Background/Purpose: Previous studies showed the largest effects of glucosamine on osteoarthritis (OA) symptoms of the knee joint and when used in an early phase of the disease. The present study evaluates the effect of a tailor made diet and exercise program (DEP) and of oral glucosamine sulphate, in a 2×2 factorial design, on the incidence of knee OA over 2.5 years in a high risk group of overweight, middle-aged females; free of clinical knee OA at baseline (ISRCTN 42823086; financed by The Netherlands Organisation for Health Research and Development). Worldwide, this is the first large RCT on prevention of knee OA. Here we present the results of the glucosamine intervention and the interaction with DEP.

Methods: 50 general practitioners contacted all registered women between 50 and 60 years. In total, 407 women met all inclusion criteria (BMI ≥ 27, no clinical knee OA (ACR criteria), no contraindications to MRI, no rheumatic diseases, no recent glucosamine usage), were invited for baseline measurements and were randomised. All subjects were instructed to dissolve and consume 1500 mg of the distributed study drug (crystalline glucosamine sulphate and placebo) each day, for 2.5 years. Pre-specified primary outcome was incidence of knee OA, defined by incidence of either K&L ≥ 2, joint space narrowing of ≥ 1.0 mm or incident clinical knee OA (ACR criteria).

Results: After 2.5 years of follow-up, forty-three women (11%) were lost to follow-up. Twenty-nine percent of all subjects reported one or more adverse events throughout the study; without difference in frequency between groups (p = 0.23). The interaction term between both interventions on the primary outcome proved to be significant (p = 0.04). Adjusted Generalized Estimated Equations showed no significant effect of glucosamine sulphate within the DEP control group (OR 0.59; 95%CI 0.31-1.12) or within the DEP intervention group (OR 1.44; 95%CI 0.83 – 2.48), for the Intention To Treat population (see table). The difference in direction of the association, however, is notable. Within subjects compliant to the study drug (≥75% of study drug, N = 250), also no significant effects of glucosamine sulphate over placebo were found (OR 0.69, 95%CI 0.32 – 1.52 and OR 1.32, 95%CI 0.70 – 2.51 respectively). Interestingly, among subjects compliant to DEP the interaction effect became stronger (p = 0.01) and, hence, the contrast of the effects in the placebo and glucosamine group more distinct (see table).

Conclusion: Although safe compared to placebo, crystalline glucosamine sulphate was ineffective for the prevention of knee OA in overweight females over 2.5 years of follow-up.

Baseline characteristics and incident OA figures for Intention To Treat and Per Protocol analyses.

ITT: Intention To Treat population (all randomized subjects). PP: Per Protocol population (compliant to intervention). DEP: diet and exercise program