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Current Therapeutic Research
V , N , J
185
Accepted for publication May 21, 2009. doi:10.1016/j.curtheres.2009.05.004
© 2009 Excerpta Medica Inc. All rights reserved. 0011-393X/$ - see front matter
The Efficacy and Tolerability of Glucosamine Sulfate in
the Treatment of Knee Osteoarthritis: A Randomized,
Double-Blind, Placebo-Controlled Trial
Nicola Giordano, MD
1
; Antonella Fioravanti, MD
2
; Panagiotis Papakostas, MD
1
;
Antonio Montella, MD
1
; Giorgio Giorgi, MD
3
; and Ranuccio Nuti, MD
1
1
Department of Internal Medicine, University of Siena, Siena, Italy;
2
Rheumatology Unit,
Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena,
Italy; and
3
Department of Pharmacology Giorgio Segre, University of Siena, Siena, Italy
ABSTRACT
Background: Osteoarthritis (OA) is the most common form of arthritis and is
often associated with disability and impaired quality of life.
Objective: The aim of the study was to assess the efficacy and tolerability of
glucosamine sulfate (GS) in the treatment of knee OA.
Methods: Consecutive outpatients affected by primary monolateral or bilateral
knee OA were enrolled in this double-blind, double-dummy, prospective, randomized,
placebo-controlled trial. One group received GS 1500 mg QD for 12 weeks, and the
other group received placebo QD for 12 weeks. The treatment period was followed by a
12-week treatment-free observation phase. Each patient was examined at baseline and
at weeks 4, 8, 12, 16, 20, and 24. The primary efficacy criteria were pain at rest and dur-
ing movement, assessed on a visual analog scale (VAS) of 0 to 100 mm. The secondary
criteria included the Western Ontario and McMaster Universities (WOMAC) index
for total pain score (W-TPS), total stiffness score (W-TSS), and total physical function
score (W-TPFS). VAS, W-TPS, W-TSS, and W-TPFS were evaluated at baseline and
at weeks 4, 8, 12, 16, 20, and 24. Analgesic drug consumption (ie, acetaminophen or
NSAIDs) was also assessed.
Results: Patient demographics were similar in the GS and placebo groups.
Of 60 randomized patients (30 per group), 56 completed the study (28 treated with
GS and 28 who received placebo). Statistically significant improvements in symptom-
atic knee OA were observed, as measured by differences in resting pain at weeks 8, 12,
and 16 (all, P < 0.05 vs placebo) and in pain during movement at weeks 12 and 16
(both, P < 0.05). W-TPS was lower with GS than placebo at weeks 8, 12, and 16 (all,
P < 0.01), and at week 20 (P < 0.05). W-TSS was also lower with GS than placebo at
weeks 8, 12, 16, and 20 (all, P < 0.05). W-TPFS was lower with GS than placebo at
weeks 8 (P < 0.05), 12 (P < 0.01), 16 (P < 0.05), and 20 (P < 0.05). Drug consump-
tion was lower in the GS group than the placebo group at weeks 8, 12, 16, and
20 (all, P < 0.05). The incidence of adverse events was 36.7% with GS and 40.0%
with placebo.
Current Therapeutic Research
186
Conclusions: GS 1500 mg QD PO for 12 weeks was associated with statisti-
cally significant reductions in pain and improvements in functioning, with decreased
analgesic consumption, compared with baseline and placebo in these patients with
knee OA. A carryover effect was detected after treatment ended. (Curr Ther Res Clin
Exp. 2009;70:185–196) © 2009 Excerpta Medica Inc.
Key words: glucosamine sulfate, knee osteoarthritis, efficacy, carryover effect,
tolerability.
INTRODUCTION
Osteoarthritis (OA) is the most frequently encountered condition in rheumatology
practice, and its prevalence is rising because of the general population’s increasing life
span.
1
Current treatment of OA includes both nonpharmacologic and pharmacologic
modalities.
2
Pharmacologic therapy has been largely confined to analgesics or NSAIDs
or selective cyclooxygenase-2 (COX-2) inhibitors (coxibs). However, the use of NSAIDs
is limited by their negative side effects on the gastrointestinal tract and on cartilage
metabolism,
3,4
and the use of coxibs is associated with an increase in cardiovascular
adverse events (AEs).
