The development of fluoroscopically assisted protocols for standardizing the radioanatomic position of the knee during serial radiographic examinations has been heralded as an advance that will enable the conduct of clinical trials of disease-modifying osteoarthritis drugs (DMOADs) with fewer patients and/or shorter duration than is feasible using conventional radiographic methods (1–3). Such protocols have used fluoroscopy to standardize knee flexion and rotation and/or angulation of the x-ray beam to achieve a reproducible image of the radiographic joint space—the surrogate for articular cartilage thickness—in which the medial tibial plateau is aligned parallel to the central ray of the x-ray beam (4–6). It has been consistently shown that these protocols afford more reproducible measurement of joint space width (JSW) in repeated examinations over intervals ranging from 1 hour to 1 month compared with the conventional weight-bearing view of the knee in full extension (4–7).
These advances notwithstanding, the cost, competing demands for equipment, and technical challenges of these standardization protocols have limited adoption of fluoroscopically assisted knee radiography in studies of the progression of knee osteoarthritis (OA) and have motivated the development of alternative, nonfluoroscopically assisted examination methods (8, 9). Such protocols use empirically derived standards for knee flexion, rotation, and beam angulation and have been reported to permit measurement of JSW that is at least as reproducible as that derived from fluoroscopically assisted knee radiography (8–10).
However, whether evidence of the superior short-term reproducibility of positioning of the joint and measurement of JSW using any examination protocol is sufficient to ensure comparable sensitivity in detection of joint space narrowing (JSN) in serial examinations of OA knees (e.g., performed a year or more apart, as would be required in a clinical DMOAD trial) has yet to be shown. This gap in our knowledge was recognized in a recent workshop convened to consider whether sufficient evidence exists to support use of any of the current knee radiography protocols (with or without fluoroscopy) for use in DMOAD studies (11). The participants, all of whom have made original contributions to this field, concluded that the most compelling evidence to support such a recommendation (i.e., from longitudinal, preferably comparative, studies of OA progression using standardized positioning protocols) is lacking, and for this reason, no current protocol could be endorsed over its alternatives (11). Accordingly, in the present study we compared the longitudinal performance (reproducibility of joint positioning and sensitivity to JSN) of the nonfluoroscopically assisted metatarsophalangeal (MTP) view (8) with its fluoroscopically assisted counterpart, the semiflexed anteroposterior (AP) view (6), in concurrent serial examinations of the same OA knees.
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The study group comprised 35 women and 14 men; 90% of the subjects were white. The mean (± SD) age of the patients was 57.7 ± 8.4 years. The majority of the subjects (53%) had a body mass index (BMI) ≥30 kg/m2. Thirty-five (71%) of the 49 subjects had bilateral knee OA according to K/L criteria (12).
Six subjects (12%) failed to return for their followup radiographic examination. Subjects lost to followup did not differ significantly with respect to age, sex, BMI, and baseline JSW from those for whom followup radiographs were obtained. Therefore, followup radiographs were available for 86 knees (43 subjects), of which 75 exhibited radiographic evidence of knee OA at baseline. The present analysis was restricted to a subsample of 52 knees with grade II or III OA severity and minimum JSW ≥1.5 mm at baseline.
Frequency and reproducibility of alignment.
Consistent with previous reports (8, 10), only 15 (29%) of 52 initial MTP views exhibited parallel alignment of the medial tibial plateau and the x-ray beam (i.e., intermargin distance ≤1.0 mm). Nonetheless, as shown in Figure 3A, the intermargin distance in the initial baseline MTP radiograph was accurately reproduced (i.e., to within an SEm of ±1 mm) in 46 (88%) of 52 repeat MTP radiographs. The correlation between intermargin distance in the initial and repeat baseline radiographs was very large (r = +0.88, P < 0.00001). However, radioanatomic alignment at baseline was not as well reproduced in MTP radiographs acquired 14 months later. As shown in Figure 3B, the intermargin distance in the initial baseline radiograph was accurately reproduced in only 28 (54%) of 52 followup MTP radiographs. The correlation between intermargin distance in the baseline and followup radiographs was significant, but was notably smaller (r = +0.45, P < 0.0001) than that between MTP radiographs acquired on the same day.
Figure 3. Plots of the intermargin distance in A, the initial baseline metatarsophalangeal (MTP) radiograph and the repeat baseline MTP radiograph, and B, the initial baseline MTP radiograph and the followup MTP radiograph (acquired 14 months later). The solid circles between the diagonal lines represent those knees in which the intermargin distance in the first examination was replicated by ±1 mm in the second examination. The broken lines represent an additional 0.20-mm margin of error for individual measurements of interbone distance.
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Reproducibility of JSW measurements.
The SEm of JSW measured in the 52 pairs of baseline MTP radiographs was 0.24 mm (coefficient of variation 5.8%).
Detection of JSN.
