PIIS1063458410003584

Osteoarthritis and Cartilage 19 (2011) 1e21
Review
Nutraceuticals: do they represent a new era in the management of

osteoarthritis? e a narrative review from the lessons taken with
five products
Y. Henrotin y *, C. Lambert y, D. Couchourel z, C. Ripoll x, E. Chiotelli z
y Bone and Cartilage Research Unit, Institute of Pathology, level 5, CHU Sart-Tilman, 4000 Liège, Belgium
z Danone Research, avenue de la Vauve, F-91767 Palaiseau cedex, France
x Naturalpha SAS, 85 rue Nelson Mandela, 59120 Loos, France
a r t i c l e i n f o s u m m a r y
Article history: Objectives: The aim of this first global systematic review on selected nutraceuticals was to synthesize and
Received 11 May 2010 evaluate scientific relevant data available in the literature. Evidences that can support health, physio-
Accepted 17 October 2010 logical or functional benefit on osteoarthritis (OA) were gathered and the level of evidence relative to
each of these ingredients was highlighted.
Keywords: Methodology: Relevant scientific data (positive or not) regarding OA were searched for five groups of
Osteoarthritis
compounds (avocado/soybean unsaponifiables (ASU), n-3 polyunsaturated fatty acids, collagen hydro-
Nutraceuticals
sylates (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 deter-
mined 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, epi-
gallocatechin-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.
Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Introduction by the loss of joint function. In addition, aging patients present

various co-morbid conditions that add to the complexity of the
Osteoarthritis (OA) is the most prevalent joint disease. It causes treatment of OA patients.
pain and disability in a large proportion of the population world- To date, there is no cure for OA. The only available treatments
wide. It is considered as the most consequential rheumatic condi- aim at reducing symptoms, as pain and inflammation, maintain
tion in terms of social-economic impacts. The incidence of the joint mobility and limit the loss of function. The main goals that the
disease increases with age. The disease evolves over decades to end ideal OA treatment has to achieve are symptom-modifying effect,
reducing pain and inflammation, and structure-modifying effect,
* Address correspondence and reprint requests to: Y. Henrotin, Bone and carti- sparing joint structure and preventing joint degradation in order to
lage Research Unit, Institute of Pathology, level 5, CHU Sart-Tilman, 4000 Liège, maintain articular function.
Belgium. Tel: 32-4-3662516.
E-mail address: yhenrotin@ulg.ac.be (Y. Henrotin).
Several guidelines, as the European League Against Rheumatism
URL: http://www.bcru.be (EULAR), the American College of Rheumatology (ACR) or the
1063-4584/$ e see front matter Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.joca.2010.10.017
2 Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21
Osteoarthritis Research Society International (OARSI) recommen- and Drug Administration (FDA). Nutraceuticals are monitored as
dations for the management of knee OA1e4 have been published for dietary supplement within the US and the definition for functional
OA management. They all recommend both non-pharmacological foods varies depending on countries. In Europe the situation is
and pharmacological approaches. The non-pharmacological inter- different with an ongoing regulatory reform tightening the existing
ventions include education and self-management, regular tele- regulatory framework. Indeed, European Food Safety Authority
phone contact, referral to a physical therapist, aerobic, muscle (EFSA) adopted Regulation 1924/2006 on the use of nutrition and
strengthening and water-based exercises, weight reduction, health claims for food in December 2006. This regulation
walking aids, knee braces, footwear and insoles, thermal modali- harmonised rules across the European Union (EU) for the use of
ties, transcutaneous electrical nerve stimulation and acupuncture. health or nutritional claims on foodstuffs, which are based on
The pharmacological treatments consist of acetaminophen, cyclo- nutrient profiles. One of its key objectives is to ensure that all
oxygenase-2 (COX-2) non-selective and selective oral non-steroidal claims made on food labels in the EU are “clear and substantiated
anti-inflammatory drugs (NSAIDs), topical NSAIDs and capsaicin, by scientific evidence”. EFSA is responsible for verifying the scien-
intra-articular injections of corticosteroids and hyaluronates, tific substantiation of the submitted claims, some of which are
glucosamine and/or chondroitin sulphate, and avocado/soybean currently in use, some of which are proposed by applicants. This
unsaponifiables (ASU) for symptom relief; glucosamine sulphate, information serves as a basis for the European Commission and
chondroitin sulphate and diacerein for possible structure-modi- Member States, which will decide whether to authorize each
fying effects and the use of opioid analgesics for the treatment of individual product claim. EFSA started to release opinions in
refractory pain1,5. Most of the pharmacological treatments available October 2009 on health claims submitted under Article 13 of the
to relieve OA symptoms present serious adverse events, as the risk regulation, covering so-called generic health claims.
of gastro-intestinal or cardiovascular adverse events with NSAIDs. The aim of this first global systematic review on selected
Moreover, this disease implies treatment or drug intake for nutraceuticals was to synthesize and evaluate scientific relevant
decades, increasing the risk of serious adverse events and the data available in the literature. Evidences that can support health,
incidence of co-morbidity factors. physiological or functional benefit on OA were gathered and the
Many efforts have been developed to find a cure to OA that can level of evidence relative to each of these ingredients was
satisfy all the above-mentioned goals. The perfect drug would be highlighted.
not only able to relieve inflammation and pain but also to slow
down, stop or even better prevent disease progression. This would Methodology
result in the maintenance of joint function, sparing joint structures
involved in OA, meaning cartilage, synovial membrane and sub- Relevant scientific data (positive or not) regarding OA were
chondral bone. searched for five groups of compounds (Table I) within in vitro
From the molecular point of view, OA joints are the site of (Table III), in vivo (Table IV), epidemiological (Table V), and clinical
inflammation and catabolism. Many key mediators have been studies (Table VI). The selection of compounds discussed in this
identified in cartilage for both pathways. Inflammation is linked to paper is arbitrary and was based mainly on the following criteria:
interleukin (IL)-1b, COX-2 expression and prostaglandin E2 (PGE2) amount of emerging science, safety of use, regulatory constrains
and nitric oxide (NO) production. Catabolism results from an (Novel Food), natural presence in food. The objective was in the end
imbalance with anabolism. The synthesis of catabolic enzymes as to identify ingredients that could support joint health, but also that
different matrix metalloproteinases (MMP-1, 3 or -13) or the dis- could be authorized in food and would be relevant to be delivered
integrin and metalloprotease with thrombospondine motifs through a food matrix.
(ADAMTS)-4 and -5 (also known as aggrecanases) is increased We have voluntary eliminated glucosamine sulphate, glucos-
resulting in the degradation of the main cartilage matrix compo- amine-HCl, and chondroitin sulphate because these natural
nents (proteoglycan (PG) and type II collagen). In parallel, the compounds are considered as drugs in some countries, and that
synthesis of the matrix components is decreased. Synovial they have been the main topic of numerous systematic review and
inflammation is directly linked to cartilage degradation. In addition, meta-analysis5,8e13. The search was performed according to the
subchondral bone is the site of strong remodeling processes following criteria: (1) only scientific data with a direct link to OA
resulting in bone sclerosis. All these factors produce the loss of the were selected; (2) only orally administered treatments were
articular integrity and the loss of joint function. selected for in vivo studies and clinical trials (CTs); (3) only publi-
Indeed, there is a strong necessity for prevention of OA. The first cations in English were considered (4) only scientific data allowing
step passes by healthy lifestyle, weight loss and nutrition, with to evaluate the effect of the compound alone were considered.
specific nutrients that could help to achieve this goal. Nutraceut- Articles describing the results of a study previously published were
icals are good candidates to help patient preventing OA or excluded. The search was performed in Pubmed/Medline database
managing their disease using them as treatment adjuvant. between January 1990 and 2010.
Nutraceutical comes from the combination of the words nutri- This search was performed using the combination of terms
tion and pharmaceutical. It corresponds to food or food product related to OA (arthrosis or osteoarthr* OR gonarthro* OR coxarthro*
that provide health and medical benefits, including prevention and OR “joint pain” OR “joint comfort” or chondro* or fibroblast* OR
treatment6,7. By definition and regulatory laws they are devoid of
adverse effects.
Table I
Nutraceuticals are good candidates for long-term prevention of Studied compounds
chronic disease, such as OA. Many compounds have already been
- n-3 PUFAs
studied and a review by Ameye and Chee6 has gathered all the
B EPA
scientific data available at that time. There are several emerging
B DHA
alternatives. It is more and more recognized that nutraceuticals B ALA
could help to maintain bone and joint health. However this is - ASU
paramount to give a critical point of view to judge the quality of the - CHs
studies. Nutraceuticals are under minimal and vague regulation. - Vitamin D
- Polyphenols
Dietary supplements do not have to be approved by the US Food
Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21 3
Table II
Results of Pubmed data search performance
Compound Total number of Total number of Nb of in vitro Nb of in vivo Nb of Nb of

