International Cartilage Repair Society

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1 Osteoarthritis and Cartilage (2008) 16, 1555e1559 ª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi: /j.joca Performance of a non-fluoroscopically assisted substitute for the Lyon schuss knee radiograph: quality and reproducibility of positioning and sensitivity to joint space narrowing in osteoarthritic knees S. A. Mazzuca Ph.D.y*, M.-P. Hellio Le Graverand M.D.z, E. Vignon M.D.x, D. J. Hunter M.B.B.S., Ph.D.k, C. G. Jackson M.D.{, V. B. Kraus M.D.#, T. M. Link M.D.yy, T. J. Schnitzer M.D.zz, A. Vaz M.D., Ph.D.xx and H. C. Charles Ph.D.kk y Indiana University School of Medicine, Indianapolis, IN, USA z Pfizer Global Research and Development, Groton, CT, USA x Universite Claude Bernard, Lyon, France k Boston University, Clinical Epidemiology Research and Training Unit, Boston, MA, USA { University of Utah School of Medicine, Salt Lake City, UT, USA # Department of Medicine, Duke University, Durham, NC, USA yy Department of Radiology, University of California, San Francisco, CA, USA zz Northwestern University, Chicago, IL, USA xx University of Arizona, College of Medicine, Tucson, AZ, USA kk Duke Image Analysis Laboratory, Durham, NC, USA Summary Objective: This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation. Methods: Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10 beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN. Results: Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P ¼ 0.002), more reproducible IMD (mean change ¼ 0.49 vs 0.91 mm, P ¼ 0.007) and more rapid JSN (mean ¼ 0.25 vs 0.02 mm/yr, P ¼ 0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P < 0.001), reproducibility of alignment (0.49 vs 1.00 mm, P < 0.001) and sensitivity to JSN (0.16 vs 0.01 mm/yr, P ¼ 0.007). Conclusion: In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original. ª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Key words: Knee osteoarthritis, Knee radiography, Osteoarthritis progression. International Cartilage Repair Society Introduction *Address correspondence and reprint requests to: Dr Steven A. Mazzuca, Indiana University School of Medicine, Department of Medicine, Rheumatology Division, Long Hospital Room 545, 1110 West Michigan Street, Indianapolis, IN , USA. Tel: ; Fax: ; smazzuca@ iupui.edu Received 3 December 2007; revision accepted 19 April Plain knee radiography by methods designed to standardize the positioning of the joint during serial examinations is the currently accepted gold standard for documenting loss of tibiofemoral joint space width (JSW) e the surrogate for articular cartilage thickness e in clinical trials of structuremodification of osteoarthritis (OA) of the knee 1e4. The most established protocols for standardized knee radiography utilize fluoroscopy to guide knee flexion and angulation of the central X-ray beam to achieve reproducible parallel alignment of the medial tibial plateau (MTP) 5,6. Parallel MTP alignment has been defined operationally as superimposition of the anterior and posterior margins of the MTP 5,7. Numerous studies have shown that, compared to serial radiographs in which MTP alignment is either consistently skewed, or variable over time, those with reproduced parallel alignment are more sensitive to radiographic joint space narrowing (JSN) in OA knees 5e10. Despite their technical advantages, fluoroscopically standardized protocols for knee radiography are of limited 1555

2 1556 S. A. Mazzuca et al.: Standardized radiography of knee osteoarthritis practicability because of costs and radiation exposure associated with fluoroscopy, as well as the scarcity of compatible equipment in many clinical centers conducting research on knee OA. These limitations have led to the development of alternative, non-fluoroscopically assisted positioning protocols 11,12 that are based on empirically derived standards for knee flexion and beam angulation. While yielding highly reproducible measurements of JSW in repeat exams over short periods of time 11e13, these simpler methods do not appear to be as sensitive to JSN in OA knees as their fluoroscopically standardized counterparts 9,10. Head-to-head comparisons of fluoroscopic and non-fluoroscopic positioning protocols in the same subjects are rare 14, but results are consistent with those of crossstudy comparisons: both have implicated skewed and/or longitudinally variable MTP alignment in the suboptimal sensitivity to JSN of non-fluoroscopic positioning protocols. Nonetheless, interest in easily exportable methods of standardized knee radiography remains high. The need for continued innovation in this area was illustrated in a recent multicenter longitudinal study of knee OA (A ), in which a direct comparison of the fluoroscopically assisted Lyon schuss (LS) radiograph 6 and its