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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Osteoarthritis Cartilage. Author manuscript; available in PMC Aug 1, 2009.
Published in final edited form as:
PMCID: PMC2701468
NIHMSID: NIHMS63501

Joint Space Narrowing and Kellgren-Lawrence Progression in Knee Osteoarthritis

An Analytic Literature Synthesis

Introduction

Osteoarthritis (OA) affects more than 21 million people in the U.S.1, with 36% of elderly Americans aged 70 or older having some degree of radiographic knee OA2, 3. The prevalence of OA continues to grow as the population ages. Currently available medications for knee OA ameliorate pain without slowing structural progression associated with the disease. Disease modifying osteoarthritis drugs (DMOADs) are still in early stages of development and testing4. In this era of active work on DMOAD development, it is critical to determine the expected ‘natural history’ rate of structural knee OA progression, as this is a key parameter that could be affected by disease modifying therapy.

Magnetic resonance imaging (MRI) may eventually eclipse plain radiography as the modality of choice for documenting structural progression in OA. However, the interpretation of cartilage findings on MRI is still evolving and plain radiography remains the standard method for assessing progression. The measurement of radiographic joint space width is the most accepted and widely-used method of assessing OA progression. As it has been shown to be sensitive to change5, joint space narrowing has remained the primary outcome by which DMOAD trials have tested drug efficacy so far6, 7. Yet, the rate of joint space narrowing among cohorts with knee OA exhibits variability8-10, potentially stemming from differences caused by changing patient characteristics and clinical status over time, inconsistent radiographic positioning of the knee during serial x-ray visits, and other technical factors8. With the promise of effective DMOAD therapy on the horizon, it is crucial to establish factors affecting the rate of joint space narrowing across various study settings.

Another common metric of OA progression is the Kellgren-Lawrence scale, traditionally used to assess the severity of radiographic knee OA. This categorical scale incorporates important radiographic features of OA (joint space narrowing and osteophyte development) into one scale of increasing severity11. The use of the Kellgren-Lawrence scale has been criticized because its individual categories are not equidistant from each other12. Consequently, estimates of the proportion of patients that progress from one category to the next may not be comparable for all starting points. Since the Kellgren-Lawrence scale is still used in clinical settings for making treatment decisions, its value in assessing knee OA progression warrants continued investigation.

The goal of this analytic review is to describe the variability in estimates of knee OA progression (joint space narrowing and Kellgren-Lawrence) from the published literature and to identify factors explaining this variability. The potential predictors we examined included study and technical factors (study design, year of study publication, study duration, sample size, reader reliability assessment, radiographic definition of OA, radiographic approach used), and cohort characteristics (age, gender, body mass index (BMI), baseline joint space width, and OA-related cohort composition).

Methods

Search strategy

We conducted a search of the PubMed database for relevant studies published between January 1985 and October 2006. We used the key words osteoarthritis and knee, in combination with one or more of the following: progression (or change), radiograph (or x-ray), joint space narrowing and Kellgren-Lawrence. The first author screened through abstracts identified by the search. For abstracts that assessed joint space narrowing, we included for further review those studies in which the patient sample had evidence of knee OA, progression was assessed radiographically over time, and sample size was greater than 10. For abstracts that assessed joint space narrowing, we included studies in which the patient sample had evidence of knee OA, progression was assessed radiographically over time, and sample size was greater than 10. Abstracts that analyzed Kellgren-Lawrence progression and examined OA incidence were also eligible for inclusion. We excluded literature reviews and studies not published in English. For abstracts that passed this screening, we retrieved the full length articles. For inclusion in our study, the manuscript had to report either change in joint space width over a specified period of time or the proportion of the population that progressed in Kellgren-Lawrence grade over a specified period. Studies that exclusively assessed osteophyte progression, used categorical scales of OA severity other than Kellgren-Lawrence, and reported proportion of population that experienced joint space narrowing (rather than differences in means) were excluded.