publications publications studies studies observational CTs interventional CTs
retrieved selected
n-3 PUFAs 1508 9 4 2 1 2
ASU 59 17 9 4 0 4
CHs 51 7 2 1 0 4
Vitamin D 2249 9 3 1 5 0
Pine bark extract 13 4 0 0 0 4
Prodelphinidins 1 1 1 0 0 0
Nobiletin 10 3 3 0 0 0
Genistein 571 3 2 1 0 0
EGCG 81 7 7 0 0 0
Resveratrol 146 6 5 1 0 0
Curcumin 231 12 12 0 0 0
Ventol 2 1 1 0 0 0
Quercetin 210 1 1 0 0 0
synov* OR subchond* OR cartilage OR collagen) and each studied inflammatory diseases as rheumatoid arthritis16,17. These studies
compound name (or abbreviation). demonstrated the beneficial effects of a higher n-3 intake. It is
The methodological quality of each CT supporting functional important to note that Western diet is richer in n-6 PUFAs (linoleic
ingredient efficacy was determined according to an assessment acid and arachidonic acid) rather than in n-3 PUFAs6.
model adapted from EFSA and FDA recommendations (EFSA, 2007;
FDA, 2003), AFSSA (“Agence Française de Sécurité Sanitaire des In vitro and preclinical data
Aliments”) guidelines (AFSSA, 2007) and other relevant refer- n-3 PUFAs have been extensively studied in various cell types,
ences6,14,15 (ANAES “Agence Nationale d’Accréditation et d’Evaluation but only few studies have assessed their anti-inflammatory or anti-
en Santé”, 2000). The quality is scored according to a set of 14 OA effects in joint cell models. Three in vitro studies have been
criteria. One point is marked for each criterion presented in the identified using bovine chondrocytes or human and bovine carti-
description of the CT. The points are then summed and the final lage explants. These studies used n-3 PUFAs alpha-linolenic acid
score allow classifying the CT quality in four different categories: (ALA), EPA and docohexanoic acid (DHA)18e20. These studies
a score below six represents a poor methodological quality, from 7 demonstrated the potency of n-3 PUFAs at reducing inflammatory
to 9 represents a medium methodological quality, from 10 to 11 mediators (IL-1a, COX-2, 5-lipoxygenase (LOX) and its activator
represents a good methodological quality and finally a score from FLAP) and also catabolic factors (MMPs or ADAMTS). Furthermore,
12 to 14 represents a very good methodological quality. recent published data have also shown that n-3 PUFAs reduced
A scientific consensus was reached between the two evaluators IL-1b-induced ADAMTS-4, -5, MMP-3, -13 and COX-2 mRNA in
(YH and CL) by considering different points: the total number of CTs bovine chondrocytes culture21.
(showing or not a beneficial effect), the quality of these CTs, the Similarly, only one animal study on n-3 PUFAs and OA has been
number of epidemiological studies showing or not a relationship, the identified in the literature22. This study investigated the effect of
heterogeneity in the body of evidence, the presence of preclinical n-3 PUFAs on rats with a marginally deficient essential fatty acid
basis and the presence of ongoing CTs. The studies were then clas- state. n-3 PUFA produced a 70% maximum decrease in the linoleic
sified as good evidence of efficacy, moderate evidence of efficacy, and arachidonic acid content of articular cartilage. n-3 PUFA also
limited evidence of efficacy but suggestive, preclinical evidence of produced a 30e40% decrease in the cartilage hexosamine content
efficacy, lack of evidence of efficacy, some evidence of inefficacy. and a 32% inhibition of PG synthesis. This is important to keep in
Scientific consensus for each ingredient is summarized in Table VII. mind that this study demonstrated that a too low n-6/n-3 ratio can
Furthermore, a search of ongoing CTs (Table VIII) was carried out be negative, as a diet with very low n-6 PUFAs intake induced
on the clinicaltrials.gov database using the term “osteoarthritis” and surface irregularities and PG depletion in cartilage of rats6,22.
each studied compound’s name, in order to complete existing Finally, the only one in vivo study testing n-3 PUFAs in client-
published data and give an overview of current research interest on owned OA dogs was just published23. The results are in favor of the
the selected ingredients. beneficial effect of n-3 PUFAs on OA dogs.
Results Epidemiological data

One observational study was identified. This study investigated
Bibliographic search results using Magnetic resonance Imaging (MRI), the association of
different fatty acids consumption with cartilage structure and bone
The results of the search performed on Pubmed/Medline data- marrow lesions (which have been shown to be associated with knee
base are described in Table II. pain and predictive of cartilage loss in knee OA)24. The main obser-
vation of this study showed that high intakes of monounsaturated,
N-3 polyunsaturated fatty acids (n-3 PUFAs) total and n-6 PUFAs are associated with increased risks of bone
marrow lesions. The results made no association between n-3 PUFAs
n-3 PUFAs (linolenic acid and eicosapentenoic acid (EPA)) are and either bone marrow lesions or cartilage volume or defects.
essential fatty acids. These compounds are candidate for the
reduction of inflammation as they can substitute arachidonic acid Clinical data
(main precursor of prostaglandins) in the synthetic pathway of The clinical data on n-3 PUFAs are limited. Two studies that
inflammatory mediators. The reduction of inflammation can also investigated the effect of natural extract or oil with high content of
have an impact on the catabolic pathways and by that way on disease n-3 PUFAs on OA symptoms were identified. One study of medium
progression. They have been widely studied in cardiovascular and quality (score: 7)25 showed that a daily intake of 10 ml of cod liver
Table III
4
Summary of the in vitro effects of the studied products on OA
Reference Product Dose and incubation In vitro model Results

duration (ID)
n-3 PUFAs
Curtis et al. 200018 EPA, DHA or ALA 10e100 mg/ml Bovine chondrocytes Dose-dependent reduction of IL-1a induced-aggrecanase expression and activity
ID: 8 h Reduction of IL-1a, TNF-a and COX-2 (with ALA) expression
Curtis et al. 2002 19
ALA or EPA 10e100 mg/ml Human OA cartilage explants Reduction of endogenous and IL-1-induced release of PG
ID: 24 h 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. 200220 EPA or ALA 10e300 mg/ml Normal bovine or Reduction of IL-1-induced inflammation and catabolism
24 h pre-treatment with EPA or ALA osteoarthritic human cartilage (reduction of GAG release, and of aggrecanase activity, loss of
and 4 days ncubation with IL-1b explants stimulated with IL-1b COX-2 and 5-LOX expression) by n-3 PUFA
No effect of n-3 PUFA on normal tissue homeostasis
Zainal et al. 200921 EPA, DHA or ALA 2.5e30 mg/ml Normal bovine articular Demonstration of the chondrocyte ability to incorporate exogenous PUFAs
8 h pre-treatment and 4 days chondrocytes stimulated with Reduction of IL-1b-induced production of cartilage degradating
Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

incubation with IL-1b IL-1b enzyme (agrecanases, MMPs) and inflammatory cytokines
Inhibition of COX-2 by n-3 PUFAs but not COX-1
ASU
Mauviel et al. 198933 ASU 0.1e10 mg/ml Synoviocytes No impact of ASU alone on collagen synthesis in synoviocytes and
ID: 24 h and 8e14 days Rabbit articular chondrocytes chondrocytes after 24 hInhibition of IL-1b-induced collagen synthesis decrease
in synoviocytes after 24 hStimulation of collagen synthesis on articular
chondrocytes after 8e14 days
Mauviel et al. 199134 ASU PiascledineÒ 10 mg/ml Rabbit articular chondrocytes Slight increase of collagen production in both cell types
ID: 48 h Human rheumatoid Partial inhibition of IL-1b-induced release of collagen in synovial
synovial cells cells and total suppression in chondrocytes
Henrotin et al. 199835 ASU mixed in 10 mg/ml Human chondrocytes Reduction of the stromelysin (MMP-3), IL-6, IL-8 and PGE2 spontaneous
three ratios ID: 72 h productionDecrease of the collagenase activity in unstimulated and stimulated
1:2 (A1S2) chondrocytes by A1S2Partial inhibition of IL-1 effects
2:1 (A2S1)
1:1 (A2S2)
Boumediene et al. 199939 ASU 10e25 mg/ml Bovine articular chondrocytes Stimulation of the expression of TGFb1, TGFb2, plasminogen
activating inhibitor-1 (PAI-1)
Henrotin et al. 2003 36
ASU (A1S2) 0.625e40 mg/ml Human OA chondrocytes Stimulation of aggrecan production and restoration of aggrecan
ID: 12 days stimulated or not with IL-1b production after IL-1b stimulation
Decrease of basal and IL-1b-stimulated MMP-3 production
Weak inhibition of IL-1b einduced TIMP reduction
Inhibition of basal production of MIP-1b, IL-6, IL-8, NO and PGE2
Stimulation of TIMP-1 production
Henrotin et al. 2006 ASU 10 mg/ml Human OA chondrocytes Prevention of the inhibitory effects of SC osteoblasts on matrix
(abstract)40 ID: 72 h co-cultured or not with components by pre-treatment of SC osteoblasts with ASU
osteoblasts (obtained from Increase of type II collagen mRNA level in co-culture with
sclerotic (SC) or non-sclerotic ASU-pretreated SC osteoblasts
(NSC) zones of OA No modification of MMP, TIMP-1, TGF-b1, TGF-b3 or iNOS
subchondral plate expression and COX-2 mRNA levels in chondrocytes when
co-cultured with ASU-pretreated SC osteoblasts
Au et al. 200738 ASU 25 mg/ml Chondrocytes Reduction of TNF-a, IL-1b, COX-2 and iNOS expression in LPS-stimulated
ID: 72 h THP-1 monocytes/macrophages chondrocytes to non-activated control levels
Reduction of PGE2 production and COX-2 and iNOS expression
Reduction of TNF-a in LPS-stimulated monocyte/macrophage
Lippiello et al. 200832 Sterols extracted from 1e10 mg/ml (sterols) Bovine chondrocytes Upregulation of non-collagenous protein and collagen synthesis as well
three ASU preparations ID: 48 h as of labelled sulphate uptake
Inhibition of IL-1-induced MMP-3 activity, PGE2 synthesis and
sulphate release
Gabay et al. 200837 ASU 10 mg/ml Mouse or human Decrease of MMP-3 and -13 expression and PGE2 synthesis
chondrocytes stimulated Inhibition of the degradation of IkBa and suppression of NF-kB translocation
with IL-1b Inhibition of Erk 1/2 but no effect on the other IL-1b-induced MAPK
Cartilage submitted to a
compressive mechanical
stress (MS)
CH
Oesser and Seifert, 200350 CH 0.5 mg/ml Bovine chondrocytes Dose-dependant increase of type II collagen secretion
ID: 48 h 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. 200651 CH Not provided (NP) Porcine articular chondrocytes Increase of PG synthesis, aggrecan expression and type II collagen biosynthesis
Glucosamine Human femoral head chondrocytes with CH
No effect of glucosamine on extracellular matrix macromolecules
(glucosamine sulphate and hydrochloride)

