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 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 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.