Vol. 3, No. 3. 1982.
Oral glucosamine sulphate in the management of arthrosis:
report on a multi-centre open investigation in Portugal
Macarlo JoKo Tapadinhas, Italo Croce Rivera and Angelo A. Bignami~li'
Orthopedic Service, Principal Military Hospital, Lisbon, Portugal, and
*Institute of Biological Chemistry, University of Pavia, Pavia, Italy
Pharmthempeutica, (1992). 3, 157.
An open study wascanied out by 252doctors throughout Portugal toassess theeffectiveness and
tolerability of oral glucosamine sulphate in the treatment of arthrosis. Patients received 1.5 g
daily in 3 divided doses over a mean period of 50*14 days. The results from 1208 patients were
analvzed and showed that the svmptoms of vain at rest, on standin~ and on exercise and limited
active and passive movements improved steadily through the treatment period. The improve
ment obtained lasted for a period of 6 to 12 weeks after the end of treatment. Obicctive
therapeutic efficacy was rated by the doctors as 'good' in 59% of patients, and 'sufficient' in a
further36%. These resultsweresimificantlv better than thoseobtained with~revious treatments
(except for injectable gluwsamine) in the same patients. Sex, age, localization of arthrosis.
concomitant illnesses or concomitant treatments did not influence the frequency of responders
to treatment. Oral glucosamine was fully tolerated by 86% o f patients, a significantly larger
proportion than that reported with other previous treatmentsand approached only by injectable
gluwsamine. The onset of possible side-effects was significantly related to pre-existing gastro
intestinal disorders and related treatments, and to concomitant diuretic treatment.
&per received: 26th February 1982
Key words: Glucosamine - osteoanhritis
For some years, glucosamine has been used as one of the most effective means to
treat arthrosis medi~ally,'~ and the recent availability of an oral form containing
glucosamine sulphate has increased the flexibility of its use. Moreover, the
possibility of oral treatment has made possible the ambulatory management of
some patients who, otherwise, would have had to report to hospital.
As is the case with most drugs, the major investigations on oral glucosamine
sulphate have been limited to relatively small groups of selected in-patients.
However, arthrosis is a very widespread illness, and for the proper evaluation
of drugs, such as this, large numbers of out-patients should be studied to assess
the effectiveness and tolerance of treatment in all possible conditions. A nation-
wide investigation was carried out in Portugal, therefore, to see whether oral
glucosamine sulphate treatment was equally as effective and as well-tolerated in
unselected ambulatory patients, irrespective of environmental conditions, con-
comitant illnesses and treatment, and of differences in medical approach, as it
had been shown to be in selected in-patient populations. The investigation was
planned so as to cover the three-quarters of a year (from September 1980 to May
1981) in which more than 90% of the diagnoses of arthrosis are concentrated. In
this way, possible seasonal variations in intensity of arthrosis are not likely to
ittfluence the results.
Om1 glueosamine sulphte in the management o f orthrosis: report on a rnultirentre open
investimion in Portugal
PATiEh'TS AND METHODS
A total o f 252 doctors distributed throughout Portugal participated in the study
and reported on 1506 patients with arthrosis. Some of the patient data sheets
could not be evaluated (incorrect diagnosis in 68 patients, lost to followup 107
patients, and incomplete data in 123 patients) so the final sample available for
analysis was 1208 patients.
The patiedts were 516 males and 692 females, ranging in age from 16 to 84 years
(mean 54.22S.D. 9.36). The distribution by decade was almost symmetrical, with
a median of 50 to 59 years. The localizations of arthrosis are reported in Table 1.
The treatment or treatments camed out for the same illness during the last
flare-up were recorded, and efficacy and tolerance rated as 'good', 'sufficient',
'insufficient' or 'withdrawal of treatment'.
Table 1. Localization of anhrosis, sex and age characteristics of the patients studied
Site No. (%)
Sex Age (yean)
Male Female Mean (*S.D.)
