Reply

To the Editor: We read with great interest the article by Lapane et al (1) regarding the effect of shortand long-term use of prescription nonsteroidal antiinflammatory drugs (NSAIDs) on symptoms and structural progression among patients with radiographically confirmed osteoarthritis (OA) of the knee. This prospective observational study suggested that long-term, but not short-term, NSAID use was associated with an a priori–defined minimally important clinical change in stiffness, physical function, and joint space width, but not pain. We appreciate the authors’ work; however, some worthwhile issues need to be explored. The authors classified 12 different kinds of NSAIDs together to assess the effect on knee OA of these drugs as a whole. Every NSAID has distinguishing characteristics with respect to therapeutic effect, safety, and price. For example, results of a recent high-quality network meta-analysis clearly indicated that naproxen, ibuprofen, and diclofenac, but not celecoxib, were statistically significantly superior to acetaminophen in terms of pain relief for patients with knee OA (2). There are 2 main types of NSAIDs: traditional NSAIDs (ibuprofen, naproxen, diclofenac, etc.) and celecoxib (the only selective NSAID currently available in America) (3). We are interested in learning about the results of this subgroup analysis (traditional versus selective NSAIDs). In addition, no information about the NSAID doses was available. The population of NSAID recipients in this study was largely heterogeneous. Consequently, we are not sure whether such conclusions have instructional significance for clinical practice. Aside from the implications for clinical practice, we are also worried about the reliability of the positive conclusion. The authors stated that long-term NSAID use was associated with clinical changes in stiffness, physical function, and joint space width. However, the 95% confidence intervals included 0, which could be interpreted as evidence that there is no real difference between long-term NSAID recipients and nonrecipients and that long-term NSAID use has no effect (4). The authors admitted that the estimates did not reach statistical significance, which indicates that a Type II error may exist. In other words, a significance test failed to identify the real clinical difference. Although the evidence showed that the a priori–defined minimally important clinical change had been reached, the possibility that the positive results of the study were due to chance could not be ruled out. We admit that the clinical significance is of importance, but we would like to emphasize the fact that statistical significance does not ensure truth and careful attention should be paid to false-positive errors. Furthermore, other issues need to be noted. First, the authors indicated that evidence regarding long-term effects of oral NSAIDs is still lacking, and their effect on structural changes in the joint has not been well established. However, the clinical efficacy and safety of celecoxib, as well as the effects of celecoxib on progression of knee OA over 2 years, have been reported previously (5,6). Second, according to the Osteoarthritis Research Society International atlas (7), joint space narrowing and formation of osteophytes should be determined for knee OA. We are curious about why the progression of osteophytes was not assessed. Third, patients in observational studies differ from those in clinical trials by, for example, the wider spectrum of coexisting illness included in observational studies, which could result in a good generalizability (8). However, the multivariable model was not adjusted for certain underlying diseases, such as diabetes mellitus and hypertension. Finally, it should be noted that safety is an extremely important index for assessing oral NSAIDs, especially for long-term use. The authors admitted that discontinuation rates of prescription NSAIDs have been reported to exceed 85% within 6 months of initiation. We would like more information regarding the side effects of NSAID use in this study. We value the contributions of Lapane et al, and we are very interested in the authors’ response to these issues.