The objective of this study was to estimate the magnitude and regional distribution of differences in cartilage thickness and subchondral bone area, associated with each of the mJSN grades 1–32,3
observed clinically in radiographic OA. In order to overcome the challenges related to large inter-subject variability in these parameters and potential confounders between groups, this study is the first to employ a between-contra-lateral knee, within-person study design, comparing knees with mJSN and no-mJSN within OA participants with unilateral mJSN. While it is well known that higher JSN grades are associated with greater cartilage loss, the between-knee, intra-person approach is particularly well suited for quantitatively estimating the magnitude of thickness differences for particular JSN grades, as it eliminates between-person confounders, such as age, sex, weight, height, BMI and others. Applying this study design, we find that the intra-person, between-knee differences become greater with higher JSN grades and that the weight-bearing femoral cartilage (cMF) displays greater JSN-related differences than the posterior femoral condyle (pMF) and MT. This indicates that the pMF may represent a less relevant location for monitoring structural progression of knee OA than the cMF. Specific subregions (central cMF, external and central MT) showed the greatest cartilage thickness differences by JSN grade and were more strongly affected than other subregions in the MFTC, suggesting that these subregions may be preferentially affected by JSN-related cartilage loss in knee OA. Knees with higher JSN grades also displayed substantially larger femorotibial subchondral bone areas, suggesting that enlargement of the subchondral bone area may occur at the later stages of radiographic OA.
Between-knee differences in cartilage thickness and subchondral bone areas among health subjects were shown to be substantially smaller than the inter-subject variability of these parameters15
. Therefore, quantitative estimates of within-person, between-contra-lateral knee comparisons of cartilage thickness and subchondral bone areas should be more reliable than those originating from between-person comparisons. Also, confounding from differences in age, sex, weight, height, BMI or others, inherent to between-person analyses, could be controlled more effectively using the within-person design than otherwise possible in comparisons between subcohorts. This does not exclude potential confounding from differences at the knee level (e.g., ligament and meniscus status, trauma history, etc.); given the interest to determine structural differences associated with radiographic JSN grades, however, the current analysis provides a more robust estimate of JSN-related differences in cartilage thickness and subchondral bone area than estimates derived from previous cross-sectional between-subject studies9,11
Previous cross-sectional studies reported significantly lower MRI-based cartilage volume or thickness values in knees with JSN than those without9
, or in those with KL grade 3 compared to KL grade 011
. These estimates, however, were not specific to JSN grades and may have suffered from confounding of between-person comparisons. The current study shows that JSN grade 1 is associated with approximately 5% difference in weight-bearing femorotibial cartilage thickness, and that the magnitude of thickness difference increases with JSN grade 2 (about 20%) and grade 3 (about 40%). With regard to preferentially affected subregions in the cartilage plates, results from this study are consistent with a previous study in women with and without radiographic OA11
The femorotibial subregions that were identified as being most strongly affected by JSN-related cartilage thickness differences in the current paper (ccMF, eMT, cMT) also agree with those that have been described to display the greatest longitudinal changes in femorotibial OA in a meta-analysis of three longitudinal studies34
. With regard to the A–P (femoral) subregions, the results show that the posterior aspect of the weight-bearing femoral condyle (cMF: 30–75°), but not the posterior aspect of the condyle (pMF) is most strongly affected. This is in agreement with longitudinal changes in the MF23
and supports previous findings that JSN is more severe when knees are flexed to 20–30°35-39
. However, it has to be kept in mind that the current results may be specific to the selection of knees based on JSN in fixed flexion radiographs, whereas use of another radiographic technique that applies greater flexion during imaging (i.e., the tunnel view) would have selected knees with somewhat more posterior JSN-related cartilage loss, and a radiographic technique applying less flexion (i.e., extended knee radiographs) selected knees with more anterior JSN-related cartilage loss.
