Skip to main content

Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence

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 [7, 8]. 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 [13–16].

Table 1 Numbers of papers remaining after each stage of the selection process of the systematic review

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 [17–20] (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).

Table 2 Criteria used for the assessment of the methodological quality of human clinical trials

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.

Table 3 Ingredients, with the scores of the trialsa, displayed by decreasing order of strength of evidence

Consequently, the scores range from -2 to +2:

â–ª A score below -0.5 corresponds to at least some evidence of inefficacy.

â–ª A score between -0.5 and +0.5 indicates a lack of evidence of efficacy because it is obtained in case of conflicting evidence or when a majority of poor-quality trials are available.

â–ª A score greater than 0.5 but less than or equal to 1 corresponds to limited evidence of efficacy because it is obtained when a majority of medium-quality trials exist in the presence of a maximum of one positive high-quality trial or when a single positive high-quality trial is available.

â–ª A score between 1.01 and 1.33 indicates moderate evidence of efficacy because it requires two positive high-quality trials in the absence of major conflicting evidence.

â–ª A score between 1.34 and 1.66 indicates good evidence of efficacy because it requires three positive high-quality trials in the absence of major conflicting evidence.

â–ª A score between 1.67 and 2.00 indicates very good evidence of efficacy because it requires four positive high-quality trials in the absence of major conflicting evidence.

Results

Out of the 2,026 identified studies, 52 RCTs that investigated the effects of functional ingredients in OA and that had their results reported in peer-reviewed full papers were identified. Historically, functional ingredients can be derived from primary food sources, from secondary food sources, from traditional medicinal products from all around the world, or from materials with no history of human exposure (for example, stanols from paper industry by-products for their cholesterol-lowering effects) [22]. The situation regarding OA is no different. Some ingredients included in this review are from primary food sources (for example, n-3 polyunsaturated fatty acids [n-3 PUFAs]), from secondary food sources (for example, ginger), from traditional medicinal products (for example, cat's claw), or from material with no history of human exposure as such (for example, 'hyperimmune' milk). The investigated nutritional interventions focused on lipids (avocado and soybean unsaponifiables [ASUs], n-3 PUFAs, lipid extracts from New Zealand green-lipped mussel, and cetyl myristoleate), on vitamins and minerals (vitamins C, E, B3, and B12, boron, a cocktail of vitamins and selenium, and a cocktail of minerals), on plant extracts (bromelain, Rosa canina, Harpagophytum procumbens, Uncaria tomentosa, and Uncaria guianensis, Salix sp., ginger, turmerics, tipi tea, soy proteins, and Boswellia serrata), on a cocktail of plant extracts (SKI306X, Gitadyl, Duhua Jushing Wan, and Articulin-F), and on a few other types of ingredients (methylsulfonlymethane, hyperimmune milk, and collagen hydrolysate).

Lipids

Avocado/soybean unsaponifiables

The most thoroughly investigated lipid mixture is Piascledine (Pharmascience, Inc., Montreal, Quebec, Canada). Piascledine is composed of one third avocado and two thirds soybean unsaponifiables (ASUs), the oily fractions that, after hydrolysis, do not produce soap [23].

Four double-blind placebo-controlled RCTs (Table 4) and one systematic review evaluated ASUs on knee and hip OA [24–28]. In two 3-month RCTs, one on knee and hip OA [24] and one solely on knee OA [25], 300 mg once a day decreased NSAID intake. No statistical difference in any primary or secondary endpoints was detected between 300 and 600 mg once a day [25]. In a 6-month RCT on knee and hip OA, 300 mg once a day resulted in an improved LFI compared with placebo [26]. ASUs had a 2-month delayed onset of action as well as residual symptomatic effects 2 months after the end of treatment. In a 2-year RCT on hip OA, 300 mg once a day did not slow down narrowing of joint space width [27]. In addition, none of the secondary endpoints (LFI, VAS of pain, NSAID intake, and patients' and investigators' global assessments) was statistically different from placebo after 1 year. However, a post hoc analysis suggested that ASUs might decrease narrowing of joint space width in patients with the most severe hip OA. In summary, although ASUs might display medium-term (several months') symptom-modifying effects on knee and hip OA, their symptom-modifying effects in the long term (>1 year) have not been confirmed. ASUs might slow down narrowing of joint space width in patients with severe hip OA, but this requires confirmation. Based on our best-evidence synthesis, good evidence is provided by ASUs for symptom-modifying effects in knee and hip OA but at the same time, there is some evidence of absence of structure-modifying effects (Table 3). A recent systematic review on ASUs recommended further investigation because three of the four rigorous RCTs suggest that ASUs is an effective symptomatic treatment, but the long-term study is largely negative [28]. However, the fact that this long-term study was primarily aiming at demonstrating structure-modifying and not symptom-modifying effects might explain why no symptomatic effects from ASUs were detected in the long-term study. Indeed, symptoms and structural damage are known to mildly correlate in OA, and the most appropriate patients to demonstrate a structure-modifying effect might not be the most appropriate to demonstrate a symptom-modifying effect. As for safety, none of the four RCTs reported significant differences in adverse effects between ASUs and placebo.

Table 4 Summary of trials on ingredients having at least a limited evidence of efficacy

In sheep with lateral meniscectomy, 900 mg once a day for 6 months reduced the loss of toluidine blue stain in cartilage and prevented subchondral sclerosis in the inner zone of the lateral tibial plateau but not focal cartilage lesions [29].

In vitro, ASUs display anabolic, anticatabolic, and anti-inflammatory effects on chondrocytes. ASUs increased collagen synthesis [30] and inhibited the spontaneous and interleukin (IL)-1β-induced collagenase activity [23, 31]. They increased the basal synthesis of aggrecan and reversed the IL1β-induced reduction in aggrecan synthesis [32]. ASUs were also shown to reduce the spontaneous and IL1β-induced production of matrix metalloproteinase (MMP)-3, IL-6, IL-8, and prostaglandin E2 (PGE2) while weakly reversing the IL1β-induced decrease in TIMP (tissue inhibiting metalloproteinase)-1 production [23, 30, 32]. One study showed that ASUs decreased the spontaneous production of nitric oxide (NO) and macrophage inflammatory protein-1β [32] while stimulating the expression of transforming growth factor-β and plasminogen activator inhibitor-1 [33]. This stimulated production of plasminogen activator inhibitor-1 could decrease MMP activation.

The effects of avocado unsaponifiables alone, of soybean unsaponifiables alone, and of three mixtures of ASUs, were compared [23, 32]. The mixtures were A1S2 (Piascledine), A2S1, and A1S1, with respective ratios of ASUs of 1:2, 2:1, and 1:1. All mixtures significantly reduced the spontaneous production of IL-6, IL-8, and PGE2 and the IL1β-induced production of PGE2. A1S2 and A1S1, but not A2S1, significantly reduced the spontaneous and IL1β-induced production of MMP-3 and the IL1β-induced increase in collagenase activity, but only A1S2 inhibited the spontaneous collagenase activity. For some parameters, avocado unsaponifiables or soybean unsaponifiables alone were as potent as mixtures. In some cases, a single source of unsaponifiables seemed to be active. In other cases, both sources of unsaponifiables were active with synergistic or counteracting effects. The superiority of Piascledine over different ASU mixtures or over avocado or soybean unsaponifiables alone thus remains to be demonstrated.

Omega-3 PUFAs

PUFAs are classified as n-3, n-6, or n-9 depending on the position of the last double bond along the fatty acid chain. In n-3, this last double bond is located between the third and fourth carbon atom from the methyl end of the fatty acid chain. The main dietary PUFAs are n-3 (such as linolenic acid and eicosapentenoic acid) and n-6 (such as linoleic acid and arachidonic acid). Omega-3 is found in soybean and canola oils, flaxseeds, walnuts, and fish oils, whereas n-6 is found in safflower, corn, soybean, and sunflower oils as well as in meat. The modern Western diet is relatively low in n-3 PUFAs and relatively high in n-6 compared with the diet in Western pre-industrialised societies or with the modern Eastern diet. The n-6/n-3 ratio is 25:1 in the modern Western diet compared with 2:1 in Western pre-industrialised societies. A high n-3 intake correlates with a low incidence of cardiovascular and inflammatory diseases [34, 35]. The utility of n-3 for OA remains to be shown. In a 24-week double-blind placebo-controlled RCT, 10 ml of cod liver oil per day containing 786 mg of eicosapentaenoic acid, in addition to treatment with NSAIDs, did not decrease the VAS of pain or disability [36].

The articular cartilage content of arachidonic acid, a n-6 precursor of the pro-inflammatory eicosanoid PGE2, correlates with OA severity [37]. n-3 and n-6 are metabolised by cyclo-oxygenases (COXs) and lipo-oxygenases (LOXs) into distinct eicosanoids. The n-6-derived eicosanoids tend to be pro-inflammatory, whereas the n-3-derived eicosanoids tend to be anti-inflammatory. Hence, a high proportion of n-3 is supposed to lead to a relative deficiency in pro-inflammatory n-6 metabolites [34]. Dietary lipid interventions in animals modified the PUFA composition of articular cartilage [38], suggesting that high n-3 intake could have a beneficial effect on cartilage metabolism. In addition to eicosanoids, the anti-inflammatory effect of n-3 could also be mediated by their newly discovered oxygenated derivatives called resolvins, which through their binding to G protein-coupled receptors act as potent antagonists of inflammation [39].

The in vitro effects of 10 to 100 μg/ml of n-3 (linolenic, eicosapentaenoic, and docosahexaenoic acids) on chondrocytes have been investigated [40–42]. n-3 did not affect the spontaneous or the IL1-induced decrease in glycosaminoglycan (GAG) synthesis, but dose-dependently inhibited the IL1-induced GAG degradation. n-3 dose-dependently decreased the IL1-induced aggrecanase activity and basal aggrecanase and collagenase activity, whereas, in contrast, n-6 stimulated the basal aggrecanase and collagenase activity. n-3 also decreased the IL1-induced mRNA expression of ADAMTS-4 (aggrecanase), COX-2, 5-LOX, FLAP (5-LOX-activating protein), IL1α, and tumour necrosis factor (TNF) α and the basal mRNA levels of these genes. Finally, n-3 decreased the basal and IL1β-induced mRNA and protein levels of MMP-3 and MMP-13. All these parameters were unaffected by n-6 PUFAs. Taken together, these results indicate that n-3 PUFAs have anticatabolic and anti-inflammatory properties. Nevertheless, too low of an n-6/n-3 ratio can be detrimental. A diet with very low levels of n-6 PUFAs induced occasional surface irregularities and localised proteoglycan depletion in cartilages in rats [38].

