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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

Development of functional limitation is thought to be unrelated to changes in severity of radiographic osteoarthritis (OA) of the knee. We evaluated the relationship of change in radiographic OA to the incidence of severe functional limitation.

Methods

Participants of the Multicenter Osteoarthritis Study, a cohort study of persons with or at high risk of knee OA, were evaluated at 0 and 30 months. Subjects were classified as having no, incident, stable, or worsening radiographic OA. Incidence of severe functional limitation was defined by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function scores (≥36.1/68) and walking speed (≤1.0 meter/second) at 30 months. The relationship of the change in radiographic OA to the incidence of severe functional limitation was evaluated by calculating risk ratios adjusted for potential confounders.

Results

Of the 2,210 subjects included (mean age 62 years, mean body mass index 30 kg/m2, 60% women), 53% had no, 6% had incident, 14% had stable, and 27% had worsening radiographic OA. Persons with incident radiographic OA had 1.9 and 1.8 times the risk by WOMAC physical function score and walking speed, respectively, to have incident severe functional limitation compared with those with no radiographic OA over 30 months. Compared with those with stable radiographic OA, persons with worsening radiographic OA had 2.2 and 2.3 times the risk of incident severe functional limitation, respectively.

Conclusion

Changes in structural disease are associated with the development of severe functional limitations in persons with or even at high risk of knee OA.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Knee osteoarthritis (OA) is the most common type of arthritis and the leading cause of difficulty with physical functioning compared with any other chronic disease (1, 2). Although it is known that the presence and severity of knee OA are associated with functional limitation (3–6), the effect of worsening disease on functional limitation is not known. Worsening of disease, or OA progression, can occur at different rates. In particular, persons with fast progression may be at greater risk for functional limitation than those with slow progression, who have more opportunity to adapt to the changes in physiology and increases in pain that may accompany worsening disease.

Previous studies report little to no association between changes in knee joint structure and physical function among subjects with knee OA. However, it is difficult to reconcile the notion that structural worsening of OA does not influence function. In the largest study to date investigating changes in disease and functional limitation, Dieppe et al reported small or null associations between changes in knee radiographs and general physical functional in 500 subjects with knee OA over 3 years (7). Similar findings have been reported in smaller studies as well (8, 9). However, these studies used non–disease-specific measures or self-report measures of function without performance-based measures, such as walking speed. Furthermore, continuous changes in disease may not result in proportional changes in function. A stronger disease–function association may exist when employing a clinically meaningful end point of severe functional limitation, such as selecting functional cut points consistent with persistent functional limitation or total joint replacement.

Thus, we examined whether persons with worsening structural disease were more likely to develop severe functional limitation compared with persons with stable or no disease. We employed an OA-specific measure of function and used both self-report and performance measures to define clinically meaningful end points of severe functional limitation.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Study sample.

Participants were recruited as part of the Multicenter Osteoarthritis Study (MOST), a large multicenter prospective cohort study of 3,026 community-dwelling persons who had or were at high risk of developing symptomatic knee OA at baseline. A more detailed description of recruitment and sampling for MOST has been published elsewhere (10). In brief, subjects ages 50–79 years were recruited from Birmingham, Alabama, and Iowa City, Iowa. Participants were defined as being at risk of developing knee OA based on known risk factors, including older age, female sex, previous knee injury or operation, and high body weight. Baseline assessments took place between May 2003 and March 2005, and followup assessments 30 months later. The MOST study protocol was approved by the Institutional Review Boards at the University of Iowa, University of California San Francisco, University of Alabama, and Boston University Medical Center.

We included subjects without end-stage structural disease or severe functional limitation at baseline based on the study criteria below to examine the association of worsening disease with the incidence of severe functional limitation at 30 months. We anticipated that subjects undergoing a new knee or hip replacement would likely improve in function. Thus, we excluded those who underwent a new total knee or hip replacement after the baseline assessment.

Study variables.

Outcome.

Our primary outcome was the incidence of severe functional limitation at 30 months. We defined severe functional limitation to represent substantial restrictions by employing cutoff scores associated with end-stage disease or poor health outcome using both self-report and performance measures. For self-report, we classified severe functional limitation as a score ≥36.1 on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function scale (scores range 0–68) (11), which is the mean score reported by persons awaiting total knee replacement (12). Because total knee replacement is typically performed in persons with a severe degree of pain and functional difficulty, this WOMAC score was applied to represent severe functional limitation. A score of 36 represents reporting at least moderate difficulty on all 17 items of the WOMAC, or extreme difficulty in 9 of the 17 items. For performance, we classified severe functional limitation as a walking speed ≤1.0 meter per second during a 20-meter walk at a usual pace. A walking speed <1.0 meter/second is a risk factor for poor health outcomes in older adults, including persistent functional limitation, hospitalization, and death (13). WOMAC and walking speed have been shown to have high test–retest reliability in subjects with knee OA (11, 14) and older adults (15).