5 2 3 9.9
16 to 75
33 to 72
20 to 83
33 to 74
3 2 ~ 7 0
More than half of the patients (629,52.1%) reported one or more concomitant
illnesses or aggravating conditions, such as depressive neurosis or obesity (Table
2). By far the more represented, however, were cardiovascular disorders (43.2% of
total reported illnesses). As a consequence, concomitant treatments had to be
oamed out in 38.9% of patients (Table 3).
Each patient received 2 capsules containing 250 mg glucosamine sulphate per
capsule Mimes daily (1.5 g per day) over a period of 50.3% 14.4 days (range 13 to 99
days), excluding those patients in whom treatment was withdrawn because of
T a b k 2. Reported concomitant illnesm
Illness No. (%)patients
Macario Jodo Tapadinhas, Ira10 Cmce Rivera and Angelo A. Bignarnini
Table 3. Concomitant non-interfering treatments given
Treatment No. (%) patients
insulin, hypocholest~olaemics,gold salts.
inefficacy within the first 2 weeks (29 patients) or because of the onset of
accessory symptoms (28 patients). The standard treatment period, therefore, was
between 6 and 8 weeks.
Glucosamine sulphate was mainly used alone or in combination with now
interfering treatments: in 16.1% of patients, however, an anti-inflammatory agent
(oxyphenbutazone, 121 patients) or an analgesic (acetaminophen, 54 patients) or
both (19 patients) were also given for a period of time. Oxyphenbutazone wasgiven
for 19216 days (range 3 to 73 days), corresponding to 39*32% of glucosamine
treatment time at an average dose of 5352247 mg daily. Acetaminophen wasgiven
for 17*14 days (range 4 to 64 days), corresponding to 36*28% of gluwsamine
treatment time at an average dose of 1115*934 mg daily.
Before the start of treatment and then after 2 weeks, after 3 to4 weeks and after
6 to 8 weeks of treatment, the doctor scored the intensity of pain at rest, pain on
standing, and pain on exercise as well as the intensity of limited active and passive
movements. Pain scores were defined as: O=painless; I =tender; 2=tender and
winced; 3=tender, winced and withdrew. Mobility scores were defined as: O=less
than 10% hindrance, 1=10% to 25% hindrance, 2=25% to 50% h~ndrance, and
3=more than 50% hindrance, with reference to the free movement of the affected
joint. Similar recording was done as much as possible in a period of 2 to 12 weeks
after the end of treatment. At the same times, accessory symptoms and possible
adverse reactions to treatment were scored and recorded upon positive question-
ing of patients. The doctors indicated the overall objective assessment of the
efficacy and safety of treatment as 'good', 'sufficient' or 'insufficient'.
Data were processed according to the paired t-test as the Wilcoxon's signed
ranks test is almost meaningless in such conditions. Frequency distributions were
tested according to the Fisher's or theX2-test, as applicable. Regression lines were
computed, with the leastsquares technique, on the raw data.
Efficacy could be rated in 1183 patients. The doctors objectively rated the thera-
peutic results as 'good' in 694 (58.7%) patients, and as 'sufficient' in 426 (36.0%).
'Insufficient' results were reported in 63 (5.3%) patients.
Om1 glucosamine sulphate in the management of alrmis: report on a multi-centre open
investigation in Portugal
It should be stressed, however, that 20 of the 63 non-responders did not respond
to the treatments previously camed out, either. On the contrary, 112 patients
who did not respond to previous treatments benefited from glucosamine adminis
An unusual profile was observed, according to the time of year when treatment
was begun, both in the number of treated patients and in the frequency of
complete therapeutic success (Figure I). The number of treated patients showed
a minimum .in December, when a nearmaximum would have been expected.
Similarly, the curve of percentage of complete therapeutic successes showed an
absolute minimum in the same month, and an absolute maximum for treatments
begun in September/October. Obviously, the holiday period in December largely
affected both visits to the doqtor and patient's compliance. Another observation
is that the earlier the treatment was instituted, the better the therapeutic results.