Vitamin D
Tetlow and Woolley, 199966 1,25-dihydroxy- 108 M Rheumatoid synovial No effect on spontaneous MMP and PGE2 production by RSF
vitamine D3 ID: 48 h fibroblasts (RSF) Reduction of IL-1b-induced MMP and PGE2 production (up to 50%) by RSF
stimulated or not with IL-1b Slight reduction of spontaneous MMP-1 and -3 production by chondrocytes
Human articular chondrocytes No effect on IL-1b-induced MMP and PGE2 production and stimulation of
stimulated or not with IL-1b IL-1b-induced MMP-3 production by chondrocytes
Cantatore et al. 200460 1,25-dihydroxy- 108 M Osteoblasts from OA subchondral Increased stimulation of osteoclacin production by maximally damaged
vitamine D3 ID: 48 h bone samples Osteoblasts compared to minimally damaged ones
Tetlow and Woolley, 200165 1,25-dihydroxy- 108 M Human articular chondrocytes No effect on MMP-1, -9 and PGE2 production
vitamine D3 ID: 48 h stimulated with TNF-a or Upregulation of MMP-3 with or without stimulation with TNF-a or PMA
phorbol myristate acetate (PMA)
Polyphenols
Ishiwa et al. 200078 Nobiletin NP Rabbit synovial fibroblasts Suppression of IL-1-induced MMP-9 mRNA expression and production
ID: NP Rabbit articular chondrocytes Reduction of IL-1-induced PGE2 production
No modification of the synthesis of total protein
Imada et al. 200877 Nobiletin 16e24 mM Normal human synovial Suppression of IL-1b-induced ADAMTS-4 and -5 mRNA expression
ID: 24 h fibroblasts
Lin et al. 200379 Nobiletin 6e64 mM Normal human synovial Suppression of IL-1b-induced production
ID: 24 h fibroblasts of PGE2 in a dose-dependant manner
Selective downregulation of COX-2 but not
COX-1 mRNA expression
Downregulation of IL-1b-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 Resveratrol and/ 2.5 mM LPS-stimulated canine Decrease of GAG release by curcumin
(abstract)86 or Curcumin ID: 5 days cartilage explants alone and in combination with resveratrol
Lev-Ari et al. 200692 Curcumin 0e20 mM OA synovial adherent cells Increased inhibitory effect of celecoxib on COX-2 activity
ID: 72 h Stimulation of the growth-inhibitory and anti-apoptotic effects of celecoxib
Schulze-Tanzil et al. 200482 Curcumin 50 mM Human chondrocytes Prevention of IL-1b-induced MMP-3 upregulation
ID: 12e48 h stimulated with IL-1b Inhibition of IL-1b-induced-type II collagen synthesis suppression
Prevention of NF-kB translocation
Shakibaei et al. 200584 Curcumin 50 mM Human articular chondrocytes Anti-apoptotic and anti-catabolic effects on IL-1b-stimulated chondrocytes
ID: 5e30 min
(continued on next page)
5
Table III (continued)
6
Reference Product Dose and incubation In vitro model Results
duration (ID)
Liacini et al. 200381 Curcumin 10e15 mM Human OA chondrocytes Inhibition of TNF-a-induced MMP-13 gene expression
ID: 24 h
Shakibaei et al. 200783 Curcumin 50 mM Human articular chondrocytes Suppression of NF-kB mediated IL-1b or TNF-a catabolic signalling pathways
ID: 72 h stimulated with IL-1b
resulting in COX-2 and MMP-9 downregulation and type II collagen upregulation
Toegel et al. 200885 Curcumin 5e50 mM Immortalized human chondrocytes No effect on aggrecan and type I and II collagen gene expression, proliferation
ID: 24e48 h (C-28/I2) stimulated with IL-1b 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)89 Curcumin 25e100 mM Equine cartilage explants Reduction of IL-1b-induced GAG release (50e100 mM)
ID: 5 days stimulated with IL-1b Decrease of PGE2 release (25e100 mM)
Clutterbuck et al. 2009 87
Curcumin 0.1e100 mM Equine cartilage explants Suppression of IL-1b-induced GAG release
ID: 5 days stimulated with IL-1b
Mathy et al. 2007 (abstract)88 Curcumin 1e30 mM Primary bovine chondrocytes No effect on cell viability
ID: 24 h stimulated with IL-1b Dose-dependant inhibition of IL-1b-induced COX-2, iNOS, IL-6 and IL-8 gene
expression, PGE2 and NO production

Chowdhury et al. 200891 Curcumin 0.01e1000 ng/ml Bovine chondrocytes cultured Inhibition of IL-1b-induced NO and PGE2 release
ID: 48 h in agarose Inhibition of 35SO4 incorporation
Mathy-Hartert et al. 2009 90
Curcumin 5e20 mM Human articular chondrocytes No effect on cell viability
ID: 12 days in alginate beads and Dose-dependent reduction of the synthesis of inflammatory mediators
human cartilage explants (NO, PGE2, IL-6, IL-8) and catabolic factor (MMP-3)
stimulated with IL-1b
Claassen et al. 200894 Genistein 1011e104 M Foetal bovine articular chondrocytes No effect on GAG release within the physiological range of concentrations
ID: 24 h Decrease of GAG release with high doses (105e104 M)
(for incubation or No effect on sulphate incorporation by chondrocytes
preincubation) Preincubation with 109e105 M enhanced the stimulatory effect of insulin
on sulphate incorporation by chondrocytes
Hooshmand et al. 200795 Genistein 50e100 mM Human chondrocytes stimulated Reduction of pro-inflammatory molecules (COX-2 and NO)
ID: 1 h by LPS No effect of YKL-40 (marker of cartilage metabolism) or IL-1b levels
preincubationþ24 h
Singh et al. 200298 EGCG 1e100 mM Human OA chondrocytes Inhibition of IL-1b-induced NO production by interfering with NF-kB activation
ID: 30 min stimulated with IL-1b
preincubationþ24 h
Ahmed et al. 200297 EGCG 100e200 mM Human OA chondrocytes Dose-dependant inhibition of NO and PGE2, iNOS and COX-2 expression
ID: 2 h stimulated with IL-1b
preincubationþ24 h
or 24 h without
preincubation
Singh et al. 200399 EGCG 5e200 mM Human OA chondrocytes stimulated Suppression of IL-1b-induced upregulation of catabolic mediators dependant
ID: 24e48 h with IL-1b on the activation of c-jun N-terminal kinase (JNK) activation
Rasheed et al. 2009102 EGCG 25-200 mM Human OA chondrocytes stimulated Inhibition of AGE-induced expression of TNF-a and MMP-13
ID: 1e2 h pre-treatment with AGE Attenuation of the AGE-induced MAP kinase signalling pathways
with EGCGþ4 days treatment Inhibition of NF-kB activation
with AGE
Ahmed et al. 2004 103
EGCG 1e200 mM Human cartilage explants and Inhibition of IL-1b-induced GAG release from human cartilage explants
ID: 72 h chondrocytes Dose-dependant inhibition of MMP-1 and MMP-13 IL-1b-induced mRNA and
protein expression in human chondrocytes
Dose-dependant inhibition of transcription activity of NF-kB and AP-1
Tokuda et al. 2008 (abstract)100 EGCG NP Osteoblast-like MC3T3-E1 cells Inhibition 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. 2009101 EGCG 10e50 mM Human synovial fibroblasts stimulated Inhibition of IL-1b-induced COX-2 expression and synthesis
ID: 12 h with IL-1b Inhibition of IL-1b-induced PGE2 and IL-8 secretion
Williamson et al. 2006 (abstract)86 Resveratrol and/or 2.5 mM Canine cartilage explants stimulated Decrease of GAG release by resveratrol alone
Curcumin ID: 5 days with LPS Inhibition of the degradative effects of LPS and decrease of GAG release by
co-treatment with resveratrol and curcumin
Dave et al. 2008105 Resveratrol 1e10 mM Human OA chondrocytes and Inhibition of IL-1b-induced and spontaneous of PGE2 and LTB4 production,
ID: 1 h pre-treatment cartilage explants stimulated and suppression of COX-2 expression
by IL-1b Spontaneous stimulation of PG and inhibition of pro-MMP-13
Prevention of OA cartilage degradation from IL-1b-induced effects
Prevention of chondrocytes apoptosis
Csaki et al. 2008106 Resveratrol 1e200 mM Human articular chondrocytes Chondroprotective effect through suppression of IL-b-, reactive oxygen species
ID: 1e24 h stimulated by IL-1b (ROS)- and tumor suppressor protein p53-production
Shakibaei et al. 2008107 Resveratrol 100 mM Human articular chondrocytes Inhibition of IL-1b-induced vascular endothelial growth factor (VEGF), MMP-3,
ID: 4 h (pre- stimulated by IL-1b MMP-9 and COX-2
treatment þ 1e32 h Suppression of apoptosis and inflammatory signalling by acting on NF-kB
(in combination
with IL-1b)
Lei et al. 2008108 Resveratrol 100 mM Rat bone marrow mesenchymal Inhibition of IL-1b-induced downregulation of type II collagen and aggrecan
ID: 24 h stem cells derived chondrocytes and increased of MMP-13 expression by reducing the translocation of NF-kB
stimulated by IL-1b and cultures Spontaneous decrease of type II collagen but no effect on aggrecan and
on chitosan-gelatine MMP-13 expression
scaffolds (CGS)

