ar2016 ARJ Research article <p>Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence</p> Ameye G Laurent laurent.ameye@rdls.nestle.com Chee SS Winnie winnie.chee@rdls.nestle.com

Nutrition and Health Department, Nestlé Research Center, Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland

 Arthritis Research & Therapy 1478-6354 2006 8 4 R127 http://arthritis-research.com/content/8/4/R127 16859534 10.1186/ar2016 4 1 2006 16 3 2006 6 6 2006 19 7 2006 19 7 2006 2006 Ameye and Chee; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The scientific and medical community remains skeptical regarding the efficacy of nutrition for osteoarthritis despite their broad acceptation by patients. In this context, this paper systematically reviews human clinical trials evaluating the effects of nutritional compounds on osteoarthritis. We searched the Medline, Embase, and Biosis databases from their inception to September 2005 using the terms random, double-blind method, trial, study, placebo, and osteoarthritis. We selected all peer-reviewed articles reporting the results of randomised human clinical trials (RCTs) in osteoarthritis that investigated the effects of oral interventions based on natural molecules. Studies on glucosamine and chondroitin sulfate were excluded. The quality of the RCTs was assessed with an osteoarthritic-specific standardised set of 12 criteria and a validated instrument. A best-evidence synthesis was used to categorise the scientific evidence behind each nutritional compound as good, moderate, or limited. A summary of the most relevant in vitro and animal studies is used to shed light on the potential mechanisms of action. Inclusion criteria were met by 53 RCTs out of the 2,026 identified studies. Good evidence was found for avocado soybean unsaponifiables. Moderate evidence was found for methylsulfonylmethane and SKI306X, a cocktail of plant extracts. Limited evidence was found for the Chinese plant extract Duhuo Jisheng Wan, cetyl myristoleate, lipids from green-lipped mussels, and plant extracts from Harpagophytum procumbens. Overall, scientific evidence exists for some specific nutritional interventions to provide symptom relief to osteoarthritic patients. It remains to be investigated whether nutritional compounds can have structure-modifying effects.

Introduction

Osteoarthritis (OA) is one of the most prevalent and disabling chronic diseases affecting the elderly. Its most prominent feature is the progressive destruction of articular cartilage which results in impaired joint motion, severe pain, and, ultimately, disability. Its high prevalence and its moderate-to-severe impact on daily life pose a significant public health problem 1.

Today, a cure for OA remains elusive. The management of OA is largely palliative, focusing on the alleviation of symptoms. Current recommendations for the management of OA include a combination of nonpharmacological interventions (weight loss, education programs, exercise, and so on) and pharmacological treatments (paracetamol, nonsteroidal anti-inflammatory drugs [NSAIDs], and so on) 2. Among these pharmacological treatments, NSAIDs, despite serious adverse effects associated with their long-term use, remain among the most widely prescribed drugs for OA 3. In this context, there is a need for safe and effective alternative treatments while the absence of any cure reinforces the importance of prevention.

Such prevention and alternative treatments could come from nutrition. It is now increasingly recognised that, beyond meeting basic nutritional needs, nutrition may play a beneficial role in some diseases 4. OA as a chronic disease is the perfect paradigm of a pathology the treatment of which could be addressed by nutrition. By nature, nutrition is better positioned to provide long-term rather than short-term health benefits. This is because, in most cases, a nutritional compound has only limited effects on its biological target and relevant and significant differences are reached only over time through a build-up effect in which daily benefits add up day after day. For this reason, and because the time window for intervention is longer in chronic diseases, such diseases should, in theory, benefit more from nutrition than do acute diseases. In addition, because the mechanisms of cartilage degradation in OA are multifactorial and some nutritional compounds (such as plant extracts) usually contain multiple active compounds that target multiple pathways, nutrition could provide an alternative to pharmacological interventions whose often monomodal mode of action may explain their partial lack of clinical efficacy in OA. The attractiveness of using nutrition for OA also lies in the detriments that it can prevent. Long-term pharmacological interventions in OA are often associated with significant adverse effects. Nutraceuticals and functional foods could provide an advantageous alternative because, by regulatory laws, they have to be devoid of adverse effects.

