- Top of page
- MATERIALS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
Osteoarthritis (OA) of the knee is a common disease, with a prevalence of 12.5% in populations ages >45 years (1). The lifetime risk of developing symptomatic knee OA is estimated as 44.7% (2), and the annual rate of progression in subjects diagnosed with knee OA has been reported as approximately 4% per year, indicating slow evolution of the disease (3). Heterogeneity of knee OA as a disease results in a wide range of clinical presentations and varying rates of progression. Identifying those patients most likely to progress or those at risk of rapid progression is important for optimal allocation of health care resources and research into therapeutic interventions (4). Additionally, the ability to identify prognostic indicators from patient history and examination would be beneficial at an individual level, allowing health care practitioners to more accurately predict the likelihood of disease progression and direct patients to appropriate interventions.
Previous systematic reviews have sought to identify predictors of knee OA progression using radiographic change (5, 6) or functional decline and change in pain (7) as outcome measures. Usual clinical practice is to gather information from both radiographs and patient-reported symptoms. Therefore, to enhance clinical relevance, the approach of this review was to include any validated clinical information for both potential predictor variables and measures of outcome. Furthermore, advances in search strategies for prognostic and nonrandomized studies, as well as more studies investigating progression, are likely to have led to additional evidence being available in the field of knee OA progression, which makes a new review both timely and relevant (8).
The aim of this study was to identify patient characteristics that can be used by health care practitioners to predict the likelihood of knee OA progression. A systematic review of the literature was performed to meet this objective.
- Top of page
- MATERIALS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
Baseline patient characteristics with strong evidence for being predictors of knee OA progression consist of age, presence of OA in multiple joints (clinical observation), varus deformity of the knee (radiographic), and radiographic features (JSN/JSW, chondrocalcinosis, severity of OA as measured by K/L grade, and osteophyte score). Additionally, findings from sensitivity analyses suggest that higher BMI is a strong predictor of progression over a longer time period (>3 years), and pain and function have strong evidence of no association with progression (quality score of ≥15). These variables are easily assessed in clinical practice and may assist health care practitioners with providing their patients with appropriate advice and interventions for managing their disease. Patients can also be reassured that moderate participation in physical activity (patient report) is unlikely to have any effect on progression. Clinicians can have confidence in these findings, as the information is drawn from high-quality studies and exhibits consistency between studies. Additionally, study samples were drawn from a variety of settings, i.e., orthopedic and rheumatology clinics as well as community-based cohorts, making findings of the review generalizable. However, the quantity of information is somewhat limited for varus alignment, multiple joint OA, radiographic features, physical activity, knee pain, and function due to low study numbers for evidence synthesis. Additionally, for some variables effect sizes are small or inconsistent. These factors should be considered before applying review findings to clinical practice (19).
Table 5 compares findings of the current and previous reviews for variables with strong evidence only. Similar findings from multiple reviews increase confidence in the conclusions. For example, strong evidence from 2 reviews, plus limited evidence from another review, identifies varus alignment as a predictor of progression. This also highlights the importance of biomechanical influences on radiographic progression of knee OA.
Table 5. Comparison of findings from systematic reviews that identify variables with strong evidence for progression of knee OA*
|Baseline variables||Current study||Belo et al, 2007 (5)||Van Dijk et al, 2006 (7)||Tanamas et al, 2009 (6)|
|Predictors|| || || || |
| Knee malalignment||Strong (varus alignment with medial JSN)†||Limited||Limited‡||Strong|
| Multiple joint/generalized OA||Strong||Strong||–||–|
| Radiographic features||Strong||Strong‡||–||–|
| Hyaluronic acid||–||Strong||–||–|
|Not associated with progression|| || || || |
| Participation in physical activity||Strong||Strong||Limited||–|
| Muscle strength||Limited||Strong||Limited (progression less likely)||–|
| Previous knee injury||Limited||Strong||–||–|
|Unclear association with progression|| || || || |
| Knee pain||Conflicting||Strong‡||Limited (predictor)||–|
There is strong evidence from 2 reviews that generalized or multiple joint OA (assessed by clinical observation) is a predictor of progression. While the precise reasons for this association are not entirely clear, it is possible that generalized OA may reflect an underlying systemic or genetic influence on cartilage that contributes to an increased likelihood of disease progression (40).
Similarly, 2 reviews found strong evidence that participation in physical activity is not significantly associated with progression, with limited evidence from another review. Physical activity included aerobic exercise, jogging, or being a member of a sports club (25, 40, 42). This lack of association with disease progression is helpful, given the many recognized health benefits associated with regular exercise.
