Methodologic challenges in studying risk factors for progression of knee osteoarthritis

Abstract

Knee osteoarthritis (OA) is the most common joint disorder among adults in the US and severity of knee radiographic OA (ROA) is strongly associated with knee pain1. Pain from knee OA accounts for a large proportion of limitations with common activities of daily living2, and it is also the main reason for total knee replacement3. Because of the impact of symptoms from knee OA, people with symptomatic knee OA may be more motivated to take steps to prevent disease progression than those without ROA. Thus, investigators and persons with knee OA are particularly interested in risk factors that are associated with ROA progression because such knowledge will provide insightful guidance for secondary prevention4. Over the past few decades, many observational studies have examined risk factors for the occurrence (i.e., incident) and worsening (i.e., progressive) of knee OA. Several risk factors (i.e., female gender, obesity, high bone mineral density (BMD), joint injury, repetitive occupational stress on joints, and certain sports) have been found to be strongly associated with an increased risk for incident knee ROA5, 6. In contrast, findings on risk factors for ROA progression have been inconclusive. Except for the level of serum hyaluronic acid and generalized OA, no other risk factor has been consistently associated with the risk of ROA progression7. Interestingly, some risk factors (e.g., high BMD, low vitamin C) increase the risk of incident knee ROA but are not associated with, or even decrease, the risk of ROA progression8-11. This paradoxical phenomenon is not limited to studies of ROA. Many studies have shown that overweight and obesity increase the risk of cardiovascular disease; however, a number of studies have also reported that among subjects with preexisting cardiovascular disease, those who are overweight or moderately obese have an improved survival and lower risk of major cardiovascular events compared with subjects with normal weight12. These findings have been termed the “obesity paradox”. Similarly, while low body mass index (BMI) is associated with increased incident chronic obstructive pulmonary disease13, it does not, however, increase the risk of recurrent exacerbations of the disease14. While the risk factors for incident events may be biologically different from those for secondary events, there are also compelling methodological explanations behind such discrepancies. In this paper, we provide several explanations that may underlie the discrepancy between findings for knee ROA progression and those for knee ROA incidence. To be consistent with most studies, we consider knees eligible for studies of ROA progression being those that have preexisting mild (K/L=2) or moderate (K/L=3) ROA at baseline. We discuss how study design, study implementation, and outcome measures in studies of ROA progression can potentially bias the effect estimates of risk factors of interest using causal diagrams15. We also present findings from several large prospective studies of ROA progression to facilitate our explanations wherever applicable.