This study demonstrated, using the OAI database and a nested case-control study design, that exposure to some of the most commonly used oral OA therapies, i.e. acetaminophen, NSAIDs, COX-2 inhibitors, narcotics, or glucosamine/chondroitin sulfate, in a range of 2– 5 years, was not associated with the occurrence of KR when compared to no exposure to such medications. However, a number of risk factors were identified as being linked to KR, including race, level of symptoms, and BMI.
Our study also revealed that the oral medications studied had a “neutral” effect on KR while controlling for the most important confounding factors known to promote such occurrences: demographics, socioeconomic status, symptom severity, radiographic grading, and structural changes assessed by quantitative MRI. These results are in contrast to those of Hafezi-Nejad et al. , also using the same OAI cohort, showing that long-term use of analgesics comprising NSAIDs, acetaminophen, and narcotics alone or in combination may be associated with radiographic progression of knee OA and increased risk of KR. Similar results on the potential deleterious effects of NSAIDs on the evolution of OA structural changes and disease outcome have already been suggested. Early studies based on the radiographic evaluation of disease progression (joint space narrowing (JSN)) in patients with OA treated with NSAIDs reported a negative impact of long-term use of diclofenac or indomethacin in hip and knee OA [4,5,6,7,8]. Another report on the effects of regular use of prescription NSAID treatment in patients with knee OA identified a reduction in JSN compared to non-users over a 4-year follow-up period , although the difference between groups was not statistically significant. However, recent observational studies and randomized controlled trials in patients with knee OA using MRI technology to assess disease progression have shown that treatment with NSAIDs such as naproxen or celecoxib (a cyclooxygenase-2 (COX-2) selective inhibitor) has a neutral effect on cartilage loss [26, 27]. Studies from our group, also using MRI technology, and the participants from the incidence and progression subcohorts of the Osteoarthritis Initiative (OAI) database have also explored the effects of NSAIDs/analgesics and glucosamine/chondroitin sulfate on disease progression by assessing the change in cartilage volume [12, 13]. The findings of these studies showed that the extent of progression of cartilage volume loss was driven by disease severity and meniscal extrusion. NSAID/analgesic treatment had no significant effect on cartilage volume loss. In the latter study , glucosamine/chondroitin sulfate treatment reduced the cartilage volume loss in participants with meniscal extrusion regardless of whether or not they were receiving NSAID/analgesic treatment.
Interestingly, the findings of Hafezi-Nejad et al.  were also not confirmed in the study of Lapane et al.  using the same OAI cohort and exploring the effects of long-term use of NSAIDs on knee OA progression also using x-rays. The greater loss of JSW in the NSAID users compared to the non-users was not statistically significant on multivariate adjusted analysis. In another study using the OAI cohort, assessment of disease progression using x-rays and MRI did not demonstrate any effects of long-term use of NSAIDs/analgesics on knee OA disease progression [12, 13]. Finally, in another population-based study, Klop et al.  also showed that long-term users of non-selective NSAIDs and coxibs did not have a different risk of KR.
The sociodemographic and clinical data from our study population, being quite similar to those from previous studies exploring the role of disease treatment on KR [8, 10, 11, 28, 29], do not explain the discrepancy in the impact of such NSAIDs. Moreover, studies in preclinical animal models of OA have provided a number of positive as well as negative findings with regard to the potential beneficial or deleterious effects of such drugs on OA structural changes [7, 9], which does not help to settle this debate.
A very important distinction of the present study compared to most others, is the use of a nested case-control design that we chose for a number of reasons. The well-recognized advantage of such a study design is that it allowed us to assess patients’ characteristics as risk factors to be evaluated at the very date of KR surgery. This is in sharp contrast to a cohort study design, in which the patient profiles are assessed at entry (baseline) into the cohort [10, 11, 30]. During the elapsed time between cohort entry and date of KR, which may be several years in most cases, the profiles of patients who undergo KR, such as symptoms, function, and medication usage, may change substantially. The nested case-control design thus allowed evaluation of patient characteristics that best represent the patient status at the time of the KR occurrence, not several years before. It is therefore important to recognize that such a study design will probably impact findings when assessing a relationship between drug exposure and risk of KR, in turn potentially explaining results different from those of recent longitudinal cohort study designs using the same OAI database , as mentioned previously.
Another important issue of our study is the use of KR as the sole marker of disease progression, which has already been established as a valid outcome in a number of studies [11, 15,16,17,18, 30, 31]. Indeed, there is a general consensus that MRI parameters assessed in knee OA, such as the medial compartment cartilage volume/thickness, can predict outcomes such as KR in a consistent manner [14,15,16,17,18]. However, findings of the present and previous studies [17, 29, 32] also indicate that the ultimate decision of the patient to undergo KR is likely multifactorial in origin and involves a large number of confounding factors that extend well beyond the severity of knee OA structural changes. In our study, however, the cartilage volume at index (KR) time as assessed by MRI was similar in both groups, suggesting that over time the factors leading to progression of cartilage volume loss up to the KR were globally balanced in both groups. One must be cautious with the interpretation that drug treatment that can accelerate disease progression, if true, may have exerted its effects on both control and KR groups. Although the effect of drug treatment on rate of disease progression was not assessed in this study, several previous studies have addressed this very specific issue, a number of which used the OAI cohort [10,11,12,13]. Based on the findings of these studies, one may be tempted to conclude that factors in addition to disease progression are very likely to influence the patient’s decision to undergo KR. The results of the present study showing that JSW at index time was not linked to the occurrence of KR certainly support this view.
