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Use of crystalline glucosamine sulfate in osteoarthritis

Authors:
  • Rottapharm Biotech

Abstract and Figures

The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents, which are generally effective only for acute symptom relief. Compounds are under investigation that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar short-term symptomatic effect, but also control disease progression in the long term. Glucosamine sulfate reverses the proinflammatory and joint-degenerating effects of interleukin-1 by inhibiting the cytokine intracellular signaling pathway. Clinical trials with the crystalline glucosamine sulfate formulation approved as a prescription drug, predominantly at the dose of 1500 mg once daily, demonstrated a specific symptom-modifying effect over short-and long-term treatment courses. Two 3-year trials suggested that the drug also has joint structure-modifying properties and, therefore, might be useful as a disease-modifying agent in osteoarthritis. However, efficacy data obtained with this prescription glucosamine sulfate formulation may not be applicable to all glucosamine products that are available as dietary supplements. Osteoarthritis is the most common form of arthritis and the most prevalent among rheu-matic diseases. It is a degenerative joint disorder with minimal signs of inflammation, which may affect all diarthrodial joints and whose most appropriate definition combines a description of the pathology of the disease with pain that occurs with joint use [1]. Osteoarthritis is partic-ularly frequent at the large, weight-bearing joints of the lower limbs. Radiographic osteoarthritic changes of the knee tibiofemoral compartment occur in 5–15% of the general population aged 35–74 years in the Western world [2]. Sympto-matic knee disease occurs in approximately 6% of US adults over 30 years of age [3], with general incidence and prevalence increasing two-to ten-fold from age 30 to 65 years [4]. The impact on disability attributable to knee osteoarthritis is similar to that due to cardiovascular disease and greater than that caused by any other medical condition in the elderly [5]. Treatment guidelines for knee and hip osteo-arthritis have been developed by both the Amer-ican College of Rheumatology (ACR) [6] and the EUropean League Against Rheumatism (EULAR) [7,8]. The two guidance documents have been developed by different procedures and, although they share some basic principles, differ with respect to the level of recommenda-tion of specific classes of drugs. This is particu-larly evident for SYmptomatic Slow Acting Drugs in OsteoArthritis (SYSADOA), the class of agents in which the drug focussed on in this review is generally included, and might be due to the differences in the regulatory status between the USA and Europe. For this and other reasons, the guidelines may soon need further updates. Both guidelines suggest that acetaminophen (paracetamol) should be the oral analgesic used initially and, if successful, the preferred long-term symptomatic agent [6–8]. Nevertheless, this pure analgesic is less effective than nonsteroidal anti-inflammatory drugs (NSAIDs) in short-term pain relief [9]. On the contrary, recent meta-analyses suggest that the efficacy of NSAIDs in osteoarthritis is not great and, in particular, their long-term use is not supported by available data [10]. Therefore, there is a need for medications that offer acceptable short-term symptom control, but in particular have a role in the medium-and long-term management of disease (symptom-modifying effect), including the possibility to delay the progression of joint structure changes (structure-modifying effect), thereby affecting the evolution of the disease and thus preventing clinically significant disease outcomes (disease-modifying effect). These aims might be achieved by drugs that, unlike unspecific symptomatic agents, might exert specific effects on osteo-arthritis pathogenesis factors. To date, glu-cosamine sulfate is probably the drug with the most extensive evidence in this regard.
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10.2217/17460816.1.4.397 © 2006 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2006) 1(4), 397–414 397
DRUG EVALUATION
Use of crystalline glucosamine sulfate
in osteoarthritis
Gabriel Herrero-
Beaumont
& Lucio C Rovati
Author for correspondence
Autonomous University of
Madrid, Rheumatology
Department, Fundación
Jiménez Díaz-Capio,
Avenida Reyes Católicos 2,
28040 Madrid, Spain
Tel.: +34 915 504 918;
Fax: +34 915 494 764;
gherrero@fjd.es
Keywords: clinical trials,
disease modification,
glucosamine sulfate,
interleukin-1, joint-space
narrowing, osteoarthritis,
pharmacokinetics, safety,
structure modification,
symptom modification
The pharmacological treatment of osteoarthritis is traditionally accomplished with
nonspecific symptomatic agents, which are generally effective only for acute symptom
relief. Compounds are under investigation that might exert specific effects on osteoarthritis
pathogenesis and thus induce at least a similar short-term symptomatic effect, but also
control disease progression in the long term. Glucosamine sulfate reverses the
proinflammatory and joint-degenerating effects of interleukin-1 by inhibiting the cytokine
intracellular signaling pathway. Clinical trials with the crystalline glucosamine sulfate
formulation approved as a prescription drug, predominantly at the dose of 1500 mg once
daily, demonstrated a specific symptom-modifying effect over short- and long-term
treatment courses. Two 3-year trials suggested that the drug also has joint structure-modifying
properties and, therefore, might be useful as a disease-modifying agent in osteoarthritis.
However, efficacy data obtained with this prescription glucosamine sulfate formulation may
not be applicable to all glucosamine products that are available as dietary supplements.
Osteoarthritis is the most common form of
arthritis and the most prevalent among rheu-
matic diseases. It is a degenerative joint disorder
with minimal signs of inflammation, which may
affect all diarthrodial joints and whose most
appropriate definition combines a description of
the pathology of the disease with pain that
occurs with joint use
[1]. Osteoarthritis is partic-
ularly frequent at the large, weight-bearing joints
of the lower limbs. Radiographic osteoarthritic
changes of the knee tibiofemoral compartment
occur in 5–15% of the general population aged
35–74 years in the Western world
[2]. Sympto-
matic knee disease occurs in approximately 6%
of US adults over 30 years of age
[3], with general
incidence and prevalence increasing two- to ten-
fold from age 30 to 65 years
[4]. The impact on
disability attributable to knee osteoarthritis is
similar to that due to cardiovascular disease and
greater than that caused by any other medical
condition in the elderly
[5].
Treatment guidelines for knee and hip osteo-
arthritis have been developed by both the Amer-
ican College of Rheumatology (ACR)
[6] and the
EUropean League Against Rheumatism
(EULAR)
[7,8]. The two guidance documents
have been developed by different procedures
and, although they share some basic principles,
differ with respect to the level of recommenda-
tion of specific classes of drugs. This is particu-
larly evident for SYmptomatic Slow Acting
Drugs in OsteoArthritis (SYSADOA), the class
of agents in which the drug focussed on in this
review is generally included, and might be due to
the differences in the regulatory status between
the USA and Europe. For this and other reasons,
the guidelines may soon need further updates.
Both guidelines suggest that acetaminophen
(paracetamol) should be the oral analgesic used
initially and, if successful, the preferred long-
term symptomatic agent
[6–8]. Nevertheless, this
pure analgesic is less effective than nonsteroidal
anti-inflammatory drugs (NSAIDs) in short-
term pain relief
[9]. On the contrary, recent
meta-analyses suggest that the efficacy of
NSAIDs in osteoarthritis is not great and, in
particular, their long-term use is not supported
by available data
[10].
Therefore, there is a need for medications that
offer acceptable short-term symptom control,
but in particular have a role in the medium- and
long-term management of disease (symptom-
modifying effect), including the possibility to
delay the progression of joint structure changes
(structure-modifying effect), thereby affecting
the evolution of the disease and thus preventing
clinically significant disease outcomes (disease-
modifying effect). These aims might be achieved
by drugs that, unlike unspecific symptomatic
agents, might exert specific effects on osteo-
arthritis pathogenesis factors. To date, glu-
cosamine sulfate is probably the drug with the
most extensive evidence in this regard.
Glucosamine sulfate
Glucosamine is a naturally occurring mono-
saccharide and a normal constituent of gly-
cosaminoglycans in the cartilage matrix and
For reprint orders, please contact:
reprints@futuremedicine.com
DRUG EVALUATION – Herrero-Beaumont & Rovati
398 Future Rheumatol. (2006) 1(4)
synovial fluid [11]. However, it also exerts specific
pharmacological effects on osteoarthritic carti-
lage and chondrocytes. Glucosamine base must
be salified for pharmaceutical use, and glu-
cosamine sulfate is the salt that was originally
developed as a prescription drug and used in the
vast majority of osteoarthritis clinical trials.
However, some recent generic over-the-counter
products and in particular a number of dietary
supplements may contain glucosamine hydro-
chloride, whose treatment effects are much less
well characterized, as will be discussed. In addi-
tion, several dietary supplements have appeared
that claim glucosamine sulfate content, but that
may be different from the prescription product
described below.
For these reasons, the present review will con-
centrate on the crystalline glucosamine sulfate for-
mulation that has been approved as a prescription
drug in Europe and elsewhere, and that is available
as a branded dietary supplement in the USA. Nev-
ertheless, high-quality clinical trials conducted
with glucosamine hydrochloride or other glu-
cosamine sulfate formulations will also be
reviewed, and their results analyzed to assess the
overall evidence available for the use of glu-
cosamine in osteoarthritis. In this respect, it must
be noted that a recent Cochrane Review identified
major differences in the results of clinical trials
conducted with the glucosamine sulfate prescrip-
tion formulation described here and those of stud-
ies conducted with other glucosamine preparations
which failed to demonstrate a similar efficacy
[12].
