
We identified seven studies registered in clinical trial registries, of which five were reported as completed; however, we were unable to find any article reporting the results of these studies. For one of the studies identified in clinical trial registries, the recruitment status was reported as unknown; the other one was reported as recruiting (see Table S1 in the elec-tronic supplementary material for details). Trends in Publication of Evidence
To visualize the trends in publication of studies on collagen derivatives in OA and cartilage repair over time, we plotted the number of studies published by year against the years of publications. Figure3shows the trends in total publication of studies (overall preclinical and Fig. 1 PRISMA flow diagram of the scoping review
clinical studies), as well as the comparative trends in publication of preclinical and clinical studies (including systematic reviews/meta-analyses), beginning from the year of the first published study (2002) to the year of the last published study (2019), at the date of our liter-ature search (February 28, 2020).
As shown by that figure, very few studies were published before 2009 (four studies in total), with an increase in publications from 2009. It is remarkable that at least one study was published by year since 2009, with picks in publications in 2009 (five studies) and 2019 (six studies). After variations in numbers of total Fig. 2 Distribution of published studies on collagen derivatives for osteoarthritis and cartilage repair, by study type
Fig. 3 Trends in publication of studies on collagen derivatives for osteoarthritis and cartilage repair [the top figure is about total publications (a) and the second
figure compares trends in publication of preclinical and clinical studies (b), including systematic reviews and meta-analyses)
publications by year, a slight tendency to a progressive increase is observed since 2016. The comparison of the trends in publications of preclinical studies to that of clinical studies shows important fluctuations in annual publi-cations of each of the two types of research. Geographical Distribution of Studies
The geographical distribution of publications is shown on choropleth world maps (Fig.4), with numbers of studies by country proportionate to color intensity: the darker the color, the higher the value. For all preclinical studies, the study country is the country of the research center in which the study was conducted. For clinical studies, the study country is the country of the leading author of the publication, which sometimes is not the country in which the study was conducted (i.e., patient recruitment country for clinical trials).
As can be seen in Fig.4, most of the studies originate from Asia. Very few preclinical studies have been conducted in European countries (three studies) and in USA (two studies). In fact, most of these studies originated from Japan (six studies) and China (three studies). Clinical studies are rather better distributed across the world, with eight studies from European coun-tries (including two systematic reviews/meta-analyses), two from Turkey, three from the USA, and seven from Asian countries (four studies from India). An important note is that none of
the identified clinical studies originated from Japan, which concentrates the highest number of preclinical studies.
Synthesis of Evidence on Collagen Derivatives
Preclinical Studies
Four in vitro studies have evaluated the effects of collagen from different sources and of dif-ferent molecular weights on articular cartilage explants (Table1). All these studies investigated collagen hydrolysate (CH). Cartilage metabo-lism and degradation outcomes, as well as levels of various inflammatory mediators, were mea-sured. Three of these studies, assessing different preparations of CH, from different sources and with different molecular weights, found that CH was either ineffective or detrimental to articular cartilage in pathological condition [41, 43, 44], suggesting that collagen prepara-tions from various sources might have different peptide composition and differ significantly in their effects on articular cartilage (see conclu-sions in Table1). All of these studies advocated for further research in this setting. None of them was supported by pharmaceutical companies.
Our systematic literature search identified 12 in vivo studies assessing the effects of collagen derivatives in different animal models (Table1). Only two of these studies [25, 47] evaluated
Fig. 4 Geographical distribution of studies on collagen derivatives for osteoarthritis and cartilage repair; a preclinical studies and b clinical studies
Table 1 Synthesis of preclinical studies on collagen derivative s in cartilage repair Firs t author (ye ar) C ountry of study ce nter Ob jective of the stud y Anim al model/sa mple size Inter vention /control Admin. route /dosage So urce of colla gen/molecular weight In vitro studies Boonma leerat (2018 ) [ 41 ] Tha iland To inve stigate the effects of diffe rent sizes of fish CH on both physio logica l and pat hologica l conditio ns Porcine articul ar cartilage explants/3 explant pieces, 10 mg each, cultur ed in a 24-well cultur e plate 1) Fish collagen hydrol ysate (FCH) with a M W of \ 3 kDa 2) FCH with a M W of 3–10 kDa 3) FCH with a M W [ 10 kDa vs. Con trol (DMEM ) 100 l g/ml of each collagen fraction (in physio logica l and pathological conditio ns) Fis h (skin and scales of ti lapia fish
[Oreochromis niloticus
]) / 1) \ 3k D a 2) 3–10 kDa 3) [ 10 kDa Fu ruzawa- Car balleda (2009 ) [ 42 ] Mex ico To evaluat e the ef fect of polyme rized -col lagen in co-cul tures of cartilage and sy novial tis sue obta ined from patients with knee OA Synov ium and cartilage from five patients with knee OA 60 explants (2 9 15 activ e and control) 1% dialyzed polyme rized -collagen vs. No treatm ent (absen ce of 1% dialyzed polyme rized-col lagen) 0.6 l gm l -1of collagen Por cine (porcine ty pe I dermal col lagen)/NA Schad ow (2013 ) [ 43 ] G ermany To evaluat e for the first time whether diffe rent bovine CH prepar ations ind eed mo dulate the me taboli sm of col lagen and pro teoglyca ns from huma n O A cartilage expl ants and determined the che mical com position of ol igopeptid es representing col lagen fragments Articul ar cartilage of OA patients/ Coll agen biosyn thesis experiments: N = 12; Ca rtilage degrad ation experiments: N =5 ; N =6 Collagen hydrolys ates (3 different prepar ations – RDH; RDH-N; CH-Al pha –) / Un treated expl ants (controls ) 0–10 mg/ml collagen hydrolysa tes B ovine origin/ 1) RDH (3,500 Da) 2) RDH-N (3, 250 Da) 3) CH-A lpha (3,300 Da )
