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Nutraceuticals: do they represent a new era in the management of osteoarthritis? – a narrative review from the lessons taken with five products

Open ArchivePublished:November 26, 2010DOI:https://doi.org/10.1016/j.joca.2010.10.017

      Summary

      Objectives

      The aim of this first global systematic review on selected nutraceuticals was to synthesize and evaluate scientific relevant data available in the literature. Evidences that can support health, physiological or functional benefit on osteoarthritis (OA) were gathered and the level of evidence relative to each of these ingredients was highlighted.

      Methodology

      Relevant scientific data (positive or not) regarding OA were searched for five groups of compounds (avocado/soybean unsaponifiables (ASU), n-3 polyunsaturated fatty acids, collagen hydrosylates (CHs), vitamin D, polyphenols) within preclinical (in vitro and in vivo), epidemiological, and clinical studies. The following criteria were evaluated to assess the methodology quality of each study: (1) study question; (2) study population; (3) primary endpoint; (4) study design (randomization, control, blinding, duration of follow up); (5) data analysis and interpretation. A scientific consensus was determined for all studied nutraceuticals to evaluate their efficacy in OA.

      Results

      The studied compounds demonstrated different potencies in preclinical studies. Most of them have demonstrated anti-catabolic and anti-inflammatory effects by various inhibitory activities on different mediators. Vitamin D showed a pro-catabolic effect in vitro and the polyphenol, Genistein, had only anti-inflammatory potency. The evaluation of the clinical data showed that ASU was the only one of the studied ingredients to present a good evidence of efficacy, but the efficient formulation was considered as a drug in some countries. Pycnogenol showed moderate evidence of efficacy, and vitamin D and collagen hydrolysate demonstrated a suggestive evidence of efficacy, whereas curcumin, epigallocatechin-3-gallate (EGCG) and resveratrol had only preclinical evidence of efficacy due to the lack of clinical data. The literature gathered for n-3 PUFA, nobiletin and genistein was insufficient to conclude for their efficacy in OA.

      Conclusion

      Additional data are needed for most of the studied nutraceuticals. Studies of good quality are needed to draw solid conclusions regarding their efficacy but nutraceuticals could represent good alternates for OA management. Their use should be driven by any recommendations.

      Keywords

      Introduction

      Osteoarthritis (OA) is the most prevalent joint disease. It causes pain and disability in a large proportion of the population worldwide. It is considered as the most consequential rheumatic condition in terms of social-economic impacts. The incidence of the disease increases with age. The disease evolves over decades to end by the loss of joint function. In addition, aging patients present various co-morbid conditions that add to the complexity of the treatment of OA patients.
      To date, there is no cure for OA. The only available treatments aim at reducing symptoms, as pain and inflammation, maintain joint mobility and limit the loss of function. The main goals that the ideal OA treatment has to achieve are symptom-modifying effect, reducing pain and inflammation, and structure-modifying effect, sparing joint structure and preventing joint degradation in order to maintain articular function.
      Several guidelines, as the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR) or the Osteoarthritis Research Society International (OARSI) recommendations for the management of knee OA
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.
      • Dieppe P.
      • et al.
      EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
      • Zhang W.
      • Doherty M.
      • Arden N.
      • Bannwarth B.
      • Bijlsma J.
      • Gunther K.P.
      • et al.
      EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      • American College of Rheumatology Subcommittee on Osteoarthritis G
      Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update.
      have been published for OA management. They all recommend both non-pharmacological and pharmacological approaches. The non-pharmacological interventions include education and self-management, regular telephone contact, referral to a physical therapist, aerobic, muscle strengthening and water-based exercises, weight reduction, walking aids, knee braces, footwear and insoles, thermal modalities, transcutaneous electrical nerve stimulation and acupuncture. The pharmacological treatments consist of acetaminophen, cyclooxygenase-2 (COX-2) non-selective and selective oral non-steroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs and capsaicin, intra-articular injections of corticosteroids and hyaluronates, glucosamine and/or chondroitin sulphate, and avocado/soybean unsaponifiables (ASU) for symptom relief; glucosamine sulphate, chondroitin sulphate and diacerein for possible structure-modifying effects and the use of opioid analgesics for the treatment of refractory pain
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis Part III: changes in evidence following systematic cumulative update of research published through.
      . Most of the pharmacological treatments available to relieve OA symptoms present serious adverse events, as the risk of gastro-intestinal or cardiovascular adverse events with NSAIDs.
      Moreover, this disease implies treatment or drug intake for decades, increasing the risk of serious adverse events and the incidence of co-morbidity factors.
      Many efforts have been developed to find a cure to OA that can satisfy all the above-mentioned goals. The perfect drug would be not only able to relieve inflammation and pain but also to slow down, stop or even better prevent disease progression. This would result in the maintenance of joint function, sparing joint structures involved in OA, meaning cartilage, synovial membrane and subchondral bone.
      From the molecular point of view, OA joints are the site of inflammation and catabolism. Many key mediators have been identified in cartilage for both pathways. Inflammation is linked to interleukin (IL)-1β, COX-2 expression and prostaglandin E2 (PGE2) and nitric oxide (NO) production. Catabolism results from an imbalance with anabolism. The synthesis of catabolic enzymes as different matrix metalloproteinases (MMP-1, 3 or -13) or the disintegrin and metalloprotease with thrombospondine motifs (ADAMTS)-4 and -5 (also known as aggrecanases) is increased resulting in the degradation of the main cartilage matrix components (proteoglycan (PG) and type II collagen). In parallel, the synthesis of the matrix components is decreased. Synovial inflammation is directly linked to cartilage degradation. In addition, subchondral bone is the site of strong remodeling processes resulting in bone sclerosis. All these factors produce the loss of the articular integrity and the loss of joint function.
      Indeed, there is a strong necessity for prevention of OA. The first step passes by healthy lifestyle, weight loss and nutrition, with specific nutrients that could help to achieve this goal. Nutraceuticals are good candidates to help patient preventing OA or managing their disease using them as treatment adjuvant.
      Nutraceutical comes from the combination of the words nutrition and pharmaceutical. It corresponds to food or food product that provide health and medical benefits, including prevention and treatment
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      • Kalra E.K.
      Nutraceutical–definition and introduction.
      . By definition and regulatory laws they are devoid of adverse effects.
      Nutraceuticals are good candidates for long-term prevention of chronic disease, such as OA. Many compounds have already been studied and a review by Ameye and Chee
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      has gathered all the scientific data available at that time. There are several emerging alternatives. It is more and more recognized that nutraceuticals could help to maintain bone and joint health. However this is paramount to give a critical point of view to judge the quality of the studies. Nutraceuticals are under minimal and vague regulation. Dietary supplements do not have to be approved by the US Food and Drug Administration (FDA). Nutraceuticals are monitored as dietary supplement within the US and the definition for functional foods varies depending on countries. In Europe the situation is different with an ongoing regulatory reform tightening the existing regulatory framework. Indeed, European Food Safety Authority (EFSA) adopted Regulation 1924/2006 on the use of nutrition and health claims for food in December 2006. This regulation harmonised rules across the European Union (EU) for the use of health or nutritional claims on foodstuffs, which are based on nutrient profiles. One of its key objectives is to ensure that all claims made on food labels in the EU are “clear and substantiated by scientific evidence”. EFSA is responsible for verifying the scientific substantiation of the submitted claims, some of which are currently in use, some of which are proposed by applicants. This information serves as a basis for the European Commission and Member States, which will decide whether to authorize each individual product claim. EFSA started to release opinions in October 2009 on health claims submitted under Article 13 of the regulation, covering so-called generic health claims.
      The aim of this first global systematic review on selected nutraceuticals was to synthesize and evaluate scientific relevant data available in the literature. Evidences that can support health, physiological or functional benefit on OA were gathered and the level of evidence relative to each of these ingredients was highlighted.

      Methodology

      Relevant scientific data (positive or not) regarding OA were searched for five groups of compounds (Table I) within in vitro (Table III), in vivo (Table IV), epidemiological (Table V), and clinical studies (Table VI). The selection of compounds discussed in this paper is arbitrary and was based mainly on the following criteria: amount of emerging science, safety of use, regulatory constrains (Novel Food), natural presence in food. The objective was in the end to identify ingredients that could support joint health, but also that could be authorized in food and would be relevant to be delivered through a food matrix.
      Table IStudied compounds
      • n-3 PUFAs
        • EPA
        • DHA
        • ALA
      • ASU
      • CHs
      • Vitamin D
      • Polyphenols
      Table IIResults of Pubmed data search performance
      CompoundTotal number of publications retrievedTotal number of publications selectedNb of in vitro studiesNb of in vivo studiesNb of observational CTsNb of interventional CTs
      n-3 PUFAs150894212
      ASU59179404
      CHs5172104
      Vitamin D224993150
      Pine bark extract1340004
      Prodelphinidins111000
      Nobiletin1033000
      Genistein57132100
      EGCG8177000
      Resveratrol14665100
      Curcumin2311212000
      Ventol211000
      Quercetin21011000
      Table IIISummary of the in vitro effects of the studied products on OA
      ReferenceProductDose and incubation duration (ID)In vitro modelResults
      n-3 PUFAs
      Curtis et al. 2000
      • Curtis C.L.
      • Hughes C.E.
      • Flannery C.R.
      • Little C.B.
      • Harwood J.L.
      • Caterson B.
      n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation.
      EPA, DHA or ALA10–100 μg/ml

      ID: 8 h
      Bovine chondrocytesDose-dependent reduction of IL-1α induced-aggrecanase expression and activity

      Reduction of IL-1α, TNF-α and COX-2 (with ALA) expression
      Curtis et al. 2002
      • Curtis C.L.
      • Rees S.G.
      • Cramp J.
      • Flannery C.R.
      • Hughes C.E.
      • Little C.B.
      • et al.
      Effects of n-3 fatty acids on cartilage metabolism.
      ALA or EPA10–100 μg/ml

      ID: 24 h
      Human OA cartilage explantsReduction of endogenous and IL-1-induced release of PG metabolites in a dose-dependant manner by n-3 PUFA but not by n-6 PUFA

      Suppression of the endogenous proteolytic activity of aggrecanase and collagenase by n-3 PUFAs

      Suppression of the mRNA expression of ADAMTS, MMP-3 and MMP-13 by n-3 PUFA

      No effect of n-3 PUFA on TIMP-1, -2 and -3
      Curtis et al. 2002
      • Curtis C.L.
      • Rees S.G.
      • Little C.B.
      • Flannery C.R.
      • Hughes C.E.
      • Wilson C.
      • et al.
      Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids.
      EPA or ALA10–300 μg/ml

      24 h pre-treatment with EPA or ALA and 4 days ncubation with IL-1β
      Normal bovine or osteoarthritic human cartilage explants stimulated with IL-1βReduction of IL-1-induced inflammation and catabolism (reduction of GAG release, and of aggrecanase activity, loss of COX-2 and 5-LOX expression) by n-3 PUFA

      No effect of n-3 PUFA on normal tissue homeostasis
      Zainal et al. 2009
      • Zainal Z.
      • Longman A.J.
      • Hurst S.
      • Duggan K.
      • Caterson B.
      • Hughes C.E.
      • et al.
      Relative efficacies of omega-3 polyunsaturated fatty acids in reducing expression of key proteins in a model system for studying osteoarthritis.
      EPA, DHA or ALA2.5–30 μg/ml

      8 h pre-treatment and 4 days incubation with IL-1β
      Normal bovine articular chondrocytes stimulated with IL-1βDemonstration of the chondrocyte ability to incorporate exogenous PUFAs

      Reduction of IL-1b-induced production of cartilage degradating enzyme (agrecanases, MMPs) and inflammatory cytokines

      Inhibition of COX-2 by n-3 PUFAs but not COX-1
      ASU
      Mauviel et al. 1989
      • Mauviel A.
      • Loyau G.
      • Pujol J.P.
      Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1.
      ASU0.1–10 μg/ml

      ID: 24 h and 8–14 days
      Synoviocytes

      Rabbit articular chondrocytes
      No impact of ASU alone on collagen synthesis in synoviocytes and chondrocytes after 24 hInhibition of IL-1β-induced collagen synthesis decrease in synoviocytes after 24 hStimulation of collagen synthesis on articular chondrocytes after 8–14 days
      Mauviel et al. 1991
      • Henrotin Y.
      • Labasse A.
      • Jaspar J.M.
      • De Groote D.
      • Zheng S.X.
      • Guillou B.
      • et al.
      Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes.
      ASU Piascledine®10 μg/ml

      ID: 48 h
      Rabbit articular chondrocytes

      Human rheumatoid synovial cells
      Slight increase of collagen production in both cell types

      Partial inhibition of IL-1β-induced release of collagen in synovial cells and total suppression in chondrocytes
      Henrotin et al. 1998
      • Henrotin Y.E.
      • Sanchez C.
      • Deberg M.A.
      • Piccardi N.
      • Guillou G.B.
      • Msika P.
      • et al.
      Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.
      ASU mixed in three ratios

      1:2 (A1S2)

      2:1 (A2S1)

      1:1 (A2S2)
      10 μg/ml

      ID: 72 h
      Human chondrocytesReduction of the stromelysin (MMP-3), IL-6, IL-8 and PGE2 spontaneous productionDecrease of the collagenase activity in unstimulated and stimulated chondrocytes by A1S2Partial inhibition of IL-1 effects
      Boumediene et al. 1999
      • Henrotin Y.E.
      • Deberg M.A.
      • Crielaard J.M.
      • Piccardi N.
      • Msika P.
      • Sanchez C.
      Avocado/soybean unsaponifiables prevent the inhibitory effect of osteoarthritic subchondral osteoblasts on aggrecan and type II collagen synthesis by chondrocytes.
      ASU10–25 μg/mlBovine articular chondrocytesStimulation of the expression of TGFβ1, TGFβ2, plasminogen activating inhibitor-1 (PAI-1)
      Henrotin et al. 2003
      • Gabay O.
      • Gosset M.
      • Levy A.
      • Salvat C.
      • Sanchez C.
      • Pigenet A.
      • et al.
      Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado-Soybean Unsaponifiables (ASU).
      ASU (A1S2)0.625–40 μg/ml

      ID: 12 days
      Human OA chondrocytes stimulated or not with IL-1βStimulation of aggrecan production and restoration of aggrecan production after IL-1β stimulation

      Decrease of basal and IL-1β-stimulated MMP-3 production

      Weak inhibition of IL-1β –induced TIMP reduction

      Inhibition of basal production of MIP-1β, IL-6, IL-8, NO and PGE2

      Stimulation of TIMP-1 production
      Henrotin et al. 2006

      (abstract)
      • Kawcak C.E.
      • Frisbie D.D.
      • McIlwraith C.W.
      • Werpy N.M.
      • Park R.D.
      Evaluation of avocado and soybean unsaponifiable extracts for treatment of horses with experimentally induced osteoarthritis.
      ASU10 μg/ml

      ID: 72 h
      Human OA chondrocytes co-cultured or not with osteoblasts (obtained from sclerotic (SC) or non-sclerotic (NSC) zones of OA subchondral platePrevention of the inhibitory effects of SC osteoblasts on matrix components by pre-treatment of SC osteoblasts with ASU

      Increase of type II collagen mRNA level in co-culture with ASU-pretreated SC osteoblasts