Chemistry
Crystalline glucosamine sulfate (Dona
®
,
Viartril-S
®
, Arthryl
®
, Xicil
®
or other trademarks
by the originator company Rottapharm, Monza,
Italy), is also known as glucosamine sulfate
sodium chloride. It is a pure substance (molecular
weight [Mw]: 573.31) synthesized from chitin of
sea origin and in which glucosamine
(Mw = 179.17), sulfate, chloride and sodium ions
are present in stoichiometric ratios of 2:1:2:2
(Fig-
ure 1)
. Glucosamine sulfate (Mw = 456.43) does
not appear to be stable, unless prepared as crystal-
line glucosamine sulfate according to this pat-
ented process
[13]. The dose is expressed as the net
content in glucosamine sulfate and, as a prescrip-
tion drug, the substance is most widely available
as sachets of powder for oral solution of 1500 mg
glucosamine sulfate to be administered once daily.
At present, it is unclear how other preparations
of glucosamine sulfate, mainly available in coun-
tries where the substance is regulated as a dietary
supplement, compare with this prescription for-
mulation in terms of active ingredient content,
purity and stability, since this information is gen-
erally not available. When formulations are
unknown, and especially in view of the absence of
appropriate bioequivalence studies (see
‘Pharmacokinetics and metabolism’ section), it is
not known how the clinical efficacy and safety
results obtained with crystalline glucosamine sul-
fate apply to these uncontrolled nutraceutical or
generic preparations, and vice versa.
Pharmacodynamics
Glucosamine is preferentially incorporated by
chondrocytes into the components of gly-
cosaminoglycan chains in intact cartilage
[14]. It
stimulates the synthesis of physiological proteo-
glycans
[15–17] and decreases the activity of cata-
bolic enzymes in the cartilage, including matrix
metalloproteases (MMPs)
[17,18]. The compound
is effective in vivo in experimental animal models
of osteoarthritis
[19,20]. For several years, the
dominant belief was that most of the activities
and the mechanism of action of glucosamine sul-
fate might be reconducted to the mere incorpo-
ration of glucosamine in glycosaminoglycans
and, thus, the stimulation of their synthesis as a
simple building block. However, this hypothesis
appears to be over-simplified. In fact, while met-
abolic effects, especially if exerted at the level of
the articular cartilage, might support a long-term
joint structure-modifying activity, they may
hardly explain the relatively short-term symp-
tom-modifying effects outlined in clinical trials.
Unsurprisingly, recent studies have demon-
strated that glucosamine concentrations that are
able to stimulate glycosaminoglycans synthesis
in vitro are high
[21] and probably largely in
excess of those that may be achieved in biological
fluids after oral administration to humans
[22].
On the other hand, selected in vitro models
illustrated that glucosamine might be metaboli-
cally effective at concentrations 100-fold lower
and compatible with those found in biological
fluids during treatment in humans
[17]. In addi-
tion, the compound may selectively cumulate in
the cartilage after repeated dosing, thereby possi-
bly providing higher local concentrations
[23]. An
alternative hypothesis has been proposed that sug-
gests looking for glucosamine metabolic activities
in tissues where extracellular glucosamine concen-
trations should be higher, including the intestine,
liver and kidney, and might modulate the com-
pound anti-arthritic effects
[24]. However, this
hypothesis appears to be premature at present.
www.futuremedicine.com 399
Glucosamine sulfate – DRUG EVALUATION
A unifying hypothesis for the compound
mechanism of action in osteoarthritis has recently
been proposed and supports the role of glu-
cosamine sulfate as both a symptom- and struc-
ture-modifying agent in osteoarthritis. This
mechanism refers to glucosamine-induced
reversal of the pro-inflammatory and joint-
degenerating effects of interleukin (IL)-1
[18,25,26].
More specifically, it inhibits the cytokine intra-
cellular signaling cascade, namely the activation
of the nuclear factor (NF)-κB pathway
[27]. In
particular, glucosamine sulfate has been shown to
inhibit the IL-1-induced activation and nuclear
translocation of active NF-κB family members in
human osteoarthritic chondrocytes
[28]. Via this
mechanism, glucosamine sulfate was able to
inhibit the gene expression and protein synthesis
of cyclooxygenase (COX)-2, selectively over
COX-1, thereby preventing the release of
prostaglandin (PG)E
2
in the culture media [28].
Several new evidences are progressively
appearing to further substantiate this mecha-
nism of inhibiting IL-1-induced expression of
genes involved in the pathophysiology of joint
inflammation and tissue destruction. NF-κB
activity is inhibited by glucosamine sulfate at the
level of both chondrocytes and synoviocytes,
with a concomitant decrease in COX-2 protein
synthesis, PGE
2
release and, in chondrocytes,
nitric oxide release, with a pattern that differs
from that of other potential anti-osteoarthritic
agents and NSAIDs
[29]. Moreover, glucosamine
sulfate consistently decreased IL-1-induced
MMP synthesis in both type of cells, while
NSAIDs tended to further increase their
production
[29].
Most of these in vitro experiments used glu-
cosamine concentrations that were higher than
those found in human plasma after therapeutic
doses (see ‘Pharmacokinetics and metabolism’),
which is common in mechanistic studies.
However, recent studies indicated that this
mechanism is operative at glucosamine concen-
trations of approximately 10 µM or lower
[30],
specifically, the concentrations found in human
plasma or synovial fluid after therapeutic doses
of crystalline glucosamine sulfate. Effective glu-
cosamine concentrations (expressed as IC
50
)
that inhibit IL-1-stimulated gene expression of
different pro-inflammatory or prodegenerative
transcripts have been reported to range
between 6.2 and 13.8 µM for IL-1 itself,
MMP-3, COX-2 and inducible nitric oxide
synthase
[30].
Another recent study confirmed that, in vitro,
glucosamine inhibits gene expression in the
osteoarthritic cartilage
[31]. Since glucosamine
inhibits both anabolic and catabolic genes, the
authors speculate that the therapeutic effects as
a potential disease-modifying agent might be
due to anticatabolic activities, rather than ana-
bolic activities. Interestingly, they also found
that glucosamine sulfate is a stronger inhibitor
of gene expression than glucosamine hydrochlo-
ride
[31], which may help to explain the different
findings of recent clinical trials with different
glucosamine salts and formulations, along with
the recent human pharmacokinetic findings.
The differences between glucosamine sulfate
and glucosamine hydrochloride might be impor-
tant at both the pharmacological and pharmaco-
kinetic levels, with sulfate concentrations
increasing after administration of glucosamine
sulfate
[32,33]. This might possibly overcome a
deficiency in inorganic sulfur caused by low lev-
els of dietary proteins (containing sulfur amino
acids) in the elderly. Sufficient sulfur is essential
for the synthesis of proteoglycans and other sul-
fur-containing metabolic intermediates (e.g.,
coenzyme A and glutathione) that are important
for chondrocyte metabolism
[32,33].
Pharmacokinetics & metabolism
For a long period, limited knowledge about glu-
cosamine pharmacokinetics (including oral bio-
availability, peak plasma levels and tissue distribu-
tion) hampered the full understanding of the rela-
tionships between the compound clinical effects
and its mechanism of action. In addition, the ina-
bility to document the compound pharmacoki-
netics and, thus, to perform bioequivalence
studies against the patented formulation of crys-
talline glucosamine sulfate approved as a prescrip-
tion drug in continental Europe and elsewhere,
favored the appearance on the market of other
undocumented glucosamine salts (e.g., hydro-
chloride), improperly stabilized glucosamine
Figure 1. Crystalline glucosamine sulfate.
O
CH
2
OH
OH
OH
NH
3
+
OH
Na
+
Cl
Cl
Na
+
O
O
S
O
O
OH
O
OH
OH
CH
2
OH
+
H
3
N
DRUG EVALUATION – Herrero-Beaumont & Rovati
400 Future Rheumatol. (2006) 1(4)
sulfate substances, different dosage forms or regi-
mens, whose clinical trial results were clearly less
favorable (as will be reviewed later).
The main limitation for the description of glu-
cosamine pharmacokinetics has been the lack of
suitable bioanalytical methods with sufficient
sensitivity and specificity for the detection of the
compound in biological fluids. Early studies tried
to elucidate the pharmacokinetics and metabo-
lism of oral glucosamine sulfate in rats, dogs and
humans, using
14
C-labeled glucosamine [23].
Although these studies provided compelling
information about the absorption, distribution
and elimination of radioactivity, they were not
fully able to differentiate the unchanged drug
from its metabolites and/or degradation prod-
ucts. When tentative specific methods for the
determination of glucosamine in human plasma
were developed, they were not suitably sensitive
to monitor the plasma concentrations of the
unchanged compound after oral administration
of therapeutic doses
[23].
More recent investigations into different
forms of oral glucosamine in rats
[34], dogs [35]
and horses [36] had to use doses much higher
than those used therapeutically in humans owing
to the high limit of quantization of the assays
employed, and their relevance to the treatment
of osteoarthritis is at least questionable. Never-
theless, the serum and synovial fluid concentra-
tions of glucosamine have been determined in
horses with reasonable assay sensitivity, after sin-
gle-dose administration of glucosamine hydro-
chloride at what the authors designated ‘human
clinically relevant’ doses, although they failed to
use an allometric scale to calculate such doses
and, therefore, their results are difficult to inter-
pret
[24]. Nevertheless, maximal glucosamine
concentrations in plasma were similar to those
later described in humans
[22,37]. Conversely, the
concentrations in the synovial fluid were at least
tenfold lower
[24].
