ARTHRITIS & RHEUMATISM Vol. 48, No. 2, February 2003, pp 385390 DOI 10.1002/art.

10765 2003, American College of Rheumatology

Detection of Radiographic Joint Space Narrowing in Subjects With Knee Osteoarthritis

Longitudinal Comparison of the Metatarsophalangeal and Semiflexed Anteroposterior Views
Steven A. Mazzuca, Kenneth D. Brandt, and Kenneth A. Buckwalter
Objective. Although recent protocols for standardized knee radiography afford highly reproducible radioanatomic alignment of the joint and measurement of joint space width (JSW) in repeat radiographs acquired on the same day, the sensitivity of these techniques to joint space narrowing (JSN) over time in subjects with knee osteoarthritis (OA) is unknown. The present study was undertaken to compare the metatarsophalangeal (MTP) view and the semiflexed anteroposterior (AP) view with respect to sensitivity to JSN in knee OA. Methods. In 49 subjects with definite knee OA, 2 MTP radiographs and 1 semiflexed AP radiograph were obtained at baseline. Each examination was repeated 14 months later. In MTP views, minimum JSW and the distance between the anterior and posterior margins of the medial tibial plateau (intermargin distance [IMD], an indicator of parallel alignment of the tibial plateau and the x-ray beam) were measured with a pair of calipers and a magnifying lens fitted with a graticule. JSW in semiflexed AP views was measured by digital image analysis. Results. The mean of within-knee standard deviations of JSW in the baseline MTP examinations (n 52 OA knees) was 0.24 mm (coefficient of variation 5.8%). Although IMDs in the 2 baseline MTP views were
Supported in part by NIH grants AR-43370 and AR-20582. Steven A. Mazzuca, PhD, Kenneth D. Brandt, MD, Kenneth A. Buckwalter, MD: Indiana University School of Medicine, Indianapolis. Address correspondence and reprint requests to Steven A. Mazzuca, PhD, Indiana University School of Medicine, Department of Medicine, Rheumatology Division, Long Hospital Room 545, 1110 West Michigan Street, Indianapolis, IN 46202-5100. E-mail: smazzuca@iupui.edu. Submitted for publication July 10, 2002; accepted in revised form October 21, 2002. 385

very highly correlated (0.88), IMDs in the serial examinations were only moderately correlated (0.45). Serial MTP views showed a small increase in mean JSW over 14 months that was not significantly greater than zero (mean SD 0.09 0.66 mm; P not significant). In contrast, concurrent semiflexed AP examinations showed a marginally significant decrease in mean JSW (0.09 0.31 mm; P 0.10). Conclusion. These results demonstrate 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. 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 (13). 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 spacethe surrogate for articular cartilage thicknessin which the medial tibial plateau is aligned parallel to the central ray of the x-ray beam (46). 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 (47). These advances notwithstanding, the cost, competing demands for equipment, and technical challenges of these standardization protocols have limited adoption

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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 (810). However, whether evidence of the superior shortterm 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. METHODS
Subject eligibility. Subjects for this study (n 43) were recruited from among participants in an ongoing study of the radiographic progression of knee OA. All subjects were 45 years of age and had definite unilateral or bilateral knee OA (grades IIIII OA severity by the Kellgren and Lawrence [K/L] criteria) (12). Procedures. Subjects were recruited during routinely scheduled return visits for followup radiographic examinations in the ongoing study of OA progression. After receiving a description of the risks and benefits of the additional radiographic examinations and providing informed consent, subjects underwent a nonfluoroscopic MTP examination in the outpatient radiology department of Indiana University Hospital; a series of additional knee views (i.e., supine lateral and skyline), as required by the parent study, were then obtained. Before each subject left the outpatient department, the MTP examination was repeated, and a fluoroscopically assisted semiflexed AP examination was then performed. Fourteen months later,

Figure 1. Positioning of the subject for radiography. For the metatarsophalangeal (MTP) view (A), the knees are placed in contact with the x-ray cassette and directly above the first MTP joints (arrow). The resulting degree of flexion of the knee (510) approximates that which is obtained with positioning for the semiflexed anteroposterior view (B), in which knee flexion is guided under fluoroscopy so that the medial tibial plateau is parallel with the central ray of the x-ray beam.

