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BioMed Central
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BMC Complementary and
Alternative Medicine
Open Access
Case report
Glucosamine and chondroitin sulfate supplementation to treat
symptomatic disc degeneration: Biochemical rationale and case
report
Wim J van Blitterswijk*
1
, Jos CM van de Nes
2
and Paul IJM Wuisman
3
Address:
1
Division of Cellular Biochemistry, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Hospital), Plesmanlaan 121, 1066CX
Amsterdam, The Netherlands,
2
Department of Neurology, Zeeuws-Vlaanderen Hospital, Terneuzen, The Netherlands and
3
Department of
Orthopedic Surgery, "Vrije Universiteit" Medical Center, Amsterdam, The Netherlands
Email: Wim J van Blitterswijk* - w.v.blitterswijk@nki.nl; Jos CM van de Nes - vdnes@planet.nl; Paul IJM Wuisman - orthop@vumc.nl
* Corresponding author
Abstract
Background: Glucosamine and chondroitin sulfate preparations are widely used as food
supplements against osteoarthritis, but critics are skeptical about their efficacy, because of the lack
of convincing clinical trials and a reasonable scientific rationale for the use of these nutraceuticals.
Most trials were on osteoarthritis of the knee, while virtually no documentation exists on spinal
disc degeneration. The purpose of this article is to highlight the potential of these food additives
against cartilage degeneration in general, and against symptomatic spinal disc degeneration in
particular, as is illustrated by a case report. The water content of the intervertebral disc is a reliable
measure of its degeneration/ regeneration status, and can be objectively determined by Magnetic
Resonance Imaging (MRI) signals.
Case presentation: Oral intake of glucosamine and chondroitin sulfate for two years associated
with disk recovery (brightening of MRI signal) in a case of symptomatic spinal disc degeneration.
We provide a biochemical explanation for the possible efficacy of these nutraceuticals. They are
bioavailable to cartilage chondrocytes, may stimulate the biosynthesis and inhibit the breakdown of
their extracellular matrix proteoglycans.
Conclusion: The case suggests that long-term glucosamine and chondroitin sulfate intake may
counteract symptomatic spinal disc degeneration, particularly at an early stage. However, definite
proof requires well-conducted clinical trials with these food supplements, in which disc de-/
regeneration can be objectively determined by MRI. A number of biochemical reasons (that
mechanistically need to be further resolved) explain why these agents may have cartilage structure-
and symptom-modifying effects, suggesting their therapeutic efficacy against osteoarthritis in
general.
Background
Lower back pain caused by disc cartilage degeneration
negatively affects quality of life and imposes an enormous
financial burden. The intervertebral disc consists of two
distinct regions: the outer series of concentric lamellae of
organized collagen fibrils, known collectively as the annu-
lus fibrosus, and the inner nucleus pulposus having a
more random collagen organization and an abundance of
Published: 10 June 2003
BMC Complementary and Alternative Medicine 2003, 3:2
Received: 10 February 2003
Accepted: 10 June 2003
This article is available from: http://www.biomedcentral.com/1472-6882/3/2
© 2003 van Blitterswijk et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted
in all media for any purpose, provided this notice is preserved along with the article's original URL.
BMC Complementary and Alternative Medicine 2003, 3 http://www.biomedcentral.com/1472-6882/3/2
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aggregating proteoglycans. Degeneration and age-related
changes in macroscopic, histologic and biochemical com-
position and structure of the annulus fibrosus and of the
nucleus pulposus have been widely reported [1–7]. Until
recently, interventions of degenerative disorders of the
spine have focused on removal of the disc rather than its
repair, which would be the preferred medical action. In
the early stages of disc degeneration, when the degenera-
tion is mostly confined to the nucleus, restore of nucleus
pulposus normal function or slow down of its degenera-
tive process (matrix breakdown) by providing certain
well-rationalized nutraceuticals may be an attractive
approach.