      No modification of MMP, TIMP-1, TGF-b1, TGF-b3 or iNOS expression and COX-2 mRNA levels in chondrocytes when co-cultured with ASU-pretreated SC osteoblasts
      Au et al. 2007
      • Boumediene K.
      • Felisaz N.
      • Bogdanowicz P.
      • Galera P.
      • Guillou G.B.
      • Pujol J.P.
      Avocado/soya unsaponifiables enhance the expression of transforming growth factor beta1 and beta2 in cultured articular chondrocytes.
      ASU25 μg/ml

      ID: 72 h
      Chondrocytes

      THP-1 monocytes/macrophages
      Reduction of TNF-α, IL-1β, COX-2 and iNOS expression in LPS-stimulated chondrocytes to non-activated control levels

      Reduction of PGE2 production and COX-2 and iNOS expression

      Reduction of TNF-α in LPS-stimulated monocyte/macrophage
      Lippiello et al. 2008
      • Mauviel A.
      • Daireaux M.
      • Hartmann D.J.
      • Galera P.
      • Loyau G.
      • Pujol J.P.
      Effects of unsaponifiable extracts of avocado/soy beans (PIAS) on the production of collagen by cultures of synoviocytes, articular chondrocytes and skin fibroblasts.
      Sterols extracted from three ASU preparations1–10 μg/ml (sterols)

      ID: 48 h
      Bovine chondrocytesUpregulation of non-collagenous protein and collagen synthesis as well as of labelled sulphate uptake

      Inhibition of IL-1-induced MMP-3 activity, PGE2 synthesis and sulphate release
      Gabay et al. 2008
      • Au R.Y.
      • Al-Talib T.K.
      • Au A.Y.
      • Phan P.V.
      • Frondoza C.G.
      Avocado soybean unsaponifiables (ASU) suppress TNF-alpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages.
      ASU10 μg/mlMouse or human chondrocytes stimulated with IL-1b

      Cartilage submitted to a compressive mechanical stress (MS)
      Decrease of MMP-3 and -13 expression and PGE2 synthesis

      Inhibition of the degradation of IκBα and suppression of NF-κB translocation

      Inhibition of Erk 1/2 but no effect on the other IL-1β-induced MAPK
      CH
      Oesser and Seifert, 2003
      • Schunck M.
      • Schulze C.H.
      • Oesser S.
      disparate efficacy of collagen hydrolysate and glucosamine on the extracellular matrix metabolism of articular chondrocytes.
      CH0.5 mg/ml

      ID: 48 h
      Bovine chondrocytesDose-dependant increase of type II collagen secretion

      No increase in type II collagen secretion by native collagens and collagen-free hydrosylate of wheat proteins (used as control)

      No effect on the expression of proteases
      Schunck et al. 2006
      • Oesser S.
      • Proksch E.
      • Schunck M.
      prophylactic treatment with a special collagen hydrosylate decreases cartilage tissue degeneration in the knee joints.
      CH GlucosamineNot provided (NP)Porcine articular chondrocytes Human femoral head chondrocytesIncrease of PG synthesis, aggrecan expression and type II collagen biosynthesis with CH

      No effect of glucosamine on extracellular matrix macromolecules (glucosamine sulphate and hydrochloride)
      Vitamin D
      Tetlow and Woolley, 1999
      • Jefferies D.
      • Farquharson C.
      • Thomson J.
      • Smith W.
      • Seawright E.
      • McCormack H.
      • et al.
      Differences in metabolic parameters and gene expression related to osteochondrosis/osteoarthrosis in pigs fed 25-hydroxyvitamin D3.
      1,25-dihydroxy-vitamine D310−8 M

      ID: 48 h
      Rheumatoid synovial fibroblasts (RSF) stimulated or not with IL-1β

      Human articular chondrocytes stimulated or not with IL-1β
      No effect on spontaneous MMP and PGE2 production by RSF

      Reduction of IL-1β-induced MMP and PGE2 production (up to 50%) by RSF

      Slight reduction of spontaneous MMP-1 and -3 production by chondrocytes

      No effect on IL-1β-induced MMP and PGE2 production and stimulation of IL-1β-induced MMP-3 production by chondrocytes
      Cantatore et al. 2004
      • Goldring M.B.
      • Goldring S.R.
      Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.
      1,25-dihydroxy-vitamine D310−8 M

      ID: 48 h
      Osteoblasts from OA subchondral bone samplesIncreased stimulation of osteoclacin production by maximally damaged Osteoblasts compared to minimally damaged ones
      Tetlow and Woolley, 2001
      • Tetlow L.C.
      • Woolley D.E.
      The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion.
      1,25-dihydroxy-vitamine D310−8 M

      ID: 48 h
      Human articular chondrocytes stimulated with TNF-α or phorbol myristate acetate (PMA)No effect on MMP-1, -9 and PGE2 production

      Upregulation of MMP-3 with or without stimulation with TNF-α or PMA
      Polyphenols
      Ishiwa et al. 2000
      • Lin N.
      • Sato T.
      • Takayama Y.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • et al.
      Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.
      NobiletinNP

      ID: NP
      Rabbit synovial fibroblasts

      Rabbit articular chondrocytes
      Suppression of IL-1-induced MMP-9 mRNA expression and production

      Reduction of IL-1-induced PGE2 production

      No modification of the synthesis of total protein
      Imada et al. 2008
      • Ishiwa J.
      • Sato T.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • Ito A.
      A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.
      Nobiletin16–24 μM

      ID: 24 h
      Normal human synovial fibroblastsSuppression of IL-1β-induced ADAMTS-4 and -5 mRNA expression
      Lin et al. 2003
      • Henrotin Y.
      • Clutterbuck A.L.
      • Allaway D.
      • Lodwig E.M.
      • Harris P.
      • Mathy-Hartert M.
      • et al.
      Biological actions of curcumin on articular chondrocytes.
      Nobiletin6–64 μM

      ID: 24 h
      Normal human synovial fibroblastsSuppression of IL-1β-induced production of PGE2 in a dose-dependant manner

      Selective downregulation of COX-2 but not COX-1 mRNA expression

      Downregulation of IL-1β-induced gene expression and production of pro-MMP-1 and pro-MMP-3

      Increased production of the endogenous MMP inhibitor, TIMP-1
      Williamson et al. 2006 (abstract)
      • Clutterbuck A.L.
      • Mobasheri A.
      • Shakibaei M.
      • Allaway D.
      • Harris P.
      Interleukin-1beta-induced extracellular matrix degradation and glycosaminoglycan release is inhibited by curcumin in an explant model of cartilage inflammation.
      Resveratrol and/or Curcumin2.5 μM

      ID: 5 days
      LPS-stimulated canine cartilage explantsDecrease of GAG release by curcumin alone and in combination with resveratrol
      Lev-Ari et al. 2006
      • Kulkarni R.R.
      • Patki P.S.
      • Jog V.P.
      • Gandage S.G.
      • Patwardhan B.
      Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study.
      Curcumin0–20 μM

      ID: 72 h
      OA synovial adherent cellsIncreased inhibitory effect of celecoxib on COX-2 activity

      Stimulation of the growth-inhibitory and anti-apoptotic effects of celecoxib
      Schulze-Tanzil et al. 2004
      • Shakibaei M.
      • John T.
      • Schulze-Tanzil G.
      • Lehmann I.
      • Mobasheri A.
      Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
      Curcumin50 μM

      ID: 12–48 h
      Human chondrocytes stimulated with IL-1βPrevention of IL-1β-induced MMP-3 upregulation

      Inhibition of IL-1β-induced-type II collagen synthesis suppression

      Prevention of NF-κB translocation
      Shakibaei et al. 2005
      • Toegel S.
      • Wu S.Q.
      • Piana C.
      • Unger F.M.
      • Wirth M.
      • Goldring M.B.
      • et al.
      Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes.
      Curcumin50 μM

      ID: 5–30 min
      Human articular chondrocytesAnti-apoptotic and anti-catabolic effects on IL-1β-stimulated chondrocytes
      Liacini et al. 2003
      • Schulze-Tanzil G.
      • Mobasheri A.
      • Sendzik J.
      • John T.
      • Shakibaei M.
      Effects of curcumin (diferuloylmethane) on nuclear factor kappaB signaling in interleukin-1beta-stimulated chondrocytes.
      Curcumin10–15 μM

      ID: 24 h
      Human OA chondrocytesInhibition of TNF-α-induced MMP-13 gene expression
      Shakibaei et al. 2007
      • Shakibaei M.
      • Schulze-Tanzil G.
      • John T.
      • Mobasheri A.
      Curcumin protects human chondrocytes from IL-l1beta-induced inhibition of collagen type II and beta1-integrin expression and activation of caspase-3: an immunomorphological study.
      Curcumin50 μM

      ID: 72 h
      Human articular chondrocytes stimulated with IL-1βSuppression of NF-κB mediated IL-1b or TNF-a catabolic signalling pathways resulting in COX-2 and MMP-9 downregulation and type II collagen upregulation
      Toegel et al. 2008
      • Williamson S.M.
      • Mobasheri A.
      • Vaughan-Thomas A.
      • Thompson N.J.
      • Shakibaei M.
      Curcumin and resveratrol reduce lipopolysaccharide mediated glycosaminoglycan release in an explant model of canine articular cartilage.
      Curcumin5–50 μM

      ID: 24–48 h
      Immortalized human chondrocytes (C-28/I2) stimulated with IL-1βNo effect on aggrecan and type I and II collagen gene expression, proliferation and morphology at low concentrations

      Cell damages at high concentrations (reduction of cell viability)

      Increase of type II collagen, MMP-3 and ADAMTS-4 expression and decrease of type I collagen expression with high concentrations
      Clutterbuck et al. 2008 (abstract)
      • Mathy-Hartert M.
      • Jacquemond-Collet I.
      • Priem F.
      • Sanchez C.
      • Lambert C.
      • Henrotin Y.
      Curcumin inhibits pro-inflammatory mediators and metalloproteinase-3 production by chondrocytes.
      Curcumin25–100 μM

      ID: 5 days
      Equine cartilage explants stimulated with IL-1βReduction of IL-1β-induced GAG release (50–100 μM)

      Decrease of PGE2 release (25–100 μM)
      Clutterbuck et al. 2009
      • Mathy M.
      • Sanchez C.
      • Priem F.
      • Henrotin Y.
      Curcumin inhibits interleukin-6, -8, nitric oxide and prostaglandin E2 synthesis by bovine chondrocytes.
      Curcumin0.1–100 μM

      ID: 5 days
      Equine cartilage explants stimulated with IL-1βSuppression of IL-1β-induced GAG release
      Mathy et al. 2007 (abstract)
      • Clutterbuck A.L.
      • Mobasheri A.
      • Rogers T.C.
      • Wiseman J.
      • Allaway D.
      • Harris P.
      Curcumin (diferuloylmethane) blocks il-1 beta stimulated glycosaminoglycan and prostaglandin e2 release from cartilage explants in an in vitro model of osteoarthritis.
      Curcumin1–30 μM

      ID: 24 h
      Primary bovine chondrocytes stimulated with IL-1βNo effect on cell viability

      Dose-dependant inhibition of IL-1β-induced COX-2, iNOS, IL-6 and IL-8 gene expression, PGE2 and NO production
      Chowdhury et al. 2008
      • Lev-Ari S.
      • Strier L.
      • Kazanov D.
      • Elkayam O.
      • Lichtenberg D.
      • Caspi D.
      • et al.
      Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells.
      Curcumin0.01–1000 ng/ml

      ID: 48 h
      Bovine chondrocytes cultured in agaroseInhibition of IL-1β-induced NO and PGE2 release

      Inhibition of 35SO4 incorporation
      Mathy-Hartert et al. 2009
      • Chowdhury T.T.
      • Salter D.M.
      • Bader D.L.
      • Lee D.A.
      Signal transduction pathways involving p38 MAPK, JNK, NFkappaB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression.
      Curcumin5–20 μM

      ID: 12 days
      Human articular chondrocytes in alginate beads and human cartilage explants stimulated with IL-1βNo effect on cell viability

      Dose-dependent reduction of the synthesis of inflammatory mediators (NO, PGE2, IL-6, IL-8) and catabolic factor (MMP-3)
      Claassen et al. 2008
      • Hooshmand S.
      • Soung do Y.
      • Lucas E.A.
      • Madihally S.V.
      • Levenson C.W.
      • Arjmandi B.H.
      Genistein reduces the production of proinflammatory molecules in human chondrocytes.
      Genistein10−11–10−4 M

      ID: 24 h(for incubation or preincubation)
      Foetal bovine articular chondrocytesNo effect on GAG release within the physiological range of concentrations

      Decrease of GAG release with high doses (10−5–10−4 M)

      No effect on sulphate incorporation by chondrocytes

      Preincubation with 10−9–10−5 M enhanced the stimulatory effect of insulin on sulphate incorporation by chondrocytes
      Hooshmand et al. 2007
      • Ham K.D.
      • Oegema T.R.
      • Loeser R.F.
      • Carlson C.S.
      Effects of long-term estrogen replacement therapy on articular cartilage IGFBP-2, IGFBP-3, collagen and proteoglycan levels in ovariectomized cynomolgus monkeys.
      Genistein50–100 mM

      ID: 1 h preincubation+24 h
      Human chondrocytes stimulated by LPSReduction of pro-inflammatory molecules (COX-2 and NO)

      No effect of YKL-40 (marker of cartilage metabolism) or IL-1β levels
      Singh et al. 2002
      • Singh R.
      • Ahmed S.
      • Malemud C.J.
      • Goldberg V.M.
      • Haqqi T.M.
      Epigallocatechin-3-gallate selectively inhibits interleukin-1beta-induced activation of mitogen activated protein kinase subgroup c-Jun N-terminal kinase in human osteoarthritis chondrocytes.
      EGCG1–100 μM

      ID: 30 min preincubation+24 h
      Human OA chondrocytes stimulated with IL-1βInhibition of IL-1β-induced NO production by interfering with NF-κB activation
      Ahmed et al. 2002
      • Singh R.
      • Ahmed S.
      • Islam N.
      • Goldberg V.M.
      • Haqqi T.M.
      Epigallocatechin-3-gallate inhibits interleukin-1beta-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: suppression of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor kappaB.
      EGCG100–200 μM

      ID: 2 h preincubation+24 h or 24 h without preincubation
      Human OA chondrocytes stimulated with IL-1βDose-dependant inhibition of NO and PGE2, iNOS and COX-2 expression
      Singh et al. 2003
      • Tokuda H.
      • Takai S.
      • Hanai Y.
      • Matsushima-Nishiwaki R.
      • Yamauchi J.
      • Harada A.
      • et al.
      (−)-Epigallocatechin gallate inhibits basic fibroblast growth factor-stimulated interleukin-6 synthesis in osteoblasts.
      EGCG5–200 μM ID: 24–48 hHuman OA chondrocytes stimulated with IL-1βSuppression of IL-1β-induced upregulation of catabolic mediators dependant on the activation of c-jun N-terminal kinase (JNK) activation
      Rasheed et al. 2009
      • Ahmed S.
      • Wang N.
      • Lalonde M.
      • Goldberg V.M.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
      EGCG25-200 μM

      ID: 1–2 h pre-treatment with EGCG+4 days treatment with AGE
      Human OA chondrocytes stimulated with AGEInhibition of AGE-induced expression of TNF-α and MMP-13

      Attenuation of the AGE-induced MAP kinase signalling pathways

      Inhibition of NF-κB activation
      Ahmed et al. 2004
      • Haqqi T.M.
      • Anthony D.D.
      • Gupta S.
      • Ahmad N.
      • Lee M.S.
      • Kumar G.K.
      • et al.
      Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea.
      EGCG1–200 μM