A very preliminary study in patients with
variously localized osteoarthritis found glu-
cosamine plasma levels up to 11.5 µM, 1.5–3 h
after ingestion of a single 1500 mg dose of glu-
cosamine sulfate. Although these peak plasma
levels were in line with those found in correct
human pharmacokinetics studies
[36], they were
not reached in all patients, possibly due to pro-
tocol limitations, as acknowledged by the
authors themselves
[22].
The complete pharmacokinetic profile of glu-
cosamine has lately been described by Persiani
and colleagues, after repeated administrations
(i.e., at steady state) of the standard crystalline
glucosamine sulfate formulation, (1500 mg
once daily), to healthy volunteers in a rigor-
ously designed pharmacokinetics study
[37].
These authors have developed and validated a
liquid chromatography method with mass spec-
trometry detection (LC-MS/MS) that has a
very low limit of quantitation
[37]. This enabled
them to detect endogenous plasma glucosamine
concentrations with distinct intrasubject varia-
bility, and to study the pharmacokinetics of the
exogenously administered compound with
higher precision. They found that glucosamine
is rapidly bioavailable from orally administered
crystalline glucosamine sulfate, with maximum
average plasma concentrations up to 100-fold
higher than endogenous levels and in the
10 µM range after approximately 3 h. Steady-
state pharmacokinetics parameters indicate that
glucosamine distributes to both the vascular
and extravascular compartments and is elimi-
nated with a half-life estimated to be approxi-
mately 15 h, thus supporting once-daily
dosing. Absolute bioavailability could not be
assessed in this study, but was estimated to be
approximately 25% with the help of other
recent animal data
[38].
Preliminary knee osteoarthritis patient data
from the same group indicate the presence of
endogenous glucosamine levels in both plasma
and synovial fluid, with distinct intrasubject
variability (particularly at the level of the lat-
ter), whose possible pathophysiological signif-
icance should be further investigated
[39]. In
these patients, repeated once-daily doses of
1500 mg crystalline glucosamine sulfate
reached similar peak plasma and synovial fluid
concentrations, with an almost 1:1 relation-
ship, which were also in the 10 µM range
[39].
These data are different from those described
in horses
[24] and call attention to possible spe-
cies-specific differences and/or on the preci-
sion of the assays employed, which appears to
be higher in the studies by Persiani and col-
leagues
[37,39]. Interestingly, the 10 µM con-
centration range found in human plasma and
synovial fluid
[21,37,39] is effective on chondro-
cytes in vitro in the inhibition of IL-1-induced
gene expression
[30]; specifically, the putative
mechanism of action of glucosamine in osteo-
arthritis. Conversely, the same concentrations
are probably insufficient to stimulate cartilage
glycosaminoglycan synthesis
[21,22]. This
finding would suggest abandoning this latter
over-simplified hypothesis.
www.futuremedicine.com 401
Glucosamine sulfate – DRUG EVALUATION
Single-dose pharmacokinetic studies with
other glucosamine formulations at the same unit
dose of 1500 mg, such as the glucosamine hydro-
chloride solid preparation used in the Glu-
cosamine/chondroitin Arthritis Intervention Trial
(GAIT) (see later), found glucosamine peak con-
centrations in plasma that were only 3 µM
[40],
that is, at least threefold lower than the steady-
state concentrations reached with 1500 mg of
crystalline glucosamine sulfate, and they might be
even lower when the 1500 mg daily dose is frac-
tioned; for example, as 500 mg three-times daily,
as in GAIT. These lower concentrations found
with glucosamine hydrochloride are less effective
in vitro on the putative mechanism of action of
glucosamine described earlier
[30].
Unfortunately, there are no pharmacokinetics
and bioavailability studies of other glucosamine
sulfate preparations and, therefore, it is impossi-
ble to comment on their clinical value relative to
the prescription formulation.
Clinical efficacy
The putative mechanism of action, described
above, supports the role of glucosamine sulfate as
both a symptom- and structure-modifying drug
in osteoarthritis.
All clinical trials performed until the end of
2004 have been systematically evaluated in a
recent Cochrane review
[12], which supersedes
two previous high-quality meta-analyses
[41,42].
This Cochrane review considered the results of all
20 eligible randomized controlled trials (RCTs)
available at that time with any glucosamine for-
mulation for symptom modification and con-
cluded that glucosamine was superior to placebo
for improvement in both pain and function, with
a moderate effect size. However, these results
were driven by the ten RCTs that evaluated the
prescription formulation of crystalline glu-
cosamine sulfate object of this review (labeled
‘Rotta preparation’ in the Cochrane review) and
which found a high effect size for pain and a
moderate effect size for function relative to pla-
cebo. Pooled results for trials using a different
glucosamine preparation failed to reach statistical
significance when compared with placebo.
Only high-quality trials conducted with any
glucosamine formulation will be considered in
this review. Given the different results out-
lined in the Cochrane Review, trials of pre-
scription crystalline glucosamine sulfate are
the main subject of this review, and they will
be reported separately from studies performed
with other formulations.
High-quality trials of crystalline glucosamine
sulfate can be classified based on their treatment
duration and aims.
Short-term trials of glucosamine sulfate for
symptom relief
Besides placebo-controlled trials, four short-term
studies compared the prescription glucosamine
sulfate formulation with an NSAID, and found
it superior in two and equivalent in two, for
treatment periods between 4 and 12 weeks
[12].
One of the studies that better describes the
short-term, symptom-modifying effect of glu-
cosamine sulfate versus both placebo and
NSAIDs has been published in abstract form
[43].
Based on the complete data and information
largely reported below, the Cochrane review
established that this study had adequate alloca-
tion concealment and the highest rated method-
ological quality for both study design and
analysis
[12]. This was a randomized, double-
blind, placebo- and active-controlled trial on
four parallel groups of patients, with mono- or
bilateral primary knee osteoarthritis, according
to the ACR criteria. Patients (a total of 319; 75%
females) had an average age of 65.5 years, a mean
body mass index (BMI) of 27.8, and a history of
daily knee pain and function limitation requir-
ing medical treatment for at least the previous
6 months. After wash-out from previous symp-
tomatic medications, they were randomly
assigned to once-daily treatment for 12 weeks
with either 1500 mg glucosamine sulfate powder
for oral solution, one 20 mg piroxicam capsule,
the combination of both glucosamine sulfate and
the NSAID, or double placebo, according to a
double-dummy technique to preserve blindness
in all groups. At the end of the 12 weeks, treat-
ments were withdrawn and patients followed-up
for a further 8 weeks. Acetaminophen (paraceta-
mol) 500 mg tablets were provided for rescue
analgesia as needed, and their use recorded on a
patient daily diary. All groups were comparable
for demographic and baseline disease characteris-
tics, the latter being of moderate severity.
Figure 2
reports the change in the primary parameter rep-
resented by the Lequesne index, whose final out-
come is reported in
Table 1. Both glucosamine
sulfate and piroxicam demonstrated a distinct
trend for improvement over placebo, evident
already after 2 weeks of treatment and similar for
the two drugs up to 4 weeks. As listed in
Table 1,
this behavior was superimposable to that demon-
strated in previous 4-week placebo-controlled
[44] or NSAID-controlled [45] trials. After
DRUG EVALUATION – Herrero-Beaumont & Rovati
402 Future Rheumatol. (2006) 1(4)
4 weeks, the improvement with glucosamine sul-
fate continued slightly more steadily than with
piroxicam (
Figure 2, left) and was superior at the
end of the 12-week treatment course. The com-
bination of glucosamine sulfate with the NSAID
tended to exhibit an insignificant faster sympto-
matic effect over the first 15 days of treatment.
Thereafter, the improvement was indistinguisha-
ble from that of glucosamine sulfate alone. Over
the 8 weeks of follow-up after drug withdrawal,
the patients previously receiving piroxicam
tended to lose most of the effect formerly
achieved (
Figure 2, right and Table 1). Conversely,
the previous beneficial effect was long-lasting in
patients who had received glucosamine sulfate
alone or in combination with the NSAID.
Recourse to paracetamol for rescue analgesia in
this trial was occasional and variable, with
minimal average consumption (<1–2 tab-
lets/day) in a similar proportion of patients,
without significant differences between groups.
Long-term trials for disease modification & new
trials for the management of disease symptoms
Glucosamine sulfate should not be regarded as a
drug for short-term symptom relief, but one for
osteoarthritis disease management. This includes
symptom modification over appropriate treat-
ment durations, specifically at least 6 months
according to current regulatory guidelines
[46],
and possibly long-term trials for both joint struc-
ture modification and symptom modification
(i.e., true disease modification). Three pivotal
trials currently satisfy these requirements for
crystalline glucosamine sulfate.
Reginster and colleagues
[47] and Pavelka and
colleagues
[48] were the first to demonstrate a
putative disease-modifying effect by a pharmaco-
logical agent in two long-term studies. In these
3-year, randomized, placebo-controlled clinical
trials, they were able to demonstrate that
glucosamine sulfate was not only able to control
the symptoms of the disease over such a
Figure 2. Mean change in the Lequesne index score (in points, with 95% confidence interval) at each visit
compared with treatment period (left), or to end of treatment values for the follow-up (right).
Patients evaluable at each visit are reported at the bottom of the figure. Baseline values, final differences and statistical analysis for the
entire intention-to-treat population are reported in
Table 1. Symbols reported in this figure represent the intention-to-treat results in the
analysis of variance for repeated measures on the curve of the timecourse of effects
[43].