Garbacki et al. 2002111 Prodelphidins isolated 1e100 mg/ml Human chondrocytes Stimulation of PG and type II collagen production by all tested prodelphidins
from Ribes nigrum ID: 5 mine12 days Decreased of PGE2 synthesis by all prodelphidins
Gallocathechin trimer Inhibition of COX-2 but not COX-1 by all prodelphidins
(CG-CG-CG), dimer
(CG-CG) or monomer
(CG-ECG)
Sato et al. 1997 (abstract)112 Quercetin NP Human synovial cells Suppression of TNF-a mediated stimulation of IL-8 and MCP-1 expression,
at least in part by inhibiting NF-kB activation
Kang et al. 2004 (abstract)113 Ventol NP Cartilage explants Inhibition of IL-1b-induced PG degradation
IkB: inhibitor of NF-kB.
7
Table IV
8
Summary of the in vivo effects of the studied products on OA
Reference Product Dose and ID In vivo model Results

n-3 PUFAs
Lippiello et al., 1990 (abstract)22 n-3 PUFA Diet with 10% menhaden fish oil Male SpragueeDawley with a “marginally 70% maximum decrease in articular cartilage content of the
(menhaden fish oil) ID: NP deficient” essential fatty acid state linoleic and arachidonic acid in the fish oil treated group
30e40% decrease in cartilage hexosamine content and 32%
inhibition of PG synthesis
Roush et al., 201023 n-3 PUFA Diet with 31-fold increase of the Client-owned dogs with OA Significant improvement of dog conditions
total omego-3 fatty acids N ¼ 127
ID: 24 weeks
ASU
Cake et al., 200028 ASU 900 mg/weekday vs placebo Ovine model of knee OA (bilateral lateral Reduction of subchondral bone sclerosis and increase of PG
ID: 6 months meniscectomy) content and of articular knee joint thickness
N ¼ 32
Altinel et al., 200742 ASU 300 mg every day or every 3 days Sheepdogs Increase of both TGF-b1 and TGF-b2 levels in knee joint fluid
ID: 3 months Control: normal diet
N ¼ 24
41
Kawcak et al., 2007 ASU (A1:S2) NP Experimentally induced OA in horses No effect on pain and lameness

ID: 70 days N ¼ 16 Reduction of the severity of cartilage erosion and synovial
haemorrhage
Increase of articular cartilage GAG synthesis
Boileau et al., 200929 ASU 10 mg/kg/day Experimental knee dog model Decrease of the size of the macroscopic lesions (tibial
ID: 8 weeks 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)52 CH (Fortigel, Gelita AG) 0.15 mg/g of body weight daily Male STR/ort (model of naturally occurring OA) Decrease of cartilage tissue degeneration in knee joints
ID: 4 months Control: albumin 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., 200267 25-hydroxyvitamin D3 0.1 mg/kg/day Pigs No effect on the incidence or severity of OA lesions, articular
supplement ID: 21 weeks N ¼ 200 PG or collagen contents
Control: commercial diet
Polyphenols
Ham et al., 200496 Genistein Equivalent of 129 mg/day Monkey model of naturally occurring OA No effect on insulin-like growth factor binding protein
Soy phytoestrogen for women after ovariectomy (IGFBP)-2 and IGFBP-3, total protein, PG or collagen levels in
ID: 3 years cartilage tissue
Elmali et al., 2005110 Resveratrol 10 mmol/kg Rabbit model of OA by transaction of the Protection against cartilage degradation (histological
Intra-articular anterior cruciate ligament evaluation)
Table V
Summary of the epidemiological data for the studied products on OA
Reference Product Population Design Results

n-3 PUFAs
Wang et al., 200824 Different types of Australian healthy Cohort Higher intakes of monounsaturated fatty
fatty acid middle-aged subjects Y: 10 acids, total and n-6 PUFAs associated with
without clinical knee OA increased risk of bone marrow lesions
Mean y: 58 No association of n-3 PUFA intake and
N ¼ 297 bone marrow lesions
No association of fatty acid intake
with cartilage volume of defects
Vitamin D
McAlindon et al., 199658 Vitamin dietary intake English patients Cohort Modest correlation between serum
and serum levels of 25- Mean y: 70.3 Y: 9e10 vitamin D and vitamin D intake
hydroxyvitamin D N ¼ 556 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., 199968 Serum levels of 25- American elderly white Cohort Association between low serum levels
hydroxyvitamin D women Y: 8 of 25-hydroxyvitamin D and radiographic
and 1,25- Y 65 changes for hip OA characterized by
dihydroxyvitamin D N ¼ 237 joint space narrowing but not osteophyte
No association between serum 1,25-
dihydroxyvitamin D and incident
changes of radiographic hip OA
Felson et al., 200769 Serum levels of 25- English adults Cohort Y: 9 No association between vitamin D
hydroxyvitamin D Mean y: 53.1 levels and structural joint degradation
N ¼ 715 (disease incidence) defined as joint
space loss on radiography
Felson et al., 200769 Serum level of 25- American adults with Cohort Y: 9 No association between vitamin D
hydroxyvitamin D knee OA levels and structural disease worsening
Mean y: 66.2 (disease progression) defined as joint space
N ¼ 388 loss on radiography and as cartilage loss on MRI
Breijawi et al., 200964 Serum levels of 25- Patients undergoing Cross-section High prevalence of low vitamin D status in
hydroxyvitamin D total hip or knee patients with knee OA
replacement
Mean y: 69e70
N ¼ 117
Bergink et al., 200963 Serum levels of 25- Knee OA patients Cohort Y: 6.5 Low dietary vitamin D intake the risk of
hydroxyvitamin D N ¼ 1248 (mean follow up time) progression of knee OA
Vitamin D influences the incidence and
progression of knee OA more particularly
in low BMD patients
oil (equivalent to 786 mg EPA) by OA patients as an adjunct to countries, ASU mixtures are delivered as over-the-counter prod-
NSAID medication was not effective to improve pain and ability. The ucts. Therefore, extrapolation of the data obtained with
use of olive oil as placebo control may have introduced a bias in the PiascledineÒ300 to other ASU mixtures must be done with an
result of this study. On the contrary, the second study of low extreme caution. The main components of ASU are the phytosterols
methodological quality (score: 4)26 showed that the consumption b-sitosterol, campesterol and stigmasterol31.
of an extract of New-Zealand green-lipped mussel rich in n-3 PUFAs
improved OA symptoms, including pain and joint function in In vitro and preclinical data
Korean OA patients. Over the last 20 years, ASU have raised a great research interest.
In vitro data are abundant. Most of in vitro studies were performed
ASU with normal or OA chondrocytes stimulated or not with IL-1b, the
key pro-inflammatory cytokine in OA physiopathology. These
ASU are derived from unsaponifiable residues of avocado and studies demonstrated that ASU contained in PiascledineÒ300
soybean oils, generally mixed in the ratio one-thirdetwo-thirds exerted positive effects on human chondrocytes by stimulating the
respectively27e30. The large majority of the in vitro and in vivo synthesis of aggrecan and extracellular matrix component as type II
data have been obtained with ASU found in PiascledineÒ300 collagen31e33 and by reducing the production of catabolic (MMP-3)
(Laboratoires Expanscience, France). The ASU contained in and pro-inflammatory (IL-8 and IL-6) mediators34. These anabolic
PiascledineÒ300 are extracted according to a patented process and anti-catabolic effects were also observed in human OA
giving them a particular formulation30. This formulation is chondrocytes35. What is more, this ASU mixture was able to
considered as a drug in France and some of the observed beneficial counteract IL-1b-induced deleterious effects on cartilage in normal
effects seem to be related to this particular formulation. In other and OA chondrocytes31e36. It reversed IL-1b-induced collagen
Table VI
10
Summary of the clinical data of the studied products on OA
Reference Product Dose and intervention Population Design Results Score