Lipid extract from New Zealand green-lipped mussel (Perna canaliculus)

The incidence of arthritis in coastal-dwelling Maoris is low, possibly due to their high consumption of green-lipped mussels. The powder and lipid extracts from this mussel have been investigated in OA (Table 4). These products contain n-3 PUFAs as well as vitamins associated or not associated with chondroitin sulfate, amino acids, and minerals [43, 44]. In a 6-month double-blind placebo-controlled RCT on knee OA, Seatoneâ„¢ (McFarlane Laboratories, Auckland, New Zeland), a mussel gonad extract, improved four endpoints (VAS of pain, functional index, and patients' and physicians' overall assessments) out of 10 investigated but only in patients with mild to moderate OA [45]. In a 3-month double-blind RCT, 350 mg of Seatoneâ„¢ three times a day improved VAS of pain in 40% of patients versus 13% in placebo [46]. In a small 3-month double-blind RCT, 1,150 mg/day of a mussel powder and 210 mg/day of a lipid extract decreased the values of a VAS of pain [47]. However, the small number of enrolled patients and the absence of placebo group, complete blinding, and baseline characteristics of the population seriously limit the relevance of this trial. No serious adverse effects have been reported. According to the best-evidence synthesis (Table 3), there is limited evidence of efficacy for green-lipped mussel in OA. This is in agreement with a recent systematic review evaluating the effectiveness of this ingredient for OA and rheumatoid arthritis [48].

In a 6-week double-blind placebo-controlled RCT in dogs, 1 g per day of a green-lipped mussel powder sprinkled on the food or on semi-moist treats or directly incorporated as 0.3% in a dry diet significantly improved total arthritic score, joint pain, and joint swelling [44, 49]. More than 50% of the dogs demonstrated a 30% or greater reduction in total arthritic score. However, it is unclear whether these dogs suffered from OA specifically, and the disease severity was not described.

Cetyl myristoleate

The oil cetyl myristoleate is the hexadecyl ester of the unsaturated fatty acid cis-9-tetradecenoic acid, commonly named myristoleic acid. Whereas myristoleic acid is commonly found in fish oils, whale oils, and dairy butter, cetyl myristoleate is known to exist only naturally in sperm whale oil and in a small gland in the male beaver. It can be synthesised by esterification of myristoleic acid. Although cetyl myristoleate is claimed to be beneficial for OA, there is lack of scientific evidence to support its efficacy. Nevertheless, a 68-day placebo-controlled single-blind RCT on severe knee OA (that is, LFI >14) concluded that three 500 mg capsules, containing 350 mg of a blend of olive oil and various cetylated fatty acids, 50 mg of lecithin, and 75 mg of fish oil, twice a day, significantly increased knee flexion compared with placebo [50] (Table 4). According to the best-evidence synthesis (Table 3), this low-quality RCT provides limited scientific evidence of efficacy for cetyl myristoleate. Hence, further research is needed to evaluate the safety and potential benefits of cetyl myristoleate and cetylated fatty acids in the treatment of OA.

Vitamins and minerals

Due to their antioxidant properties, vitamins could have beneficial effects in OA [51, 52]. Usually, antioxidant defences neutralise most reactive oxygen species (ROS) by enzymes such as superoxide dismutase, catalase, and peroxidase or by small antioxidant molecules. However, when ROS are produced in increased amounts like in OA, the antioxidant capacity of cells and tissues can become insufficient to detoxify the ROS, which then contribute to cartilage degradation by inhibiting matrix synthesis, directly degrading matrix molecules, or activating MMPs (reviewed in [53]).

The effects of vitamins C, E, and B on OA have been formally investigated in RCTs (see below). One obvious candidate not yet evaluated is vitamin D (vit D). Pathophysiological changes in OA affect periarticular bone, and normal bone metabolism requires vit D. Hence, suboptimal levels of vit D may impair bone metabolism and predispose to OA. In addition, the expression of vit D receptors is upregulated in human OA chondrocytes [54]. The Framingham study found a threefold increase in risk of OA progression for patients in the middle and lowest tertiles of serum levels of 25-vit D [55]. Low serum levels of vit D also predicted loss of joint space and osteophyte growth. The Study of Osteoporotic Fractures in women found that the risk of incident hip OA defined by joint space narrowing was increased for patients in the middle and lowest tertiles of serum levels of 25-vit D3 [56]. Based on these data, an RCT testing the efficacy of vit D may be required.

Vitamin C

Vitamin C (vit C) is a common term used for L-ascorbic acid, dehydro-L-ascorbic acid (the oxidised from of L-ascorbic acid), and L-ascorbic acid salts (sodium, potassium, and calcium L-ascorbate). L-ascorbic acid constitutes the majority (80%-90%) of vit C in food. It is found in rose hips, blackcurrants, and citrus fruits but can also be synthesised from glucose.

The Framingham epidemiological study found a threefold reduction in risk of OA progression for both the middle and highest tertiles of vit C intake and an inverse association between vit C intake and cartilage loss [57]. No association was found between vit C intake and osteophyte growth or rate of apparition of the disease. In this study, vit C intake was assessed using a food frequency questionnaire, which can induce errors and bias. In a 14-day double-blind crossover RCT on knee and hip OA, 1 g twice a day of calcium ascorbate was more efficient than placebo in decreasing VAS of pain [58] (Table 4). Although the quality of the RCT was high (Table 3), the measured effect was small (a 4.6-mm decrease from a starting basal level of 50 mm) and obtained with a dose equal to the upper tolerable intake level for adults (that is, the highest level of daily intake from food, water, and supplements which is likely to pose no risk of adverse health effects for almost all individuals in the general population), well above the current recommended daily allowances (RDAs) of 60 to 200 mg per day. The long-term safety of such high doses of vit C in elderly patients with OA needs to be evaluated, and efficacy needs to be confirmed by longer RCTs.

Guinea pigs, like humans, possess a nonfunctional gene for L-gulono-γ-lactone oxidase, which makes them unable to synthesise ascorbic acid and dependent on dietary ascorbic acid to prevent scurvy. In guinea pigs, a 'megadose' of 150 mg per day of ascorbic acid decreased the severity of surgically induced knee OA [59, 60] but increased severity of spontaneous OA [61], despite the ability of ascorbic acid to increase cartilage collagen content. A third guinea pig trial stated, on the contrary, without providing any details, that a fivefold increase of ascorbic acid to the drinking water (equivalent to 1 g per liter) had a slight chondroprotective effect on the development of spontaneous lesions but not on surgically induced OA [62]. In view of these conflicting results and in the absence of strong evidence of efficacy in humans, it was recommended that vit C intakes for OA not exceed the current RDA [61].

Articular cartilage accumulates ascorbic acid [63]. In chondrocytes, ascorbic acid and dehydroascorbate are transported, respectively, through the sodium-dependent vit C transporter (SVCT)-2 [64] and the glucose transporter GLUT 1 [65]. In OA, the majority of vit C is expected to be transported through SVCT-2 [65]. Ascorbic acid serves as a cofactor for prolyl and lysyl hydroxylases, enzymes crucial in collagen synthesis. In vitro, ascorbate and ascorbic acid increased protein and proteoglycan synthesis by articular chondrocytes [64, 66, 67] and increased the mRNA levels of type I and II collagen [64, 68] and aggrecan and α-prolyl 4-hydroxylase [64]. It decreased the lipopolysaccharide (LPS)-induced GAG release [69]. It also affected the activities of lysosomal enzymes, decreasing the activities of arylsulfatase A and arysulfatase B, an N-acetylgalactosaminidase-4-sulfatase, but increasing the activity of acid phosphatase in normal and OA chondrocytes [66].

Ascorbic acid can cross-link collagen and other proteins by non-enzymatic glycation, leading to the formation of advanced glycation endproducts (AGEs). Threose, a metabolite of ascorbic acid, increases the AGE content of articular cartilage in vitro [70]. These cross-links increase the stiffness of the collagen network, which is hypothesised to increase cartilage susceptibility to OA. High in vitro levels of ascorbic acid (756 μM) also increased protein carbonylation, one type of oxidative damage [64]. However, when guinea pigs were fed with diets containing different levels of ascorbic acid, no changes in the AGE content of articular cartilage were detected [61].

Vitamin E

Natural vitamin E (vit E) comprises eight different forms, α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol, produced solely by plants. One of the richest food sources of vit E is edible plant oils. Synthetic α-tocopherols (the eight other possible side-chain stereoisomers besides the natural one) and their esters (α-tocopherylsuccinate and α-tocopherylacetate) also exist. α-Tocopherylacetate is often used commercially because vit E esterification protects it from oxidation. In the human body, the ester is rapidly cleaved by cellular esterases making natural vit E available.

Five RCTs have tested the natural form of vit E or α-tocopherylacetate. Two trials concluded that vit E was more efficient than placebo in decreasing pain. In a small 10-day single-blind crossover RCT on mainly spondylosis, 600 mg of vit E per day was superior to placebo as assessed by a patient questionnaire [71], whereas in a 6-week double-blind RCT on OA, 400 IU of α-tocopherylacetate once a day was superior to placebo as assessed by a joined patients' and doctors' global assessment of pain [72]. One trial suggested that vit E was no less efficient than diclofenac in decreasing pain. In a 3-week double-blind RCT on OA, no significant difference was found between 544 mg of α-tocopherylacetate three times a day and 50 mg diclofenac three times a day on VAS of pain [73]. However, the two most recent trials failed to show any benefit over placebo on knee OA. In a 6-month double-blind RCT, 500 IU of vit E a day showed no symptomatic benefit over placebo as assessed by WOMAC [74], whereas in a 2-year double-blind RCT, 500 IU of vit E a day showed no symptomatic or structure-modifying benefit over placebo as assessed by magnetic resonance imaging or WOMAC, respectively [75]. Although three out of the five RCTs concluded that vit E decreased pain, the two longest, largest, and highest-quality trials (Table 3) failed to detect any symptomatic or structural effects in knee OA. This suggested that, at least for knee OA, vit E alone has no medium-term beneficial effect. According to the best-evidence synthesis (Table 3), there is no evidence of symptom-modifying efficacy for vit E and some evidence of inefficacy regarding structure-modifying effects. No significant adverse event was reported.