Figwe L Distribution of patients by the month of starting treatment as a percentage of total
number of patients (solid line) and the percentage of complete therapeutic successes in
each time group (dotted line)
Sept.1 NwDec. Ian. Fkb.Mu Apri
The efficacy rating of treatment wasdifferently distributed between 'good' and
'sufficient' according to different localization of arthrosis. Three groups could be
identified, homogeneous within the groups and heterogeneous between (X2-test,
Average results (54% to 61% 'good' ratings) were reported with the present
treatment when the localization was vertebral column, knee, tibio-tarsal joint, or
small joints. Arthrosis of the hip or polyarticular arthrosis apparently required a
longer period of treatment to lead to average results. Better than average results
were obtained in patients with arthrosis of the shoulder or elbow.
No influence of sex or age of patients was observed: the results were evenly
distributed between males and females and in the different decades, according to
the frequency observed in each indication.
A significant difference in the distribution of results was observed according to
the concomitant illnesses or treatments. The X2-test showed a different distribu-
Macario Jodo Tapadinhas Ifalo Croce Rivem and Angelo A. Bignomini
Table 4. Overall therapeutic result in relation to localization o f arthrosis:
number (%I of patients
Localization Efficacy rating
Good Sufficient Insufficient
426 (36) 63 (5)
tion of efficacy rating, compared with that observed in the patients without
concomitant illnesses, in the case of obesity or gastro-duodenal disorders (Table
5). This did not shift the proportion of responders versus non-responders, but
simply shifted that between 'good' and 'sufficient' results. This may be easily
explained by the fact that overweight is an aggravating factor in arthrosis and such
patients, moreover, might need a dose adjustment. On the other hand, patients
with concomitant gastro-duodenal disorders are likely not to take the full dosage
of an oral treatment for all the necessary time.
Table 5. Overall therapeutic result in relation to concomitant illnesses: number of patients
Illness Efficacy rating
Good Sufficient Insufficient
the test compared the distribution of responders vs. non-responden
compared with "None". Both differences were not significant when
A similar situation was observed when diuretics were used concomitantly (Table
6). whereas the administration of both an analgesic and an anti-inflammatory
agent significantly improved the proportion of 'good' to 'sufficient' efficacy
ratings without, however, modifying that of responders to non-responders. The
concomitant use of either the analgesic or the anti-inflammatory agent did not
modify the overall efficacy rating.
Om/ ghrcosamine sulphate in the management of arthpsir: report on o mulri-c.ntre open
investigation in hrtugal
Table 6. Overall therapeutic result in relation to concomitant treatments: number o f patients
Treatment Efficacy rating
45 1 252 35
*F0.05. %'-test compared with "None". Both differences were not significant when the ten
compared the distribution of responders vs. non-responders
As will be seen from figure 11, there was a significant (60.001) progressiveand
constant reduction in the overall intensity of articular symptoms during treat-
ment. Moreover, the intensity of the individual pain and mobility assessments
recorded at any test time was significantly reduced in comparison with the
previous observation period (Table 7).