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Figure 2. Radioanatomic alignment of the medial tibial plateau and x-ray beam of the same knee, examined 14 months apart. A, Parallel alignment in the baseline radiograph is indicated by superimposition of the anterior and posterior margins of the medial tibial plateau (arrows). B, In the followup radiograph, alignment is not parallel, and the intermargin distance is 1 mm (arrows).

subjects returned for followup knee examinations that were carried out according to the same protocols, except that only a single MTP examination was performed. MTP knee radiographs. The radiology technologists who participated in this study had been instructed in the performance of the MTP knee examination by its developer, in preparation for their orientation for a multicenter clinical trial of a purported DMOAD, which was conducted concurrently with the present study. The positioning protocol for the MTP knee view is described in detail elsewhere (8,10). Briefly, the x-ray tube was positioned so that the central ray of the x-ray beam was parallel to the floor and perpendicular to the film cassette. The subject stood on a 17 14inch template with slight external rotation of the feet so that they formed a 15 angle from the neutral sagittal axis, based on guidelines printed on the template. The first MTP joint of each foot was positioned on a reference line directly below, and aligned with, the front of the film cassette (Figure 1A). The subject then bent both knees until the anterior surface of each knee touched the middle and front of the film cassette, after which the bilateral posteroanterior radiograph was acquired. Following the initial examination, an outline of each foot was drawn

on the template to facilitate repositioning of the joint for the subsequent repeat and followup examinations. Semiflexed AP knee radiographs. Each knee was imaged separately. The x-ray tube was positioned so that the central ray of the x-ray beam was parallel to the floor and perpendicular to the film cassette (Figure 1B). Under fluoroscopy, the knee was flexed slightly (510) and the foot rotated until the medial tibial plateau was aligned parallel with the central ray of the x-ray beam and the tibial spines were centered beneath the femoral notch. The technical standard for tibial plateau alignment was superimposition 1 mm of the anterior and posterior margins of the MTP (6). Measurement of JSW. Manual measurements of minimum medial-compartment JSW were obtained from MTP views with a screw-adjustable pair of calipers, according to the method described by Lequesne (13). The points of the calipers were used to measure interbone distance on the radiograph and then to prick a sheet of paper, on which the distance between the pinpricks was measured with a 2 magnifying lens fitted with a 10-mm graticule with 0.2-mm divisions. The standard error of repeated measurements (SEm) of this procedure (i.e., the square root of the mean of within-knee

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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.

variances, based on 4 blinded measurements of JSW in MTP images of 20 randomly selected knees) was estimated to be 0.18 mm (coefficient of variation 4.4%). Minimum medial JSW in the semiflexed AP view was measured using specialized edge-detection software (xJSW) developed by Lynch et al (14). Radiographs were converted to digitized images using a Lumiscan 75 laser film digitizer (Lumisys, Sunnyvale, CA), which can scan 14 17inch films at 2,000 2,500 pixels with a 100-m focal spot. All JSW measurements were corrected for magnification, as reflected by the projected image of a magnification marker (a 6.35-mm chrome steel ball encased in methyl methacrylate) that was affixed with tape to the lateral aspect of the knee, over the head of the fibula, before each semiflexed AP examination. Measurement of intermargin distance. The degree of alignment of the medial tibial plateau and the x-ray beam was measured manually as the distance between anterior and posterior margins of the medial tibial plateau (Figure 2). Utilizing the method described by Lequesne (13), the points of the calipers were used to measure intermargin distance on the radiograph in the region where JSW was narrowest and then to transfer the pinpricks to a sheet of paper. The distance was measured using the same magnifying lens and graticule described above. Satisfactory alignment was defined as an intermargin distance of 1 mm. Statistical analysis. All analyses were restricted to knees with grade II or III radiographic severity and baseline JSW 1.5 mm. A random-effects analysis of variance (ANOVA) model was used to estimate the reproducibility of JSW measurements in repeat baseline MTP views (15). Subject was the random effect. The root mean square error from the ANOVA model was used as the estimate of the SEm and was used to specify the 95% confidence interval of JSW measurements in MTP radiographs acquired the same day. The repro-

ducibility of radioanatomic positioning of the knee (intermargin distance) in repeated and serial MTP radiographs was described using Pearsons product-moment correlation coefficients. Paired t-tests for correlated data were used to determine whether the means of JSN estimates measured over 14 months in MTP and semiflexed AP views were significantly greater than zero.

RESULTS 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

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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* Minimum JSW, mm Protocol MTP Semiflexed AP Baseline 4.17 1.43 3.90 1.13 14 months 4.26 1.41 3.83 1.11 Change in JSW, mm 0.09 0.66 0.09 0.31 P (2-tailed) 0.33 0.10

* Values are the mean SD.

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. 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). DISCUSSION 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 trendtoward 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

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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) deformityfactors 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.

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