This study investigates the relation of compartment-specific structural radiographic knee and MRI cartilage status at baseline with medial femorotibial cartilage thickness loss over one year as measured by 3 Tesla MRI. The results indicate that knees with more advanced medial femorotibial disease display greater cartilage loss than those with less advanced disease. Osteophytes, which represent early radiographic features of OA, did not predict cartilage loss in the current study, but knees with medial JSN tended to exhibit greater cartilage loss in the MFTC than those without JSN, although the relation was not significant. Subchondral femoral sclerosis (radiography), denuded subchondral bone area (MRI), and lower cartilage thickness (in MRI) at baseline displayed significant relations with at least some of the outcome measures of medial cartilage loss, all of these representing measures of relatively advanced disease. Whereas in the entire cohort the greatest SRM was -0.33 (change in cMFTC), the SRM was -0.47 in knees with grades 2/3 medial JSN, -0.46/-0.47 in knees with tibial and femoral subchondral sclerosis, and -0.64 in knees with denuded areas in the weight-bearing femur.
The subcohort examined here was the first one made public by the OA Initiative. It represents a stratified random sample of subjects with complete baseline and 12-month imaging data available as of April 2006, with strata roughly equal by gender and clinical/imaging site. Although it was not intended to be a random sample of the entire progression subcohort, the156 subjects analyzed show baseline characteristics similar to the entire OA Initiative progression subcohort (n = 1389; age range 45 to 79 years; 57% women with an age of 61.5 ± 8.9 years and a BMI of 30.8 ± 5.4; 43% men with an age of 61.1 ± 9.3 years and a BMI of 29.8 ± 4.1). A breakdown of calculated KLGs for all right knees for the entire progression subcohort in comparison with the subsample investigated here (2% vs. 11% KLG 0, 13% vs. 19% KLG1, 31% vs. 36% KLG 2, 39% vs. 30% KLG 3, and 15% vs. 4% KLG 4) shows that the current sample included more cases with no or possible radiographic OA (KLG0/1) and fewer cases with severe radiographic OA (KLG4) than the right knees of the entire progression subcohort, but both samples span all grades of radiographic OA.
Although a larger set of image data has been made public by the OA Initiative, central and compartment-specific radiographic readings (on which these analyses relied) have so far only been performed for the subsample used in this analysis. The statistical power of the current study is therefore limited by the relatively small sample size, which also introduces the potential problem of type 2 error, given the relatively large number of features examined. However, the features examined have been analyzed, but were not interpreted in isolation, in that most of the features found to be associated with higher rates of cartilage loss and greater SRMs were features of advanced structural disease. The current results should nevertheless be viewed as exploratory and must be confirmed in another (larger) sample, before recruitment approaches are based on any of the radiographic or MRI features investigated here. Also, the specific radiographic and MRI features studied must be seen in the context of other potentially predisposing risk factors, such as meniscal extrusion and damage [20
], bone marrow alterations [21
], focal cartilage defects [24
], and limb alignment [26
], as some of these may be directly or indirectly associated with the described compartment-specific radiographic or MRI features.
Additionally, there exist other potential predisposing factors of structural progression, for which less clear evidence or even contradictory results have been provided, including pain, joint function, physical activity levels [31
], synovitis (effusion) [32
], sex hormone levels [33
], and serum or urine biomarkers [35
], which eventually need to be taken into account. Another limitation of the study is that, given the limited number of cases and the greater progression observed in the MFTC in this subcohort [9
], the analysis was deliberately limited to MFTC outcomes, whereas some participants also showed progression in the lateral compartment. Only femorotibial, but not femoropatellar, radiographic features were analyzed, again because of the limited sample size, and because no femoropatellar readings have yet been provided by the OA Initiative. Only the right knee was analyzed, because the MRI sequence used for cartilage morphometry (FLASH) was only acquired in the right, but not in the left knees [17
], so that not all knees displayed radiographic and/or symptomatic OA. This, however, allowed us to examine the potential predictive value of radiographic and MRI features across knees with a relatively wide range of radiographic status. The decision to analyze the FLASH sequence acquired in all right knees, rather than the DESS sequence that was available for both knees, was made to allow to directly link the results to previous findings in other cohorts, which have to date been based on FLASH or SPGR sequences.