      ID: 72 h
      Human cartilage explants and chondrocytesInhibition of IL-1β-induced GAG release from human cartilage explants

      Dose-dependant inhibition of MMP-1 and MMP-13 IL-1β-induced mRNA and protein expression in human chondrocytes

      Dose-dependant inhibition of transcription activity of NF-κB and AP-1
      Tokuda et al. 2008 (abstract)
      • Huang G.S.
      • Tseng C.Y.
      • Lee C.H.
      • Su S.L.
      • Lee H.S.
      Effects of (−)-epigallocatechin-3-gallate on cyclooxygenase 2, PGE(2), and IL-8 expression induced by IL-1beta in human synovial fibroblasts.
      EGCGNPOsteoblast-like MC3T3-E1 cellsInhibition of the fibroblast growth factor (FGF)-2-stimulated synthesis of IL-6 at least in part through the suppression of p44/p42 and the p38 Map kinase pathways
      Huang et al. 2009
      • Rasheed Z.
      • Anbazhagan A.N.
      • Akhtar N.
      • Ramamurthy S.
      • Voss F.R.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes.
      EGCG10–50 μM

      ID: 12 h
      Human synovial fibroblasts stimulated with IL-1βInhibition of IL-1β-induced COX-2 expression and synthesis

      Inhibition of IL-1β-induced PGE2 and IL-8 secretion
      Williamson et al. 2006 (abstract)
      • Clutterbuck A.L.
      • Mobasheri A.
      • Shakibaei M.
      • Allaway D.
      • Harris P.
      Interleukin-1beta-induced extracellular matrix degradation and glycosaminoglycan release is inhibited by curcumin in an explant model of cartilage inflammation.
      Resveratrol and/or Curcumin2.5 μM

      ID: 5 days
      Canine cartilage explants stimulated with LPSDecrease of GAG release by resveratrol alone

      Inhibition of the degradative effects of LPS and decrease of GAG release by co-treatment with resveratrol and curcumin
      Dave et al. 2008
      • Csaki C.
      • Keshishzadeh N.
      • Fischer K.
      • Shakibaei M.
      Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro.
      Resveratrol1–10 μM

      ID: 1 h pre-treatment
      Human OA chondrocytes and cartilage explants stimulated by IL-1βInhibition of IL-1β-induced and spontaneous of PGE2 and LTB4 production, and suppression of COX-2 expression

      Spontaneous stimulation of PG and inhibition of pro-MMP-13

      Prevention of OA cartilage degradation from IL-1β-induced effects

      Prevention of chondrocytes apoptosis
      Csaki et al. 2008
      • Shakibaei M.
      • Csaki C.
      • Nebrich S.
      • Mobasheri A.
      Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis.
      Resveratrol1–200 μM

      ID: 1–24 h
      Human articular chondrocytes stimulated by IL-1βChondroprotective effect through suppression of IL-β-, reactive oxygen species (ROS)- and tumor suppressor protein p53-production
      Shakibaei et al. 2008
      • Lei M.
      • Liu S.Q.
      • Liu Y.L.
      Resveratrol protects bone marrow mesenchymal stem cell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitory effect of interleukin-1beta.
      Resveratrol100 μM

      ID: 4 h (pre-treatment+1–32 h (in combination with IL-1β)
      Human articular chondrocytes stimulated by IL-1βInhibition of IL-1β-induced vascular endothelial growth factor (VEGF), MMP-3, MMP-9 and COX-2

      Suppression of apoptosis and inflammatory signalling by acting on NF-κB
      Lei et al. 2008
      • Elmali N.
      • Baysal O.
      • Harma A.
      • Esenkaya I.
      • Mizrak B.
      Effects of resveratrol in inflammatory arthritis.
      Resveratrol100 μM

      ID: 24 h
      Rat bone marrow mesenchymal stem cells derived chondrocytes stimulated by IL-1β and cultures on chitosan-gelatine scaffolds (CGS)Inhibition of IL-1β-induced downregulation of type II collagen and aggrecan and increased of MMP-13 expression by reducing the translocation of NF-κB

      Spontaneous decrease of type II collagen but no effect on aggrecan and MMP-13 expression
      Garbacki et al. 2002
      • Sato M.
      • Miyazaki T.
      • Kambe F.
      • Maeda K.
      • Seo H.
      Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells.
      Prodelphidins isolated from Ribes nigrum

      Gallocathechin trimer (CG-CG-CG), dimer (CG-CG) or monomer (CG-ECG)
      1–100 μg/ml

      ID: 5 min–12 days
      Human chondrocytesStimulation of PG and type II collagen production by all tested prodelphidins

      Decreased of PGE2 synthesis by all prodelphidins

      Inhibition of COX-2 but not COX-1 by all prodelphidins
      Sato et al. 1997 (abstract)
      • Kang K.
      • Hwang H.J.
      • Hong D.H.
      • Park Y.
      • Kim S.H.
      • Lee B.H.
      • et al.
      Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture.
      QuercetinNPHuman synovial cellsSuppression of TNF-α mediated stimulation of IL-8 and MCP-1 expression, at least in part by inhibiting NF-κB activation
      Kang et al. 2004 (abstract)
      • Anand P.
      • Kunnumakkara A.B.
      • Newman R.A.
      • Aggarwal B.B.
      Bioavailability of curcumin: problems and promises.
      VentolNPCartilage explantsInhibition of IL-1β-induced PG degradation
      IkB: inhibitor of NF-κB.
      Table IVSummary of the in vivo effects of the studied products on OA
      ReferenceProductDose and IDIn vivo modelResults
      n-3 PUFAs
      Lippiello et al., 1990 (abstract)
      • Lippiello L.
      • Fienhold M.
      • Grandjean C.
      Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega-3 fatty acids.
      n-3 PUFA

      (menhaden fish oil)
      Diet with 10% menhaden fish oil

      ID: NP
      Male Sprague–Dawley with a “marginally deficient” essential fatty acid state70% maximum decrease in articular cartilage content of the linoleic and arachidonic acid in the fish oil treated group

      30–40% decrease in cartilage hexosamine content and 32% inhibition of PG synthesis
      Roush et al., 2010
      • Roush J.K.
      • Dodd C.E.
      • Fritsch D.A.
      • Allen T.A.
      • Jewell D.E.
      • Schoenherr W.D.
      • et al.
      Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs.
      n-3 PUFADiet with 31-fold increase of the total omego-3 fatty acids

      ID: 24 weeks
      Client-owned dogs with OA

      N=127
      Significant improvement of dog conditions
      ASU
      Cake et al., 2000
      • Boileau C.
      • Martel-Pelletier J.
      • Caron C.
      • Cheng S.
      • Msika P.
      • Guillou G.B.
      • et al.
      Protective effects of total fraction of avocado/soybean unsaponifiables (ASU) on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and MMP-13.
      ASU900 mg/weekday vs placebo

      ID: 6 months
      Ovine model of knee OA (bilateral lateral meniscectomy)

      N=32
      Reduction of subchondral bone sclerosis and increase of PG content and of articular knee joint thickness
      Altinel et al., 2007
      • Lequesne M.
      • Maheu E.
      • Cadet C.
      • Dreiser R.L.
      Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip.
      ASU300 mg every day or every 3 days

      ID: 3 months
      Sheepdogs

      Control: normal diet

      N=24
      Increase of both TGF-β1 and TGF-β2 levels in knee joint fluid
      Kawcak et al., 2007
      • Altinel L.
      • Saritas Z.K.
      • Kose K.C.
      • Pamuk K.
      • Aksoy Y.
      • Serteser M.
      Treatment with unsaponifiable extracts of avocado and soybean increases TGF-beta1 and TGF-beta2 levels in canine joint fluid.
      ASU (A1:S2)NP

      ID: 70 days
      Experimentally induced OA in horses

      N=16
      No effect on pain and lameness

      Reduction of the severity of cartilage erosion and synovial haemorrhage

      Increase of articular cartilage GAG synthesis
      Boileau et al., 2009
      • Msika P.
      • Baudouin C.
      • Saunois A.
      • Bauer T.
      Avocado/soybean unsaponifiables, ASU EXPANSCIENCEtrade mark, are strictly different from the nutraceutical products claiming ASU appellation.
      ASU10 mg/kg/day

      ID: 8 weeks
      Experimental knee dog modelDecrease of the size of the macroscopic lesions (tibial plateaus) compared to control

      Decrease in the severity of cartilage lesions (tibial plateaus and femoral condyles)

      Decrease in the scores of all histological parameters (structural changes, cellularity, Safranin-O staining and pannus invasion on the femoral condyles)

      No difference on the tibial plateaus for Safranin-O and pannus invasion

      Reduction of iNOS production in cartilage

      Reduction of the total histological changes and cellular infiltration in synovium
      CH
      Oesser et al., 2008 (abstract)
      • Nakatani S.
      • Mano H.
      • Sampei C.
      • Shimizu J.
      • Wada M.
      Chondroprotective effect of the bioactive peptide prolyl-hydroxyproline in mouse articular cartilage in vitro and in vivo.
      CH (Fortigel, Gelita AG)0.15 mg/g of body weight daily

      ID: 4 months
      Male STR/ort (model of naturally occurring OA)

      Control: albumin
      Decrease of cartilage tissue degeneration in knee joints

      Decrease of the incidence of severe joint degradation and in the determinate grade of OA in comparison to the untreated control
      Vitamin D
      Jefferies et al., 2002
      • Lane N.E.
      • Gore L.R.
      • Cummings S.R.
      • Hochberg M.C.
      • Scott J.C.
      • Williams E.N.
      • et al.
      Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group.
      25-hydroxyvitamin D3 supplement0.1 mg/kg/day

      ID: 21 weeks
      Pigs

      N=200

      Control: commercial diet
      No effect on the incidence or severity of OA lesions, articular PG or collagen contents
      Polyphenols
      Ham et al., 2004
      • Ahmed S.
      • Rahman A.
      • Hasnain A.
      • Lalonde M.
      • Goldberg V.M.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes.
      Genistein

      Soy phytoestrogen
      Equivalent of 129 mg/day for women

      ID: 3 years
      Monkey model of naturally occurring OA after ovariectomyNo effect on insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3, total protein, PG or collagen levels in cartilage tissue
      Elmali et al., 2005
      • Garbacki N.
      • Angenot L.
      • Bassleer C.
      • Damas J.
      • Tits M.
      Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity.
      Resveratrol10 μmol/kg

      Intra-articular
      Rabbit model of OA by transaction of the anterior cruciate ligamentProtection against cartilage degradation (histological evaluation)
      Table VSummary of the epidemiological data for the studied products on OA
      ReferenceProductPopulationDesignResults
      n-3 PUFAs
      Wang et al., 2008
      • Wang Y.
      • Wluka A.E.
      • Hodge A.M.
      • English D.R.
      • Giles G.G.
      • O’Sullivan R.
      • et al.
      Effect of fatty acids on bone marrow lesions and knee cartilage in healthy, middle-aged subjects without clinical knee osteoarthritis.
      Different types of fatty acidAustralian healthy middle-aged subjects without clinical knee OA

      Mean y: 58

      N=297
      Cohort

      Y: 10
      Higher intakes of monounsaturated fatty acids, total and n-6 PUFAs associated with increased risk of bone marrow lesions

      No association of n-3 PUFA intake and bone marrow lesions

      No association of fatty acid intake with cartilage volume of defects
      Vitamin D
      McAlindon et al., 1996
      • Radin E.L.
      • Rose R.M.
      Role of subchondral bone in the initiation and progression of cartilage damage.
      Vitamin dietary intake and serum levels of 25-hydroxyvitamin DEnglish patients

      Mean y: 70.3

      N=556
      Cohort

      Y: 9–10
      Modest correlation between serum vitamin D and vitamin D intake

      Increased risk of knee OA progression (global score including joint space narrowing, osteophytosis and sclerosis) for low levels of vitamin D and vitamin D intake

      Association between low vitamin D serum levels and knee loss of cartilage as assessed by joint space and osteophyte growth (disease progression)

      No association between vitamin D intake and serum level of vitamin D and knee OA incidence
      Lane et al., 1999
      • Felson D.T.
      • Niu J.
      • Clancy M.
      • Aliabadi P.
      • Sack B.
      • Guermazi A.
      • et al.
      Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies.
      Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin DAmerican elderly white women

      Y65

      N=237
      Cohort

      Y: 8
      Association between low serum levels of 25-hydroxyvitamin D and radiographic changes for hip OA characterized by joint space narrowing but not osteophyte

      No association between serum 1,25-dihydroxyvitamin D and incident changes of radiographic hip OA
      Felson et al., 2007
      • Ding C.
      • Parameswaran V.
      • Burgess J.
      • Cicuttini F.
      • Jones G.
      Serum level of vitamin d, winter sun exposure knee radiographic osteoarthritis and knee cartilage loss in older adults: the Tasmania Older Adult Cohort (TASOAC) Study.
      Serum levels of 25-hydroxyvitamin DEnglish adults

      Mean y: 53.1

      N=715
      Cohort Y: 9No association between vitamin D levels and structural joint degradation (disease incidence) defined as joint space loss on radiography
      Felson et al., 2007
      • Ding C.
      • Parameswaran V.
      • Burgess J.
      • Cicuttini F.
      • Jones G.
      Serum level of vitamin d, winter sun exposure knee radiographic osteoarthritis and knee cartilage loss in older adults: the Tasmania Older Adult Cohort (TASOAC) Study.
      Serum level of 25-hydroxyvitamin DAmerican adults with knee OA

      Mean y: 66.2

      N=388
      Cohort Y: 9No association between vitamin D levels and structural disease worsening (disease progression) defined as joint space loss on radiography and as cartilage loss on MRI
      Breijawi et al., 2009
      • Tetlow L.C.
      • Woolley D.E.
      Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro.
      Serum levels of 25-hydroxyvitamin DPatients undergoing total hip or knee replacement

      Mean y: 69–70

      N=117
      Cross-sectionHigh prevalence of low vitamin D status in patients with knee OA
      Bergink et al., 2009
      • Breijawi N.
      • Eckardt A.
      • Pitton M.B.
      • Hoelzl A.J.
      • Giesa M.
      • von Stechow D.
      • et al.
      Bone mineral density and vitamin D status in female and male patients with osteoarthritis of the knee or hip.
      Serum levels of 25-hydroxyvitamin DKnee OA patients

      N=1248
      Cohort Y: 6.5 (mean follow up time)Low dietary vitamin D intake the risk of progression of knee OA

      Vitamin D influences the incidence and progression of knee OA more particularly in low BMD patients
      Table VISummary of the clinical data of the studied products on OA
      ReferenceProductDose and intervention duration (ID)PopulationDesignResultsScore (1–14)
      n-3 PUFAs
      Stammers et al., 1992
      • Stammers T.
      • Sibbald B.
      • Freeling P.
      Efficacy of cod liver oil as an adjunct to non-steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice.
      Cod liver oil

      (EPA)
      10 ml (786 mg EPA)/

      dayID: 24 weeks
      English middle-ages and old patients with OA

      Y: 49–87

      N=86
      Double-blind, placebo-controlled trialNo effect on pain and ability compared to olive oil

      (Cod liver oil was used as an adjunct to NSAIDs)
      7
      Cho et al., 2003
      • Cho S.H.
      • Jung Y.B.
      • Seong S.C.
      • Park H.B.
      • Byun K.Y.
      • Lee D.C.
      • et al.
      Clinical efficacy and safety of Lyprinol, a patented extract from New Zealand green-lipped mussel (Perna Canaliculus) in patients with osteoarthritis of the hip and knee: a multicenter 2-month clinical trial.
      Lyprinol® extract from New-Zealand green-lipped mussel rich in n-3 PUFAs (EDA, DHA, DPA)four capsules/day