In this regard, the use of natural glucosamine and chon-
droitin sulfate (CS) as food additives against degeneration
of articular cartilage at other locations has recently
received much attention [8–16]. Most emphasis was laid
upon the reported beneficial effect of glucosamine and CS
on osteoarthritis of the knee, and the general conclusion
was that the results were promising but the evidence
insufficient. A major concern was the poor quality of the
primary studies, some of which may have been biased by
company sponsorship [8]. Another weak point was the
variable/questionable quality of some of these food sup-
plements. Despite these concerns, one may be impressed
by the large number of papers (more than a hundred; only
a few cited here) that almost without exception reported
beneficial effects of these supplements in osteoarthritis
patients, horses and small animals. Glucosamine as well
as CS, alone or in combination, appeared effective against
osteoarthritis of the knee (by far the most studies [9–11]),
finger joints [17,18] and hip [17], and may thus possibly
have beneficial effects on cartilage of all joints, including
the intervertebral disc. Remarkably, a clear biochemical
rationale behind the reported effects of glucosamine and
CS is lacking in the literature.
Here we report on a case of symptomatic spinal disc
degeneration, in which oral intake of regular doses of glu-
cosamine and CS for two years may have promoted carti-
lage regeneration of a partly degenerated intervertebral
disc. In addition, we discuss the biochemistry of cartilage
degeneration and of possible regeneration by these sup-
plements. Matrix repair is feasible at early stages of degra-
dation [19] and involves restoration of
glycosaminoglycan structure and associated water content
(to be discussed below). This is most easily monitored by
magnetic resonance imaging, particularly T2-weighted
MRI [20]. Sequential MRI-imaging studies have recently
likewise been employed successfully in longitudinal stud-
ies of lumbar disc degeneration [21] and to monitor heal-
ing of fractured and herniated intervertebral discs [22,23].
The present case report shows, for the first time, MRI data
on the lumbar spine following oral intake of a supple-
ment of glucosamine and CS.
Case presentation
A 56 year-old man presented in September 1999 with fre-
quent/recurrent low-back pain and ischialgic complaints,
which existed for more than 15 years. His lumbar mobil-
ity was maintained by daily moderate physical exercises
and free-time sport (tennis). He continued these activities
when he volunteered to take a daily glucosamine- and CS-
based food supplement, capsules of Cosamin
®
DS
(Nutramax Laboratories, Inc., Edgewood, MD), for two
years. Each capsule contained 500 mg glucosamine.HCl
(FCHG49
®
) and 400 mg of 95% low molecular weight (16
kDa) sodium chondroitin sulfate (TRH122
®
; purified
from bovine trachea), and 66 mg manganese ascorbate
(an essential cofactor for glycosyltransferases in prote-
oglycan biosynthesis). The patient took 3 capsules (2 in
the morning, one in the evening) during the first 9
months; and 2 capsules (in the morning) for the remain-
der of the 2 yrs period.
Clinical finding
The patient felt a gradual improvement of the range of
motion and functioning of his back, with less pain, start-
ing about 6 months after first supplement intake. At the
end of the 2 years period, his back felt stronger and more
flexible, and was capable of withstanding heavier work
loads without pain. Apart from this improvement, the
overall physical condition of the patient remained
unchanged during this period. Of note, the patient did not
experience any adverse effect of these nutraceuticals.
Magnetic resonance imaging finding
MR imaging, using a 1.5 T Somatom machine (Siemens,
Erlangen, Germany), on the lumbar spine was performed
at the onset and after one and two years of supplement
intake. To exclude possible diurnal variation of the disc
water content, MRIs were taken at the same time of the
day (in the morning). Imaging parameters were the fol-
lowing: T2-weighted sequence (turbo spin echo), spine
array coil, repetition time 4000 ms, echo time 90 ms, slice
thickness 4 mm, separation between slices 0.4 mm, in-
plane matrix 512 × 512 pixels, in-plane pixel size 0.8 mm
× 0.8 mm.
During the two years time period, improvement of the
structural quality of the disc cartilage (associated with
increased water content) was clearly visible by brightening
of the T2-weighted MRI signal, as shown in Figure 1. The
L3-4 disc showed an initial protrusion, which decreased in
time, while the MRI signal normalized in time. During the
two years, L3-4 disc height restored slightly (5–10%). Disc
L4-5 showed signs of an advanced state of degeneration,
and no improvement but also no worsening of this disc
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Figure 1
Disc cartilage regeneration during 2 years of supplement intake. T2-weighted MR images of lumbar spine, made in
September 1999 (start of supplement intake), 2000 and 2001. Note the increase of MRI signal of disc L3-4 (thick arrows) and
disappearance of focal disc protrusion (thin arrow) of this disc. Note that the fully degenerated L4-5 disc remains unchanged.