*p < 0.001 versus placebo;
p < 0.01 versus piroxicam (treatment period);
§
p < 0.05 versus placebo;
p < 0.05 versus piroxicam
(follow-up period).
Treatment
-6
-5
-4
-3
-2
-1
0
1
Lequesne index change (points)
024 128141620
Weeks
Placebo
Piroxicam
Glucosamine sulfate
Combination
Number of patients:
Placebo 77 75 72 66 59 52 45 41
Piroxicam 86 86 77 68 59 52 45 42
Glucosamine sulfate 79 79 78 77 77 75 73 72
Combination
77 75 74 73 72 67 61 59
Follow-up
*
*
*
§
610 18
www.futuremedicine.com 403
Glucosamine sulfate – DRUG EVALUATION
Table 1. Mean change in the Lequesne algo-functional index from baseline in crystalline glucosamine sulfate high-quality trials of different
treatment durations.
Noack [44] Rovati [43] Herrero-Beaumont [58] Pavelka [48]
Placebo
n = 120
GS
n=121
Placebo
n=77
GS
n=79
Piroxicam
n=86
Combination*
n=77
Placebo
n=104
GS
n = 106
Acetaminophen
n = 108
Placebo
n = 101
GS
n = 101
Baseline 10.6 ± 3.5 10.6 ± 3.6 10.4 ± 3.0 10.3 ± 3.0 10.8 ± 3.0 11.1 ± 3.3 10.8 ± 2.6 11.0 ± 3.1 11.1 ± 2.7 8.9 ± 2.3 9.0 ± 2.3
Change from baseline
4 weeks -2.3
(-2.9 to
-1.7)
-3.2
(-3.9 to -2.6)
p = 0.037 vs
placebo
12 weeks -0.7
(-1.4 to
-0.1)
-4.8
(-5.4 to -4.2)
p < 0.001 vs placebo
p < 0.001 vs
piroxicam
NS vs combination
-2.9
(-3.5 to -2.2)
p < 0.001 vs
placebo
p = 0.003 vs
combination
-4.5
(-5.2 to -3.7)
p < 0.001 vs
placebo
6 months -1.9
(-2.6 to
-1.2)
-3.1
(-3.8 to -2.3)
p = 0.032 vs
placebo
-2.7
(-3.3 to -2.1)
NS vs placebo
3 years -0.8
(-1.1 to
-0.5)
-1.7
(-2.2 to -1.2)
p = 0.002 vs
placebo
Change from end of treatment
8 weeks 0.2
(-0.6 to
1.1)
0.4
(-0.1 to 0.9)
NS vs placebo
p=0.02 vs
piroxicam
NS vs combination
1.8
(1.2 to 2.4)
p=0.01 vs
placebo
0.6
(-0.1 to 1.3)
Intention-to-treat (ITT) approach by the last observation carried forward, except in Pavelka [48] where a worst-case scenario was employed. The lower row reports the mean change from the end of treatment scores,
after drug withdrawal, in the only study where this assessment was performed (see also
Figure 2), with an ITT approach on all treatment period completers, assuming return to baseline values for early withdrawals.
Statistical analysis by analysis of variance, with correction for multiple comparisons by Dunnett pairwise comparisons in Herrero-Beaumont [58], or by the Tukey test, after covariating on baseline and end-of-
treatment scores, respectively, in Rovati [43]. Two high-quality trials could not be included in this table: the study by Müller-Fassbender [45] versus ibuprofen for using a modified version of the Lequesne index and
whose results for GS at 4 weeks are superimposable to those of Noack [44] and not different from those obtained for ibuprofen 1200 mg/day; the long-term placebo-controlled study by Reginster [47] for using the
WOMAC index only and whose results at 3 years are superimposable to those of Pavelka [48] who used the WOMAC index as a secondary end point.
Data are mean ± SD for baseline scores and mean with 95% confidence interval for changes.
*Combination of glucosamine sulfate + piroxicam.
GS: Glucosamine sulfate; NS: Not significant; SD: Standard deviation; WOMAC: Western Ontario and Macmaster osteoarthritis index.
DRUG EVALUATION – Herrero-Beaumont & Rovati
404 Future Rheumatol. (2006) 1(4)
long-term treatment course, but could also signif-
icantly decrease the progression of joint structure
changes in patients with mild-to-moderate oste-
oarthritis of the knee. The data were particularly
strong in the subgroup of female postmenopausal
patients
[49].
Joint structure changes were principally
assessed by monitoring radiographic joint space
narrowing. The results are summarized in
Table 2
and illustrate a similar quantitative effect in the
two trials, as previously acknowledged
[42]. Reser-
vations have been expressed that these results were
obtained with the full extension knee radiographic
view, a technique that, although state-of-the-art at
the time of the trials, might be less efficient than
newer semiflexed views, and the results might
have been biased by the marked symptom
improvement by glucosamine sulfate
[48]. In fact,
improvement in pain might improve the degree of
knee extension and artifactually increase the tibio-
femoral joint radiographic space, by changing the
medial tibial plateau alignment with the x-ray
beam
[50]. However, it has recently been demon-
strated that pain was not a confounder in joint
space narrowing assessment in these trials
[51].
Indeed, the long-term symptom-modifying
effect in the two long-term trials was termed
‘impressive
[52]. Other reports have questioned the
significance of this symptom improvement
[53];
however, this has been recently reassessed and
found to be clinically relevant
[54], although the
effect size is small due to the mild symptom
characteristics of the patients at enrolment.
In addition, preliminary follow-up data of these
patient cohorts suggest that, on average, 5 years
after the end of the two long-term trials and drug
withdrawal, the patients who had received glu-
cosamine sulfate were less likely to undergo total
joint replacement
[55,56]. If confirmed, these data
would indicate that glucosamine sulfate might
indeed affect the progression of osteoarthritis,
preventing clinically significant disease out-
comes. This finding might be explained by the
symptom- and structure-modifying effect
achieved during the treatment period, in terms
of clinically relevant response. In particular, a
recent position paper suggested that ‘failure’ to
treatment might be a good predictor of joint sur-
gery and a proper surrogate outcome during
long-term clinical trials for disease modification
in osteoarthritis
[57]. When this group of experts
assessed the proportion of ‘failures’, defined as a
joint space narrowing of at least 0.5 mm, and
less than 20% improvement in the Western
Ontario and MacMaster OA Index (WOMAC)
pain subscale, in the two long-term studies by
Reginster and colleagues and by Pavelka and col-
leagues, they found that there were 41% failures
overall with glucosamine sulfate versus 60% on
placebo (p = 0.003)
[57].
The most recent pivotal study assessed the role
of glucosamine sulfate in the management of knee
osteoarthritis symptoms over 6 months in com-
parison with placebo and with a reference drug
represented by acetaminophen (paracetamol)
[58];
in other words, the preferred long-term sympto-
matic medication indicated by current osteo-
arthritis practice guidelines
[6,7]. The Glucosamine
Unum In Die (once-a-day) Efficacy (GUIDE)
trial evaluated 318 patients (88% women) rand-
omized to double-dummy placebo, or 1 g aceta-
minophen tablets three-times daily, or to the
standard prescription formulation of glucosamine
sulfate soluble powder 1500 mg once daily (hence
the acronym of the study). The data reported in
Table 1 illustrate that the mean improvement in
the Lequesne index with glucosamine sulfate was
significantly higher than with placebo. Con-
versely, the improvement with acetaminophen
failed to reach statistical significance versus pla-
cebo. The clinical relevance of the effect size of
glucosamine sulfate on the primary outcome in
Table 2. Radiographic joint space width (mean ± SD) and 3-year JSN at the narrowest point of the medial
tibio–femoral compartment of the knee joint, as reported by Reginster
[47] and Pavelka [48].
Study (sample size) Enrolment JSW 3-year JSN Ref.
Placebo GS (mean ±
SD; mm)
Placebo GS (mean ± 95% CI; mm)
Reginster (n = 106,106) 3.95 ± 1.24 3.82 ± 1.32 -0.40 (-0.56 to -0.24) -0.07* (-0.22 to 0.07) [47]
Pavelka (n = 101,101) 3.63 ± 1.57 3.89 ± 1.48 -0.19 (-0.29 to -0.09)
-0.04
(-0.06 to 0.14)
[48]
*p = 0.003 and
p = 0.001 versus placebo.
CI: Confidence interval; GS: Glucosamine sulfate; JSW: Joint space width; JSN: Joint space narrowing; SD: Standard deviation.
www.futuremedicine.com 405
Glucosamine sulfate – DRUG EVALUATION
this trial is witnessed by the higher proportion of
treatment responders according to the Osteo-
arthritis Research Society (OARSI-A) criteria:
39.6 versus 21.2% with placebo (p = 0.007).
Acetaminophen also had more responders than
placebo, although at a lower degree of significance
(33.3%; p = 0.047).