Exposure.

All participants underwent bilateral weight-bearing posteroanterior and lateral fixed flexion radiographic evaluations of the knee, as described elsewhere (10). Two experienced readers blinded to clinical data graded joint space narrowing (JSN) and osteophytes using the Osteoarthritis Research Society International atlas (16) in both tibiofemoral and patellofemoral joints (both graded 0–3). The presence of JSN and osteophytes in the tibiofemoral joint was also graded according to Kellgren/ Lawrence (K/L) criteria (grades 0–4). Any disagreements between readers were adjudicated by 3 readers to reach consensus. We defined radiographic OA based on radiographic findings in either the tibiofemoral or patellofemoral joints. For the tibiofemoral joint this was a K/L grade ≥2. For the patellofemoral joint this was an osteophyte score ≥2, or any JSN score ≥2 with any osteophyte, sclerosis, or cyst score of ≥1 on a lateral plain view film (17, 18). The interrater reliability by weighted kappa for the K/L grade at baseline was 0.80.

Radiographic status was defined in 4 categories: no radiographic OA, incident radiographic OA, stable radiographic OA, and worsening radiographic OA. We defined no radiographic OA as subjects who did not have radiographic OA at baseline or at 30 months in either knee. We defined incident radiographic OA as subjects who did not have radiographic OA at baseline in at least 1 knee, and who at 30 months met criteria for radiographic OA in the previously nondiseased knee and had no radiographic OA or no change in radiographic status in the other knee. We defined stable radiographic OA as subjects who had radiographic OA at baseline and had no change in JSN or K/L grades over 30 months in radiographic status in that knee and no radiographic OA, no change in radiographic OA, or an existing total knee replacement in the other knee. Lastly, we classified worsening radiographic OA as subjects with radiographic OA at baseline and increases in either K/L or JSN grades over 30 months in either knee. Subjects were classified according to the “worse” knee. For example, subjects with no change in K/L or JSN grades in 1 knee but worse K/L or JSN grades in the other were classified as worsening radiographic OA. Similarly, subjects with no change in K/L or JSN grades in 1 knee and incident radiographic OA in the other were classified as incident radiographic OA.

Potential confounders.

The following baseline factors were considered as potential confounders based on existing literature linking them to function (10, 19–23): age, sex, and race; body mass index (BMI) computed from standardized weight and height assessments; depressive symptoms measured with the Center for Epidemiologic Studies Depression Scale (CES-D) (24); the presence of low back, hip, or foot pain recorded from self-report; and comorbidities estimated with a validated self-report measure, the modified Charlson comorbidity index (25). Because our interest was to examine the effect of change in radiographic OA status on the incidence of severe functional limitation, we did not adjust for knee pain given its role as a likely intermediate.

Statistical analysis.

We first examined whether differences in physical function among the different radiographic status categories at baseline were clinically meaningful. Based on previous literature, this was a difference of >6.2 of 68 for WOMAC (26) and a difference of >0.10 meters per second for walking speed (27, 28). To examine the relationship of change in radiographic status to the incidence of severe functional limitation at 30 months, we used regression methods with a log-link function and robust SEs to obtain risk ratios (RRs) (29). All analyses were adjusted for age, sex (male/female), race (white, other), BMI, presence of depressive symptomatology (CES-D score ≥16, yes/no) (24), comorbidities (none, ≥1), and low back, hip, or foot pain presence (yes/no). Age and BMI were entered as continuous variables. Analyses were conducted for incidence of severe functional limitation measured by self-report (WOMAC) and performance (walking speed). Subjects meeting criteria for severe functional limitation at baseline were excluded from these incidence analyses. To determine whether subjects with worsening structural disease were more likely to develop severe functional limitation, we conducted 2 separate analyses. In the first, we examined the association of incident radiographic OA with severe functional limitation incidence over 30 months among those with no radiographic OA at baseline. In the second, we evaluated the relationship of worsening of radiographic OA to severe functional limitation incidence among those with radiographic OA at baseline. We also compared the incidence of severe functional limitation among subjects with stable radiographic OA with those with no radiographic OA. Lastly, we examined the relationship of change in radiographic status with change in WOMAC physical function and walking speed as a continuous outcome. We found change scores to be approximately normally distributed (Kolmogorov-Smirnov test not statistically significant); therefore, we applied t-tests and multiple linear regression adjusting for the aforementioned potential confounders.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Of the 3,026 MOST subjects at baseline, 461 had end-stage radiographic OA at baseline. At 30 months, 74 had a new total joint replacement, 249 had incomplete data, and 32 were lost to followup. Of the 2,210 remaining subjects, the mean age was 62 years, mean BMI was 30 kg/m2, and 106 and 354 had severe functional limitation at baseline measured by self-report and performance, respectively. The majority of subjects were women (60%), white (85%), reported pain elsewhere besides the knee (76%), and did not have any comorbidities (68%) (Table 1). There were 1,173 subjects (53%) with no radiographic OA, 127 (6%) with incident radiographic OA, 310 (14%) with stable radiographic OA (i.e., no change in disease), and 600 (27%) with worsening of existing radiographic OA over the course of the observation period.