Table 1 continued First author (ye ar) C ountry of study ce nter Ob jective of the stud y Anima l model/sample size Interve ntion/c ontrol A dmin. route/d osage So urce of colla gen/molecular weight Schad ow (2017 ) [ 44 ] G ermany To analyze com merciall y availabl e fish and po rcine CHs. Spec ifically, to exam ine wheth er these CHs: (a) mod ulate the sy nthesis of type II collagen and inhibit the loss of proteoglycan from human OA kn ee cartilage; (b) affect IL-6 trans-si gnaling and the aggrecanas es and MMP s tha t medi ate the deg radation of cartil age in OA ; and (c) de termine thei r pe ptide com position Articular cartil age of OA patients/ Coll agen biosyn thesis experiments: n = 4–5 Car tilage degradation experiments: n =6 Collagen hydrolysa tes (3 different prepar ations : Mobifor te ; FGH; FGH-N) / Un treated control s from the same joint 0–10 mg/ml CH Porcine or igin/ Mobifort e (3. 120 Da) Fish or igin/ Peptan F 2000 (2. 000 Da) Fish or igin/ Peptan F 5000 (5. 000 Da) In vivo stud ies Bagi (2017 ) [ 25 ] USA To test the ab ility of un denatur ed native chi cken type II collagen administer ed orall y at the time of cartil age inju ry im posed by PMMT to prev ent the exce ssive deteri oration and im prove the heal ing of articul ar cartilage Lewis rats/ 1) P MMT/ UC -II (Activ e): 10 2) P MMT/ vehicl e: 10 3) Na ı¨ve rats (intact control) : 10 4) Sha m surgery: 10 Undenatured nativ e type II collagen (UC-I I) vs 1) Vehic le treatment; 2) In tact control 3) Sha m surgery control (all with no treatm ent) Or al/ 0.66 mg /kg/day Chick en/NA Dai (2018) [ 45 ] China To develop a nov el type II collagen that is cost -effective, non-imm unogenic, and mi ght have an anti-inflamm atory effect on OA .( … ). Finally, rat mod els with surger y-ind uced OA were used to eval uate the OA -relie ving effect of SCII to mimic the mi nimally invasive therapy in clinics Sprague–Dawley (SD ) rats/ 24 male adult rats divided into 4 groups (3 with induced OA, 1 sham group) Squid collagen type II (fo r two ACLT ? pMMx grou ps – different dosages) vs Pho sphate bu ffered saline (sham group and ACLT ? pMMx group) In tra-articular injection/ SCII 3 mg/ml or SCII 10 mg/ml, (100 l l/joint cav ity) once a week, for 5 week s Squ id cartil age/ 110 kDa
Table 1 continued Fi rst author (ye ar) Count ry of stud y center Objective of th e stud y Anim al mo del/sample size Inter vention /contro l Admi n. route /dosage Source of collagen/molec ular weight Da i (2018) [ 26 ] China To eval uate a new ly de veloped squ id type II collagen (SCII) fo r re pairing OA -induced cartilage lesions Male SD rats/18 SD rats, 12 of which received ACLT ? pMMx surger y to induce OA (the other 6 rats re ceived sham surgery) Squ id collagen ty pe II (AC LT ? pMMx ? SCII grou p) vs Phosphat e buffered saline (for sham surgery gro up and ACLT ? pMMx gro up) Intra-articular injection/ 10 mg /ml SCII (100 l l/ joint cavity), once a wee k, for 5 weeks Squid cartilage/ NA Da r (2017 ) [ 46 ] USA To exam ine the impact of orall y administer ed hydrolyzed type 1 collagen (hCol1) in a m odel of posttrau matic OA (PTO A) Male C57B L/6J mi ce/4 grou ps of 6 m ic e each (2 active and 2 contr ol grou ps) Hyd rolyzed type 1 col lagen (incorp orated into hazelnu t cream) vs Haz elnut cr eam vehicle alone (Nu tella ) Oral/ Low do se (LD, 3.8 mg ) or high dose (H D, 38 mg ) hCol1, once dail y Bovine/ 2000 Da Di Cesa re Ma nnelli (2 013) [ 47 ] Italy To eval uate the role of lo w dos es of native type II collagen in the rat mo del of OA induced by sodiu m monoio doac etate (MIA) Male Sprag ue–Dawley rats / 4 grou ps of 12 ani mals eac h Na tive ty pe II collagen vs CM C (vehicl e solutio n) Oral/ 1,3, or 10 mg kg -1collagen daily Porcine H ashida (2003) [ 48 ] Japan To inve stigate the effects of or ally administer ed collagen and gluco samine on cartilage repair Rabb its N = 27; divided into two grou ps of 2-and 3-week experim ental duration G1: 12 G2: 15 Each group was divid ed into sub-groups of 3 rabbits Wat er-solub le collagen (S-co llagen) vs 1) D-gl ucosamine 2) S-collagen ? D-gl ucosamine (CoG grou p) 3) Contro l 4) glycine (onl y for the 3 weeks grou p) Oral/ 8m l of S-collagen pe r day (2.4 g as collagen content). The CoG group had 8 m l of S-col lagen and 1 g of D -glucos amine every day Cocks comb (degraded by proteinase to various si zes of peptide)/ 500, 1000, and 10,000 Da
Table 1 continued Firs t author (ye ar) C ountry of study ce nter Ob jective of the stud y Anim al model/sa mple size Inter vention /control Admin. route /dosage So urce of colla gen/molecular weight Isaka (2017 ) [ 49 ] Ja pan To inve stigate the ef fect of CP on articul ar cartil age in OA by me asuring levels of se rum biomar kers for type II col lagen, (… ), as well as the histo pathol ogical changes occur ring, in experim ental AC LT mo del rats. Add itional ly, the eff ect of CP on ty pe II collagen de gradation and MMP -13 expres sion was inve stigated usin g im munoh istochem ical staining Sprague–Daw ley rats/ To tal: 28, 7 pe r grou p, 4 groups 1) Control group 2) Sham -operated grou p 3) ACLT grou p withou t C P 4) ACLT grou p with CP Collagen peptides (i n standard laborator y diet) vs. Standard laborator y diet withou t collagen peptides (fo r control , sham-operated and AC LT without CP groups) Oral/ 5.0–6 .7 g/kg/day CP (determined ba sed on the body weight and food intake) NA /NA Na katani (2009 ) [ 50 ] Ja pan To exam ine the prote ctive effect of CH and it s specific dipeptid e, Pro-Hyp (prolyl -hydr oxypro line), in relation to prima ry de genera tive articu lar cartilage of mi ce Mice (Ten-week-old mal e C57BL/ 6J mi ce)/ 4 groups of six mice each (total: 24): Collagen hydrol ysate (CH contained approximately 6% Pro-Hyp) in diet/ vs 1) Standard diet 2) Gluten (in die t) 3) Pro-Hyp (i n diet) Oral/ 5g porcine Skin gelatin/ 100 g of diet Por cine skin gelatin/ Av erage molecu lar wei ght of 500 0 D a Na raoka (2013 ) [ 51 ] Ja pan Fir st, to examine the therap eutic eff ects of col lagen tripeptide (Ctp) in rabbit os teoarthritis and, second, to explore a sy nergetic effect with hyaluronan (H A) Female Ja panese white rabbits / Four groups of 18 rabbits each (total: 72) Collagen tripeptid e (Ctp) vs 1) Norma l saline 2) HA 3) Ctp ? HA Intra-articular injection/ 3.0 mg/ml Ctp dissolved in saline; or 3.0 mg/ml Ctp/H A in which Ctp was disso lved in H A solution Fr om gelatin de rived from pig skin conta ining type I and ty pe III col lagen/ NA