Data extraction

We extracted the following study and technical factors: study design (observational or randomized control trial (RCT)), year of publication, whether radiograph reader reliability tests were conducted or cited, sample size, length of follow-up, and radiographic view used. Year of publication was included to address potential secular trends in radiographic methods. Radiographic views included: standing antero-posterior (AP), metatarsal phalangeal (MTP), fixed-flexion PA (postero-anterior), semiflexed AP, and Lyon Schuss. We also extracted descriptive characteristics of the study population, including proportion female, mean age, mean BMI and mean baseline joint space width (defined as the smallest interbone distance across the knee joint)6. We defined three cohort types based upon the definition of disease: incident OA (no disease at baseline and progression to any higher Kellgren-Lawrence grade), prevalent OA (disease at baseline and progression to any higher Kellgren-Lawrence grade at follow-up), and ‘combination’, which included subjects with both incident and prevalent OA (progression to any higher Kellgren-Lawrence grade, irrespective of grade at baseline). We also extracted data pertinent to the two main outcomes: 1) change in joint space width over the follow-up period and 2) proportion of the study population that progressed at least one Kellgren-Lawrence grade over the follow-up period. We refer to the latter as the risk of Kellgren-Lawrence progression.

Analysis

Definition of Outcome Variables

Estimates of change in joint space width over the follow-up period (referred to as joint space narrowing throughout this report) were converted to annual rates. Similarly estimates for Kellgren-Lawrence progression were converted to annual risks of progression. For studies that reported estimates of progression for multiple cohorts, we included all estimates in our analyses. Thus, it was possible for a given manuscript to report more than one progression estimate (see Tables Tables11 and and2).2). For studies that reported on change at various intervals in the same patients, only the estimate from the longest follow-up time was included. For RCTs, we extracted data from the placebo arm only. For studies that reported change in Kellgren-Lawrence scale in each (left, right) knee individually, we used estimates for the right knee only.

Table 1
Study characteristics of the reviewed manuscripts: joint space narrowing
Table 2
Study characteristics of the reviewed manuscripts: Kellgren-Lawrence progression

Analysis of Joint Space Narrowing

For the joint space narrowing analysis, we grouped the 5 radiographic approaches observed in the literature into 3 categories: 1) full extension included the standing AP view, 2) semi-flexed with fluoroscopy included the semiflexed AP and Lyon Schuss views, and 3) semi-flexed without fluoroscopy included the MTP and fixed-flexion PA views.

Analysis of progression in Kellgren-Lawrence grade

Since only one study assessing Kellgren-Lawrence progression used fluoroscopic methods, we collapsed the three radiographic approach categories to include only full extension and semi-flexed.

Three studies reported separate estimates of Kellgren-Lawrence progression when OA was defined as Kellgren-Lawrence ≥ 1 and Kellgren-Lawrence ≥ 2. To avoid double-counting these cohorts, we ran two separate Kellgren-Lawrence models. Both models included all Kellgren-Lawrence estimates from manuscripts that define OA either way, but not both. The first model included the estimates derived when OA was defined as Kellgren-Lawrence ≥ 2 for these three studies. The second model included the three estimates derived when OA was defined as Kellgren-Lawrence ≥ 1.

Statistical Analysis

We performed meta-regression analyses examining the effects of radiographic approach, study design, year of study publication, length of follow-up, whether reader reliability was tested, and cohort characteristics such as mean age and proportion female, on each outcome: joint space narrowing or Kellgren-Lawrence progression. In addition, for the joint space narrowing model, we included mean baseline joint space width and mean BMI as predictors. For the Kellgren-Lawrence models, we included OA definition and cohort composition. We then examined various hypothesis-driven interactions in all models.

In both the joint space narrowing and Kellgren-Lawrence models, observations were weighted by the sample size of the cohort from which the observation was derived. All statistical analyses were performed at a 5% level of significance using SAS statistical software version 9.1 (SAS Institute, Cary, NC).

Results

The results of the search are depicted in Figure 1. Of 239 manuscripts identified through our PubMed search, 34 both met the inclusion criteria and did not meet the exclusion criteria. These 34 studies comprise the study sample. An overview of the characteristics of each of the included studies is presented in Tables Tables11 and and22.

Figure 1
Manuscript search and selection process.

Joint Space Narrowing Progression

Crude analysis

Of the 27 estimates that assessed joint space narrowing, 85% included some measure of reader reliability. Sample sizes ranged from 11 to 312, with a mean of 103 ± 81 subjects across all study groups under consideration. All studies had a greater proportion of females than males. Length of follow-up ranged from 8 months to 72 months with a mean of 26 ± 16 months. Fifteen estimates were derived from RCTs, and the remaining 12 were derived from observational studies. Eleven out of 27 estimates used full extension radiographic approach; eight used semi-flexed approach without fluoroscopy; and eight used semi-flexed approach with fluoroscopy (see Figure 2). Joint space narrowing estimates ranged from -0.10mm/year (indicating an increase in joint space width over time) to 0.70mm/year. The mean annual joint space narrowing across all estimates was 0.13 ± 0.15mm/year.