There are inconsistent findings for the remaining variables in Table 5. For example, in the current review, combined radiographic features have strong evidence of being predictive of progression. In contrast, Belo et al (5) report strong evidence that radiologic severity is not associated with progression, having arrived at a different interpretation from similar studies.
Dissimilar review objectives may have contributed to disparity in findings. Belo et al (5) included articles with progression defined by radiographic measures only. Unlike the current review, they did not require inclusion of clinical features at baseline. Tanamas et al (6) conducted a review focused solely on the role of alignment as a predictor; van Dijk et al (7) concentrated on studies with changes in functional status or pain. Additionally, the pool of articles in each review was affected by decisions such as date of search, search strategies, and inclusion/exclusion criteria. Inclusion of different source studies contributes to the diversity of conclusions in the reviews. For example, age was found to be a strong predictor in the current review and conflicting in another. However, only 1 study contributed results on age to both reviews (40).
As previously mentioned, the number of studies will also affect the strength of evidence and may have contributed to the disparity in findings between reviews. Relatively few studies were included in the current review for variables such as function and pain. This makes synthesis of evidence susceptible to change with the addition or deletion of articles from the analysis. This point is reinforced by results of a sensitivity analysis that raised the threshold for high-quality studies to ≥70%. The exclusion of 1 study (26) changed the evidence from conflicting to strong so that pain and function were not significantly associated with progression. Tables 3 and 4 highlight the low number of studies from which the level of evidence is calculated.
There was a wide range of outcome measures used in included studies. Results of a sensitivity analysis revealed that age remained a strong predictor when assessed with change in function (26, 33, 42); however, evidence became conflicting when using radiographic outcome measures (23, 34, 40), exemplifying how the choice of outcome measure for knee OA progression can influence results. However, there are no universally accepted outcome measures and most have recognized limitations. For radiographs, these include the slow rate of progression and the fact that early disease may not be manifested in radiographic features (4, 50). Outcome measures describing change in pain or function lack responsiveness, with limited evidence that they deteriorate over a 3-year period (7). Levels of pain or function may reflect short-term fluctuations in disease activity rather than progression. Alternatives such as magnetic resonance imaging (MRI) changes or biomarkers were not utilized in this review due to uncertainty about their responsiveness in detecting progression, lack of standardized or universally accepted scoring methods, and their lack of a clear relationship to clinical symptoms (4, 50). In addition, they may lack clinical utility due to cost and technical requirements, being more suited to use in the research environment.
The focus of this systematic review was to identify predictive variables that could be easily assessed in routine clinical practice. This resulted in exclusion of some studies that used sophisticated equipment or analytical techniques, making it possible that other predictors of knee OA progression have been missed. Other limitations of the current review relate to shortcomings of included studies. Prognostic studies have been criticized for poor quality and variable methodology (18). The potential impact on the current findings was addressed with the assessment of bias tool. Results in Table 2 suggest that conclusions from this review could be at risk of selection bias and attrition bias due to weaknesses in included studies. Improving selection and reporting of study participants, especially response rates at different stages, and reasons for dropouts would address these biases and should be incorporated into future research. Two-thirds of reviewed studies addressed confounding by age and sex, although there may be other potential confounders not investigated in these studies, so it is not possible to conclude definitively that confounding was absent (13). However, the requirement for adjusted or multivariate analyses in this review should have minimized the effect of confounding.
The lack of standardized methods of assessment for baseline variables in addition to the variety of outcome measures already outlined are areas that should be addressed in future research. Consistent measures would make pooling of results and meta-analysis more likely and thereby strengthen the body of evidence and confidence in the findings. This approach may need to be tempered if new methods for defining progression are validated and adopted as best practice (e.g., MRI changes or biomarkers) (4, 50).
Identification of predictors of long-term progression is an area requiring further research. Existing, well-designed, and adequately powered studies can indicate known variables worthy of further investigation, rather than searching for new predictors (17).
This systematic review has summarized current evidence for baseline characteristics that predict progression of knee OA. It has also highlighted areas where methodology is lacking and possible directions for future research. All of the variables identified with strong evidence as predictors (varus alignment, presence of OA in multiple joints, age, radiographic features, and BMI) can be easily evaluated and utilized in clinical practice. Additionally, knowledge that participation in physical activity is not associated with progression should be used to encourage patients to remain active. Patients can also be reassured that the presence of baseline pain and limitation of function is not associated with progression. There are numerous other potential predictors where current evidence is limited or conflicting. They provide a direction for future research, which should be undertaken using existing standardized and validated methods of assessment and outcome measurement.