duration (ID) (1e14)
n-3 PUFAs
Stammers Cod liver oil 10 ml (786 mg EPA)/ English middle-ages and Double-blind, placebo- No effect on pain and ability compared to olive 7
et al., (EPA) dayID: 24 weeks old patients with OA controlled trial oil
199225 Y: 49e87 (Cod liver oil was used as an adjunct to NSAIDs)
N ¼ 86
Cho et al., LyprinolÒ extract from four capsules/day Korean patients with hip or Multicenter open trial Improvement of OA signs and symptoms (pain 4
200326 New-Zealand green- ID: 8 weeks knee OA VAS, joint function LFI)
lipped mussel rich in Y: 40e75
n-3 PUFAs (EDA, DHA, DPA) N ¼ 60
ASU
Lequesne PiascledineÒ 300 mg (capsule) French patients with Prospective, multicenter, No structural effect (joint space width) (primary 11.5
et al., ID: 2 years regular pain due to primary randomized, parallel group, outcome)
200243 hip OA double-blind, placebo- Reduction of the progression of joint space loss
Y: 50e80 controlled trial in the subgroup with advanced space
N ¼ 108 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
Appelboom PiascledineÒ 300 or 600 mg Belgian patients with Prospective multicenter, Decrease of NSAID and analgesic intake 11
et al., ID: 3 months primary knee OA under double-blind, randomized, (primary outcome), compared to placebo from
200144 analgesics and/or NSAIDs parallel group, placebo- the first month
Y:45e80 controlled trial No difference between 300 mg and 600 mg
Decrease of LFI (improvement noticed from the
second month) and pain by VAS
Maheu PiascledineÒ 300 mg (capsule) French patients with Prospective, randomized, Decrease of LFI scores (primary outcome) after 6 14
et al., ID: 6 months þ 2 month symptomatic primary hip double-blind, placebo- months, compared to baseline and placebo
199845 post)treatment follow up or knee OA controlled multicenter trial groups
Y: 45e75 Reduction of pain by VAS, overall functional
N ¼ 164 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
Blotman et PiascledineÒ 300 mg French patients with Prospective, randomized, Reduction of NSAID consumption
al., 1997 ID: 3 months symptomatic knee or hip double-blind, placebo- (primary outcome)
(abstract)46 OA requiring NSAID controlled, parallel-group Improvement of LFI compared to placebo
therapy trial No difference in pain score between ASU and
Mean y: 62.9 placebo
N ¼ 163
CH
Clark et al., CH 10 g/day American physically active Prospective, randomized- Improvement of joint pain, increase of mobility 8
200854 (liquid formulation) ID: 24 weeks healthy adults without placebo-controlled, double- and reduction of dependency to analgesics in
degenerative joint disease blind trial patients consuming CH dietary supplement
but with joint pain Control: xanthan
Mean y: 20.1
N ¼ 97
Moskowitz CH 10 g/day Patients with knee OA Multicenter, prospective, No statistically significant improvement in 9
et al., ID: 24 weeks þ 8 weeks (Germany, UK, US) randomized, double-blind, Western Ontario and McMaster Universities
200056 post-treatment washout Y: 45e81 placebo-controlled trial (WOMAC) pain score, function score and patient
N ¼ 389 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)
Zuckley CH 10 g/day with calcium Patients with symptoms Randomized, double-blind, Improvement of certain strength and work
et al., (300 mg/day) and of mild knee OAMean placebo-controlled trial performance tests (improvement of knee
200455 vitamin C (60 mg/day) y: 57N ¼ 190 functional mobility on isometric and isokinetic
ID: 14 weeks testings)
Greater effects on patients with more severe OA
Benito-Ruiz CH 10 g/day Patients with primary OA Randomized, double-blind, Improvement of knee joint comfort as assessed 13
et al., ID: 6 months Mean y: 59 multicenter controlled trial by VAS and WOMAC
200957 N ¼ 250
Polyphenols
Belcaro et PycnogenolÒ NP OA patients with elevated Placebo-controlled trial Decrease of plasma-free radicals compared to

al, 200875 ID: 3 months C-reactive protein and baseline
plasma-free radicals Decrease of plasma C-reactive protein level
N ¼ 35 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, PycnogenolÒ 150 mg/day Slovakian patients with Prospective, double-blind, Improvement of WOMAC index (pain, stiffness 13
200872 ID: 3 months mild to moderate OA placebo-controlled, single and global score compared to both baseline and
Y: 25e65 centre study placebo group, physical function compared to
N ¼ 100 baseline only) and alleviation of pain by VAS
compared to placebo
Diminution of analgesic use compared to
baseline and increase use in placebo group
Belcaro et PycnogenolÒ 100 mg/day Patients with knee OA and Double-blind, placebo- Improvement of WOMAC index (pain, stiffness, 11
al, 200876 ID: 3 months disability Mean y: 47.6 controlled randomized trial physical function and global scores), well-being
e48.6 of patients and social functions compared to the
N ¼ 156 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
Farid et al, PycnogenolÒ 150 mg/day Patients with knee OA Double-blind, placebo- Improvement of WOMAC index (pain, physical 11
200774 ID: 3 months Y: 25e65 controlled randomized trial function and global score but not stiffness) from
N ¼ 37 with parallel-group design second month compared to baseline and
placebo
Reduced use of medication (NSAID and COX-2
inhibitor) compared to placebo
11
Table VII formulations produced similar effect on IL-1b, COX-2 and iNOS in
Summary of scientific consensus on the reviewed ingredients LPS-stimulated chondrocytes37 and were also shown to enhance
Ingredient Scientific consensus transforming growth factor (TGF)-b production in bovine articular
n-3 PUFA Lack of evidence of efficacy chondrocytes38. The ASU contained in PiascledineÒ300 were also
ASU Good evidence of efficacy shown to have beneficial effects on osteoblasts and synoviocytes.
CH Limited evidence of efficacy but suggestive Indeed, this compound prevented inhibitory effect of osteoblasts on
Vitamin D Limited evidence of efficacy but suggestive
chondrocyte matrix component synthesis39 and reversed IL-1b-
Nobiletin Lack of evidence of efficacy
Curcumin Preclinical evidence of efficacy induced collagenase production by synoviocytes33.
Genistein Lack of evidence of efficacy Four in vivo studies with ASU were identified. They were per-
EGCG Preclinical evidence of efficacy formed in four different animal models of OA and they all support
Resveratrol Preclinical evidence of efficacy the beneficial effect of PiascledineÒ300 in OA. PiascledineÒ300
Pycnogenol Moderate evidence of efficacy
Probiotics Lack of evidence of efficacy
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 models27,28,40. In addition, one in vivo
release, MMP-3, MMP-13, and PGE2 production in normal chon- study in dogs without any diagnosed joint disease suggests an
drocytes31,33,34,36. It was also shown that ASU mixture contained in effect of ASU by increasing growth factors (TGF-b1 and 2) involved
PiascledineÒ300 restored aggrecan production and inhibited MMP- in extracellular matrix synthesis41. All these preclinical studies
3 synthesis in OA chondrocytes stimulated with IL-1b35. Other ASU strongly support anti-OA properties for ASU mixtures.
Table VIII
Summary of the ongoing CTs for the studied products on OA
Product Population Design Primary outcome measure Sponsor Stage

ASU Patients with hip OA Multicenter, randomized, Effect of treatment on joint Laboratoires Expanscience Completed
(PiascledinÒ 300) Age: 45e75 years double-blind, placebo- space narrowing
Enrollement: NP controlled trial evaluated on X-ray
Duration: 3 years
Treatment: PiascledineÒ
300
CH solution Patients with knee OA Treatment, randomized, Effect of collagen hydrolysis GELITA Completed
10 g/day Age: 49e90 years double-blind on knee cartilage measured
Enrollement: 30 (subject, caregiver, investigator, by MRI
outcome assessors),
placebo-controlled,
parallel assignment,
safety-efficacy study
Vitamin D Patients with Treatment, randomized, Cartilage volume loss (MRI) National Institute of Arthritis Ongoing,
(cholecalciferol) symptomatic knee OA double-blind Knee symptoms (WOMAC) and Musculoskeletal and Skin not
2 000 UI/day Age: 45e90 years (subject, caregiver, investigator, Diseases (NIAMS) recruiting
(capsule) Enrollement: 146 outcomes assessor), parallel Office of Dietary Supplement
assignment, efficacy study (ODS)
Duration: 2 years
Treatments: vitamin D3
2 000 UI daily or placebo
Vitamin D Patients undergoing Treatment, randomized, Pain and function of the University of Zurich Recruiting
(cholecalciferol) uni-lateral total knee double-blind operated and non-operated Harvard School of Public
2 000 UI/day replacement (subject, caregiver, investigator, knee Health
(capsule) due to sever OA outcomes assessor), Rate of falls Tufts University
Age: 60 years dose comparison, Boston University
Enrollement: 80 parallel assignment, efficacy study
Duration: 2 years
Treatments: vitamin D3
2 000 UI or 800 UI daily
Curcuma domestica Patients with knee OA Treatment, randomized, Change in mean WOMAC Mahidol University Not yet
1 500 mg/day (oral) Age: 50e75 years double-blind pain scale National research Council of open for
divided into 3 times Enrollement: 396 (subject, outcomes assessor), Thailand patient
for 28 days active control, recruitment
parallel assignment,
safety/efficacy study
Duration: 28 days
Treatments: curcuma domestica or
ibuprofen (1 200 mg/day)
Highly bioavailable Patients with knee OA Treatment, randomized, placebo- Pain assessment using VAS Bioxtract S.A. Recruiting
turmeric extract Age: 40e80 years controlled, double-blind, parallel NuKleus
(ArantalÒ) Enrollement: 280 assignment, efficacy/tolerance study
four capsules/day Duration: 15 days
Treatment: turmeric extract
(ArantalÒ) or placebo
Clinical data chondroprotective effect of CH was also confirmed in an other