Only a few papers investigated the in vitro effects of vit E on chondrocytes. Tiku et al. [76] showed that when chondrocytes were submitted to an oxidative burst, vit E reduced the catabolism of collagen by preventing the protein oxidation mediated by aldehydic downproducts of lipid peroxidation. Vit E strongly increased the sulfate incorporation while slightly reducing the glucosamine incorporation [77], suggesting that it increased GAG sulfatation or that it increased GAG synthesis while reducing glycoproteins or glycolipids synthesis. Like vit C, vit E affected the activities of lysosomal enzymes: it decreased the activities of arylsulfatase A and of acid phosphatase in cultures of human articular chondrocytes [77]. However, vit E did not affect the LPS-induced catabolism of GAGs [69] and did not prevent synoviocyte apoptosis induced by superoxide anions [78].

Vitamins B

In a 3-month double-blind RCT of high quality (Table 3), a megadose of niacinamide (vitamin B3, 500 mg six times per day) was more efficient than placebo in reducing drug intake and symptoms but not pain [79] (Table 4). Such a high dose is 2 orders of magnitude above the upper tolerable intake level and is of concern [80].

A 2-month double-blind crossover RCT in hand OA comparing 6,400 μg of folate with or without 20 μg of cobalamin (vitamin B12) daily, to placebo, had no significant effects on mean hand grip values [81].

Cocktail of vitamins and selenium

Two cocktails of vitamins with added selenium, a component of the antioxidative enzyme glutathione peroxidase, have been investigated. In a small pilot 6-month double-blind placebo-controlled RCT, a mixture of vitamins A, C, and E (in undisclosed amounts) and 144 μg of selenium per day had no effect on VAS of pain or stiffness [82]. Vitamins A, C, E, B2, and B6 and selenium decreased OA incidence and severity in STR/1N mice, possibly through an antioxidant effect because the expression of two antioxidative enzymes, glutathione peroxidase and superoxide dismutase, was increased in cartilage [83].

Boron

Femoral OA bone contains less boron, a nonmetallic trivalent chemical element, than does normal bone [84], suggesting that boron might have a beneficial effect in OA. A small 8-week double-blind placebo-controlled RCT suggested that 6 mg/day, taken as sodium tetraborate decahydrate, was more efficient than placebo in reducing a patients' assessment scale of symptoms [85] (Table 4). This RCT, however, is of low quality (Table 3); hence, longer and higher-quality RCTs are required to evaluate thoroughly the benefits of boron for OA.

Cocktail of minerals

Sierrasil, a cocktail of 36 minerals from the Sierra Mountains in the U.S., was tested at two doses (2 or 3 g/day) and at a dose of 2 g/day with a cat's claw extract (100 mg/day) in an 8-week double-blind placebo-controlled RCT on knee OA [86]. None of these treatments was more effective at relieving symptoms than placebo as assessed by WOMAC or VAS of pain.

Phytochemicals and plant extracts

Bromelain

Bromelain is a crude, aqueous extract obtained from both the stems and immature fruits of the pineapple plant (Ananas comosus Merr, mainly var Cayenne from the family of bromeliaceae), which contains a number of proteolytic enzymes. Bromelain was suggested to have anti-inflammatory, analgesic, antioedematous, antithrombic, and fibrinolytic effects, although many of the studies describing these properties were of poor quality ([87], and reviewed in [88]). Three different preparations containing bromelain mixed with diverse enzymes have been tested in nine trials on knee OA ([87, 89, 90] for a review and references therein). Bromelain was taken in tablets coated to resist stomach digestion at a daily dose ranging from 270 to 1,890 mg. All trials might have been insufficiently powered, were of short duration (3 to 6 weeks), and enrolled OA patients with flare-up episodes. Most used the LFI as a primary endpoint. Although bromelain was as effective or more effective effective than 100 to 150 mg of diclofenac per day in seven trials, it was also not more efficient than placebo in two other trials. This absence of efficacy over placebo, coupled with the fact that in some diclofenac-controlled trials the LFI or other functional endpoints continued to decrease in both groups even 4 weeks after the end of treatment [91, 92], suggested a possible spontaneous resolution of the flare-up episode rather than a real efficacy of the treatment. Longer trials of higher quality were advocated to confirm the efficacy of bromelain [87]. The best-evidence synthesis indicates a limited evidence of efficacy based on five trials (Tables 3 and 4). Lack of sufficiently detailed data prevented the inclusion of the four other trials.

In one trial, a high dose of bromelain (945 mg/day) induced a higher incidence of adverse effects and dropouts compared with diclofenac [92], whereas in another trial, a lower dose (270 mg/day) induced a higher dropout rate due to adverse effects than diclofenac [90]. Together, these two reports question the safety and tolerability of bromelain.

Rosa canina

A standardised rose-hip powder made from the seeds and husks of the fruits from a subtype of R. canina (Hyben Vitalâ„¢ produced by Hyben Vital International, Langeland, Denmark), the common wild-briar rose of English hedgerows, was evaluated in three RCTs. In a 4-month double-blind RCT on hip and knee OA, 2,500 mg of this powder twice a day did not improve active or passive mobility (joint rotation, flexion, and extension) more than placebo, except for passive hip flexion [93]. In a 3-month crossover double-blind RCT, 2,500 mg of Rosa powder twice a day decreased pain (as measured by a categorical scale) more efficiently than placebo when placebo was given first but not when it was given second [94]. No pain difference was found when the two groups were compared before crossover either. This RCT, which enrolled patients with OA in various joints, did not include any washout period. In a 3-month crossover double-blind RCT on knee and hip OA which included a 3-week washout period, 2,500 mg of Rosa powder twice a day was more effective than placebo in decreasing WOMAC pain after 3 weeks of treatment but not after 3 months [95]. The lack of significance after 3 months could have been due to the decreased paracetamol consumption observed when patients were under active treatment. At 3 months, the Rosa treatment decreased the WOMAC function and stiffness subscales (secondary endpoints) more efficiently than placebo. According to the best-evidence synthesis, there is a lack of scientific evidence for R. canina extracts. However, the last RCT suggests that R. canina powder might have some efficacy. Hence, further research on this extract is required before making any conclusion about its efficacy or lack of efficacy. No major side effects were reported in these three RCTs.

Daily intake of 45 g of rose hip powder reduced chemotaxis of peripheral blood neutrophils and serum creatinine and C-reactive protein (CRP) levels in healthy and OA subjects [96, 97].

Harpagophytum procumbens(devil's claw)

H. procumbens, also called devil's claw, is a South African plant that grows in regions bordering the Kalahari. Secondary tuberous roots are used to prepare powders or extracts, which were tested in several RCTs (reviewed in [98]). Product standardisation is based on the content of harpagoside, the principal compound found in the raw material. In all RCTs, the harpagoside content was similar and greater than 50 mg/day.

In a 2-month double-blind RCT on spine and knee OA, 670 mg of powder three times a day was more efficient than placebo in reducing VAS of pain [99] (Table 4). In a 4-month double-blind diacerhein-controlled RCT on hip and knee OA with flare-up episodes at inclusion, 2.6 g of powder/day was no less efficient than 200 mg of diacerhein per day in improving VAS of pain [100, 101]. Devil's claw was also better tolerated than diacerhein. A systematic review of the efficacy of Harpagophytum for OA concluded that there is limited evidence of efficacy for ethanolic extract when providing less than 30 mg of harpagoside per day in the treatment of knee and hip OA and moderate evidence of efficacy for the use of powder when providing 60 mg of harpagoside daily in the treatment of spine, hip, and knee OA [102]. The best-evidence synthesis used here (Table 3) indicates a limited evidence of efficacy. Whether the efficacy differs between patients with flare-up episodes or without is currently not clear. The need for larger, better designed RCTs with higher doses has been advocated before making categorical recommendations for Harpagophytum [98]. No safety concerns appeared from the 4,300 patients, who received Harpagophytum products. In an uncontrolled surveillance study, 0.8 g of an aqueous extract three times a day reduced blood sedimentation time and CRP levels [103]. An extract reduced the IL1β-induced production of MMP-1, MMP-3, and MMP-9 proteins by chondrocytes [104].

Uncaria tomentosa and Uncaria guianensis(cat's claw)

Cat's claw is a vine from the basin of the Amazon River. There are two species, U. tomentosa and U. guianensis, that are traditionally used in South America for their anti-inflammatory properties. The bark and the root are prepared as an extract in hot water. Product standardisation is based on alkaloid content, although U. guianensis extracts are more potent than U. tomentosa extracts in vitro despite a much lower alkaloid content [105]. Because numerous HPLC (high-performance liquid chromatography) fractions are biologically active in vitro, in vivo efficacy might be due to multiple compounds.

In a small 4-week double-blind RCT on knee OA, 100 mg of an extract from U. guianensis once a day was more efficient than placebo in reducing pain associated with activity but not pain at rest or at night [106] (Table 4). There was no statistical difference between groups in reported adverse effects in this trial, although cat's claw has been reported as nephrotoxic [107]. According to the best-evidence synthesis (Table 3), this low-quality RCT does not provide scientific evidence of efficacy for cat's claw. If cat's claw is proven efficacious in the future, a carefully controlled process of production will probably be required to prevent any nephrotoxicity.

Salix sp.(willow bark)

The anti-inflammatory, antipyretic, and analgesic effects of willow bark have been known since antiquity. Willow bark contains salicin, which is rapidly metabolised into salicylic acid. The acetylated derivative of salicylic acid is known as aspirin. Willow bark extracts are usually standardised based on salicin content even if salicin might not be the major active compound.

In a 2-week double-blind RCT on knee and hip OA, an amount of extract corresponding to 240 mg of salicin a day was more efficient than placebo in reducing WOMAC pain subscore, but the effect was small [108]. Another 6-week double-blind RCT comparing the effects of another willow bark extract at the same dose with placebo and diclofenac 50 mg twice a day on knee and hip OA confirmed the efficacy of diclofenac but failed to detect any significant difference between willow bark and placebo on WOMAC pain subscore [109]. In another 2-month RCT, a cocktail of five plants, which included 100 mg of willow bark, failed to conclusively demonstrate an analgesic effect [110]. Skin allergic reactions have been linked to Salix ingestion in 3% to 11% of patients [111]. The best-evidence synthesis (Table 3) indicates a lack of evidence of efficacy for Salix extracts.

Ginger and turmeric

The Zingiberaceae family includes gingers and turmerics. Ginger is a very popular spice with a world production of 100,000 tons a year. It is used in traditional Japanese Kampo, Ayurvedic, and Chinese medicine as an anti-inflammatory agent for musculoskeletal diseases. Three RCTs evaluated ginger extracts prepared from the rhizomes of Zingiber officinale and Alpinia galanga.

