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Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis
A 3-Year, Randomized, Placebo-Controlled, Double-blind Study
Karel Pavelká, MD, PhD;
Jindriska Gatterová, MD;
Marta Olejarová, MD;
Stanislav Machacek, MD;
Giampaolo Giacovelli, PhD;
Lucio C. Rovati, MD
Arch Intern Med. 2002;162:2113-2123.
ABSTRACT
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Background Conventional symptomatic treatments for osteoarthritis do not favorably
affect disease progression. The aim of this randomized, placebo-controlled
trial was to determine whether long-term (3-year) treatment with glucosamine
sulfate can modify the progression of joint structure and symptom changes
in knee osteoarthritis, as previously suggested.
Methods Two hundred two patients with knee osteoarthritis (using American College
of Rheumatology criteria) were randomized to receive oral glucosamine sulfate,
1500 mg once a day, or placebo. Changes in radiographic minimum joint space
width were measured in the medial compartment of the tibiofemoral joint, and
symptoms were assessed using the algo-functional indexes of Lequesne and WOMAC
(Western Ontario and McMaster Universities).
Results Osteoarthritis was of mild to moderate severity at enrollment, with
average joint space widths of slightly less than 4 mm and a Lequesne index
score of less than 9 points. Progressive joint space narrowing with placebo
use was -0.19 mm (95% confidence interval, -0.29 to -0.09
mm) after 3 years. Conversely, there was no average change with glucosamine
sulfate use (0.04 mm; 95% confidence interval, -0.06 to 0.14 mm), with
a significant difference between groups (P = .001).
Fewer patients treated with glucosamine sulfate experienced predefined severe
narrowings (>0.5 mm): 5% vs 14% (P = .05). Symptoms
improved modestly with placebo use but as much as 20% to 25% with glucosamine
sulfate use, with significant final differences on the Lequesne index and
the WOMAC total index and pain, function, and stiffness subscales. Safety
was good and without differences between groups.
Conclusion Long-term treatment with glucosamine sulfate retarded the progression
of knee osteoarthritis, possibly determining disease modification.
INTRODUCTION
OSTEOARTHRITIS IS the most common form of arthritis. Symptomatic disease
in the knee occurs in approximately 6% of US adults 30 years and older,1 and results of community-based surveys have shown
that the general incidence and prevalence increases 2- to 10-fold from age
30 to 65 years, with further increases thereafter.2 Overall,
osteoarthritis of the knee is particularly common, and radiographic osteoarthritic
changes of the tibiofemoral compartment occur in 5% to 15% of people aged
35 to 74 years in the Western world.3 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.4 Although pathologic and radiographic
evidence of osteoarthritis is poorly correlated with symptoms, the most appropriate
definition of osteoarthritis is one that combines the pathology of the disease
with pain that occurs with joint use, as concluded in a recent National Institutes
of Health conference that reviewed the disease and its risk factors.5 Treatment approaches have also been reviewed,6 and the American College of Rheumatology7 and
the European League Against Rheumatism3 issued
guidelines for the medical management of osteoarthritis. In the absence of
a cure for the disease, current therapeutic modalities are primarily aimed
at reducing pain and improving joint function by the use of nonspecific symptomatic
agents. However, at least some conventional nonsteroidal anti-inflammatory
drugs (NSAIDs), which are the most widely used nonspecific symptomatic agents,
have been shown to negatively affect the progression of osteoarthritis.8 Even the newest and possibly safer NSAIDs, the cyclooxygenase-2
selective inhibitors,9 did not favorably modify
the long-term progression of the disease in terms of joint structure changes
compared with conventional NSAIDs.10 For this
reason, much attention is being given to more specific compounds that may
affect some of the mechanisms underlying the disease, thus delaying progression
of the disease and limiting disability in the long term.3, 7 Glucosamine
sulfate, the pharmaceutical derivative of the naturally occurring aminomonosaccharide
glucosamine, a constituent of glycosaminoglycans in cartilage matrix and synovial
fluid,11 was reviewed for its short-term effects
on disease symptoms12-13 and has
recently been shown to delay the long-term progression of knee osteoarthritis
in terms of joint structure changes and symptoms.14 These
results have been welcomed with enthusiasm by most of the scientific community15 but in some cases with some reservations,16 mainly because such impressive data need to be appropriately
confirmed. The present trial was designed and conducted in parallel, to eventually
confirm independently and possibly extend the results on the long-term (3-year)
effects of glucosamine sulfate therapy on the progression of knee osteoarthritis
structural modifications and symptoms.