Table 1 continued First author (yea r) Coun try of study cente r Ob jective of the study Animal model/sample size Interve ntion/c ontrol A dmin. route/d osage So urce of collag en/mole cular weight Ohara (2010) [ 52 ] Ja pan To study the effects of Pro-Hyp on glyc osamin oglyca ns synthe sis usin g in vitro cu ltured sy novium cells and oral ingest ion of collagen hydrolys ates in a gui nea pig model of OA Dunkin-Ha rtley guinea pigs/ G1: 12 (Distilled water ) G2: 12 (fish scale type I CH) G3: 10 (porcine skin type I CH) Fish sc ale type I collagen hydrolysa tes & Porcine skin type I collagen hydrolysa tes vs. Distil led water Or al/ 0.84 g/kg/ day (5 days pe r wee k) Fish scale & porcine skin / NA Ohnis hi (2013 ) [ 53 ] Ja pan To inves tigate the corr elation between OA severity and concent ration of serum bioma rkers such as keratan sulfate (KS), hyal uronic acid (H A), and chondr oitin sulfate (CS) 846 epit ope. To re search the eff ect of gluco samine and fish collagen pe ptide (FCP) on ACLT in rabbits . T o assess the cor relations between serum bioma rkers and histo logical findin gs Rabbits (female Japanese albino)/ 4 grou ps of 3 rabb its eac h Fish col lagen peptides (F CP) vs. 1) Tap water (c ontrol) 2) G lucosamine 3) FCP and gluco samine Or al/ 1.0 g of powdered FCP/ day or 1.0 g of FCP and 1.0 g of gluco samine daily Fish collagen pe ptides (FCP) from skins of Gadiformes spec ies/ Average molecu lar wei ght of 3000 Da Xu (2007 ) [ 54 ] China To explor e therap eutic ef fects of oral chick en col lagen type II (CC II) on rat OA and anal yze concom itant changes in the level of MMP -13, MMP -9, cathepsin K and thei r mRN A level as well as tissue inhibito r of matrix me tallopro teinase (TI MP)1 mRNA level in articu lar cartilage of osteoa rthritic rats Wistar rats/ To tal: 132 G1: 36 (OA rats —placebo) G2: 24 (Collagen 20 l g/day) G3: 24 (Collagen 80 l g/day) G4: 24 (Excipient) G5: 24 (Rat s without OA — placebo ) Chicken collagen ty pe II (CC II) vs. 1) Placeb o (saline solution) 2) E xcipient (0.25% manni tol) Or al/ 20 l g/day (0. 002% CCII solutio n 1 ml) or 80 l g/day (0. 008% CCII solutio n 1 ml) Chick en/ NA
Table 1 continued First author (ye ar) Br and nam e (man ufacture r) Fund ing sourc e o r spons or of the study Treatm ent or stud y Duratio n Auth ors’ con clusion Aeras of unc ertainty/f uture dir ections of rese arch, as suggested b y the authors of the publicatio ns In vitro studies Boonma leerat (2018 ) [ 41 ] NA / (Hain an Hu ayan B iotech Co., Ltd. , Hai kou, China ) Tha iland Cente r of E xcellence for In novation in Ch emistry (PERCH -CIC ) for the financial supp ort 28 days All three fractio ns FCH had no effect on cartilage me tabolism in physio logica l condit ion, but smal l and me dium fractio ns had adv erse ef fect on cartilage in path ological conditio n. Tak en together , variou s sizes of FCH sho wed different effects on cartil age me tabolism. Ther efore, diffe rent sizes of FCH play diffe rent role s on cartilage met abolism, espe cially in the pathol ogical conditio n The different sizes of FCH had diffe rent effects on gene and protein expres sion in both physio logica l and pathological studies on the cho ndrocyte me tabolism. Their ability to indu ce cellular si gnaling is an interesting area for inve stigatio n Furuza wa-Car balleda (2009 ) [ 42 ] NA Supp orted by grants from The National Counc il of Sc ience and Technology 7 days The add ition of polyme rized-t ype I collagen to cartilage and synov ial tissue co-cul tures induced up-regul ation of cho ndrocytes proliferation and cartil age extra cellular matrix prote ins productio n (COM P, type II collagen and pro teoglyca ns) as well as an anti-infl ammatory cytokine (IL-10) and the do wn-mod ulation of pro-infl ammatory cytokines (IL-1 b and TN F-a ). It is poss ible that this me chanism mi ght contrib ute to indu ce tissue regenera tion and down -regula tion of inflamm ation in OA NA
Table 1 continued Firs t autho r (ye ar) Br and nam e (man ufacture r) Funding sou rce or sp onsor of the study T reatmen t o r stud y Duration Auth ors’ conclus ion Aer as of unc ertain ty/future direc tions of resea rch, as suggested b y the authors of the publ ications Sc hadow (2013 ) [ 43 ] RD H, Pept an TM B 500 0 & RD H-N, Pep tan TM B 2000 (Ro usselot SAS, Pute aux, France); CH-Al pha (Gelita Hea lth Prod ucts G mbH, Eber bach, G ermany) Support ed in part by a grant of the DRB-Fou ndatio n. No additional external funding receiv ed for this study Coll agen biosyn thesis: 24 h Cart ilage de gradation in the ab sence of 5. 0 ng/ml IL-1 b : 6 days; In the presen ce of IL-1 b and NO: 3 days Our study has cle arly elabo rated for the first ti me that CHs fro m var ious sourc es differ significantly with respec t to both their chem ical compositio n of ol igopeptid es representing collagen fragments as well as thei r effects on hum an articu lar cartilage. Since marked effects on hum an chond rocytes were observed , de pending on the CHs prepa ration investi gated, our in vitro study indica tes tha t CHs used as nutraceut icals might be eith er ineffective or even detrimental to OA cartilage Meta bolized collagen fragments or other collagen hydrolys ate prepa ration s might conta in therap euticall y useful pe ptides. Thu s, thei r biomedic al pro pertie s have to be studied tho roughly both in vitro and in animal as well as clinica ltrials before being applied as safe and effective nutraceu ticals in patients Sc hadow (2017 ) [ 44 ] Mob iforte (Astr id Twa rdy GmbH, Un terfo ¨hring , G ermany) FGH, Pept an F 500 0; & FGH-N, Peptan F 200 0 (Roussel ot SAS, Puteaux, Fr ance) Support ed in part by a grant from the DRB fou ndation, Europe an Structu ral Funds