Osteoarthritis (OA) is one of the most common chronic diseases and represents a tremendous burden on the aging population and on the economics of health care systems (1, 2). Although OA has for some time been considered a “boring” degenerative disease that is almost inevitably associated with aging, the recent declaration of the Bone and Joint Decade (3) is meant to increase awareness of the disease and to promote advances in the understanding of its pathophysiology, diagnosis, and treatment. Population-based epidemiologic studies have identified genetic and environmental risk factors in OA (4–7) and have revealed that symptoms correlate poorly with structural changes observed on radiographs (4, 8). However, radiography has the potential disadvantages that cartilage cannot be delineated directly (9), results are valid only for the medial (but not lateral) femorotibial compartment (10), and there may be interactions with processes other than cartilage loss, such as meniscal subluxation (11). The current view of OA pathophysiology is therefore based on indirect evidence of joint destruction (joint space and osteophytes), although articular cartilage has been identified as the key tissue in the disease process.
New techniques have been proposed for the surgical treatment of OA, such as subchondral microfracture (12), autologous cartilage transplantation (mosaic plasty ), autologous chondrocyte implantation (14), matrix-assisted chondrocyte implantation, and others (15). In addition, strong interest is currently directed at developing orally administrable compounds that offer the ability to delay or stop the structural changes involved in the OA process (16). Two recent studies (17, 18) have suggested that an orally administered dietary supplement, glucosamine sulfate, is capable of producing structure modification in OA. These conclusions have been based on measurements of joint space narrowing on radiographs, but it has been argued that the observed effects may have been due to a change in joint position on standing extended radiographs, following symptomatic relief (19). This ongoing discussion highlights the need for an efficient, validated, and robust technique for quantitative assessment of cartilage status in OA that can be used in clinical trials to assess disease progression and response to treatment within reasonable time intervals. In fact, one of the most severe obstructions in the process of validation of new drugs has been the lack of reliable markers for therapeutic efficacy in vivo.
Magnetic resonance imaging (MRI) has the distinct advantage that it can delineate articular cartilage (the target tissue) directly and noninvasively. Three-dimensional (3-D) image protocols with high spatial resolution and innovative image analysis methods have made it possible to determine articular cartilage morphology in the human knee joint with high technical validity (accuracy) and precision (20–23). However, most studies have focused on the investigation of cartilage in normal joints, and only small-scale technical validation studies have been conducted in OA patients (20, 21, 24). In this context, total knee arthroplasty (TKA) provides a unique opportunity for validating measurements in vivo, because the patient can be imaged prior to surgery, and the excised tissue analyzed after the operation. Moreover, a wide range of cartilage destruction is observed, with some compartments demonstrating only mild, but others more severe, structural changes.
Previous studies have confirmed that cartilage volume can be measured with satisfactory validity in patients with OA (20, 21, 24) if appropriate MRI protocols are used. The 3-D capabilities of MRI and current image analysis techniques further permit differentiation between the process of reduction in cartilage thickness of remaining cartilage fragments and a decrease in cartilaginous joint surface area or increase in denuded (eroded) joint surface area.
The objective of this study was to comprehensively test the technical validity of quantitative measures of cartilage morphology in OA patients prior to TKA. Technical validity refers to the degree to which a measurement (and variation in measurements between subjects) corresponds to the true value. Technical validity must be distinguished from surrogate validity, which is the ability to measure a surrogate marker associated with clinical outcome; the current study addresses the former. Specifically, we tested the hypothesis that quantitative MRI (qMRI) can be used to accurately measure the percentage of cartilaginous or denuded joint surface area, as well as the thickness of remaining cartilage fragments.
- Top of page
- PATIENTS AND METHODS
Figure 3 shows the correlation of values calculated using qMRI-based measures with those obtained from direct morphologic measurements. Comparison between surfaces indicated that accuracy errors tended to be smallest in the patella and highest in the medial tibia, but errors were relatively small for all surfaces (Table 1).
Figure 3. Linear relationship between quantitative magnetic resonance imaging (MRI) and direct morphologic measurements of a, cartilaginous joint surface area, b, percent cartilaginous joint surface area, c, cartilage volume, and d, cartilage thickness.