PATIENTS AND METHODS
STUDY POPULATION
Outpatients of both sexes aged 45 to 70 years with primary knee osteoarthritis
were eligible to participate in the study if they fulfilled the following
predefined criteria. The diagnosis of knee osteoarthritis of the medial femorotibial
compartment was based on the clinical and radiological criteria of the American
College of Rheumatology.17 Disease stage was
based on the Kellgren and Lawrence radiographic system,18 which
grades osteoarthritis on a severity scale from 0 to 4 based on the assumed
sequential appearance of osteophytes, joint space loss, subchondral sclerosis,
and cyst formation. Minimum symptom severity was ensured by using a Lequesne
algo-functional index19 score of at least 4
points, whereas patients with an index value higher than 12 points were excluded
so as not to jeopardize the knee full extension for the radiographic evaluation
(see the "Assessment of Joint Structure Changes" subsection). Other principal
exclusion criteria were a history of clinically significant articular and
rheumatic diseases other than osteoarthritis, including inflammatory rheumatic
diseases, or that may cause secondary osteoarthritis, including a history
of traumas or lesions of the knee joint and severe articular inflammation
as confirmed by physical examination (eg, a finding of severe joint effusion)
at inclusion; evidence of rapidly progressive osteoarthritis obtained before
the trial; overweight, defined as a body mass index (calculated as weight
in kilograms divided by the square of height in meters) greater than 27; clinically
significant alterations in hematologic variables and renal, hepatic, and metabolic
functions in the opinion of the investigator (including a history of clinically
evident diabetes mellitus); and systemic or intra-articular corticosteroid
therapy in the previous 3 months.
STUDY DESIGN
The trial was conducted according to a randomized, placebo-controlled
design in a single center at the Prague Institute of Rheumatology between
June 29, 1995, and January 20, 1999. The protocol was approved by the institutional
review board of the center, and patients provided written informed consent.
Patients were screened at a baseline visit that included a physical examination,
a knee radiograph according to a standardized method, a symptom questionnaire,
and routine safety laboratory tests. After enrollment, patients were randomized
to the study medication and were followed up until completion of a 3-year
treatment course. Clinic visits were performed quarterly and included symptom
assessment, and standardized knee radiographs and routine safety laboratory
tests were performed at the end of each year.
TREATMENTS AND BLINDING AND RANDOMIZATION PROCEDURES
In this trial, we used crystalline glucosamine sulfate, that is, the
original glucosamine sulfate described in most of the literature12-14 and
available as a prescription drug for osteoarthritis in several European and
other countries and as a nutritional supplement in the United States (Dona,
Viartril-S, or Xicil; Rotta Research/Rottapharm Group, Monza, and Rotta Pharmaceuticals
Inc, Wall, NJ). The product was used in its once-a-day formulation (packets
of powder for oral solution), with a net content equivalent to 1500 mg of
glucosamine sulfate. Patients were randomized to double-blind treatment with
either 1500 mg of glucosamine sulfate or placebo packets identical in external
appearance and content consisting of the inactive excipients only. The study
medication was taken once a day for 3 years. Compliance to the study medication
was determined by asking the patients about missed doses and by counting unused
packets.
Patients received randomization numbers sequentially from a secret randomization
list that was computer generated in blocks of 4 by individuals who had no
contact with the persons who assigned patients to study groups, performed
any assessments on patients, evaluated the radiographs at the end of the study,
or performed the statistical analysis. The block size was also masked from
all investigators involved in the trial. The clinical research center was
given a single-sealed, opaque envelope for each patient that contained the
treatment code and was to be opened only in a medical emergency. Treatment
assignment was thus concealed, and masking was successfully achieved during
the study since no sealed envelope was opened voluntarily or accidentally
or was tampered with during the study.
Acetaminophen in 500-mg tablets was provided for rescue analgesia as
needed, and its use was recorded in a patient daily diary. No other pharmacologic
treatments for osteoarthritis or other formulations containing analgesics
were allowed. Among physical therapies, only hydrotherapy, exercise, and ultrasound,
alone or in combination, were allowed if the patient was following a stable
regimen.
ASSESSMENT OF JOINT STRUCTURE CHANGES
Joint structure changes were assessed on serial radiographs performed
according to the standardized technique recommended by the current guidelines20-21 and as Pavelká et al22 described previously. Radiographs were taken for
each patient at enrollment and after 1, 2, and 3 years of treatment by the
same technician in the radiology unit of the center using a single x-ray machine
(Siere graph C; Siemens, Erlangen, Germany). Anteroposterior, weightbearing
radiographs were obtained with the patient's heels and toes together and the
knees in full extension. The x-ray beam was horizontal, and the central ray
was fluoroscopically directed to the center of the joint space at the level
of the tibial tubercle. The x-ray cassette film was placed 115 cm from the
tube. Repositioning of the patient for subsequent radiographs was guided by
the original film, and the same radiographic settings (ie, kilovolts, milliamperes,
and milliseconds) were used.
