This longitudinal study provides new and interesting information about the risk factors associated with the rapid advancement of the disease progression (cartilage loss) in patients with symptomatic OA. It also brings to light new and unique information about the topographical loss of cartilage in the different subregions of the knee and the associated risk factors. Moreover, the impact of the location and rate of cartilage loss on the evolution of OA symptoms over time was thoroughly explored. Treatment with risedronate did not interfere with the actual results of the study as the drug was shown to have no significant effect on the loss of cartilage volume [7
], on other structural changes, or on the disease symptoms or JSW changes over time [7
The global (continuous) analysis of these data was previously done and provides very informative findings [7
]. However, to further explore the risk factors that are selectively associated with more rapid disease progression, we performed analysis of cartilage volume loss by quartile in which we segregated the first quartile (greatest loss) from the fourth (least loss). Patients from the first quartile are of particular interest from a clinical perspective as they are likely to have the worst prognosis and are therefore at greater risk of surgical intervention for joint replacement. Moreover, they are of special interest for DMOAD studies as they may be the most likely to respond to treatment [27
The results of this study with regard to the quartile analysis show that OA patients experiencing the greatest risk of cartilage loss (first quartile), and more particularly in the medial compartment, were female and had a higher BMI. There was, however, no difference at baseline in disease symptoms or patient function. Interestingly, these patients showed a significantly narrower JSW. From a structural point of view, severe medial meniscal tear and/or extrusion or subchondral bone marrow hypersignal predominantly in the lateral compartment were clearly the most significant risk factors (Table ). These are in line with some of our findings from previous analyses [2
] and with the work of other investigators [9
]. There are, however, some exceptions. For instance, the association of the extent of cartilage loss with disease symptoms and, more precisely, with the WOMAC and SF-36 scores was lost, although a trend was found for the SF-36. We believe that this may be due to a type II error given that the groups of patients in the present analysis were relatively small. However, other explanations are also possible (for example, the cross-sectional nature of this type of analysis which also imposes limitations on our results).
These results are of great interest and have practical implications as they show that factors that can predict disease progression can be identified at the time that patients are included in clinical studies, as previously mentioned. These findings may also have particular relevance to DMOAD trials, as the selection of patients who present little or no progression of structural changes, specifically cartilage loss over time, represents a major challenge. This is particularly true with respect to the calculation of the number of patients to be included in a clinical trial. It also raises the important issue of the relevance of performing patient stratification at baseline during clinical trials.
Our findings on the key role played by the meniscus in OA cartilage pathology and loss nicely complement a number of previous reports. For example, MRI studies that have examined the role of meniscal lesions in OA and non-OA populations have reported that these changes [28
] are correlated with a greater risk of cartilage loss [9
]. The findings of this study are supported by both univariate and multivariate analyses. Similar findings were reported with meniscal malposition in patients with symptomatic knee OA [9
] and in patients who had undergone partial meniscectomy [31
]. Taken together, these findings stress the very important role played by the meniscal structure and positioning in protecting the integrity of cartilage in both healthy and OA individuals. Our data, however, clearly point to the fact that by far the greatest risk was associated with the presence of a complete (severe) extrusion of the medial meniscus. These findings support the hypothesis that the meniscus exerts a direct protective effect by reducing the physical contact between the cartilage surfaces. They also point to a protective effect of the meniscus even in the presence of degenerative changes as long as it remains in its normal positioning.
The present study showed that bone marrow hypersignal was also a risk factor for rapid loss of cartilage for the global knee and in the medial compartment. Interestingly, it was the presence of a bone hypersignal in the lateral compartment that was found to be the most significant risk factor. The relationship between bone marrow hypersignal and severity of knee OA cartilage lesions was first shown by Hunter and colleagues [29
] and Felson and colleagues [32
]. The compartmental edema was correlated with local cartilage loss as well as with limb alignment (medial lesions being associated with varus limbs and lateral lesions with valgus limbs). In the present study, any patients with clinically significant malalignment were excluded. However, although an examination was performed, there was no precise measurement of joint alignment. Thus, no firm conclusion can be arrived at as to the role played by malalignment in the present study. The exact reasons for the relationship between the presence of bone marrow hypersignal in the lateral compartment and the rapid loss of cartilage in the medial compartment remain unexplained and require further exploration. Though speculative, one possible explanation could be that patients experiencing such damage tend to shift their weight, putting more biomechanical stress on the lateral compartment.