The current paper focused on the relationship between clinically observed JSN grades and both the magnitude and spatial distribution of actual “quantitative” femorotibial cartilage loss. The relatively large standard deviation of the side differences observed highlights previous observations that JSN is not exclusively related to quantitative cartilage loss, but is also influenced by other factors, including technical limitations of radiography (i.e., variable alignment of the tibia with the X-ray beam)4,5
, meniscus extrusion6-8
, weight-bearing conditions with X-rays but non-weight-bearing conditions with MRI, and others. A recent paper addressed the specific relationship of minimum joint space width (mJSW in weight-bearing Lyon Schuss view) with (sub) regional femorotibial cartilage thickness and meniscal position (medial and posterior subluxation) in non-weight-bearing MRI40
. The authors reported that, across OA and non-OA participants with different stages of radiographic disease, two thirds of the variation in mJSW was explained by regional femorotibial cartilage thickness measures, KL grade, and meniscal coverage40
. The MT cartilage thickness measures and the central subregion of the weight-bearing medial femur (ccMF) played a consistent role in the variations in mJSW observed across all KL grades; ccMF cartilage and percent meniscal coverage best explained the differences in mJSW found between those subjects with definite JSN and those without40
. These findings are consistent with our current observation that cMF (and particularly ccMF) display larger JSN-related differences (Z
-scores) than MT and its subregions.
In the current paper, quantitative differences in cartilage thickness were computed between-contra-lateral knees to quantitatively estimate the cartilage thickness loss related to specific JSN grades. In this context, it must be kept in mind that radiographic JSN was measured from weight-bearing radiographs, while MRI was acquired in the supine, non-weight-bearing position. The quantitative MRI-based cartilage parameters might therefore possibly change when being also acquired under weight-bearing conditions. Although the spatial (in-plane) resolution of the sagittal DESSwe sequence was 310 μm × 460 μm, smaller side differences of mean cartilage thickness were reported, because these were averaged over several participants and many thousand thickness measurements in each knee. Given an average size of the tAB of 11.1 cm2 for MT and 17.2 cm2 for MF, the mean thickness value for each subregion (five in MT and nine in MF) relied on approximately 2000 measurements per person. Nevertheless, thickness differences between knees were only reported to the nearest 10 μm.
A limitation of this study is its relatively small sample size, especially for knees with OARSI mJSN grade 3. However, there are few OA subjects who fulfilled the inclusion criteria for this study (mJSN in one knee, no-mJSN in the contra-lateral knee, and no [or less than medial] lateral JSN in either knee), and the cases were selected from a large cohort (first half of the OAI; n = 2678). Cases exhibiting mJSN grade 0 in one and OARSI mJSN grade 3 in the contra-lateral knee are relatively rare (only 6.3% of those in the OAI cohort that exhibit definite radiographic OA in at least one knee), and subjects with such large side difference in mJSN may have a different OA patho-physiology, including post-traumatic OA, previous knee surgery or previous infection. This difference in OA patho-physiology may have potential implications on the spatial distribution of cartilage thickness differences observed, but the “spatial pattern” of relative side differences in cartilage thickness was similar for this group and that with mJSN grade 2.
Previous studies reported contradictory information regarding whether subchondral bone areas are larger in participants with radiographic JSN than in those without9,11
and were not specificto JSN grade. Longitudinal studies reported an increase in subchondral bone area with time, but the observations were made both in OA participants41,42
and in healthy subjects42,43
. Therefore, previous studies were not conclusive on whether the increase in subchondral bone area observed longitudinally was specificto OA, or simply a function of the aging process. The results of the current study suggest that lower JSN grades (specifically grade 1) are not associated with increases in subchondral bone size, but higher JSN grades (grade 3 in the tibia, and grades 2 and 3 in the femur) are. These findings suggest that an increase in subchondral bone area occurs in advanced radiographic OA.
In conclusion, this study provides quantitative estimates of differences in cartilage thickness associated with specific medial radiographic JSN grades 1–3. JSN grade 1 was associated with small (Z-scores up to −0.6 only) between-knee differences in mJSN vs no-JSN knees in cartilage thickness and no differences in subchondral bone area. Higher JSN grades were found to be associated with larger cartilage thickness differences, and with substantially larger subchondral bone areas than contra-lateral knees without JSN, suggesting that enlargement of subchondral bone occurs in advanced OA. Within the MFTC, the weight-bearing femoral condyle (cMF) displayed relatively greater JSN-related differences than the MT and posterior femoral condyle (pMF). Specific subregions (central cMF, external and central MT) showed the greatest differences between JSN and no-JSN knees and were more strongly affected than other subregions in the MFTC.