Joint health: What degree of evidence is necessary to support health claims for food supplements, taking glucosamine as an example?

Arthropathies present a major challenge for the public health system, both in terms of epidemiology and health economics, particularly against the background of demographic changes in the Western world. Much attention must be paid to prevention, because of the limited options and high technical and financial expenditure with respect to treatment. Among other factors, nutrition plays an important role. However, many and various unsolved questions must be answered before health claims for food constituents in the field of joint health can be established for use as consumer information, as will be described taking glucosamine as an example. These questions will be discussed and possible alternatives to conventional practice considered.


Introduction
The World Health Organisation (WHO) has characterised two conditions as "high burden diseases with no curative treatments": osteoarthritis and Alzheimer's disease [1]. Currently, 540,000 knee re- The pathobiology of the onset and early progression of joint disease, including osteoarthritis, is still poorly defined. There is no sharp threshold between health and disease, and the onset of a disease can be described as a multidimensional ongoing process, with different organ systems in the same individual exhibiting varying sensitivities. This is also true for joint disease [5].
We aim to illustrate these problems with the example of research into glucosamine, an amino sugar and building block in the formation of glycosaminoglycans (GAGs), a major constituent of joint cartilage. We will discuss whether it is reasonable to demand "convincing, fully conclusive evidence" for an association between intervention with glucosamine and a preventive effect to support maintenance of joint health, or whether we should accept "evidence with high probability" in order to allow for correctly worded health-oriented consumer information to be given, especially in light of the aforementioned critical situation in health care. Due to the current legal situation with the requirement for "convincing evidence", the European Food Safety Authority (EFSA) has rejected all applications to obtain health claims for substances in the field of joint health, with the exception of vitamin C for the normal function of cartilage.

