CTx Dan Chondroitin1

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Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritispatients 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. Kjaeryy Institute of Sports Medicine Copenhagen and Center for Healthy Aging, Faculty of Health Sciences,Bispebjerg Hospital, DK-2400 NV, University of Copenhagen, DenmarkzDepartment of Clinical Sciences, Section for Rheumatology, Lund University, SwedenxDepartment of Experimental Medical Sciences, Section for Connective Tissue Biology, Lund University, SwedenkDepartment 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 combinationwith 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 withglucosamine (n 12), ibuprofen (n 12) or placebo (n 12) during 12 weeks of strength training of both legs with focus on the quadricepsmuscle. Strength tests (5 repetition maximum), blood and urine sampling were performed before and after the training period. Serum COMPand 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 re-duced in the glucosamine-treated group after the training period ( P 0.012), whereas they did not change in the two other groups. Glucos-amine reduced COMP statistically significant 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 significantly in any of the three experimental groups.

Conclusion: Serum COMP decreased significantly over the 12-week training period when treatment with glucosamine was added to the train-ing 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.

Introduction

Approximately 8e10% of all men and women have osteoar-thritis (OA) in one or more of their joints, which causes dis-

ability, pain and reduced quality of life1

. The diseaseaffects the cartilage, synovium, subchondral bone, tendonsand muscles surrounding the joint. There are a number ofestablished risk factors for OA in the knee such as age, in-creased body mass index (BMI), previous injury or surgeryof the knee, and genetic factors. Studies also suggest that

reduced quadriceps strength is a risk factor as well as a con-sequence of OA in the knee2e5. It has repeatedly beenshown, that exercise reducespain and improves function insubjects with OA of the knee6e9. These beneficial effects

are seen in protocols including both strength and endurancetraining10e17. To our knowledge, it is not known whetherphysical training affects cartilage homeostasis in thesepatients.

Cartilage oligomeric matrix protein (COMP) is a prominentcomponent of cartilage matrix18. This glycoprotein hasa role in governing assembly of type II collagen fibres in car-tilage, and in cooperationwithother matrix proteins it stabi-lizes the collagen network19,20. Patients withkneeOA haveincreased serum concentrations of COMP21e27. Further-more, studies suggest that increased levels of serumCOMP are related to progressive joint damage in kneeOA measured by radiography over a 5-year period28,29.COMP levels are also modified in response to acute exer-cise; an acute bout of exercise elevates serum COMP in

1Trial Registration: Clinical Trials.gov Identifier: NCT00833157.*Address correspondence and reprint requests to: Dr Susanne G.

Petersen, Institute of Sports Medicine Copenhagen and Center forHealthy Aging, Faculty of Health Sciences, Building 8, BispebjergHospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV,Denmark. Tel: 45-35-31-39-48; Fax: 45-35-31-27-33; E-mail:[email protected]

Received 2 February 2009; revision accepted 8 July 2009.

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

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mailto:[email protected]:[email protected]


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healthy adults30,31 as well as in patients with knee OA25,whereas 6 weeks of chronic training did not influence thecirculating levels of COMP25.

Urinary level of c-telopeptide of type-2 collagen (CTX-II)is a putative marker of collagen degradation, and found tobe increased in OA patients32e35. Moreover, in patientswith established knee or advanced hip OA, serum CTX-II

is associated with radiological progression over short-termperiods34,36. Also a long-term study over 5 years showsthat progression of OA is associated with increased urinaryCTX-II37. Finally, a study of young, healthy athletes showsthat sport activities such as running significantly increaseurinary CTX-II levels, whileactivities like swimming do notaffect levels of this marker38.

OA is often treated with non-steroidal anti-inflammatorydrugs (NSAIDs) or glucosamine1,6,39e41. These treatmentsmay relieve pain, but their effects on cartilage and syno-vium metabolism in patients with OA are controversial42,43.In vitrostudies have suggested that NSAIDs may reduce orincrease44e47 the synthesis of cartilage proteoglycans.

