We found that persons who developed or had worsening of ROA over 30 months were more likely to develop severe limitations in function compared with those without existing disease and those with stable disease, respectively. These findings suggest that it is not just the presence, but rather the change (i.e., development or worsening) in structural disease at the knee that is important for the incidence of severe functional limitation in persons with knee OA. Specifically, we found that both persons with worsening of existing disease and those who developed radiographic disease had about a two fold risk of developing severe functional limitation as compared with their counterparts. In contrast, we found that persons with stable disease had a similar risk of severe functional limitation incidence as those with no disease. Hence, it is not the mere presence of structural disease at the knee that is important for the development of severe functional limitation, but rather the worsening of structural disease in both persons with or without radiographic disease at baseline.
Thus, our results support the notion that worsening disease is an important and relevant risk factor for severe functional limitation in persons with knee OA. We also recently demonstrated that a strong association between structure and symptoms does exist when confounding is adequately addressed(30
). However, this is in contrast to the existing literature, which highlights a discordance between structural disease with patients symptoms, such as pain and function(31
). A recent systematic review concluded that radiographic knee OA is an imprecise guide to the future presence or absence of pain or functional limitation(33
). While this may be true when examining the relation of worsening of structural disease to smaller incremental changes in function, our findings suggest an association exists between worsening disease and clinically meaningful endpoints of function. For instance, we did not find significant differences between persons with incident or worsening disease compared with those with no ROA or stable disease when function was measured continuously. However when characterizing functional loss as substantial, a relationship emerges between worsening of structural disease and severe functional limitation. This may point to the ‘noise’ or sensitivity to change associated with such functional measures, limiting the ability to precisely measure small changes, particularly when there can be substantial between-person variability. Furthermore, it is questionable if such small changes, if detected, are clinically relevant or meaningful to the patient or provider. Thus, employing a strategy to highlight persons who decline below a clinically meaningful endpoint may be more fruitful in understanding the influence changes in structural disease may have on poor functional outcomes.
We selected definitions of severe limitations in function from values consistent with persons awaiting total knee replacement and who were at risk of poor health outcomes. In addition, we performed sensitivity analyses using cutoffs for severe functional limitation ranging from 35 to 37/68 for WOMAC physical function and 0.95 to 1.05 m/s for walking speed, and found similar results. It is noteworthy that differences in WOMAC physical function and walking speed at baseline among radiographic status categories were not clinically meaningful and far from thresholds values for severe limitations in function. This indicates that persons with worsening disease were not closer to threshold values of severe functional limitation at baseline compared with those with stable or no disease.
We found worsening of structural disease of the knee to be a risk factor for the development of severe functional3 limitation regardless of whether it is measured by self-report (WOMAC physical function) or performance (walking speed during a 20 meter walk). These outcomes examine different aspects of physical function; walking speed focuses on one specific functional task, while WOMAC assesses a much broader spectrum of 17 daily activities ranging from sitting to going shopping. Despite this difference, we found persons with incident or worsening disease to have an increased risk of severe functional limitation regardless of whether measured by self-report or performance, compared with those with no or stable disease, respectively. This is consistent with previous literature, where at least a moderate correlation (r >0.3) between self-report and performance based measures of physical function has been reported in persons with hip osteoarthritis(34
), and older adults(35
Why are persons with worsening structural disease more likely to have severe functional limitation compared with those with stable or no disease? Worsening disease is likely associated with knee pain and muscular weakness(30
). Other consequences include decreased proprioception and instability or buckling(40
). All of these impairments could result in the development of functional limitation. One possible reason why those with worsening structural disease are more prone to severe functional limitation is that they have less time to adapt to the development of these underlying impairments due to progressive disease, versus those with stable or slowly progressive disease.
There are some limitations to our study. First, we had a limited number of persons who had an onset of severe functional limitation in this sample, which limits our ability to precisely estimate the effect of change in ROA status with severe functional limitation. This may be due in part to inadequate sample size and/or insufficient follow-up time for such changes to occur. Second, given that our study examined changes in disease with changes in function, we cannot infer causality or directionality directly from our data. While it is plausible that limited function may cause worsening of disease, this seems unlikely, particularly for those who developed incident knee ROA. Third, we did not specifically examine persons whose knee radiographs worsened from KL grade 0 to 1 as this group was too small to precisely estimate effects, and instead included them within the no ROA group. However, when we examined this group separately, we found no substantial differences for risk of severe functional limitation compared with persons with no ROA at baseline and 30 months, albeit without adequate precision due to the small numbers. Fourth, given the complex nature of the effects of function from total joint replacement, persons with existing or new total joint replacement may have had different functional outcomes compared with those without replacements. To address this issue we separately analyzed our data first excluding those with existing joint replacements at baseline and second including persons with new joint replacements. We used observed outcomes and also assigned persons with new joint replacement as having developed severe functional limitation, a reasonable assumption given that persons awaiting total joint arthroplasty are likely do so in part due to functional decline. We found similar effect estimates across all of these analyses, although the effect estimates were highest when incident severe limitation in function was assumed for persons with new joint replacement. Fifth, we were unable to examine the association of change in OA status taking into account unilateral versus bilateral ROA changes given the complexity of the numerous possible combinations that can occur in two knees within a person. Lastly, we did not specifically examine the role of impairments due to disease, such as knee pain or muscular weakness, proprioception, and knee instability, on the development of severe functional limitation because these are likely intermediates on the causal pathway. That is, the effects of structural disease on function is a reflection of the varying contributions of these associated impairments that can influence function. Investigation of the mechanisms by which structural disease can lead to functional decline is of interest for future studies.
Our study has some important clinical implications. First, changes in structural disease are relevant for the development of severe functional limitations in persons with or even those at high risk of knee OA. Though previous literature found structural disease to not be important for functional limitation, our results suggest otherwise when using meaningful clinical endpoints to define function. Persons who have worsening or new structural disease over 30 months are at a 1.8 to 2.5 fold higher risk of developing substantial limitations in daily functional activities, such as walking, climbing stairs, and getting up from a chair compared with those without disease or stable disease. Second, not only should clinicians be aware of the presence of structural disease, but also be aware of the speed of change in disease in persons with or at high risk of knee OA. While no current intervention is known to halt the progression of OA, rehabilitation such as strengthening exercises and self management approaches have been shown to minimize functional limitations in persons with knee OA(45
). Thus, persons at risk for developing incident or worsening disease may be the most appropriate candidates for early referral to rehabilitation.