The results of four CTs, all double-blind placebo-controlled and study investigating both in vitro and in vivo effect in mice52. CH was
randomized, were published and identified in the literature. demonstrated to protect cartilage against degradation induced by
All of these studies used the same pharmaceutical product, phosphorus injection. The same study showed that CH prevented
PiascledineÒ300, which is under drug authorization (AMM). All of chondrocyte differentiation into mineralized chondrocytes.
them investigated the beneficial effects of PiascledineÒ300 on
patients with symptomatic OA. All of them were conducted in Clinical data
patients with primary knee or hip OA and were by the way focusing Only three relevant CTs were identified in the literature. The first
on OA treatment. OA outcomes were NSAID/analgesics medication study investigated the effect of CH supplementation in healthy
replacement, pain, function and structural changes (joint space nar- adult without degenerative joint disease but with joint pain. This
rowing). They studied the potential of symptom-modifying effect of study of medium methodological quality (score: 8)53 showed that
PiascledineÒ300 and one of them was interested in the structure- CH dietary supplement can improve joint pain, mobility and reduce
modifying effect of ASU. Three out of the four evaluated studies were analgesic medication in healthy active adults without degenerative
of good methodological quality (Lequesne et al, 200242, score: 11.5; joint disease. The CH supplementation can then improve knee
Appelboom et al, 200143, score: 11; Maheu et al, 199844, score: 14). function during joint-stressing activities. These observations were
The only one study assessing efficacy of PiascledineÒ300 in also reported in a scientific communication54 in patients with
modifying articular structure failed to show any structural effect in symptomatic mild OA patients. The second report of medium
patients with hip OA in spite of its long duration (2 years)42. However, methodological quality (score: 9)55 mentioned a better effect of CH
a subgroup analysis suggested an effect in patients with the most compared to placebo in severe OA patients than in the overall
severe hip OA, supporting further studies in this population group. studied population. More recently, in another relevant CT of very
Data suggested that PiascledineÒ300 decreased NSAID/anal- good methodological quality (score: 13), the joint function
gesic intake in the medium term (3e6 months) for patients with improvement after CH treatment was shown in patients with
hip or knee OA43e45. However, the only long-term study (2 years) primary OA56.
did not show any effect of PiascledineÒ300 on the NSAID
consumption in patients with hip OA42. Nevertheless, the later was Vitamin D
designed to detect radiographic changes more than to study the
changes in symptoms. This could explain the fact that no difference OA was traditionally considered as a cartilage disease, charac-
was observed on clinical parameters (function, pain and NSAIDs terized by cartilage degeneration. But many evidences, as osteo-
consumption). In contrast, data regarding pain and patient’s global phytosis, subchondral bone sclerosis and cyst formation have
assessment are more conflicting42e45. PiascledineÒ300 treatment grown up and demonstrated the prominent role played by sub-
seemed to improve patient’s function assessed by LFI (Lequesne chondral bone in OA pathophysiology57. Some studies even indicate
Functional Index) or VAS (Visual Analog Scale)43e45. that bone alteration could precede cartilage changes58. But whether
A recent meta-analysis evaluating these four clinical studies bone abnormalities, such as bone sclerosis, initiate or are simply
concluded PiascledineÒ300 was efficient for reducing pain and involved in the progression of cartilage degradation is under
improving function in OA46. discussion59e61.
Normal bone metabolism depends on the presence of vitamin D,
Collagen hydrosylates (CHs) a compound derived mostly from cutaneous exposure to ultraviolet
and from the diet in a lesser extent. Suboptimal levels of vitamin D
CH is obtained by the enzymatic hydrolysis of collagenous may have adverse effects on calcium metabolism, osteoblastic
tissues (bone, hide or hide split) form mammals. The main char- activity, matrix ossification and bone density. Low serum levels of
acteristic of CH is its amino acid composition, which is identical to vitamin D may increase the progression of knee OA62 and may
type II collagen, thus providing high levels of glycine and proline, impair the ability of bone to respond optimally to OA pathophysi-
two amino acids essential for the stability and regeneration of ologic processes and may predispose patients to joint degrada-
cartilage47. This product is generally recognized as a safe food tion57. High prevalence of low vitamin D status has been
ingredient by regulatory agencies. CH is well digested and is pref- demonstrated in persons with knee OA63. Moreover, in low bone
erentially accumulated in cartilage48. Although clinical use of CH is mineral density (BMD) patient, the level of vitamin D seemed to
associated with minimal adverse effects, some gastro-intestinal influence the incidence and progression of the disease62. Some
side effects, as fullness and unpleasant taste, have been described. studies have consequently investigated the relationship between
In most studies, CH was administered alone in a water solution. vitamin D and OA. The main drawback is that they are all obser-
However, it seems that CH is well absorbed and digested in other vational. Most of them have looked at the association of vitamin D
food matrix, such as fermented milk47. serum level rather than vitamin D intake with OA.
In vitro and preclinical data In vitro and preclinical data

Few preclinical data on the effect of CH on OA were identified in Three in vitro studies investigating the role of 1,25-dihydroxy-
the literature. The search retrieved only one in vitro study assessing vitamin D3 in the pathophysiology of OA are available59,64,65. These
the stimulation of articular cartilage matrix by CH in cultured studies used different cell models: synovial fibroblasts, chon-
bovine chondrocytes49. This study demonstrated the stimulatory drocytes or osteoblasts. Data showed that 1,25-dihydroxyvitamin
potency of CH on type II collagen and PG synthesis, as well as D3 had no inhibitory effect on articular catabolic enzymes and on
aggrecan expression by chondrocytes. This result was also reported a potent pro-inflammatory mediators but rather upregulated
in a scientific communication on CH effect in porcine chon- catabolic enzymes (MMP-1 and -3) in human articular chon-
drocytes50. In addition, an in vivo study with STR/ort mice which drocytes64, 65. Interestingly, 1,25-dihydroxyvitamin D3 exerts
spontaneously developed OA51 has shown that long-term CH a positive effect on rheumatoid synovial fibroblasts by reducing
supplementation may decrease OA cartilage degeneration and MMP and PGE2 production65. In addition, 1,25-dihydroxyvitamin
delay the progression of OA. These results are in favor of a disease- D3-induced osteocalcin production appears to be increased in OA
modifying effect of CH and its potential efficacy in OA. The osteoblasts compared to healthy one, which can cause an increase
in bone metabolism resulting in bone sclerosis and osteophyte reducing NSAIDs or COX-2 inhibitor medication, suggesting that
formation59. PycnogenolÒ could be used as an effective adjuvant treatment. Data
Only one in vivo study was identified. This study evaluated the strongly support the pain-alleviating effect of PycnogenolÒ. Despite
impact of a supplementation of vitamin D3 (25-hydroxyvitamin some discordant results, physical function and stiffness seem to be
D3) on OA in pigs66. The supplementation revealed no effect on the improved by intake of PycnogenolÒ in OA subjects. All these studies
incidence or the severity of OA lesions, articular PG and collagen are of good to very good quality (Farid et al, 200773 and Belcaro et al,
content. 200875, score: 11; Cisar et al, 200871, score: 13).
Clinical data Nobiletin

