Osteoarthritis and Cartilage (2010) 18, 34e40

2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.joca.2009.07.004

Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis

patients in response to physical training1
S. G. Peterseny*, T. Saxnez, D. Heinegardx, M. Hanseny, L. Holmy, S. Koskineny, C. Stordaly,
H. Christensenk, P. Aagaard{ and M. Kjaery
y Institute of Sports Medicine Copenhagen and Center for Healthy Aging, Faculty of Health Sciences,
Bispebjerg Hospital, DK-2400 NV, University of Copenhagen, Denmark
z Department of Clinical Sciences, Section for Rheumatology, Lund University, Sweden
x Department of Experimental Medical Sciences, Section for Connective Tissue Biology, Lund University, Sweden
k Department of Radiology, Bispebjerg Hospital, University of Copenhagen, Denmark
{ Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Denmark
Summary
Objective: To investigate changes in levels of serum cartilage oligomeric matrix protein (COMP) and urine c-telopeptide of type-2 collagen
(CTX-II) as markers for cartilage turnover in patients with osteoarthritis (OA) of the knee, in response to muscle strength training in combination
with treatment with glucosamine, ibuprofen or placebo.
Design: A 12-week double blind, placebo controlled, randomized study.
Method: Thirty-six elderly patients with bilateral tibiofemoral knee OA determined by radiography were randomly assigned to treatment with
glucosamine (n 12), ibuprofen (n 12) or placebo (n 12) during 12 weeks of strength training of both legs with focus on the quadriceps
muscle. Strength tests (5 repetition maximum), blood and urine sampling were performed before and after the training period. Serum COMP
and urinary CTX-II were measured by enzyme-linked immunosorbent assay (ELISA).
Results: All three groups increased their muscle strength following 12 weeks of strength training (P < 0.001). Serum COMP levels were reduced in the glucosamine-treated group after the training period (P 0.012), whereas they did not change in the two other groups. Glucosamine reduced COMP statistically signicant compared to both placebo and ibuprofen; the mean reduction with glucosamine was 13% vs
placebo (P 0.0378) and 17% vs ibuprofen (P 0.0122).
Urinary CTX-II levels did not change signicantly in any of the three experimental groups.
Conclusion: Serum COMP decreased signicantly over the 12-week training period when treatment with glucosamine was added to the training regimen. This suggests an effect by glucosamine on the response of the OA cartilage to a period of joint loading in humans with knee OA.
2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Key words: Glucosamine, Dietary supplement, NSAID, Ibuprofen, Exercise, Knee osteoarthritis, Cartilage oligomeric matrix protein,
c-Telopeptide of type II collagen.

reduced quadriceps strength is a risk factor as well as a consequence of OA in the knee2e5. It has repeatedly been
shown, that exercise reduces pain and improves function in
subjects with OA of the knee6e9. These benecial effects
are seen in protocols including both strength and endurance
training10e17. To our knowledge, it is not known whether
physical training affects cartilage homeostasis in these
patients.
Cartilage oligomeric matrix protein (COMP) is a prominent
component of cartilage matrix18. This glycoprotein has
a role in governing assembly of type II collagen bres in cartilage, and in cooperation with other matrix proteins it stabilizes the collagen network19,20. Patients with knee OA have
increased serum concentrations of COMP21e27. Furthermore, studies suggest that increased levels of serum
COMP are related to progressive joint damage in knee
OA measured by radiography over a 5-year period28,29.
COMP levels are also modied in response to acute exercise; an acute bout of exercise elevates serum COMP in

Introduction
Approximately 8e10% of all men and women have osteoarthritis (OA) in one or more of their joints, which causes disability, pain and reduced quality of life1. The disease
affects the cartilage, synovium, subchondral bone, tendons
and muscles surrounding the joint. There are a number of
established risk factors for OA in the knee such as age, increased body mass index (BMI), previous injury or surgery
of the knee, and genetic factors. Studies also suggest that
1

Trial Registration: Clinical Trials.gov Identier: NCT00833157.