The mean (± SD) of the minimum JSW in the MTP views of 52 OA knees was 4.17 ± 1.43 mm at baseline (Table 1). Fourteen months later, the mean (± SD) JSW in MTP views had increased to 4.26 ± 1.41 mm. The observed change in mean JSW (mean ± SD +0.09 ± 0.66 mm) was not significantly different from zero. In contrast, JSW measured in concurrent, fluoroscopically assisted semiflexed AP examinations indicated narrowing of JSW over 14 months that, on average, approached statistical significance (mean ± SD −0.09 ± 0.31 mm; P = 0.10).
Table 1. Joint space width (JSW) at baseline and 14 months, and change in JSW in 52 osteoarthritic knees imaged according to protocols for the metatarsophalangeal (MTP) and semiflexed anteroposterior (AP) views*
|Protocol||Minimum JSW, mm||Change in JSW, mm||P (2-tailed)|
|MTP||4.17 ± 1.43||4.26 ± 1.41||+0.09 ± 0.66||0.33|
|Semiflexed AP||3.90 ± 1.13||3.83 ± 1.11||−0.09 ± 0.31||0.10|
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The purpose of this investigation was to document the sensitivity with which alternative protocols for standardizing the radioanatomic positioning of the knee in serial x-ray examinations detect JSN in subjects with knee OA. These results address a gap in our knowledge that was identified during a recent workshop on radiographic outcomes for DMOAD trials in which the participants, all of whom had performed original investigations in this field, concluded that a specific protocol for standardized knee radiography could not be recommended at that time because of the scarcity of published accounts of the longitudinal performance of these protocols in studies of OA progression (11). Notably, the present study addresses the key question of the cost–benefit tradeoff associated with the choice of a protocol that relies on empirically derived standards for knee flexion, rotation, and angulation of the x-ray beam versus one in which the radioanatomic positioning of the knee is guided by fluoroscopy.
In our examination of the performance of the nonfluoroscopically assisted MTP protocol, we confirmed that the radioanatomic position of the knee and measurements of minimum JSW in the medial compartment of the OA knee were reproduced very accurately in repeat MTP views acquired on the same day. However, the position of the knee at baseline (specifically, the degree of alignment between the medial tibial plateau and the x-ray beam) was not well reproduced in MTP examinations 14 months later. As a result, the mean and variability of estimates of JSN obtained using this technique were such that a true decrease in mean JSW (i.e., one that could be confidently considered to be significantly greater than zero) could not be detected in serial MTP views. Indeed, the tendency in longitudinal MTP data was toward a biologically improbable increase in mean JSW (+0.09 mm) over 14 months.
In contrast, concurrent semiflexed AP radiographs, in which fluoroscopically guided positioning resulted in parallel radioanatomic alignment of the medial tibial plateau in >90% of serial pairs of radiographs, showed an opposite trend—toward JSN (mean change in JSW −0.09 mm). Because the variability of JSN in semiflexed AP views was less than half that in MTP views (0.31 mm and 0.66 mm, respectively), the small decrease in mean JSW measured in the semiflexed AP views approached statistical significance.
The failure of the MTP protocol used in the present study to detect JSN in OA knees within 14 months is not likely to have been due to faulty execution by the radiology technologists, who had been trained in the protocol by its developer and who performed MTP examinations for a large multicenter clinical trial conducted concurrently with the present study. We previously observed that these technologists performed the MTP examination with short-term reproducibility comparable with that described in the original report on this protocol (10). Their facility in performing MTP examinations is again apparent in the reproducibility of positioning of the knee in repeat baseline radiographs (Figure 3A). Moreover, none of the radiographs generated for this study (or for the concurrent clinical trial) failed to pass quality control criteria established for the MTP protocol by Buckland-Wright et al (8). Nonetheless, the reproducibility of radioanatomic positioning of the knee deteriorated over 14 months, and the sensitivity of MTP radiographs suffered accordingly.
A possible explanation for the poor longitudinal performance of the MTP view in the present study is that, although positioning of the subject for this examination (i.e., with first MTP joints and patellae coplanar with the front surface of the x-ray cassette) fixes the radioanatomic alignment of the tibial plateau and the horizontal x-ray beam, it does not prevent changes in the femorotibial angle from examination to examination. A change in the femorotibial angle alters the points of contact between the femur and tibia and may reveal (or obscure) focal lesions in cartilage on the posterior aspect of the femoral condyle (16). Such changes can alter the appearance of radiographic JSW in an unpredictable way (11).
The manner in which a patient loads the knee during the MTP examination may be affected by factors such as lower extremity muscle strength, knee pain, or structural (varus-valgus) deformity—factors that are unlikely to change in repeat examinations on the same day, but which can change over the course of a year or more in patients with knee OA. We have shown that changes in knee pain can affect the appearance of radiographic JSW in the conventional standing AP view (17). The MTP view may be similarly influenced. The importance of such factors could be determined in a direct longitudinal comparison of the MTP view and alternative protocols that standardize the femorotibial angle, such the Lyon schuss and fixed-flexion views (5, 9).
The present study represents the experience in a single clinical center, with data from a modest number of subjects. Therefore, these results should not be construed as definitive with regard to the suitability of specific protocols for standardized knee radiography for use in a DMOAD trial. However, these data demonstrate clearly that evidence of the short-term reproducibility of a radiographic protocol is an insufficient basis on which to predict the quality of its longitudinal performance.