In this study glucosamine had little effect on the intensity of pain in patients with osteoarthritis of the knee. This is the first study to report negative findings in the use of oral glucosamine to treat osteoarthritis, and thus our findings contradict those reported in other prospective trials of this treatment. One trial of 200 patients showed that glucosamine 1.5 g/day was as effective as ibuprofen 1.2 g/day in bringing about a reduction in pain scores on the Lequesne index.2
A trial of 40 patients with osteoarthritis of the knee found that glucosamine 1.5 g/day was statistically superior to ibuprofen 1.2 g/day in reducing pain scores at 8 weeks.3
Glucosamine was less effective than ibuprofen when patients were assessed at 4 weeks. The largest study included 252 patients and found that glucosamine 1.5 g/day was superior to placebo in reducing pain scores on the Lequesne index.4
It is not clear why there is disagreement between the results of our study and those of previous investigations. In this study, patients tended to be older, heavier, and had had arthritis longer than participants in other trials, suggesting that our patients had more pronounced arthropathy, which can be seen when radiographic findings from this study are compared to the largest placebo-controlled study.4
Although methods of grading knee radiographs differed slightly between studies, more patients in our study had more severe disease than patients in other studies, suggesting more pronounced joint pathology. It is possible that patients with more severe disease may not respond as readily to glucosamine as patients with less severe arthropathy. This would make theoretical sense in that glucosamine is believed to be a precursor of proteoglycans. Proteoglycans are thought to be instrumental in helping cartilage retain water and in promoting formation of an elastic layer, factors which may improve the functional characteristics of cartilage.12
Older patients with a longer history of arthritis may have more damage to their cartilage and the cartilage could thus be less responsive to the effects of glucosamine. Additional studies are required to examine the effects of glucosamine treatment in patients with osteoarthritis of a longer duration.
Another reason for our negative results could be that 2 months of treatment was insufficient to effect clinical improvement in our patients. Other studies involving apparently healthier patients have found clinical improvement within 4-8 weeks of initiating treatment. The largest study of glucosamine identified significant benefit when it was compared with placebo at 4 weeks of treatment but not in the preceding weeks.4
One trial found superior pain relief after 8 weeks of treatment with glucosamine when compared with ibuprofen.2
The efficacy of glucosamine when given for longer than 8 weeks is uncertain.
Any trial that has a negative finding raises the prospect of a type II error. With 100 patients, we estimated that we would have an 80% chance of detecting a difference between the two groups of 1.1 points in scores on the visual analog scale. This would have represented a 31% reduction in pain scores at rest and a 21% reduction while walking when compared with placebo. It is difficult to assess what change in score is clinically significant when measuring the intensity of pain. One large study in which patients with knee osteoarthritis were treated with piroxicam used a 30% difference in scores as an indicator of efficacy13
; piroxicam achieved this efficacy measure more often than placebo. Another large study using oxaprozin and nabumetone found a statistically significant 35% to 48% difference from baseline in scores on the visual analog scale.14
We observed practically no difference between the groups when absolute visual analog scores were compared. There was a slight difference in favor of glucosamine when the change in score was compared with the score at rest, however, this did not approach statistical significance. We believe that a much larger cohort of patients would be necessary to achieve significance in a trial of this sort in a similar group of patients.
It is unclear whether the addition of chondroitin sulfate to glucosamine would have influenced the outcome of this study. This combination is available in health food stores and is advertised extensively. Chondroitin has been shown to stimulate the production of proteoglycans and hyaluronic acid and to inhibit the proteolytic enzymes which may damage cartilage.15
Chondroitin has been shown to be more effective than placebo in reducing pain in patients with osteoarthritis of the knee.16,17
Only one controlled study has compared this combination with placebo in patients with osteoarthritis.18
In this double-blind crossover study of 21 servicemen glucosamine with chondroitin was superior to placebo in reducing scores of pain intensity on the visual scale after 8 weeks of treatment. It is not clear if chondroitin contributed to the reduction in pain found in this study since other trials have suggested that 3-6 months of treatment are needed to derive any benefit from this compound. The National Institutes of Health are planning a study of 1000 patients that will compare the efficacy of glucosamine, glucosamine and chondroitin, and placebo in the treatment of osteoarthritis to clarify the role of combination treatment. In our patients with osteoarthritis of the knee glucosamine was no better than placebo in reducing the intensity of pain.