In a double-blind RCT on knee OA, after crossover at 6 months, but not at 3 months before crossover, 250 mg of an extract of Z. officinale four times a day reduced VAS of pain and handicap more efficiently than placebo [112]. In a 6-week double-blind RCT on knee OA, 255 mg of an extract of Z. officinale and A. galanga twice a day was more efficient than placebo in reducing knee pain on standing up based on the percentage of responders [113]. The RCT suffered from incomplete blinding, and the beneficial effects were small and not observed on WOMAC and quality of life [114]. Finally, a 3-month three-way crossover double-blind RCT compared the efficacy of another ginger extract with ibuprofen and placebo in knee and hip OA but failed to demonstrate a difference between placebo and ginger extract as assessed by VAS of pain and LFI [115]. The best-evidence synthesis (Table 3) indicates a lack of evidence of efficacy. In two RCTs, a higher number of adverse effects and higher dropout rates related to adverse effects in ginger groups [112, 113] question the safety of these extracts.

In vitro, ginger extract decreased the IL1β- and LPS-induced production of NO and PGE2 by OA cartilage [116]. In synoviocytes, it decreased the IL1β- or TNF-α-induced expression of TNF-α mRNA and protein, the TNF-α-induced production of COX2, and the TNF-α-induced activation of nuclear factor (NF)-κB by reducing the protein level of the NF-κB inhibitor IκB [117].

An extract prepared from the Indian and Javanese turmerics Curcuma domestica and Curcuma xanthorriza, was tested on hip and elbow OA in an 8-week double-blind randomised trial in dogs [118]. No significant difference on the kinetic gait analysis was found between extract and placebo.

Flavonoids

Flavonoids, a group of polyphenolic compounds widely distributed throughout the plant kingdom, are thought to contribute to the health benefits of diets rich in fruits and vegetables. The in vivo effects of several flavonoids (tea-containing catechins, soy isoflavones) have been reported in the literature.

The effect of tipi tea (Petiveria alliacea), a tea used as an antirheumatic medicine, on knee and hip OA was evaluated in a small 1-week crossover double-blind RCT against a placebo tea [119]. No significant differences as assessed in pain scores or functional assessment were found.

Regarding isoflavones, a 3-month double-blind RCT on knee OA failed to show that 40 g daily of soy protein, containing a total of 88 mg of soy isoflavones, was more efficient than a milk-based protein placebo in reducing symptoms as assessed by questionnaires on pain and quality of life [120]. Use of milk-based proteins as a placebo is confounding because milk could be effective in OA (see 'Milk and hyperimmune milk' section). Soy but not milk proteins increased serum levels of insulin-like growth factor-1, an anabolic factor for chondrocytes.

Boswellia serrata

The gummy oleoresin from the bark of B. serrata, a tree from northwest India, is used for inflammatory diseases in Ayurvedic medicine. In an 8-week double-blind crossover RCT on knee OA, 333 mg of the gum three times a day was more efficient than placebo in reducing pain, loss of movement, and swelling scores [121]. In a 3-month double-blind RCT, 500 mg three times a day of a cocktail of B. serrata and turmeric (Curcuma longa) decreased categorical scales of joint pain, tenderness, and effusion [122]. According to the best-evidence synthesis, these RCTs provide no evidence of efficacy (Table 3).

B. serrata in combination with an extract from the root of Withania somnifera, the oleoresin of C. longa, and a zinc complex was tested in a 6-month double-blind crossover RCT [123]; 650 mg twice a day of this cocktail, called Articulin-F, was more efficient than placebo in reducing pain and disability scores. According to the best-evidence synthesis, this RCT indicates a lack of evidence of efficacy (Table 3).

Cocktails of plant extracts

SKI306X is a cocktail of extracts prepared from three plants (dried roots from Clematis mandshurica and Trichosantes kirilowii and dried flower and stem from Prunella vulgaris) used for the treatment of inflammatory diseases in Far East Asia. It is clinically approved for the treatment of OA in Korea [124]. In a 4-week double-blind RCT on knee OA, 200, 400, and 600 mg three times a day were more efficient than placebo in reducing VAS of pain, with no significant difference between the three doses [125] (Table 4). In another 4-week double-blind RCT on knee OA, 200 mg three times a day was not less efficient than 100 mg of diclofenac (sustained release) once a day in reducing VAS of pain [126]. According to the best-evidence synthesis, these two high-quality RCTs provide moderate evidence for the efficacy of SKI306X in OA. Although generally well tolerated, three severe adverse events occurred in the SKI306X group (compared with 11 for diclofenac).

In rats, SKI306X did not cause significant gastric damage up to an oral dose of 2 g/kg and suppressed the diclofenac induced gastric damage [124]. In rabbits, 200 mg/kg per day reduced the OA-like histological changes in collagenase-injected knees [127]. In vitro, SKI306X and the T. kirilowii extract, but not the other two plant extracts, reduced the IL1α-induced GAG release [127]. Synergistic effects between the three extracts present in SKI306X are suspected because the proportion of T. kirilowii is insufficient to fully explain the product potency.

The effects of Gitadyl, an herbal formulation containing extracts from feverfew, American aspen, and milfoil, at a dose of 260 mg three times a day were compared with the effects of 400 mg of ibuprofen three times a day in a 42-day double-blind crossover RCT. Both treatments failed to significantly change pain or the patients' ability to walk as assessed by four point scales [128].

In a 4-week double-blind RCT on knee OA, 3 g three times a day of Duhuo Jisheng Wan, a traditional Chinese cocktail of 15 plants, improved the LFI and multiple VAS of pain and stiffness as efficiently as 25 mg of diclofenac three times a day [129] (Table 4). Duhuo Jisheng Wan had a slower onset of action than diclofenac but an equal rate of adverse events, an observation that questions its safety. According to the best-evidence synthesis, there is limited scientific evidence to support the efficacy of Duhuo Jisheng Wan (Table 3).

Others

Methylsulfonylmethane

Methylsulfonylmethane (MSM) is the oxidised form of dimethyl sulfoxide. It is found in very low amounts in fruits, corn, tomatoes, tea, coffee, and milk. Two RCTs qualified to be evaluated in this systematic review (Table 4). In a 12-week double-blind placebo-controlled RCT on knee OA, 500 mg of MSM three times a day, used alone or in combination with 500 mg of glucosamine HCl three times a day, significantly improved a Likert scale of pain and LFI [130]. The combination of both ingredients was not more efficacious than each ingredient used alone. In a second 12-week double-blind placebo-controlled RCT on knee OA, 3 g of MSM given twice daily was more efficient than placebo in decreasing WOMAC pain and functional scores [131]. According to the best-evidence synthesis (Table 3), MSM provides moderate evidence of efficacy for knee OA.

Milk and hyperimmune milk

A cross-sectional epidemiological study suggested that the frequency of symptomatic knee OA was lower in milk consumers [132] but did not take into account body mass index, an important potential confounding factor [133]. Although no trial tested regular milk, one canine and two human double-blind RCTs tested hyperimmune milk. This milk is produced by cows that are immunised with intestinal bacteria antigens. It is enriched in high-molecular weight immunoglobulins (IgG) and is claimed to contain anti-inflammatory low-molecular weight components. A concentrated form of this milk was used in the RCTs. A 6-week human RCT failed to show that 355 ml a day of a fruit-flavoured beverage fortified with hyperimmune milk, vitamins B12, C, and E, and iron and zinc was more efficient than placebo in improving WOMAC [134]. In a 6-week three-arm RCT, 2 g twice a day of the milk preparation was not less efficient than 500 mg three times a day of glucosamine sulfate in improving WOMAC [135]. Unfortunately, a difference in symptomatic basal levels between treatment and placebo groups makes the placebo group of this RCT useless. Because none of these trials used regular milk as placebo, it is not known if hyperimmune milk has an effect different than regular milk. According to the best-evidence synthesis, there is a lack of scientific evidence of efficacy for hyperimmune milk.

In an 8-week RCT on dogs with musculoskeletal impairment, 1 g twice a day was more efficient than placebo in improving function as assessed by a newly developed questionnaire addressed to the pet owners [136]. Veterinarians' examination did not confirm these results. The absence of a precise diagnostic at enrolment and of any validation of the questionnaire limits the relevance of this study.

Collagen hydrolysate

Collagen hydrolysate is produced by enzymatic digestion of gelatin, which itself is produced by hydrolysis of collagen extracted from animal bones and skin.

In a 24-week multi-country double-blind placebo-controlled RCT on knee OA, 10 g/day did not improve the WOMAC index [137]. The dropout rate was high. Post hoc analysis suggested that the hydrolysate could be more efficient in severe OA. A 60-day double-blind crossover placebo-controlled RCT on knee and hip OA compared 10 g/day of collagen hydrolysate, gelatin, gelatin + glycin + CaHPO4*2H2O, or egg albumin [138]. The gelatin preparations were not significantly different from each other and were superior to egg albumin in reducing pain as assessed by a patient questionnaire. According to the best-evidence synthesis (Table 3), these two RCTs lack evidence of efficacy for collagen hydrolysate.

In vitro, type I or type II collagen hydrolysate dose-dependently increased type II collagen synthesis by chondrocytes, whereas native collagen and collagen-free hydrolysate did not [139]. The average molecular weight of collagen peptides in the hydrolysate ranges from 2 to 6 kDa. Ex vivo intestinal sac experiments suggested that peptides up to 15 kDa can be absorbed. In mice, a significant and long-lasting (>96 hours) accumulation of 14C-labeled collagen hydrolysate was observed in articular cartilage compared with 14C-labeled proline [140].

Discussion

Fifty-three RCTs investigating the effects of functional ingredients in OA met the inclusion criteria for this systematic review. The functional ingredients tested in these RCTs were lipids (ASUs, n-3 PUFAs, lipid extracts from New Zealand green-lipped mussel, and cetyl myristoleate), vitamins and minerals (vitamins C, E, B3, and B12, boron, a cocktail of vitamins and selenium, and a cocktail of minerals), plant extracts (bromelain, R. canina, H. procumbens, U. tomentosa and U. guianensis, Salix sp., ginger, turmerics, tipi tea, soy proteins, and B. serrata), a cocktail of plant extracts (SKI306X, Gitadyl, Duhua Jushing Wan, and Articulin-F), and a few other types of ingredients (methylsulfonlymethane, hyperimmune milk, and collagen hydrolysate). Eighteen of these functional ingredients had their efficacy supported by at least one RCT (Table 3).