5,6
Acetaminophen is better tolerated than NSAIDs and coxibs
but does not always provide adequate pain relief.
7,8
Studies have been performed to
identify agents able to prevent, delay, or stabilize the pathologic changes that occur
in OA joints, thereby limiting disease progression.
9–11
These drugs have been classi-
fied as disease-modifying or structure-modifying OA drugs.
12,13
Glucosamine sulfate
(GS) is a structure-modifying aminomonosaccharide, acting as a preferred substrate
for the biosynthesis of glycosaminoglycan chains and, subsequently, for the produc-
tion of aggrecan and other proteoglycans of the articular cartilage.
14,15
Moreover, GS
stimulates the synthesis of cartilage matrix and inhibits the activity of catabolic en-
zymes, including metalloproteinases.
16,17
In OA animal models, GS is reported to
reduce the severity of cartilage histologic lesions and synovial inflammation.
18
Several
GS actions can be explained on the basis of the inhibition of nuclear factor LB activa-
tion, induced by interleukin-1β, and, consequently, of the transcription of several
genes regulating the synthesis of cytokines, chemokines, adhesion molecules, and
enzymes (eg, COX-2, inducible nitric oxide synthase, metalloproteinases); all of these
agents are associated with synovial inflammation and cartilage disruption in OA.
19,20
Several clinical trials of treatments for OA have reported significant symptomatic
effects and a positive tolerability profile for GS.
21–25
The effects of GS are supported by data from 2 long-term (ie, 3-year), randomized,
controlled, double-blind studies in patients with knee OA treated with GS 1500 mg
QD PO
26,27
; however, more recent studies had dissimilar results.
28,29
The aim of the
present study was to prospectively evaluate the efficacy and tolerability of GS, in
comparison with placebo, in the treatment of patients with symptomatic knee OA.
PATIENTS AND METHODS
This was a prospective, randomized, double-blind, double-dummy, placebo-controlled
trial. The study protocol followed the principles of the Declaration of Helsinki and
187
N. Giordano et al.
was approved by the ethics committee of the University of Siena’s hospital. Consecu-
tive outpatients of both sexes who were diagnosed with primary monolateral or bilat-
eral knee OA and met the American Rheumatism Association criteria
30
were enrolled
in the study from February to September 2007. The patients were studied at the De-
partment of Internal Medicine of the University of Siena. To be eligible, patients had
to be symptomatic for ≥3 months before enrollment and have a radiologic grade
between I and III, as measured with the Kellgren-Lawrence method.
31
Exclusion cri-
teria were hematologic disorders, renal disease, liver disease, diabetes mellitus, acute
illness, neoplasms, other rheumatic diseases, disabling comorbid conditions that would
make it impossible for the patient to visit the research center, pregnancy or nursing,
and a body mass index >30 kg/m
2
. The exclusion criteria were confirmed clinically
and, if necessary, by laboratory and instrumental findings. Patients with grade-IV OA
(Kellgren-Lawrence) and those who had had joint lavage, arthroscopy, or treatment
with hyaluronic acid or other disease-modifying agents during the previous 6 months,
or who had been treated with intra-articular corticosteroids during the past 3 months,
were excluded from the study.
Having satisfied the screening criteria and after signing an informed consent form,
patients were randomized 1:1 to 2 groups using a computer-generated table of ran-
dom numbers. One group received GS 1500 mg QD for 12 weeks as sachets of powder
for oral solution; the other group received a double-dummy placebo formulation that
was identical in look, taste, and smell to the active medication but contained only
inactive excipients; this placebo was administered at the same time and for the same
duration as the active study drug. Placebo and active drugs were prepared by the labo-
ratory of the Department of Pharmacology Giorgio Segre of the University of Siena.
Double-blinding conditions were successfully achieved for all patients. Twelve weeks
later, patients discontinued the drug or placebo intake, but remained under clinical
observation for the following 12 weeks to evaluate a possible GS carryover effect.