There is no consensus on the definition of nutraceuticals and functional foods. The term 'nutraceutical' was coined from 'nutrition' and 'pharmaceutical' in 1989 by DeFelice and was originally defined as 'a food (or part of the food) that provides medical or health benefits, including the prevention and/or treatment of a disease' 5. In a policy paper in 1999, Zeisel distinguished whole foods from the natural bioactive chemical compounds derived from them and available in a non-food matrix by using the term 'functional foods' to describe the former and nutraceuticals to describe the latter 6. Under this newer definition (which we will use in the rest of this paper), nutraceuticals are thus functional ingredients sold as powders, pills, and other medicinal forms not generally associated with food. The term nutraceutical has no regulatory definition and is not recognised by the U.S. Food and Drug Administration, which uses instead the term 'dietary supplements' 7. Some functional ingredients are sold as nutraceuticals in some countries but as drugs (that is, requiring medical prescription) in others. Compared with a nutraceutical/dietary supplement, a functional food is a food or drink product consumed as part of the daily diet 78. It can be distinguished from a traditional food 'if it is satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects in a way which is relevant to either the state of well-being and health or the reduction of the risk of a disease' 9. A food product can be made functional by eliminating a deleterious ingredient, by adding a beneficial ingredient, by increasing the concentration of an ingredient known to have beneficial effects, or by increasing the bioavailability or stability of a beneficial ingredient 10. In this paper, the beneficial ingredient supposed to provide the health benefit in a functional food or nutraceutical will be called functional ingredient. The functional ingredient in a functional food or in a nutraceutical/dietary supplement can be a macronutrient (for example, n-3 fatty acids), a micronutrient (for example, vitamins), or an ingredient with little or no nutritive value (for example, phytochemicals) 10.

In this context, the public interest in the benefits that nutrition could provide for OA is high. Numerous lay publications advertise the use of a whole range of nutraceuticals and functional foods for OA, and up to one out of five patients with OA uses such nonprescribed alternative medications 11, despite the fact that the mechanism of action of these products is often speculative and their efficacy not always supported by rigorous scientific studies. The aim of this paper was thus to review the available scientific evidence supporting the efficacy of the functional ingredients targeting OA and explaining their mechanism of action.

Materials and methods

Identification and selection of the literature

Systematic literature searches were performed to identify all human randomised clinical trials (RCTs) related to nutrition and OA. Computer databases used were Medline, Embase, and Biosis (searched from their respective inceptions to September 2005). Preliminary trial searches targeting specifically nutrition/nutraceuticals with lists of keywords such as 'food', 'supplements', 'plant', 'nutrition', 'vitamins', 'mineral', and 'nutraceuticals' performed poorly. Numerous valid trials that were already known to us were not selected by such searches. Hence, to be as exhaustive as possible, we changed our strategy and, instead of focusing on nutrition, devised a systematic search aiming at selecting all clinical trials in OA. This search of clinical trials in OA was fine-tuned for each database. Medline was searched by using the following strategy: random* AND (double-blind method [mh] OR (trial? OR stud??? OR placebo)) AND osteoarthritis [mh]. Embase was searched with the following keywords: (double near blind OR trial? OR stud??? OR placebo) AND osteoarthritis. Biosis was searched with the following keywords: random* AND (double near blind OR trial? OR stud??? OR placebo) AND osteoarthritis. These searches generated 1,519, 324, and 678 studies, respectively.

After the identical studies in the three searches were eliminated, the 2,026 remaining studies were individually screened based on their title and (if required) abstract or full content (Table 1). To be eligible for inclusion, a study had to fulfil all the following criteria: (a) to be a human RCT, (b) to investigate solely OA or (if investigating OA with other diseases) to report the results related to OA separately, (c) to be a peer-reviewed full paper (no restrictions on language), and (d) to investigate the effects of dietary/oral interventions focusing on natural molecules (as opposed to synthetic molecules). This last criterion is somewhat arbitrary. Its purpose was to separate the nutritional interventions from the pharmacological ones, a task which is far from trivial. Functional nutrition is a recent rapidly evolving field set at the border between foods and drugs, which explains why some ingredients, such as glucosamine, chondroitin sulphate, or S-adenosyl-L-methionine (SAMe), are registered as drugs in some countries but used in functional foods or as nutraceuticals in others. Because of this last criterion, studies focusing on SAMe were excluded from this review. Indeed, although a natural physiologic precursor of endogenous sulfated compounds, SAMe in its native form degrades rapidly and only stabilised synthetic forms have been used in scientific studies 12. Studies dealing with glucosamine HCl, glucosamine sulphate, and chondroitin sulfate were excluded because several high-quality meta-analyses on these molecules have recently been published 13141516.