Figure 1 1 . Changes in the sum of symptom scores during treatment: mean (S.E.M.) m r e s
'pc0.001, paired t-test. Significance of difference compared with previous asSeS.Sment time
The results (59% 'good') could be considered as indicating a rather less degree o f
efficacy compared with the fast pain management afforded by anti-inflammatory
Macario Jodo Tapndinhnr, Italo Crme Riven and Angelo A. Bignamini
Table 7. Changes in symptom scores during treatment with oral glucosamine sulphate:
mean (CS.D.) scores for all ~atients assessed, excluding dropouls
Assessment Initial After 2
Pain at resf
Pain on standing
Pain on exercise
Limited active movements
Limited passive movements
Sum of scores 8.7*3.4 6.023.1 3.6r3.0 2.5C2.6
Note: each mean score was significantly lower (eO.001) than the previous one (paired t-test)
agents. It must be observed, however, that the present investigation was on
arthrosis, where pure management of pain is secondary to the recovery of
independent mobility. This could easily be verified; only 146 of the reported
patients were on their first treatment. whereas 510 had already received one
treatment. and 552 two previous treatments. It was possible, therefore, to make a
comparison o f the results obtained with oral glucosamine sulphate versus those
obtained with 1614 other treatments. They were mainly represented by non-
steroidal anti-inflammatory drugs (37%), steroids (IS%), topical dmgs (15%). that
jointly were considered anti-inflammatory agents (1077 treatments). Tissue
extracts, mainly cartilage polysaccharides, accounted for 18%. or 287 treatments.
Injectable glucosamine accounted for 12%. or 1 9 1 treatments, and several other
treatments of,,which the major were vitamins, accounted for 4%,or 59 treatments.
The proportion of responders to oral glucosamine sulphate was the highest among
the reported treatments, significantly higher than any other. except injectable
glucosamine (Figure 111).
re I . Percentage of responders to oral glucosamine sulphate and previous treatments
Oral glucosamine sulphate (n=1183)
Injectable glucosamine (n=191)
Cartilage extracts (11~287)
Anti-inflammatory agents (11~1077)
Other treatments (n=59)
Significance of difference of distribution compared with oral glucosamine
Om1 glucosamine sulphate in the management of arthrosis: report on a multi-centre open
investigation in Portugal
Moreover, the course of symptoms after the end of treatment may give a hint to
the reliability of the improvement obtained and on its possible duration. Out of the
1151 patients for whom the course of symptoms could be evaluated, 197 (17%)
were seen at 2 weeks, 116 (10%) at 4 weeks, and 31 (3%) in a period of 6 to 12 weeks
after the end of treatment. The course of symptoms (Rgure IV) indicates that,
after a small improvement still recorded 2 and 4 weeks after the end of treat-
ment, a non-significant increase in intensity of Symptoms was observed at longer
periods, indicating that a stabilization or follow-up treatment, even intermittent,
may be helpful to maintain control of the arthrosis. The variations observed after
the end of treatment, however, could not be time-related with a regression curve.
The major component of the decrease in intensity early after treatment was the
decrease in pain at rest. The major component of the increase in symptom
intensity post-treatment was an increase in the intensity of pain on exercise.
Figure N. Changes in the sum of symptom scores after the end of treatment and without
maintenance: mean (+-S.E.M.) scores
Time (weeks) after treatment
Note: none of the changes from the previous assessment times were significant
The evaluation of the tolerability of treatment must rely only on the physician's
objective evaluation and on patient's complaints record. Indeed, apart from it
being well known already that glucosamine does not induce modifications in the
laboratory tests, it would have been almost impossible to obtain meaningful data
from tests carried out in different laboratories with different methods.
Tolerability could be evaluated in all 1208 patients, and resulted in itsassessment
as being 'complete' in 1041 (86%). It was defined as 'sufficient' in a further 137
patients, and only in 30 (2.5%) was it defined as 'insufficient'. Among these
patients, treatment was withdrawn in 28.
The prevalence of limited tolerability appeared to be strongly associated with
the presence of concomitant illnesses and their relevant treatments. Whereas
Macario JoUo Tapadinhas, Italo Croce Rivera and Angelo A. Bignomini
1031 patients without gastrc-intestinal illnesses were free of complaints compared
with 118 (10.3%) who complained, among the 113 with gastro-duodenal illnesses,
28 (19.9%, or twice as much in proportion) complained o f some accessory
symptom, mainly gastric (F0.001, X2-test). Similarly, concomitant treatments
were given in 36% of the patients who did not complain, and in 54% of those who
did. Thii proportion increased from 5% to 14% for antaciddanti-ulcer treatments,
and from 5% to 11% of diuretic treatments. In both these cases, the distribution
of objective tolerance ratings was significantly different (F0.01 and pi0.02,
respectively, X2-test) in comparison with that observed in patients without added
treatments. No variation in tolerability rating was observed in the presence of
diabetes, cardiovascular or liver disorders, or with treatments such as hypo-
tensives, hypoglycaemics, digitalis or tranquilliers.