For the duration of the study, it was recommended that patients not modify their
therapeutic program (for both drug treatments and physical therapy) unless an AE
occurred and required management. In particular, they were instructed to avoid cor-
ticosteroids and hyaluronic acid infiltrations, arthroscopic surgery, and joint lavage,
and to avoid treatment with disease-modifying OA drugs. These recommendations were
verified by anamnesis and clinical evaluation of the patients at each visit. Violation of the
protocol was cause for exclusion. For rescue analgesia, patients were allowed acetamino-
phen 500 mg, diclofenac 150 mg, piroxicam 20 mg, naproxen 750 mg, or aceclofenac
200 mg, all of which were to be used as needed and noted daily in a diary.
All patients underwent general medical evaluation and rheumatologic examination
by the same physician before the start of the study. For patients with bilateral OA, the
most compromised knee was used as the reference. All demographic, anamnestic, and
clinical data were collected using a standardized questionnaire.
Each patient was examined at baseline and at weeks 4, 8, 12, 16, 20, and 24 after
randomization. All patients were examined and underwent masked assessment by the
same physician at the Department of Internal Medicine. Following the Osteoarthritis
Research Society International guidelines,
32
clinical assessments at each examination
Current Therapeutic Research
188
included: pain at rest and pain with movement on a visual analog scale (VAS) of 0 to
100 mm, with 0 representing the absence of pain; Western Ontario and McMaster
Universities (WOMAC) index for knee OA,
33,34
measured as total pain score (W-TPS),
total stiffness score (W-TSS), and total physical function score (W-TPFS); and analge-
sic or NSAID consumption, reported in a daily diary given to each patient, calculated
by daily values for 4 weeks.
All patients underwent the following biochemical analyses at baseline and weeks
4, 8, and 12: erythrocyte sedimentation rate; C-reactive protein; serum glucose levels;
creatinine; complete blood count; electrolytes; aspartate and alanine aminotransferases;
and urinalysis.
Treatment tolerability was assessed by recording AEs reported by the patients in a
daily diary or observed by the physician at each clinic visit. The diary was handed to the
investigators at the end of the study, and serious AEs were to be immediately reported;
therefore, patients with serious AEs were immediately removed from the trial.
Statistical Analysis
Power analysis (α = 0.05; C = 0.80) determined that a sample size of 20 patients in
each group was needed to detect a decrease ≥15, with an SD of 20, in VAS score at week
12 of the study. Thirty patients were enrolled per group to allow for dropouts.
Regarding statistical analysis, response to treatment was analyzed for all patients
who entered the randomized trial (intent-to-treat analysis). According to the protocol,
the last-observation-carried-forward approach was used for patients who did not com-
plete the study. All parameters of this study were reported as mean (SD) values. For
all tests, P < 0.05 was considered to be statistically significant. The t or χ
2
test was
used to demonstrate the homogeneity of the baseline variables between the 2 groups.
To evaluate whether there was any overall effect of GS therapy compared with placebo
over time, a 2-way analysis of variance for repeated measures was performed, with the
clinical assessments (VAS, W-TPS, W-TSS, W-TPFS, and NSAID/analgesic consump-
tion) as dependent variables and group allocation (GS or placebo) and time (baseline
and weeks 4, 8, 12, 16, 20, and 24) as factors. Post hoc analyses were performed with
a Bonferroni correction when necessary. The χ
2
test was used to compare percentages
of AEs. For all statistical analyses, SAS version 9.0 (SAS Institute Inc., Cary, North
Carolina) was used.
RESULTS
Sixty patients satisfied the eligibility criteria and were included in the study (Figure).
Baseline comparison of the GS and placebo groups showed no statistically significant
differences in demographics, clinical characteristics, or radiologic features (Table I).
No statistically significant differences in NSAID and analgesic intake were noted
between groups at baseline (Table I). Furthermore, at baseline, all biochemical pa-
rameters were in normal ranges for all patients. Two subjects (6.7%) in each group
withdrew from the study. In the GS group, 1 patient (3.3%) withdrew because of
heartburn that developed 2 weeks after treatment initiation, and another (3.3%) with-
drew because of a diffuse itch that developed in the first week of treatment (Figure).