*Address correspondence and reprint requests to: Dr Susanne G.
Petersen, Institute of Sports Medicine Copenhagen and Center for
Healthy Aging, Faculty of Health Sciences, Building 8, Bispebjerg
Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV,
Denmark. Tel: 45-35-31-39-48; Fax: 45-35-31-27-33; E-mail:
sp12@bbh.regionh.dk
Received 2 February 2009; revision accepted 8 July 2009.

34

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Osteoarthritis and Cartilage Vol. 18, No. 1

healthy adults30,31 as well as in patients with knee OA25,
whereas 6 weeks of chronic training did not inuence the
circulating levels of COMP25.
Urinary level of c-telopeptide of type-2 collagen (CTX-II)
is a putative marker of collagen degradation, and found to
be increased in OA patients32e35. Moreover, in patients
with established knee or advanced hip OA, serum CTX-II
is associated with radiological progression over short-term
periods34,36. Also a long-term study over 5 years shows
that progression of OA is associated with increased urinary
CTX-II37. Finally, a study of young, healthy athletes shows
that sport activities such as running signicantly increase
urinary CTX-II levels, while activities like swimming do not
affect levels of this marker38.
OA is often treated with non-steroidal anti-inammatory
drugs (NSAIDs) or glucosamine1,6,39e41. These treatments
may relieve pain, but their effects on cartilage and synovium metabolism in patients with OA are controversial42,43.
In vitro studies have suggested that NSAIDs may reduce or
increase44e47 the synthesis of cartilage proteoglycans.
Very few studies have examined the effects of NSAIDs or
glucosamine on CTX-II levels in OA patients33,48e50. It seems
that only one pilot study has examined the effect of NSAID
(Nimesulide) on serum COMP levels in OA patients51. To
our knowledge, no studies have yet investigated the effect
of glucosamine on serum COMP levels in OA patients.
The purpose of this study was to investigate, whether 12
weeks of muscle strength training in combination with treatment with glucosamine or ibuprofen (an NSAID), affects
levels of serum COMP (primary outcome) and urinary
CTX-II (secondary outcome), as indicators of cartilage turnover, in patients with OA of the knee. A placebo-group was
included for control.
Methods
DESIGN
A 12-week double blind, placebo controlled, randomized study of adults with
OA of the knee. Staff personnel not involved in the project randomly assigned
patients to the three groups using a random number table, and other personnel
prepared the medication for each patient. All study personnel and participants
were blinded to treatment assignment for the duration of the study.

PARTICIPANTS AND CRITERIA

To detect changes in levels of serum COMP of 10% or more at a signicance
level of 0.05 with a power of 0.8, and taking into account the inter- and intra-individual variation as well as variation in the methods, approximately 10 individuals were required in each group. In total 36 patients (20 women, 16 men);
aged 50e70 years with bilateral tibiofemoral OA of the knee, based upon radiographs, were recruited in the period January 2005 to January 2006 in Copenhagen (Denmark) via advertisement in a local newspaper. Subjects were
prescreened via telephone or face-to-face interview. Straight anterioreposterior radiographs of both knees were obtained, with the patient standing. An experienced reader classied each knee for severity of OA using the Kellgren and
Lawrence (KL) grading system, with scores from 1 to 452. Inclusion criteria
were age between 50 and 70 years with radiographic evidence of bilateral
knee OA (KL-score of 1e4) who met the American College of Rheumatology
(ACR) clinical53 and radiographic classication criteria.
At inclusion a medical doctor examined the patients and established
a medical record for each patient. Normal kidney and liver function was veried by analyses of serum creatinine and alkaline phosphatase. All patients
were negative for rheumatoid factor and their serum uric acid was normal.
Patients were excluded if they had severe health problems such as cardiovascular disease, active cancer, diabetes, kidney or liver diseases, excess
alcohol use (>21 alcoholic drinks per week) or severe overweight
(BMI > 35). Furthermore none of the subjects had any history of injury or operation in the knee, planned kneeejoint replacement, other rheumatologic
diseases, previous gastric ulcer, and none were allergic to the contents of
ibuprofen or glucosamine. Being physically active (bicycling or walking)
was not an exclusion criterion, but none of the subjects trained regularly or
performed strength training prior to the inclusion in the present study. Prior
to the study, all subjects provided written informed consent to participate in

the study. The experimental protocol was approved by the local Ethical Committee for Copenhagen and Frederiksberg Communities (KF 01-189/04). All
procedures followed were in accordance with the ethical standards of the
Helsinki Declaration of 1975, as revised in 2000.