Table 1. Subject characteristics*
 All subjects (n = 2,210)
  • *

    Values are the number (percentage) unless otherwise indicated. BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale.

Age, mean ± SD years61.9 ± 7.9
Women1,315 (60)
White1,885 (85)
BMI, mean ± SD kg/m230.2 ± 5.6
CES-D score ≥16270 (12)
Low back, hip, or foot pain1,670 (76)
No comorbidity1,500 (68)

In our first set of analyses, we examined the group of participants who had no radiographic OA at baseline. Among subjects who continued to have no radiographic OA at followup, 19 (2%) of 1,137 and 51 (5%) of 1,069 had developed severe functional limitation by self-report and performance, respectively, while of the subjects who developed incident radiographic OA, 5 (4%) of 119 and 12 (11%) of 105 had new severe functional limitation, respectively. There were no clinically meaningful differences in function at baseline. Subjects with incident radiographic OA were 1.9 and 1.8 times more likely to have incident severe functional limitation by self-report and performance, respectively, compared with those with no radiographic OA (adjusted RR 1.9 [95% confidence interval (95% CI) 0.8–4.8] for self-report and adjusted RR 1.8 [95% CI 1.0–3.3] for performance) (Table 2).

Table 2. Risk of severe functional limitation as measured by WOMAC physical function and walking speed during a 20-meter walk among subjects without radiographic OA at baseline*
 Baseline scores, mean ± SDIncident severe functional limitation/total (%)Adjusted RR (95% CI)
  • *

    WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; OA = osteoarthritis; RR = risk ratio; 95% CI = 95% confidence interval.

  • Severe functional limitation defined as WOMAC physical function scores ≥36.1.

  • Adjusted for age, sex, body mass index, race, depressive symptoms, number of comorbidities, and pain at lower extremity sites other than the knee.

WOMAC physical function (range 0–68)   
 No radiographic OA8.5 ± 9.219/1,137 (2)1.0 (reference)
 Incident radiographic OA12.1 ± 10.15/119 (4)1.9 (0.8–4.8)
Walking speed (meters/second)   
 No radiographic OA1.30 ± 0.1751/1,069 (5)1.0 (reference)
 Incident radiographic OA1.26 ± 0.1612/105 (11)1.8 (1.0–3.3)

In our second set of analyses, we examined the group of participants who had existing radiographic OA at baseline. Among those with stable radiographic OA at followup, 8 (3%) of 287 and 13 (5%) of 262 had new severe functional limitation by self-report and performance, respectively, and among subjects with worsening radiographic OA, 33 (6%) of 544 and 62 (12%) of 498 had developed severe functional limitation, respectively. There were no clinically meaningful differences in function at baseline. Those with worsening radiographic OA had 2.2 and 2.3 times greater risk of severe functional limitation by self-report and performance, respectively, than those with stable radiographic OA (adjusted RR 2.2 [95% CI 1.1–4.7] for self- report and adjusted RR 2.3 [95% CI 1.3–4.1] for performance) (Table 3).

Table 3. Risk of severe functional limitation as measured by WOMAC physical function and walking speed during the 20-meter walk among subjects with radiographic OA at baseline*
 Baseline scores, mean ± SDIncident severe functional limitation/total (%)Adjusted RR (95% CI)
  • *

    See Table 2 for definitions.

  • Severe functional limitation defined as WOMAC physical function scores ≥36.1.