To summarise the strength of scientific evidence behind a functional ingredient, we used a mathematically based best-evidence synthesis. This best-evidence synthesis allowed us to categorise the functional ingredients as having a limited, moderate, or good record of efficacy. According to this best-evidence synthesis (Table 3), good evidence exists for ASUs. Moderate evidence exists for methylsulfonylmethane and SKI306X, a cocktail of plant extracts. Limited evidence exists for the Chinese cocktail of plant extracts Duhuo Jisheng Wan, for cetyl myristoleate, for lipids from green-lipped mussels, and for plant extracts from H. procumbens. Limited evidence also exists for vitamins B3 and C and bromelain, but the small effects obtained, the high doses used, or the experimental design employed questions the clinical relevance and/or safety of these functional ingredients. The other interventions lacked scientific evidence either because of their rather poor design or because of contradicting available evidence. Among these interventions that lacked evidence of efficacy, vit E is unique: it is the only nutritional intervention whose lack of symptom-modifying and structure-modifying effects in knee OA is reported in high-quality RCTs. Despite the fact that our best-evidence synthesis considers each functional ingredient as a single entity, the evidence of efficacy and the safety record of plant extracts should be considered to be product-specific given that the composition of an extract from a same plant can vary widely between manufacturers.

All 18 functional ingredients evaluated in Table 3 were tested under a nutraceutical/dietary supplement form in the RCTs, except for hyperimmune milk incorporated in a functional drink. Depending on the regulatory laws of each country, these functional ingredients are sold as drugs, nutraceuticals (dietary supplements), or functional foods in association with health claims of variable strength. Although most ingredients are sold mostly as nutraceuticals today, some such as SKI306X and ASUs require a prescription and are sold as drugs, at least in some countries (Korea for SKI306X and several European countries for ASU). Similarly, the vitamins and some of the lipids reviewed here are sold mostly as nutraceuticals but can also be incorporated in functional foods (up to a country-specific defined maximal dose) because they have GRAS (generally recognised as safe) status. Regarding collagen hydrolysate specifically, its GRAS status and its advertised therapeutic dose (10 g) make it more practical to be used in a functional food than in a nutraceutical. Ideally, the efficacy of a functional food should be directly evaluated in an RCT (by providing to the enrolled patients the final commercial product) because the incorporation of a functional ingredient into a complex food matrix could potentially modify its efficacy, either by increasing or on the contrary by decreasing its bioavailability.

Conclusion

In summary, this review demonstrates that nutrition can improve the symptoms of declared OA. However, the role of nutrition in slowing down progression of the disease remains to be seen. The very few RCTs, which used structure-modifying variables as primary endpoints, were unable to demonstrate a benefit, but the area deserves further investigation. As a whole, nutritional research in OA is only in its infancy. Only a few ingredients have been tested, and research remains based mainly on a pharmacological type of approach (one molecule/one target) rather than on a nutritional, more holistic type of approach (multiple ingredients/multiple targets). The full potency of nutrition for patients with declared OA thus remains to be evaluated. In parallel, and except for a few longitudinal epidemiological studies on vitamins, no study has evaluated the value of nutrition in the prevention of OA. Although these studies are of utmost importance, the size, the duration, and hence the prohibitive cost of such studies, particularly in the form of human intervention trials, keep them beyond our reach for the time being. This situation will probably persist at least until we considerably improve our prognostic tools to detect those 'healthy' subjects at high risk of developing OA in their near future.

Appendix

Comparative discussion on the value of the Jadad and OA scores to evaluate the quality of clinical trials on OA

To evaluate the quality of the RCTs, we used two scores: the previously validated Jadad score [21], which can be used to score any type of clinical trials, and a new OA score designed especially for this study and tailor-made for OA clinical trials. According to these two scoring systems, the quality of the RCTs was highly heterogeneous. Based on the OA score, the quality of the trials ranged from 33% to 100% (with a mean of 65 and a median of 67) (Table 2). Based on the Jadad score, the quality of the trials ranged from 20% (that is, a score of 1 out of a possible maximum of 5) to 100% (that is, a score of 5) with an average and median score of 80%. Conceptual differences in design exist between the two scoring systems. The Jadad score evaluates only the randomisation method, the double-blinding method, and the report of dropouts, whereas the OA score is more comprehensive. Between the two authors, the reproducibilities of the two instruments were similar (approximately 92%–93%). Although the two scores were overall quite consistent with each other, divergence sometimes emerged between them due to their different designs ([47, 72, 85, 110, 115, 121, 135]; Table 3). Due to its higher complexity, the OA score was more powerful than the Jadad score in discriminating the quality of the trials. Indeed, several trials, despite a maximal Jadad score and 1 point allocated to the three criteria of the OA score evaluated in the Jadad score (that is, criteria numbers 4, 6, and 11), ended up with very different OA scores, ranging from 0.42 to 1 (compare, for example, the scores of [26] and [47] in Table 3). Based on this observation and in agreement with published guidelines recommending the development and use of disease-specific scoring systems for systematic reviews [141], the OA score seems more accurate than the Jadad score in evaluating the quality of RCTs on OA.

Abbreviations

AGE:

= advanced glycation endproduct

ASU:

= avocado soybean unsaponifiable

COX:

= cyclo-oxygenase

CRP:

= C-reactive protein

GAG:

= glycosaminoglycan

GRAS:

= generally recognised as safe

IL:

= interleukin

LFI:

= Lequesne functional index

LOX:

= lipo-oxygenase

LPS:

= lipopolysaccharide

MMP:

= matrix metalloproteinase

MSM:

= methylsulfonylmethane

NF:

= nuclear factor

NO:

= nitric oxide

NSAID:

= nonsteroidal anti-inflammatory drug

OA:

= osteoarthritis

PGE2:

= prostaglandin E2

PUFA:

= poly-unsaturated fatty acid

RCT:

= randomised clinical trial

RDA:

= recommended daily allowance

ROS:

= reactive oxygen species

SAMe:

= S-adenosyl-L-methionine

TNF:

= tumour necrosis factor

VAS:

= visual analog scale

vit:

= vitamin

WOMAC:

= Western Ontario and McMaster universities [index].

References

  1. Yelin E: The economics of osteoarthritis. Osteoarthritis. Edited by: Brandt KD, Doherty M, Lohmander LS. 2003, Oxford: Oxford University Press, 17-21.

    Google Scholar 

  2. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, et al: EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003, 62: 1145-1155. 10.1136/ard.2003.011742.

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Abramson SB: The role of NSAIDs in the treatment of osteoarthritis. Osteoarthritis. Edited by: Brandt KD, Doherty M, Lohmander LS. 2003, Oxford: Oxford University Press, 251-258.

    Google Scholar 

  4. German B, Schiffrin EJ, Reniero R, Mollet B, Pfeifer A, Neeser JR: The development of functional foods: lessons from the gut. Trends Biotechnol. 1999, 17: 492-499. 10.1016/S0167-7799(99)01380-3.

    CAS  PubMed  Google Scholar 

  5. Kalra EK: Nutraceutical – definition and introduction. AAPS PharmSci. 2003, 5: E25-10.1208/ps050325.

    PubMed  Google Scholar 

  6. Zeisel SH: Regulation of "nutraceuticals". Science. 1999, 285: 1853-1855. 10.1126/science.285.5435.1853.

    CAS  PubMed  Google Scholar 

  7. Halsted CH: Dietary supplements and functional foods: 2 sides of a coin?. Am J Clin Nutr. 2003, 77: 1001S-1007S.

    CAS  PubMed  Google Scholar 

  8. Roberfroid MB: Defining functional foods. Functional Foods. Concept to Product. Edited by: Gibson GR, Williams CM. 2000, Boca Raton: CRC Press, 1-18.

    Google Scholar 

  9. Diplock AT, Aggett PJ, Ashwell M, Bornet F, Fern FB, Roberfroid MB: Scientific concepts of functional foods in Europe: consensus document. Br J Nutr. 1999, 81 (Suppl 1): S1-S27.

    CAS  Google Scholar 

  10. Roberfroid MB: Concepts and strategy of functional food science: the European perspective. Am J Clin Nutr. 2000, 71: 1660S-1664S.

    CAS  PubMed  Google Scholar 

  11. Ramsey SD, Spencer AC, Topolski TD, Belza B, Patrick DL: Use of alternative therapies by older adults with osteoarthritis. Arthritis Rheum. 2001, 45: 222-227. 10.1002/1529-0131(200106)45:3<222::AID-ART252>3.0.CO;2-N.

    CAS  PubMed  Google Scholar 

  12. Bottiglieri T: S-Adenosyl-L-methionine (SAMe): from the bench to bedside – molecular basis of a pleitropic molecule. Am J Clin Nutr. 2002, 76: 1151S-1157S.

    CAS  PubMed  Google Scholar 

  13. Leeb BF, Schweitzer H, Montag K, Smolen JS: A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol. 2000, 27: 205-211.

    CAS  PubMed  Google Scholar 

  14. McAlindon TE, LaValley MP, Gulin JP, Felson DT: Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000, 283: 1469-1475. 10.1001/jama.283.11.1469.

    CAS  PubMed  Google Scholar 

  15. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med. 2003, 163: 1514-1522. 10.1001/archinte.163.13.1514.

    CAS  PubMed  Google Scholar 

  16. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, Hochberg MC, Wells G: Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2005, CD002946-2

  17. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000, 43: 1905-1915. 10.1002/1529-0131(200009)43:9<1905::AID-ANR1>3.0.CO;2-P.

  18. FDA. Draft guidance for industry. Clinical development programs for drugs, devices, and biological products intended for the treatment of osteoarthritis (OA). [http://www.fda.gov/ohrms/dockets/98fr/980077gz.pdf]

  19. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, Buckwalter J, Dougados M, Ehrlich G, Lequesne M, et al: Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage. 1996, 4: 217-243. 10.1016/S1063-4584(05)80101-3.

    CAS  PubMed  Google Scholar 

  20. Recommendations for the registration of drugs used in the treatment of osteoarthritis. Group for the respect of ethics and excellence in science (GREES): osteoarthritis section. Ann Rheum Dis. 1996, 55: 552-557.

  21. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996, 17: 1-12. 10.1016/0197-2456(95)00134-4.