Figure 2
Annual joint space narrowing stratified by study design and radiographic approach. Circles represent individual mean joint space narrowing estimates. Circle area is proportional to sample size of corresponding cohort. Means within study design and radiographic ...

Multivariate findings

Overall, observational studies had a mean rate of joint space narrowing of 0.17mm/year (95%CI, 0.11-0.22), compared with 0.08mm/year (95%CI, 0.04-0.12) for RCTs (see Figure 2), adjusting for radiographic approach, follow-up time, and gender. The effect of radiographic approach depended on study design (p for interaction = 0.02) (see Figure 2). Adjusted mean rates of joint space narrowing were similar for full extension across both study designs (0.13mm/year for observational studies and 0.18mm/year for RCTs). Observational studies that used either semi-flexed approach reported larger narrowing estimates compared to RCTs that used the same approach. We did not find a statistically significant association between radiographic approach and joint space narrowing among observational studies. However, among RCTs, full extension was associated with greater narrowing compared to the semi-flexed without fluoroscopy approach. We found no statistically significant difference in narrowing between full extension and semi-flexed with fluoroscopy among RCTs, but the minimal overlap in confidence intervals between the two groups is suggestive of a difference (see Figure 2).

We found a suggestive negative linear relationship (β=-0.0025, p=0.06) between joint space narrowing and longer follow-up time (see Figure 4A). Our data did not provide evidence of a linear relationship between joint space narrowing estimates and gender (β=0.0020, p=0.16). We did not find an association between rates of joint space narrowing and mean age, mean BMI, reader reliability, and year of publication. Baseline joint space width was highly correlated with study design and radiographic approach, and thus was not included in the final model.

Figure 4
Association of OA progression (joint space narrowing (4A) and Kellgren-Lawrence (4B)) and study duration. Circles represent individual estimates of the proportion of the cohort that progressed by at least one Kellgren-Lawrence grade per year of follow-up ...

Kellgren-Lawrence progression

Crude analysis

Of the 18 estimates of Kellgren-Lawrence progression derived from the literature, 89% included some measure of reader reliability. Sample sizes ranged from 58-1115 with a mean of 334 +/- 314 subjects. All studies had a greater proportion of females than males. Length of follow-up varied from 24 months to 132 months with a mean of 69 months ± 31. Eleven out of 13 studies were observational studies, and the remaining two were RCTs. Ten out of 13 used full extension radiographic approach, while the remaining three used semi-flexed approach. In our ‘Kellgren-Lawrence ≥ 2′ model, five estimates were derived from OA definition Kellgren-Lawrence ≥ 1 and 13 from Kellgren-Lawrence ≥ 2. In our ‘Kellgren -Lawrence ≥ 1′ model, eight estimates were derived from OA definition Kellgren-Lawrence ≥ 2. The annual estimates of progression by at least one Kellgren-Lawrence grade ranged from 1.0% to 19.6%, with an overall mean risk of progression of 5.6% ± 4.9%.

Multivariate findings

Main analysis: ‘Kellgren-Lawrence ≥ 2′ model

Risk of Kellgren-Lawrence progression was associated with a shorter follow-up time (β=-0.0010, p<0.01) and with cohort composition (p<0.01). We found a suggestive association between Kellgren-Lawrence progression and OA definition (p=0.09). Studies with ‘combination’ cohorts (subjects with both incident and prevalent OA) had a greater risk of progression than those studies with incident or prevalent cohorts alone (8.0% vs. 2.4% (p<0.01) and 3.9% (p=0.05), respectively) (see Figure 3). Studies that defined OA as Kellgren-Lawrence ≥ 2 had a greater risk of progression than those studies that defined OA as Kellgren-Lawrence ≥ 1 (6.2% vs. 3.3%). As seen in Figure 4B, a negative linear relationship exists between risk of Kellgren-Lawrence progression and follow-up time. We did not find an association between Kellgren-Lawrence progression and radiographic approach, gender, age, year of publication, study design, or reader reliability.

Figure 3
Annual risk of Kellgren-Lawrence progression stratified by cohort composition. Circles represent individual estimates of the proportion of the cohort that progressed by at least one Kellgren-Lawrence grade per year of follow-up time. Circle area is proportional ...

Sensitivity analysis: ‘Kellgren-Lawrence ≥ 1′ model

We repeated the Kellgren-Lawrence model with the estimates derived from OA defined as Kellgren-Lawrence ≥ 1 instead of from Kellgren-Lawrence ≥ 2 for the three studies that presented both, in order to assess the sensitivity of the model to OA definition. Multivariate findings were similar in both models, except for the effect of radiographic approach. In the Kellgren-Lawrence ≥ 1 model, studies using full extension had a greater adjusted risk of progression than those using semi-flexed approach (7.0% vs. 3.6%, p<0.01).