These results suggest that glucosamine sulfate
might be the preferred symptomatic medication
in knee osteoarthritis vis a vis current practice
guidelines, if employed at the standard dose regi-
men of the prescription formulation of this and
the previously described pivotal trials. On the
other hand, these results are at odds with those
of the National Institutes of Health (NIH)-sup-
ported GAIT study, where the glucosamine-
treated group demonstrated only a nonsignifi-
cant trend of efficacy
[59]. This large, 6-month
trial compared glucosamine, given as dietary
supplement glucosamine hydrochloride 500 mg
three-times daily or chondroitin sulfate, or their
combination, with placebo and with celecoxib as
a reference standard. The overall results might be
clouded by the huge placebo effect (60%), and
by an insufficiently controlled use of the rescue
analgesic medication, since even the reference
standard medication produced disappointing,
although statistically significant, efficacy results
compared with placebo
[60]. Conversely, none of
the supplements was significantly superior to
placebo
[59]. Glucosamine hydrochloride at the
dose of 500 mg three-times daily was used only
in one previous RCT whose results were mostly
negative
[61]. Indeed, the editorial accompanying
the GAIT study states that the NIH finding for
glucosamine is not surprising, given the non-
conventional glucosamine formulation used,
since all previous favorable trials have been con-
ducted with the glucosamine sulfate prescription
preparation
[62]. As described in the ‘Pharmaco-
dynamics’ and ‘Pharmacokinetics’ sections ear-
lier, the peak glucosamine plasma levels achieved
with the NIH hydrochloride formulation are
much lower
[40] than with the prescription sul-
fate formulation used in GUIDE
[37,39] and,
therefore, they might not share the same phar-
macological properties
[30]. In addition, sulfates
have been suggested as an important component
of the glucosamine mechanism of action
[32].
Interestingly, the most significant results in
GAIT were achieved in a subgroup analysis in
more severe patients when glucosamine hydro-
chloride was combined with chondroitin
sulfate
[59], presumably increasing the sulfate
plasma levels
[33], if not even those of
glucosamine metabolites, to concentrations
closer to those achieved with the prescription
glucosamine sulfate formulation used in GUIDE
and the other pivotal trials.
Overall assessment of the symptom-modifying
effect of crystalline glucosamine sulfate in both
short- & long-term clinical trials
Table 1 demonstrates a coherence of results for
symptomatic improvement with glucosamine
sulfate over short-to-medium-term treatment
courses ranging from 4 weeks to 6 months
[43–45,58].
The magnitude of the effect also appears to be
comparable, with the exception of one trial where
it is higher mainly due to a lower placebo
response
[43].
In the trials where a comparison with a non-
specific symptomatic medication is performed, glu-
cosamine sulfate might provide similar symptom
relief after the first 2–4 weeks
[43,45] and it might
lean towards superiority in studies of 3–6 months
duration
[43,58], including a persistent effect after
drug withdrawal, compared with a progressive loss
of effect, for example, with NSAIDs
[43].
In the long-term trial by Pavelka that used the
Lequesne index as the primary symptom out-
come, the effect size relative to placebo on this
parameter is similar to that observed in shorter
trials
[48], as suggested by the data in Table 1 and
as acknowledged by the Cochrane review
[12].
Few published trials of crystalline sulfate used
the WOMAC index as a symptom outcome (i.e.,
only the long-term trials of Reginster
[47] and
Pavelka
[48]), and reported a significant differ-
ence on the total index and on both pain and
function subscales. While the difference on the
total index is clearly clinically relevant, the
Cochrane review indicates that the standardized
mean difference for WOMAC pain and function
is not significant, suggesting an effect size that
might not be clinically relevant
[12]. However,
when the effect size is calculated according to the
standard formula
(Table 3), it is statistically signif-
icant for both parameters in both trials, again
with a coherence of results between the two. The
effect size is small (i.e., between 0.20 and 0.50),
but this is not surprising in long-term, 3-year,
placebo-controlled trials in patients with mild
disease characteristics. In addition, this effect size
is of the same magnitude as that of NSAIDs for
their preferential application, in other words,
over short-term treatment courses
[10].
Therefore, it confirms that glucosamine sulfate
may be an appropriate agent for the long-term
management of knee osteoarthritis.
DRUG EVALUATION – Herrero-Beaumont & Rovati
406 Future Rheumatol. (2006) 1(4)
To date, no demographic characteristics have
been identified that enable the prediction of
which patients will benefit from the administra-
tion of glucosamine sulfate. From a clinical point
of view, effective symptom modification can be
observed in patients with different baseline
severity, ranging from mild-to-moderate symp-
toms in the long-term trials
[47,48] to moderate-
to-severe in shorter studies
[43–45]. On the other
hand, the subgroup analysis of the GAIT study,
with all limitations deriving from the use of
glucosamine hydrochloride at a low unit dose,
suggests potentially higher efficacy in more
severe patient subgroups
[59].
Subanalyses from the long-term studies by
Reginster
[47] suggest that symptom modification
is achieved irrespective of baseline joint structure
damage
[63]. Conversely, structure modification
appears to be more effective in patients with
milder joint changes when treatment is
started
[64].
Clinical studies conducted with other
glucosamine formulations
The GAIT study is among the most important
trials performed with glucosamine and is the larg-
est
[59]. Its negative results have been summarized
earlier. Unfortunately, it has been conducted with
glucosamine hydrochloride at the dose of
500 mg three-times daily, specifically with a sub-
stance, formulation and dose that are different
from those of the prescription glucosamine sul-
fate used in all latest trials, and whose different
pharmacokinetic, and probably pharmacody-
namic, patterns have been discussed previously.
In addition, the high placebo response and the
diverging findings in the disease severity sub-
group analysis have raised several questions
[60],
and an opportunity has probably been lost to
clarify some of glucosamine clinical effects in a
large and independent trial
[62].
GAIT appears at least to confirm that glu-
cosamine hydrochloride given at a dose of
500 mg three-times daily might not be a pre-
ferred option, as previously suggested by
Houpt
[61]. In this latter study, a formulation and
dose of glucosamine hydrochloride, similar to
that used in GAIT, produced only limited and
nonsignificant benefit over placebo on the symp-
toms of knee osteoarthritis in a relatively small
group of 101 patients treated for 8 weeks. There-
fore, it is not known if glucosamine hydrochlo-
ride is as effective as glucosamine sulfate in the
treatment of osteoarthritis
[12].
However, three high-quality trials of glu-
cosamine sulfate have been published that were
not able to replicate the favorable effects on
symptom modification that have been described
in the previous sections of this review
[65–67]. All
these trials used dietary supplement glucosamine
sulfate preparations whose purity and stability
are not described, since these are not prescription
products. In addition, nothing is known about
the bioavailability of the active ingredient, glu-
cosamine, relative to the prescription formula-
tion: this would be an essential prerequisite of
any generic product, before any comparison can
be made with the reference standard. The lack of
this information is indeed surprising. Finally,
most of the preparations used in these trials frac-
tioned the total daily dose in two or three
administrations, and this may further decrease
the active ingredient peaks in plasma and other
biological fluids that have been demonstrated to
be effective in vitro
[30].
In a 6-month, randomized, double-blind, pla-
cebo-controlled study, Hughes and Carr tested a
glucosamine sulfate formulation never tested pre-
viously (potassium chloride glucosamine sulfate,
plus vitamin C, calcium carbonate and manga-
nese) in a small cohort of heterogenous patients
with differing knee osteoarthritis severity
[65].
Almost 50% of them were taking NSAIDs at
Table 3. Effect size of glucosamine
sulfate versus placebo on WOMAC pain
and function.
Outcome GS effect size
(95% CI)
Ref.
WOMAC pain
Reginster 0.27 (0.002–0.54) [48]
Pavelka 0.30 (0.03–0.58) [48]
Two studies pooled 0.27 (0.08–0.46)
WOMAC function
Reginster 0.32 (0.05–0.59) [47]
Pavelka 0.32 (0.04–0.60) [48]
Two studies pooled 0.31 (0.11–0.50)
Effects are calculated after 3 years in long-term trials of
Reginster [47] and Pavelka [48]. Effect sizes have been
calculated with their 95% CI according to the standard
method with bias correction by Hedges (1985), as the
difference between the mean change from baseline for
the verum and placebo groups, divided by the pooled
SD. Results are presented separately for the two studies
and, after standardizing the results on a 0–100 mm VAS,
for the two studies pooled.
CI: Confidence interval; GS: Glucosamine sulfate;
OA: Osteoarthritis; SD: Standard deviation; VAS: Visual
analog scale; WOMAC: Western Ontario and
Macmaster OA index.
www.futuremedicine.com 407
Glucosamine sulfate – DRUG EVALUATION
enrolment and were allowed to continue using
them during the study, which may also account
for the high placebo response and the lack of
difference between treatments.
In the study by McAlindon, administration
of glucosamine over 12 weeks was not superior
to placebo for symptom modification in knee
osteoarthritis
[66]. The study was entirely
conducted over the internet, and the primary
aim of the study was to determine the
feasibility of such an approach
[68]. It is not
clear how this primary aim might have inter-
fered with the added evaluation of glucosamine
effectiveness, also given the inclusive eligibility
criteria, the unbalanced randomization for
several baseline characteristics and the lack of
direct patient observation, as discussed by the
authors
[66].
Cibere and colleagues conducted a placebo-
controlled discontinuation trial in a small
group of 137 current users of glucosamine sup-
plements who had reported at least moderate
improvement in knee osteoarthritis pain
[67].
There were no differences in the incidence of
disease flare between glucosamine and placebo
over 6 months after randomization. Although
this study design is very interesting, glu-
cosamine sulfate has been described, similarly
to other symptomatic slow-acting drugs in
osteoarthritis, to produce a carry-over effect on
symptoms after both short-
[43] and long-term
clinical use
[55,56], which may confound the
assessments in a discontinuation trial. In fact,
almost 60% of patients did not relapse during
the 6-month observation period in this study.
