Following an application from Merck Consumer Healthcare, submitted pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Belgium, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver an opinion on the scientific substantiation of a health claim related to glucosamine and maintenance of normal joint cartilage.
The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence.
The food constituent that is the subject of the health claim is glucosamine, formulated as glucosamine sulphate or hydrochloride. The Panel considers that glucosamine is sufficiently characterised.
The claimed effect is “contributes to the maintenance of normal joint cartilage”. The target population as proposed by the applicant is the general population, and in particular people exposing their joints to high mechanical load, for example through extensive sports activities or obesity, and people with joint cartilage deterioration due to normal ageing. From the information provided, the Panel notes that the claimed effect relates to the maintenance of joint cartilage. The Panel considers that the maintenance of normal joint cartilage is a beneficial physiological effect.
In the original application, the applicant identified a total of 61 references as being pertinent to the health claim. These references comprised 20 references describing 12 human intervention studies, 13 reviews on the effects of glucosamine supplementation on maintenance of joints, four animal studies on the effects of glucosamine on joints, 14 in vitro studies on the effects of glucosamine on cartilage cells/tissues, nine studies in humans and/or animals on the bioavailability of glucosamine, and one unpublished narrative review.
Nineteen references were provided that report on 11 human intervention studies. These studies addressed the effects of glucosamine sulphate or glucosamine hydrochloride on joint-related outcomes in patients with clinical diagnosis of degenerative osteoarthritis (OA), mainly of the knee. The applicant proposed that results from these studies in patients with OA could be extrapolated to subjects without OA on the assumption that cartilage degeneration occurs by the same metabolic pathways and mechanisms during progression of OA as in pre-arthritic conditions, and that glucosamine may be expected to have similar effects on joint tissues with and without OA.
The Panel notes that while a number of factors which may contribute to cartilage degeneration in the development (onset) and progression of OA have been identified, the term OA denotes a number of pathological degenerative processes of one or more joints of complex and variable aetiology for which no common pathological pathway has been described. The Panel also notes, in particular, that the pathobiology of the onset and early progression of OA is poorly defined. The evidence provided by consensus opinions/reports from authoritative bodies indicates that normal cells and tissues are genetically (gene expression) and functionally different from osteoarthritic cells and tissues and therefore may respond differently to intervention with exogenous substances. The Panel also notes that the evidence provided for the proposed mechanisms which would explain an effect of glucosamine on joint cartilage is weak. The Panel considers that results from studies in subjects with OA relating to the treatment of symptoms of this disease (e.g. erosion of articular cartilage, and reduced function of joints) with glucosamine cannot be extrapolated to the target population. Therefore, no scientific conclusions can be drawn from the studies on patients with OA for the substantiation of the claimed effect in subjects without OA.
One publication which reported on two studies (i.e. one observational cross-sectional study and one open-label intervention study) in subjects without osteoarthritis was provided. Both studies used urinary concentrations of type II collagen fragments as outcome measures. The authors stated that fragments of type II collagen were targeted as biomarkers of cartilage synthesis (C‑terminal type II procollagen peptide, CPII) and breakdown (C‑terminal crosslinking peptide, CTX‑II; neoepitope C2C) since type II collagen is one of the major constituents of cartilage and represents 90‑95 % of the total collagen content in cartilage.
The cross-sectional study was performed to assess the validity of type II collagen fragments in urine as outcome measures of joint damage. Urinary concentrations of type II collagen fragments were assessed in 21 male soccer players and in 10 male college students who did not participate in any college athletics. Urinary concentrations of CTX-II, but not of C2C, were reported to be significantly higher in soccer players than in the control subjects (p<0.01), whereas urinary concentrations of CPII were not significantly different between the groups. The ratio of CTX‑II/CPII in soccer players was significantly higher than that in controls (p<0.05). The Panel considers that the evidence provided does not establish that changes in urinary concentrations of type II collagen fragments can be used to predict joint cartilage degradation.
The open label intervention was conducted in the sample of soccer players, who received either 1.5 g (n=9) or 3 g (n=10) of glucosamine hydrochloride per day for three months. The Panel notes that no information was provided on the method used for allocating the subjects to either group, and also notes the absence of a placebo control group. Urine samples were collected at baseline, at the end of the 3‑month intervention with glucosamine, and three months after glucosamine withdrawal. The endpoints of the study were urinary concentrations of CTX‑II, C2C and CPII, and the CTX‑II/CPII ratio. The Panel notes that only within-group comparisons between baseline, end of the intervention and follow up were reported, and that no statistical comparisons were made for baseline-adjusted changes in urinary analytes between the two glucosamine-treated groups. The Panel notes the methodological limitations of the study and considers that no conclusions can be drawn from this study with respect to the effects of glucosamine hydrochloride on urinary concentrations of type II collagen fragments. The Panel also notes that the evidence provided does not establish that changes in urinary CTX-II, C2C, CPII or the ratio of CTX‑II/CPII over periods of three months can predict net changes in joint cartilage in the proposed target population. The Panel considers that no conclusions can be drawn from this study for the scientific substantiation of an effect of glucosamine on maintenance of joint cartilage.
The applicant also provided studies on the bioavailability of glucosamine in humans and animals. While these studies show that some dietary glucosamine is taken up into blood and synovial fluid, the Panel considers that uptake of glucosamine into cartilage cells would be very limited under in vivo conditions.
A number of references were provided on studies performed in animals and in vitro. The Panel considers that the evidence provided in the in vitro studies in support of the proposed mechanisms by which dietary glucosamine could contribute to the maintenance of joint cartilage in humans is weak, and that it was not established that results from animal studies could predict an effect of glucosamine on joint cartilage in humans.
In weighing the evidence, the Panel took into account that no human studies were provided from which conclusions could be drawn on the effect of dietary glucosamine on the maintenance of cartilage in individuals without osteoarthritis, and that the evidence provided in the in vitro and animal studies in support of the biological plausibility for a possible contribution of dietary glucosamine to the maintenance of joint cartilage in humans is weak.
The Panel concludes that a cause and effect relationship has not been established between the consumption of glucosamine and maintenance of normal joint cartilage in individuals without osteoarthritis.