Very few studies have examined the effects of NSAIDs orglucosamine on CTX-IIlevels inOA patients33,48e50.Itseems

that only one pilot study has examined the effect of NSAID(Nimesulide) on serum COMP levels in OA patients51. Toour knowledge, no studies have yet investigated the effectof glucosamine on serum COMP levels in OA patients.

The purpose of this study was to investigate, whether 12weeks of muscle strength training in combination with treat-ment with glucosamine or ibuprofen (an NSAID), affectslevels of serum COMP (primary outcome) and urinaryCTX-II (secondary outcome), as indicators of cartilage turn-over, in patients with OA of the knee. A placebo-group wasincluded for control.

Methods

DESIGN

A 12-week doubleblind,placebo controlled,randomized studyof adultswithOA of the knee. Staff personnel not involved in the project randomly assignedpatientsto thethreegroupsusing a randomnumbertable, andotherpersonnelprepared the medication for each patient. All study personnel and participantswere blinded to treatment assignment for the duration of the study.

PARTICIPANTS AND CRITERIA

Todetectchangesin levelsof serumCOMPof 10%or more ata significancelevel of0.05witha power of0.8,and taking intoaccount theinter- and intra-in-dividual variationas well as variation in themethods, approximately10 individ-uals were required in each group. In total 36 patients (20 women, 16 men);aged 50e70yearswithbilateral tibiofemoralOA of theknee,based upon radio-graphs, were recruited in the period January 2005 to January 2006 in Copen-hagen (Denmark) via advertisement in a local newspaper. Subjects wereprescreenedviatelephone or face-to-face interview. Straight anterioreposte-rior radiographs of both knees were obtained, with thepatient standing. An ex-

periencedreader classifiedeachkneefor severityof OAusing theKellgren andLawrence (KL) grading system, with scores from 1 to 452. Inclusion criteriawere age between 50 and 70 years with radiographic evidence of bilateralknee OA (KL-score of 1e4) who met the American College of Rheumatology(ACR) clinical53 and radiographic classification criteria.

At inclusion a medical doctor examined the patients and establisheda medical record for each patient. Normal kidney and liver function was ver-ified by analyses of serum creatinine and alkaline phosphatase. All patientswere negative for rheumatoid factor and their serum uric acid was normal.Patients were excluded if they had severe health problems such as cardio-vascular disease, active cancer, diabetes, kidney or liver diseases, excessalcohol use (>21 alcoholic drinks per week) or severe overweight(BMI> 35). Furthermore none of the subjects had any history of injury or op-eration in the knee, planned kneeejoint replacement, other rheumatologicdiseases, previous gastric ulcer, and none were allergic to the contents ofibuprofen or glucosamine. Being physically active (bicycling or walking)was not an exclusion criterion, but none of the subjects trained regularly orperformed strength training prior to the inclusion in the present study. Priorto the study, all subjects provided written informed consent to participate in

the study. The experimental protocol was approved by the local Ethical Com-mittee for Copenhagen and Frederiksberg Communities (KF 01-189/04). Allprocedures followed were in accordance with the ethical standards of theHelsinki 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 five from both the ibuprofen andplacebo-group had previously taken glucosamine. They were instructed tostop the intake at least 1 month before the study began. Patients were ran-domly assigned to one of three medication groups. They were administeredglucosamine (n 12), NSAID (n 12) or placebo (n 12). The administra-tion of placebo and glucosamine was started 4 weeks before the training,but active NSAID treatment was initiated only 1 week before ( Fig. 1). Wechose to initiate the administration of glucosamine 4 weeks before trainingin order to ensure that glucosamine levels were adequate. Furthermore, ithas been shown that ibuprofen works more quickly than glucosamine, whichhas to be given atleast 2 weeks before you can expect a potential effect onOA symptoms54,55. Subjects in the glucosamine-group were given glucos-amine sulphate tablets (Ferrosan) of 500 mg three times a day and subjectsin the NSAID group were given tablets of 600 mg of ibuprofen (Nycomed)twice a day. Placebo tablets were identically supplied and formulated asthe glucosamine or ibuprofen tablets except that they contained no medicine.The treatment was blinded to the patients, so that all subjects were suppliedthe same amount of pills (five a day) that had similar appearance. To ensurecompliance, the subjects returned the empty packages every week to a lab

