Glucosamine/chondroitin combined with exercise for the treatment
of knee osteoarthritis: a preliminary study
S. P. Messier Ph.D.y*, S. Mihalko Ph.D.y, R. F. Loeser M.D.z, C. Legault Ph.D.x, J. Jolla M.S.y,
J. Pfruender M.S.y, B. Prosser B.S.y, A. Adrian B.S.y and J. D. Williamson M.D., M.P.H.k
yDepartment of Health and Exercise Science, Wake Forest University, Winston-Salem,
NC 27109, United States
zSection on Molecular Medicine, Wake Forest University, Winston-Salem, NC 27109, United States
xSection on Biostatistics, Wake Forest University, Winston-Salem, NC 27109, United States
kSection on Gerontology and Geriatric Medicine, Wake Forest University, Winston-Salem,
NC 27109, United States
Objective: This preliminary study sought to determine whether using 1500/1200 mg of glucosamine hydrochloride and chondroitin sulfate (GH/
CS) is effective, both separately and combined with exercise, compared to a placebo plus exercise program in improving physical function,
pain, strength, balance, and mobility in older adults with knee osteoarthritis (OA).
Methods: This double-blind, placebo-controlled, randomized clinical trial lasted 12 months. Participants included 89 older adults (age? 50
years) with knee OA randomized to either GH/CS or placebo group. Phase I was a 6-month trial comparing the effects of assignment to either
GH/CS or placebo. Phase II added 6 months of exercise for both groups. The primary outcome measure was Western Ontario and McMaster
University Osteoarthritis Index (WOMAC) function, and secondary outcome measures included WOMAC pain, 6-min walk, balance, and knee
Results: Of the 89 randomized participants, 72 (81%) completed the study. The median pill compliance was 94% and 95% in Phase I, and, in
Phase II, 97% and 91% for the GH/CS and placebo groups, respectively. Median exercise compliance during Phase II was 77% for the GH/CS
group and 78% for the placebo group. WOMAC function and pain did not differ significantly between the groups at 6- or 12-month follow-up.
There were also no significant differences between the groups in 6-min walk or knee strength; however, balance was better in the placebo
group with approximately a 10% difference compared to the GH/CS group.
Conclusions: The GH/CS group was not superior to the placebo group in function, pain, or mobility after both phases of the intervention (pill
only and pill plus exercise).
ª 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Key words: Glucosamine, Chondroitin, Exercise, Knee osteoarthritis, Nutraceutical, Dietary supplement.
Recently, osteoarthritis (OA) treatment using glucosamine
and chondroitin has gained widespread use. Classified as
prescription drugs in continental Europe, glucosamine and
chondroitin are less regulated dietary supplements in the
United States and Great Britain. Several studies have
shown that glucosamine sulfate was effective in reducing
pain and other OA symptoms compared to a placebo1e3.
In contrast, Rindone et al.4found no difference in knee
pain between glucosamine sulfate and a placebo. The re-
sults of several meta-analyses suggest that the effect of glu-
cosamine sulfate ranges from a modest, short-term effect
on pain to structural efficacy5e8. McAlindon et al.6noted
that the available studies had design and data analysis
flaws, including small number of participants, small treatment
effects, short duration, publication bias, selective publication
of positive trials, unaccounted-for use of concomitant pain
medications, and lack of intent-to-treat analysis.
In a more recent meta-analysis, Richy et al.5concluded
that 1500 mg of glucosamine sulfate taken for 3 years slows
the degenerative process. This conclusion was based pri-
marily on the strength of two long-term randomized clinical
trials that showed significant improvements in self-reported
physical function and significantly less OA knee disease
progression after 3 years of treatment2,9. Preliminary data
from the glucosamine unum in die efficacy (GUIDE) trial
performed in Europe found patients using glucosamine sul-
fate for 6 months had significantly less knee pain than a pla-
cebo3. Recent evidence from the glucosamine/chondroitin
arthritis intervention trial (GAIT), a Phase III clinical trial,
found no difference in overall Western Ontario and McMas-
ter University Osteoarthritis Index (WOMAC) pain scores
after 24 weeks of receiving either glucosamine hydrochlo-
ride (GH), chondroitin sulfate (CS), glucosamine plus
*Address correspondence and reprint requests to: Dr Stephen P.