All radiographs in a patient set were read for all evaluations concomitantly
by 2 trained independent readers masked to treatment assignment and to the
sequence of assessments, which was randomized. The primary outcome measure
was represented by joint space width changes in the narrowest medial compartment
of the tibiofemoral joint,20-21 that
is, in the signal joint. Changes in joint space width in the contralateral
knee of patients with bilateral disease were analyzed as a secondary variable.
Joint space width was measured by visual reading according to a validated
method23 at the joint's narrowest point using
an x10 magnifying lens graduated in 0.1-mm intervals. When the 2 independent
readings were within 0.3 mm, the mean of the 2 values was taken. In the case
of a difference greater than 0.3 mm, the radiograph was reinterpreted separately
by both readers until the difference was within 0.3 mm. The intraobserver
error for each reader was estimated on 40 randomly selected radiographs measured
8 times in random order in 10 days: the coefficient of variation was 1.91%
for one reader and 2.71% for the other. The interobserver error was estimated
on all radiographs: the coefficient of variation was 2.64% before reinterpretation
and 2.53% after reinterpretation.
Among secondary end points for joint structure modification, radiographic
features of osteoarthritis other than joint space narrowing (marginal osteophytes
and subchondral sclerosis, separately assessed for each medial and lateral
femoral condyle and tibial plateau in both knees) were scored for severity
on a scale from 0 to 3 according to a validated atlas24;
the baseline and final (or last available) radiographs were taken for this
evaluation.
ASSESSMENT OF SYMPTOM CHANGE
Symptoms of knee osteoarthritis were evaluated at clinic visits primarily
by using the algo-functional severity index of Lequesne,19 a
validated, disease-specific questionnaire addressing in a single index knee
pain (5 questions scored on a 0-2 scale, with 0 indicating absent and 2 indicating
severe), function limitation (4 questions, same scale), and maximum distance
walked (1 question scored on a 0-6 distance scale, with 0 indicating ability
to walk unlimited distances and 6 indicating ability to walk <100 m); the
worst possible total score is 24 points. In addition, we also used the WOMAC
(Western Ontario and McMaster Universities) knee osteoarthritis index,25 another validated and disease-specific questionnaire
separately addressing severity of joint pain (5 questions), stiffness (2 questions),
and limitation of physical function (17 questions) in the 48 hours before
assessment. The Likert scale version of the WOMAC index was used, with each
question scored on a scale from 0 to 5, with 0 indicating none and 5 indicating
extreme; 25, 10, and 85 points, therefore, are the worst possible severity
scores for pain, stiffness, and limitation of physical function, respectively.
SECONDARY EFFICACY AND SAFETY END POINTS
Consumption of acetaminophen for rescue analgesia was calculated from
the patient daily dairy. Withdrawal rates were computed with the reason for
dropout. Safety was investigated by recording the occurrence of adverse events
and by results of routine yearly laboratory tests.
STATISTICAL ANALYSIS
The sample size was calculated on the basis of the data available for
the technique used for measurement of joint space width, assuming a difference
of 0.33 mm between groups in joint space narrowing after 3 years26;
with type I error of .05 and type II error of .10 in a 2-tailed test and a
high predicted coefficient of variation of the measurement (8%-10%), 86 (rounded
to 100) patients per group were calculated to be necessary.26
The primary efficacy outcome measure was therefore the difference between
groups in the change in joint space width, that is, in joint space narrowing
after 3 years in the patient's narrowest medial compartment of the tibiofemoral
joint at enrollment. The primary analysis was performed in the intent-to-treat
population, which consisted of all randomized patients. The intent-to-treat
approach was carried out according to a worst-case scenario analysis: patients
who did not complete the treatment course or had not undergone the final 3-year
radiograph were assigned a poor outcome, corresponding to the final average
change recorded in the per-protocol completer population in the placebo group.27 Results are expressed as the difference between final
group means and 95% confidence intervals, with P values
based on analysis of variance (ANOVA). The robustness of this approach was
challenged by a second intent-to-treat analysis performed by the random sampling
method to avoid repeatedly assigning the same value to a series of missing
values.28 With this method, missing end point
values were replaced with values selected randomly from the distribution of
all end point values in the 2 treatment groups combined. To lower the sampling
error, 50 such datasets were constructed and analyzed independently using
ANOVA, and the median of the significance values was taken.28
Similar methods were used for the secondary outcome, represented by
the difference in joint space narrowing after the first and second years of
treatment. In addition, we arbitrarily set a cutoff value of more than 0.5-mm
joint space narrowing to represent severe joint structure damage progression,
which is in the range of previous suggestions29 and
as recently reported in other studies14, 22:
we compared the proportion of all randomized patients reaching such a progression
cutoff value by using the exact  2 test. We also calculated
the number needed to treat, which is the number of patients who have to be
treated with the active medication to prevent 1 event represented by such
a progression: the number needed to treat is the reciprocal of the absolute
risk reduction, consisting of the difference in event rates between groups.30 The exact 2 test was also used to
compare between groups the proportion of patients with changes of at least
1 point in the scale from 0 to 3 for the secondary radiographic features of
osteoarthritis (osteophytes and subchondral sclerosis) at the end point (ie,
after 3 years or on an earlier radiograph with such a change in case of early
dropout).
