Longitudinal performance evaluation and validation of fixed-flexion radiography of the knee for detection of joint space loss

Authors

  • Michael C. Nevitt,

    Corresponding author
    1. University of California, San Francisco
    • Department of Epidemiology and Biostatistics, University of California, San Francisco, 185 Berry Street, Lobby 4, Suite 5700, San Francisco, CA 94107
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  • Charles Peterfy,

    1. Synarc, San Francisco, California
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    • Dr. Peterfy owns stock and/or holds stock options in Synarc. Synarc provides centralized image and biochemical analysis services and subject recruitment for clinical trials to pharmaceutical, biotechnology, and medical device companies, including but not limited to Abbott, Alexion, Allergan, Amgen, Astra-Zeneca, Aventis, Bayer, Biogen Idec, Bristol-Myers Squibb, Centocor, Elan, Eli Lilly, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pfizer, Procter & Gamble, Roche, Serono, Servier, and Wyeth.

  • Ali Guermazi,

    1. Synarc, San Francisco, California
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  • David T. Felson,

    1. Boston University Medical Center, and Boston University School of Medicine, Boston, Massachusetts
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  • Jeff Duryea,

    1. Brigham and Women's Hospital, and Harvard University Medical School, Boston, Massachusetts
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  • Thasia Woodworth,

    1. Roche, Rheinfelden, Switzerland
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    • Dr. Woodworth owns stock and/or holds stock options in Pfizer and Novartis.

  • Hepei Chen,

    1. National Institute on Aging, Bethesda, Maryland
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  • Kent Kwoh,

    1. University of Pittsburgh, and Pittsburgh Department of Veterans Affairs Health Care System, Pittsburgh, Pennsylvania
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  • Tamara B. Harris

    1. National Institute on Aging, Bethesda, Maryland
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Abstract

Objective

The ability of nonfluoroscopically guided radiography of the knee to assess joint space loss is an important issue in studies of progression and treatment of knee osteoarthritis (OA), given the practical limitations of protocols involving fluoroscopically guided radiography of the knee. We evaluated the ability of the nonfluoroscopically guided fixed-flexion radiography protocol to detect knee joint space loss over 3 years.

Methods

We assessed the same-day test–retest precision for measuring minimum joint space width (JSW), the sensitivity for detection of joint space loss using serial films obtained a median of 37 months (range 23–47 months) apart, and the relationship of joint space loss to radiographic and magnetic resonance imaging (MRI) measures of knee OA. Participants were men and women (ages 70–79 years) with knee pain who were participating in the Health, Aging, and Body Composition Study. We assessed baseline radiographic OA and measured JSW using a computerized algorithm. Serial knee MRIs obtained over the same interval were evaluated for cartilage lesions.

Results

A total of 153 knees were studied, 35% of which had radiographic OA at baseline. The mean ± SD joint space loss for all knees over 3 years was 0.24 ± 0.59 mm (P < 0.001 for change). In knees with OA at baseline, the mean ± SD joint space loss over 3 years was 0.43 ± 0.66 mm (P < 0.001), and in knees with joint space narrowing at baseline, joint space loss was 0.50 ± 0.67 mm (P < 0.001). Joint space loss and its standardized response mean increased with the severity of baseline joint space narrowing and with the presence of cartilage lesions at baseline and worsening during followup.

Conclusion

Radiography of the knee in the fixed-flexion view provides a sensitive and valid measure of joint space loss in multiyear longitudinal studies of knee OA, without the use of fluoroscopy to aid knee positioning.

Serial radiographs remain the gold standard (and regulatory agency–approved) method of assessing cartilage loss in osteoarthritis (OA) of the knee. Although radiography does not permit direct visualization of cartilage, the minimum medial tibiofemoral interbone distance, or joint space width (JSW), parallels articular cartilage thickness in knees radiographed in a moderately flexed, weight-bearing position (1). Weight-bearing is essential to displace intervening joint fluid and bring the opposing cartilage surfaces into contact. Flexion of the knee is required to avoid artifactual increases in apparent cartilage thickness that occur when the knee is fully extended (2, 3). In addition, flexion allows imaging of a more posterior sectional plane of the femoral cartilage, the location of peak load during walking and stair climbing and a location of early cartilage loss in OA (4–6).

Joint space loss, a key measure of disease progression in patients with knee OA, is estimated by comparing measurements of JSW between serial radiographs of the knee. Variability in positioning the knee during radiography can have a substantial influence on measured JSW (7–10). Several radiography protocols use fluoroscopic guidance as an aid to standardize and reproduce knee positioning (1, 9, 11), and these protocols have demonstrated excellent test–retest precision for measuring medial tibiofemoral JSW. In addition, nonfluoroscopically guided knee radiography protocols have been developed that fix the radioanatomic position of the knee in a manner designed to be reproducible between examinations, and these have also been shown to have excellent test–retest precision for measuring JSW (12–14).

Short-term measurement precision demonstrated under controlled conditions, however, does not guarantee that a method can precisely and accurately assess joint space loss in a large, multicenter, longitudinal study lasting several years. In these circumstances, a variety of factors can impede reproducible radiographic technique and positioning. These factors include changes in radiographer performance due to staff turnover, deterioration of morale and drift in technique, OA-related changes in anatomy (deterioration of ligamentous support, increasing mediolateral laxity, flexion contracture), changes in leg musculature, and the waxing and waning of knee pain. Consequently, the ability of a radiography technique to detect joint space loss must be assessed directly from repeat films obtained over time intervals during which real changes in joint space and other potentially confounding changes are likely to occur.