Upper panels and lower panels represent two consecutive images of planes 4 mm apart.
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(endplates morphologically unchanged) over the 2 years
period.
Discussion of MRI finding
This case report illustrates the value of MRI to monitor
disc quality improvement in the lumbar spine. After oral
intake of glucosamine and CS for two years, an increased
water retention (and less bulging/protrusion) in the par-
tially degenerated L3-4 disc was seen, but not in the
almost fully degenerated L4-5 disc, where probably little
or no functional chondrocytes are left. These findings
agree with a clinical study where radiographically mild
forms of knee osteoarthritis showed significant improve-
ment by supplement intake, while severe osteoarthritis
did not [24]. Likewise, in (explant) tissue culture, the
capacity for cartilage recovery after interleukin-1-induced
matrix degradation was inversely related to the severity of
degradation [19].
Of course, a single case reported does not prove that the
nutraceuticals have caused the remarkable disc improve-
ment. Recovery sometimes happens spontaneously and/
or concomitant with an improval of overall physical con-
dition (although the latter is not true in the present case).
Normalizing MRI signals have, for example, also been
described in a case of spontaneously healed herniated
discs [23]. Yet, it is unlikely that a disc recovery to an
extent shown in Figure 1 would have happened spontane-
ously at an age of almost 60 year, and by chance concom-
itant with the supplement intake. Usually, degenerative
disc changes have been shown (also by MRI) to be age-
related and progressive, and may even be present in
almost all normal (asymptomatic) individuals older than
50 years [7,25].
That glucosamine and CS might have a beneficial effect on
degenerating discs is in line with the many papers suggest-
ing such positive effects on cartilage degeneration (oste-
oarthritis) in general [8–16]. Further support is derived
from a review of recent biochemical data, to be discussed
below.
Biochemical and physiological background of interverte-
bral disc degeneration
The intervertebral disc consists of a central, deformable
nucleus pulposus, and an outer ring of concentric, colla-
gen-rich lamellae known as the annulus fibrosis. The
nucleus pulposus mainly consists of a complex extracellu-
lar matrix deposited by relatively few cells, the chondro-
cytes. The matrix in dics resembles that in other articular
cartilages, being composed of hyaluran-bound proteogly-
cans, strengthened by collagen fibres [26,27]. Most of the
matrix mass consists of glycosaminoglycans (GAGs), i.e.
very long chains of sugar units, negatively charged by
many carboxyl- and sulfate groups. These charged groups
are neutralized by cations, which, in turn, attract and
retain large quantities of water by osmotic forces. These
forces equilibrate with the tensile forces of the collagen
network and the external forces on the disks. The bio-
chemical composition thus offers the central matrix the
unique capacity to create a hydraulic space of fixed vol-
ume and alterable dimension. The proteoglycans undergo
slow continual breakdown and renewal (turnover). The
breakdown is accomplished by extracellular proteases
such as aggrecanase [28] and metalloproteinases [29–33],
while renewed synthesis occurs by the activity of, and
within chondrocytes. During cartilage degeneration, met-
abolic turnover is increased and matrix degradation
exceeds the de novo synthesis [34]. The result is a hyper-
trophic (chondroblastic) response of chondrocytes, and a
progressive loss of proteoglycans [35], charged sulfate
groups [36] and water retention.
Chondroitin sulfate (CS) is a repeating disaccharide unit
in the GAG polymer. One of the sugars in this disaccha-
ride is N-acetylgalactosamine with sulfate groups at the 4
and/or 6 position of the hexose ring. Maturation and age-
ing causes a shift from 4- to 6-sulfation and a high degree
of 4,6-disulfation at the GAG terminal residues, which is
much decreased in degenerated cartilage [36]. Apparently,
the hypermetabolic chondrocytes in degenerating discs
have insufficient capacity to make functional full-size pro-
teoglycans with the correct sulfation for sufficient water
retention.