For symptom modification, similar to structure modification, the final
changes after 3 years in scores on the Lequesne index and the WOMAC index
(the latter separately assessed for the total index and for the pain, stiffness,
and physical function subscales) were selected as appropriate summary measures
for the primary symptom outcome31 and were
analyzed as described for joint space narrowing. However, mainly for descriptive
purposes, the behavior of the principal variable, represented by the mean
change in the Lequesne index score, was also plotted on a time-response curve
for the worst-case scenario intent-to-treat population, and the results were
analyzed by using repeated-measures ANOVA.
To exclude that improvement in knee pain throughout the study might
have improved a patient's ability to adopt the fully extended knee position
required for radiography, consequently resulting in an artifactual, apparent
increase in joint space width, the following posthoc analysis was performed.
Three-year completers in both groups were selected on the basis of an improvement
in the WOMAC pain subscale score equal to at least the average improvement
in the best treatment group at the end of the study. The average improvement
in the WOMAC pain subscale score and the change in joint space width were
then calculated for this subset of patients in the placebo and glucosamine
sulfate groups and are briefly presented for descriptive analysis purposes.
Other secondary analyses included comparison of the mean number of days
with rescue medication intake using ANOVA. Withdrawal and dropout rates were
compared between groups using the exact 2 or Fisher exact
tests, as appropriate. The baseline group characteristics were compared using
the exact 2 test and ANOVA for categorical and continuous
variables, respectively. All reported P values are
2-sided.
RESULTS
Of 385 patients who underwent screening, 202 were randomized into the
study (Figure 1). A larger proportion
of patients did not complete the 3-year treatment course with placebo than
with glucosamine sulfate, but the difference (46% vs 35%) was not statistically
significant (P = .15), and there were no significant
differences between groups in the reasons for dropping out. All randomized
patients (101 in each treatment group) were included in the intent-to-treat
population, whereas the per-protocol population consisted of all patients
who completed the study only. Table 1 gives
the comparable baseline characteristics of the 2 groups. Knee osteoarthritis
was long-standing (>10 years) and was of mild to moderate severity on average.
Patients were similarly distributed between a Kellgren and Lawrence grading
of 2 or 3, with a mean symptom severity score of less than 9 points on the
Lequesne index and scores of similar magnitude on the WOMAC index scales.
This was also reflected in the baseline values of the primary outcome measure,
represented by joint space width in the signal joint, which was slightly below
4 mm and without differences between the glucosamine sulfate and placebo groups
(P = .24 and P = .50 for
the intent-to-treat and per-protocol populations, respectively).
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Figure 1. Flowchart of patient disposition.
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Table 1. Demographic and Baseline Clinical Characteristics of Intent-to-Treat
(All Randomized) and per-Protocol Evaluable Patients*
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Most patients in the 2 groups (77% and 66% taking placebo and glucosamine
sulfate, respectively) had bilateral knee osteoarthritis at enrollment. Average
symptom scores and signal joint space width were similar between these 2 subgroups
and to the values of the overall patient population in Table 1 (data not shown). However, by definition, the average (SD)
joint space width in the contralateral joint was larger than in the signal
joint: 4.72 (1.53) mm and 4.90 (1.39) mm in the placebo and glucosamine sulfate
subgroups, respectively.
A small proportion of patients, 27% taking placebo and 22% taking glucosamine
sulfate, used any of the physical treatments allowed throughout the study
(hydrotherapy, exercise, and ultrasound), alone or in combination, without
any difference between groups. Compliance to the study medication was good,
with at least 86% of patients reporting more than 90% drug intake at clinic
visits in either group.
JOINT STRUCTURE CHANGES
In patients completing each year of treatment with placebo, there was
progressive joint space narrowing, that is, a loss in joint space width (Figure 2). Conversely, there was no average
joint space narrowing in patients receiving glucosamine sulfate, with a significant
difference compared with the placebo group at each point. The final difference
at 3 years between the 2 groups in the per-protocol population was 0.36 mm
(95% confidence interval, 0.13-0.59 mm) (Figure 2). Table 2 gives
the changes in joint space width according to the intent-to-treat, worst-case
scenario principal analysis, which confirmed the significant difference between
the glucosamine sulfate and placebo groups at each year of treatment. The
statistical significance of the primary outcome after 3 years was confirmed
for consistency by the random sampling intent-to-treat analysis, where the
median significance was P<.001.