MEDICATION
Four patients from each group were previously treated with NSAID. Seven
patients from the glucosamine-group and ve from both the ibuprofen and
placebo-group had previously taken glucosamine. They were instructed to
stop the intake at least 1 month before the study began. Patients were randomly assigned to one of three medication groups. They were administered
glucosamine (n 12), NSAID (n 12) or placebo (n 12). The administration of placebo and glucosamine was started 4 weeks before the training,
but active NSAID treatment was initiated only 1 week before (Fig. 1). We
chose to initiate the administration of glucosamine 4 weeks before training
in order to ensure that glucosamine levels were adequate. Furthermore, it
has been shown that ibuprofen works more quickly than glucosamine, which
has to be given at least 2 weeks before you can expect a potential effect on
OA symptoms54,55. Subjects in the glucosamine-group were given glucosamine sulphate tablets (Ferrosan) of 500 mg three times a day and subjects
in the NSAID group were given tablets of 600 mg of ibuprofen (Nycomed)
twice a day. Placebo tablets were identically supplied and formulated as
the glucosamine or ibuprofen tablets except that they contained no medicine.
The treatment was blinded to the patients, so that all subjects were supplied
the same amount of pills (ve a day) that had similar appearance. To ensure
compliance, the subjects returned the empty packages every week to a lab
technician not involved in other parts of the study. For further control, NSAID
levels in the blood were traced in the beginning of the training period, as well
as after 6 and 12 weeks. If any of the patients experienced severe pain during the training period, they were allowed to take rescue medicine 50 mg
tramadol (synthetic, monoagonistic opioid), which unlike NSAID does not inuence prostaglandin synthesis. Alternatively the subjects were offered
acupuncture.

TRAINING AND TESTING

All three groups of patients performed a strength training program with
both legs for 12 weeks. The program consisted of bilateral progressive
strength training of the leg muscles with focus on the quadriceps muscles.
Training was carried out over three sessions per week, 36 sessions in total,
with a minimum of 30 sessions required for all subjects (representing a minimum of 83.3% participation). After a 10 min warm up on a stationary bicycle,
the subjects performed sitting knee extension and leg-press exercises with
one leg at a time in adjustable leg-press and knee-extension machines
(Technogym International). Physiotherapists or physical educated personnel
attended every training session and instructed the subjects performing the
exercises. Training intensity was changed from 15 to 8 repetition maximum
(RM) (4 sets  12e8 repetitions) from week 0 to 7 to avoid injuries, and was
thereafter maintained at 8 RM (4e5 sets  8 repetitions) for the remaining
training period. (Denition: 8 RM refers to the maximum load an individual
can exert in an exercise no more or no less than eight times with his/her maximal effort.) The relative workload was 70e80% of 1 RM through all 12
weeks, and training load was adjusted on a weekly basis. Furthermore, 5
RM strength tests were performed in the rst week of the study, after 6
weeks, and in the last week of the training study (Fig. 1). 5 RM tests were
performed both in the knee extension and in the leg-press machine. After every strength training session, subjects were given a 200 ml chocolate milk
drink (Matilde classic, Arla), which is known to ensure optimal muscle protein
synthesis56.

URINE AND BLOOD SAMPLING

Before and after the 12-week strength training blood and urine samples
were collected from the subjects (Fig. 1), who were asked to limit their

Fig. 1. Time-schedule.

