In the present study, symptoms improved with glucosamine sulfate use to a significantly larger extent than in the placebo group. The fact that symptoms tended to slightly improve also with placebo therapy is not surprising in a long-term trial in which the principal effort is to keep the patient in the study, with several clinic visits and assessments being performed. Actually, there was a statistically nonsignificant trend for a higher proportion of withdrawals in the placebo than in the glucosamine sulfate group, which may reflect lower treatment satisfaction in the control group. Other large, prospective studies36 on the natural history of the disease also did not show a worsening in pain severity after 3 years, notwithstanding the fact that most patients reported an overall worsening of their condition. In any case, symptom improvement with placebo therapy was limited to a few percentage points, whereas patients receiving glucosamine sulfate reported an average 20% to 25% improvement in pain and function according to the per-protocol analysis and 15% to 20% by the intent-to-treat approach adopted, which is in agreement with the effect size reported in similar studies.14 Such results were obtained by assessment using the Lequesne index19 and were confirmed for consistency using the WOMAC index,25 that is, the 2 most widely used algo-functional indexes of the severity of knee osteoarthritis.20,21 Besides reporting the final symptom score, we analyzed the development of the symptomatic effect of glucosamine sulfate during treatment and found a steadily developing effect over the first year that then remained constant until completion of the study after 3 years. These results on osteoarthritis symptoms have already attracted much attention,15 and one should consider that they have been obtained in patients with mainly mild to moderate disease and in a long-term study that may not be optimal to fully appreciate the development and effect size of the improvement. Indeed, short-term studies specifically designed with such an aim have already described the pattern of the symptomatic effect of glucosamine sulfate use and have recently been reviewed.12,13 These studies showed a significantly better effect than placebo therapy and at least similar to that of conventional NSAID use in the first 4 weeks of treatment,44,45 with improvement in pain and function up to 40% to 50% relative to basal conditions within 12 weeks,46 that is, a moderate to large effect size12,13 and a carryover effect at drug withdrawal.46 The present study, together with other similar experiences,14 completes the pattern of the effects of glucosamine sulfate for long-term chronic treatment, as demanded lately by the scientific community.47,48 As a possible limitation in this regard, although the patient population in our study is largely representative of the general population with knee osteoarthritis, we excluded obese patients and those with metabolic diseases that may be responsible for secondary osteoarthritis. In addition, as expected in a placebo-controlled, long-term trial, we included a limited number of patients with severe disease.