technician not involved in other parts of the study. For further control, NSAIDlevels in the blood were traced in the beginning of the training period, as wellas after 6 and 12 weeks. If any of the patients experienced severe pain dur-ing the training period, they were allowed to take rescue medicine 50 mgtramadol (synthetic, monoagonistic opioid), which unlike NSAID does not in-fluence prostaglandin synthesis. Alternatively the subjects were offeredacupuncture.

TRAINING AND TESTING

All three groups of patients performed a strength training program withboth legs for 12 weeks. The program consisted of bilateral progressivestrength 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 min-imum 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 personnelattended every training session and instructed the subjects performing theexercises. Training intensity was changed from 15 to 8 repetition maximum(RM) (4 sets 12e8 repetitions) from week 0 to 7 to avoid injuries, and wasthereafter maintained at 8 RM (4e5 sets 8 repetitions) for the remainingtraining period. (Definition: 8 RM refers to the maximum load an individualcan exert in an exercise no more or no less than eight times with his/her max-imal effort.) The relative workload was 70e80% of 1 RM through all 12weeks, and training load was adjusted on a weekly basis. Furthermore, 5RM strength tests were performed in the first week of the study, after 6weeks, and in the last week of the training study (Fig. 1). 5 RM tests wereperformed both in the knee extension and in the leg-press machine. After ev-ery strength training session, subjects were given a 200 ml chocolate milkdrink (Matilde classic, Arla), which is known to ensure optimal muscle proteinsynthesis56.

URINE AND BLOOD SAMPLING

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

Fig. 1. Time-schedule.

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physical activity before sampling. No formal training was carried out for a min-imum of 48 h prior to blood and urine sampling. On the day of the samplingthe subjects met in the laboratory after having consumed a standardized,regular breakfast. Venous blood samples were drawn and serum preparedin a standard way and stored at 80C until analysis. The subjects them-selves collected the urine in the morning (first morning void), before theymet in the laboratory. The urine samples were stored at 20C untilmeasurement.

COMP AND CTX-II ANALYSIS

Serum COMP was measured by a sandwich ELISA (COMPELISA; Ana-Mar Medical AB, Lund, Sweden). Urinary CTX-II was measured bya compet-itive ELISA (Cartilaps, Nordic Bioscience, Herlev, Denmark)57. UrinaryCTX-II measurements were corrected for urinary creatinine measured bya standard colorimetric assay using a kit from Konelab (Espoo, Finland).

Biomarkers were analyzed in duplicate in ELISA by trained labtechnicians.

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-trans-formed dependent variable (marker-level) to improve approximation of the

normal distribution. To evaluate the combined effect of training and treatmentover time within each group, paired t tests were used. The change in log-transformed marker-level from pre to post treatment was compared betweengroups using an analysis of variance model with treatment as factor and log-transformed pre-treatment marker-level as a covariate. Treatment differ-ences were estimated from the model and 95% confidence intervals werecalculated. The results in the text are expressed as relative changes ob-tained by back-transforming the estimates from the model.

Pvalues< 0.05 were considered significant, and all tests were two tailed.

Results

The total number of persons prescreened viatelephoneor face-to-face interview during the recruitment period was181 (Fig. 2). Of these, 36 were randomized, and 145 were

Fig. 2. Progress of participants throughout the trial.

Table I

Baseline characteristics of participants in the three groupsGlucosamine Ibuprofen Pl acebo

Sample size 12 11 12Gender 7F/5 M 7F/4 M 7F/5 MAge (years) 62.2 3.4 61.7 5.2 63.1 4.7Body weight (kg) 78 14 83 17 82 14Height (cm) 168 11 172 9 169 9BMI (kg m2) 27.3 3.3 27.9 3.9 28.3 3.2X-ray (KL-score) 2.5 0.8 2.3 1.0 2.2 1.0COMP baseline(U/L)

13.6 /O 1.3 14.3 /O 1.3 13.8/O 1.4

CTX-II baseline(ng/mmol)

514.3/O 2.2 327.2/O 1.6 304.6/O 1.6

Data for continuous measures are meanSD. Data for bio-markers are backtransformed factor means /O factor SD.