189
N. Giordano et al.
In the placebo group, 1 subject (3.3%) withdrew because of constipation that devel-
oped during the first week of treatment, and the other (3.3%) for reported drug in-
effectiveness during the fourth week (Figure).
Table II compares the differences in the efficacy outcome parameters between pa-
tients receiving GS and those receiving placebo. VAS pain scores were significantly
lower with GS than placebo during rest at weeks 8, 12, and 16, and during motion at
Population screened
(N = 92)
Randomized
(n = 60)
Not included because:
Inclusion criteria not met (n = 20)
Exclusion criteria met (n = 12)
Allocated to GS
(n = 30)
Analyzed
(n = 30)
Lost to follow-up (n = 2)
1 Week (n = 1)
2 Weeks (n = 1)
Analyzed
(n = 30)
Allocated to placebo
(n = 30)
Lost to follow-up (n = 2)
1 Week (n = 1)
4 Weeks (n = 1)
Figure. Flow diagram of a double-blind, double-dummy, prospective, randomized, placebo-
controlled trial of glucosamine sulfate (GS) 1500 mg QD PO or placebo QD PO for
12 weeks in patients with osteoarthritis of the knee.
Current Therapeutic Research
190
weeks 12 and 16 (all, P < 0.05). W-TPS was significantly lower with GS than placebo
at weeks 8, 12, and 16 (all, P < 0.01) and at week 20 (P < 0.05). W-TSS was signifi-
cantly lower with GS than placebo at weeks 8, 12, 16, and 20 (all, P < 0.05). W-TPFS
was lower with GS than placebo at weeks 8 (P < 0.05), 12 (P < 0.01), 16 (P < 0.05),
and 20 (P < 0.05). NSAID and analgesic consumption was lower with GS than pla-
cebo at weeks 8, 12, 16, and 20 (all, P < 0.05).
Regarding VAS, a statistically significant decrease baseline in pain during rest was
observed within the GS group at week 8 (P < 0.05), weeks 12 and 16 (both, P < 0.001),
and week 20 (P < 0.05) (Table II). Moreover, in the GS group, pain during movement
decreased significantly from baseline at weeks 12 and 16 (both, P < 0.05). With GS,
W-TPS and W-TPFS were significantly lower than baseline at weeks 8 (both, P < 0.05),
12 (both, P < 0.001), 16 (W-TPS, P < 0.001; W-TPFS, P < 0.05), and 20 (both,
P < 0.05). W-TSS was significantly lower from baseline at weeks 8, 12, 16, and
20 (all, P < 0.05). No statistically significant differences from baseline were observed
at any time point for VAS values, W-TPS, W-TPFS, or W-TSS in the placebo group.
NSAID and analgesic consumption decreased in the GS group at weeks 4, 8, 12,
and 16 (all, P < 0.05). NSAID and analgesic consumption did not change signifi-
cantly from baseline at any time point in the placebo group (Table II).
The rates of the most commonly occurring AEs did not significantly differ between
groups. Table III shows the type and frequency of the most common AEs that occurred
during the treatment period. AEs were reported in 11 patients (36.7%) in the GS group
and 12 patients (40.0%) in the placebo group. Two patients (6.7%) receiving GS and
2 patients (6.7%) receiving placebo experienced >1 AE; all of these patients experienced
Table I. Demographic and baseline clinical characteristics of patients with osteoarthritis
of the knee who were randomized to receive glucosamine sulfate (GS) 1500 mg
QD PO or placebo QD PO for 12 weeks, based on the intent-to-treat analysis
(n = 30 in each group).
Variable GS Placebo
Age, mean (SD), y 57.2 (7.2) 58.09 (8.3)
Sex, no. (%)
Female 21 (70.0) 21 (70.0)
Male 9 (30.0) 9 (30.0)
White race, no. (%) 30 (100.0) 30 (100.0)
Body mass index, mean (SD), kg/m
2
22 (7.1) 23 (6.0)
Disease duration, mean (SD), y 6.2 (4.8) 6.4 (4.7)
Kellgren-Lawrence score of disease severity, no. (%)
I 3 (10.0) 3 (10.0)
II 12 (40.0) 12 (40.0)
III 15 (50.0) 15 (50.0)
Previous NSAID/acetaminophen intake, no. (%) 20 (66.7) 19 (63.3)
191
N. Giordano et al.
Table II. Efficacy results in patients with osteoarthritis of the knee who were randomized to receive glucosamine sulfate (GS)
1500 mg QD PO or placebo QD PO for 12 weeks, based on the intent-to-treat analysis (n = 30 in each group). Values
are given as mean (SD).