Discussion

The goal of this analytic review was to describe the variability in estimates of knee OA progression (joint space narrowing and Kellgren-Lawrence) from the published literature and to identify factors explaining this variability. We performed a thorough systematic search and analytic synthesis of the published peer-reviewed literature on radiographic progression of knee osteoarthritis. Using these sources, we derived estimated annual rates of joint space narrowing and risks of Kellgren-Lawrence progression in populations with knee OA. We used meta-regression to study the association of these measures of OA structural progression with cohort characteristics and study features, in an attempt to explain the variability in estimates. A better understanding of the true rate of progression would assist clinicians in providing patients with an evidence-based trajectory of disease and timing of appropriate treatments. These estimates may also inform research on the development and testing of DMOADS.

We found a mean rate of joint space narrowing of 0.13 ± 0.15mm/year across all estimates. This value falls within the range reported by other investigators. Pavelka et al. reported annual rates of progression of joint space narrowing of 0.06mm/year to 0.60 mm/year10. Our finding is also consistent with the range reported by Vignon et al. of 0.10-0.15mm/year in hip and knee joints6. Secondly, we found a mean annual risk of progression in Kellgren-Lawrence grade of 5.6% ± 4.9%. To the best of our knowledge there are no published reports summarizing OA progression based on Kellgren-Lawrence grade. Both metrics exhibited variability, with standard deviations similar to the means.

This is the first literature review to our knowledge that comprehensively reports OA progression estimates and attempts to quantitatively explain the variability inherent in these estimates, adjusting for important covariates. To rigorously investigate these questions, we also used weighted regression techniques, which helped to eliminate the effect of sample size on the parameter estimates.

We demonstrated that estimates of joint space narrowing exhibit variability, partly explained by differences in radiographic approach and study design (see Figure 2). We found that among observational studies, those that used full extension approach, while not statistically significant, tended to report lower estimates of narrowing than those that used either semi-flexed approach. This is consistent with findings by Wolfe et al., who reported that, in a clinic-based observational cohort, greater narrowing was seen in Lyon Schuss semi-flexed view (uses fluoroscopy) and MTP semi-flexed view (no fluoroscopy) when both were compared to standing AP view (full extension). No difference was reported between the Lyon Schuss view and the MTP view, further supporting our finding that the use of fluoroscopy in the semi-flexed approach has little impact on the joint space narrowing estimates (see Figure 2)13. Recently, a shift towards non-fluoroscopic methods has occurred because they are less costly and easier to use, with little tradeoff in imaging quality and reproducibility14. Overall, full extension exhibited greater variability compared with both semi-flexed methods. Variability in serial radiographs in full extension may result from differences in knee positioning or changes in pain status at repeated x-ray visits, as patients with OA may be unable to adopt the fully extended position due to a joint pain flare6. Semi-flexed views employ various methods to standardize knee positioning and foot rotation to minimize variability. Such methods include MTP and patella alignment with film cassette (MTP semi-flexed)13, x-ray beam angulation in line with medial tibial plateau (Lyon Schuss semi-flexed view)15, and fluoroscopy.

The lower mean narrowing observed among subjects participating in RCTs utilizing either semi-flexed approach may suggest systematic differences in selection criteria for RCTs as compared to observational studies. Trials tend to set more stringent inclusion and exclusion criteria, resulting in a more homogeneous population. Moreover, the populations that participate in RCTs and observational studies may differ according to other important and unmeasured confounders, potentially resulting in the observed differences. RCTs may also be better funded to obtain radiographs of consistent method, quality, and timing. However, while randomized controlled trials are the best approach to testing efficacy questions, their samples are selected and typically are not as generalizable to clinical populations as observational studies.