The strength of the current study is that it uses validated quantitative MRI technology as a measure of structural disease progression, which has been shown to be more powerful in revealing risk factor associations than semi-quantitative scoring of cartilage status [28
]. Cartilage loss, as measured with MRI over relatively short periods (1 or 2 years), has been shown to be associated with cartilage loss over longer periods (4.5 years) [36
] and with a clinical outcome of OA, specifically knee arthroplasty [37
], which makes it a very promising surrogate endpoint. Also, the current analysis relied on central radiographic readings of the OA Initiative imaging data, which was adjudicated in case of discrepancy between two independent readers, and has been shown to deviate in a substantial number of cases from the site readings used for the purpose of recruiting participants for the OA Initiative [11
]. Despite the many structural features examined and lack of statistical significance for some of these, the features suggestive of advanced disease pointed towards greater longitudinal cartilage loss compared with knees with less advanced disease.
Felson and colleagues [38
] reported that higher osteophyte scores modestly increased the risk of OA progression (defined by increasing JSN over 30 months), in particular when compartment-specific relations were analyzed. The authors mentioned that this association became weaker to non-significant when adjusting for limb alignment. Wolfe and Lane [39
] reported that JSN at baseline was a strong predictor of OA progression (defined by advancing to radiographic JSN grade 3) in more than 1500 patients, whereas BMI and osteophytes were less predictive and only contributed in participants with no JSN at baseline. Mazzuca and colleagues [40
] also found the progression of JSN over 30 months to be inversely related to baseline joint space width (JSW) and Le Graverand and colleagues [41
] the reduction in JSW to be greater in knees with JSN at baseline, using fluoroscopically standardized knee radiographs. In contrast to these and our current findings, Bruyere and colleagues [42
] reported patients in the highest quartile of baseline JSW to experience more severe cartilage loss than those in the lowest quartile and thus recommended the inclusion of participants with less severe OA (high JSW, no JSN) in disease-modifying OA drug trials.
Few studies have so far investigated the relationship between MRI-based cartilage loss and radiographic features of OA at baseline. Raynauld and colleagues [21
] found no significant association of MRI-based cartilage loss over 24 months with the radiographic JSW at baseline. However, another analysis from the same group [22
] reported that cartilage loss in the central aspects of the femorotibial cartilage plates was associated with smaller JSW and higher grades of JSN at baseline, and the results of our current analysis are in agreement with these findings. Wluka and colleagues [43
] reported the initial cartilage volume (in MRI) to be the most significant determinant of tibial cartilage loss (volume change with MRI), participants with high initial cartilage volume experiencing more severe cartilage loss than those with smaller cartilage volumes at baseline. Our current results are in direct disagreement with these observations in that we find a greater cartilage loss in participants with low initial cartilage thickness and with already denuded subchondral bone at baseline.
To our knowledge, no previous study has identified a relation between subchondral bone sclerosis at baseline and MRI-based cartilage loss. Buckland-Wright [44
] observed that the subchondral cortical plate and adjacent trabeculae thicken in OA, often prior to the onset of JSN. However, it was also reported that sclerosis did not increase in knees until the medial JSW was less than 1.5 mm. Bruyere and colleagues [45
] found tibial bone mineral density (BMD) as measured by dual x-ray absorptiometry to independently predict medial JSN over a one-year period in radiography, with patients in the lowest BMD quartile experience less JSN than those in the highest quartile. These observations are supported by our current MRI-based findings of increased cartilage loss in participants with subchondral sclerosis.
The greatest sensitivity to change (SRM) in this study was observed in subcohorts selected by baseline denuded area and initial cartilage thickness in MRI (up to -0.64). From the standpoint of recruiting patients for clinical trials, it must, however, be remembered that MRI is very costly and therefore cannot realistically be used as a screening tool. Using compartment-specific features of fixed flexion radiographs (specifically JSN and subchondral sclerosis), however, the SRM increased from -0.33 in the entire cohort to -0.47 for those with JSN grade 2 or 3 or participants with subchondral sclerosis. Such increases in SRM involve substantial savings in either the cohort size or the study duration in clinical trials and may thus justify the use of radiography as a screening tool in disease-modifying OA drug efficacy studies. Although it is currently unclear at which radiographic stage of radiographic OA disease-modifying drugs will be most effective, the current data can provide a reasonable basis for power calculations of the number or participants (with specific radiographic features) entered into a trial, if the effect of a disease-modifying OA drug is to be demonstrated.