Grant 26,220, 220,005 and VEGA Agency Grant 2/014 5/17 Coll agen sy nthesis: 24 h Cart ilage de gradation: 6 days Based on our cu rrent and earl ier [Scha dow, 201 3] in vitro findin gs, we conclud e that: (a) the term ‘‘coll agen hydr olysate’ ’i s the generic name of a hete rogeneo us group of nonfibril lating collagenous peptide mixtur es; and (b) CHs do not stimulate type II collagen biosyn thesis in human articular cartil age. Fu rther, due to the high variability in pe ptide compositio n between CH prepa rations, n o effect can be extrapolated from a C H to another mixtu re. Thus, each orally adm inistered CH prepar ation must be carefully anal yzed in vitro and in vivo reg arding pleio tropic effects before this peptide mixtu re can be attes ted to be an effective and safe nutraceut ical for patients The distin ct activities on OA cartil age are attribut ed to the diffe rences of the peptide comp osition , and the extent to which a singl e oligopep tide or a combin atio n of oligopept ides, aggregates, and me tabolized peptides contrib utes in vivo to the majo r com ponents of joint tissues remains to be determined
Table 1 continued Firs t autho r (ye ar) Br and nam e (man ufacture r) Fund ing sourc e o r spons or of th e stud y Treatm ent or stud y Duratio n Auth ors’ con clusion Aer as of uncertain ty/futu re dir ections of rese arch, as sug gested by the autho rs of the pub lications In viv o stud ies B agi (2017 ) [ 25 ] UC-II (Inte rHealth , B enicia, CA ) Supp orted by Pfizer Con sumer Hea lthcare 8 week s Study re sults de monstrate that a cli nically relevant daily dose of UC-I I when appli ed imme diately after injury can impro ve the mech anical fun ction of the injured knee and prevent excessive dete rioration of articul ar cartilage Bet ter addr ess joint fun ctionality and impact of disuse and load bearing on cartilage me tabolism, use of radiol abeled com pound to assess me taboli sm and tissue distrib ution of UC-II and use of adeq uate im munolog ical, histo-chemica l and mole cular methods to add ress som e of the lin gering questions re garding mechanism of actio n of ‘‘slow -acting’ ’ pro duct such as UC-I I Da i (2018 ) [ 45 ] NA (The auth ors, usin g Ca rtilage of Peru squid pro vided by Shang hai Fish eries (Th e authors Re search Ins titute) Supp orted by grants from Nationa l N atural Sc ience Foundation of China, and Sha nghai Sci-Te ch Committee Fou ndatio n 5 week s These data sugge sted that the newly de veloped SCII could not only av oid the immunogeni c risks of collagen derived from terre strial ani mals, but mor e impo rtantly, provide new choice for the control and treatment of OA NA Da i (2018 ) [ 26 ] NA (The auth ors, usin g cartil age of Per u squ id pro vided by Shang hai Fish eries Re search In stitute) Supp orted by grants from Nationa l N atural Sc ience Foundation of China, Shangh ai Sc i-Tech Committee Foundation-Pujiang Pr ogram, and Na tional Key Research and Dev elopme nt Progr am of China 5 week s Our findin gs show that SCII immunomod ulates M2 activation of macroph ages to skew the local OA micr oenvironm ent towards a pro -chond rogenic atmosph ere, and pro motes cartilage repair under inflammatory conditio n. It shows great po tential for SCII to be a nov el biomat erial fo r cartil age repair in OA NA
Table 1 continued Firs t autho r (ye ar) Brand nam e (manufac turer) Funding sourc e o r sp onsor of the study Treatm ent or stud y Duratio n Auth ors’ con clusion Aer as of uncertain ty/futu re dir ections of rese arch, as suggest ed by the authors of the pub lications Da r (2017 ) [ 46 ] Peptan B200 0, Rousselo t Supported by Rousse lot B VBA, and grants from NI H/NIAM S 16 week s Ove rall, these results suggest that hCol 1 is cho ndropro tective and anti-inflamma tory in po sttraumatic OA, se tting the stage for further me chanistic study and eval uation of joint struct ural mod ificatio ns and potent ial disease-mo difying effect s in a human cli nical trial An open ques tion that is yet to be answered for hCol 1 and other nutraceutica ls that are purp orted to be joint pro tective ,including type 2 collagen-based preparations, glucosamine and cho ndroitin sulfate, re lates to thei r m echanism of actio n Di Cesa re Ma nnelli (2013 ) [ 47 ] NA (Bioibe rica, Spain) Funded by the Italian Ministry of In structio n, University and Re search and by the University of Flo rence 13 days These results de scribe the preclinical efficacy of lo w dos ages of native type II col lagen as pain re liever by a mechanism that involves a pro tective effect on cartil age This evidence hig hlights the interest fo r further inve stigatio n about the mechanism of low dose collagen and its relevance in osteoar thritis thera py Hash ida (2003 ) [ 48 ] (Nippon H am Packers, CO., Toky o) NA 2 and 3wee ks G lcN and the collagen peptides were effective not onl y for cartilage damage repair, but also fo r incr easing norm al cartilage prote oglycan and glyc osamin o-glycan content. Thes e eff ects were not obser ved for the administr ation of D-gl ucose, and only a partial effect was observ ed fo r glycine, which is the main com ponent amino acid of the collagen pe ptides. Simul taneous administr ation of col lagen and GlcN gav e a fairl y enhanced heal ing on restor ation of cartil age injur ies Fu rther inve stigatio n is re quired to dete rmine the effect of each amino acid of collagen on cartil age re pair Isak a (2017) [ 49 ] NA/ (Nitt a Gelat in, Inc., Os aka, Japan) Supported in part by a grant from the Stra tegic Research Fou ndatio n Grant-aided Pr oject for Privat e Universities from Ministr y of Education, Cul ture, Spo rt, Sc ience and Technology, Japan 8 wee ks The re sults of the presen t study sugge st that CP has the po tential to exert cho ndroprot ective actio n on O A by inhibiting MMP -13 expr ession and type II collagen degeneration Fu rther studies inve stigating the components of CP, such as Pro-Hyp ,are requ ired to eluci date the detailed mech anism behind the benefi cial effect of CP on joint health
Table
1
continued
First author (yea