36

S. G. Petersen et al.: Glucosamine alters cartilage turnover

Fig. 2. Progress of participants throughout the trial.

physical activity before sampling. No formal training was carried out for a minimum of 48 h prior to blood and urine sampling. On the day of the sampling
the subjects met in the laboratory after having consumed a standardized,
regular breakfast. Venous blood samples were drawn and serum prepared
in a standard way and stored at 80 C until analysis. The subjects themselves collected the urine in the morning (rst morning void), before they
met in the laboratory. The urine samples were stored at 20 C until
measurement.

normal distribution. To evaluate the combined effect of training and treatment

over time within each group, paired t tests were used. The change in logtransformed marker-level from pre to post treatment was compared between
groups using an analysis of variance model with treatment as factor and logtransformed pre-treatment marker-level as a covariate. Treatment differences were estimated from the model and 95% condence intervals were
calculated. The results in the text are expressed as relative changes obtained by back-transforming the estimates from the model.
P values < 0.05 were considered signicant, and all tests were two tailed.

COMP AND CTX-II ANALYSIS

Serum COMP was measured by a sandwich ELISA (COMPELISA; AnaMar Medical AB, Lund, Sweden). Urinary CTX-II was measured by a competitive ELISA (Cartilaps, Nordic Bioscience, Herlev, Denmark)57. Urinary
CTX-II measurements were corrected for urinary creatinine measured by
a standard colorimetric assay using a kit from Konelab (Espoo, Finland).
Biomarkers were analyzed in duplicate in ELISA by trained lab
technicians.

Results
The total number of persons prescreened via telephone
or face-to-face interview during the recruitment period was
181 (Fig. 2). Of these, 36 were randomized, and 145 were

STATISTICAL ANALYSIS
Statistical Analysis System (SAS, Version 9.2, SAS Institute, Cary, NC)
was used to analyze the data. Analyses were performed on the log-transformed dependent variable (marker-level) to improve approximation of the

Table I
Baseline characteristics of participants in the three groups
Glucosamine

Ibuprofen

Placebo

Sample size
12
11
12
Gender
7F/5 M
7F/4 M
7F/5 M
Age (years)
62.2  3.4
61.7  5.2
63.1  4.7
Body weight (kg)
78  14
83  17
82  14
Height (cm)
168  11
172  9
169  9
2
27.3  3.3
27.9  3.9
28.3  3.2
BMI (kg m )
X-ray (KL-score)
2.5  0.8
2.3  1.0
2.2  1.0
COMP baseline 13.6 /O 1.3
14.3 /O 1.3
13.8 /O 1.4
(U/L)
CTX-II baseline
514.3 /O 2.2 327.2 /O 1.6 304.6 /O 1.6
(ng/mmol)
Data for continuous measures are mean  SD. Data for biomarkers are backtransformed factor means /O factor SD.

Fig. 3. Leg-press 5 RM tests. All groups increased signicantly in

strength (***P  0.001).

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Osteoarthritis and Cartilage Vol. 18, No. 1

(95  1%) in training sessions. No patient reported any side

effects of the project drugs during the study. The blood samples that were analyzed for ibuprofen, revealed that all patients in the ibuprofen group took their medication as they
were instructed, and none from the two other groups took
any ibuprofen during the project. Three subjects (two from
the placebo-group, and one from the ibuprofen group) used
the rescue medicine tramadol for a short period (<5 days)
during the study, two because of training related pain, and
one because of tooth-pain. Furthermore, two persons were
treated with acupuncture (both of them belonged to the ibuprofen group, one of them was also treated with tramadol).
MUSCLE STRENGTH

Following 12 weeks of strength training, all three groups

increased their muscle strength (P < 0.001) as measured
in the 5 RM tests in both the leg-press (Fig. 3) and the
knee-extension machine (Fig. 4).
Fig. 4. Knee extension 5 RM tests. All groups increased signicantly in strength (**P  0.01, ***P  0.001).