<p>Table 1</p>

Numbers of papers remaining after each stage of the selection process of the systematic review

Raw hits from all sources

2,026

Number of studies reviewed for inclusion criteria after reading the title

121

Number of studies excluded because: administration was not oral

of pharmacological interventions

they did not report the result of a clinical trial

clinical trials were not randomised

results already reported in another paper (duplicate reports)

-23

-13

-30

-2

-2

Number of RCTs found during the reviewing process by serendipity and added to the review

+2

Number of RCTs matching inclusion criteria and reviewed here

53

Number of negative RCTs that concerned nutritional intervention for which no positive RCT was found

-11

Number of RCTs the quality of which was scored (Table 3)

42

To look for further unidentified RCTs that met our inclusion criteria, a second search in PubMed was performed with OA and the name of each ingredient found through the primary search and also by screening the reference lists of all relevant articles identified. Finally, for all ingredients used in the RCTs selected that way, a systematic search limited to PubMed was performed to identify in vitro and animal studies related to this ingredient and articular cartilage. Among these studies, the most relevant ones were selected, and their results were reported to shed light upon the potential mechanisms of actions of these nutritional interventions.

Quality assessment

This systematic review focuses on statistical differences in primary endpoints between treatment groups and considers the trials efficacious if the difference between groups was significant (P < 0.05) in placebo-controlled trials and not significant in NSAID-controlled trials. When no primary endpoint was mentioned, effects on visual analog scales (VASs), Lequesne functional index (LFI), and Western Ontario and McMaster universities (WOMAC) index were preferentially reported if available and used for the evaluation of efficacy.

The quality of each RCT related to a functional ingredient the efficacy of which was supported at least by one RCT was scored according to a standard set of 12 criteria based on published recommendations for the design of clinical trials in patients with OA 17181920 (Table 2). One point was assigned to each criterion that was met. If the criterion was not met or was not described at all, no point was assigned. The points were summed and divided by 12 in order to express the quality score as a percentage. A minus was placed in front of the score if the RCT did not support the efficacy of the intervention. Both authors scored the RCTs independently. Divergence was resolved by consensus after discussion. An RCT was considered of high quality when its OA-specific score was greater than or equal to 75%. Both authors also scored the RCTs with the validated Jadad score 21. To determine and validate the robustness of our OA-specific score, the inter-individual variabilities of the two scores were calculated on the 42 graded RCTs. The inter-individual variabilities of the two scores were comparable and equaled 7% and 8%, respectively (that is, 7% to 8% of the individual criteria of the two scores end up with a different point between the two authors of this study).

<p>Table 2</p>

Criteria used for the assessment of the methodological quality of human clinical trials

Item

Criterion

Study population

1.

Patients with radiographically confirmed osteoarthritis or selected according to American College of Rheumatology guidelines

2.

Age, gender, and body mass index reported and not statistically different between groups

3.

Efficacy assessed on a single anatomical joint (for example, knee)

Trial design

4.

Randomisation

5.

Placebo-controlled study

6.

Double-blind study

7.

Duration of at least 3 months

8.

Selection of a single primary endpoint before beginning of trial

9.

Sample size based on power calculation

Analysis and data presentation

10.

Data analysed according to the intention-to-treat principle

11.

Reported dropout rate not more than 25%

12.

Report of adverse effects

Best-evidence synthesis

A global score was then calculated to summarise the strength of evidence available for each functional ingredient (Table 3). To take into account the quality and quantity of RCTs, the global score was calculated by adding a factor to the mean quality score of the RCTs (that is, 0.33 when two positive high-quality RCTs were available, 0.66 when three positive high-quality RCTs were available, and 1.00 when four positive high-quality RCTs were available). Likewise, when two, three, or four negative high-quality RCTs were available, 0.33, 0.66, or 1, respectively, was subtracted from the mean quality score of the RCTs. Adding a factor gives more weight to the high-quality trials and helps to prevent the 'dilution' of the outcomes of high-quality trials when numerous low-quality trials exist. It also distinguishes the functional ingredients supported only by one, two, three, or four high-quality trials, which would otherwise end up with the same global score.

<p>Table 3</p>

Ingredients, with the scores of the trialsa, displayed by decreasing order of strength of evidence

Nutritional intervention Trial (Author's name/year) [reference number]

Was treatment efficient?

OA score

Jadad score of the RCT

Global score of the functional ingredients

Criterion number

Totalscore of the RCT

1

2

3

4

5

6

7

8

9

10

11

12

Avocado soybean unsaponifiables

1.58

Blotman 1997 [24]

Yes

1

1

0

1

1

1

1

1

1

1

1

1

0.92

5

Maheu 1998 [26]

Yes

1

1

1

1

1

1

1

1

1

1

1

1

1

5

Appelboom 2001 [25]

Yes

1

0

1

1

1

1

1

1

0

1

1

1

0.83

3

Lequesne 2002 [27]b

No

1

1

1

1

1

1

1

1

1

1

0

1

-0.92

5

-0.92

Methylsulfonylmethane

1.21

Usha 2004 [130]

Yes

1

1

1

1

1

1

1

0

1

1

1

1

0.92

5

Kim 2006 [131]

