Review 71
Nutrafoods (2015) 14:71-77
DOI 10.1007/s13749-015-0018-9
Joint health: What degree of evidence is necessary
to support health claims for food supplements,
taking glucosamine as an example?
Jürgen Bernhardt, Christof Jaenicke, Peter Prock, Ulrich Schneider
Received: 22 December 2014 / Accepted: 13 May 2015
The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract
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 replacements
and 760,000 hip replacements are performed
in Europe per year. Hence, interventions
that support joint health and mobility and help to
delay the progression of joint cartilage degradation
are increasingly important, especially against the
background of a continuously growing elderly population
[2, 3]. Nutritional management plays an
important role in the maintenance of tissues and
organs in a healthy state and can support better
health in old age, avoiding the unnecessary use of
medication and surgery or loss of viability and
quality of life. Nutritional management means the
adequate supply of essential vitamins and minerals,
as well as other valuable nutrients and food components
through a varied and balanced diet, which
may be complemented in a targeted way by concentrated
sources of these substances (for example,
Keywords:
glucosamine
jointhealth
healthclaims
nutrition
degreeofevidence
1 3
Correspondence to:
Jürgen Bernhardt
j.bernhardt@biotesys.de
Jürgen Bernhardt (•)
BioTeSys GmbH
Schelztorstr. 54–56
73728 Esslingen, Germany
j.bernhardt@biotesys.de
tel +49 711 31057150
fax +49 711 31057151
Christof Jaenicke
analyze&realize GmbH
Berlin, Germany
Peter Prock
European Nutraceutical Association
Basel, Switzerland
Ulrich Schneider
Osteoarthritis Research Center
Tegernsee, Germany
72
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 [6–11]. 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.
Although the reasons for this are manifold, one
fundamental problem is the paucity of generally
accepted singular biomarkers as indicators of the
risk to health presented by chronic diseases [4]. Elevated
LDL cholesterol, which is usually referenced
in connection with the topic of biomarkers, is actually
one of the very few good examples. However,
for most diseases there are no clear links between
biomarkers and the disease risk or maintenance of
health, which is why much effort is being made to
establish such biomarkers; they are essential for
preventive nutrient research.
A clear causal relationship is always desirable in research,
and a high degree of evidence must be
sought. At the same time, however, it is important
to consider in a reasoned manner the fundamental
limitations of such a compulsive requirement.
Often in nutrient research it is not possible to draw
clear conclusions on (patho-)physiological processes
from individual factors or biomarkers. Instead, an
overall view of the findings at various levels is
needed to describe the physiological network and
to demonstrate a causal relationship between a food
constituent and the influence on human health.
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.
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different cartilage matrix compounds reach the
synovial fluid and enter the systemic circulation.
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 [20–22]. In the
latter case, a correlation between reduction in CTXII
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 activof
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 promotes
anabolic actions while inhibiting catabolic
processes in the cartilage. The benefit of glucosamine
has not only been demonstrated in inflamed
chondrocytes and osteoarthritic chondrocytes
with early disease-related signs, but also in
normal chondrocytes [12].
Furthermore, mechanistic animal models, which
allow the investigation of a defined stress on a particular
healthy tissue, have demonstrated supporting
effects of glucosamine on metabolic imbalances
in the joints [13–15].
Thus, in vitro and animal models provide clear supportive
evidence for the mode of action and beneficial
role of glucosamine on the maintenance of
joints in a healthy state.
Most of the human clinical trials examining the
efficacy of glucosamine have been carried out in
patients suffering from knee osteoarthritis. Structural
changes of joint space width or changes of
joint functionality (like morning stiffness and pain)
can be measured in this diseased population.
However, in the “healthy”, pre-arthritic population,
changes in cartilage mass or symptomatic disturbances
of joint functionality are not measurable or
experienced. Up to now, no methods have been
available for the detection of minimal structural
changes in cartilage. This is true for imaging techniques,
even those as accurate as magnetic resonance
imaging (MRI), and this accordingly hampers
endpoint measurements in healthy people. This
current gap could be closed by identifying biomarkers
of joint metabolism, which change in diseased
as well as healthy states, and which may be affected
by supplemental glucosamine.