either disqualied or not interested in participation. The

most common reason for disqualication were lack of
knee OA on X-ray or unilateral OA (28%), major health
problems that met exclusion criteria (22%), previous kneetrauma or operation (19%), age under 50 or over 70
(10%), other rheumatologic diseases (5%), regular training
(8%), previous gastric ulcer (4%) or intolerance/allergy towards contents of glucosamine or ibuprofen (4%). Of the
36 randomized participants, 35 subjects completed the
study. The one subject belonging to the ibuprofen group
withdrew for personal reasons. During the analysis for serum COMP, one blood sample (pre-treatment) was missing
on another subject from the Ibuprofen group, but this was
not the case when analyzing for CTX-II. There were no differences between the groups with respect to subject characteristics at the inclusion of the study (Table I).
All participants were physically active on a light to moderate level (bicycling or walking) but none of them trained regularly or performed strength training prior to inclusion in the
present study.
Upon completion of the training period, there was no difference between the groups with regard to participation

BIOMARKERS

After the 12 weeks of muscle strength training, there was

a 13% decrease in serum COMP levels (P 0.012) in the
glucosamine-treated group (Fig. 5). In contrast, no signicant change in serum COMP levels was seen after the
training period neither in the placebo nor in the ibuprofen
group. Glucosamine reduced COMP signicantly compared
to the changes with both placebo and ibuprofen; the mean
reduction with glucosamine was 13% vs placebo (95% condence interval: 24e1%, P 0.0378) and 17% vs ibuprofen
(95% condence interval: 28e4%, P 0.0122). There was
no statistically signicant difference between ibuprofen
and placebo (Table II).
Regarding CTX-II levels in our study, no signicant
changes were observed in any of the three experimental
groups (Fig. 6). Interestingly, however, patients from the glucosamine-treated group with high baseline CTX-II levels
(above normal average 1 standard deviation) responded
with slightly reduced CTX-II levels after the training (P 0.1).

Discussion
The present experiment demonstrated that in response to
a period of muscle strength training (12 weeks) muscle

Fig. 5. Levels of serum COMP (on a logarithmic scale) pre and post 12-week of strength training. Each line represents an individual patient.
We observed a statistical signicant decrease in serum COMP levels in the glucosamine-group (P 0.012).

38

S. G. Petersen et al.: Glucosamine alters cartilage turnover

Table II
Mean effects of treatments, with the log-transformed pre-treatment
value of the dependent marker as a covariate
Glucosamine vs
placebo

Ibuprofen vs
placebo

COMP 13 (24 to 1)* 4 (10 to 20)

CTX-II 38 (19 to 135) 39 (16 to 132)

Glucosamine vs
ibuprofen
17 (28 to 4)*
1 (42 to 69)

Data are mean percent, in parentheses 95% condence

intervals.
*Star signies the presence of statistically signicant treatment
effect, here seen as a difference in serum levels of COMP between
glucosamine and placebo (P 0.038) and between glucosamine
and ibuprofen (P 0.012).

strength improved to a similar degree (around 50%) whether

individuals were treated with NSAID (ibuprofen), glucosamine or placebo (Figs. 2 and 3). Training per se did not
seem to induce changes in circulating levels of markers for
cartilage degradation, which is in line with previous ndings25. Analyses of the specic medication-effect, revealed
that glucosamine decreased COMP signicantly compared
to treatment with placebo or ibuprofen. Clearly, from these
data it is not possible to elucidate whether this reduction in serum COMP levels transforms into a better clinical status in
these patients. From earlier ndings it is doubtful as to
whether glucosamine per se has any benecial effect on
OA symptoms42. Whereas some studies show a benecial
clinical effect of glucosamine per se42,58e60 others have
found no difference between glucosamine treatment and placebo groups61e63. A general critique of some of the previous
studies has been that they were small, had poor design and
aws in the data analysis, and that there has been a potential
for sponsor bias64e66. Furthermore, to our knowledge only
one study has previously tried to combine physical training
with glucosamine in knee OA patients62. In that study, no signicant effect of the treatment was found after 6 months of
combined treatment, either on function, pain or mobility62.
Muscle strength in that study showed similar alterations, in
that they did not nd any major difference between glucosamine and placebo groups. Post hoc analysis from the study
of Messier, did, however, indicate that more pill-compliant OA
subjects had more improvements in pain and mobility than
less compliant individuals. Taken together, our present ndings suggest an effect by glucosamine on the response of
the OA cartilage to a period of joint loading in humans with
knee OA.