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Figure 2. Joint space narrowing in patients
completing each year of the study. The number of evaluable patients in the
placebo and glucosamine sulfate groups, respectively, was 84 and 83 at year
1, 57 and 68 at year 2, and 55 and 65 at year 3. Error bars represent SEM.
Asterisk indicates P .05 vs placebo; dagger, P<.01
vs placebo.
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Table 2. Intent-to-Treat Cumulative Joint Space Narrowing at Each Year
of Treatment*
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The number of patients experiencing severe joint space narrowing, according
to the arbitrary cutoff value of greater than 0.5 mm, was 14 in the placebo
group and 5 in the glucosamine sulfate group (P =
.05) (Figure 3). The number of patients
needed to be treated with glucosamine sulfate to prevent such a progression
in joint structure deterioration is therefore 11. Also, the secondary radiographic
features of osteoarthritis showed a favorable outcome in the glucosamine sulfate
group in that there were only 4 of 66 patients with worsened atlas osteophyte
scores at the end point in at least 1 joint compartment compared with 11 of
56 patients receiving placebo (P = .03) (Figure 4). Most worsenings occurred in the
signal joint, although for 4 patients with bilateral disease (2 in each group),
they occurred in the contralateral knee. The joint compartment most often
affected by osteophyte worsening was the medial tibial plateau, followed by
the medial femoral condyle. No patient in either group had a change in the
subchondral sclerosis score.
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Figure 3. Proportion of all randomized patients
(n = 101 in each group) with joint space narrowing greater than 0.5 mm throughout
the study.
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Figure 4. Proportion of patients reaching
the end point who had worsening osteophyte atlas scores (n = 56 receiving
placebo and n = 66 receiving glucosamine sulfate).
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In patients with bilateral knee osteoarthritis, the intent-to-treat
signal joint space changes were of the same magnitude as those reported for
the overall patient population in Table
2 (data not shown), with a similar statistically significant difference
in favor of glucosamine sulfate therapy (P = .004).
In the contralateral joint, patients receiving placebo underwent significant
joint space narrowing (–0.13 mm; 95% confidence interval, –0.23
to –0.03 mm) that did not occur in those receiving glucosamine sulfate
(–0.04 mm; 95% confidence interval, -0.12 to 0.05 mm), although
the difference between the 2 subgroups was not statistically significant (P = .17).
SYMPTOM CHANGES
Pain and function limitation decreased in completers in both treatment
groups according to the Lequesne index (Figure
5) and WOMAC index (Figure 6)
scores. However, the improvements were significantly larger in patients receiving
glucosamine sulfate, with score reductions of 20% to 25% compared with baseline.
The final change in the WOMAC index joint stiffness subscale, although of
smaller size, showed a significant difference in favor of glucosamine sulfate
use too (Figure 6D). These results
were confirmed by the principal analysis according to the intent-to-treat
worst-case scenario approach (Table 3),
where the magnitude of the improvements was again larger in the glucosamine
sulfate group: approximately 20% on the Lequesne index and approximately 15%
on the WOMAC total index and pain or function subscales (with the smaller
changes in the stiffness subscale being nevertheless again statistically significant).
The median significance between groups in the intent-to-treat analysis performed
according to the random sampling approach for consistency was also statistically
significant (P<.001 and P =
.002 for the Lequesne index and the WOMAC total index, respectively).
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Figure 5. Per-protocol analysis of mean
change in the Lequesne index score after 3 years. Error bars represent SEM.
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Figure 6. Per-protocol analysis of mean
change in the WOMAC (Western Ontario and McMaster Universities) total index
(A) and pain (B), function (C), and stiffness (D) subscale scores after 3
years. Error bars represent SEM.
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Table 3. Intent-to-Treat Change in Symptom Scores After 3 Years Compared
With Baseline Scores*
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The intent-to-treat pattern of the Lequesne index at the quarterly clinic
visits is shown in Figure 7. The
glucosamine sulfate group had progressive and constant improvement compared
with the placebo group, especially during the first year and maintained during
the second and third years (P = .004 between groups
on the ANOVA for repeated measures). Symptom changes followed the same pattern
in patients with bilateral disease (data not shown).
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Figure 7. Intent-to-treat Lequesne index
score mean change at clinic visits throughout the study. Analysis of variance
for repeated measures: P = .004 between treatments. Error bars
represent SEM.
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There were no statistically or clinically significant differences between
treatment groups in the consumption of acetaminophen for rescue analgesia,
which was minor and variable in most patients. Approximately 30% to 40% of
patients in both groups consistently took acetaminophen at or above the average
of once every 3 days, without an apparent relationship with joint structure
or symptom outcomes.