The intervertebral disc is avascular. Nutrition and stimula-
tion of chondrocytes depends only on diffusion via two
routes: the annular route, through which the disc receives
nutrients directly from the surrounding vascular plexus,
and the vertebral route through the endplates of the verte-
bral bodies, which are supplied with a capillary bed
[37,38]. The relative importance of the two routes for disc
metabolism remains undetermined. Nutrient diffusion is
believed to be facilitated by moderate intermittent hydro-
static pressure, e.g. during physical exercise. However,
excessive or prolonged load on the intervertebral joints
may cause injuries that affect disc integrity. Disc degener-
ation commences around the vertebral endplate [3–5],
often after impairment of the vascular bed system, which
interrupts nutrition via the vertebral route [38]. Together
with ageing and/or genetic factors, this promotes prote-
oglycan breakdown and other phenotypic changes in the
disc [33,39]. The eventual result of this imbalance in
molecular turnover is matrix resorption and dehydration
of the nucleus and of the annulus fibrosus, resulting in
reduction of disc height and further progression of the
degeneration process, leading to clinical symptoms such
as lower back pain.
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Glucosamine and chondroitin sulfate may stimulate bio-
synthesis and inhibit breakdown of proteoglycans in
degenerated cartilage
The inability of chondrocytes to make sufficient and full-
sized extracellular matrix molecules may be caused by
age-related dedifferentiation [40], conceivably with
defects in the activity of specific glycosyl- and/or sul-
fotransferases that add sugar units, one by one, and sulfate
groups to the growing GAG chains [41]. Alternatively,
reduced nutrient sugar supply to chondrocytes may lead
to a loss of proteoglycan production and disc degenera-
tion [42], most probably caused by a shortage of appropri-
ate sugar precursors that the cell normally makes itself for
delivery to its own proteoglycan 'factory', the Golgi appa-
ratus. If so, administration of pre-made, ready-to-use
sugar units, such as glucosamine and CS, as a food supple-
ment, could help, provided that sufficient amounts are
absorbed and can reach, via the blood stream and the end-
plates, the GAG-producing machinery in chondrocyte's
Golgi apparatus. The effect of these food supplements on
cartilage proteoglycan synthesis should be most revealing
under experimental conditions where proteoglycans
undergo rapid replacement and endogenous precursors
might therefore be limiting. For example, cartilage in (rab-
bit) knees has been damaged by chymopapain injection,
and joint recovery (new synthesis of proteoglycans) was
then studied with or without oral glucosamine treatment
[43]. Glucosamine significantly increased the sulfated
GAG content in these joints. This implies that glu-
cosamine may likewise promote GAG synthesis in case of
cartilage degeneration, characterized by high proteogly-
can turnover. For CS (alone), experimental studies of this
particular type have not been published, but orally
administered radiolabeled CS was found back in synovial
fluid and partly incorporated in joint cartilage [44].
Pharmacokinetic studies have been performed in animals
and man. For CS, bioavailability ranged from 5–15% [44–
46]. CS is administered at a relatively low molecular
weight (14–17 kDa), important for gastrointestinal
absorption [44,46], and is further depolymerized but not
completely degraded [44,47,48]. Peak levels of CS in
plasma were reached between 2 and 5 hr after oral admin-
istration of a single dose, and significant accumulation
was found upon multiple dosing [45]. Glucosamine was
better absorbed, reportedly about 90%, leading to an
absolute bioavailability of 12–44% [45,49]. It was partly
and persistently incorporated in articular cartilage
[10,49].
In vitro studies have confirmed that exogenous (radiola-
beled) glucosamine and CS are both taken up by chondro-
cytes and indeed used to build their extracellular matrix
[47,50,51]. Administration of sufficient glucosamine may
boost GAG synthesis in degenerated chondrocytes if
endogenous glucosamine is a limiting factor [43] and/or
if glycosyltransferases are downregulated, e.g. by inter-
leukin-1β [52]. In addition to that, it may be speculated
that exogenous CS, with sulfate groups already attached,
may help to restore the impaired sulfation of degenerated
GAGs, provided that its N-acetylgalactosamine-sulfate
units are liberated in the cell and then serve as substrates
for the glycosyltransferases in the Golgi. The latter is not
unlikely since these enzymes can use more than one type
of hexose unit [41]. However, this speculative idea needs
experimental testing.
Glucosamine and CS may also be chondroprotective
through inhibition of matrix breakdown. Glucosamine
inhibits interleukin-1β-induced proteoglycan catabolism
by inhibition of the cleavage enzyme aggrecanase [28],
and of the production of inflammatory mediators (pros-
taglandin E2, nitric oxide) [52–55] and metalloprotein-
ases [52–54], and the downregulation of
glucuronosyltransferase [52]. CS is anti-inflammatory and
may inhibit several (cartilage-destructive) proteases and
cytokines secreted by leukocytes and chondrocytes [10].