r) Brand name (manu facturer) Fund ing sourc e o r spons or of the stud y Trea tment or stud y Durat ion A uthors’ conclus ion Aeras of uncertain ty/future dir ections of research, as suggest ed by the authors of the publicatio ns Nakatani (2009 ) [ 50 ] NA / (N itta Gelatin; Osaka, Japan) NA 3 wee ks This study im plies that the bioactiv e pe ptide, Pr o-Hyp, is deri ved not only from collagen in living tis sues but also from dietary supp lemen ts such as gelatin, and that it fun ctions in target ti ssues Further studies are necessary to inve stigate the ef fects of CH supplements. Als o, unde rstanding the mech anism of actio n of CH on chondrocyte different iation would provide a ration al basis fo r the development of chondr oprotectiv e therap ies for damaged joints Naraoka (2013 ) [ 51 ] NA / (Cent ral Research Insti tute, Jellice Corp.; Send ai, Japan) NA 15 wee ks P eriodical injections of Ctp and Ctp/HA delayed progr ession of cartil age de generation of early osteoa rthritis indu ced by anterior cr uciate ligament trans ection in rabbits . This effect appears to be exerted by promo tion of type II collagen synthesis predo mi nantly Further exam ination is needed to determine the optimal do se, frequency and dura tion of Ctp injection thera py for the OA knee, ba sed on in vitro studies and several additional in vivo studies Ohara (2010 ) [ 52 ] NA / (N itta Gelatin, Osaka, Japan) NA 4 wee ks Thes e results sugge st that food-d erived Hyp -containing pe ptides can affect the PGs and morpho logical changes assoc iated with ost eoarthritic cartilage, which mi ght be medi ated by stimulation of hyaluronic acid pro ductio n in the synoviu m NA Ohnis hi (2013 ) [ 53 ] NA / (Y aizu Suisank agaku Industr y Co., Ltd., Shizuo ka, Japan) NA 4 wee ks Fr om our present results, oral administ ration of FCP and/ or gluco samine effect ively controll ed cartilage deg radation in an AC LT mod el. E stimation of variou s biomar kers for arthr itis will be useful for assessing the progr ession of cartilaginous de gradation; in this presen t study, the de tected level s of H A and CS 846 correl ated with the histo logica l findin gs, sugge sting that es timatio n of H A and CS 846 might be useful for monitor ing OA pro gress ion. How ever, there were no signifi cant differences betw een the control and treat ment grou p conce ntrations These results indica te that there are individua l diffe rences fo r each biomark er; therefore, a longer-ter m experim ent sho uld be conducted to evaluate the si gnificance of the biomar kers in the ACLT mod el. Our re sults indica te the possibil ity that the measured concent rations of biomark ers can be used in addition to histolo gical finding s to evaluat e cartilage injury
undenatured collagen (UC), also known as native collagen. The other ten studies investi-gated collagen hydrolysate (CH); two of them used atelocollagen, administered by intra-artic-ular injection [26, 45]. The two studies on UC used different rat models of OA, different dosages of orally administered collagen (see Table 1), and measured different outcomes [25, 47]. In Bagi et al. [25], the endpoints included the weight-bearing capacity of front and hind legs, serum biomarkers of bone and cartilage metabolism, analyses of subchondral and cancellous bone at the tibial epiphysis and metaphysis, cartilage pathology at the medial tibial plateau using histological methods, and the presence of possible fractures or other bone abnormalities. In the study by Di Cesare Man-nelli et al. [47], the following outcomes were measured: The decrease of articular pain, pos-tural unbalance measured as hind-limb weight-bearing alterations, motor activity, cartilage degradation measured by the decrease of plasma and urine levels of cross-linked C-telopeptide of type II collagen (CTX-II). Although these two studies did not consider the same outcomes, they all concluded that UC have protective effect on articular cartilage. Likewise, the stud-ies on CH, investigating collagen from various sources and at different dosages, all concluded that this compound has a chondroprotective effect.
Clinical Studies
All the retrieved clinical trials and observational studies were designed to assess the efficacy and/ or safety of collagen derivatives in OA patients. The main characteristics and findings of these studies are summarized in Table2. Almost all of these studies included patients with knee OA; only one RCT [67] and two observational stud-ies [74,75] included patients with hand, hip, or knee OA. The clinical trials investigated UC and CH, and there were more RCTs on CH than on UC.
Five clinical trials investigated UC, among which only two studies were RCTs against pla-cebo, namely the studies by Stancˇı´k et al. [68] and Lugo et al. [64]. The first study investigated undenatured type I collagen (COL-I), and the second was on undenatured type II collagen
Table
1
continued
First author (year)
Brand nam e (manufac turer) Funding sou rce or sp onsor of the study Treatm ent or stud y Duratio n Auth ors’ con clusion Aeras of unc ertaint y/future directions of rese arch, as suggested b y the authors of the publicatio ns Xu (2007) [54 ] NA/ (Shangh ai inst itute of herbal biolog y, Shanghai, China ) NA 8 week s Oral CC II re duced articul ar cartilage de gradation of osteoa rthritic rats and may pro bably be a pot ent drug can didate for OA treatm ent The exact me chanism by which CCII reduced the OA cartilage damage re mains uncer tain and can not be answ ered within the scope of this study ACLT anterio r cruciate ligament transection, Admi n . administ ration, CH collagen hydrol ysate, CMC 1% carboxy methylcel lulose sodiu m salt , CP collagen peptides, GlcN D -gluco samine, MM P mat rix metalloproteinas e, MW molecu lar weight, NA inform ation not available, OA osteoar thritis, PM MT partial m edial meniscect omy tear, pM Mx partial m edial menis cectomy, SC II squ id type II collagen