There is evidence in vitro that physiologic concentrations

of glucosamine can induce a diminished proteolytic activity
of matrix metalloproteinase and increased synthesis of aggrecan67. Furthermore, some animal studies have shown
that glucosamine can stimulate the regeneration of cartilage68,69. It is thus possible that the altered COMP levels
we now observe reect an altered cartilage metabolism,
and if sustained over a long time this might inuence joint
morphology and clinical presentation.
Regarding CTX-II levels in our study, no signicant
changes were observed in any of the three experimental
groups. Interestingly, however, patients from the glucosamine-treated group with high baseline CTX-II levels responded with slightly reduced CTX-II levels after the
training. This is in agreement with previous ndings, where
glucosamine treatment decreased se-CTX-II more in OA
patients with high cartilage turnover than in patients with
a lower cartilage turnover33. Thus, a higher turnover of cartilage components may be associated with a higher likelihood of response to treatment with glucosamine.
Acute exercise has been shown to inuence circulating
levels of COMP25,31, and even moderate amounts of dynamic exercise like walking or gymnastics have been
shown to lead to 10e20% elevated circulating levels of
COMP immediately after the event, both in healthy individuals31 and in OA patients25. It is, however, important to
note that serum levels of COMP are normalized already
30 min after exercise25,31 implying that the effect was rather
an effect of clearance than a metabolic effect. However, the
patients in our study were investigated at least 24 h after the
last training bout, and it is unlikely that acute exercise inuenced our results. Only after very extreme exercise bouts
like a marathon run in healthy individuals, was up to 24 h required for normalization of COMP levels30. Furthermore, our
sampling of blood in the OA patients was performed at the
same time of the day, to avoid any inuence of diurnal variation in COMP concentrations70,71. In the present study
only circulating levels of COMP were determined, and exact
evaluation of changes in the joint is therefore not possible.
However, as cartilage is a major contributor to circulating
COMP levels72,73, the reduction in COMP levels most likely
represents reduced degradation of cartilage in the loaded
joints. It could, however, also represent changes in extracartilage degradation of COMP, since COMP is not only
found in cartilage, but also in tendon, ligaments, intervertebral discs, etc74. However, it is shown that the concentration
of COMP in these tissues is very low in compare to

Fig. 6. Urine CTX-II levels (on a logarithmic scale) pre and post 12-weeks strength training. Each line represents an individual patient. No
signicant alterations in CTX levels were observed in any of the groups.

Osteoarthritis and Cartilage Vol. 18, No. 1

cartilage74, so even though there might have been a small
change in concentration of COMP in the extra-cartilage tissues, it constitutes a very small amount of the circulating
COMP levels. Finally, an alternative, which cannot be ruled
out is that our ndings may indicate, that the synthesis and
release of newly synthesized COMP-molecules is decreased with glucosamine treatment.
In conclusion, glucosamine modied the effect of physical
strength training in elderly OA patients, in that serum COMP
was signicantly reduced over the 12-week training period
when glucosamine was added to the training regimen.
This suggests an effect of glucosamine on the response
of the OA cartilage to a period of joint loading in humans
with knee OA.

Conict of interest
DH and TS are cofounders and minor shareholders in
AnaMar Medical.

Acknowledgements
We thank all the patients for their time and devotion to the
study. Additionally, we thank the laboratory at Lund University for analyzing the serum samples for COMP, Ann Christina R. Reimann and Ann-Marie Sedstrom for their
technical assistance, and Katja Heinegaard and Abigail
Mackey for writing assistance. Finally we thank Nina Beyer
for advises on patient testing and training protocols, and Sren Reitelseder, Troels Gravers Pedersen, Trine Honnens de
Lichtenberg, Lone Hrdum Larsen, Signe :stergaard, Ina
Wieland for their assistance with exercising the patients.
This was work was supported by the Danish Rheumatism Association, Danish Ministry of Health, Nordea Foundation and
IMK (Ib Mogens Kristiansen) Almene Fond.

Supplementary material
Supplementary material associated with this article can
be found, in the online version, at doi:10.1016/j.joca.
2009.07.004.

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