The evaluation of cartilage loss by means of subregional analysis provides most interesting information. The loss was much greater in the medial compartment for both femoral condyles and tibial plateaus. This sensitivity to change being greater in the medial compartment was somewhat expected as patients selected for this study had baseline OA that was predominant in this particular compartment. These data support the validity of such outcome measures. On the femoral condyle, the loss was found in the central and anterior sections, followed by the trochlear area. These findings are in line with the work of Amin and colleagues [4
] in patients with knee OA with meniscal lesions and that of Biswal and colleagues [30
] in patients with meniscal tears who had undergone meniscectomies, with the exception that the preferential loss of cartilage occurring at the posterior medial femoral condyle found in these two studies was not confirmed in our OA population. The loss of cartilage on the lateral condyle followed the same pattern as the medial condyle but with the loss being less pronounced. The loss of cartilage on the tibial plateaus was identified mainly in the central area, which is not covered by the menisci. In addition, the pattern of loss in transversal subregions was found to be different between the two plateaus; in the medial plateau a greater loss was found in the anterior area, whereas on the lateral plateau it was on the posterior area. These differences point to the possibility that risk factors leading to cartilage loss could have been different in each tibial plateau. The low incidence of meniscal lesions in the lateral compartment [2
] points to the likelihood that other factors, such as bone marrow hypersignal, may play a more predominant role at that level, as indicated by the results from the quartile analysis. However, on the medial side, the preferential loss of cartilage in the central and anterior areas correlates closely with the high prevalence of tear/extrusion at that level, since no posterior lesions could be found in these patients [2
Comparative data from the MRI and x-rays indicate that the MRI is a more comprehensive tool for globally identifying factors that are predictive of the progression of the disease. Both the JSN and the cartilage volume loss were found to be positively correlated with the worsening of pain. The cartilage loss also correlates with the patient global score, and JSN with the loss of function. However, there was not good concordance between the two methods, with the exception of the WOMAC pain. Again, this may be due to the limitations imposed by the univariate analysis.
This study also provides clear evidence of a correlation between the loss of cartilage on weight-bearing areas and OA disease symptoms. The predictive value of the SF-36 indicates that the patients at high risk of progression are usually more disabled by the disease. They also experienced an increase in the level of knee pain, and, to a lesser extent, joint stiffness over time as the disease progressed. The relationship between the worsening in the WOMAC scores with the loss of cartilage on the central portion of the tibial plateau is intriguing. The level of significance of these findings for the WOMAC pain is greater than those previously reported for the loss of cartilage volume in the entire medial compartment [7
]. Moreover, the trend toward correlation with joint stiffness is a new and most interesting finding, as there is, to date, very little information of this kind originating from longitudinal studies. However, from cross-sectional studies, there have been reports of the correlation of knee pain with full-thickness cartilage defects [3
] and bone marrow lesions [3
]. Such a study discriminating subregions is of great significance in DMOAD trials as the effect of drug treatment on structural changes needs to be correlated with disease symptoms.
Our findings provide new information about the possible correlation between the loss of cartilage volume assessed by MRI and the loss of JSW assessed by x-ray. Previous studies conducted by our group [7
] demonstrated the absence of correlation between the loss of cartilage volume in the entire medial compartment and the JSW in patients with knee OA. These findings were in line with the previous report of Amin and colleagues [4
]. However, in the present study, a very strong correlation was found between the JSN and the loss of cartilage in the central area of the medial femoral condyle and, to a lesser extent, with the loss on the medial central tibial plateau. These findings are in close accordance with patient knee positioning during x-ray exams. Therefore, the standard x-ray technique and consequently JSW measurement commonly used in clinical trials accurately assess the focal loss of cartilage in patients with knee OA in the medial condyle and plateau subregions. Compared with x-rays, MRI presents significant advantages in assessing the change in cartilage volume/thickness in all the other subregions and compartments of the knee in addition to providing information on other structural changes, including the meniscus and subchondral bone. The latter are most relevant in identifying predictive factors of disease progression. Moreover, the evaluation of changes in both medial and lateral compartments is imperative given that a recent study demonstrated that some drugs may have a preferential chondroprotective effect on the loss of cartilage in the lateral compartment [27
This study has obvious limitations, the main one being the relatively small number of patients included in the analyses. New studies are under way or have been recently completed [27
] and should provide additional information and hopefully confirm the present findings. Another limitation is the fact that some patients received treatment with risedronate. All efforts have been made to ensure that this had no impact on the actual findings; the published data from the entire patient cohort analysis are certainly supportive to that effect [13