EFFECT OF SYMPTOM IMPROVEMENT ON JOINT STRUCTURE CHANGES
To exclude that the significantly higher symptom improvement achieved
with glucosamine sulfate use at the end of the study could have biased the
joint space width radiological assessment, completers in the 2 groups were
selected according to a threshold of improvement of at least 2 points on the
WOMAC index pain subscale (corresponding to the average intent-to-treat improvement
with glucosamine sulfate use). There were more patients above this threshold
in the glucosamine sulfate group (41 vs 27), but the 2 patient subsets had
comparable baseline WOMAC index pain scores and joint space widths (data not
shown) and comparable mean pain improvement after 3 years (Figure 8A) of almost 4 points on the WOMAC index pain subscale,
that is, of more than 50% compared with their mean baseline scores. Notwithstanding
this major pain relief, the placebo patient subset underwent definite joint
space narrowing compared with the glucosamine sulfate subset (Figure 8B), with a difference that was at the limits of statistical
significance (P = .06) despite the small sample size
in this subanalysis and in the same range as that observed in the overall
study population.
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Figure 8. Pain improvement (A) and joint
space narrowing (B) in the subset of patients reporting major pain relief
(27 patients receiving placebo and 41 receiving glucosamine sulfate). Error
bars represent SEM. WOMAC indicates Western Ontario and McMaster Universities.
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TREATMENT SAFETY
Overall, 64% of patients receiving placebo and 66% receiving glucosamine
sulfate reported at least 1 adverse event during the 3 years of study. Table 4 gives the proportion of patients
reporting adverse events according to body system; there were no statistically
significant differences between groups in the proportion or pattern of adverse
events. The most frequently reported complaints were attributable to the gastrointestinal
tract and liver systems and consisted predominantly of transient episodes
of abdominal pain and dyspeptic symptoms: 3 patients in each group dropped
out of the study for abdominal pain, dyspepsia, or nausea; 2 additional patients
in the placebo group dropped out for diarrhea or cholecystitis. Musculoskeletal
reports were mainly for osteoarthritis-related symptoms or back pain; however,
1 patient in each group was withdrawn for developing episodes of possible
gout arthritis, and, in 2 patients taking glucosamine sulfate, probable rheumatoid
arthritis was diagnosed after treatment started and was classified as an adverse
event, although it was most likely preexisting; finally, 1 patient taking
placebo dropped out because of a hip fracture. Cardiovascular events consisted
predominantly of episodes of increased blood pressure or recurrent manifestations
of preexisting ischemic heart disease in this elderly population: 1 patient
receiving placebo was withdrawn because of a stroke, and in the glucosamine
sulfate group 1 male patient with a 6-year history of ischemic heart disease
with previous myocardial infarctions, cardiac failure, and recent coronary
bypass died of a fatal myocardial infarction before completing 3 months of
treatment with the study medication. Skin and appendage disorders were represented
mainly by cutaneous rash episodes: 1 patient receiving placebo was withdrawn
because of an allergic exanthema and 1 receiving glucosamine sulfate because
of eczema. As expected, a high proportion of patients reported seasonal upper
respiratory tract infections. Reports of urinary tract infections were also
common in both groups. Among metabolic and nutritional problems, 4 patients
developed clinically evident diabetes mellitus during the study (3 were taking
placebo [1 dropout] and 1 was taking glucosamine sulfate). Routine safety
laboratory test results did not show significant differences between groups.
No patient underwent knee joint replacement during the study, but 2 patients
in the placebo group underwent hip replacement for osteoarthritis or a traumatic
lesion.