Overall, 186complaints were recorded from 146patients. ,These may be divided
into digestive or non-digestive (Table 8) and were classified as 'slight' in 55% of
cases, 'moderate' in 32%. and only rarely (13%) as 'severe'. All the reported
complaints were reversible. The onset was observed at 7.0k8.0 days of treatment
(range 1 to 42 days). These symptoms disappeared on average after 8.6k12.6 days
(range 1 to 83 days) when the treatment was continued, whereas when it was
withdrawn, they disappeared on average in 3.0k1.6 days.
Table 8. Details of complaints reported during treatment
Symptom No. of
The other 1062 (88%) patients did not complain of any accessory symptom,
upon questioning, throughout the whole treatment period. The tolerability of the
last treatment given to the same patients was rated as 'good' in only 61% of cases.
Treatment with oral glucosamine sulphate was significantly better tolerated than
Om1 glucosamine sulphafe in the management of arthmis: repon on n multi-centre open
investi~afion in Porru~al
any of the previously administered treatments, including injectable glucosamine,
which had the added disadvantage o f intolerance to injection technique; and even
so it was by far the best tolerated among the previously administered treatments
Flpre V. Percentage of patients with complete tolerance of treatment with oral glucasamine
sulphate compared with that of other previous treatments
Oral gluuMamine sulphate (n=1208)
Injectable glucxamine (n=191)
Cartilage extracts (n=287)
Anti-inflammatory agents (n=1077)
Other treatments (n=59)
Significanci 'difference in distribution cornpardwith oral
The objective evaluation of the usehlness of any medicament is and will continue
to be a controversial matter. Several trial designs have. been developed to try to
avoid bias from subjective influence, natural history of disease, general medical
care, etc., s o that finally an assessment of whether and to what extent a drug is
actually effective can be made. All such designs, however, are complicated
enough so as to be restricted to small numbers of patients, usually hospital
in-patients, in a few selected centres. The danger is not to test the actual popula-
tion of patients in their real environment, and to overlook the clinical aspects in
favour of laboratory data.
The present clinical investigation tried to overcome most of such limitations by
testing over 1500 patients, or a little more than 1 in 10,000 patients with arthrosis
in Portugal. The geographic distribution almost paralleled the actual distribution
of population and o f doctors in the country and the trial period was designed so as
to cover all the possible cyclic highs and lows of the disease tested.
The frequency o f non-responders to the treatment was very limited (5.3%), and
was mainly of patients who did not respond to any treatment. However, the results
showed that a significant proportion of patients (9.3%) who had not responded to
previous treatments did benefit from oral glucosamine sulphate treatment.
Macario Jodo Tapadinhas, Iralo Croce Rivera and Angelo A. Big~mini
Although each individual symptom showed an improvement evenly distributed
throughout the treatment period, nevertheless the major action of glucosamine
wasobservedon pain at rest, painon standing and limited passive movement. This
pattern is complementary to that of analgesic anti-inflammatory agents, which are
generally more effective in pain on exercise and limited active movements, and
which exert their maximal action within the first 2 weeks of treatment. This
observation suggests that an initial period of combined treatment, perhaps of
injectable glucosamine with analgesic anti-inflammatory agents, might be useful
in those patients with significant inflammatory or painful components.
The efficacy of oral glucosamine sulphate was significantly greater than any o f
the previously used treatments (anti-inflammatories. cartilage extracts, vitamins).
Only injectable glucosamine compared well in efficacy with oral glucosamine,
though with less fully satisfactory results (38% vs. 59%), possibly because of too
short a treatment period.