Download figure to PowerPoint
Table 1. Validation of quantitative magnetic resonance imaging in osteoarthritis patients in vivo, versus direct morphologic analysis*
| ||Absolute difference, %||Systematic difference, %||Correlation (r)||Standard error y/x, %|
|Patella|| || || || |
| Mean thickness||4.3||−1.8||0.97||4.7|
|Medial tibia|| || || || |
| Mean thickness||12.3||0.4||0.72||13.7|
|Lateral tibia|| || || || |
| Mean thickness||10.0||−4.7||0.94||10.7|
|All surfaces|| || || || |
| Mean thickness||8.9||−2.2||0.92||9.6|
The random differences for the surface areas (original bone interface and percent cartilaginous surface) were ∼8% for the patella and the medial and lateral tibia, with the qMRI-based values being significantly lower (P < 0.01) than those obtained by direct image analysis (Table 1). Pairwise random errors in estimates of the percentage of cartilage (or denuded) surface ranged from ±3.6% (lateral tibia) to ±5.5% (medial tibia), but there was no systematic over- or underestimation by qMRI (Table 1). Pairwise differences in cartilage volume ranged from ±6.6% (patella) to ±11.5% (medial tibia), with a slight qMRI overestimation in the patella (5.1%; P < 0.05) and lateral tibia (3.6%; P not significant) and a slight underestimation in the medial tibia (−3.1%; P not significant). The mean cartilage thickness of the remaining cartilage fragment displayed random differences between ±4.3% in the patella and ±12.3% in the medial tibia, with no systematic difference between qMRI and direct morphologic analysis (Table 1). The high correlation coefficients (r ≥ 0.92, except for the cartilage thickness in the medial tibia) and relatively small standard errors confirmed a high linear relationship between values derived from qMRI and those measured morphologically.
- Top of page
- PATIENTS AND METHODS
In this study we demonstrated that MRI-based quantitative measurement of the original bone interface area (including both cartilaginous and denuded joint areas, but not peripheral osteophytes), cartilaginous joint surface areas, and thickness of the remaining cartilage fragments displayed a high degree of technical accuracy in a relatively large sample of patients who underwent TKA. The standard errors and absolute, pairwise differences between qMRI results and those obtained with independent methods were generally <10%. The systematic (and statistically significant) difference between qMRI and direct image analysis is most likely due to enlargement of the foil when it is flattened for the purpose of direct measurements of areas with image analysis. Although release cuts were made to minimize this, enlargement of the foil during unfolding cannot be entirely eliminated.
Errors in estimating the percentage of the cartilage surface and cartilage thickness tended to be higher for the medial tibia compared with the lateral tibia and patella. This may be partly due to the more advanced stage of OA in the medial femorotibial compartment, since the majority of TKA patients had varus OA. Similarly, two previous studies in unselected cadavers also showed higher between-method deviations in results in the medial tibia compared with the lateral tibia and patella (30, 31), with higher errors potentially being due to the higher degree of congruity and larger contact area of the medial femorotibial compartment (26).
Recent studies have demonstrated an annual loss of cartilage volume of ∼5% in the tibia (32) and patella (33) of patients with OA. Given the satisfactory level of technical accuracy observed in this study, qMRI may be used to distinguish the effect of cartilage thinning of remaining cartilage fragments from that of a decrease in cartilaginous joint surface area (increase in denuded joint surface area), both of which may lead to a loss of cartilage volume. This may help to identify how cartilage loss occurs in OA, and whether different types of insults produce similar or different quantitative outcomes. Because a reduction in cartilaginous area may be accompanied by swelling of the remaining cartilage (34), separating these two variables is potentially more effective than using cartilage volume alone.
A limitation of the current study is that only the technical validity of the measurements, but not the surrogate validity, was addressed. The surrogate validity of these parameters requires further testing in longitudinal studies, exploring their efficacy over measurement of cartilage volume alone, or over radiographic measurement of joint space width. Changes in radiographic joint space width occur when the cartilage thins at the joint surface area where the measurement is made. Analysis of the percentage of cartilaginous (or denuded) joint surface area with qMRI, however, is site-independent and may potentially represent a more objective quantifiable parameter in OA. Disadvantages of qMRI, however, include the cost of image acquisition, limited access to MRI scanner time, limited availability of dedicated software applications, and the fact that MRIs are acquired under non–weight bearing conditions.
In a recent cross sectional study (35), we have demonstrated that T scores (differences between a patient value and the mean value of young healthy adults of the same sex, divided by the standard deviation in young healthy adults) show better discrimination between patients and healthy subjects when MRI-based measurements of cartilage volume are normalized to the total original bone interface area. This normalization was shown to be superior in relation to normalization of body weight and height. The current analysis shows that measurement of the original bone interface area in patients with advanced OA is not only reproducible and useful, but also technically valid, despite the presence of peripheral osteophytes. In the context of cross-sectional analysis, the percentage of denuded joint area may also be potentially used as an inclusion/exclusion criterion for clinical trials. Cartilage volume, in contrast, is problematic as an inclusion criterion because larger individuals with larger bones display larger cartilage volume (36), independent of OA changes.
In conclusion, this study demonstrated that qMRI permits quantification of the original bone interface area, the percentage of cartilaginous (denuded) surface area, and the thickness of the remaining cartilage fragments with high technical validity (accuracy), if adequate MR sequences and image analysis tools are used. Future longitudinal studies must test the surrogate validity of these parameters and determine whether this analysis is advantageous over measurement of radiographic joint space narrowing or of cartilage volume alone.