The majority of available evidence on the efficacy of vitamin D in
the treatment or in the prevention of OA comes from epidemio- Nobiletin is a citrus polymethoxyflavone which was proven to
logical data. Most of them investigated the relationship between have pharmacological actions as anti-inflammatory, anti-tumor
vitamin D serum levels and joint structure parameters (joint space proliferation and anti-tumor invasion and metastasis in vitro and in
narrowing, osteophytes, cartilage loss and volume). A total of four vivo76. This product has been exclusively studied in vitro in synovial
studies have assessed this relationship57,67,68 and only one has fibroblasts and in articular chondrocytes. Nobiletin was able to
investigated the association of vitamin D intake and OA57. This inhibit the production of catabolic factors (MMP-3 and -9,
study revealed that low levels of vitamin D intake are related to an ADAMTS-4 and 5) and of mediators of inflammation (PGE2) in
increased risk of OA progression but no correlation was made with rabbit and human synovial fibroblasts76e78. Nobiletin was also
OA incidence. Interestingly, in this study, vitamin D intake modestly showed to activate the MMP inhibitor (TIMP-1)78. This inhibitory
correlated with vitamin D serum levels. In addition, one other study potential was also demonstrated in rabbit articular chondrocytes77.
was found to evaluate the prevalence of vitamin D deficiency in Nobiletin demonstrated a potential to inhibit cartilage degradation.
individuals with OA63. This study revealed a high prevalence of low This chondroprotective potency should be further documented.
vitamin D status in patients with knee OA. The other studies
investigating the association between vitamin D serum level (25- Curcumin
vitamin D) and joint structure parameters gave inconsistent data.
Two of them showed a relationship between vitamin D serum level Curcumin (diferuloylmethane) is the major component of
and OA parameters such as joint space narrowing and/or cartilage turmeric, a yellow spice derived from the plant Curcuma longa and
volume in the knee or hip joint67,69. An other study did not show a potent anti-oxidant. It has been extensively investigated due to its
any association between vitamin D serum level and joint space loss anti-tumor, anti-oxidant and anti-inflammatory and analgesic
in hip OA patients68. This difference could be explained by the fact properties. We have recently reviewed the biological activities of
that the population of this study was younger than the population curcumin79. The anti-OA potential of curcumin has been widely
of the other two. However no linear association was found when OA studied in vitro. Twelve studies were found. They were all carried out
was assessed with a structural global score57,70. These studies in chondrocytes or on articular cartilage explants. Curcumin was able
suggested a U-shaped relationship. Serum Vitamin D level is to downregulate catabolic and degradative effect observed in carti-
reported to be predictive of knee OA, when measured by quartiles lage explants or chondrocytes stimulated with IL-1b, LPS or tumor
with the lowest risk in the middle quartile70. necrosis factor (TNF). Curcumin inhibited the production of MMP-3,
-9 and -1380e82 and restored type II collagen and GAG synthesis81e85.
Polyphenols Curcumin positive effect on GAG release was confirmed86. In addition,
curcumin demonstrated potent anti-inflammatory properties by
Research on the effect of dietary polyphenols on human health inhibiting key inflammatory mediators (IL-6, IL-8, PGE2, NO) and
has developed considerably in the past 10 years. The results enzymes (COX-2 and iNOS)87e90 and anti-catabolic properties by
strongly support the role of polyphenols in the prevention of inhibiting MMP-3 synthesis89. Curcumin has also demonstrated anti-
degenerative diseases. The anti-oxidant properties of polyphenols apoptotic activity on chondrocytes83 and growth-inhibitory and pro-
have been widely studied, but it has become clear that the mech- apoptotic effects on synovial adherent cells, which are the main
anisms of action go beyond the modulation of oxidative stress. source of inflammatory mediators and other mediators of cartilage
Some researchers have investigated the potential effect of some degradation, all of them playing key role in the pathogenesis of
polyphenols in OA. Only pine bark extract-PycnogenolÒ has been arthritis91. This is important to note that one study has reported
tested in CTs. a toxic effect of curcumin used at high dosage (50 mM) without any
beneficial effect in cartilage matrix84. This study was performed in
Pine bark extract-PycnogenolÒ a novel immortalized human OA chondrocytes model, which can
explain the discordance with previous studies.
PycnogenolÒ is a special standardized extract from the bark of No clinical data are available for the effect of curcumin in OA.
the French maritime pine (Pinus pinaster). This extract represents However, one study tested the clinical efficacy of a herbomineral
a concentrate of polyphenols, containing several phenolic acids, formulation containing a component rich in curcumin in subjects
catechin, taxifolin and procyanidins with various biological and with OA in a randomized, double-blind, placebo-controlled, cross-
clinical effects71. No-preclinical or in vitro data were found for over study92. Positive results in pain management and mobility
PycnogenolÒ and OA. However, the anti-oxidant and anti-inflam- were obtained in the treated group. Curcumin in OA is a current
matory profile of PycnogenolÒ and its inhibitory effect on MMPs research interest.
and iNOS are well documented in conditions other than OA72,73.
The symptom-modifying effect of PycnogenolÒ has been rela- Genistein
tively well documented in OA patients. The search retrieved four
CTs 71,73e75. They assessed the impact of PycnogenolÒ in patients Genistein is one of the several known isoflavones and is found in
with knee OA in a medium term (3 months). These studies indicate soybeans and soy products. Genistein is considered as a phytoes-
that the daily intake of 150 mg of PycnogenolÒ alleviated OA trogen. Clinical observations have suggested a relationship
symptoms. All studies showed that PycnogenolÒ was effective in between OA and a changed estrogen metabolism in menopausal
women. Moreover phytoestrogens have been shown to ameliorate vitro study has investigated the effect of prodelphinidins. This study
various menopausal symptoms93. The effect of phytoestrogens, showed potential in vitro effects on human chondrocytes. Prodel-
including genistein, has been studied on articular cartilage matrix phinidins seemed to increase PG and type II collagen and inhibited
metabolism and inflammation. Nevertheless, the data for genistein PGE2 synthesis by acting on COX-2110. These data are in favor of
and OA are limited. The in vitro and preclinical data are not additional preclinical evaluations.
consistent to support a beneficial effect of genistein on articular
cartilage. Genistein does not affect cartilage metabolism93,94 but Quercetin
could have an anti-inflammatory effect by suppressing COX-2 but
not NO production94. In addition, the consumption of an extract of Quercetin is a plant-derived flavonoid. Anti-inflammatory and
soy phytoestrogen in animal failed to modify cartilage metabolism anti-oxidant properties have been suggested for this nutraceutical.
in ovariectomised monkey95. Additional experiments are needed to Only one in vitro study in human synovial cells has been identi-
clarify the potential benefit of genistein in articular cartilage fied111. This study demonstrated potential anti-inflammatory effect
metabolism. by the inhibition of TNF-a mediated-IL-8 and monocyte chemo-
attractant protein-1 (MCP-1) expression. This suggested a potential
Epigallocatechin-3-Gallate (EGCG) anti-arthritic effect but further preclinical investigations are
needed especially in OA.
EGCG is a major component of the polyphenolic fraction of green
tea and exhibits anti-oxidant, anti-tumor and anti-mutagenic Ventol
activities. The in vitro effect of EGCG is well documented. Most of the
available data on EGCG and OA come from experiments performed in Ventol is a phlorotannin-rich natural agent derived from Eck-
vitro in human chondrocytes looking at the anti-inflammatory effect lonia cava with anti-oxidant and anti-inflammatory activities112.
of EGCG. Data suggest that EGCG exerts an anti-inflammatory effect One in vitro study on cartilage explants has shown the inhibition of
on OA chondrocytes by inhibiting the production of key inflamma- PG degradation after IL-1a stimulation. This should be further
tory mediators (NO, PGE2, COX-2 and iNOS)96e98. This anti-inflam- studied to confirm the anti-OA potential of this compound.
matory effect has also been observed in osteoblasts by the inhibition
of IL-699 and synovial fibroblasts by the inhibition of COX-2 Discussion
expression and synthesis and by the inhibition of PGE2 and IL-8
secretion100. Additional anti-inflammatory and anti-catabolic OA is a debiliting chronic disease with a serious need of alter-
effects have been demonstrated for EGCG in human chondrocytes. native treatments that could help patients to preserve their joint
Indeed, EGCG can inhibit the TNF-a and MMP-13 production function and therefore maintain a certain quality of life. We have
induced by advanced glycation end products (AGEs) which are here summarized most of the published effects of some nutra-
responsible for cartilage mechanical properties loss101. This effect ceuticals. Many results have been highlighted and the quality of the
could happen through the attenuation of MAP kinase activation and studies addressed.
inhibition of nuclear factor kB (NF-kB) activation. This is supported Globally, we can conclude to a lack of evidence for most of the
by the previous report of anti-catabolic activity and inhibitory effect studied compounds. The review by Ameye and Chee6 has also
on NF-kB and AP-1 signalling102. Finally, this is of interest to note that analyzed the available studies at that time for ASU, n-3 PUFAs and
the polyphenolic fraction of green tea can prevent the onset of CH. The same conclusions as ours were made, meaning that there
arthritis and the severity of the disease in mice collagen-induced are no strong clinical data available. So, there is a need for addi-
arthritis103. Complementary experiments are necessary in order to tional preclinical studies and CTs of good quality. In addition, this is
confirm the anti-inflammatory effect of EGCG on OA in vivo. important to note that the potencies demonstrated in preclinical
studies for most compounds are not concordant with their clinical
Resveratrol 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
Resveratrol is a stilbene that is naturally present at high in CTs. An other explanation could come from the fact that
concentration in grape skin and red wine. It has significant anti- preclinical studies deal most of the time with early stages of the
inflammatory and anti-oxidant properties which could be benefi- disease whereas CTs involve patients at later stages. This can justify
cial in OA104. Only in vitro studies were identified for this the discordance between preclinical data and clinical and epide-
compound. A total of five studies were performed in cartilage miological observations.
explants and chondrocytes85,104e107. These studies indicated that Many efforts have been carried out to find a cure for OA. OA