  • Adjusted for age, sex, body mass index, race, depressive symptoms, number of comorbidities, and pain at lower extremity sites other than the knee.

WOMAC physical function (range 0–68)   
 Stable radiographic OA14.4 ± 10.08/287 (3)1.0 (reference)
 Worsening radiographic OA14.8 ± 10.633/544 (6)2.2 (1.1–4.7)
Walking speed (meters/second)   
 Stable radiographic OA1.25 ± 0.1513/262 (5)1.0 (reference)
 Worsening radiographic OA1.25 ± 0.1662/498 (13)2.3 (1.3–4.1)

There was no statistically significant difference in risk of severe functional limitation among subjects with stable radiographic OA compared with those with no radiographic OA as measured by self-report or performance (adjusted RR 1.4 [95% CI 0.6–3.0] and 0.7 [95% CI 0.4–1.3], respectively).

Greater decline occurred on average for both self-report and performance outcomes measured continuously for subjects with incident radiographic OA compared with those with no radiographic OA, and for subjects with worsening radiographic OA compared with those with stable radiographic OA. However, these differences did not meet statistical significance (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

We found that subjects who developed or had worsening of radiographic OA 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 of the knee that is important for the incidence of severe functional limitation in persons with knee OA. Specifically, we found that both subjects with worsening of existing disease and those who developed radiographic disease had an approximately 2-fold risk of developing severe functional limitation as compared with their counterparts. In contrast, we found that subjects with stable disease had a similar risk of severe functional limitation incidence as those with no disease. Therefore, 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, 32). 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). Although this may be true when examining the relationship of worsening of structural disease to smaller incremental changes in function, our findings suggest that an association exists between worsening disease and clinically meaningful end points of function. For instance, we did not find significant differences between subjects with incident or worsening disease compared with those with no radiographic OA 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 whether 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 end point may be more fruitful in understanding the influence changes that 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 of 68 for WOMAC physical function score and from 0.95 to 1.05 meters/second for walking speed, and found similar results. It is noteworthy that differences in WOMAC physical function scores and walking speed at baseline among radiographic status categories were not clinically meaningful and were far from the threshold values for severe limitations in function. This indicates that subjects with worsening disease were not closer to the 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 functional limitation regardless of whether it was 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, whereas WOMAC assesses a much broader spectrum of 17 daily activities, ranging from sitting to going shopping. Despite this difference, we found subjects 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. This is consistent with previous literature, in which at least a moderate correlation (r > 0.3) between self-report and performance-based measures of physical function have been reported in persons with hip OA (34) and older adults (35–37).

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, 38, 39). Other consequences include decreased proprioception and instability or buckling (40–44). 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 in comparison with those with stable or slowly progressive disease.

There are some limitations to our study. First, we had a limited number of subjects who had an onset of severe functional limitation in this sample, which limits our ability to precisely estimate the effect of change in radiographic OA status with severe functional limitation. This may be due in part to inadequate sample size and/or insufficient followup 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. Although it is plausible that limited function may cause worsening of disease, this seems unlikely, particularly for those who developed incident radiographic knee OA.

Third, we did not specifically examine subjects whose knee radiographs worsened from K/L grade 0 to 1 because this group was too small to precisely estimate effects, and instead we included them within the no radiographic OA group. However, when we examined this group separately, we found no substantial differences for risk of severe functional limitation compared with subjects with no radiographic OA 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, subjects 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 subjects with new joint replacements. We used observed outcomes and also assigned subjects with new joint replacement as having developed severe functional limitation, a reasonable assumption given that persons awaiting total joint arthroplasty are likely to 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 subjects with new joint replacement.

Fifth, we were unable to examine the association of change in OA status taking into account unilateral versus bilateral radiographic OA changes given the complexity of the numerous possible combinations that can occur in 2 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. Although previous literature found structural disease not to be important for functional limitation, our results suggest otherwise when using meaningful clinical end points to define function. Persons who have worsening or new structural disease over 30 months are at a 1.8–2.5-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 with stable disease. Second, not only should clinicians be aware of the presence of structural disease, but they should also be aware of the speed of change in disease in persons with or at high risk of knee OA. Although 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 (45–47). Thus, persons at risk for developing incident or worsening disease may be the most appropriate candidates for early referral to rehabilitation.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. White had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. White, Zhang, Niu, Keysor, Nevitt, Lewis, Torner, Neogi.

Acquisition of data. Nevitt, Lewis, Torner.

Analysis and interpretation of data. White, Zhang, Niu, Keysor, Nevitt, Lewis, Torner, Neogi.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
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