In addition, the baseline characteristics were
imbalanced between groups, with an over-
whelming majority of male patients and a more
severe disease in the glucosamine group.
Finally, since patients were required to remain
on the dose of glucosamine that they were tak-
ing before the study, 35–40% of patients were
randomized to a dose of 1000 mg/day or less,
while all successful clinical trials have been
performed with a dose of 1500 mg of
glucosamine sulfate.
Given these limitations in study design and
the use of noncharacterized glucosamine prepa-
rations, it is not clear how this clinical trial
experience should be considered in the assess-
ment of glucosamine efficacy in osteoarthritis.
As a minimum and in agreement with the find-
ings of the Cochrane Review, it is suggested
that there may be differences in efficacy
between the prescription formulation of
crystalline glucosamine sulfate and dietary sup-
plement glucosamine preparations. Safety was
good in all these clinical studies.
Safety & postmarketing surveillance
All studies and meta-analyses have recognized the
good overall safety profile of glucosamine sulfate
and of glucosamine in general.
Table 4 reports the
proportion of patients with adverse events in the
most important short-term clinical trials and in
pivotal long-term trials of crystalline glucosamine
sulfate (with the exclusion of the GUIDE study,
whose complete results are currently unpub-
lished). Withdrawals due to adverse events, lack
of efficacy or other reasons are also reported.
There were never statistically or clinically signifi-
cant differences between glucosamine sulfate and
placebo in the incidence of adverse events or of
safety-related withdrawals. On the other hand, in
comparative trials, the incidence of adverse
events and related withdrawals was always signif-
icantly higher in the reference groups receiving
conventional NSAIDs than in the glucosamine
sulfate group, with the majority of adverse events
in the NSAID-treated patients being obviously
referred to the gastrointestinal tract.
Although at a significantly lower incidence
than with conventional NSAIDs, the low propor-
tion of adverse events with glucosamine sulfate are
related to the gastrointestinal system and consist
of mild and transient abdominal pain, nausea,
dyspepsia, diarrhea or constipation. Headache,
drowsiness and fatigue have also been reported.
Uncommon adverse events are represented by
depressed mood, vertigo and skin rash. With
regard to the latter, cross-reactions in patients with
seafood allergy are unlikely, due to the purifica-
tion process that excludes the presence of protein
residues in the starting material of sea origin.
Overall, the incidence of these adverse events
taken together is lower than 15% in the princi-
pal short-term studies, as shown in
Table 3. In the
pivotal trials of Reginster and colleagues
[47] and
Pavelka and colleagues
[48], the long-term
exposure implies a higher incidence of adverse
events, which is nevertheless identical to that of
placebo and has the same pattern as that sum-
marized above. In these long-term studies,
musculoskeletal events were also reported, but
they are probably related to the primary rheu-
matic condition. Cardiovascular events were
also common in this elderly population, but
they were not related to the study medication
and major events occurred with an incidence
similar to placebo
[69].
DRUG EVALUATION – Herrero-Beaumont & Rovati
408 Future Rheumatol. (2006) 1(4)
Glucosamine is an amino monosaccharide
that can enter the hexosamine pathway (one of
the alternative routes of glucose metabolism)
and thereby increases insulin resistance, as sug-
gested by animal experimental studies using
suprapharmacological intravenous doses of the
compound
[70]. Although this remains an area of
attention, human studies with extremely high
intravenous
[71] or even intra-arterial [72] glu-
cosamine doses indicated that such a mecha-
nism is probably not operating in humans,
where insulin sensitivity, secretion or action
were not affected. More recently, a study in
healthy volunteers with oral repeated doses of a
glucosamine sulfate formulation at 1500 mg
daily, demonstrated no changes in serum insulin
or blood glucose levels with 3-h glucose toler-
ance test
[73]. Another placebo-controlled study
showed that patients with Type 2 diabetes
receiving a glucosamine and chondroitin sulfate
combination for 3 months had no change in
their diabetes management, or in hemoglobin
A1c concentrations
[74]. Finally, fasting plasma
glucose levels were not modified in former
short-term studies with crystalline glucosamine
sulfate, as well as in the long-term trial by
Reginster
[75], while in the 3-year study by
Pavelka, four patients developed diabetes during
the study, but three were on placebo and only
one on glucosamine sulfate
[48]. Other lab-
oratory evaluations never detected significant
abnormalities in hematological or other
metabolic parameters.
Interactions with other drugs are unlikely,
since glucosamine is mainly absorbed via glucose
transporters and does not compete for general
absorption mechanisms; in addition, it is mainly
metabolized independently of the cytochrome
P450 enzyme system
[76].
Since crystalline glucosamine sulfate is a pre-
scription drug in several countries of the world,
it is subject to strict postmarketing surveillance
Table 4. Proportion of patients with adverse events and of withdrawals from crystalline glucosamine sulfate
high-quality trials of different treatment duration (see
Table 1).
Study Groups Patients with
adverse events (%)
Patients withdrawn due to Ref.
Adverse
events
(%)
Lack of
efficacy
(%)
Other
reasons
(%)
Noack Placebo (n = 126) 10.3 6.3 0.0 1.6 [44]
GS (n = 126) 6.3 4.0 0.0 2.4
p-value GS versus placebo NS NS - -
Müller-Fassbender Ibuprofen (n = 99) 35.4 7.1 1.0 4.0 [45]
GS (n = 100) 6.0 1.0 1.0 0.0
p-value GS versus ibuprofen <0.001 0.035 - -
Rovati Placebo (n = 77) 24.7 5.2 7.8 10.4 [43]
GS (n = 79) 15.2 0.0 1.3 1.3
Piroxicam (n = 86) 41.9 20.9 3.5 8.1
Combination* (n = 77) 36.4 2.6 0.0 3.9
p-value GS versus placebo NS NS - -
p-value GS versus piroxicam <0.001 <0.001 - -
p-value GS versus combination 0.003 NS - -
p-value piroxicam versus combination NS 0.003 - -
Reginster Placebo (n = 106) 93 17.0 4.7 11.3 [47]
GS (n = 106) 94 19.8 2.8 13.2
p-value GS versus placebo NS NS - -
Pavelka Placebo (n = 101) 64 9.9 5.0 30.7 [48]
GS (n = 101) 66 7.9 7.9 18.8
p-value GS versus placebo NS NS - -
Statistical analysis by the two-tailed
χ
2
or Fisher exact tests, as appropriate.
*Combination of GS plus piroxicam.
GS: Glucosamine sulfate; NS: Not significant.
www.futuremedicine.com 409
Glucosamine sulfate – DRUG EVALUATION
analysis. The latest Periodic Safety Update
Report estimates an exposure of over 14 million
patients in the period 1995–2005, with few
adverse drug reaction reports that do not modify
the good safety pattern described above.
Regulatory affairs
Crystalline glucosamine sulfate is approved as a
medicinal product, generally as a prescription
drug, for the treatment of osteoarthritis or the
symptoms of osteoarthritis in 22 countries of the
European Union and in several countries of East-
ern Europe, Asia and Latin America, totalling
56 countries.
Based on the results of clinical trials, the most
widely approved dosing regimen of the prescrip-
tion medication is 1500 mg glucosamine sulfate
once daily, given as an oral soluble powder of
crystalline glucosamine sulfate. In some coun-
tries, glucosamine-based medicinal products are
available over-the-counter in variable regimens,
often as solid oral formulations of other
glucosamine salts (e.g., hydrochloride).
In the USA, glucosamine-containing products
are considered dietary supplements beacause of
the provisions of the Dietary Supplement Health
and Education Act of 1994
[77]. This favored the
appearance on the market of different glu-
cosamine products, which are not subject to any
pharmaceutical control by the US FDA and the
authorities of the countries that adopted a similar
approach. In fact, the active ingredient content of
several of these products has recently been ques-
tioned
[78]. Whether this had an impact on the
disappointing results of some recent clinical trials
using these formulations
[65–67], together with
their problematic study design described above, is
unknown. In other trials, where pharmaceutical
grade of the dietary supplement formulation used
was assured, such as in the NIH GAIT study
[59],
other factors described above, such as the use of
previously undocumented glucosamine salts (i.e.,
hydrochloride), at different dose regimens and
with consequent differences in pharmacokinetic
and pharmacological behavior, may have played
arole.
Conclusion
Crystalline glucosamine sulfate is a specific symp-
tom-modifying drug in osteoarthritis for both
short- and long-term treatment courses, whose
use is largely supported by different high-quality
clinical trials. Two 3-year trials also suggested that
the drug has joint structure-modifying properties
and therefore might be a disease-modifying agent
and among the first-choice medications for the
management of osteoarthritis. Actually, long-term
follow-up of patients participating in the 3-year
trials hypothesized that previous treatment with
glucosamine sulfate might prevent patients’ disa-
bility and recourse to joint surgery, particularly
total knee replacement.
The clinical evidence for efficacy and safety
has been the object of rigorous systematic
reviews and meta-analyses, and resulted in the
inclusion of the drug in currently available prac-
tice guidelines. While the ACR recommenda-
tions date back to the year 2000
[6], in other
words, prior to the most intriguing new evi-
dence, and classify the compound among the
experimental agents, the EULAR guidelines for
knee osteoarthritis
[7] attribute to glucosamine
sulfate the highest level of evidence, 1A, and the
highest strength of recommendation, A, for the
management of disease symptoms, along with
only six out of the 34 pharmacological and non-
pharmacological treatment modalities consid-
ered
[7]. Conversely, the evidence at the level of
the hip is still scanty
[8].