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Table 4. Patients Reporting at Least 1 Adverse Event During the 3-Year
Study, by Body System*
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COMMENT
Results of the present trial show that long-term oral administration
of glucosamine sulfate for 3 years can delay the natural progression of knee
osteoarthritis. Symptoms of joint pain and limitation of function significantly
improved throughout the study in the glucosamine sulfate group compared with
the placebo group, and, especially, patients receiving glucosamine sulfate
did not undergo, on average, the progressive joint structure changes radiologically
observed in patients taking placebo. These results are of particular relevance
in that they independently confirm and extend the results of another recent
study.14 Glucosamine sulfate, therefore, is
the first agent that meets the current requirements to be classified as a
symptom- and structure-modifying drug in osteoarthritis, according to the
definition of scientific organizations,20-21 as
acknowledged by regulatory agencies.32-33
Structural effects have been evaluated on standardized radiographs by
measuring the change in width of medial tibiofemoral joint space as the primary
outcome, as recommended by expert consensus.20-21,32-33 Measurement
was performed at the joint's narrowest point by visual inspection with the
aid of a magnifying glass, that is, using the gold standard, accepted method.21, 23 A sound protocol with 2 independent,
masked readers, resulting in low interobserver and intraobserver variability,
has been preferred to one of the different methods of digital image analysis
that measure either mean joint space or a specific distance in the joint and
that have also been suggested to decrease variability.21 By
this method, we found a natural rate of joint space narrowing in the placebo
group that was below 0.1 mm/y, that is, in the same range detected by large,
observational, community-based studies34-35 or
clinic-based populations36 and slower than
proposed in earlier studies possibly biased by the small number of patients
included or by short follow-up.37 In addition,
the rate of joint space narrowing in our control group was similar to that
recently reported in other long-term randomized controlled trials.14, 22 Glucosamine sulfate therapy prevented
this naturally occurring slow joint space narrowing. This effect was evident
after the first and second years of treatment, although the loss in space
width in the placebo group was not linear and increased especially during
the third year, thus confirming an observation that had already been proposed.14 The final difference in the change in joint space
width between the glucosamine sulfate and placebo groups in patients completing
3 years of treatment was similar to the figure we used for our sample size
calculation and that was suggested by experts to define an effective treatment.26 This per-protocol analysis result was then confirmed
by an intent-to-treat approach on all randomized patients that adopted 2 different
methods to evaluate the robustness of the findings.
In addition, treatment with glucosamine sulfate dramatically decreased
the proportion of patients with clinically substantial joint space loss, as
defined by an arbitrary cutoff value previously suggested.14, 29 Patients
who experience such structural damage may be more subject to future disability:
the reduction in this absolute risk with glucosamine sulfate use allowed calculation
of a sufficiently low number needed to treat of 11. This means that 11 patients
have to be treated with glucosamine sulfate to prevent 1 from experiencing
clinically substantial joint space loss. This way of presenting joint space
narrowing data, besides being more easily interpretable, has been suggested
to be more relevant in clinical terms.38 A
similar trend in favor of glucosamine sulfate therapy for retarding joint
space narrowing was found in the less affected knee in patients with bilateral
osteoarthritis, which would support the opportunity for early intervention
with this compound. This aspect needs further evaluation.
Precise measurement of joint space width depends on correct standardization
of the radiographic technique.21 In the present
study, we used the state-of-the-art technique available at the time of study
design and still advised by the current recommendations,21 that
is, with the knee in full extension. However, recent evidence39 suggests
that different radiographic views, for example, with the semiflexed knee,
may improve precision and avoid having the presence of pain or functional
limitation impair the possibility of knee full extension. How much this theoretical
limitation translates into real bias is unclear,15 but
the discussion seems to be mostly academic and may affect any long-term clinical
study that uses techniques that are state-of-the-art at the time of study
design but that inexorably undergo substantial refinement by the time of study
completion. In any case, in our study, this did not seem to represent a bias
on the final results. In fact, pain and function limitation were of mild to
moderate severity at enrollment and did not prevent knee full extension. Moreover,
they improved in both treatment groups (although with a clinically and statistically
significant difference in favor of glucosamine sulfate therapy), thus excluding
that joint space narrowing observed in the placebo group with this radiographic
technique should be mainly an artifact of symptom worsening. Furthermore,
several studies have repeatedly shown that symptom and structure changes are
poorly correlated in osteoarthritis,40 and
even the long-term effects of glucosamine sulfate use on symptoms occur irrespective
of the outcome on joint space width.14 However,
the ultimate evidence that knee pain and its improvement were not confounders
of the radiographic assessment of joint space narrowing progression came from
our analysis of the subgroup of patients who experienced major pain relief
regardless of treatment with placebo or glucosamine sulfate. Indeed, this
did not prevent joint space narrowing with placebo compared with glucosamine
sulfate use.
In addition, and for the first time, to our knowledge, in a randomized,
controlled, intervention trial, we used a validated atlas24 to
score secondary radiographic features of osteoarthritis, that is, features
other than joint space width. Although the results are preliminary and should
be interpreted with caution because this was not a primary outcome measure,
substantially more patients taking placebo vs glucosamine sulfate worsened
their osteophyte score. It is unlikely that this finding is biased by the
radiographic technique adopted, and it would therefore confirm an overall
beneficial effect of glucosamine sulfate therapy in the progression of joint
structure changes. This preliminary finding also loosens the pressure on the
ongoing discussion about the relevance of radiographic joint space width as
the only determinant of joint structure modification in knee osteoarthritis.