      ID: 8 weeks
      Korean patients with hip or knee OA

      Y: 40–75

      N=60
      Multicenter open trialImprovement of OA signs and symptoms (pain VAS, joint function LFI)4
      ASU
      Lequesne et al., 2002
      • Appelboom T.
      • Schuermans J.
      • Verbruggen G.
      • Henrotin Y.
      • Reginster J.Y.
      Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.
      Piascledine®300 mg (capsule)

      ID: 2 years
      French patients with regular pain due to primary hip OA

      Y: 50–80

      N=108
      Prospective, multicenter, randomized, parallel group, double-blind, placebo-controlled trialNo structural effect (joint space width) (primary outcome)

      Reduction of the progression of joint space loss in the subgroup with advanced space narrowing (post-hoc analysis)

      No difference for clinical parameters (secondary outcomes) between ASU and placebo groups (LFI, global pain on VAS, NSAID use and patient’s global assessment) over the first year follow up
      11.5
      Appelboom et al., 2001
      • Maheu E.
      • Mazieres B.
      • Valat J.P.
      • Loyau G.
      • Le Loet X.
      • Bourgeois P.
      • et al.
      Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.
      Piascledine®300 or 600 mg

      ID: 3 months
      Belgian patients with primary knee OA under analgesics and/or NSAIDs

      Y:45–80
      Prospective multicenter, double-blind, randomized, parallel group, placebo-controlled trialDecrease of NSAID and analgesic intake (primary outcome), compared to placebo from the first month

      No difference between 300 mg and 600 mg

      Decrease of LFI (improvement noticed from the second month) and pain by VAS
      11
      Maheu et al., 1998
      • Blotman F.
      • Maheu E.
      • Wulwik A.
      • Caspard H.
      • Lopez A.
      Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.
      Piascledine®300 mg (capsule)

      ID: 6 months+2 month post)treatment follow up
      French patients with symptomatic primary hip or knee OA

      Y: 45–75

      N=164
      Prospective, randomized, double-blind, placebo-controlled multicenter trialDecrease of LFI scores (primary outcome) after 6 months, compared to baseline and placebo groups

      Reduction of pain by VAS, overall functional disability and patient’s overall assessment efficacy

      More important improvement in hip OA patients

      No difference in NSAID consumption except for the period ranging from 6 to 8 months

      Beneficial effects measured by LFI, pain by VAS and functional disability started after 2 months (delayed action)

      Prolonged effect of ASU, persisting 2 months after treatment discontinuation
      14
      Blotman et al., 1997 (abstract)
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials.
      Piascledine®300 mg

      ID: 3 months
      French patients with symptomatic knee or hip OA requiring NSAID therapy

      Mean y: 62.9

      N=163
      Prospective, randomized, double-blind, placebo-controlled, parallel-group trialReduction of NSAID consumption (primary outcome)

      Improvement of LFI compared to placebo

      No difference in pain score between ASU and placebo
      CH
      Clark et al., 2008
      • Zuckley L.
      • Angelopoulou K.
      • Carpenter M.S.S.
      • Meredith B.A.
      • Kline G.
      • Rowinski M.
      • et al.
      Collagen hydrosylate improves joint function in adults with mild symptoms of osteoarthritis of the knee.
      CH

      (liquid formulation)
      10 g/day

      ID: 24 weeks
      American physically active healthy adults without degenerative joint disease but with joint pain

      Mean y: 20.1

      N=97
      Prospective, randomized-placebo-controlled, double-blind trial

      Control: xanthan
      Improvement of joint pain, increase of mobility and reduction of dependency to analgesics in patients consuming CH dietary supplement8
      Moskowitz et al., 2000
      • Benito-Ruiz P.
      • Camacho-Zambrano M.M.
      • Carrillo-Arcentales J.N.
      • Mestanza-Peralta M.A.
      • Vallejo-Flores C.A.
      • Vargas-Lopez S.V.
      • et al.
      A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort.
      CH10 g/day

      ID: 24 weeks+8 weeks post-treatment washout
      Patients with knee OA (Germany, UK, US)

      Y: 45–81

      N=389
      Multicenter, prospective, randomized, double-blind, placebo-controlled trialNo statistically significant improvement in Western Ontario and McMaster Universities (WOMAC) pain score, function score and patient global assessment for the total study group

      Pain reduction and functional improvement in German patients but not in global patient evaluation

      Tendency to be more effective in severe OA (post-hoc analysis)
      9
      Zuckley et al., 2004
      • Moskowitz R.W.
      Role of collagen hydrolysate in bone and joint disease.
      CH10 g/day with calcium (300 mg/day) and vitamin C (60 mg/day)

      ID: 14 weeks
      Patients with symptoms of mild knee OAMean y: 57N=190Randomized, double-blind, placebo-controlled trialImprovement of certain strength and work performance tests (improvement of knee functional mobility on isometric and isokinetic testings)

      Greater effects on patients with more severe OA
      Benito-Ruiz et al., 2009
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      CH10 g/day

      ID: 6 months
      Patients with primary OA

      Mean y: 59

      N=250
      Randomized, double-blind, multicenter controlled trialImprovement of knee joint comfort as assessed by VAS and WOMAC13
      Polyphenols
      Belcaro et al, 2008
      • Belcaro G.
      • Cesarone M.R.
      • Errichi S.
      • Zulli C.
      • Errichi B.M.
      • Vinciguerra G.
      • et al.
      Treatment of osteoarthritis with Pycnogenol. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects.
      Pycnogenol®NP

      ID: 3 months
      OA patients with elevated C-reactive protein and plasma-free radicals

      N=35
      Placebo-controlled trialDecrease of plasma-free radicals compared to baseline

      Decrease of plasma C-reactive protein level compared to baseline and placebo group

      Decrease of fibrinogen level compared to baseline

      No difference for plasma-free radicals, C-reactive protein and fibrinogen in placebo group

      Decrease of systemic inflammatory markers
      Cisar et al, 2008
      • Grimm T.
      • Schafer A.
      • Hogger P.
      Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol).
      Pycnogenol®150 mg/day

      ID: 3 months
      Slovakian patients with mild to moderate OA

      Y: 25–65

      N=100
      Prospective, double-blind, placebo-controlled, single centre studyImprovement of WOMAC index (pain, stiffness and global score compared to both baseline and placebo group, physical function compared to baseline only) and alleviation of pain by VAS compared to placebo

      Diminution of analgesic use compared to baseline and increase use in placebo group
      13
      Belcaro et al, 2008
      • Imada K.
      • Lin N.
      • Liu C.
      • Lu A.
      • Chen W.
      • Yano M.
      • et al.
      Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice.
      Pycnogenol®100 mg/day

      ID: 3 months
      Patients with knee OA and disability Mean y: 47.6–48.6 

      N=156
      Double-blind, placebo-controlled randomized trialImprovement of WOMAC index (pain, stiffness, physical function and global scores), well-being of patients and social functions compared to the beginning and to placebo group

      Increase of patient performance

      Decrease of oedema

      Decrease of analgesic (NSAID) medication compared to the beginning and to placebo group
      11
      Farid et al, 2007
      • Belcaro G.
      • Cesarone M.R.
      • Errichi S.
      • Zulli C.
      • Errichi B.M.
      • Vinciguerra G.
      • et al.
      Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol.
      Pycnogenol®150 mg/day

      ID: 3 months
      Patients with knee OA

      Y: 25–65

      N=37
      Double-blind, placebo-controlled randomized trial with parallel-group designImprovement of WOMAC index (pain, physical function and global score but not stiffness) from second month compared to baseline and placebo

      Reduced use of medication (NSAID and COX-2 inhibitor) compared to placebo
      11
      We have voluntary eliminated glucosamine sulphate, glucosamine-HCl, and chondroitin sulphate because these natural compounds are considered as drugs in some countries, and that they have been the main topic of numerous systematic review and meta-analysis
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis Part III: changes in evidence following systematic cumulative update of research published through.
      • Hochberg M.C.
      • Clegg D.O.
      Potential effects of chondroitin sulfate on joint swelling: a GAIT report.
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      • Vangsness Jr., C.T.
      • Spiker W.
      • Erickson J.
      A review of evidence-based medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis.
      • Huskisson E.C.
      Glucosamine and chondroitin for osteoarthritis.
      • Scarpellini M.
      • Lurati A.
      • Vignati G.
      • Marrazza M.G.
      • Telese F.
      • Re K.
      • et al.
      Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”.
      • Sawitzke A.D.
      • Shi H.
      • Finco M.F.
      • Dunlop D.D.
      • Bingham 3rd, C.O.
      • Harris C.L.
      • et al.
      The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.
      . The search was performed according to the following criteria: (1) only scientific data with a direct link to OA were selected; (2) only orally administered treatments were selected for in vivo studies and clinical trials (CTs); (3) only publications in English were considered (4) only scientific data allowing to evaluate the effect of the compound alone were considered. Articles describing the results of a study previously published were excluded. The search was performed in Pubmed/Medline database between January 1990 and 2010.
      This search was performed using the combination of terms related to OA (arthrosis or osteoarthr* OR gonarthro* OR coxarthro* OR “joint pain” OR “joint comfort” or chondro* or fibroblast* OR synov* OR subchond* OR cartilage OR collagen) and each studied compound name (or abbreviation).
      The methodological quality of each CT supporting functional ingredient efficacy was determined according to an assessment model adapted from EFSA and FDA recommendations (EFSA, 2007; FDA, 2003), AFSSA (“Agence Française de Sécurité Sanitaire des Aliments”) guidelines (AFSSA, 2007) and other relevant references
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      • Bornhoft G.
      • Maxion-Bergemann S.
      • Wolf U.
      • Kienle G.S.
      • Michalsen A.
      • Vollmar H.C.
      • et al.
      Checklist for the qualitative evaluation of clinical studies with particular focus on external validity and model validity.
      • Schneeman B.
      FDA’s review of scientific evidence for health claims.
      (ANAES “Agence Nationale d’Accréditation et d’Evaluation en Santé”, 2000). The quality is scored according to a set of 14 criteria. One point is marked for each criterion presented in the description of the CT. The points are then summed and the final score allow classifying the CT quality in four different categories: a score below six represents a poor methodological quality, from 7 to 9 represents a medium methodological quality, from 10 to 11 represents a good methodological quality and finally a score from 12 to 14 represents a very good methodological quality.
      A scientific consensus was reached between the two evaluators (YH and CL) by considering different points: the total number of CTs (showing or not a beneficial effect), the quality of these CTs, the number of epidemiological studies showing or not a relationship, the heterogeneity in the body of evidence, the presence of preclinical basis and the presence of ongoing CTs. The studies were then classified as good evidence of efficacy, moderate evidence of efficacy, limited evidence of efficacy but suggestive, preclinical evidence of efficacy, lack of evidence of efficacy, some evidence of inefficacy. Scientific consensus for each ingredient is summarized in Table VII.
      Table VIISummary of scientific consensus on the reviewed ingredients
      IngredientScientific consensus
      n-3 PUFALack of evidence of efficacy
      ASUGood evidence of efficacy
      CHLimited evidence of efficacy but suggestive
      Vitamin DLimited evidence of efficacy but suggestive
      NobiletinLack of evidence of efficacy
      CurcuminPreclinical evidence of efficacy
      GenisteinLack of evidence of efficacy
      EGCGPreclinical evidence of efficacy
      ResveratrolPreclinical evidence of efficacy
      PycnogenolModerate evidence of efficacy
      ProbioticsLack of evidence of efficacy
      Furthermore, a search of ongoing CTs (Table VIII) was carried out on the clinicaltrials.gov database using the term “osteoarthritis” and each studied compound’s name, in order to complete existing published data and give an overview of current research interest on the selected ingredients.
      Table VIIISummary of the ongoing CTs for the studied products on OA
      ProductPopulationDesignPrimary outcome measureSponsorStage
      ASU

      (Piascledin® 300)
      Patients with hip OA

      Age: 45–75 years

      Enrollement: NP
      Multicenter, randomized, double-blind, placebo-controlled trial

      Duration: 3 years

      Treatment: Piascledine® 300
      Effect of treatment on joint space narrowing evaluated on X-rayLaboratoires ExpanscienceCompleted
      CH solution

      10 g/day
      Patients with knee OA

      Age: 49–90 years

      Enrollement: 30
      Treatment, randomized, double-blind (subject, caregiver, investigator, outcome assessors), placebo-controlled, parallel assignment, safety-efficacy studyEffect of collagen hydrolysis on knee cartilage measured by MRIGELITACompleted
      Vitamin D

      (cholecalciferol)

      2 000 UI/day

      (capsule)
      Patients with symptomatic knee OA

      Age: 45–90 years

      Enrollement: 146
      Treatment, randomized, double-blind (subject, caregiver, investigator, outcomes assessor), parallel assignment, efficacy study

      Duration: 2 years

      Treatments: vitamin D3 2 000 UI daily or placebo
      Cartilage volume loss (MRI)

      Knee symptoms (WOMAC)
      National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

      Office of Dietary Supplement (ODS)
      Ongoing, not recruiting
      Vitamin D

      (cholecalciferol)

      2 000 UI/day

      (capsule)
      Patients undergoing uni-lateral total knee replacement due to sever OA

      Age: 60 years

      Enrollement: 80
      Treatment, randomized, double-blind (subject, caregiver, investigator, outcomes assessor), dose comparison, parallel assignment, efficacy study

      Duration: 2 years Treatments: vitamin D3 2 000 UI or 800 UI daily
      Pain and function of the operated and non-operated knee

      Rate of falls
      University of Zurich

      Harvard School of Public Health

      Tufts University

      Boston University
      Recruiting
      Curcuma domestica 1 500 mg/day (oral) divided into 3 times for 28 daysPatients with knee OA

      Age: 50–75 years

      Enrollement: 396
      Treatment, randomized, double-blind (subject, outcomes assessor), active control, parallel assignment, safety/efficacy study

      Duration: 28 days

      Treatments: curcuma domestica or ibuprofen (1 200 mg/day)
      Change in mean WOMAC pain scaleMahidol University

      National research Council of Thailand
      Not yet open for patient recruitment
      Highly bioavailable turmeric extract

      (Arantal®)

      four capsules/day
      Patients with knee OA

      Age: 40–80 years

      Enrollement: 280
      Treatment, randomized, placebo-controlled, double-blind, parallel assignment, efficacy/tolerance study

      Duration: 15 days

      Treatment: turmeric extract (Arantal®) or placebo
      Pain assessment using VASBioxtract S.A.

      NuKleus
      Recruiting

      Results

      Bibliographic search results

      The results of the search performed on Pubmed/Medline database are described in Table II.

      N-3 polyunsaturated fatty acids (n-3 PUFAs)

      n-3 PUFAs (linolenic acid and eicosapentenoic acid (EPA)) are essential fatty acids. These compounds are candidate for the reduction of inflammation as they can substitute arachidonic acid (main precursor of prostaglandins) in the synthetic pathway of inflammatory mediators. The reduction of inflammation can also have an impact on the catabolic pathways and by that way on disease progression. They have been widely studied in cardiovascular and inflammatory diseases as rheumatoid arthritis
      • Calder P.C.
      • Yaqoob P.
      Omega-3 polyunsaturated fatty acids and human health outcomes.
      • Darlington L.G.
      • Stone T.W.
      Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders.
      . These studies demonstrated the beneficial effects of a higher n-3 intake. It is important to note that Western diet is richer in n-6 PUFAs (linoleic acid and arachidonic acid) rather than in n-3 PUFAs
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      .