resveratrol can have beneficial effects. It has demonstrated anti- management is a challenge for physicians and rheumatologists.
inflammatory and anti-apoptotic properties104,106. Resveratrol Many alternatives are now available but recommendations have to
inhibited catabolic factors as MMPs and pro-inflammatory media- be done. Nutraceuticals is one of these alternatives. They have great
tors as PGE2 and COX-2, and stimulated the synthesis of matrix potential in OA but there is a need of strongly substantiated data.
components (PG, GAG, type II collagen)104,106,107. These effects could Many questions still remain to be addressed. Where should be
prevent cartilage degradation. In addition, cartilage protection may the line between food and drugs drawn? This issue is well illus-
be achieved with intra-articular injection of resveratrol. This was trated by ASU mixture. ASU are considered as prescribed drugs in
observed both in anterior cruciate ligament transaction OA model France, but as food supplement in other countries. The prescribed
and LPS-induced arthritis model in rabbit108,109. These preclinical drug, PiascledineÒ300, is now recommended for the treatment of
evaluations indicate an interesting potential of resveratrol in OA OA symptoms. These recommendations are based on strong clinical
but additional in vivo studies are needed. evidence. However, in vitro studies have demonstrated that some of
the beneficial effects of PiascledineÒ300 were related to its
Prodelphinidins particular formulation resulting of a patented extraction process,
and were not observed with other formulation (personal commu-
Prodelphinidins are a type of condensed tannins and are nication). This extraction process is responsible for specific changes
composed of gallocatechin and epigallocathechin110. Only one in in the unsaponifiable fractions of avocado and soybean that could
explain their particular effects. This means that the natural food could play in the prevention of OA. Two CTs are ongoing on cur-
ingredient has underwent some modifications that are related to cumin to determine whether the consumption of a plant extract
particular biological effects. Therefore, ASU should be chemically with high curcumin content alleviates pain in subjects with OA.
analyzed before to be considered as a food supplement or a nutra- Furthermore, one CT was just completed with CH. It was the first
ceutical. Nutraceutical is a broad term to qualify any product one interested in the structure-modifying effect of the studied
derived from food source that provides extra health benefits. This compound. The results are not yet available. Additional CTs should
definition fails to precise whether a modified product derived from assess the potential of nutraceuticals in a long-term use in OA and
food source can be considered as a nutraceutical. The line between should also be interested in their structure-modifying effect which
a nutraceutical and a drug is thin. Other criterion that can help to is the great challenge in seeking new OA treatment.
distinguish between a drug, food supplement, and nutraceuticals We have shown here that most of the studied compounds could
are the oral dose administrated and the bioavailability. Food have beneficial effects in the treatment of OA, even if we still need
supplement should be administrated at concentration found in the more evidence. They could represent great alternatives for OA
normal diet. Bioavailability would be a great criterion to demon- management. We have only detailed here the information for a few
strate the potent efficacy of a product. For example, the pharma- compounds but others can also represent great potential. Indeed,
cokinetic of curcumin has been studied113 and many parameters other lipids, vitamins, minerals or plant extracts have also been
that are opposed to curcumin efficacy have been described. In demonstrated to be effective in OA. Probiotics could also be
human, the serum concentrations of curcumin after an oral massive considered for the treatment of OA. Several studies have
dose of 4, 6 or 8 g/day reach 0.5, 0.6 and 1.8 mM respectively. These highlighted the importance of intestinal flora in inflammatory
concentrations are below the concentration showing a biological auto-immune diseases, such as rheumatoid arthritis. Beneficial
activity in vitro. However, new formulation of curcumin114 has anti-inflammatory properties and modulatory effect of immune
enhanced cellular uptake, increased bioactivity in vitro and response of probiotics on rheumatoid arthritis were demonstrated
improved bioavailability in vivo. This is in favor of a better efficacy, in animals121e123. In addition, the consumption of lactobacilli con-
meaning that the anti-inflammatory and other potencies of cur- tained in a yogurt demonstrated the preventive and curative effects
cumin could be even more effective. Curcumin would become by on T-cell-dependent experimental arthritis by reducing the
the way a potent anti-inflammatory agent. For this reason, a clinical intensity of inflammation and joint destruction in animals124. In the
study has been initiated with complexed curcumin in patients with same way, CTs have evaluated the effects of probiotics on the
knee OA. This complexed curcumin (ArantalÒ) showed a 7000 activity and on the symptoms of rheumatoid arthritis125,126. The
times increased solubility. Can it be considered as a food supple- positive findings of these studies suggested the need of comple-
ment any longer? This critical point can also be illustrated by mentary studies on the effects on probiotic bacteria in rheumatoid
resveratrol. The pharmacokinetic of resveratrol can be modified by arthritis. There is a lack of data on the effect of probiotics on OA in
the addition of glycosyl groups that improved its absorption115. This the literature. The potential effect of probiotics on OA has not been
process could be applied to other polyphenols to increase their extensively studied but the data on their effect in arthritis suggest
bioavailability. that they could have a potential interest in OA.
Can nutraceuticals still be considered as food supplement when
used under drug formulation? These modifications should also be Conclusion
controlled and regulated. Moreover, food nutrients can target
multiple pathways compared to monomodal mode of action of We have gathered here all the studies and CTs about some
drugs. For example, some natural anti-oxidant peptides have also nutraceuticals. Some results are really promising and encouraging.
been identified in porcine CH116. CH has hypotensive potential117,118. The main concern remains the quality of studies. There is a need of
This is an additional advantage for the use of CH. Moreover, it has serious and well designed studies that could answer most of the
recently been demonstrated that some nutraceuticals are even questions regarding the safety and efficacy of such compounds. This
more effective when used in combination. It has been shown for could help their recommendation for OA treatment.
EGCG and ASU119 and resveratrol and curcumin120. Safety and Many studies have been carried out in order to highlight the
toxicity of nutraceuticals added alone or in combination should also potency of several nutraceuticals for the treatment of OA. Nutra-
be addressed, especially if bioavailability and biological activity are ceuticals offer a large variety of products with a wide range of
increased. Pharmacokinetic of all these compounds should be effects. They open new and large horizons for the treatment of
described and safety monitoring should be done. chronic disease as OA. Clinical endpoints for foods should be
For these reasons, the safety and effectiveness of these products reconsidered. Further investigations are needed but nutraceuticals
are under strict regulation in Europe. The problem is that the are not negligible for OA management. They should be considered
criterion of evaluation for clinical studies are defined as for phar- as potent adjuvant treatments with NSAIDs for example. Early
maceutic standards and this penalizes foods in terms of effect size markers development would also enable to build prevention
and also of absence of acute effect. OA as a chronic disease has strategies for food, in absence of cure treatment for OA.
a long time window for intervention and should benefit from
functional food alternatives to pharmacological interventions to Author contributions
improve subjects’ quality of life day after day.
We have also searched for the ongoing CTs with nutraceuticals. Conception and design of the study: YH, EC.
They are all summarized on Table VIII and given an overview of the Acquisition of data: CL, DC, CR.
current research interest on the selected ingredients. The number Analysis and interpretation of data: YH, EC, CL, DC, CR.
of ongoing trials supports the growing interest to identify their role Preparation of manuscript: YH, EC, DC.
in OA treatment. Two CTs are ongoing in order to evaluate the Final approval of manuscript: YH, CL, DC, CR, EC.
efficacy of vitamin D supplementation on pain, mobility and joint
structure in OA patients. Because of their high quality (long dura- Conflict of interest
tion and strong study design) these results will be valuable for the YH is a consultant for BioXtract and Danone. He is also the coor-
determination of the role that could play vitamin D supplementa- dinator of the CTs on curcuma operated by BioXtract. (ArantalÒ;
tion in OA. More evidences are needed regarding the role that it NCT00992004). Naturalpha was financed by Danone to set-up
scoring methodology, perform the identification, selection and evaluation of clinical studies with particular focus on external
scoring of relevant studies for the review. Other authors declare no validity and model validity. BMC Med Res Methodol
conflict of interest. 2006;6:56.
15. Schneeman B. FDA’s review of scientific evidence for health
Acknowledgments claims. J Nutr 2007;137:493e4.
16. Calder PC, Yaqoob P. Omega-3 polyunsaturated fatty acids
The authors would like to thank Eric Chappuis and Adeline and human health outcomes. Biofactors 2009;35:266e72.
Pierre for their active role in the quality assessment methodology 17. Darlington LG, Stone TW. Antioxidants and fatty acids in the
set-up and for performing the literature search. amelioration of rheumatoid arthritis and related disorders.
Br J Nutr 2001;85:251e69.
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Osteoarthritis and Cartilage 19 (2011) 1e21

Nutraceuticals: do they represent a new era in the management of

Introduction by the loss of joint function. In addition, aging patients present

Compound Total number of Total number of Nb of in vitro Nb of in vivo Nb of Nb of

Results Epidemiological data

Reference Product Dose and incubation In vitro model Results

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

IkB: inhibitor of NF-kB.

Reference Product Dose and ID In vivo model Results

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Reference Product Population Design Results

Reference Product Dose and intervention Population Design Results Score

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Y. Henrotin et al. / Osteoarthritis and Cartilage 19 (2011) 1e21

Product Population Design Primary outcome measure Sponsor Stage

Clinical data chondroprotective effect of CH was also conﬁrmed in an other

In vitro and preclinical data In vitro and preclinical data

Clinical data Nobiletin

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