empirically based, non-fluoroscopic counterpart [i.e., the fixed-flexion (FF) view 11 ] was planned. The seven clinical centers in this study employed a heterogeneous array of C-arm and rad-fluoro (R&F) configurations to perform the LS examination. Some configurations were technically challenging, and fluoroscopes at two centers were retired during the study. To preserve the capacity of all centers to perform standardized knee radiography with optimal joint-specific beam angulation, the coordinating center for the study developed and implemented in three of the centers a modified LS procedure that eschewed fluoroscopy in favor of multiple acquisitions of plain knee radiographs 15. The number of acquisitions in each examination (four maximum) was governed by the radioanatomic alignment of the MTP apparent in the radiograph. If the first radiograph, acquired with 10 caudal angulation, exhibited skewed alignment, the exam was repeated. Each iteration of the exam occurred with a small adjustment of beam angulation until parallel MTP alignment was achieved. Herein we describe the performance of the modified LS knee radiograph with respect to the quality and reproducibility of positioning and its sensitivity to progressive JSN in OA knees. Materials and methods OVERVIEW Seventy-four subjects with definite knee OA from seven clinical centers in the United States underwent LS and FF X-ray examinations at baseline and 1 year later. For subjects at four centers (N ¼ 47), the LS examination followed the original protocol described by Piperno et al. 6, by which fluoroscopy was used to guide angulation of the central X-ray beam to achieve superimposition of the anterior and posterior margins of the MTP (Fig. 1). For subjects at three centers (N ¼ 27), a modified LS exam was performed at one or both times, beginning with an image acquired with 10 caudal beam angulation. If superimposition of the anterior and posterior margins of the MTP was not apparent [i.e., if the inter-margin distance (IMD) at the midpoint of the MTP appeared >1.5 mm], up to three additional images were obtained with small adjustments of angulation until the IMD was 1.5 mm. Quality control (QC) of LS radiographs was performed both locally and centrally (see below), and repeat LS exams were indicated when MTP alignment was not parallel. SUBJECTS AND SIGNAL KNEES All subjects were women with body mass index (BMI) 30 kg/m 2 and symptomatic unilateral or bilateral knee OA at baseline. Designation of the signal knee was based on the presence of grade 2 or 3 radiographic OA by Kellgren and Lawrence (K&L) criteria 16 and minimum medial JSW >2.0 mm in the LS radiograph. In subjects with unilateral knee OA, the signal knee was the one affected by OA. In subjects with bilateral disease, the signal knee was the more symptomatic joint, as determined by the pain scale of the Western Ontario and McMaster Universities (WOMAC) OA Index 17. If pain scores for both knees were identical, the knee with the more advanced radiographic changes of OA was designated the signal knee. If knees were identical with respect to pain and radiographic severity of OA, the knee in the subject s dominant leg (e.g., the one the subject would use to kick a ball) was selected for longitudinal observation. KNEE RADIOGRAPHY AND QC Shoes were removed for all radiographic knee examinations. Subjects were instructed to distribute their body weight evenly across both knees. Knee flexion and rotation for all knee examinations were standardized in schuss position by use of a SynaFlexerÔ positioning frame (Synarc, Inc.; San Francisco, CA). The foot was placed against a V-shaped wedge on the floor of the frame (fixing external rotation at 10 ) with the great toe touching the anterior wall [Fig. 1(A)]. Knees and thighs were pressed directly against the wall of the frame, the outer surface of which was in contact with the film cassette or upright tabletop of the radiographic unit. In this fashion, coplanar alignment of the great toe, patella and thigh resulted in standardized, reproducible positioning of the knee in approximately 20 of flexion. The X-ray beam was centered on the joint line, and the posteroanterior (PA) knee radiograph acquired. All seven clinical centers acquired FF radiographs according to the protocol described by Peterfy et al. 11 with standard 10 caudal angulation of the central X-ray beam. Four clinical centers performed all LS examinations according to procedures originally described by Piperno et al. 6, which entailed use of fluoroscopy to ascertain the knee-specific beam angle that resulted in superimposition (1.5 mm) of the anterior and posterior margins of the MTP [Fig. 1(B)]. The 1.5-mm QC criterion was adopted to take advantage of 3-mm reference beads that were imbedded in the SynaFlexer frame to serve as markers of radiographic magnification. After