In the present study we also explored the cumulative exposure to oral OA therapies measured in different time windows, from 2 to 5 years before the date of the KR, to evaluate their impact in different scenarios to yield robustness of our analyses. Interestingly, these analyses did not show any time frame trends, shorter or longer, that would significantly promote greater risk of KR. Windows of 6 to 8 years of exposure to oral OA therapies were also considered, but the number of available patients was too small for statistical inference.
The results of the study are reassuring and clinically relevant since they tackle the confounding role of any oral intervention to treat pain as a “last resort” prior to inevitable surgery, creating a spurious association between drug usage and the risk of KR, in turn suggesting a deleterious role of the medication via a channeling bias. Moreover, presence of severe comorbidities, frequently encountered with severe OA, are usually perceived by orthopedic surgeons as promoting perioperative risks and, as such, they are less inclined to recommend surgery for these patients. These same comorbidities may also preclude the use of NSAIDs and narcotics for these “morbid” patients, hence yielding spurious correlation between use of these medications and more KRs being performed.
Our study has a number of strengths. First, it was conducted using the large OAI database, representative of a North American population with fairly open access to usual care for knee OA, including KR, based on patient and physician preferences in a context of a real-world scenario. Second, to our knowledge, this is among the first studies that allowed stratification of risk of KR by extent of exposure to oral OA medication versus no exposure, which is paramount when trying to establish a cause-effect of medication on an ultimate outcome such as KR. We chose a priori a 3-year window of oral OA medication exposure based on a clinical rationale and the design of previous studies [17, 30, 31]. Third, per the OAI design, we have great certainty about the knee OA diagnosis and its KR indication based on detailed information on demographics, symptoms, imaging, and drug use for both patients and their matched controls. Fourth, medical data were routinely recorded by investigators including rheumatologists and orthopedic surgeons without a study hypothesis, yielding a “nested” case-control study, hence minimizing the possibility of recall bias, which plagues conventional retrospective chart review studies. Last, the excellent matching yielded from our control selection strategy, as shown in the baseline characteristics comparison, is reassuring, as control selection is always an important issue for nested case-control designs as poor choices may yield very different conclusions.
Limitations of this study include the fact that it did not allow identification of any specific drug class. For instance, the impossibility of defining a specific NSAID name within the database is a limitation as some NSAIDs, such as for example indomethacin, may prove to be more deleterious than others [4,5,6,7,8,9]. The data provided on drug usage were obtained by self-administered questionnaire and not by a traditional pill count, which is used to assess adherence and persistence to medication in most clinical trials. This could underestimate true prolonged and cumulative usage of these medications. We have nonetheless tried to establish a “dose-effect” response using categories we have coined levels of “exposure”: no exposure, occasional (exposure 1–79%), or regular (≥ 80%) medication usage, acknowledging such limitation.
The study design also did not allow comprehensive assessment of the influence of confounding factors, as some of the data used were only available at baseline and not at the index time of KR. Despite attempts to adjust for several confounders, causal interpretation of the findings is restricted, and residual confounding must be considered when interpreting the results.
Furthermore, this study focused on patients with severe OA in need of surgery; other beneficial or deleterious associations with chronic use of oral OA drugs and subclinical structural damage, as seen using quantitative MRI for example, may be found in subjects with less severe OA.
It was also impossible to assess the knee OA disease duration since onset of symptoms or date of OA diagnosis was not collected in the OAI dataset. Knee OA duration could have a significant impact on the cumulative and progressive joint damage, but we were unfortunately unable to control for it.
Statistical power may also be an issue since, by selecting subjects that had a KR but also had almost all demographic, clinical and MRI information, patient number was reduced from more than 4674 subjects to a mere 218 cases of KR, which is somewhat limited for performing multivariate analyses.
Finally, actual KR occurrences may be considered by some as an inadequate outcome for a comprehensive severe progressive OA definition. In fact, in the present work, we did not assess knee OA progression using imaging outcomes such as JSW or cartilage thickness/volume loss prior to the KR. The rate of such progression might accelerate while nearing the KR occurrence, which may or may not be associated with oral OA medication use. However, as already mentioned, the cartilage volume at index (KR) time as assessed by MRI was similar in both groups, suggesting that over time the factors leading to progression of cartilage volume loss up to the KR were globally balanced in both groups. Despite the great clinical success of KR, the criteria on which surgery is performed are not uniform. Apart from symptoms and radiographic status, surgical indication depends on willingness, comorbidity, access to health care, socioeconomic status, etc. A validated KR “indication” as a clinical outcome, as suggested by the OARSI/Outcome Measures in Rheumatology (OMERACT) group  could help in that regard for future studies.