Complete tolerability of oral glucosamine was reported by a significantly larger
proportion of patients than with any other treatment. This, however, may be
biased bv the fact that some of the vrevious treatments were in iniectable form,
thus with a higher risk of adverse reactions. The presence of concomitant illnesses
or the concomitant administration of other treatments did not influence the
efficacy and safety of oral glucosamine sulphate, except in few instances. Obesity
was related to a significant shift from 'good' to 'sufficient' therapeutic results.
Similarly, gastro-duodenal illnesses and their relevant treatment, or treatment
with diuretics, shifted from 'good' to 'sufficient' the overall rating of both efficacy
and tolerance. In none of these conditions, however, was the proportion of
responders decreased or that of intolerance increased.
Fmm the reported data, it was impossible to identify whether any complaint
could be attributed to unwanted reactions to the drug itself, or rather to the
presence o f concomitant illnesses or treatments. With the exception of the few
reported cases in which dose adjustment should be made or the injectable dosage
form preferred, treatment with oral glucosamine sulphate, therefore, was fully
compatible with the concomitant illnesses and treatments usually encountered in
The results of this investigation, covering 1506 patients reported on by 252
doctors throughout Portugal, therefore, leads us to conclude that ambulatory oral
treatment with glucosamine sulphate manages most arthmsis patients to full or
partial recovery, whatever the localization of their arthrosis, concomitant illnesses
or treatments, though a dose adjustment may be required in obese patients and in
those receiving concomitant diuretic treatment. The improvement appears to last
for a period of 6 to 12 weeks after the end of treatment, after which time a new
course of treatment is indicated to control possible symptomatic recurrence.
Treatment was well tolerated in the majority of patients, as possible adverse
reactions appeared in only 12.1% of patients. These were mainly light to moderate
epigastric pain or tenderness, heartburn, diarrhoea, nausea, dyspepsia, vomiting
and drowsiness. Patients with gastro-duodenal illnesses, however, may perhaps be
better treated with parenteral glucosamine.
Oml~lucosamine sulphate in d e management of arfhrosis: mporf on a muhi-centre open
invesri8afion in Portugal
In summary, according to these data, oral glucosamine sulphate is a useful
medication for the basic ambulatory management of arthrosic patients. It is
convenient for patients and doctors, and combines efficacy with a high degree
of tolerability. If necessary, it can be used together with other treatments for
concomitant illnesses or with anti-inflammatory analgesic% in patients in whom
inflammation and pain are severe components of the arthrosic disease.
We wish to thank all the doctors throughout Portugal who participated in this investigation and
without whom it would have been impossible tocollect the invaluabledata on so many arthrosis
patients to produce this report.
1. Crolle, G.. and D'Este. E.. (1980). Glucosamine sulphate for the management of arthrosis:
a controlled clinical investigation. cur^ Mod. Res. Opin.. 7, 104.
2. D'Ambrosio, E . , Casa, B., Bompani. R., Scali, G., and Scali, M.. (1981). Gluwsamine
sulphate: a controlled clinical investigation in arthrosis. Pharmthempeufica. 2,504.
3. Drovanti, A,, Bignamini, A. A,, and Rovati, A. L, (1980). Therapeutic activity of oral
glucosamine sulphate in osteoanhmsis: a placebo conmlled doubleblind trial. Clin. the^, 3,
4. Hunold, H . . (1981). Ergebnisse einer Kunzeittherapie mit Dona 200-S. Z. Allg. Med., 57,
5. Mund-Hovm. W. D.. (1980). Konservative Behandlune von Wubenslulen-ArIhrosen mit
Glukosamins;lphat und ~hen~lbutaxon. Eine kontrollicrt;~tudie. Thempiewoche. 30,5922.
6. Mund-Hovm. W. D.. (1980). Die Behandlung von Hulk und Knieaelenk-arthrosen. Z. Alls.
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