The variability in progression along the Kellgren-Lawrence scale was explained in part by differences in follow-up time, OA definition, and cohort composition (see Figures Figures33 and and4B).4B). We found that a higher risk of Kellgren-Lawrence progression was associated with full extension in the Kellgren-Lawrence ≥1 model. The full extension view of the knee may be optimal for visualizing osteophytes, and thus may explain why a higher risk of Kellgren-Lawrence progression was seen in those studies that used full extension view compared with semi-flexed view. This may also explain why the majority of studies that reported Kellgren-Lawrence progression employed full extension view. This is consistent with findings by Wolfe et al., who reported that standing AP (fully extended) radiographs accumulated a greater mean osteophyte score (OARSI atlas) compared to Lyon Schuss semi-flexed radiographs13. The differential ability of the two radiographic approaches to show osteophytes may also explain why radiographic approach did not matter in the analysis using Kellgren-Lawrence ≥ 2 as the OA definition, but was significantly associated with risk of progression when OA was defined as Kellgren-Lawrence ≥ 1. Full extension may show more “possible osteophytes” (i.e. Kellgren-Lawrence = 1) than semi-flexed. When OA is defined as Kellgren-Lawrence ≥ 2, it is possible that each radiographic approach shows “definite osteophytes” equally well. However, it should be noted that sensitivity of the model to radiographic approach may simply be due to the small number of studies and estimates, resulting in a difference in only three estimates affecting the significance of the finding.

The difference in follow-up time seen in joint space narrowing studies and Kellgren-Lawrence studies also warrants discussion. As seen in Figures 4A and 4B, a negative linear relationship exists between both joint space narrowing and risk of Kellgren-Lawrence progression and follow-up time. It is important to note that the mean follow-up time for joint space narrowing studies was 26 months compared to 63 months for Kellgren-Lawrence studies. The shorter duration of joint space narrowing studies precludes comparisons across longer follow-up durations. The risk of Kellgren-Lawrence progression decreases as follow-up time increases, demonstrating that progression of OA as measured by the Kellgren-Lawrence scale may not be constant over time. This may reflect the biology of OA progression, suggesting it may plateau. On the other hand, this association may simply indicate that the Kellgren-Lawrence scale is ordinal but not interval. Kellgren-Lawrence grades 1 to 2 track the growth of osteophytes, while Kellgren-Lawrence grades 3 to 4 track joint space narrowing. Since the two ends of the scale reflect different pathological processes that involve different tissues, the amount of disease progression from one grade to the next should not be considered equal throughout the scale12. There is also a ceiling effect at Kellgren-Lawrence grade 4, since progression beyond >50% narrowing cannot be captured. It is possible that longer studies tend to accumulate more patients with Kellgren-Lawrence grade 4 who cannot progress any further along the scale, resulting in slower rates of progression.

Our review had several limitations. First, we identified several limitations in this literature which may have affected our results. Across eligible studies, documented risk factors for progressive knee OA were not universally reported. Risk factors for knee OA progression include BMI, varus-valgus alignment, dynamic load, concurrent OA in other joints, synovitis, ligamentous laxity, and bone marrow edema lesions16. BMI, in particular, has been confirmed as a risk factor for incident OA, but multiple studies have found that BMI is only a weak predictor of joint space narrowing compared with radiographic evidence such as initial joint space width or narrowing17, 18. We did not find an association between mean BMI and joint space narrowing. However, four studies did not report mean BMI, limiting our capacity to see an effect. A majority of the reviewed Kellgren-Lawrence studies (8/13) did not report mean BMI of their cohorts; thus we were unable to include this in the Kellgren-Lawrence models. However, the literature suggests the effect of BMI on our progression estimates would likely be modest19.

We focused our analyses on radiographic -- not MRI -- progression of osteoarthritis. We acknowledge that MRI is a powerful modality for imaging the arthritic knee. However, the interpretation of longitudinal changes in joint structures seen on MRI is undergoing intensive discussion20 and assessment of plain radiographs remains the most well accepted approach to structural progression at present.

In addition, approximately sixty percent of the joint space narrowing manuscripts limited their patient samples to those with Kellgren-Lawrence grades of less than four or joint space width > 2mm at baseline, while none of the Kellgren-Lawrence manuscripts noted any exclusion of those with advanced disease. Thus, narrowing estimates derived from these studies may not be representative of the entire OA population.

A better understanding of the true rate of progression would assist clinicians in providing patients with an evidence-based trajectory of disease and timing of appropriate treatments. These estimates may also inform research on the development and testing of DMOADS. In particular, these data should help investigators estimate sample sizes when designing DMOAD trials. Our data also support the need for standardized radiographic protocols to assess the progression of OA. The optimal protocol is one that is sensitive to change, reproducible, accurate, and constant across study settings and study populations. As there may be trade offs in establishing a standard radiographic approach, this decision should be undertaken carefully with involvement of a full complement of stakeholders.

Acknowledgments

Support: National Institutes of Health (NIAMS) RO1 AR 053112, K24 AR 02123

Footnotes

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