Table 2 Synthesis of clinical studies on collagen derivatives in OA patients First author (yea r) Count ry of stud y center Study typ e Target pop ulation Int erventio n/cont rol Administration route/ dosag e Source of collagen/molecular weight Clinical trials Bagchi (2002) [ 55 ] USA Open-l abel pilot stud y Five hum an sub jects with OA or rheuma toid arth ritis Un denatur ed type II collagen (UC-I I)/no contr ol Oral/ daily dose of 10 mg UC-II Chicken/NA Bakilan (2016 ) [ 56 ] Turkey RCT (single -blind -outcome assessors were bl inded) Knee OA patients Na tive type II collagen plu s ace tamino phen (AC ? CII ) vs. ace tamino phen (AC) Oral/ 1500 mg /day of acetaminophen plus 10 mg/da y of native type II collagen Chicken/NA Benito-R uiz (2009 ) [ 57 ] Ecuador RCT (double -blind) Knee OA patients Coll agen hydr olysate vs. Placeb o Oral/ 10 g/day NA/3500 Da Bernard o (2012 ) [ 58 ] Philippine RCT (single blind, open-labeled) Knee OA patients Coll agen hydr olysate vs. standard treat ment usin g oral NSAID s Oral/ 400 mg/caps ule, 3 capsules daily NA/ Crowl ey (2009 ) [ 59 ] Canada RCT (double -blind) Knee OA patients Un denatur ed ty pe II collagen (UC-II ) vs. gluco samine HCl ? CS (G ? C) Oral/ daily dose of 40 mg UC-II containing 10 m g of bioactive un denatured type II collagen NA/NA Furuzaw a-Carba lleda (2009 ) [ 60 ] Mexico RCT (double -blind, placebo -controll ed) Knee OA patients Pol ymerized -collagen (pepsinized or atel opeptid e porcine type I de rmal col lagen) vs. Placeb o Intra-articular (IA ) injection/ 12 IA injections of 2 m l of polyme rized-collagen (16.6 mg of collagen) Porcine /NA Jiang (2014 ) [ 61 ] China RCT (single -center, randomized , dou ble-blind) Knee OA patients Coll agen pe ptides (CP)/ Placeb o (ma ltodextrin) Oral/ 8 g collagen pe ptides daily Bovine origin/ Kumar (2015 ) [ 62 ] India 2 RCT s (doub le-blind): One study with P C P and the second with BCP Knee OA patients 1. Pork skin collagen peptide (P CP) vs. pla cebo 2. Bovi ne bone collagen peptide (BCP) vs. placebo Oral/ 5 g two times daily 1. Pork/N A 2. Bovi ne/NA Lee (2019 ) [ 63 ] Repub lic of Korea RCT (doub le-blind) Patie nts with knee joint pain due to OA , chond romalacia, or other cartilage def ects; Type I ateloco llagen (Bi oColla gen) vs. Placebo Intra-articular/ a 3-m l do se as a si ngle injection Pork/N A
Table 2 continued First author (yea r) Country of study center Study typ e Target pop ulation Int erventio n/control A dministrat ion route/d osage So urce of coll agen/molecular weight Lugo (2016 ) [ 64 ] India RCT (double -blind) Knee OA pat ients Un denatured ty pe II collagen (UC -II) vs. Placeb o vs. G H ? CS Or al/ adaily dose of UC-I I (4 0 mg) Ch icken (Chick en ste rnum cartil age)/NA Marti n Marti n (2016 ) [ 65 ] Italy RCT (double -blind) Knee OA pat ients Coll agen MD-k nee vs. sodiu m hyal uronate (SUPA RTZ ) In tra-articular/ 29 injecta ble ampou les of 2. 0 m l once a wee k, for 5 consecutive weeks Por cine/30 0,000 Da ltons McAl indon (2011 ) [ 66 ] USA RCT (double -blind, pilot trial) Knee OA pat ients Coll agen hydr olysate (CH) vs. Placebo Or al/ 10 g of C H in 10 m l water NA /NA Schau ss (2012 ) [ 67 ] USA RCT (double -blind) Hips and/ or knee OA patients B ioCell Collagen (BCC ), a hydrol yzed chi cken stern al cartilage extract vs. Placeb o Or al/ 2capsu les (1 g) of BCC, 2 ti mes dail y 1 capsu le = 300 mg hydrolyzed col lagen type II ? 100 mg CS ? 50 mg HA Ch icken/ *1.5 -2.5 kDa Stanc ˇı´ k (2012 ) [ 68 ] Slovakia RCT (double -blind) Knee OA pat ients Un denatured ty pe I collagen (COL -I) vs. Placeb o Or al/ 19 8 m g pure lyo philized col lagen type I in capsule B ovine/NA Trc ˇ (2011) [ 69 ] Czech Republic RCT (double -blind) Knee OA pat ients Enzy matic hydrolyzed collagen vs. gluco samine sulphate Or al/ 10 g, once daily NA /NA Observ ational studies Azeem (2019) [ 70 ] India Open-l abel observational study Knee OA pat ients UC-II (undenatured type II collagen)/no contr ol Or al/ dail y capsu le of 40 g of UC-II Obta ined fro m chi cken ste rnum/ NA De Luca (2019 ) [ 71 ] Italy Retros pective study Knee OA pat ients An injectabl e collagen form ulation consist ing of bovine hydrol yzed type I col lagen (Chondr oGrid) / No control In tra-articular injection/ Three 2 m l (4 m g) CG injections, the first two 15 days apart, and the third one 30 days after the second B ovine/ \3k D a
Table 2 continued First author (year) C ountry of study ce nter Study typ e Target population Inter vention /contro l Adm inistratio n route/dosage So urce of colla gen/molecular weight Kilinc (2018 ) [ 72 ] Tur key Prospect ive, single-center ,open-label study (obser vational) Grade 2 to 3 K-L grade knee OA patients Pr omerim (hydrolyzed fish collagen) / No control Oral/ 720 -mg P romerim for the first 15 days after admission, and then 360 mg for the second 15 days Fish /NA Mehra (2019 ) [ 73 ] In dia Non-i nterventional, prospec tive, multicentric real life study Patients with OA of knee Un denatured collagen type II col lagen (UC II) / No control Oral/ 40 mg (which yields 1.2 mg of UC II pe r capsule) pe r day NA /NA Puigd ellivol (2019) [74 ] Spa in Observational, open, multicenter clinical trial with a sing le treatm ent group Knee and/or hip OA patients Nu tritional supplement (hyd rolyzed collagen ? CS ? GS ? devil’s claw ? other com pounds) / No control grou p Oral/ 1 9 3 tablets/ day (500 mg hydrol yzed collagen; 180 mg CS; 140 mg G S; and 50 mg de vil’s claw/tabl et) NA Scarpel lini (2008) [75 ] Ital y Observational retro spective 1-year follow-up study Knee, hand, or hip OA pat ients Gluco samine 100 0 m g ? CS 100 0 m g ? native COLL II par tially hydrol yzed 2 m g (GCC ) vs. Glucosamine 1000 mg ? CS 100 0 m g (GC) Oral/ gluco samine 100 0 m g ? CS 1000 mg ? native COL LII part ially hydrol yzed 2 m g NA /NA
Table 2 continued First author (yea r) Brand nam e (manu facturer) Funding sou rce or spons or of th e study Study duration Sample size Auth ors’ con clusion Aeras of unc ertaint y/future direc tions of research, as sug gested by the authors of th e pub lications Clinical trials Bagchi (2002) [ 55 ] UC-II (InterHealth Nutraceuticals , Benicia, CA) NA 42 days 5 subjects (femal es, ages 58–7 8 years) UC-I I may serve as a novel therap eutic tool in joint infl ammatory conditio ns and sy mptoms of OA and RA NA Bakilan (2016 ) [ 56 ] NA (Bi oiberi ca S.A., Spa in) No funding was receiv ed 3 month s A C ? CII : 20 AC : 19 The re sults of the presen t trial do not show eviden ce that native type II col lagen reduce cartilage de structio n; ho wever, it has been demonst rated tha t native type II collagen is effective in the sympto matic treat ment of patient s with knee OA when used conco mitantl y with acetaminophen NA Benito-R uiz (2009 ) [ 57 ] Colnatu r (Protein SA, Girona , Spain) Funded by Protein, S.A. (Gi rona) 6 month s CH: 126 PCB: 124 CH is safe and eff ective and war rants further consid eration as a food ingred ient The role of CH in patient s with OA and low or high meat intake is wo rthy of further research Ber nardo (2012 ) [ 58 ] Genacol (JCS Pharmaceuticals, Inc.) NA 6 month s CH: 55 NS AIDs: 58 The adm inistratio n of 1200 mg of CH dail y for a pe riod of 6 month s has a beneficial im pact on pain sympto ms and joint funct ion in patients with OA The auth ors ‘‘recomm end extending the dura tion of the observation period in the intake of CH to further study its eff ectivity in impro ving the medial knee joint space of an ost eoarthritic knee’ ’ Crowl ey (2009 ) [ 59 ] UC-II /