Measure Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Resting pain on VAS
GS 42.0 (24.2) 38.32 (21.6) 30.01 (20.0)*
†
25.4 (19.9)
†‡
28.32 (20.9)
†‡
33.27 (20.6)* 40.38 (23.2)
Placebo 40.89 (23.6) 41.15 (22.3) 40.53 (21.9) 41.0 (20.5) 41.82 (23.0) 42.00 (21.3) 41.33 (22.3)
Moving pain on VAS
GS 70.10 (17.3) 68.49 (18.0) 60.03 (18.4) 59.38 (19.3)*
†
60.19 (20.0)*
†
65.24 (20.8) 70.22 (21.3)
Placebo 71.96 (18.4) 71.58 (19.0) 70.83 (19.0) 70.2 (20.4) 71.33 (19.3) 70.25 (20.0) 71.69 (19.4)
W-TPS
GS 51.2 (8.3) 48.80 (9.0) 40.32 (10.4)*
§
30.56 (11.5)
‡§
31.85 (12.4)
‡§
41.22 (13.9)*
†
47.75 (14.5)
Placebo 50.03 (6.4) 51.35 (6.8) 52.23 (6.9) 53.3 (7.1) 52.81 (6.7) 51.75 (6.5) 51.05 (6.7)
W-TSS
GS 49.0 (3.1) 47.81 (3.4) 38.25 (4.0)*
†
35.65 (4.1)*
†
37.34 (3.8)*
†
38.42 (3.9)*
†
47.78 (3.3)
Placebo 47.93 (2.3) 46.92 (2.5) 47.08 (3.0) 48.0 (3.3) 48.51 (3.2) 47.53 (3.4) 48.03 (3.3)
W-TPFS
GS 52.16 (12.3) 47.89 (12.4) 40.85 (12.9)*
†
32.82 (13.2)
‡§
41.21 (14.2)*
†
43.11 (13.8)*
†
51.85 (12.5)
Placebo 53.94 (14.1) 54.21 (14.4) 54.30 (14.7) 55.1 (14.9) 53.98 (14.2) 54.11 (14.0) 53.27 (14.0)
Daily NSAID/analgesic
consumption
GS 12.10 (3.9) 8.20 (2.8)* 7.80 (2.9)*
†
6.60 (3.1)*
†
7.6 5 (2 . 8)*
†
8.30 (2.8)
†
9.75 (3.1)
Placebo 11.90 (3.1) 9.80 (2.9) 10.40 (2.8) 10.30 (2.8) 10.85 (2.8) 11.60 (2.9) 12.25 (2.9)
VAS = visual analog scale of 0 to 100 mm; W-TPS = Western Ontario and McMaster Universities (WOMAC) index for total pain score; W-TSS = WOMAC
index for total stiffness score; W-TPFS = WOMAC index for total physical function score.
*P < 0.05 versus baseline.
†
P < 0.05 versus placebo.
‡
P < 0.001 versus baseline.
§
P < 0.01 versus placebo.
Current Therapeutic Research
192
2 events. Serious AEs occurred in 2 patients (6.7%) from the GS group and 1 patient
(3.3%) from the placebo group; therefore, they were withdrawn from the study.
DISCUSSION
The results of this study suggest that GS is associated with statistically significant
improvements in symptomatic knee OA as measured by changes in pain, stiffness, and
function compared with baseline and placebo. However, the clinical significance of
these small changes is not known and requires further research.
Results of previous research suggest that GS, unlike NSAIDs, is not appropriate for
short-term analgesia, but is suitable for medium- to long-term management of knee
OA, producing global clinical improvements.
22,25,35
The structural effects of the drug
on OA were confirmed by our study because most of the reductions in pain and im-
provements in functioning appeared to persist after therapy ended. In fact, once study
treatment was stopped, the symptomatic benefits observed at the end of treatment in
the GS group persisted for an additional 6 to 8 weeks, indicating a carryover effect.