acquisition of the LS radiograph, the radiologic technologist was instructed to confirm that superimposition seen in the fluoroscope was captured by the radiograph (i.e., that the subject did not move). If skewed MTP alignment was apparent in the LS radiograph (i.e., if the IMD was >1.5 mm), the examination was repeated once, and the LS radiograph with MTP alignment closer to parallel (i.e., with the smaller IMD) was accepted. The modified LS examination 15 introduced at three clinical centers began with positioning of the knee as described above and an initial acquisition with 10 caudal angulation of the X-ray beam. If MTP alignment in the initial image was skewed (i.e., IMD > 1.5 mm), the technologist was instructed to repeat the examination with a 1-unit caudal or cranial increment in the beam angle (1e2, depending on the calibration of the equipment or bubble goniometer) and to evaluate whether MTP alignment in the repeat radiograph was satisfactorily parallel. Up to two further iterations of the procedure, with further adjustment of the beam angle, were permitted to identify the inclination that resulted in a LS radiograph exhibiting parallel MTP alignment. That angle was recorded for use in follow-up examinations. In addition to the QC measures exercised by local technologists, LS radiographs also were evaluated centrally within 2e4 weeks of acquisition to confirm parallel MTP alignment. Digital image analysis was performed to measure the IMD at the midpoint of the medial compartment. Radiologic technologists were directed to repeat LS radiographs when the IMD measured centrally was >1.5 mm. MENSURAL PROCEDURES Medial tibiofemoral JSW and IMD in digital images were measured with validated edge-detection software (Holy s software-beta19ô, UCLB, Lyon, France). Within limits defined by the operator to exclude marginal osteophytes, the software defined the contours of the medial femoral condyle and tibial plateau and identified the location of minimum JSW. The edgedetection capacity of the software was used also to define the anterior and posterior margins of the MTP, the distance between which was measured at the midpoint of the medial compartment. All measures were transformed into millimeters, based on magnification markers imbedded in the positioning frame. The intra-reader reproducibility [coefficient of variation (CV)] of minimum medial JSW, based on blinded repeat measurement of a random sample of 39 LS radiographs, was 0.8%. The CV of IMD estimates was 8.8%. STATISTICAL ANALYSIS LS and FF protocols were compared with respect to the quality and reproducibility of radioanatomic MTP alignment and sensitivity to JSN. The quality

3 Osteoarthritis and Cartilage Vol. 16, No B A C Fig. 1. Positioning of the subject for the FF and LS radiographs and examples of parallel and skewed alignment of the MTP with the X-ray beam. Panel A illustrates schuss positioning of the subject for both examinations. The pelvis, patella and great toe are positioned coplanar with the film cassette (knee flexion 20 ). The FF protocol uses a fixed 10 caudal angulation of the X-ray beam. In the LS protocol, fluoroscopy is used to adjust the beam angle to superimpose (1 mm) the anterior and posterior margins of the MTP. An IMD 1 mm (arrow) indicates parallel radioanatomic alignment of the MTP (panel B). Panel C illustrates skewed MTP alignment signified by IMD > 1 mm (arrows). of alignment was represented as the IMD measured at the midpoint of the medial tibiofemoral compartment. Reproducibility of alignment was expressed as the absolute value of the difference between IMD values at baseline and month 12 (D IMD ). For both variables, smaller values were more desirable (i.e., represented more parallel and better reproduced alignment, respectively). JSN was quantified as baseline JSW minus month-12 JSW. Sensitivity to JSN also was expressed as the standardized response mean [SRM ¼ mean JSN divided by the standard deviation (SD) of JSN]. Within two subgroups of subjects (i.e., those undergoing the modified and original LS examinations), paired t tests were used to compare IMD, D IMD and JSN values obtained from LS and FF radiographs. Given the within-subject nature of all comparisons, the significance of differences observed between LS and FF protocols was not adjusted for age, BMI or clinical center. Results Mean age (SD) of subjects was 58 8 years. Mean BMI was kg/m 2. Forty-one of 74 subjects (55%) had K&L grade 3 radiographic severity of OA in the signal knee at baseline; the remainder had grade 2 OA severity. Fifteen of 27 subjects at centers adopting the modified LS procedure were examined without fluoroscopy at baseline and follow-up; their results were highly similar to those of the 12 subjects at centers where the modified LS procedure was initiated after their fluoroscopically assisted baseline