Fig. 3. Leg-press 5 RM tests. All groups increased significantly instrength (***P 0.001).

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


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either disqualified or not interested in participation. Themost common reason for disqualification were lack ofknee OA on X-ray or unilateral OA (28%), major healthproblems that met exclusion criteria (22%), previous knee-trauma or operation (19%), age under 50 or over 70(10%), other rheumatologic diseases (5%), regular training(8%), previous gastric ulcer (4%) or intolerance/allergy to-wards contents of glucosamine or ibuprofen (4%). Of the36 randomized participants, 35 subjects completed thestudy. The one subject belonging to the ibuprofen groupwithdrew for personal reasons. During the analysis for se-rum COMP, one blood sample (pre-treatment) was missingon another subject from the Ibuprofen group, but this wasnot the case when analyzing for CTX-II. There were no dif-ferences between the groups with respect to subject char-acteristics at the inclusion of the study (Table I).

All participants were physically active on a light to moder-ate level (bicycling or walking) but none of them trained reg-ularly or performed strength training prior to inclusion in thepresent study.

Upon completion of the training period, there was no differ-ence between the groups with regard to participation

(95 1%) in training sessions. No patient reported any sideeffects of the project drugs during the study. The blood sam-ples that were analyzed for ibuprofen, revealed that all pa-tients in the ibuprofen group took their medication as theywere instructed, and none from the two other groups tookany ibuprofen during the project. Three subjects (two fromthe placebo-group, and one from the ibuprofen group) used

the rescue medicine tramadol for a short period (


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strength improved to a similar degree (around 50%) whetherindividuals were treated with NSAID (ibuprofen), glucos-amine or placebo (Figs. 2 and 3). Training per se did notseem to induce changes in circulating levels of markers forcartilage degradation, which is in line with previous find-ings25. Analyses of the specific medication-effect, revealedthat glucosamine decreased COMP significantly comparedto treatment with placebo or ibuprofen. Clearly, from thesedata it is notpossibleto elucidatewhether this reductionin se-rum COMP levels transforms into a better clinical status inthese patients. From earlier findings it is doubtful as towhether glucosamine per se has any beneficial effect onOA symptoms42. Whereas some studies show a beneficialclinical effect of glucosamine per se42,58e60 others havefound no difference between glucosamine treatment andpla-cebo groups61e63. A general critique of some of the previousstudies has been that they were small, had poor design andflaws in the data analysis, and that there has been a potentialfor sponsor bias64e66. Furthermore, to our knowledge onlyone study has previously tried to combine physical trainingwith glucosamine in knee OA patients62. Inthat study, nosig-nificant effect of the treatment was found after 6 monthsofcombined treatment, either on function, pain or mobility62.Muscle strength in that study showed similar alterations, inthat they did not find any major difference between glucos-amine and placebo groups.Post hocanalysis from the studyof Messier, did, however, indicate that more pill-compliant OAsubjects had more improvements in pain and mobility thanless compliant individuals. Taken together, our present find-ings suggest an effect by glucosamine on the response ofthe OA cartilage to a period of joint loading in humans withknee OA.

There is evidencein vitrothat physiologic concentrationsof glucosamine can induce a diminished proteolytic activityof matrixmetalloproteinase and increased synthesis of ag-grecan67. Furthermore, some animal studies have shownthat glucosamine can stimulate the regeneration of carti-lage68,69. It is thus possible that the altered COMP levelswe now observe reflect an altered cartilage metabolism,

and if sustained over a long time this might influence jointmorphology and clinical presentation.