    CAS  PubMed  Google Scholar 

  22. Schilter B, Andersson C, Anton R, Constable A, Kleiner J, O'Brien J, Renwick AG, Korver O, Smit F, Walker R, et al: Guidance for the safety assessment of botanicals and botanical preparations for use in food and food supplements. Food Chem Toxicol. 2003, 41: 1625-1649. 10.1016/S0278-6915(03)00221-7.

    CAS  PubMed  Google Scholar 

  23. Henrotin YE, Labasse AH, Jaspar JM, De Groote DD, Zheng SX, Guillou GB, Reginster JY: Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes. Clin Rheumatol. 1998, 17: 31-39. 10.1007/BF01450955.

    CAS  PubMed  Google Scholar 

  24. Blotman F, Maheu E, Wulwik A, Caspard H, Lopez A: Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial. Rev Rhum Engl Ed. 1997, 64: 825-834.

    CAS  PubMed  Google Scholar 

  25. Appelboom T, Schuermans J, Verbruggen G, Henrotin Y, Reginster JY: Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study. Scand J Rheumatol. 2001, 30: 242-247. 10.1080/030097401316909602.

    CAS  PubMed  Google Scholar 

  26. Maheu E, Mazieres B, Valat JP, Loyau G, Le Loet X, Bourgeois P, Grouin JM, Rozenberg S: Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum. 1998, 41: 81-91. 10.1002/1529-0131(199801)41:1<81::AID-ART11>3.0.CO;2-9.

    CAS  PubMed  Google Scholar 

  27. Lequesne M, Maheu E, Cadet C, Dreiser RL: Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip. Arthritis Rheum. 2002, 47: 50-58. 10.1002/art1.10239.

    CAS  PubMed  Google Scholar 

  28. Ernst E: Avocado-soybean unsaponifiables (ASU) for osteoarthritis – a systematic review. Clin Rheumatol. 2003, 22: 285-288. 10.1007/s10067-003-0731-4.

    CAS  PubMed  Google Scholar 

  29. Cake MA, Read RA, Guillou B, Ghosh P: Modification of articular cartilage and subchondral bone pathology in an ovine meniscectomy model of osteoarthritis by avocado and soya unsaponifiables (ASU). Osteoarthritis Cartilage. 2000, 8: 404-411. 10.1053/joca.1999.0315.

    CAS  PubMed  Google Scholar 

  30. Mauviel A, Daireaux M, Hartmann DJ, Galera P, Loyau G, Pujol JP: Effects of unsaponifiable extracts of avocado/soy beans (PIAS) on the production of collagen by cultures of synoviocytes, articular chondrocytes and skin fibroblasts. Rev Rhum Mal Osteoartic. 1989, 56: 207-211.

    CAS  PubMed  Google Scholar 

  31. Mauviel A, Loyau G, Pujol JP: Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1. Rev Rhum Mal Osteoartic. 1991, 58: 241-245.

    CAS  PubMed  Google Scholar 

  32. Henrotin YE, Sanchez C, Deberg MA, Piccardi N, Guillou GB, Msika P, Reginster JY: Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes. J Rheumatol. 2003, 30: 1825-1834.

    CAS  PubMed  Google Scholar 

  33. Boumediene K, Felisaz N, Bogdanowicz P, Galera P, Guillou GB, Pujol JP: Avocado/soya unsaponifiables enhance the expression of transforming growth factor beta1 and beta2 in cultured articular chondrocytes. Arthritis Rheum. 1999, 42: 148-156. 10.1002/1529-0131(199901)42:1<148::AID-ANR18>3.0.CO;2-U.

    CAS  PubMed  Google Scholar 

  34. Darlington LG, Stone TW: Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. Br J Nutr. 2001, 85: 251-269.

    CAS  PubMed  Google Scholar 

  35. Calder PC: n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond). 2004, 107: 1-11.

    CAS  Google Scholar 

  36. Stammers T, Sibbald B, Freeling P: Efficacy of cod liver oil as an adjunct to non-steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice. Ann Rheum Dis. 1992, 51: 128-129.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Lippiello L, Walsh T, Fienhold M: The association of lipid abnormalities with tissue pathology in human osteoarthritic articular cartilage. Metabolism. 1991, 40: 571-576. 10.1016/0026-0495(91)90046-Y.

    CAS  PubMed  Google Scholar 

  38. Lippiello L, Fienhold M, Grandjean C: Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega-3 fatty acids. Arthritis Rheum. 1990, 33: 1029-1036.

    CAS  PubMed  Google Scholar 

  39. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN: Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005, 201: 713-722. 10.1084/jem.20042031.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Curtis CL, Hughes CE, Flannery CR, Little CB, Harwood JL, Caterson B: n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation. J Biol Chem. 2000, 275: 721-724. 10.1074/jbc.275.2.721.

    CAS  PubMed  Google Scholar 

  41. Curtis CL, Rees SG, Cramp J, Flannery CR, Hughes CE, Little CB, Williams R, Wilson C, Dent CM, Harwood JL, et al: Effects of n-3 fatty acids on cartilage metabolism. Proc Nutr Soc. 2002, 61: 381-389. 10.1079/PNS2002174.

    CAS  PubMed  Google Scholar 

  42. Curtis CL, Rees SG, Little CB, Flannery CR, Hughes CE, Wilson C, Dent CM, Otterness IG, Harwood JL, Caterson B: Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids. Arthritis Rheum. 2002, 46: 1544-1553. 10.1002/art.10305.

    CAS  PubMed  Google Scholar 

  43. Halpern GM: Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol). Allerg Immunol (Paris). 2000, 32: 272-278. 10.1159/000028950.

    CAS  Google Scholar 

  44. Bui LM, Bierer TL: Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Vet Ther. 2003, 4: 397-407.

    PubMed  Google Scholar 

  45. Audeval B, Bouchacourt P: Efficacy of Perna canaliculus green-lipped mussel extract in gonarthrosis: a double-blind placebo-controlled trial. Gazette Médicale. 1986, 93: 111-116.

    Google Scholar 

  46. Gibson RG, Gibson SL, Conway V, Chappell D: Perna canaliculus in the treatment of arthritis. Practitioner. 1980, 224: 955-960.

    CAS  PubMed  Google Scholar 

  47. Gibson SLM, Gibson RG: The treatment of arthritis with a lipid extract of Perna canaliculus: a randomized trial. Complement Ther Med. 1998, 6: 122-126. 10.1016/S0965-2299(98)80003-4.

    Google Scholar 

  48. Cobb CS, Ernst E: Systematic review of a marine nutriceutical supplement in clinical trials for arthritis: the effectiveness of the New Zealand green-lipped mussel Perna canaliculus. Clin Rheumatol. 2006, 25: 275-284. 10.1007/s10067-005-0001-8.

    PubMed  Google Scholar 

  49. Bierer TL, Bui LM: Improvement of arthritic signs in dogs fed green-lipped mussel (Perna canaliculus). J Nutr. 2002, 132: 1634S-1636S.

    CAS  PubMed  Google Scholar 

  50. Hesslink R, Armstrong D, Nagendran MV, Sreevatsan S, Barathur R: Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol. 2002, 29: 1708-1712.

    CAS  PubMed  Google Scholar 

  51. McAlindon T, Felson DT: Nutrition: risk factors for osteoarthritis. Ann Rheum Dis. 1997, 56: 397-400.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Sowers M, Lachance L: Vitamins and arthritis. The roles of vitamins A, C, D, and E. Rheum Dis Clin North Am. 1999, 25: 315-332. 10.1016/S0889-857X(05)70070-3.

    CAS  PubMed  Google Scholar 

  53. Henrotin Y, Kurz B, Aigner T: Oxygen and reactive oxygen species in cartilage degradation: friends or foes?. Osteoarthritis Cartilage. 2005, 13: 643-654. 10.1016/j.joca.2005.04.002.

    CAS  PubMed  Google Scholar 

  54. Tetlow LC, Woolley DE: Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro. Osteoarthritis Cartilage. 2001, 9: 423-431. 10.1053/joca.2000.0408.

    CAS  PubMed  Google Scholar 

  55. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Wilson PW, Jacques P: Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996, 125: 353-359.

    CAS  PubMed  Google Scholar 

  56. Lane NE, Gore LR, Cummings SR, Hochberg MC, Scott JC, Williams EN, Nevitt MC: Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group. Arthritis Rheum. 1999, 42: 854-860. 10.1002/1529-0131(199905)42:5<854::AID-ANR3>3.0.CO;2-I.

    CAS  PubMed  Google Scholar 

  57. McAlindon TE, Jacques P, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Levy D, Felson DT: Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis?. Arthritis Rheum. 1996, 39: 648-656.

    CAS  PubMed  Google Scholar 

  58. Jensen NH: [Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebo-controlled cross-over trial in general practice]. Ugeskr Laeger. 2003, 165: 2563-2566.

    PubMed  Google Scholar 

  59. Schwartz ER, Oh WH, Leveille CR: Experimentally induced osteoarthritis in guinea pigs: metabolic responses in articular cartilage to developing pathology. Arthritis Rheum. 1981, 24: 1345-1355.

    CAS  PubMed  Google Scholar 

  60. Schwartz ER: The modulation of osteoarthritic development by vitamins C and E. Int J Vitam Nutr Res Suppl. 1984, 26: 141-146.

    CAS  PubMed  Google Scholar 

  61. Kraus VB, Huebner JL, Stabler T, Flahiff CM, Setton LA, Fink C, Vilim V, Clark AG: Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model. Arthritis Rheum. 2004, 50: 1822-1831. 10.1002/art.20291.

    CAS  PubMed  Google Scholar 

  62. Meacock SC, Bodmer JL, Billingham ME: Experimental osteoarthritis in guinea-pigs. J Exp Pathol (Oxford). 1990, 71: 279-293.

    CAS  Google Scholar 

  63. Stabler TV, Kraus VB: Ascorbic acid accumulates in cartilage in vivo. Clin Chim Acta. 2003, 334: 157-162. 10.1016/S0009-8981(03)00225-0.

    CAS  PubMed  Google Scholar 

  64. Clark AG, Rohrbaugh AL, Otterness I, Kraus VB: The effects of ascorbic acid on cartilage metabolism in guinea pig articular cartilage explants. Matrix Biol. 2002, 21: 175-184. 10.1016/S0945-053X(01)00193-7.

    CAS  PubMed  Google Scholar 

  65. McNulty AL, Stabler TV, Vail TP, McDaniel GE, Kraus VB: Dehydroascorbate transport in human chondrocytes is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in the joint. Arthritis Rheum. 2005, 52: 2676-2685. 10.1002/art.21254.