examinations (data not shown). The median number of iterations of the modified LS examination required to produce a knee radiograph that satisfied central QC criteria for parallel radioanatomic alignment of the MTP was 2 (range 1e4). Mean caudal angulation (SD) was Comparisons of modified LS and FF radiographs with respect to quality and reproducibility of MTP alignment and sensitivity to JSN are presented in Table I. Modified LS examinations required only two iterations of the imaging protocol to produce a radiograph that satisfied central QC criteria for parallel radioanatomic alignment of the MTP (maximum four). In contrast, IMD was >1.5 mm in 15 of 27 FF images. Accordingly, mean baseline IMD in modified LS radiographs was significantly smaller than that in concurrent FF radiographs (0.89 vs 2.06 mm, P ¼ 0.002). Moreover, modified LS radiographs exhibited significantly more reproducible MTP alignment than FF radiographs. Mean D IMD for LS radiographs was 0.49 mm, compared to 0.91 mm with FF radiographs (P ¼ 0.007). Mean JSN (SD) in the 27 signal knees that underwent the modified LS examination at baseline and/or month 12 was mm; in concurrent FF radiographs, mean JSN was mm (P ¼ 0.005). SRMs for the modified LS and FF protocols were 0.46 and 0.05, respectively. Parallel comparisons of original LS and FF radiographs are presented also in Table I. The differences between original LS and FF radiographs with respect to radioanatomic positioning of the knee and sensitivity to JSN were highly similar in both magnitude and statistical significance to those observed between modified LS and FF procedures. Discussion Despite the growing interest in magnetic resonance imaging (MRI) and other emerging technologies (e.g., serum or urine markers of articular cartilage degradation and repair) as methods by which to monitor structural progression of knee OA, plain knee radiography utilizing validated protocols for standardizing the radioanatomic position of the joint in serial examinations remains the recommended approach for documenting loss of tibiofemoral cartilage thickness in clinical trials of purported disease-modifying OA drugs (DMOADs) 1e4. The continued acceptance of standardized knee radiography for DMOAD trials is due in large part to the strong track record of fluoroscopically assisted positioning for enabling high degrees of reproducibility in measurements of tibiofemoral JSW e the surrogate for articular

4 1558 S. A. Mazzuca et al.: Standardized radiography of knee osteoarthritis Table I Comparison of LS and FF knee radiography protocols with respect to quality and reproducibility of radioanatomic positioning of the knee and sensitivity to medial tibiofemoral JSN Clinical centers without fluoroscopy (N ¼ 27 knees) Clinical centers with fluoroscopy (N ¼ 47 knees) Modified LS (Mean SD) FF (Mean SD) P-value Original LS (Mean SD) FF (Mean SD) P-value IMD, mm <0.001 D IMD, mm <0.001 JSN, mm SRM Abbreviations: D IMD ¼ 12-month change in IMD; JSN ¼ 12-month JSN. cartilage thickness 18 e and remarkable sensitivity to radiographic JSN 19. While the procedures for current standardization protocols differ in terms of the element of positioning that is guided by fluoroscopy (i.e., flexion of the knee vs angulation of the X-ray beam), the common standard for these protocols is to produce a knee radiograph in which the MTP is aligned in parallel with the central ray of the X-ray beam. The technical advantages of these protocols notwithstanding, fluoroscopically assisted knee radiography is becoming increasingly impracticable in the United States due to the limited availability of compatible fluoroscopic equipment in clinical centers conducting research on knee OA. For this reason, as well as for cost and patient safety considerations, teams of investigators have developed alternative standards for knee flexion and beam angulation that were derived empirically to maximize the likelihood of parallel MTP alignment 11,12. The FF protocol used in the present study utilized schuss positioning and 10 caudal angulation based on PA fluoroscopic examinations performed by Peterfy et al. 11 on a sample of OA and normal knees in schuss position. This standard was very similar to the typical angulation required in the present study to obtain modified LS radiographs with parallel MTP alignment (mean ¼ 9.7 ). JSW measurements from non-fluoroscopically assisted knee radiographs, including the FF view, are as reproducible as those obtained from their fluoroscopically guided counterparts 11e13. However, biological variability in the anatomy of the human knee often results in skewed radioanatomic alignment of the MTP despite empirical standards for optimal knee flexion and beam angulation 9,10,14. This limitation has been associated with decreased sensitivity to JSN in serial radiographs without benefit of