Regarding CTX-II levels in our study, no significantchanges were observed in any of the three experimentalgroups. Interestingly, however, patients from the glucos-amine-treated group with high baseline CTX-II levels re-sponded with slightly reduced CTX-II levels after thetraining. This is in agreement with previous findings, whereglucosamine treatment decreased se-CTX-II more in OApatients with high cartilage turnover than in patients witha lower cartilage turnover33. Thus, a higher turnover of car-tilage components may be associated with a higher likeli-hood of response to treatment with glucosamine.

Acute exercise has been shown to influence circulatinglevels of COMP25,31, and even moderate amounts of dy-

namic exercise like walking or gymnastics have beenshown to lead to 10e20% elevated circulating levels ofCOMP immediately after theevent, both in healthy individ-uals31 and in OA patients25. It is, however, important tonote that serum levels of COMP are normalized already30 min after exercise25,31 implying that the effect was ratheran effect of clearance than a metabolic effect. However, thepatients in our study were investigated at least 24 h after thelast training bout, and it is unlikely that acute exercise influ-enced our results. Only after very extreme exercise boutslike a marathon run in healthy individuals,was up to 24 h re-quired for normalization of COMP levels30. Furthermore, oursampling of blood in the OA patients was performed at thesame time of the day, to avoid any influence of diurnal var-iation in COMP concentrations70,71. In the present study

only circulating levels of COMP were determined, and exactevaluation of changes in the joint is therefore not possible.However, as cartilage is a major contributor to circulatingCOMP levels72,73, the reduction in COMP levels most likelyrepresents reduced degradation of cartilage in the loaded

joints. It could, however, also represent changes in extra-cartilage degradation of COMP, since COMP is not onlyfound in cartilage, but also in tendon, ligaments, interverte-bral discs, etc74. However, it is shown that the concentrationof 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. Nosignificant alterations in CTX levels were observed in any of the groups.

Table IIMean effects of treatments, with the log-transformed pre-treatment

value of the dependent marker as a covariate

Glucosamine vsplacebo

Ibuprofen vsplacebo

Glucosamine vsibuprofen

COMP 13 (24 to1)* 4 (10 to 20) 17 (28 to 4)*CTX-II 38 (19 to 135) 39 (16 to 132) 1 (42 to 69)

Data are mean percent, in parentheses 95% confidence

intervals.

*Star signifies the presence of statistically significant treatment

effect, here seen as a difference in serum levels of COMP between

glucosamine and placebo (P 0.038) and between glucosamineand ibuprofen (P 0.012).



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cartilage74, so even though there might have been a smallchange in concentration of COMP in the extra-cartilage tis-sues, it constitutes a very small amount of the circulatingCOMP levels. Finally, an alternative, which cannot be ruledout is that our findings may indicate, that the synthesis andrelease of newly synthesized COMP-molecules is de-creased with glucosamine treatment.

In conclusion, glucosamine modified the effect of physicalstrength training in elderly OA patients, in that serum COMPwas significantly reduced over the 12-week training periodwhen glucosamine was added to the training regimen.This suggests an effect of glucosamine on the responseof the OA cartilage to a period of joint loading in humanswith knee OA.

Conflict of interest

DH and TS are cofounders and minor shareholders inAnaMar Medical.

AcknowledgementsWe thank all the patients for their time and devotion to thestudy. Additionally, we thank the laboratory at Lund Univer-sity for analyzing the serum samples for COMP, Ann Chris-tina R. Reimann and Ann-Marie Sedstrom for theirtechnical assistance, and Katja Heinegaard and AbigailMackey for writing assistance. Finally we thank Nina Beyerfor advises on patient testing and training protocols, and S-ren Reitelseder, Troels Gravers Pedersen, TrineHonnens deLichtenberg, Lone Hrdum Larsen, Signe :stergaard, InaWieland for their assistance with exercising the patients.This waswork wassupported by theDanish Rheumatism As-sociation, Danish Ministry of Health, Nordea Foundation andIMK (Ib Mogens Kristiansen) Almene Fond.

Supplementary material

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

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