    CAS  PubMed  Google Scholar 

  66. Schwartz ER, Adamy L: Effect of ascorbic acid on arylsulfatase activities and sulfated proteoglycan metabolism in chondrocyte cultures. J Clin Invest. 1977, 60: 96-106.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Daniel JC, Pauli BU, Kuettner KE: Synthesis of cartilage matrix by mammalian chondrocytes in vitro. III. Effects of ascorbate. J Cell Biol. 1984, 99: 1960-1969. 10.1083/jcb.99.6.1960.

    CAS  PubMed  Google Scholar 

  68. Sandell LJ, Daniel JC: Effects of ascorbic acid on collagen mRNA levels in short term chondrocyte cultures. Connect Tissue Res. 1988, 17: 11-22.

    CAS  PubMed  Google Scholar 

  69. Tiku ML, Gupta S, Deshmukh DR: Aggrecan degradation in chondrocytes is mediated by reactive oxygen species and protected by antioxidants. Free Radic Res. 1999, 30: 395-405.

    CAS  PubMed  Google Scholar 

  70. Verzijl N, DeGroot J, Ben ZC, Brau-Benjamin O, Maroudas A, Bank RA, Mizrahi J, Schalkwijk CG, Thorpe SR, Baynes JW, et al: Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 2002, 46: 114-123. 10.1002/1529-0131(200201)46:1<114::AID-ART10025>3.0.CO;2-P.

    CAS  PubMed  Google Scholar 

  71. Machtey I, Ouaknine L: Tocopherol in osteoarthritis: a controlled pilot study. J Am Geriatr Soc. 1978, 26: 328-330.

    CAS  PubMed  Google Scholar 

  72. Blankenhorn G: [Clinical effectiveness of Spondyvit (vitamin E) in activated arthroses. A multicenter placebo-controlled double-blind study]. Z Orthop Ihre Grenzgeb. 1986, 124: 340-343.

    CAS  PubMed  Google Scholar 

  73. Scherak O, Kolarz G, Schodl C, Blankenhorn G: [High dosage vitamin E therapy in patients with activated arthrosis]. Z Rheumatol. 1990, 49: 369-373.

    CAS  PubMed  Google Scholar 

  74. Brand C, Snaddon J, Bailey M, Cicuttini F: Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann Rheum Dis. 2001, 60: 946-949. 10.1136/ard.60.10.946.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Wluka AE, Stuckey S, Brand C, Cicuttini FM: Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002, 29: 2585-2591.

    CAS  PubMed  Google Scholar 

  76. Tiku ML, Shah R, Allison GT: Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis. J Biol Chem. 2000, 275: 20069-20076. 10.1074/jbc.M907604199.

    CAS  PubMed  Google Scholar 

  77. Schwartz ER: Effect of vitamins C and E on sulfated proteoglycan metabolism and sulfatase and phosphatase activities in organ cultures of human cartilage. Calcif Tissue Int. 1979, 28: 201-208. 10.1007/BF02441237.

    CAS  PubMed  Google Scholar 

  78. Galleron S, Borderie D, Ponteziere C, Lemarechal H, Jambou M, Roch-Arveiller M, Ekindjian OG, Cals MJ: Reactive oxygen species induce apoptosis of synoviocytes in vitro. Alpha-tocopherol provides no protection. Cell Biol Int. 1999, 23: 637-642. 10.1006/cbir.1999.0424.

    CAS  PubMed  Google Scholar 

  79. Jonas WB, Rapoza CP, Blair WF: The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res. 1996, 45: 330-334. 10.1007/BF02252945.

    CAS  PubMed  Google Scholar 

  80. McKenney JM, Proctor JD, Harris S, Chinchili VM: A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994, 271: 672-677. 10.1001/jama.271.9.672.

    CAS  PubMed  Google Scholar 

  81. Flynn MA, Irvin W, Krause G: The effect of folate and cobalamin on osteoarthritic hands. J Am Coll Nutr. 1994, 13: 351-356.

    CAS  PubMed  Google Scholar 

  82. Hill J, Bird HA: Failure of selenium-ace to improve osteoarthritis. Br J Rheumatol. 1990, 29: 211-213.

    CAS  PubMed  Google Scholar 

  83. Kurz B, Jost B, Schunke M: Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis Cartilage. 2002, 10: 119-126. 10.1053/joca.2001.0489.

    CAS  PubMed  Google Scholar 

  84. Helliwell TR, Kelly SA, Walsh HP, Klenerman L, Haines J, Clark R, Roberts NB: Elemental analysis of femoral bone from patients with fractured neck of femur or osteoarthrosis. Bone. 1996, 18: 151-157. 10.1016/8756-3282(95)00440-8.

    CAS  PubMed  Google Scholar 

  85. Newnham RE: Essentiality of boron for healthy bones and joints. Environ Health Perspect. 1994, 102 (Suppl 7): 83-85.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Miller MJ, Mehta K, Kunte S, Raut V, Gala J, Dhumale R, Shukla A, Tupalli H, Parikh H, Bobrowski P, et al: Early relief of osteoarthritis symptoms with a natural mineral supplement and a herbomineral combination: a randomized controlled trial [ISRCTN38432711]. J Inflamm (Lond). 2005, 2: 11-

    Google Scholar 

  87. Brien S, Lewith G, Walker A, Hicks SM, Middleton D: Bromelain as a treatment for osteoarthritis: a review of clinical studies. Evid Based Complement Alternat Med. 2004, 1: 251-257. 10.1093/ecam/neh035.

    PubMed Central  PubMed  Google Scholar 

  88. Maurer HR: Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. 2001, 58: 1234-1245. 10.1007/PL00000936.

    CAS  PubMed  Google Scholar 

  89. Tilwe GH, Beria S, Turakhia NH, Daftary GV, Schiess W: Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthrosis of knee joint: an open randomized controlled clinical trial. J Assoc Physicians India. 2001, 49: 617-621.

    CAS  PubMed  Google Scholar 

  90. Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M: Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study. Clin Rheumatol. 2004, 23: 410-415. 10.1007/s10067-004-0902-y.

    PubMed  Google Scholar 

  91. Klein G, Kullich W: Short-term treatment of painful osteoarthritis of the knee with oral enzymes. Clin Drug Invest. 2000, 19: 15-23. 10.2165/00044011-200019010-00003.

    CAS  Google Scholar 

  92. Singer F, Oberleitner H: Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus diclofenac. Wien Med Wochenschr. 1996, 146: 55-58.

    CAS  PubMed  Google Scholar 

  93. Warholm O, Skaar S, Hedman E, Molmen HM, Eik L: The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial. Curr Ther Res. 2003, 64: 21-31. 10.1016/S0011-393X(03)00004-3.

    PubMed Central  PubMed  Google Scholar 

  94. Rein E, Kharazmi A, Winther K: A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial. Phytomedicine. 2004, 11: 383-391. 10.1016/j.phymed.2004.01.001.

    CAS  PubMed  Google Scholar 

  95. Winther K, Apel K, Thamsborg G: A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial. Scand J Rheumatol. 2005, 34: 302-308. 10.1080/03009740510018624.

    CAS  PubMed  Google Scholar 

  96. Kharazmi A, Winther K: Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo. Inflammopharmacology. 1999, 7: 377-386.

    CAS  PubMed  Google Scholar 

  97. Winther K, Rein E, Kharazmi A: The anti-inflammatory properties of rose-hip. Inflammopharmacology. 1999, 7: 63-68.

    CAS  PubMed  Google Scholar 

  98. Chrubasik S, Conradt C, Black A: The quality of clinicaltrials with Harpagophytum procumbens. Phytomedicine. 2003, 10: 613-623. 10.1078/094471103322331647.

    CAS  PubMed  Google Scholar 

  99. Lecomte A, Costa JP: Harpagophytum and osteoarthritis: a double-blind placebo-controlled trial. 37°2 Le Magazine. 1992, 15: 27-30.

    Google Scholar 

  100. Chantre P, Cappelaere A, Leblan D, Guedon D, Vandermander J, Fournie B: Efficacy and tolerance of Harpagophytum procumbens versus diacerhein in treatment of osteoarthritis. Phytomedicine. 2000, 7: 177-183.

    CAS  PubMed  Google Scholar 

  101. Leblan D, Chantre P, Fournie B: Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine. 2000, 67: 462-467.

    CAS  PubMed  Google Scholar 

  102. Gagnier JJ, Chrubasik S, Manheimer E: Harpagophytum procumbens for osteoarthritis and low back pain: a systematic review. BMC Complement Altern Med. 2004, 4: 13-23. 10.1186/1472-6882-4-13.

    PubMed Central  PubMed  Google Scholar 

  103. Wegener T, Lupke NP: Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.). Phytother Res. 2003, 17: 1165-1172. 10.1002/ptr.1322.

    PubMed  Google Scholar 

  104. Schulze-Tanzil G, Hansen C, Shakibaei M: Effect of a Harpagophytum procumbens DC extract on matrix metalloproteinases in human chondrocytes in vitro. Arzneimittelforschung. 2004, 54: 213-220.

    CAS  PubMed  Google Scholar 

  105. Sandoval M, Okuhama NN, Zhang XJ, Condezo LA, Lao J, Angeles' FM, Musah RA, Bobrowski P, Miller MJ: Anti-inflammatory and antioxidant activities of cat's claw (Uncaria tomentosa and Uncaria guianensis) are independent of their alkaloid content. Phytomedicine. 2002, 9: 325-337. 10.1078/0944-7113-00117.

    CAS  PubMed  Google Scholar 

  106. Piscoya J, Rodriguez Z, Bustamante SA, Okuhama NN, Miller MJ, Sandoval M: Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis. Inflamm Res. 2001, 50: 442-448. 10.1007/PL00000268.

    CAS  PubMed  Google Scholar 

  107. Jha V, Chugh KS: Nephropathy associated with animal, plant, and chemical toxins in the tropics. Semin Nephrol. 2003, 23: 49-65. 10.1053/snep.2003.50003.

    CAS  PubMed  Google Scholar 

  108. Schmid B, Ludtke R, Selbmann HK, Kotter I, Tschirdewahn B, Schaffner W, Heide L: Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebo-controlled, double blind clinical trial. Phytother Res. 2001, 15: 344-350. 10.1002/ptr.981.

    CAS  PubMed  Google Scholar 

  109. Biegert C, Wagner I, Ludtke R, Kotter I, Lohmuller C, Gunaydin I, Taxis K, Heide L: Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials. J Rheumatol. 2004, 31: 2121-2130.