Messier, Ph.D., J.B. Snow Biomechanics Laboratory, Department
of Health and Exercise Science, Wake Forest University, P.O.
Box 7868, Reynolda Station, Winston-Salem, NC 27109, United
States. Tel: 1-336-758-5849; Fax: 1-336-758-4680; E-mail: mess
Received 20 June 2006; revision accepted 9 April 2007.
OsteoArthritis and Cartilage (2007) 15, 1256e1266
ª 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
chondroitin, celecoxib, or a placebo10. A recent Cochrane
review concluded that clinical trials using the Rotta Pharma-
ceutical preparation of glucosamine sulfate were more
effective than studies using other glucosamine sulfate for-
mulas; however, the results were not uniformly positive7.
Some people have suggested that a combination of glu-
cosamine and CS is efficacious in OA. Two studies reported
that a combination of glucosamine, chondroitin, and manga-
nese ascorbate significantly improved pain in adults with
knee OA11,12. Similarly, a combination therapy that included
glucosamine, chondroitin, and vitamin C improved temporo-
mandibular joint pain in 40 out of 50 participants13. Second-
ary results from the GAIT trial found a beneficial effect in the
combination of glucosamine and chondroitin, however, only
in participants with moderate to severe pain10. Taken to-
have beneficial effects (effect sizes 0.44 and 0.78 for glucos-
amine and chondroitin, respectively) on joint pain from OA14.
Exercise is a proven non-pharmacologic treatment for knee
pain, and strength and does not exacerbate disease progres-
drochloride and chondroitin sulfate (GH/CS) therapy combined
with exercise would be additive, resulting in greater improve-
ments in function, pain, and mobility than exercise alone. We
proposed a two-phase, short-term, preliminary study in older
adults with knee OA to compare the effects of GH plus CS to
a placebo (Phase I) on function, pain, mobility, strength, and
balance, and the added effects of exercise therapy (Phase II).
Patients and methods
The glucosamine/chondroitin and training exercise study
(GATES) was a 12-month, double-blind, placebo-controlled,
randomized clinical trial (RCT) of older adults with knee OA.
Phase I was a 6-month trial designed to compare the effects
of assignment to either a combination of GH/CS or a pla-
cebo. Phase II added identical 6-month exercise programs
for both groups. The study was conducted at the Wake For-
est University Clinical Research Center with the approval of
the University’s Institutional Review Board.
Recruitment techniques included phone calls and mail-
ings to participants in previous knee OA clinical trials who
had provided consent for notification of future trials; adver-
tisements in local newspapers; and informational sessions
at senior centers, assisted-living facilities, and local
churches. Recruitment was open to people aged ?50 years
with radiographic evidence of mild to moderate knee OA
(KellgreneLawrence grade IIeIII20) who met the American
College of Theumatology (ACR) classification criteria21. Re-
cruitment specifically targeted minority groups by placing
ads in a local minority newspaper and sending letters an-
nouncing the trial to minority churches. Dates for recruit-
ment were August 2002eDecember 2003. Recruitment
waves began every 3 months and follow-up at 6 (FU6)
and 12 (FU12) months. The study ended in December 2004.