InterHealth Nutraceutical, Inc.,
Benicia , C A Support ed by Inter Health Research Cente r, CA 90 days UC-II : 26 G ? C: 26 UC-I I supp lemen tation showed improvement in dail y activit ies sugges ting an improvement in overall quality of life in the patients receiving UC-II NA Furuza wa-Car balleda (2009 ) [ 60 ] NA Support ed by grants from The Nationa l Counc il of Science and Technology 6 month s Collagen: 27 Placeb o: 26 Pol ymerized collagen is safe and effective in the treatm ent of knee OA Cont inuing research is needed to estab lish the potentia l effic acy and increase our un derstanding of the biolog y, phar macolo gy, and pharmacokinet ics of this biodrug
Table 2 continued Firs t autho r (ye ar) Br and nam e (man ufacture r) Fund ing sourc e or sponsor o f the stud y Study duration Sample size A uthors’ conclus ion Aer as of uncertain ty/futu re dir ections of research, as sugg ested by th e authors of th e pub lications Jia ng (2014 ) [ 61 ] Pep tan B 200 0 (Ro usselot) NA 6 month s Collagen peptides : 46 Placebo: 48 The present study demo nstrates a clear beneficial ef fect of CP (P eptan ) treatment on joint pain and function in pat ients with mi ld knee OA. Their safety re cord and de monstr ated abse nce of side effects mak e C P a valuable alt ernative sympto m-mo difying treatment fo r OA. Thus, they presen t a highly useful nutraceu tical to help maintain the qualit y of life during ageing (… ) More inves tigations should be initia ted in future to confi rm the effic acy of CP as a protect ive facto r of cartil age in rand omized, placebo -control led clinica lstudies of bigger scale, and with diver se patient characterist ics (… ). In add ition, mech anistic and biochemi cal paramete rs (e.g., MR I, uCT X-I, uCT X-2) could be assess ed, and eff orts coul d be made to investi gate the pot ential diffe rences betw een CP pro ducts from diffe rent sou rces and diffe rent pro ductio n processes Ku mar (2015 ) [ 62 ] 1. PCP: (Nitt a G elatin Inc., Ja pan) 2. BCP: (Nitta G elatin India Ltd ) NA 13 week s Collagen: 20 Placebo: 10 (for each separate study) The study clearly demons trates tha t both PCP and BCP are ef fective supp lemen ts for the im provement in ove rall phys ical pro blems associated with OA and thereb y help to im prove the quality of life NA Lee (2019 ) [ 63 ] Ca rtiZol (Sewo n Cell ontech, Se oul, Kor ea) NA 24 week s Car tiZol: 101; placebo : 99 The results sho w tha t an intra-articular injection of atel ocollagen effectively all eviates knee pain, as int ended. Ther efore, the intra-a rticular injection of atelocollagen can be consider ed an alternative solutio n to controlling kn ee pain due to OA and diver se cartilage defect s Add itional studies with a longer fol low-up pe riod of at least 24 months may be necessa ry to dete rmine any additional effect of intra-ar ticular injection of ty pe I atelocollagen Lugo (2016 ) [ 64 ] UC-II (Chick Ca rt Inc. , Fort Smith, AR) Spo nsored by In terHealth Nu traceutica ls, In c. Benicia , CA 180 days UC-I I: 63 Placebo: 58 GH ? CS: 65 This study found that UC -II, a n utritiona l ingred ient conta ining unde natured type II collagen, significantly im proved kn ee function in OA subjects by day 180, com pared to placebo and to GC, and was well toler ated Add itional studies that eluci date the mech anism for this supp lement’s actions are war ranted
Table 2 continued First author (yea r) Brand name (man ufacture r) Funding sou rce or sp onsor of the study Study duration Sample size Authors’ conclus ion Aera s o f unc ertaint y/future directions of rese arch , as suggested b y the authors of the publicatio ns Marti n Marti n (2016 ) [ 65 ] MD-K nee (Guna S.p.a., Mil an, Italy ) Funded by Guna S.p.a., Milan, Italy 6 month s MD-K nee: 32 SUPA RTZ : 32 This study sho ws that both preparations exert simi lar clinical effects as assessed through multip le out come measures . MD-K nee is effect ive on kn ee OA sympto ms ove r 6 month s after a 5-weekly injection course, and it is equa lly effective as the reference sodium hyaluronate Further studies are warranted in order to verify whether the sympto matic effect of MD-K nee is assoc iated with a halting of kn ee OA pro gress ion McAl indon (2011 ) [ 66 ] Fortigel (Gelita AG) Funded by Gelita AG 48 week s CH: 15 Placeb o: 15 We have been able to deploy dGEM RIC (dela yed gadolinium enhanced MRI of cartilage) in a pilot clinical trial of a develop mental pro duct for knee OA and have de tected apparent changes in ti bial cartilage proteogl ycan conce ntration within a 6-month observation peri od Limita tions of this stud y prec luded an anal ysis of the relationship of macr oscopic cartilage damage to the dGEM RIC and T2 measures, which are ques tions of interes t that cou ld be add ressed in future approp riately desi gned studies Schau ss (2012 ) [ 67 ] BioC ell Collagen (Bi oCell Tec hnology, Newp ort B each, CA, USA) Funded by
BioCell Technology, Newpor