      In vitro and preclinical data

      n-3 PUFAs have been extensively studied in various cell types, but only few studies have assessed their anti-inflammatory or anti-OA effects in joint cell models. Three in vitro studies have been identified using bovine chondrocytes or human and bovine cartilage explants. These studies used n-3 PUFAs alpha-linolenic acid (ALA), EPA and docohexanoic acid (DHA)
      • Curtis C.L.
      • Hughes C.E.
      • Flannery C.R.
      • Little C.B.
      • Harwood J.L.
      • Caterson B.
      n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation.
      • Curtis C.L.
      • Rees S.G.
      • Cramp J.
      • Flannery C.R.
      • Hughes C.E.
      • Little C.B.
      • et al.
      Effects of n-3 fatty acids on cartilage metabolism.
      • Curtis C.L.
      • Rees S.G.
      • Little C.B.
      • Flannery C.R.
      • Hughes C.E.
      • Wilson C.
      • et al.
      Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids.
      . These studies demonstrated the potency of n-3 PUFAs at reducing inflammatory mediators (IL-1α, COX-2, 5-lipoxygenase (LOX) and its activator FLAP) and also catabolic factors (MMPs or ADAMTS). Furthermore, recent published data have also shown that n-3 PUFAs reduced IL-1β-induced ADAMTS-4, -5, MMP-3, -13 and COX-2 mRNA in bovine chondrocytes culture
      • Zainal Z.
      • Longman A.J.
      • Hurst S.
      • Duggan K.
      • Caterson B.
      • Hughes C.E.
      • et al.
      Relative efficacies of omega-3 polyunsaturated fatty acids in reducing expression of key proteins in a model system for studying osteoarthritis.
      .
      Similarly, only one animal study on n-3 PUFAs and OA has been identified in the literature
      • Lippiello L.
      • Fienhold M.
      • Grandjean C.
      Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega-3 fatty acids.
      . This study investigated the effect of n-3 PUFAs on rats with a marginally deficient essential fatty acid state. n-3 PUFA produced a 70% maximum decrease in the linoleic and arachidonic acid content of articular cartilage. n-3 PUFA also produced a 30–40% decrease in the cartilage hexosamine content and a 32% inhibition of PG synthesis. This is important to keep in mind that this study demonstrated that a too low n-6/n-3 ratio can be negative, as a diet with very low n-6 PUFAs intake induced surface irregularities and PG depletion in cartilage of rats
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      • Lippiello L.
      • Fienhold M.
      • Grandjean C.
      Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega-3 fatty acids.
      .
      Finally, the only one in vivo study testing n-3 PUFAs in client-owned OA dogs was just published
      • Roush J.K.
      • Dodd C.E.
      • Fritsch D.A.
      • Allen T.A.
      • Jewell D.E.
      • Schoenherr W.D.
      • et al.
      Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs.
      . The results are in favor of the beneficial effect of n-3 PUFAs on OA dogs.

      Epidemiological data

      One observational study was identified. This study investigated using Magnetic resonance Imaging (MRI), the association of different fatty acids consumption with cartilage structure and bone marrow lesions (which have been shown to be associated with knee pain and predictive of cartilage loss in knee OA)
      • Wang Y.
      • Wluka A.E.
      • Hodge A.M.
      • English D.R.
      • Giles G.G.
      • O’Sullivan R.
      • et al.
      Effect of fatty acids on bone marrow lesions and knee cartilage in healthy, middle-aged subjects without clinical knee osteoarthritis.
      . The main observation of this study showed that high intakes of monounsaturated, total and n-6 PUFAs are associated with increased risks of bone marrow lesions. The results made no association between n-3 PUFAs and either bone marrow lesions or cartilage volume or defects.

      Clinical data

      The clinical data on n-3 PUFAs are limited. Two studies that investigated the effect of natural extract or oil with high content of n-3 PUFAs on OA symptoms were identified. One study of medium quality (score: 7)
      • Stammers T.
      • Sibbald B.
      • Freeling P.
      Efficacy of cod liver oil as an adjunct to non-steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice.
      showed that a daily intake of 10 ml of cod liver oil (equivalent to 786 mg EPA) by OA patients as an adjunct to NSAID medication was not effective to improve pain and ability. The use of olive oil as placebo control may have introduced a bias in the result of this study. On the contrary, the second study of low methodological quality (score: 4)
      • Cho S.H.
      • Jung Y.B.
      • Seong S.C.
      • Park H.B.
      • Byun K.Y.
      • Lee D.C.
      • et al.
      Clinical efficacy and safety of Lyprinol, a patented extract from New Zealand green-lipped mussel (Perna Canaliculus) in patients with osteoarthritis of the hip and knee: a multicenter 2-month clinical trial.
      showed that the consumption of an extract of New-Zealand green-lipped mussel rich in n-3 PUFAs improved OA symptoms, including pain and joint function in Korean OA patients.

      ASU

      ASU are derived from unsaponifiable residues of avocado and soybean oils, generally mixed in the ratio one-third–two-thirds respectively
      • Cake M.A.
      • Read R.A.
      • Guillou B.
      • Ghosh P.
      Modification of articular cartilage and subchondral bone pathology in an ovine meniscectomy model of osteoarthritis by avocado and soya unsaponifiables (ASU).
      • Boileau C.
      • Martel-Pelletier J.
      • Caron C.
      • Cheng S.
      • Msika P.
      • Guillou G.B.
      • et al.
      Protective effects of total fraction of avocado/soybean unsaponifiables (ASU) on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and MMP-13.
      • Msika P.
      • Baudouin C.
      • Saunois A.
      • Bauer T.
      Avocado/soybean unsaponifiables, ASU EXPANSCIENCEtrade mark, are strictly different from the nutraceutical products claiming ASU appellation.
      • Henrotin Y.
      Avocado/soybean unsaponifiable (ASU) to treat osteoarthritis: a clarification.
      . The large majority of the in vitro and in vivo data have been obtained with ASU found in Piascledine®300 (Laboratoires Expanscience, France). The ASU contained in Piascledine®300 are extracted according to a patented process giving them a particular formulation
      • Henrotin Y.
      Avocado/soybean unsaponifiable (ASU) to treat osteoarthritis: a clarification.
      . This formulation is considered as a drug in France and some of the observed beneficial effects seem to be related to this particular formulation. In other countries, ASU mixtures are delivered as over-the-counter products. Therefore, extrapolation of the data obtained with Piascledine®300 to other ASU mixtures must be done with an extreme caution. The main components of ASU are the phytosterols β-sitosterol, campesterol and stigmasterol
      • Lippiello L.
      • Nardo J.V.
      • Harlan R.
      • Chiou T.
      Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes.
      .

      In vitro and preclinical data

      Over the last 20 years, ASU have raised a great research interest. In vitro data are abundant. Most of in vitro studies were performed with normal or OA chondrocytes stimulated or not with IL-1β, the key pro-inflammatory cytokine in OA physiopathology. These studies demonstrated that ASU contained in Piascledine®300 exerted positive effects on human chondrocytes by stimulating the synthesis of aggrecan and extracellular matrix component as type II collagen
      • Lippiello L.
      • Nardo J.V.
      • Harlan R.
      • Chiou T.
      Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes.
      • Mauviel A.
      • Daireaux M.
      • Hartmann D.J.
      • Galera P.
      • Loyau G.
      • Pujol J.P.
      Effects of unsaponifiable extracts of avocado/soy beans (PIAS) on the production of collagen by cultures of synoviocytes, articular chondrocytes and skin fibroblasts.
      • Mauviel A.
      • Loyau G.
      • Pujol J.P.
      Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1.
      and by reducing the production of catabolic (MMP-3) and pro-inflammatory (IL-8 and IL-6) mediators
      • Henrotin Y.
      • Labasse A.
      • Jaspar J.M.
      • De Groote D.
      • Zheng S.X.
      • Guillou B.
      • et al.
      Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes.
      . These anabolic and anti-catabolic effects were also observed in human OA chondrocytes
      • Henrotin Y.E.
      • Sanchez C.
      • Deberg M.A.
      • Piccardi N.
      • Guillou G.B.
      • Msika P.
      • et al.
      Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.
      . What is more, this ASU mixture was able to counteract IL-1β-induced deleterious effects on cartilage in normal and OA chondrocytes
      • Lippiello L.
      • Nardo J.V.
      • Harlan R.
      • Chiou T.
      Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes.
      • Mauviel A.
      • Daireaux M.
      • Hartmann D.J.
      • Galera P.
      • Loyau G.
      • Pujol J.P.
      Effects of unsaponifiable extracts of avocado/soy beans (PIAS) on the production of collagen by cultures of synoviocytes, articular chondrocytes and skin fibroblasts.
      • Mauviel A.
      • Loyau G.
      • Pujol J.P.
      Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1.
      • Henrotin Y.
      • Labasse A.
      • Jaspar J.M.
      • De Groote D.
      • Zheng S.X.
      • Guillou B.
      • et al.
      Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes.
      • Henrotin Y.E.
      • Sanchez C.
      • Deberg M.A.
      • Piccardi N.
      • Guillou G.B.
      • Msika P.
      • et al.
      Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.
      • Gabay O.
      • Gosset M.
      • Levy A.
      • Salvat C.
      • Sanchez C.
      • Pigenet A.
      • et al.
      Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado-Soybean Unsaponifiables (ASU).
      . It reversed IL-1β-induced collagen release, MMP-3, MMP-13, and PGE2 production in normal chondrocytes
      • Lippiello L.
      • Nardo J.V.
      • Harlan R.
      • Chiou T.
      Metabolic effects of avocado/soy unsaponifiables on articular chondrocytes.
      • Mauviel A.
      • Loyau G.
      • Pujol J.P.
      Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1.
      • Henrotin Y.
      • Labasse A.
      • Jaspar J.M.
      • De Groote D.
      • Zheng S.X.
      • Guillou B.
      • et al.
      Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes.
      • Gabay O.
      • Gosset M.
      • Levy A.
      • Salvat C.
      • Sanchez C.
      • Pigenet A.
      • et al.
      Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado-Soybean Unsaponifiables (ASU).
      . It was also shown that ASU mixture contained in Piascledine®300 restored aggrecan production and inhibited MMP-3 synthesis in OA chondrocytes stimulated with IL-1β
      • Henrotin Y.E.
      • Sanchez C.
      • Deberg M.A.
      • Piccardi N.
      • Guillou G.B.
      • Msika P.
      • et al.
      Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes.
      . Other ASU formulations produced similar effect on IL-1β, COX-2 and iNOS in LPS-stimulated chondrocytes
      • Au R.Y.
      • Al-Talib T.K.
      • Au A.Y.
      • Phan P.V.
      • Frondoza C.G.
      Avocado soybean unsaponifiables (ASU) suppress TNF-alpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages.
      and were also shown to enhance transforming growth factor (TGF)-β production in bovine articular chondrocytes
      • Boumediene K.
      • Felisaz N.
      • Bogdanowicz P.
      • Galera P.
      • Guillou G.B.
      • Pujol J.P.
      Avocado/soya unsaponifiables enhance the expression of transforming growth factor beta1 and beta2 in cultured articular chondrocytes.
      . The ASU contained in Piascledine®300 were also shown to have beneficial effects on osteoblasts and synoviocytes. Indeed, this compound prevented inhibitory effect of osteoblasts on chondrocyte matrix component synthesis
      • Henrotin Y.E.
      • Deberg M.A.
      • Crielaard J.M.
      • Piccardi N.
      • Msika P.
      • Sanchez C.
      Avocado/soybean unsaponifiables prevent the inhibitory effect of osteoarthritic subchondral osteoblasts on aggrecan and type II collagen synthesis by chondrocytes.
      and reversed IL-1β-induced collagenase production by synoviocytes
      • Mauviel A.
      • Loyau G.
      • Pujol J.P.
      Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1.
      .
      Four in vivo studies with ASU were identified. They were performed in four different animal models of OA and they all support the beneficial effect of Piascledine®300 in OA. Piascledine®300 treatment prevents cartilage degradation (decrease in cartilage lesion severity, increase in cartilage thickness) by stimulating matrix component production as glycosaminoglycans (GAG) and PGs content in experimental models
      • Cake M.A.
      • Read R.A.
      • Guillou B.
      • Ghosh P.
      Modification of articular cartilage and subchondral bone pathology in an ovine meniscectomy model of osteoarthritis by avocado and soya unsaponifiables (ASU).
      • Boileau C.
      • Martel-Pelletier J.
      • Caron C.
      • Cheng S.
      • Msika P.
      • Guillou G.B.
      • et al.
      Protective effects of total fraction of avocado/soybean unsaponifiables (ASU) on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and MMP-13.
      • Kawcak C.E.
      • Frisbie D.D.
      • McIlwraith C.W.
      • Werpy N.M.
      • Park R.D.
      Evaluation of avocado and soybean unsaponifiable extracts for treatment of horses with experimentally induced osteoarthritis.
      . In addition, one in vivo study in dogs without any diagnosed joint disease suggests an effect of ASU by increasing growth factors (TGF-β1 and 2) involved in extracellular matrix synthesis
      • Altinel L.
      • Saritas Z.K.
      • Kose K.C.
      • Pamuk K.
      • Aksoy Y.
      • Serteser M.
      Treatment with unsaponifiable extracts of avocado and soybean increases TGF-beta1 and TGF-beta2 levels in canine joint fluid.
      . All these preclinical studies strongly support anti-OA properties for ASU mixtures.