The pharmacological events that support the
clinical effects of glucosamine sulfate in osteo-
arthritis appear to be related to the inhibition of
the IL-1 intracellular signaling pathway and, thus,
of cytokine-induced gene expression. These phar-
macological effects are achieved in vitro at drug
concentrations found in plasma and synovial fluid
of knee osteoarthritis patients after oral adminis-
tration of the standard therapeutic doses. Differ-
ences in the clinical effects with generic or dietary
supplement glucosamine hydrochloride formula-
tions may indeed be related to differences in dose
regimens and in pharmacokinetics, which may
lead to differences in the pharmacological proper-
ties. In addition, the presence of sulfates in the
prescription drug formulation, which is stabilized
according to a patented process, has also been
suggested to be important from the point of view
of favoring some of the compound pharmaco-
metabolic characteristics, which might not be
shared by glucosamine hydrochloride. Con-
versely, preparations of glucosamine sulfate, other
than the prescription formulation, manifest dif-
ferences in quality and dose regimens that would
require appropriate pharmacokinetic and
bioequivalence assessment
[78]. Since this is not
currently available, it is impossible to apply the
efficacy and safety results obtained with crystal-
line glucosamine sulfate to these other prepara-
tions and vice versa, as already noted in the recent
Cochrane review
[12].
DRUG EVALUATION – Herrero-Beaumont & Rovati
410 Future Rheumatol. (2006) 1(4)
Future perspective
Glucosamine sulfate is the first pharmacologi-
cal agent for which a combined symptom- and
structure-modifying effect has been demon-
strated in appropriate long-term clinical trials.
While this evidence is still unique within the
treatment of osteoarthritis, future studies of
new drugs should take into account this expe-
rience and the evolving technology in outcome
measurement and clinical trial performances.
Symptoms of the disease will need to be
assessed over appropriate treatment durations,
in other words, for at least 6 months and for the
duration necessary to evaluate joint structure
changes, if any. The clinical relevance of the
symptom change should be determined based
on appropriate patient-reported outcomes.
To date, joint structure-modifying activity
has been evaluated mainly by plain radiogra-
phy, quantitatively monitoring joint space nar-
rowing as a surrogate for cartilage loss and
adopting a qualitative assessment for bone
reactive changes. More recent radiographic
techniques are emerging to assess these out-
comes with more accuracy and precision, and
must be adopted in clinical trials after their
validation is completed. In the meantime,
other imaging techniques may prove more
powerful in detecting cartilage quantitative
and qualitative changes, as well as the modifi-
cations in other joint structures and tissues: the
best candidate technique in this respect is
magnetic resonance imaging.
Whichever technique is employed, changes
in joint structure should be clinically relevant
in terms of their association with favorable
symptom outcomes or by modifying the natu-
ral history of the disease. In addition, long-term
trial outcomes should focus on parameters of
patient’s disability, quality of life and disease
management. The latter should prospectively
assess a possible decrease in the recourse to sur-
gical total joint replacement, once this evalua-
tion can be standardized, and focus on
appropriate pharmacoeconomic evaluations.
Besides the general remarks above, future
studies of glucosamine sulfate might explore
the effects of the substance when administered
by the parenteral route, either systemically
(e.g., by the intramuscular route), or locally
(i.e., intra-articularly), despite the good oral
bioavailability reviewed here. In addition, the
potential of combination therapy with other
drugs, either symptomatic medications or
potential disease-modifying agents, deserves
further attention.
Finally, glucosamine sulfate has been studied
mainly in clinical trials of primary osteoarthritis.
Anecdotical evidence of efficacy in secondary
osteoarthritis, including post-traumatic disease
or sport injury and rehabilitation, has been
reported and would require confirmation in
appropriately designed studies. Given its puta-
tive mechanism of action, the potential of the
compound in the prevention of osteoarthritis
might also be investigated.
Executive summary
Chemistry
Crystalline glucosamine sulfate is the stabilized form of glucosamine sulfate, specifically, the glucosamine salt used as a
prescription drug in osteoarthritis.
Glucosamine, sulfate, chloride and sodium ions are present in stoichiometric ratios of 2:1:2:2.
Other glucosamine salts (e.g., hydrochloride) and substances are widely used as dietary supplements, and may not share the
same properties.
Mechanisms of action
•Different in vitro studies demonstrated that glucosamine sulfate has both anabolic properties (stimulating the synthesis of
proteoglycans) and anticatabolic activities (inhibiting the effects of enzymes, such as metalloproteases).
However, the mere incorporation of the aminosugar in glycosaminoglycans and stimulation of their synthesis as a simple building
block is unlikely, due to the high concentrations required.
The substance mechanism of action appears to be rather due to glucosamine-induced reversal of the pro-inflammatory and
joint-degenerating effects of interleukin (IL)-1.
This effect is probably accomplished by inhibition of the cytokine intracellular signaling patway, namely of the activation of
nuclear factor (NF)-κB.
Indeed, glucosamine sulfate inhibits IL-1-stimulated gene expression of cyclooxygenase (COX)-2, inducible nitric oxide synthase
(iNOS), cytokines and metalloproteases at glucosamine concentrations found in human plasma (10 µM) and synovial fluid after
administration of glucosamine sulfate at standard oral doses.
Sulfate may contribute to the mechanism of action of glucosamine sulfate, overcoming a possible deficiency in inorganic sulfur in
the elderly. This provides an additional mechanism compared with other glucosamine salts (e.g., hydrochloride), besides a possibly
different pharmacokinetic behavior.
www.futuremedicine.com 411
Glucosamine sulfate – DRUG EVALUATION
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The terminal elimination half-life from human plasma is approximately 15 h.
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Safety & tolerability
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In comparative trials, safety was significantly better than that of conventional NSAIDs.
The low proportion of adverse events consists mainly of mild and transient episodes of abdominal pain, nausea, dyspepsia, diarrhea,
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Cross-reactions in patients with seafood allergy are unlikely, owing to the purification process that eliminates protein residues in the
starting material of sea origin.
Human studies failed to demonstrate an effect on glucose metabolism, although this remains an area of attention due to the possible
interaction with the hexosamine pathway.
Glucosamine sulfate is not expected to interact with other drugs (with rare exceptions), as it does not interfere with general absorption
mechanisms and is not metabolized by the cytochrome P450 system.
Dosage & administration
The most widely studied and approved prescription formulation is available as sachets of oral soluble powder of crystalline
glucosamine sulfate, equivalent to 1500 mg glucosamine sulfate, to be administered once daily.
Executive summary
DRUG EVALUATION – Herrero-Beaumont & Rovati
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Affiliations
Gabriel Herrero-Beaumont, MD
Autonomous University of Madrid,
Rheumatology Department, Fundación Jiménez
Díaz-Capio, Avenida Reyes Católicos 2, 28040
Madrid, Spain
Tel.: +34 915 504 918;
Fax: +34 915 494 764;
gherrero@fjd.es
Lucio C Rovati,
MD
Clinical Pharmacology Department,
Rottapharm, Monza, Italy
Tel.: +39 039 739 0318;
Fax: +39 039 739 0371;
lucio.rovati@rotta.com
... Наиболее солидную доказательную базу имеет глюкозамин [17] -моносахарид и естественный компонент ГАГ суставного матрикса и синовиальной жидкости. Глюкозамин оказывает специфическое влияние на остеоартритический хрящ и стимулирует синтез хондроцитами полноценного экстрацеллюлярного матрикса, прежде всего, наиболее важной его составляющей -протеогликанов -и гиалуроновой кислоты (табл. ...
... Глюкозамин синтезируется из хитина морского происхождения и содержит несколько солей [17]. Применяются две его соли -сульфат и гидрохлорид. ...
... Во всех протоколах исследований и метаанализах не было статистических или клинически значимых различий количества и выраженности нежелательных явлений при приеме глюкозамина по сравнению с плацебо. В то же время в сравнительных исследованиях НПВП чаще вызывали нежелательные явления, чем глюкозамин [17]. Метаанализ рандомизированных контролируемых испытаний показал, что наиболее часто встре- ...
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Glucosamine sulfate, or hydrochloride, and chondroitin sulfate are natural components of cartilaginous intercellular substance. In osteoarthrosis (OA), they exert a pronounced symptom-modifying effect and, when used long, they can also inhibit the X-ray progression of OA. The combination drugs that comprise glucosamine and chondroitin have some advantage over each component. These agents include teraflex. The efficacy of these pharmacological agents seems to be associated with their anti-inflammatory properties rather than with the stimulated synthesis of cartilaginous matrix.
... The subject of GlcN.S as a nutraceutical has been reviewed by Aghazadeh-Habashi and Jamali (2011), Anderson, Nicolosi, and Borzelleca (2005), Deal and Moskowitz (1999), Herrero-Beaumont and Rovati (2006), Ibrahim, Gilzad-Kohan, Aghazadeh-Habashi, and Jamali (2012), Kean and Thanou (2010), Laverty, Sandy, Celeste, Vachon, Marier, and Plaas (2005), Matheson and Perry (2003), Muzzarelli (2006), Noak et al. (1994), Tamai et al. (2002), Towheed (2003), and Welch et al. (2012), among others. ...