fluoroscopy, compared to fluoroscopically guided examinations. The results from the four clinical centers that used fluoroscopy throughout the present study to aim the X-ray beam before acquisition of LS radiographs confirm these observations. The need for easily exportable methods for knee radiography that are highly sensitive to progressive JSN in knee OA is critical. This need arose in the present study as investigators from seven clinical centers adapted their imaging equipment to the standards of the LS protocol. Only two of the sites had angulating tables with fluoroscopic capability, and one of these sites retired the equipment during the study. The remaining centers had portable C-arm fluoroscopic capability that, to varying degrees, proved logistically difficult to use as the units could not be lowered to knee height. Customized stairs were fabricated by the coordinating center and shipped to the sites to enable investigators to perform PA fluoroscopic examinations required by the LS protocol. Knee-specific beam angles determined under fluoroscopy were transferred to general X-ray systems for acquisition of LS radiographs. While these adaptations indeed succeeded in preserving the sensitivity to JSN associated with LD knee radiography (Table I), enduring logistical difficulties in three centers compelled the coordinating center to innovate further and develop a hybrid examination methodology 15 that blended elements of the already similar LS and FF examinations. The key feature of the modified LS protocol was the immediate determination by the radiologic technologist (subject to further central QC) of the quality of radioanatomic alignment of the MTP and iterative, empirically driven repeat acquisitions until alignment was satisfactorily parallel. A limit of three repeat acquisitions kept X-ray exposure (and cost) well below that which would have accompanied fluoroscopy. Our data suggest that the modified LS radiograph was similar in performance to the fluoroscopically guided original in terms of both the quality and reproducibility of positioning and sensitivity to JSN. The modified LS protocol also was notably superior on all counts to the FF procedure, which did not provide for knee-to-knee variation in the anatomy of the MTP. It should be acknowledged that this study utilized only a modest number of subjects with knee OA (N ¼ 74). However, any threat that small sample size may pose to the generalizability of our results is offset to a considerable degree by the fact that these data came from examinations performed at seven academic medical centers across the United States. The results of this head-to-head comparison of standardized positioning protocols are not an isolated set of observations. Rather, this analysis confirms the critical importance of parallel alignment to the sensitive measurement of JSN that has been suggested by several crossstudy comparisons and reviews 5e10,14,19. While an X-ray examination that can require up to four iterations to satisfy QC criteria may present logistical challenges to a busy clinical radiology department, our experience in the present study suggests that the typical modified LS examination takes no more time than the fluoroscopically assisted original protocol e especially in light of the growing availability of digital X-ray systems. Moreover, the cost (and radiation exposure) associated with additional (typically one) plain radiographs is less than that associated with fluoroscopy. We, therefore, endorse the modified LS procedure for use in multicenter clinical studies of knee OA that require highly standardized, sensitive methods for detecting disease progression. Conflict of interest Dr Hellio Le Graverand is an employee of Pfizer. Drs Mazzuca, Vignon and Charles receive consulting fees from Pfizer. All investigators received grants from Pfizer to conduct the A study.

5 Osteoarthritis and Cartilage Vol. 16, No Ethics approval: The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with local Institutional Review Board, informed consent regulations, and International Conference on Harmonization Good Clinical Practices Guidelines. Acknowledgments We are grateful to the dedicated group of A Study Coordinators whose skills were essential in assuring the successful conduct of this research: Emily Brown, Sandra Chapman, Eugene Dunkle, Kristen Fredley, Donna Gilmore, Joyce Goggins, Mohsen Haddad-Kaveh, Norine Hall, Thelma Munoz, and Kim Tally. We also would like to thank Sharmila Majumdar, Julia Crim, Maureen Ainslie, the Duke Image Analysis Laboratory staff and Charles Packard for their invaluable efforts in conducting this study. References 1. Lequesne M, Brandt K, Bellamy N, Moskowitz R, Menkes CJ, Pelletier JP, et al. Guidelines for testing slow-acting drugs in osteoarthritis. 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