Inclusion criteria included age? 50 years with radiographic
evidence of mild to moderate knee OA (KellgreneLawrence
grade IIeIII20) who met the ACR clinical21, and radiographic
classification criteria or confirmation of mild to moderate radio-
currently participating in another intervention study. Exclusion
criteria included dementia (Mini-Mental State Examination
[MMSE]< 24); active cancer other than skin cancer; anemia
(participants with an hematocrit (HCT)< 32 (or a hemoglobin
rum creat>2); hepatic disease (the effects of hepatic disease
on the response to exercise or GH/CS that are metabolized in
sistedatleast128 min6 min;completionofmorethan20 minof
formal exercise per week during the past 3 months; planned
ity to swallow a test pill; allergy to shellfish; exposure to
glucosamine and/or chondroitin in the 6 months prior to ran-
domization; unwilling to discontinue current arthritis medica-
tions during the 2-week washout period and 12-month
intervention period, with the exception of a rescue medication;
less than 80% compliance rate during run-in period (see Mea-
surements and procedures); failure to complete graded exer-
cise test (GXT); required human assistance with activities
related to knee pain (e.g., walking up and down stairs; getting
in or out of a chair, etc.); recent knee surgeries, or knee injec-
tions such as cortisone and hyaluronic acid; and inability to
read or speak English.
PHASE I: GH/CS VS PLACEBO
Prior to randomization, participants underwent a 2-week
run-in, washout period; that is, they discontinued all over-
the-counter or prescription medications. These medications
and the number of patients using them at baseline were
non-steroidal anti-inflammatory drugs (NSAIDs): 16, 18;
acetaminophen: 46, 37; aspirin: 25, 26; narcotic: 4, 1; and
migraine analgesic: 5, 3 for the treatment and placebo
groups, respectively. Rescue medication (acetaminophen:
maximum dosage 4 g d?1) and any other necessary medi-
cations unrelated to OA were permitted. All participants re-
ceived an unblinded 2-week supply of the placebo (three
pills per day). At the end of the 2-week period, the bottles
were returned to the study staff. Pill compliance was calcu-
lated as the number of pills taken/number prescribed.
A compliance rate below 80% was an exclusion criterion.
After the run-in/washout period, participants were random-
ized to either a glucosamine/chondroitin group or a placebo
with 1500/1200 mg of unlabeled GH/CS per day for 6 months.
The participants were given a choice of either once or three
times per day regimens. The control group took a placebo
of identical size, color, and shape at the same frequency.
Both groups attended six healthy lifestyle classes on such
topics as living with OA, healthy eating, and exercise, de-
signed to keep participants interested and involved in the
study until the beginning of Phase II. Each participant also
met monthly with a research interventionist to monitor study
compound and rescue medication use (pill counts), to review
Osteoarthritis and Cartilage Vol. 15, No. 11
relevant outcomes to antirheumatic drug therapy in pa-
tients with osteoarthritis of the hip or knee. J Rheuma-
tol 1988 Dec;15(12):1833e40.
24. Bellamy N. Outcome measurement in osteoarthritis
clinical trials. J Rheumatol Suppl 1995 Feb;43:
25. Penninx BW, Messier SP, Rejeski WJ, Williamson JD,
DiBari M, Cavazzini C, et al. Physical exercise and
the prevention of disability in activities of daily living
in older persons with osteoarthritis. Arch Intern Med
2001 Oct 22;161(19):2309e16.
26. Folstein MF, Folstein SE, McHugh PR. A practical
method for grading the cognitive state of patients for
the clinician. J Psychiatr Res 1975;12:189e98.
27. Jensen RC, Warren B, Laursen C, Morrissey MC. Static
pre-load effect on knee extensor isokinetic concentric
and eccentric performance. Med Sci Sports Exerc
28. Blaszczyk JW, Lowe DL, Hansen PD. Ranges of pos-
tural stability and their changes in the elderly. Gait
29. Whitney RJ. The stability provided by the feet during
manoeuvres whilst standing. J Anat 1962 Jan;96:
30. Michel BA,Stucki G,
Vignon E, Bruehlmann P, et al. Chondroitins 4 and
6 sulfate in osteoarthritis of the knee: a randomized,
controlled trial. Arthritis Rheum 2005 Mar;52(3):
31. Pham T, van der HD, Altman RD, Anderson JJ,
Bellamy N, Hochberg M, et al. OMERACT-OARSI ini-
tiative: osteoarthritis research society international set
of responder criteria for osteoarthritis clinical trials
revisited. Osteoarthritis Cartilage 2004 May;12(5):
32. Du J, White N, Eddington ND. The bioavailability and
pharmacokinetics of glucosamine hydrochloride and
chondroitin sulfate after oral and intravenous single
dose administration in the horse. Biopharm Drug Dis-
pos 2004 Apr;25(3):109e16.
33. Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF,
Plaas AH. Synovial fluid levels and serum pharmaco-
kinetics in a large animal model following treatment
with oral glucosamine at clinically relevant doses.
Arthritis Rheum 2005 Jan;52(1):181e91.
34. Setnikar I, Giachetti C, Zanolo G. Absorption, distribu-
tion and excretion of radioactivity after a single intrave-
nous or oral administration of [14C] glucosamine to the
rat. Pharmatherapeutica 1984;3(8):538e50.
35. PersianiS, RodaE,
Giacovelli G, Roda A. Glucosamine oral bioavailability
and plasma pharmacokinetics after increasing doses
of crystalline glucosamine sulfate in man. Osteoarthri-
tis Cartilage 2005 Dec;13(12):1041e9.
Frey D, De Vathaire F,
36. Persiani S, Locatelli M, Fiorentino S, Rovati LC, Roda
A. Absolute bioavailability of glucosamine after admi-
nistration of crystalline glucosamine sulfate in rats.
In: Proceedings of the American College of Rheuma-
tology Annual Meeting, 5 A.D. Nov 15, San Diego,
37. Persiani S, Rotini R, Trisolini G, Rovati LC, Locatelli M,
Roda A. Glucosamine plasma and synovial fluid con-
centrations before and after oral administration of
crystalline glucosamine sulfate in knee osteoarthritis
patients. In: Proceedings of the American College of
Rheumatology Annual Meeting, 5 A.D. Nov 15, San
38. Clegg DO, Reda DJ, Harris CL, Klein MA. The efficacy
of glucosamine and chondroitin sulfate in patients with
painful knee osteoarthritis (OA): the Glucosamine/
Chondroitin Arthritis Intervention Trial (GAIT), 5 A.D.
Nov 16, San Diego, 2005.
39. Poolsup N, Suthisisang C, Channark P, Kittikulsuth W.
Glucosamine long-term treatment and the progression
of knee osteoarthritis: systematic review of random-
ized controlled trials. Ann Pharmacother 2005 Jun;
40. Hoffer LJ, Kaplan LN, Hamadeh MJ, Grigoriu AC,
Baron M. Sulfate could mediate the therapeutic effect
of glucosamine sulfate. Metabolism 2001 Jul;50(7):
41. Adebowale A, Du J, Liang Z, Leslie JL, Eddington ND.
The bioavailability and pharmacokinetics of glucos-
amine hydrochloride and low molecular weight chon-
droitin sulfate after single and multiple doses to
beagle dogs. Biopharm Drug Dispos 2002 Sep;23(6):
42. Cho SY, Sim JS, Jeong CS, Chang SY, Choi DW,
Toida T, et al. Effects of low molecular weight chon-
droitin sulfate on type II collagen-induced arthritis in
DBA/1J mice. Biol Pharm Bull 2004 Jan;27(1):
43. Baici A, Horler D, Moser B, Hofer HO, Fehr K,
Wagenhauser FJ. Analysis of glycosaminoglycans in
human serum after oral administration of chondroitin
sulfate. Rheumatol Int 1992;12(3):81e8.
44. Lippiello L, Woodward J, Karpman R, Hammad TA.
In vivo chondroprotection and metabolic synergy of
glucosamine and chondroitin sulfate. Clin Orthop
45. Eckstein F, Glaser C. Measuring cartilage morphology
with quantitative magnetic resonance imaging. Semin
Musculoskelet Radiol 2004;8(4):329e53.
46. Hudelmaier M, Glaser C, Hohe J, Englmeier KH,
Reiser M, Putz R, et al. Age-related changes in
the morphology and deformational behavior of knee
joint cartilage. Arthritis Rheum 2001 Nov;44(11):
S. P. Messier et al.: Glucosamine/chondroitin exercise