t Beach, CA , USA 70 days BCC : 40 Placeb o: 40 BioCell Coll agen (BC C) was well tole rated and fou nd to be effective in manag ing OA -associated sympto ms over the study period, thereby improving patient’s activities of daily living. BioC ell Collagen (BCC ) can be considered a potentia l comple ment to curren t O A therapies Further studies are needed to elucidat e how this dietary supp lement delivers its clinica l benefi ts, especially in terms of pot entially reg enerating cartilage. Determining which subpop ulation of OA patients, at wha t do se, is mor e likely to benefi t fro m BCC remains unansw ered Stanc ˇı´ k (2012 ) [ 68 ] Cola fit (Dac om Pharm a s.r.o. , Czec h Repub lic) NA 3 ? 1 month s COL-I : 29 Placeb o: 29 The findin gs of this study ind icate tha t unde natured collagen type I is an effective treatm ent for sympto matic kn ee OA ,even with a remote carry-over effect. In addition, it also has a very good safety profile NA Trc ˇ(2011 ) [ 69 ] Cola tech (NA) NA 3 month s Colat ech :4 7 GS : 46 Colatech has demons trated to be effic ient in impro ving cli nical status in kn ee OA (KOA ) patients , with significant im provement in pain sc ores, functiona l joint statu s and a better quality of life. It demonst rated clinica lly better ef ficacy than GS after 2, 4, 8, and 12 weeks of treatment NA
Table
2
continued
First author (year)
Brand name (manu facture r) Fund ing sourc e o r spons or of the stud y Study durati on Sample size Auth ors’ con clusion Aer as of unc ertain ty/future direc tions of research, as suggest ed by the authors of the pub lications Observa tional stud ies Azeem (2019) [ 70 ] UC-I I (NA) NA 120 days 100 This study showed that UC-II ,a food ingredient conta ining type II un denatured collagen, signifi cantly impro ved knee fun ction in a patient with OA kn ee joint after 120 days of observ atio n Unt il we conduct longer tes ts, it remains an open quest ion wheth er a slow-acting addit ive, such as UC-II, can affect the biomec hanica l condit ion of the knee with OA sufficient to impro ve the knee’s ROM (knee flexio n range) De Luca (2019) [71] Chondr oGrid (CG) , (Bi oteck, Arcugna no, Italy) NA 6 months 20 pat ients Re sults of the presen t stud y (… ) indicate (tha t) CG may be a safe and eff ective adju vant in the treat ment of sympto matic knee OA by intr a-articular injection The overall result s are extremel y pro mising and hig hlight the need for further contr olled prospec tive studies to inve stigate the full extent of the beneficial effects of CG treatm ent and wheth er intra-ar ticular CG injection may be more beneficial than oth er non-phar macolo gical treatments already available in the clinica l pra ctice Kilinc (2018) [ 72 ] NA (NA) No financial suppor t receiv ed 1 month 92 pat ients The re sults of this singl e-center, open-label clinica l stud y de monstrate that Prom erim is a viabl e natur al treatm ent option for treating knee OA NA Mehra (2019) [ 73 ] DUPA CT (W ockhardt Ltd., Mum bai) No fun ding sou rces 90 days 291 patients enrolled Evidence form this Indi an real-life study suggests that UC II is safe and effective in treatment of OA in rou tine clinical practice. Its consu mption is associated with reductio n in pain, sti ffness, and im proved fun ctional mobility of pat ients with OA , which can im prove their quality of life NA Puigdelliv ol (2019) [74 ] Artipotect NA 6 months 130 patients The findin gs de scribed in this pilot stud y sugges t that nu tritiona l supplementation with Artip otect was safe and effective in reducing articu lar pain and impro ving lo comoto r fun ctions and quality of life in ind ividuals with OA Future long-term stud ies with a lar ge sample si ze may be needed to clarify the effect of Artipotect supplementation on locomoto r functions. (… ) Finally, since Artipotect is a comp lex supplement, further studies will be needed to clarify the contrib ution of each component on the effectiveness observ ed
(UC-II). The other three studies on UC investi-gated all type II collagen: The study by Bagchi et al. [55] is a very small pilot study with no control group, associated to an in vitro mecha-nistic exploration study; according to the results from our literature search, this was the very first publication on collagen derivatives in OA and cartilage repair. In all of the five clinical trials on UC, orally administered UC was used (see Table2).
We identified ten clinical trials on CH, three of which used intra-articular CH and seven oral CH. Among the studies on CH, one investigated atelocollagen, which was intra-articularly injected [63]. Contrary to studies on UC, most clinical trials on CH in OA were placebo-con-trolled trials.
Most of the clinical trials on collagen derivatives (UC and CH) were relatively short-term studies (3–6 months), the longest study duration of currently available studies being 11 months (only one study). In addition, it is worth noting that almost all of these studies are of relatively small in size. Despite variations in dosages and sources of collagen, all of these studies on UC and CH concluded on positive effects in OA patients (see Table2for details).
Three major systematic reviews, all with meta-analysis, have evaluated the effects of collagen derivatives in OA patients [27,28,31]. These systematic reviews included different individual studies (Table3), depending on their publication date and their selection criteria. The two latest systematic reviews/meta-analyses [28, 31] concluded on beneficial symptomatic effects of supplementation with collagen derivatives, but all advocated for longer clinical trials in larger populations to establish their therapeutic effects in OA patients.
DISCUSSION
The aim of this study was to systematically review the body of evidence on collagen derivatives in OA and cartilage repair, and describe the nature and trends of current research and research findings in this setting.
Our systematic literature search indicates that there are relatively few studies, both
Table
2
continued
First author (yea
r) Br and nam e (man ufacture r) Fund ing sou rce or sp onsor of the stud y Study duratio n Sample size Auth ors’ con clusion Aeras of unc ertainty /future directions of rese arch, as suggest ed by the autho rs of the publicatio ns Scarpel lini (2008 ) [ 75 ] NA NA 1 year GCC : 57 GC: 47 COLL II could represent a further protect ive facto r in OA cartilage Further studies are necessa ry to confir m the efficacy of COL LII as a prote ctive facto r of O A cartilage, and the potentia l sig nificance of uCTX-I as a further marker to assess the evolution of EOA bone damage CS chond roitin sulfate, COLL II type II collagen, EOA er osive osteoar thritis, GH gluco samine hydroc hloride, HA hyaluro nic acid, NA inform ation not available, RCT randomized control led trial, uC TX-I urin ary C-termina l cros s-linking telopeptides of type I collagen, USA Un ited Stat es of America