      Clinical data

      The results of four CTs, all double-blind placebo-controlled and randomized, were published and identified in the literature. All of these studies used the same pharmaceutical product, Piascledine®300, which is under drug authorization (AMM). All of them investigated the beneficial effects of Piascledine®300 on patients with symptomatic OA. All of them were conducted in patients with primary knee or hip OA and were by the way focusing on OA treatment. OA outcomes were NSAID/analgesics medication replacement, pain, function and structural changes (joint space narrowing). They studied the potential of symptom-modifying effect of Piascledine®300 and one of them was interested in the structure-modifying effect of ASU. Three out of the four evaluated studies were of good methodological quality (Lequesne et al, 2002
      • Lequesne M.
      • Maheu E.
      • Cadet C.
      • Dreiser R.L.
      Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip.
      , score: 11.5; Appelboom et al, 2001
      • Appelboom T.
      • Schuermans J.
      • Verbruggen G.
      • Henrotin Y.
      • Reginster J.Y.
      Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.
      , score: 11; Maheu et al, 1998
      • Maheu E.
      • Mazieres B.
      • Valat J.P.
      • Loyau G.
      • Le Loet X.
      • Bourgeois P.
      • et al.
      Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.
      , score: 14).
      The only one study assessing efficacy of Piascledine®300 in modifying articular structure failed to show any structural effect in patients with hip OA in spite of its long duration (2 years)
      • Lequesne M.
      • Maheu E.
      • Cadet C.
      • Dreiser R.L.
      Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip.
      . However, a subgroup analysis suggested an effect in patients with the most severe hip OA, supporting further studies in this population group.
      Data suggested that Piascledine®300 decreased NSAID/analgesic intake in the medium term (3–6 months) for patients with hip or knee OA
      • Appelboom T.
      • Schuermans J.
      • Verbruggen G.
      • Henrotin Y.
      • Reginster J.Y.
      Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.
      • Maheu E.
      • Mazieres B.
      • Valat J.P.
      • Loyau G.
      • Le Loet X.
      • Bourgeois P.
      • et al.
      Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.
      • Blotman F.
      • Maheu E.
      • Wulwik A.
      • Caspard H.
      • Lopez A.
      Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.
      . However, the only long-term study (2 years) did not show any effect of Piascledine®300 on the NSAID consumption in patients with hip OA
      • Lequesne M.
      • Maheu E.
      • Cadet C.
      • Dreiser R.L.
      Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip.
      . Nevertheless, the later was designed to detect radiographic changes more than to study the changes in symptoms. This could explain the fact that no difference was observed on clinical parameters (function, pain and NSAIDs consumption). In contrast, data regarding pain and patient’s global assessment are more conflicting
      • Lequesne M.
      • Maheu E.
      • Cadet C.
      • Dreiser R.L.
      Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip.
      • Appelboom T.
      • Schuermans J.
      • Verbruggen G.
      • Henrotin Y.
      • Reginster J.Y.
      Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.
      • Maheu E.
      • Mazieres B.
      • Valat J.P.
      • Loyau G.
      • Le Loet X.
      • Bourgeois P.
      • et al.
      Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.
      • Blotman F.
      • Maheu E.
      • Wulwik A.
      • Caspard H.
      • Lopez A.
      Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.
      . Piascledine®300 treatment seemed to improve patient’s function assessed by LFI (Lequesne Functional Index) or VAS (Visual Analog Scale)
      • Appelboom T.
      • Schuermans J.
      • Verbruggen G.
      • Henrotin Y.
      • Reginster J.Y.
      Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study.
      • Maheu E.
      • Mazieres B.
      • Valat J.P.
      • Loyau G.
      • Le Loet X.
      • Bourgeois P.
      • et al.
      Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.
      • Blotman F.
      • Maheu E.
      • Wulwik A.
      • Caspard H.
      • Lopez A.
      Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.
      .
      A recent meta-analysis evaluating these four clinical studies concluded Piascledine®300 was efficient for reducing pain and improving function in OA
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials.
      .

      Collagen hydrosylates (CHs)

      CH is obtained by the enzymatic hydrolysis of collagenous tissues (bone, hide or hide split) form mammals. The main characteristic of CH is its amino acid composition, which is identical to type II collagen, thus providing high levels of glycine and proline, two amino acids essential for the stability and regeneration of cartilage
      • Walrand S.
      • Chiotelli E.
      • Noirt F.
      • Mwewa S.
      • Lassel T.
      Consumption of a functional fermented milk containing collagen hydrolysate improves the concentration of collagen-specific amino acids in plasma.
      . This product is generally recognized as a safe food ingredient by regulatory agencies. CH is well digested and is preferentially accumulated in cartilage
      • Bello A.E.
      • Oesser S.
      Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature.
      . Although clinical use of CH is associated with minimal adverse effects, some gastro-intestinal side effects, as fullness and unpleasant taste, have been described.
      In most studies, CH was administered alone in a water solution. However, it seems that CH is well absorbed and digested in other food matrix, such as fermented milk
      • Walrand S.
      • Chiotelli E.
      • Noirt F.
      • Mwewa S.
      • Lassel T.
      Consumption of a functional fermented milk containing collagen hydrolysate improves the concentration of collagen-specific amino acids in plasma.
      .

      In vitro and preclinical data

      Few preclinical data on the effect of CH on OA were identified in the literature. The search retrieved only one in vitro study assessing the stimulation of articular cartilage matrix by CH in cultured bovine chondrocytes
      • Oesser S.
      • Seifert J.
      Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen.
      . This study demonstrated the stimulatory potency of CH on type II collagen and PG synthesis, as well as aggrecan expression by chondrocytes. This result was also reported in a scientific communication on CH effect in porcine chondrocytes
      • Schunck M.
      • Schulze C.H.
      • Oesser S.
      disparate efficacy of collagen hydrolysate and glucosamine on the extracellular matrix metabolism of articular chondrocytes.
      . In addition, an in vivo study with STR/ort mice which spontaneously developed OA
      • Oesser S.
      • Proksch E.
      • Schunck M.
      prophylactic treatment with a special collagen hydrosylate decreases cartilage tissue degeneration in the knee joints.
      has shown that long-term CH supplementation may decrease OA cartilage degeneration and delay the progression of OA. These results are in favor of a disease-modifying effect of CH and its potential efficacy in OA. The chondroprotective effect of CH was also confirmed in an other study investigating both in vitro and in vivo effect in mice
      • Nakatani S.
      • Mano H.
      • Sampei C.
      • Shimizu J.
      • Wada M.
      Chondroprotective effect of the bioactive peptide prolyl-hydroxyproline in mouse articular cartilage in vitro and in vivo.
      . CH was demonstrated to protect cartilage against degradation induced by phosphorus injection. The same study showed that CH prevented chondrocyte differentiation into mineralized chondrocytes.

      Clinical data

      Only three relevant CTs were identified in the literature. The first study investigated the effect of CH supplementation in healthy adult without degenerative joint disease but with joint pain. This study of medium methodological quality (score: 8)
      • Clark K.L.
      • Sebastianelli W.
      • Flechsenhar K.R.
      • Aukermann D.F.
      • Meza F.
      • Millard R.L.
      • et al.
      24-week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain.
      showed that CH dietary supplement can improve joint pain, mobility and reduce analgesic medication in healthy active adults without degenerative joint disease. The CH supplementation can then improve knee function during joint-stressing activities. These observations were also reported in a scientific communication
      • Zuckley L.
      • Angelopoulou K.
      • Carpenter M.S.S.
      • Meredith B.A.
      • Kline G.
      • Rowinski M.
      • et al.
      Collagen hydrosylate improves joint function in adults with mild symptoms of osteoarthritis of the knee.
      in patients with symptomatic mild OA patients. The second report of medium methodological quality (score: 9)
      • Moskowitz R.W.
      Role of collagen hydrolysate in bone and joint disease.
      mentioned a better effect of CH compared to placebo in severe OA patients than in the overall studied population. More recently, in another relevant CT of very good methodological quality (score: 13), the joint function improvement after CH treatment was shown in patients with primary OA
      • Benito-Ruiz P.
      • Camacho-Zambrano M.M.
      • Carrillo-Arcentales J.N.
      • Mestanza-Peralta M.A.
      • Vallejo-Flores C.A.
      • Vargas-Lopez S.V.
      • et al.
      A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort.
      .

      Vitamin D

      OA was traditionally considered as a cartilage disease, characterized by cartilage degeneration. But many evidences, as osteophytosis, subchondral bone sclerosis and cyst formation have grown up and demonstrated the prominent role played by subchondral bone in OA pathophysiology
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      . Some studies even indicate that bone alteration could precede cartilage changes
      • Radin E.L.
      • Rose R.M.
      Role of subchondral bone in the initiation and progression of cartilage damage.
      . But whether bone abnormalities, such as bone sclerosis, initiate or are simply involved in the progression of cartilage degradation is under discussion
      • Cantatore F.P.
      • Corrado A.
      • Grano M.
      • Quarta L.
      • Colucci S.
      • Melillo N.
      Osteocalcin synthesis by human osteoblasts from normal and osteoarthritic bone after vitamin D3 stimulation.
      • Goldring M.B.
      • Goldring S.R.
      Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.
      • Martel-Pelletier J.
      • Pelletier J.P.
      Is osteoarthritis a disease involving only cartilage or other articular tissues?.
      .
      Normal bone metabolism depends on the presence of vitamin D, a compound derived mostly from cutaneous exposure to ultraviolet and from the diet in a lesser extent. Suboptimal levels of vitamin D may have adverse effects on calcium metabolism, osteoblastic activity, matrix ossification and bone density. Low serum levels of vitamin D may increase the progression of knee OA
      • Bergink A.P.
      • Uitterlinden A.G.
      • Van Leeuwen J.P.
      • Buurman C.J.
      • Hofman A.
      • Verhaar J.A.
      • et al.
      Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam Study.
      and may impair the ability of bone to respond optimally to OA pathophysiologic processes and may predispose patients to joint degradation
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      . High prevalence of low vitamin D status has been demonstrated in persons with knee OA
      • Breijawi N.
      • Eckardt A.
      • Pitton M.B.
      • Hoelzl A.J.
      • Giesa M.
      • von Stechow D.
      • et al.
      Bone mineral density and vitamin D status in female and male patients with osteoarthritis of the knee or hip.
      . Moreover, in low bone mineral density (BMD) patient, the level of vitamin D seemed to influence the incidence and progression of the disease
      • Bergink A.P.
      • Uitterlinden A.G.
      • Van Leeuwen J.P.
      • Buurman C.J.
      • Hofman A.
      • Verhaar J.A.
      • et al.
      Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam Study.
      . Some studies have consequently investigated the relationship between vitamin D and OA. The main drawback is that they are all observational. Most of them have looked at the association of vitamin D serum level rather than vitamin D intake with OA.

      In vitro and preclinical data

      Three in vitro studies investigating the role of 1,25-dihydroxyvitamin D3 in the pathophysiology of OA are available
      • Cantatore F.P.
      • Corrado A.
      • Grano M.
      • Quarta L.
      • Colucci S.
      • Melillo N.
      Osteocalcin synthesis by human osteoblasts from normal and osteoarthritic bone after vitamin D3 stimulation.
      • Tetlow L.C.
      • Woolley D.E.
      Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro.
      • Tetlow L.C.
      • Woolley D.E.
      The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion.
      . These studies used different cell models: synovial fibroblasts, chondrocytes or osteoblasts. Data showed that 1,25-dihydroxyvitamin D3 had no inhibitory effect on articular catabolic enzymes and on a potent pro-inflammatory mediators but rather upregulated catabolic enzymes (MMP-1 and -3) in human articular chondrocytes
      • Tetlow L.C.
      • Woolley D.E.
      Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro.
      • Tetlow L.C.
      • Woolley D.E.
      The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion.
      . Interestingly, 1,25-dihydroxyvitamin D3 exerts a positive effect on rheumatoid synovial fibroblasts by reducing MMP and PGE2 production
      • Tetlow L.C.
      • Woolley D.E.
      The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion.
      . In addition, 1,25-dihydroxyvitamin D3-induced osteocalcin production appears to be increased in OA osteoblasts compared to healthy one, which can cause an increase in bone metabolism resulting in bone sclerosis and osteophyte formation
      • Cantatore F.P.
      • Corrado A.
      • Grano M.
      • Quarta L.
      • Colucci S.
      • Melillo N.
      Osteocalcin synthesis by human osteoblasts from normal and osteoarthritic bone after vitamin D3 stimulation.
      .
      Only one in vivo study was identified. This study evaluated the impact of a supplementation of vitamin D3 (25-hydroxyvitamin D3) on OA in pigs
      • Jefferies D.
      • Farquharson C.
      • Thomson J.
      • Smith W.
      • Seawright E.
      • McCormack H.
      • et al.
      Differences in metabolic parameters and gene expression related to osteochondrosis/osteoarthrosis in pigs fed 25-hydroxyvitamin D3.
      . The supplementation revealed no effect on the incidence or the severity of OA lesions, articular PG and collagen content.

      Clinical data

      The majority of available evidence on the efficacy of vitamin D in the treatment or in the prevention of OA comes from epidemiological data. Most of them investigated the relationship between vitamin D serum levels and joint structure parameters (joint space narrowing, osteophytes, cartilage loss and volume). A total of four studies have assessed this relationship
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      • Lane N.E.
      • Gore L.R.
      • Cummings S.R.
      • Hochberg M.C.
      • Scott J.C.
      • Williams E.N.
      • et al.
      Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group.
      • Felson D.T.
      • Niu J.
      • Clancy M.
      • Aliabadi P.
      • Sack B.
      • Guermazi A.
      • et al.
      Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies.
      and only one has investigated the association of vitamin D intake and OA
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      . This study revealed that low levels of vitamin D intake are related to an increased risk of OA progression but no correlation was made with OA incidence. Interestingly, in this study, vitamin D intake modestly correlated with vitamin D serum levels. In addition, one other study was found to evaluate the prevalence of vitamin D deficiency in individuals with OA
      • Breijawi N.
      • Eckardt A.
      • Pitton M.B.
      • Hoelzl A.J.
      • Giesa M.
      • von Stechow D.
      • et al.
      Bone mineral density and vitamin D status in female and male patients with osteoarthritis of the knee or hip.
      . This study revealed a high prevalence of low vitamin D status in patients with knee OA. The other studies investigating the association between vitamin D serum level (25-vitamin D) and joint structure parameters gave inconsistent data. Two of them showed a relationship between vitamin D serum level and OA parameters such as joint space narrowing and/or cartilage volume in the knee or hip joint
      • Lane N.E.
      • Gore L.R.
      • Cummings S.R.
      • Hochberg M.C.
      • Scott J.C.
      • Williams E.N.
      • et al.
      Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group.
      • Ding C.
      • Parameswaran V.
      • Burgess J.
      • Cicuttini F.
      • Jones G.
      Serum level of vitamin d, winter sun exposure knee radiographic osteoarthritis and knee cartilage loss in older adults: the Tasmania Older Adult Cohort (TASOAC) Study.
      . An other study did not show any association between vitamin D serum level and joint space loss in hip OA patients
      • Felson D.T.
      • Niu J.
      • Clancy M.
      • Aliabadi P.
      • Sack B.
      • Guermazi A.
      • et al.
      Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies.
      . This difference could be explained by the fact that the population of this study was younger than the population of the other two. However no linear association was found when OA was assessed with a structural global score
      • McAlindon T.E.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • Aliabadi P.
      • Weissman B.
      • et al.
      Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study.
      • Javaid M.
      • Tolskykh I.
      • Neogi T.
      • Guermazi A.
      • Curtis J.
      • Torner J.
      • et al.
      Non-linear association between baseline serum 25(OH) vitamin d concentration and incident radiographic knee OA: the MOST Study.
      . These studies suggested a U-shaped relationship. Serum Vitamin D level is reported to be predictive of knee OA, when measured by quartiles with the lowest risk in the middle quartile
      • Javaid M.
      • Tolskykh I.
      • Neogi T.
      • Guermazi A.
      • Curtis J.
      • Torner J.
      • et al.
      Non-linear association between baseline serum 25(OH) vitamin d concentration and incident radiographic knee OA: the MOST Study.
      .

      Polyphenols

      Research on the effect of dietary polyphenols on human health has developed considerably in the past 10 years. The results strongly support the role of polyphenols in the prevention of degenerative diseases. The anti-oxidant properties of polyphenols have been widely studied, but it has become clear that the mechanisms of action go beyond the modulation of oxidative stress. Some researchers have investigated the potential effect of some polyphenols in OA. Only pine bark extract-Pycnogenol® has been tested in CTs.