... Crystalline GlcN.S (Dona ® , Viartil ® , Arthryl ® , Xicil ® and other trademarks of Rottapharma, Italy) is a pure substance in which the monosaccharide is present in stoichiometric ratios of 2:1:2:2 with sulphate, chloride and sodium ions respectively; this patented combination confers stability to the preparation (Grant & Gracy, 2000;Herrero-Beaumont & Rovati, 2006). GlcN.S is considered a specific drug for osteoarthritis, effective for relief of symptoms as NSAIDs, but much better tolerated (Qiu, Gao, Giacovelli, Rovati, & Setnikar, 1998). ...
... Moreover, the NaCl salt present in the GlcN.S formulation is approximately 21% by weight, thus the administration of 1500 mg of product carries 315 mg of NaCl that, although it increases the daily intake of salt, does not seem to be a quantity capable to influence blood pressure and renal function (Herrero-Beaumont & Rovati, 2006). ...
Article
Oral supplementation of chondroitin sulphate plus glucosamine helps repair the articular surface in osteoarthritis. Chondroitin-S reduces the concentration of the pro-inflammatory cytokines and transcription factor involved in inflammation. GlcN.S enhances cartilage specific matrix components and prevents collagen degeneration in chondrocytes by inhibiting hydrolytic enzymes, and preventing the oxidation of lipids and proteins. Chondroitin-S plus GlcN.S are slow-acting drugs that alleviate pain and partly restore joint function in OA patients. Orally administered pharmaceutical-grade chondroitin-S plus GlcN.S stabilize the joint space narrowing and significantly decrease the number of patients with new erosive OA. They are safe and no adverse events have ever been reported; they are recommended by EULAR and OARSI. The cost/effectiveness of the oral chondroitin-S plus GlcN.S therapy derives from the reduction of costs for physiotherapy, and for gastroprotective and non-steroidal drugs. The synergistic association of these two world-widely preferred nutraceuticals is a step forward in the management of OA.
... The subject of GlcN.S as a nutraceutical has been reviewed by Aghazadeh-Habashi and Jamali (2011), Anderson, Nicolosi, and Borzelleca (2005), Deal and Moskowitz (1999), Herrero-Beaumont and Rovati (2006), Ibrahim, Gilzad-Kohan, Aghazadeh-Habashi, and Jamali (2012), Kean and Thanou (2010), Laverty, Sandy, Celeste, Vachon, Marier, and Plaas (2005), Matheson and Perry (2003), Muzzarelli (2006), Noak et al. (1994), Tamai et al. (2002), Towheed (2003), and Welch et al. (2012), among others. ...
... Crystalline GlcN.S (Dona ® , Viartil ® , Arthryl ® , Xicil ® and other trademarks of Rottapharma, Italy) is a pure substance in which the monosaccharide is present in stoichiometric ratios of 2:1:2:2 with sulphate, chloride and sodium ions respectively; this patented combination confers stability to the preparation (Grant & Gracy, 2000;Herrero-Beaumont & Rovati, 2006). GlcN.S is considered a specific drug for osteoarthritis, effective for relief of symptoms as NSAIDs, but much better tolerated (Qiu, Gao, Giacovelli, Rovati, & Setnikar, 1998). ...
... Moreover, the NaCl salt present in the GlcN.S formulation is approximately 21% by weight, thus the administration of 1500 mg of product carries 315 mg of NaCl that, although it increases the daily intake of salt, does not seem to be a quantity capable to influence blood pressure and renal function (Herrero-Beaumont & Rovati, 2006). ...
Article
Oral supplementation of chondroitin sulphate plus glucosamine helps repair the articular surface in osteoarthritis. Chondroitin-S reduces the concentration of the pro-inflammatory cytokines and transcription factor involved in inflammation. GlcN.S enhances cartilage specific matrix components and prevents collagen degeneration in chondrocytes by inhibiting hydrolytic enzymes, and preventing the oxidation of lipids and proteins. Chondroitin-S plus GlcN.S are slow-acting drugs that alleviate pain and partly restore joint function in OA patients. Orally administered pharmaceutical-grade chondroitin-S plus GlcN.S stabilize the joint space narrowing and significantly decrease the number of patients with new erosive OA. They are safe and no adverse events have ever been reported; they are recommended by EULAR and OARSI. The cost/effectiveness of the oral chondroitin-S plus GlcN.S therapy derives from the reduction of costs for physiotherapy, and for gastroprotective and non-steroidal drugs. The synergistic association of these two world-widely preferred nutraceuticals is a step forward in the management of OA.
... The more important steps that the conversion of chitin to the primary glucosamine by de-N-acetylation/ hydrolyzation of chitin (B) enzymatic crystallization of GlcNAc to obtained the chitin (C) [67]. The biodegradation of biomass is accessed to obtain the necessary intermediate compounds of GlcN-6-P [71][72][73][74][75][76][77][78]. Similarly, procedure B is carried out by deacetylation-hydrolyzation method scheme 6. ...
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The enzymatic modification of glucosamine (GlcN) and its derivatives have a keen interest for researchers due to the natural abundance of its bio-sourced such as chitin. The recent progress for understanding the role of glucosamine based on various novel approaches for enzymatic synthesis in the field of medicinal chemistry and food supplements. These developments led to improve chemo-selective protection and/or deprotection of amino-sugar during chain enhancement and allow the simultaneous regioselective reaction of functionally relevant acetyl, phosphate, or sulfate groups. In this review, we give an overview of current strategies on the synthesis of therapeutically relevant glucosamine containing derivatives.
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Objective The present work was led by a multidisciplinary panel of experts and proposes an extensive review on the use of prescription crystalline glucosamine sulfate (pCGS) in the multimodal treatment of osteoarthritis (OA) applicable in Ukraine and other Commonwealth of Independent States (CIS) countries. Methods A panel of rheumatologists, orthopedic surgeons, and field experts from Ukraine and CIS regions discussed the management of OA. Literature was systematically searched using Medline, EMBASE, CIHNAL, and Cochrane Library databases. The 2-day meeting critically reviewed the available literature, treatment algorithms, pharmacoeconomic aspects, and real-world instances to form a multimodal approach based both on real-life clinical practice and systematic literature research for the management of OA in Ukraine and CIS countries. Expert Opinion pCGS plays a pivotal role in the stepwise approach to OA treatment. If it is necessary (step 1), the combined use of pCGS with paracetamol and topical nonsteroidal anti-inflammatory drugs (NSAIDs) has been recommended. If symptoms persist, oral NSAIDs and intra-articular (IA) hyaluronic acid or corticosteroids are added to the therapy (step 2) of pCGS in the patients. In case of insufficient relief and severe OA (step 3), pCGS along with oral NSAIDs, IA corticosteroids, and duloxetine have been recommended. Patient stratification with regular monitoring and careful alterations in treatment were advocated. Conclusions This expert opinion article recommends a modified approach to the existing guidelines incorporating pCGS in treatment modality of OA in Ukraine and CIS countries. Extensive use of pCGS targets early symptomatic relief in OA while limiting the adverse effects due to long-term use of analgesics and NSAIDs.
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Objectives: To evaluate the efficacy and safety of combined glucosamine and chondroitin (GC) in the treatment of knee osteoarthritis (OA). Methods: Randomized, double-blind, placebo-controlled trial. Patients with knee OA and total Lequesne scores (Leqt) between 5 and 13 and Kellgren-Lawrence grades 2 or 3 were randomized to a 12-week treatment with combined glucosamine sulfate (1,5g) and chondroitin sulfate (1,2g) or placebo, followed by a 12-week follow-up period. Paracetamol was used as recue medication. Results: A reduction of mean Leqt was present in both treatment groups, which was more evident in those patients receiving GC. The difference between both treatment groups was apparent on week 4 and increased up to the end of the treatment, although not reaching statistical significance (p = 0,1643 and p = 0,0681 for intend-to-treat [ITT] and per-protocol [PP] populations, respectively). Paracetamol use was significantly higher by placebo patients in ITT (p = 0,0394) and PP (0,0257) populations. GC patients showed lower Leqt scores during the follow-up period versus placebo (p = 0,1061 and p =0,0494 for ITT and PP populations, respectively). Mean Leqt started to increase immediately after the end of the treatment only in placebo group, while an additional reduction was observed in GC group, which highlighted the residual therapeutic effect of the combination. Both treatment groups were similar regarding adverse events reporting. Conclusions: The results were consistent regarding the effectiveness of the combination GC, which showed to be safe and well tolerated.
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The paper presents the current views of the effects of nonsteroidal anti-inflammatory drugs on the mechanisms of development of inflammation in osteoarthrosis and their action on the metabolism of chondrocytes and extracellular substance of the articular cartilage. It also gives the results of numerous studies of the efficacy and safety of meloxicam in osteoarthrosis and the data supporting its chondroprotective properties
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The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents, which are generally effective only for acute symptom relief. Compounds are under investigation that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar short-term symptomatic effect, but also control disease progression in the long term. Glucosamine sulphate (CAS 29031-19-4) reverses the proinflammatory and joint-degenerating effects of interleukin-1 by inhibiting the cytokine intracellular pathway. Clinical trials with the crystalline glucosamine sulphate formulation (CGS; dona) approved as a medicinal drug, predominantly used at the oral dose of 1,500 mg once daily, demonstrated a specific symptom-modifying effect on knee osteoarthritis over short- and long-term treatment courses. Two 3-year trials suggested that the drug also has joint structure-modifying properties and, therefore, might be useful as a disease-modifying agent in osteoarthritis.