Yes

1

0

1

1

1

1

1

0

1

1

1

1

0.83

5

SKI306X

1.12

Jung 2001 [125]

Yes

1

1

1

1

1

1

0

1

1

1

0

1

0.83

4

Jung 2004 [126]

Yes

1

0

1

1

0

1

0

1

1

1

1

1

0.75

5

Vitamin B3

0.75

Jonas 1996 [79]

Yes

1

1

0

1

1

1

1

0

1

0

1

1

0.75

5

Vitamin C

0.75

Jensen 2003 [58]

Yes

1

0

0

1

1

1

0

1

1

1

1

1

0.75

5

Duhuo Jisheng Wan

0.67

Teekachunhatean 2004 [129]

Yes

1

1

1

1

0

1

0

0

0

1

1

1

0.67

3

Lipids from Perna canaliculus

0.58

Gibson 1980 [46]

Yes

1

0

0

1

1

1

1

0

0

0

1

1

0.58

4

Audeval 1986 [45]

Yes

1

0

1

1

1

1

1

1

0

0

1

1

0.75

4

Gibson 1998 [47]

Yes

1

0

0

1

0

1

1

0

0

0

1

0

0.42

5

Cetyl myristoleate

0.58

Hesslink 2002 [50]

Yes

1

1

1

1

1

1

0

0

0

0

1

0

0.58

3

Harpagophytum procumbens

0.54

Lecomte 1992 [99]

Yes

0

0

0

1

1

1

0

0

0

0

0

1

0.33

3

Chantre 2000 [100]

Yes

1

0

0

1

0

1

1

1

1

1

1

1

0.75

5

Bromelain

0.53

Singer 1996 [92]

Yes

1

0

1

1

0

1

0

0

0

1

1

1

0.58

4

Klein 2000 [91]

Yes

1

0

1

1

0

1

0

1

0

1

1

0

0.58

4

Singer 2001 [142]

Yes

1

0

1

1

0

1

0

0

0

1

1

1

0.58

4

Tilwe 2001 [89]

Yes

1

0

1

1

0

0

0

0

0

1

0

0

0.33

2

Akhtar 2004 [90]

Yes

1

1

1

1

0

1

0

0

0

1

0

1

0.58

4

Boron

0.50

Newnham 1994 [85]

Yes

1

0

0

1

1

1

0

0

0

0

1

1

0.50

4

Uncaria guianensis

0.50

Piscoya 2001 [106]

Yes

1

0

1

1

1

1

0

0

0

0

0

1

0.50

3

Boswellia serrata

0.48

Kulkarni 1991 [123]c

Yes

1

0

0

1

1

1

1

0

0

0

0

1

0.50

3

Badria 2003 [122]

Yes

0

0

1

1

1

1

1

0

0

0

0

0

0.42

3

Kimmatkar 2003 [121]

Yes

1

0

1

1

1

1

0

0

0

0

1

0

0.50

5

Ginger

0.42

Bliddal 2000 [115]

No

1

0

0

1

1

1

0

0

1

0

1

1

-0.58

5

Altman 2001 [113]

Yes

1

1

1

1

1

0

0

1

0

1

1

1

0.75

3

Wigler 2003 [112]

Yes

1

0

1

1

1

1

1

0

0

1

0

1

0.67

5

Vitamin E

0.17

Machtey 1978 [71]

Yes

1

0

0

1

1

0

0

1

0

0

1

1

0.50

1

Blankenhorn 1986 [72]

Yes

1

0

0

1

1

1

0

0

0

0

1

1

0.50

4

Scherak 1990 [73]

Yes

1

0

0

1

0

1

0

0

0

0

1

1

0.42

3

Brand 2001 [74]

No

1

0

1

1

1

1

1

1

1

1

1

1

-0.92

5

Wluka 2002 [75]b

No

1

1

1

1

1

1

1

1

1

1

1

0

-0.92

5

-0.92

'Hyperimmune' milk

-0.09

Colker 2002 [134]

No

0

1

1

1

1

1

0

1

0

0

1

1

-0.67

4

Zenk 2002 [135]

Yes

0

1

0

1

0

1

0

1

0

0

1

1

0.50

5

Collagen hydrolysate

-0.17

Adam 1991 [138]

Yes

1

0

0

1

1

1

0

0

0

0

0

0

0.33

3

Moskowitz 2000 [137]

No

1

0

1

1

1

1

1

0

0

1

0

1

-0.67

3

Salix sp.

-0.25

Mills 1996 [110]d

No

0

0

0

1

1

1

0

0

0

0

1

1

-0.42

5

Schmid 2001 [108]

Yes

1

1

0

1

1

1

0

1