No published studies on knee OA have described any other molecule with a similar
carryover effect. The observed carryover effect may be related to reports that GS stimu-
lates the anabolic activities of cartilage and inhibits the catabolic enzymes and inflam-
matory mediators that are responsible for articular OA damage.
14–16,19,20
The reduction in NSAID or analgesic consumption noted in the GS group supports
the drug’s efficacy. This decrease reached statistical significance at 4 weeks after thera-
py began, continued for the remainder of treatment duration, and lasted for 8 weeks
after treatment cessation.
Our results are not consistent with those of the recent multicenter, double-blind,
placebo- and active-controlled Glucosamine/chondroitin Arthritis Intervention Trial
Table III. Type and frequency of adverse events in patients with
osteoarthritis of the knee who were randomized to receive
glucosamine sulfate (GS) 1500 mg QD PO or placebo QD PO
for 12 weeks, based on the intent-to-treat analysis (n = 30
in each group). Data are no. (%).
Adverse Event GS Placebo
Any event 11 (36.7) 12 (40.0)
Musculoskeletal pain 5 (16.7) 4 (13.3)
Flu syndrome 2 (6.7) 3 (10.0)
Constipation 2 (6.7) 4 (13.3)
Headache 1 (3.3) 2 (6.7)
Diarrhea 1 (3.3) 1 (3.3)
Itch 1 (3.3) –
Heartburn 1 (3.3) –
193
N. Giordano et al.
(GAIT)
28
for the treatment of pain in 1583 patients randomly assigned to receive
1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both gluco-
samine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks.
In GAIT, the primary outcome measure was a 20% decrease in knee pain from base-
line to week 24. The glucosamine hydrochloride 500 mg TID failed to show a signifi-
cant difference in efficacy versus placebo over a 6-month treatment period. However,
glucosamine hydrochloride produces glucosamine plasma levels at least 3 times lower
than those achieved by GS 1500 mg QD
36–38
; therefore, its pharmacologic effects may
be reduced. Furthermore, sulfates may play a role in the mechanism of action of glu-
cosamine.
39
Regarding the recent study by Rozendaal et al,
29
we believe that it is not
possible to apply their conclusions to other settings (such as the present trial) because
their study evaluated GS efficacy in 222 patients affected by hip OA who underwent
2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily.
Future research should study the efficacy of GS in systemic OA.
GS treatment was well tolerated in this study. The type and frequency of AEs were
similar between the GS and placebo groups, and they were generally of minor clinical
significance. Only 2 patients (6.7%) in the GS group and 1 patient (3.3%) in the
placebo group experienced serious AEs (heartburn and itch in the GS group, and con-
stipation in the placebo group) that resulted in their withdrawal from the study.
Routine laboratory parameters remained within normal ranges during GS treatment,
supporting the tolerability profile of this agent. In particular, glucose serum levels re-
mained within normal limits, contradicting a previous report that GS increased insu-
lin resistance.
40
This study had a number of limitations: the duration of the study was short, the
sample was small, and the inclusion of patients with knee OA alone was insufficient
to determine whether GS could be useful in the treatment of systemic OA. Further-
more, our patients had relatively mild knee pain at baseline, compared with that in
classic studies of OA, in which a criterion for enrollment was a disease flare after the
discontinuation of NSAIDs.
41,42
However, only patients with moderate to severe pain
were treated with GS or other chondroprotective agents in those studies.
CONCLUSIONS
GS 1500 mg QD PO for 12 weeks was associated with statistically significant reduc-
tions in pain and improvements in functioning, with decreased analgesic consump-
tion, compared with baseline and placebo in these patients with knee OA. A carryover
effect was detected after treatment ended.
ACKNOWLEDGMENT
The authors wish to thank Sybilla Hoffer for her assistance with language and gram-
mar in revisions to this article.
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Address correspondence to: Nicola Giordano, MD, Department of
Internal Medicine, University of Siena, Viale Bracci, 1, 53100, Siena, Italy. E-mail:
giordanon@unisi.it