During the synthesis and degradation of cartilage,
Nutrafoods (2015) 14:71-77
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structure cannot be measured in healthy people,
due to the very slow progression of changes in joint
structure, beneficial effects on biomarkers can already
be demonstrated, one of several possible endpoints
mentioned by the EFSA (see below).
Discussion
In 2012, the EFSA refused a health claim application
for glucosamine containing the aforementioned scientific
relationships documented in the literature
up to 2010 [28]. The main reason for the refusal
was the argument that there are no convincing intervention
studies on healthy subjects. Furthermore,
findings from studies with a diseased population –
people with osteoarthritis – were not acknowledged.
In May 2012, the EFSA published a guidance paper
on the scientific requirements for health claims related
to bone, joints, skin and oral health [29], suggesting
possible endpoints for suitable studies. However,
the interesting fact here is that, with the
exception of the mention of biomarkers, these are
endpoints that do not permit a measurable positive
change after intervention in healthy subjects (functional
changes, pain, stiffness, width of the joint
space). Starting from this point of view, it must be
stressed that the “convincing evidence” from the
general healthy population in the classical sense required
is simply not possible with the research
means available today. In contrast, a large number
of high-quality research results show that there are
many factors that are strongly indicative of a causal
relationship between glucosamine and benefits for
joint function and joint health (bioavailability, uptake,
physiological function and effects, based on
chemical, mechanistic, and human data), as stated
above. Overall, looking at the results of all the scientific
work carried out up to 2010, it can be stated
that the question of a benefit of glucosamine for
the general healthy population can be answered
positively with high probability; convincing evidence
already exists for the diseased state [30].
More research supporting the beneficial role of glucosamine
in terms of joint health has been pubity,
which is also of interest in the area of joint
health. A recent study by Navarro et al. (2015) verified
that supplementation with glucosamine and
chondroitin significantly reduced C-reactive protein
(CRP) levels in healthy overweight individuals.
Proteomic profiles indicated that cytokine activity
and other inflammation-related pathways were significantly
decreased [23]. The strength of this study
is that effects of supplementation were shown in a
healthy but at-risk population in terms of joint
health due to their overweight. These results are
again supported by in vitro and animal studies
demonstrating the anti-inflammatory properties of
glucosamine [24, 25] as well as human observational
data, which show an association between
glucosamine users and lower concentrations of CRP
levels and prostaglandin-metabolites (PGE-M) [26].
In a study by Damlar et al. (2015), the effect of a
glucosamine/chondroitin supplement was evaluated
in young women (average 29 years) with internal
temporomandibular joint derangements in
early and intermediate stages. Joint overload plays
an essential role in the aetiology. Inflammatory
markers were measured in the synovial fluid. Supplementation
with glucosamine and chondroitin
significantly reduced inflammatory markers compared
to a control group using a narcotic analgesic,
confirming the anti-inflammatory properties at the
site of action [27].
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
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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 controlled
trial in the prevention of osteoarthritis. In
the glucosamine arm of Runhaar et al.’s study
(2015), the first preventive effects of glucosamine
against the incidence of knee osteoarthritis after
2.5 years were shown (OR 0.60; 95% CI: 0.31–1.12)
in a high-risk group of middle-aged women with a
body mass index (BMI) ≥27 kg/m2
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.
Furthermore, food constituents have to be by defiNutrafoods
(2015) 14:71-77
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Conflict of interest
Jürgen Bernhardt and Christof Jaenicke declare that they have
been sponsored by the Glucosamine Alliance for drafting the
article. Peter Prock and Ulrich Schneider declare that they have
no conflict of interest.
Open Access
This article is distributed under the terms of the Creative Commons
Attribution 4.0 International License (http:// crea-tivecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution,
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appropriate credit to the original author(s) and the source, provide
a link to the Creative Commons license, and indicate if changes
were made.
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