      Pine bark extract-Pycnogenol®

      Pycnogenol® is a special standardized extract from the bark of the French maritime pine (Pinus pinaster). This extract represents a concentrate of polyphenols, containing several phenolic acids, catechin, taxifolin and procyanidins with various biological and clinical effects
      • Cisar P.
      • Jany R.
      • Waczulikova I.
      • Sumegova K.
      • Muchova J.
      • Vojtassak J.
      • et al.
      Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis.
      . No-preclinical or in vitro data were found for Pycnogenol® and OA. However, the anti-oxidant and anti-inflammatory profile of Pycnogenol® and its inhibitory effect on MMPs and iNOS are well documented in conditions other than OA
      • Grimm T.
      • Schafer A.
      • Hogger P.
      Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol).
      • Farid R.
      • Mirfeizi Z.
      • Mirheidari M.
      • Rezaieyazdi Z.
      • Mansouri H.
      • Esmaelli H.
      • et al.
      Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis.
      .
      The symptom-modifying effect of Pycnogenol® has been relatively well documented in OA patients. The search retrieved four CTs
      • Cisar P.
      • Jany R.
      • Waczulikova I.
      • Sumegova K.
      • Muchova J.
      • Vojtassak J.
      • et al.
      Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis.
      • Farid R.
      • Mirfeizi Z.
      • Mirheidari M.
      • Rezaieyazdi Z.
      • Mansouri H.
      • Esmaelli H.
      • et al.
      Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis.
      • Belcaro G.
      • Cesarone M.R.
      • Errichi S.
      • Zulli C.
      • Errichi B.M.
      • Vinciguerra G.
      • et al.
      Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol.
      • Belcaro G.
      • Cesarone M.R.
      • Errichi S.
      • Zulli C.
      • Errichi B.M.
      • Vinciguerra G.
      • et al.
      Treatment of osteoarthritis with Pycnogenol. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects.
      . They assessed the impact of Pycnogenol® in patients with knee OA in a medium term (3 months). These studies indicate that the daily intake of 150 mg of Pycnogenol® alleviated OA symptoms. All studies showed that Pycnogenol® was effective in reducing NSAIDs or COX-2 inhibitor medication, suggesting that Pycnogenol® could be used as an effective adjuvant treatment. Data strongly support the pain-alleviating effect of Pycnogenol®. Despite some discordant results, physical function and stiffness seem to be improved by intake of Pycnogenol® in OA subjects. All these studies are of good to very good quality (Farid et al, 2007
      • Farid R.
      • Mirfeizi Z.
      • Mirheidari M.
      • Rezaieyazdi Z.
      • Mansouri H.
      • Esmaelli H.
      • et al.
      Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis.
      and Belcaro et al, 2008
      • Belcaro G.
      • Cesarone M.R.
      • Errichi S.
      • Zulli C.
      • Errichi B.M.
      • Vinciguerra G.
      • et al.
      Treatment of osteoarthritis with Pycnogenol. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects.
      , score: 11; Cisar et al, 2008
      • Cisar P.
      • Jany R.
      • Waczulikova I.
      • Sumegova K.
      • Muchova J.
      • Vojtassak J.
      • et al.
      Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis.
      , score: 13).

      Nobiletin

      Nobiletin is a citrus polymethoxyflavone which was proven to have pharmacological actions as anti-inflammatory, anti-tumor proliferation and anti-tumor invasion and metastasis in vitro and in vivo
      • Imada K.
      • Lin N.
      • Liu C.
      • Lu A.
      • Chen W.
      • Yano M.
      • et al.
      Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice.
      . This product has been exclusively studied in vitro in synovial fibroblasts and in articular chondrocytes. Nobiletin was able to inhibit the production of catabolic factors (MMP-3 and -9, ADAMTS-4 and 5) and of mediators of inflammation (PGE2) in rabbit and human synovial fibroblasts
      • Imada K.
      • Lin N.
      • Liu C.
      • Lu A.
      • Chen W.
      • Yano M.
      • et al.
      Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice.
      • Ishiwa J.
      • Sato T.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • Ito A.
      A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.
      • Lin N.
      • Sato T.
      • Takayama Y.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • et al.
      Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.
      . Nobiletin was also showed to activate the MMP inhibitor (TIMP-1)
      • Lin N.
      • Sato T.
      • Takayama Y.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • et al.
      Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.
      . This inhibitory potential was also demonstrated in rabbit articular chondrocytes
      • Ishiwa J.
      • Sato T.
      • Mimaki Y.
      • Sashida Y.
      • Yano M.
      • Ito A.
      A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.
      . Nobiletin demonstrated a potential to inhibit cartilage degradation. This chondroprotective potency should be further documented.

      Curcumin

      Curcumin (diferuloylmethane) is the major component of turmeric, a yellow spice derived from the plant Curcuma longa and a potent anti-oxidant. It has been extensively investigated due to its anti-tumor, anti-oxidant and anti-inflammatory and analgesic properties. We have recently reviewed the biological activities of curcumin
      • Henrotin Y.
      • Clutterbuck A.L.
      • Allaway D.
      • Lodwig E.M.
      • Harris P.
      • Mathy-Hartert M.
      • et al.
      Biological actions of curcumin on articular chondrocytes.
      . The anti-OA potential of curcumin has been widely studied in vitro. Twelve studies were found. They were all carried out in chondrocytes or on articular cartilage explants. Curcumin was able to downregulate catabolic and degradative effect observed in cartilage explants or chondrocytes stimulated with IL-1β, LPS or tumor necrosis factor (TNF). Curcumin inhibited the production of MMP-3, -9 and -13
      • Liacini A.
      • Sylvester J.
      • Li W.Q.
      • Huang W.
      • Dehnade F.
      • Ahmad M.
      • et al.
      Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes.
      • Schulze-Tanzil G.
      • Mobasheri A.
      • Sendzik J.
      • John T.
      • Shakibaei M.
      Effects of curcumin (diferuloylmethane) on nuclear factor kappaB signaling in interleukin-1beta-stimulated chondrocytes.
      • Shakibaei M.
      • John T.
      • Schulze-Tanzil G.
      • Lehmann I.
      • Mobasheri A.
      Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
      and restored type II collagen and GAG synthesis
      • Schulze-Tanzil G.
      • Mobasheri A.
      • Sendzik J.
      • John T.
      • Shakibaei M.
      Effects of curcumin (diferuloylmethane) on nuclear factor kappaB signaling in interleukin-1beta-stimulated chondrocytes.
      • Shakibaei M.
      • John T.
      • Schulze-Tanzil G.
      • Lehmann I.
      • Mobasheri A.
      Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis.
      • Shakibaei M.
      • Schulze-Tanzil G.
      • John T.
      • Mobasheri A.
      Curcumin protects human chondrocytes from IL-l1beta-induced inhibition of collagen type II and beta1-integrin expression and activation of caspase-3: an immunomorphological study.
      • Toegel S.
      • Wu S.Q.
      • Piana C.
      • Unger F.M.
      • Wirth M.
      • Goldring M.B.
      • et al.
      Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes.
      • Williamson S.M.
      • Mobasheri A.
      • Vaughan-Thomas A.
      • Thompson N.J.
      • Shakibaei M.
      Curcumin and resveratrol reduce lipopolysaccharide mediated glycosaminoglycan release in an explant model of canine articular cartilage.
      . Curcumin positive effect on GAG release was confirmed
      • Clutterbuck A.L.
      • Mobasheri A.
      • Shakibaei M.
      • Allaway D.
      • Harris P.
      Interleukin-1beta-induced extracellular matrix degradation and glycosaminoglycan release is inhibited by curcumin in an explant model of cartilage inflammation.
      . In addition, curcumin demonstrated potent anti-inflammatory properties by inhibiting key inflammatory mediators (IL-6, IL-8, PGE2, NO) and enzymes (COX-2 and iNOS)
      • Mathy M.
      • Sanchez C.
      • Priem F.
      • Henrotin Y.
      Curcumin inhibits interleukin-6, -8, nitric oxide and prostaglandin E2 synthesis by bovine chondrocytes.
      • Clutterbuck A.L.
      • Mobasheri A.
      • Rogers T.C.
      • Wiseman J.
      • Allaway D.
      • Harris P.
      Curcumin (diferuloylmethane) blocks il-1 beta stimulated glycosaminoglycan and prostaglandin e2 release from cartilage explants in an in vitro model of osteoarthritis.
      • Mathy-Hartert M.
      • Jacquemond-Collet I.
      • Priem F.
      • Sanchez C.
      • Lambert C.
      • Henrotin Y.
      Curcumin inhibits pro-inflammatory mediators and metalloproteinase-3 production by chondrocytes.
      • Chowdhury T.T.
      • Salter D.M.
      • Bader D.L.
      • Lee D.A.
      Signal transduction pathways involving p38 MAPK, JNK, NFkappaB and AP-1 influences the response of chondrocytes cultured in agarose constructs to IL-1beta and dynamic compression.
      and anti-catabolic properties by inhibiting MMP-3 synthesis
      • Mathy-Hartert M.
      • Jacquemond-Collet I.
      • Priem F.
      • Sanchez C.
      • Lambert C.
      • Henrotin Y.
      Curcumin inhibits pro-inflammatory mediators and metalloproteinase-3 production by chondrocytes.
      . Curcumin has also demonstrated anti-apoptotic activity on chondrocytes
      • Shakibaei M.
      • Schulze-Tanzil G.
      • John T.
      • Mobasheri A.
      Curcumin protects human chondrocytes from IL-l1beta-induced inhibition of collagen type II and beta1-integrin expression and activation of caspase-3: an immunomorphological study.
      and growth-inhibitory and pro-apoptotic effects on synovial adherent cells, which are the main source of inflammatory mediators and other mediators of cartilage degradation, all of them playing key role in the pathogenesis of arthritis
      • Lev-Ari S.
      • Strier L.
      • Kazanov D.
      • Elkayam O.
      • Lichtenberg D.
      • Caspi D.
      • et al.
      Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells.
      . This is important to note that one study has reported a toxic effect of curcumin used at high dosage (50 μM) without any beneficial effect in cartilage matrix
      • Toegel S.
      • Wu S.Q.
      • Piana C.
      • Unger F.M.
      • Wirth M.
      • Goldring M.B.
      • et al.
      Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes.
      . This study was performed in a novel immortalized human OA chondrocytes model, which can explain the discordance with previous studies.
      No clinical data are available for the effect of curcumin in OA. However, one study tested the clinical efficacy of a herbomineral formulation containing a component rich in curcumin in subjects with OA in a randomized, double-blind, placebo-controlled, cross-over study
      • Kulkarni R.R.
      • Patki P.S.
      • Jog V.P.
      • Gandage S.G.
      • Patwardhan B.
      Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study.
      . Positive results in pain management and mobility were obtained in the treated group. Curcumin in OA is a current research interest.

      Genistein

      Genistein is one of the several known isoflavones and is found in soybeans and soy products. Genistein is considered as a phytoestrogen. Clinical observations have suggested a relationship between OA and a changed estrogen metabolism in menopausal women. Moreover phytoestrogens have been shown to ameliorate various menopausal symptoms
      • Claassen H.
      • Briese V.
      • Manapov F.
      • Nebe B.
      • Schunke M.
      • Kurz B.
      The phytoestrogens daidzein and genistein enhance the insulin-stimulated sulfate uptake in articular chondrocytes.
      . The effect of phytoestrogens, including genistein, has been studied on articular cartilage matrix metabolism and inflammation. Nevertheless, the data for genistein and OA are limited. The in vitro and preclinical data are not consistent to support a beneficial effect of genistein on articular cartilage. Genistein does not affect cartilage metabolism
      • Claassen H.
      • Briese V.
      • Manapov F.
      • Nebe B.
      • Schunke M.
      • Kurz B.
      The phytoestrogens daidzein and genistein enhance the insulin-stimulated sulfate uptake in articular chondrocytes.
      • Hooshmand S.
      • Soung do Y.
      • Lucas E.A.
      • Madihally S.V.
      • Levenson C.W.
      • Arjmandi B.H.
      Genistein reduces the production of proinflammatory molecules in human chondrocytes.
      but could have an anti-inflammatory effect by suppressing COX-2 but not NO production
      • Hooshmand S.
      • Soung do Y.
      • Lucas E.A.
      • Madihally S.V.
      • Levenson C.W.
      • Arjmandi B.H.
      Genistein reduces the production of proinflammatory molecules in human chondrocytes.
      . In addition, the consumption of an extract of soy phytoestrogen in animal failed to modify cartilage metabolism in ovariectomised monkey
      • Ham K.D.
      • Oegema T.R.
      • Loeser R.F.
      • Carlson C.S.
      Effects of long-term estrogen replacement therapy on articular cartilage IGFBP-2, IGFBP-3, collagen and proteoglycan levels in ovariectomized cynomolgus monkeys.
      . Additional experiments are needed to clarify the potential benefit of genistein in articular cartilage metabolism.

      Epigallocatechin-3-Gallate (EGCG)

      EGCG is a major component of the polyphenolic fraction of green tea and exhibits anti-oxidant, anti-tumor and anti-mutagenic activities. The in vitro effect of EGCG is well documented. Most of the available data on EGCG and OA come from experiments performed in vitro in human chondrocytes looking at the anti-inflammatory effect of EGCG. Data suggest that EGCG exerts an anti-inflammatory effect on OA chondrocytes by inhibiting the production of key inflammatory mediators (NO, PGE2, COX-2 and iNOS)
      • Ahmed S.
      • Rahman A.
      • Hasnain A.
      • Lalonde M.
      • Goldberg V.M.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes.
      • Singh R.
      • Ahmed S.
      • Islam N.
      • Goldberg V.M.
      • Haqqi T.M.
      Epigallocatechin-3-gallate inhibits interleukin-1beta-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: suppression of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor kappaB.
      • Singh R.
      • Ahmed S.
      • Malemud C.J.
      • Goldberg V.M.
      • Haqqi T.M.
      Epigallocatechin-3-gallate selectively inhibits interleukin-1beta-induced activation of mitogen activated protein kinase subgroup c-Jun N-terminal kinase in human osteoarthritis chondrocytes.
      . This anti-inflammatory effect has also been observed in osteoblasts by the inhibition of IL-6
      • Tokuda H.
      • Takai S.
      • Hanai Y.
      • Matsushima-Nishiwaki R.
      • Yamauchi J.
      • Harada A.
      • et al.
      (−)-Epigallocatechin gallate inhibits basic fibroblast growth factor-stimulated interleukin-6 synthesis in osteoblasts.
      and synovial fibroblasts by the inhibition of COX-2 expression and synthesis and by the inhibition of PGE2 and IL-8 secretion
      • Huang G.S.
      • Tseng C.Y.
      • Lee C.H.
      • Su S.L.
      • Lee H.S.
      Effects of (−)-epigallocatechin-3-gallate on cyclooxygenase 2, PGE(2), and IL-8 expression induced by IL-1beta in human synovial fibroblasts.
      . Additional anti-inflammatory and anti-catabolic effects have been demonstrated for EGCG in human chondrocytes. Indeed, EGCG can inhibit the TNF-α and MMP-13 production induced by advanced glycation end products (AGEs) which are responsible for cartilage mechanical properties loss
      • Rasheed Z.
      • Anbazhagan A.N.
      • Akhtar N.
      • Ramamurthy S.
      • Voss F.R.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes.
      . This effect could happen through the attenuation of MAP kinase activation and inhibition of nuclear factor κB (NF-κB) activation. This is supported by the previous report of anti-catabolic activity and inhibitory effect on NF-κB and AP-1 signalling
      • Ahmed S.
      • Wang N.
      • Lalonde M.
      • Goldberg V.M.
      • Haqqi T.M.
      Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
      . Finally, this is of interest to note that the polyphenolic fraction of green tea can prevent the onset of arthritis and the severity of the disease in mice collagen-induced arthritis
      • Haqqi T.M.
      • Anthony D.D.
      • Gupta S.
      • Ahmad N.
      • Lee M.S.
      • Kumar G.K.
      • et al.
      Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea.
      . Complementary experiments are necessary in order to confirm the anti-inflammatory effect of EGCG on OA in vivo.