    CAS  PubMed  Google Scholar 

  110. Mills SY, Jacoby RK, Chacksfield M, Willoughby M: Effect of a proprietary herbal medicine on the relief of chronic arthritic pain: a double-blind study. Br J Rheumatol. 1996, 35: 874-878.

    CAS  PubMed  Google Scholar 

  111. Chrubasik S, Kunzel O, Model A, Conradt C, Black A: Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain. Rheumatology (Oxford). 2001, 40: 1388-1393. 10.1093/rheumatology/40.12.1388.

    CAS  Google Scholar 

  112. Wigler I, Grotto I, Caspi D, Yaron M: The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis. Osteoarthritis Cartilage. 2003, 11: 783-789. 10.1016/S1063-4584(03)00169-9.

    CAS  PubMed  Google Scholar 

  113. Altman RD, Marcussen KC: Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001, 44: 2531-2538. 10.1002/1529-0131(200111)44:11<2531::AID-ART433>3.0.CO;2-J.

    CAS  PubMed  Google Scholar 

  114. Marcus DM, Suarez-Almazor ME: Is there a role for ginger in the treatment of osteoarthritis?. Arthritis Rheum. 2001, 44: 2461-2462. 10.1002/1529-0131(200111)44:11<2461::AID-ART424>3.0.CO;2-H.

    CAS  PubMed  Google Scholar 

  115. Bliddal H, Rosetzsky A, Schlichting P, Weidner MS, Andersen LA, Ibfelt HH, Christensen K, Jensen ON, Barslev J: A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage. 2000, 8: 9-12. 10.1053/joca.1999.0264.

    CAS  PubMed  Google Scholar 

  116. Shen CL, Hong KJ, Kim SW: Effects of ginger (Zingiber officinale Rosc.) on decreasing the production of inflammatory mediators in sow osteoarthrotic cartilage explants. J Med Food. 2003, 6: 323-328. 10.1089/109662003772519877.

    CAS  PubMed  Google Scholar 

  117. Frondoza CG, Sohrabi A, Polotsky A, Phan PV, Hungerford DS, Lindmark L: An in vitro screening assay for inhibitors of proinflammatory mediators in herbal extracts using human synoviocyte cultures. In Vitro Cell Dev Biol Anim. 2004, 40: 95-101. 10.1290/1543-706X(2004)040<0095:AIVSAF>2.0.CO;2.

    CAS  PubMed  Google Scholar 

  118. Innes JF, Fuller CJ, Grover ER, Kelly AL, Burn JF: Randomised, double-blind, placebo-controlled parallel group study of P54FP for the treatment of dogs with osteoarthritis. Vet Rec. 2003, 152: 457-460.

    CAS  PubMed  Google Scholar 

  119. Ferraz MB, Pereira RB, Iwata NM, Atra E: Tipi. A popular analgesic tea: a double-blind cross-over trial in osteoarthritis. Clin Exp Rheumatol. 1991, 9: 205-206.

    CAS  PubMed  Google Scholar 

  120. Arjmandi BH, Khalil DA, Lucas EA, Smith BJ, Sinichi N, Hodges SB, Juma S, Munson ME, Payton ME, Tivis RD, et al: Soy protein may alleviate osteoarthritis symptoms. Phytomedicine. 2004, 11: 567-575. 10.1016/j.phymed.2003.11.001.

    CAS  PubMed  Google Scholar 

  121. Kimmatkar N, Thawani V, Hingorani L, Khiyani R: Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – a randomized double blind placebo controlled trial. Phytomedicine. 2003, 10: 3-7. 10.1078/094471103321648593.

    CAS  PubMed  Google Scholar 

  122. Badria FA, El-Farahaty T, Shabana AA, Hawas SA, El-Batoty MF: Boswellia-curcumin preparation for treating knee osteoarthritis. Altern Complement Ther. 2002, 8: 341-348. 10.1089/107628002761574635.

    Google Scholar 

  123. Kulkarni RR, Patki PS, Jog VP, Gandage SG, Patwardhan B: Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol. 1991, 33: 91-95. 10.1016/0378-8741(91)90167-C.

    CAS  PubMed  Google Scholar 

  124. Kim JH, Rhee HI, Jung IH, Ryu K, Jung K, Han CK, Kwak WJ, Cho YB, Joo JH: SKI306X, an oriental herbal mixture, suppresses gastric leukotriene B4 synthesis without causing mucosal injury and the diclofenac-induced gastric lesions. Life Sci. 2005, 77: 1181-1193. 10.1016/j.lfs.2004.11.040.

    CAS  PubMed  Google Scholar 

  125. Jung YB, Roh KJ, Jung JA, Jung K, Yoo H, Cho YB, Kwak WJ, Kim DK, Kim KH, Han CK: Effect of SKI 306X, a new herbal anti-arthritic agent, in patients with osteoarthritis of the knee: a double-blind placebo controlled study. Am J Chin Med. 2001, 29: 485-491. 10.1142/S0192415X01000502.

    CAS  PubMed  Google Scholar 

  126. Jung YB, Seong SC, Lee MC, Shin YU, Kim DH, Kim JM, Jung YK, Ahn JH, Seo JG, Park YS, Lee CS, et al: A four-week, randomized, double-blind trial of the efficacy and safety of SKI 306 X: a herbal anti-arthritic agent versus diclofenac in osteoarthritis of the knee. Am J Chinese Medicine. 2004, 32: 291-301. 10.1142/S0192415X04001941.

    CAS  Google Scholar 

  127. Choi JH, Choi JH, Kim DY, Yoon JH, Youn HY, Yi JB, Rhee HI, Ryu KH, Jung K, Han CK, et al: Effects of SKI 306X, a new herbal agent, on proteoglycan degradation in cartilage explant culture and collagenase-induced rabbit osteoarthritis model. Osteoarthritis Cartilage. 2002, 10: 471-478. 10.1053/joca.2002.0526.

    PubMed  Google Scholar 

  128. Ryttig K, Schlamowitz PV, Warnoe O, Wilstrup F: [Gitadyl versus ibuprofen in patients with osteoarthrosis. The result of a double-blind, randomized cross-over study]. Ugeskr Laeger. 1991, 153: 2298-2299.

    CAS  PubMed  Google Scholar 

  129. Teekachunhatean S, Kunanusorn P, Rojanasthien N, Sananpanich K, Pojchamarnwiputh S, Lhieochaiphunt S, Pruksakorn S: Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892]. BMC Complement Altern Med. 2004, 4: 19-27. 10.1186/1472-6882-4-19.

    PubMed Central  PubMed  Google Scholar 

  130. Usha PR, Naidu MUR: Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clinical Drug Investigation. 2004, 24: 353-363. 10.2165/00044011-200424060-00005.

    CAS  PubMed  Google Scholar 

  131. Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF: Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage. 2006, 14: 286-294. 10.1016/j.joca.2005.10.003.

    CAS  PubMed  Google Scholar 

  132. Kacar C, Gilgil E, Tuncer T, Butun B, Urhan S, Sunbuloglu G, Yildirim C, Arikan V, Dundar U, Oksuz MC, et al: The association of milk consumption with the occurrence of symptomatic knee osteoarthritis. Clin Exp Rheumatol. 2004, 22: 473-476.

    CAS  PubMed  Google Scholar 

  133. Bijlsma JW: Milk consumption and osteoarthritis: a doubtful connection. Clin Exp Rheumatol. 2004, 22: 387-388.

    CAS  PubMed  Google Scholar 

  134. Colker CM, Swain M, Lynch L, Gingerich DA: Effects of a milk-based bioactive micronutrient beverage on pain symptoms and activity of adults with osteoarthritis: a double-blind, placebo-controlled clinical evaluation. Nutrition. 2002, 18: 388-392. 10.1016/S0899-9007(01)00800-0.

    CAS  PubMed  Google Scholar 

  135. Zenk JL, Helmer TR, Kuskowski MA: The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial. Current Therapeutic research. 2002, 63: 430-442. 10.1016/S0011-393X(02)80049-2.

    CAS  Google Scholar 

  136. Gingerich DA, Strobel JD: Use of client-specific outcome measures to assess treatment effects in geriatric, arthritic dogs: controlled clinical evaluation of a nutraceutical. Vet Ther. 2003, 4: 56-66.

    PubMed  Google Scholar 

  137. Moskowitz RW: Role of collagen hydrolysate in bone and joint disease. Semin Arthritis Rheum. 2000, 30: 87-99. 10.1053/sarh.2000.9622.

    CAS  PubMed  Google Scholar 

  138. Adam M: Therapy for osteoarthritis: which effects have preparations of gelatin?. Therapiewoche. 1991, 38: 2456-2461.

    Google Scholar 

  139. Oesser S, Seifert J: Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen. Cell Tissue Res. 2003, 311: 393-399.

    CAS  PubMed  Google Scholar 

  140. Oesser S, Adam M, Babel W, Seifert J: Oral administration of (14)C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). J Nutr. 1999, 129: 1891-1895.

    CAS  PubMed  Google Scholar 

  141. Khan KS, ter Riet G, Popay J, Nixon J, Kleijnen J: Phase 5: study quality assessment in undertaking systematic reviews of research on effectiveness. Undertaking Systematic Reviews of Research on Effectiveness. CRD's Guidance for Those Carrying Out or Commissioning Reviews. Edited by: Khan KS, ter Riet G, Glanville J, Sowden AJ, Kleijnen J. 2001, York: York Publishing Services Ltd, 45-65.

    Google Scholar 

  142. Singer F, Singer C, Oberleitner H: Phlogenzym versus diclofenac in the treatment of activated osteoarthritis of the knee. Int J Immunother. 2001, 17: 135-141.

    CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Maria-Luisa Brambilla for performing the literature searches and Inge-Lise Nielsen, Birgit Holst, and Alfred Jann for their help in translating the German and Danish studies. The authors are employees of Nestec S.A. Nestec S.A. financed this manuscript, including the article-processing charge. No other source of funding was used.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laurent G Ameye.

Additional information

Competing interests

Both authors are employees of Nestec S.A.

Authors' contributions

LGA conceived the review, collected and read the quoted references, scored the clinical trials, drafted Tables 1, 2, 3, and wrote the manuscript. WSSC scored the clinical trials, drafted Table 4, and revised the final version of the manuscript. Both authors read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ameye, L.G., Chee, W.S. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Arthritis Res Ther 8, R127 (2006). https://doi.org/10.1186/ar2016

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/ar2016

Keywords