CS inhibited bradykinin- or chymopapain-induced prote-
oglycan depletion from articular cartilage (mimicking nat-
ural degeneration) [56,57].
When combined, glucosamine and CS, in an animal oste-
oarthritis model, were more effective than the compounds
alone [58]. Clinical studies in animals [59,60] and man
[24,61] have further indicated that the combination ther-
apy is effective, and allows a significant drop in NSAID
use by osteoarthritis patients.
From this fundamental overview, it may be concluded
that oral glucosamine and CS can pass the gastrointestinal
tract and can indeed reach articular cartilage, probably
also intervertebral discs, where it may have at least a chon-
droprotective effect and, quite possibly, a regenerative
effect. At the same time, however, it is fair to say that the
biochemical details are still far from understood and need
further investigation.
Conclusions
Numerous studies on these nutraceuticals related to carti-
lage degeneration reached the obvious conclusion that it
is necessary to conduct more randomized double-blind,
placebo-controlled trials [9–11,14–18]. In addition to
that, we consider it also important to generate additional
evidence, such as shown here, that directly relates to the
structural improvement of cartilage by these nutraceuti-
cals, both in animal models and in man. Restoration of
the sulfated proteoglycan matrix leads to more water
retention and, therefore, measuring the water content of
cartilage is an indisputable quality measure. The tech-
nique suited for that purpose is T2-weighted MRI, as
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illustrated in Figure 1. More signal (brightness) means
more water content!
Published (positive) effects of glucosamine or CS on joint
structure and cartilage morphology in man have thus far
been limited to osteoarthritis of the knee and finger joints
[13,18,62]. These studies involved scanning electronmi-
croscopy [62], measurement of interarticular space and/or
osteophyte appearance by X-rays [13,18]. The present case
showed, for the first time, normalizing MRI signals of a
degenerated disc in the lumbar spine, suggesting (but not
proving) that, indeed, this food supplement may have
gradually led to anatomic improvement of the disc.
Since discs are avascular and the compounds have to
reach the chondrocytes via intermittent pressure-depend-
ent diffusion, we surmise, in agreement with a recent
study [21], that it may have been important that the
patient maintained spine mobility by sport activities to
facilitate disc regeneration.
Contrary to NSAIDs, no significant adverse clinical, hema-
tological, hemostatic or other side effects were found in
any clinical study using glucosamine and/or CS supple-
mentation [8–10,24]. The present case is no exception in
this regard. Contrary to degenerated cartilage, these die-
tary supplements had no apparent effects on normal car-
tilage metabolism, as determined by ex vivo
35
S
incorporation into GAGs, or
35
S release from prelabeled
cartilage explants [58]. This may suggest a tropism of these
agents for cartilage in the reactive state, characterized by
enhanced proteoglycan turnover [34]. Glucosamine/CS
does not contribute to insulin resistance in diabetics
[10,63], probably because the pharmacokinetics and tis-
sue distribution of glucosamine/CS and glucose are differ-
ent [49].
In conclusion, we discussed the scientific rationale behind
the therapeutic use of oral glucosamine and CS against
cartilage degeneration, and illustrated the possible effi-
cacy in a case of spinal disc degeneration. Evaluation by
MRI is relatively simple and without burden to the patient
since the technique is nondestructive and no contrast
agents are needed. Therefore, it is justified to conduct
more definitive trials focusing on (disc) cartilage mor-
phology, to unambiguously prove or disprove the benefi-
cial affects of these supplements. An objective analysis
method, MRI, as shown here could further add credence
to such studies.
Competing interests
None declared.
Authors' contributions
Author 1 (WJvB) is a cell biologist/ biochemist (PhD). He
took the initiative of this study and wrote the manuscript
in close communication with the co-authors. Author 2
(JCMvdN) is the practising neurologist (MD) who treated
and clinically evaluated the patient. Author 3 (PIJMW) is
a professor in orthopedic surgery (MD, PhD) who pro-
vided addidional input in this study based on his recog-
nized lumbar spine expertise.
Acknowledgement
We thank Kenneth G.A. Gilhuys for assistance in preparing the MRI figures.
Written consent was obtained from the patient for publication of the
patient's details.
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