      Resveratrol

      Resveratrol is a stilbene that is naturally present at high concentration in grape skin and red wine. It has significant anti-inflammatory and anti-oxidant properties which could be beneficial in OA
      • Dave M.
      • Attur M.
      • Palmer G.
      • Al-Mussawir H.E.
      • Kennish L.
      • Patel J.
      • et al.
      The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production.
      . Only in vitro studies were identified for this compound. A total of five studies were performed in cartilage explants and chondrocytes
      • Williamson S.M.
      • Mobasheri A.
      • Vaughan-Thomas A.
      • Thompson N.J.
      • Shakibaei M.
      Curcumin and resveratrol reduce lipopolysaccharide mediated glycosaminoglycan release in an explant model of canine articular cartilage.
      • Dave M.
      • Attur M.
      • Palmer G.
      • Al-Mussawir H.E.
      • Kennish L.
      • Patel J.
      • et al.
      The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production.
      • Csaki C.
      • Keshishzadeh N.
      • Fischer K.
      • Shakibaei M.
      Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro.
      • Shakibaei M.
      • Csaki C.
      • Nebrich S.
      • Mobasheri A.
      Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis.
      • Lei M.
      • Liu S.Q.
      • Liu Y.L.
      Resveratrol protects bone marrow mesenchymal stem cell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitory effect of interleukin-1beta.
      . These studies indicated that resveratrol can have beneficial effects. It has demonstrated anti-inflammatory and anti-apoptotic properties
      • Dave M.
      • Attur M.
      • Palmer G.
      • Al-Mussawir H.E.
      • Kennish L.
      • Patel J.
      • et al.
      The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production.
      • Shakibaei M.
      • Csaki C.
      • Nebrich S.
      • Mobasheri A.
      Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis.
      . Resveratrol inhibited catabolic factors as MMPs and pro-inflammatory mediators as PGE2 and COX-2, and stimulated the synthesis of matrix components (PG, GAG, type II collagen)
      • Dave M.
      • Attur M.
      • Palmer G.
      • Al-Mussawir H.E.
      • Kennish L.
      • Patel J.
      • et al.
      The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production.
      • Shakibaei M.
      • Csaki C.
      • Nebrich S.
      • Mobasheri A.
      Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis.
      • Lei M.
      • Liu S.Q.
      • Liu Y.L.
      Resveratrol protects bone marrow mesenchymal stem cell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitory effect of interleukin-1beta.
      . These effects could prevent cartilage degradation. In addition, cartilage protection may be achieved with intra-articular injection of resveratrol. This was observed both in anterior cruciate ligament transaction OA model and LPS-induced arthritis model in rabbit
      • Elmali N.
      • Baysal O.
      • Harma A.
      • Esenkaya I.
      • Mizrak B.
      Effects of resveratrol in inflammatory arthritis.
      • Elmali N.
      • Esenkaya I.
      • Harma A.
      • Ertem K.
      • Turkoz Y.
      • Mizrak B.
      Effect of resveratrol in experimental osteoarthritis in rabbits.
      . These preclinical evaluations indicate an interesting potential of resveratrol in OA but additional in vivo studies are needed.

      Prodelphinidins

      Prodelphinidins are a type of condensed tannins and are composed of gallocatechin and epigallocathechin
      • Garbacki N.
      • Angenot L.
      • Bassleer C.
      • Damas J.
      • Tits M.
      Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity.
      . Only one in vitro study has investigated the effect of prodelphinidins. This study showed potential in vitro effects on human chondrocytes. Prodelphinidins seemed to increase PG and type II collagen and inhibited PGE2 synthesis by acting on COX-2
      • Garbacki N.
      • Angenot L.
      • Bassleer C.
      • Damas J.
      • Tits M.
      Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity.
      . These data are in favor of additional preclinical evaluations.

      Quercetin

      Quercetin is a plant-derived flavonoid. Anti-inflammatory and anti-oxidant properties have been suggested for this nutraceutical. Only one in vitro study in human synovial cells has been identified
      • Sato M.
      • Miyazaki T.
      • Kambe F.
      • Maeda K.
      • Seo H.
      Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells.
      . This study demonstrated potential anti-inflammatory effect by the inhibition of TNF-α mediated-IL-8 and monocyte chemoattractant protein-1 (MCP-1) expression. This suggested a potential anti-arthritic effect but further preclinical investigations are needed especially in OA.

      Ventol

      Ventol is a phlorotannin-rich natural agent derived from Ecklonia cava with anti-oxidant and anti-inflammatory activities
      • Kang K.
      • Hwang H.J.
      • Hong D.H.
      • Park Y.
      • Kim S.H.
      • Lee B.H.
      • et al.
      Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture.
      . One in vitro study on cartilage explants has shown the inhibition of PG degradation after IL-1α stimulation. This should be further studied to confirm the anti-OA potential of this compound.

      Discussion

      OA is a debiliting chronic disease with a serious need of alternative treatments that could help patients to preserve their joint function and therefore maintain a certain quality of life. We have here summarized most of the published effects of some nutraceuticals. Many results have been highlighted and the quality of the studies addressed.
      Globally, we can conclude to a lack of evidence for most of the studied compounds. The review by Ameye and Chee
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      has also analyzed the available studies at that time for ASU, n-3 PUFAs and CH. The same conclusions as ours were made, meaning that there are no strong clinical data available. So, there is a need for additional preclinical studies and CTs of good quality. In addition, this is important to note that the potencies demonstrated in preclinical studies for most compounds are not concordant with their clinical efficacy. This could be explained by the doses used in vitro and in animal models that are most of the time higher that the ones used in CTs. An other explanation could come from the fact that preclinical studies deal most of the time with early stages of the disease whereas CTs involve patients at later stages. This can justify the discordance between preclinical data and clinical and epidemiological observations.
      Many efforts have been carried out to find a cure for OA. OA management is a challenge for physicians and rheumatologists. Many alternatives are now available but recommendations have to be done. Nutraceuticals is one of these alternatives. They have great potential in OA but there is a need of strongly substantiated data.
      Many questions still remain to be addressed. Where should be the line between food and drugs drawn? This issue is well illustrated by ASU mixture. ASU are considered as prescribed drugs in France, but as food supplement in other countries. The prescribed drug, Piascledine®300, is now recommended for the treatment of OA symptoms. These recommendations are based on strong clinical evidence. However, in vitro studies have demonstrated that some of the beneficial effects of Piascledine®300 were related to its particular formulation resulting of a patented extraction process, and were not observed with other formulation (personal communication). This extraction process is responsible for specific changes in the unsaponifiable fractions of avocado and soybean that could explain their particular effects. This means that the natural food ingredient has underwent some modifications that are related to particular biological effects. Therefore, ASU should be chemically analyzed before to be considered as a food supplement or a nutraceutical. Nutraceutical is a broad term to qualify any product derived from food source that provides extra health benefits. This definition fails to precise whether a modified product derived from food source can be considered as a nutraceutical. The line between a nutraceutical and a drug is thin. Other criterion that can help to distinguish between a drug, food supplement, and nutraceuticals are the oral dose administrated and the bioavailability. Food supplement should be administrated at concentration found in the normal diet. Bioavailability would be a great criterion to demonstrate the potent efficacy of a product. For example, the pharmacokinetic of curcumin has been studied
      • Anand P.
      • Kunnumakkara A.B.
      • Newman R.A.
      • Aggarwal B.B.
      Bioavailability of curcumin: problems and promises.
      and many parameters that are opposed to curcumin efficacy have been described. In human, the serum concentrations of curcumin after an oral massive dose of 4, 6 or 8 g/day reach 0.5, 0.6 and 1.8 μM respectively. These concentrations are below the concentration showing a biological activity in vitro. However, new formulation of curcumin
      • Anand P.
      • Nair H.B.
      • Sung B.
      • Kunnumakkara A.B.
      • Yadav V.R.
      • Tekmal R.R.
      • et al.
      Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo.
      has enhanced cellular uptake, increased bioactivity in vitro and improved bioavailability in vivo. This is in favor of a better efficacy, meaning that the anti-inflammatory and other potencies of curcumin could be even more effective. Curcumin would become by the way a potent anti-inflammatory agent. For this reason, a clinical study has been initiated with complexed curcumin in patients with knee OA. This complexed curcumin (Arantal®) showed a 7000 times increased solubility. Can it be considered as a food supplement any longer? This critical point can also be illustrated by resveratrol. The pharmacokinetic of resveratrol can be modified by the addition of glycosyl groups that improved its absorption
      • Biasutto L.
      • Marotta E.
      • Bradaschia A.
      • Fallica M.
      • Mattarei A.
      • Garbisa S.
      • et al.
      Soluble polyphenols: synthesis and bioavailability of 3,4′,5-tri(alpha-D-glucose-3-O-succinyl) resveratrol.
      . This process could be applied to other polyphenols to increase their bioavailability.
      Can nutraceuticals still be considered as food supplement when used under drug formulation? These modifications should also be controlled and regulated. Moreover, food nutrients can target multiple pathways compared to monomodal mode of action of drugs. For example, some natural anti-oxidant peptides have also been identified in porcine CH
      • Li B.
      • Chen F.
      • Wang X.
      • Ji B.
      • Wu Y.
      Isolation and identification of antioxidative peptides from porcine collagen hydrolysate by consecutive chromatography and electrospray ionization-mass spectrometry.
      . CH has hypotensive potential
      • Zhang Y.
      • Kouguchi T.
      • Shimizu M.
      • Ohmori T.
      • Takahata Y.
      • Morimatsu F.
      chicken collagen hydrolysate protects rats from hypertension and cardiovascular damage.
      • Faria M.
      • da Costa E.L.
      • Gontijo J.A.
      • Netto F.M.
      Evaluation of the hypotensive potential of bovine and porcine collagen hydrolysates.
      . This is an additional advantage for the use of CH. Moreover, it has recently been demonstrated that some nutraceuticals are even more effective when used in combination. It has been shown for EGCG and ASU
      • Heinecke L.F.
      • Grzanna M.W.
      • Au A.Y.
      • Mochal C.A.
      • Rashmir-Raven A.
      • Frondoza C.G.
      Inhibition of cyclooxygenase-2 expression and prostaglandin E2 production in chondrocytes by avocado soybean unsaponifiables and epigallocatechin gallate.
      and resveratrol and curcumin
      • Csaki C.
      • Mobasheri A.
      • Shakibaei M.
      Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis.
      . Safety and toxicity of nutraceuticals added alone or in combination should also be addressed, especially if bioavailability and biological activity are increased. Pharmacokinetic of all these compounds should be described and safety monitoring should be done.
      For these reasons, the safety and effectiveness of these products are under strict regulation in Europe. The problem is that the criterion of evaluation for clinical studies are defined as for pharmaceutic standards and this penalizes foods in terms of effect size and also of absence of acute effect. OA as a chronic disease has a long time window for intervention and should benefit from functional food alternatives to pharmacological interventions to improve subjects’ quality of life day after day.
      We have also searched for the ongoing CTs with nutraceuticals. They are all summarized on Table VIII and given an overview of the current research interest on the selected ingredients. The number of ongoing trials supports the growing interest to identify their role in OA treatment. Two CTs are ongoing in order to evaluate the efficacy of vitamin D supplementation on pain, mobility and joint structure in OA patients. Because of their high quality (long duration and strong study design) these results will be valuable for the determination of the role that could play vitamin D supplementation in OA. More evidences are needed regarding the role that it could play in the prevention of OA. Two CTs are ongoing on curcumin to determine whether the consumption of a plant extract with high curcumin content alleviates pain in subjects with OA. Furthermore, one CT was just completed with CH. It was the first one interested in the structure-modifying effect of the studied compound. The results are not yet available. Additional CTs should assess the potential of nutraceuticals in a long-term use in OA and should also be interested in their structure-modifying effect which is the great challenge in seeking new OA treatment.
      We have shown here that most of the studied compounds could have beneficial effects in the treatment of OA, even if we still need more evidence. They could represent great alternatives for OA management. We have only detailed here the information for a few compounds but others can also represent great potential. Indeed, other lipids, vitamins, minerals or plant extracts have also been demonstrated to be effective in OA. Probiotics could also be considered for the treatment of OA. Several studies have highlighted the importance of intestinal flora in inflammatory auto-immune diseases, such as rheumatoid arthritis. Beneficial anti-inflammatory properties and modulatory effect of immune response of probiotics on rheumatoid arthritis were demonstrated in animals
      • Cobelens P.M.
      • Heijnen C.J.
      • Nieuwenhuis E.E.
      • Kramer P.P.
      • van der Zee R.
      • van Eden W.
      • et al.
      Treatment of adjuvant-induced arthritis by oral administration of mycobacterial Hsp65 during disease.
      • So J.S.
      • Kwon H.K.
      • Lee C.G.
      • Yi H.J.
      • Park J.A.
      • Lim S.Y.
      • et al.
      Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions.
      • So J.S.
      • Lee C.G.
      • Kwon H.K.
      • Yi H.J.
      • Chae C.S.
      • Park J.A.
      • et al.
      Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis.
      . In addition, the consumption of lactobacilli contained in a yogurt demonstrated the preventive and curative effects on T-cell-dependent experimental arthritis by reducing the intensity of inflammation and joint destruction in animals
      • Baharav E.
      • Mor F.
      • Halpern M.
      • Weinberger A.
      Lactobacillus GG bacteria ameliorate arthritis in Lewis rats.
      . In the same way, CTs have evaluated the effects of probiotics on the activity and on the symptoms of rheumatoid arthritis
      • Hatakka K.
      • Martio J.
      • Korpela M.
      • Herranen M.
      • Poussa T.
      • Laasanen T.
      • et al.
      Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis–a pilot study.
      • Nenonen M.T.
      • Helve T.A.
      • Rauma A.L.
      • Hanninen O.O.
      Uncooked, lactobacilli-rich, vegan food and rheumatoid arthritis.
      . The positive findings of these studies suggested the need of complementary studies on the effects on probiotic bacteria in rheumatoid arthritis. There is a lack of data on the effect of probiotics on OA in the literature. The potential effect of probiotics on OA has not been extensively studied but the data on their effect in arthritis suggest that they could have a potential interest in OA.

      Conclusion

      We have gathered here all the studies and CTs about some nutraceuticals. Some results are really promising and encouraging. The main concern remains the quality of studies. There is a need of serious and well designed studies that could answer most of the questions regarding the safety and efficacy of such compounds. This could help their recommendation for OA treatment.
      Many studies have been carried out in order to highlight the potency of several nutraceuticals for the treatment of OA. Nutraceuticals offer a large variety of products with a wide range of effects. They open new and large horizons for the treatment of chronic disease as OA. Clinical endpoints for foods should be reconsidered. Further investigations are needed but nutraceuticals are not negligible for OA management. They should be considered as potent adjuvant treatments with NSAIDs for example. Early markers development would also enable to build prevention strategies for food, in absence of cure treatment for OA.

      Author contributions

      Conception and design of the study: YH, EC.
      Acquisition of data: CL, DC, CR.
      Analysis and interpretation of data: YH, EC, CL, DC, CR.
      Preparation of manuscript: YH, EC, DC.
      Final approval of manuscript: YH, CL, DC, CR, EC.

      Conflict of interest

      YH is a consultant for BioXtract and Danone. He is also the coordinator of the CTs on curcuma operated by BioXtract. (Arantal®; NCT00992004). Naturalpha was financed by Danone to set-up scoring methodology, perform the identification, selection and scoring of relevant studies for the review. Other authors declare no conflict of interest.

      Acknowledgments

      The authors would like to thank Eric Chappuis and Adeline Pierre for their active role in the quality assessment methodology set-up and for performing the literature search.

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