Although this variable is currently advised as the primary outcome in trials
of disease modification,20-21,32-33 and
its relevance remains of primary importance, results of recent studies suggest
that loss of joint space in the early stages of osteoarthritis may be due
in part to meniscal extrusion and not only to articular cartilage erosion.41 Moreover, plain radiography may not be the ideal
tool to measure tibiofemoral joint space,42 unless
careful protocols that include use of fluoroscopy are used to standardize
the radioanatomic position of the knee,42 as
in our study. Therefore, other radiographic features of osteoarthritis might
be favorably affected by treatment with glucosamine sulfate. In particular,
osteophytes have been indicated to be better associated with pain in knee
osteoarthritis.43
In the present study, symptoms improved with glucosamine sulfate use
to a significantly larger extent than in the placebo group. The fact that
symptoms tended to slightly improve also with placebo therapy is not surprising
in a long-term trial in which the principal effort is to keep the patient
in the study, with several clinic visits and assessments being performed.
Actually, there was a statistically nonsignificant trend for a higher proportion
of withdrawals in the placebo than in the glucosamine sulfate group, which
may reflect lower treatment satisfaction in the control group. Other large,
prospective studies36 on the natural history
of the disease also did not show a worsening in pain severity after 3 years,
notwithstanding the fact that most patients reported an overall worsening
of their condition. In any case, symptom improvement with placebo therapy
was limited to a few percentage points, whereas patients receiving glucosamine
sulfate reported an average 20% to 25% improvement in pain and function according
to the per-protocol analysis and 15% to 20% by the intent-to-treat approach
adopted, which is in agreement with the effect size reported in similar studies.14 Such results were obtained by assessment using the
Lequesne index19 and were confirmed for consistency
using the WOMAC index,25 that is, the 2 most
widely used algo-functional indexes of the severity of knee osteoarthritis.20-21 Besides reporting the final symptom
score, we analyzed the development of the symptomatic effect of glucosamine
sulfate during treatment and found a steadily developing effect over the first
year that then remained constant until completion of the study after 3 years.
These results on osteoarthritis symptoms have already attracted much attention,15 and one should consider that they have been obtained
in patients with mainly mild to moderate disease and in a long-term study
that may not be optimal to fully appreciate the development and effect size
of the improvement. Indeed, short-term studies specifically designed with
such an aim have already described the pattern of the symptomatic effect of
glucosamine sulfate use and have recently been reviewed.12-13 These
studies showed a significantly better effect than placebo therapy and at least
similar to that of conventional NSAID use in the first 4 weeks of treatment,44-45 with improvement in pain and function
up to 40% to 50% relative to basal conditions within 12 weeks,46 that
is, a moderate to large effect size12-13 and
a carryover effect at drug withdrawal.46 The
present study, together with other similar experiences,14 completes
the pattern of the effects of glucosamine sulfate for long-term chronic treatment,
as demanded lately by the scientific community.47-48 As
a possible limitation in this regard, although the patient population in our
study is largely representative of the general population with knee osteoarthritis,
we excluded obese patients and those with metabolic diseases that may be responsible
for secondary osteoarthritis. In addition, as expected in a placebo-controlled,
long-term trial, we included a limited number of patients with severe disease.
Although we standardized the consumption of a rescue medication to acetaminophen
only, contrary to the study by Reginster et al,14 in
which selected NSAIDs were also used, we did not observe a difference between
groups in its consumption either. These data seem to confirm that consumption
of rescue analgesics is not a valid outcome measure in osteoarthritis trials,
possibly being subject to different confounding factors.21
Several experimental studies have now elucidated the mechanism of action
of glucosamine sulfate in osteoarthritis. First, a wide and recently reviewed
pharmacokinetic experience49 has shown that
after oral administration, glucosamine sulfate is bioavailable and reaches
the articular cartilage. Glucosamine is preferentially incorporated by the
chondrocytes into the components of the glycosaminoglycan chains in the intact
cartilage,50 stimulates the synthesis of physiological
proteoglycans,51-53 and
decreases the activity of catabolic enzymes, including metalloproteases.52-54 In addition, there
is increasing evidence54-56 that
the compound reverses some of the negative effects of interleukin 1 on cartilage
metabolism. Such activities on cartilage should be responsible for the long-term
effects of glucosamine sulfate, especially those on joint structure changes.16 Conversely, the rapid effects on symptoms observed
for shorter treatment courses12-13,44-46 are
better explained by the mild anti-inflammatory effects exerted by the suppression
of superoxide-radical generation57 or the inhibition
of inducible nitric oxide synthesis and, selectively, of the cyclooxygenase-2
pathway.58
The mechanism of action of glucosamine sulfate supports the good safety
of the compound, largely described during short-term treatment12-13 as
being without differences from placebo44, 46 but
significantly better than with conventional NSAIDs.45-46 Our
study confirmed another observation14 of a
similarly good treatment tolerance over long-term administrations, with no
differences fr |