The role of glucosamine in joint physiology
Glucosamine is a well-characterised amino sugar and building block in the formation of glycosaminoglycans (GAGs), a major constituent of joint cartilage. Glucosamine is synthesised by the body and in addition can be taken up as food including supplements.
Various studies (animal and human) have provided significant scientific evidence for the bioavailability and the uptake of glucosamine into joints. It has been shown that supplemental glucosamine reaches the site of action, i.e., the joints and the synovial fluid [6][7][8][9][10][11]. Supplemental glucosamine can therefore be utilised by the cells to maintain the balance between the breakdown and synthesis in the form of dietary supplements). The fact that certain food constituents can have positive health effects is already well accepted. One example for cardiovascular health is the maintenance of healthrelated biomarkers and risk factors such as lowdensity lipoprotein (LDL) cholesterol levels, blood pressure and blood glucose levels. In other health areas, current scientific knowledge supporting a relationship between a food ingredient and a beneficial health effect may be promising, but convincing, fully conclusive evidence is very often lacking. This is particularly true of the early and subclinical changes with which health promotion is primarily concerned. It is important to consider the polyvalent nature, small effect size and often homeostatic control of nutrients. When judging the level of evidence, these striking differences between drugs and nutrients should be taken into account [5]. The situation is no different in research into joint health. Biomarkers of cartilage homeostasis have been identified that may reflect early changes in the development of osteoarthritis in vivo.
Fragments of C-terminal cross-linked telopeptides of type II collagen (CTX-II) have been shown to be one of the most reliable biomarkers for cartilage degradation [16]. Components of type II collagen are recognised as valuable biomarkers for joint disorders [17]. Moreover, the ratio of type II collagen breakdown to synthesis markers can be used for predicting the progression of joint damage [18,19].
A study by Christgau et al. (2004) documented a reduction in the elevated CTX-II levels seen in osteoarthritic patients showing high cartilage turnover, upon supplementation with 1500 mg of glucosamine sulphate daily [20]. The reduction in CTX-II translates into a reduction in cartilage catabolism. In addition, Yoshimura et al. (2009) showed that in soccer players, who represent a nondiseased population group with a high work load and a high risk of developing osteoarthritis, the urinary CTX-II level was elevated after intense training.
Glucosamine supplementation significantly reduced initially elevated levels of CTX-II in the soccer players [21]. This work is supported by recent findings of Momomura et al. (2013), who demonstrated that glucosamine could dose-dependently prevent type II collagen degradation while maintaining synthesis in comparison to placebo in a group of bicycle racers. The authors concluded that glucosamine may exert a chondroprotective action in athletes of various sports [22]. In conclusion, recent literature provides evidence that CTX-II urinary levels can be positively affected by glucosamine supplementation in the healthy and diseased states [20][21][22]. In the latter case, a correlation between reduction in CTX-II and degenerative structural changes of cartilage (inhibition of joint space loss) by glucosamine has already been proven.
Besides the influence on cartilage markers, glucosamine may also exert anti-inflammatory activ-of the extracellular cartilage matrix (homeostasis).
Persistent or permanent metabolic imbalances favouring the breakdown of cartilage material will culminate in the process of cartilage degeneration, which is one important factor resulting in permanently impaired joint function and potentially in osteoarthritis.
In vitro research has shown that glucosamine pro- Taken as a whole, therefore, this shows that there are many factors that are strongly indicative of a causal relationship between the beneficial role of glucosamine and the maintenance of joint health, in terms of bioavailability, uptake, physiological function and effects, based on chemical, mechanistic and human data. This is a scientific approach with a high, but not conclusive, degree of evidence, summarising the existing data on glucosamine in osteoarthritic patients (in whom joint space narrowing/changes in joint structure and biomarkers of joint degeneration can be measured) and extrapolating these data to non-diseased populations.
Although joint space narrowing/changes in joint Nutrafoods (2015) 14:71-77 nition safe substances with an outstanding riskbenefit ratio. In contrast, the situation for pharmaceutical products is completely different, which is why convincing evidence must be presented here to show a risk-benefit ratio that justifies their use.
However, it is a fundamentally flawed approach to apply all the principles of research into disease treatment as such to research into health maintenance and prevention, which is usually the rationale for carrying out research in nutritional science [34].
In view of these considerations, grading of evidence should be taken into account and classified accordingly in the global assessment of health claims. Recent findings may further be confirmed in the future by new data obtained, for instance, as a result of newly developed, more sensitive technical methods.
Such new findings, for example, might give deeper insight into the mechanisms of the pathobiology of the onset (and progression) of osteoarthritis, which will possibly move the evidence level from "high probability" to "convincing", even for the prevention of osteoarthritis in the healthy population. In any event, in the meantime, the consumer should be able to receive information on promising emerging science, e.g., using qualified language for a health claim.
Currently, no applications for joint health claims have been successful in the EU, with the exception of vitamin C for the normal function of cartilage.
As things stand, this means that for the time being consumers will not be informed about the potential beneficial effects that food constituents such as glucosamine, a structural component of cartilage, may have on their joints. They will not be able to experience potential benefits in the early stages of emerging science and make informed choices. Ultimately, they may miss out on valuable health benefits. Therefore, when assessing applications for possible health claims for food constituents, we advocate the integration of additional elements, namely grading of evidence, consideration of the risk-benefit ratio and last, but not least, epidemiological and health economic factors.
lished since the EFSA assessment. The Hohenheimer consensus conference provided recommendations for further research to better understand the polyvalent nature of glucosamine in a healthy population [31]. As outlined above, the anti-inflammatory properties of glucosamine in the general population [23] were confirmed and another study suggesting chondroprotective activity of glucosamine in athletes (bicycle racers) was published [22]. Furthermore, the research is now (2015) very much to the fore with the first randomised con- in a high-risk group of middle-aged women with a body mass index (BMI) ≥27 kg/m 2 and without clinical signs of knee osteoarthritis at baseline [32].
Taken together, the recent scientific research strengthens the level of high probability for the benefit of glucosamine in joint health.
In light of the epidemiological and health economic problems in the field of joint health, the question must be asked whether it is always reasonable to demand "convincing, fully conclusive evidence" or whether we should accept "evidence with high probability" in order to allow for correctly worded health-oriented consumer information. In practice, this affects consumers who would use such a food constituent because of diverse risk factors such as obesity, excessive joint loading, advanced age and possibly mild pain, but without any diagnosable osteoarthritis.
Grading of evidence is standard practice in other areas of preventive medicine. For instance, in their pioneering report on the risk of cancer in connection with nutrition and physical activity, the World Cancer Research Fund (WCRF) together with the American Institute of Cancer Research (AICR) [33] most certainly does distinguish between different degrees of evidence.