The sensitivity of fluoroscopically positioned flexed-knee radiography to detect significant joint space loss in knees with OA has been demonstrated in longitudinal studies of 12–30 months duration (5, 11, 15–17). However, there are no similar longitudinal data for the nonfluoroscopically guided flexed-knee radiography protocols. Such data would be of great interest, because the use of fluoroscopy presents substantial practical, logistic, budgetary, and other challenges, including the technical difficulty of the procedure, limited availability of suitable fluoroscopy equipment, and additional radiation exposure of the patient (3, 18).

We evaluated the performance of the nonfluoroscopically guided fixed-flexion radiography protocol (13) for assessment of medial tibiofemoral joint space loss. Our objectives were to evaluate short-term test–retest precision for measuring JSW, to determine the sensitivity of this method for detection of joint space loss over 3 years, and to evaluate the association of joint space loss with measures of radioanatomic positioning and OA severity, the latter including baseline x-ray findings and tibiofemoral cartilage damage assessed with magnetic resonance imaging (MRI).

PATIENTS AND METHODS

Patients.

Participants were drawn from the Health, Aging, and Body Composition (Health ABC) Study, a longitudinal study of weight-related diseases that contribute to disability in 3,075 men and women, ages 70–79 years, who were able to walk at least one-quarter of a mile and climb 10 steps without difficulty at baseline. The study was approved by the institutional review boards at the University of Tennessee and the University of Pittsburgh, the 2 clinical sites for the study. In patients who reported knee OA symptoms in at least 1 knee, bilateral knee radiographs and knee MRIs were obtained at the second or third annual clinic visit. Symptoms of OA were defined as “pain, aching or stiffness on most days for at least 1 month” during the past 12 months, or moderate or worse knee pain in the last 30 days during any activity, as assessed using the Western Ontario and McMaster Universities Osteoarthritis Index pain scale (19). Followup knee radiographs and knee MRIs were obtained in these patients at the fifth or sixth annual visit, depending on whether their baseline imaging was done at the second or third visit. At the followup visit, repeat knee films (with repositioning) were obtained in 29 patients, in order to assess short-term test–retest precision for measuring JSW.

The present analysis was limited to patients for whom followup knee radiographs were acquired by October 2002, and who did not have bilateral end-stage disease (Kellgren/Lawrence [K/L] [20] grade 4 or Osteoarthritis Research Society International [OARSI] atlas [21] grade 3 joint space narrowing) or primarily lateral compartment joint space narrowing in either knee. Three hundred twenty-eight patients met these criteria, and a random sample of 80 patients was selected, using a random number generator, for detailed radiographic measurements as part of a study comparing 3 radiography protocols (22).

Imaging protocols.

Radiography.

Bilateral posteroanterior knee films were obtained with the patient standing, knees flexed to 20–30 degrees, and feet internally rotated 10 degrees (13). Knees were imaged together on 14 × 17–inch film using a focus-to-film distance of 72 inches. The degree of knee flexion and foot rotation was fixed for each patient, using a plexiglass frame (SynaFlexer; Synarc, San Francisco, CA) for positioning. The great toes, patellae of both knees, and both thighs were touching the anterior wall of the frame, which in turn contacts the bucky tray so that the patellae are within a few centimeters of the film cassette. The x-ray beam was angled 10 degrees caudally, centered midway between the 2 knees at the level of the popliteal crease.

Radiography technicians were trained by an experienced research technician using a written operations manual as instructional material. A half-day training session took place at each radiology site involved in the study. Technicians were certified after successfully passing a central review of 10 radiographs obtained with the study protocol. During the study, 3 certified technicians were at one of the sites, and 5 technicians were at the other site. A half-day on-site refresher training session was held ∼3 months after study start and again just prior to the start of followup imaging. Radiographs were reviewed centrally by a trained research assistant, and repeat films were requested in instances of incomplete anatomic coverage, poor exposure, poor beam centering, or incorrect beam angle as indicated by visual assessment of the relative position of 2 columns of metallic beads on the SynaFlexer positioning frame.

MRI.

MRI studies were performed at baseline and followup, at each clinical center, using a Signa 1.5T whole-body clinical scanner (General Electric Signa, Milwaukee, WI) with a standard unilateral, commercial circumferential knee coil. The “short” protocol consisted of 3 sequences: 1) axial views were T2-weighted fast spin-echo (FSE) including the entire patella (acquisition time 30 seconds), 2) sagittal views were T2-weighted FSE, including the entire synovial cavity, with frequency-selective fat suppression (acquisition time 4 minutes, 30 seconds), and 3) coronal views were T2-weighted FSE (acquisition time 4 minutes).

Assessment of knee images.

Radiographs.

The baseline hard-copy films were evaluated by a single expert reader at Boston University for K/L grades and OARSI atlas grades (23) for osteophytes and joint space narrowing in the medial and lateral compartments. As part of a study comparing 3 radiograph acquisition techniques (22), rulers were used on baseline and followup films of right knees to manually measure the minimum medial tibiofemoral JSW and mid–medial tibial plateau alignment, a measure of radioanatomic positioning defined by the distance between the anterior and posterior rims of the medial tibial plateau at its center (1). Measurements were made on baseline and followup films individually, with the reader blinded to chronologic order and without the reader viewing the paired film. The intraclass correlation coefficients (ICCs) (interreader and intrareader reliability) for manual measurements of JSW were 0.98 and 0.90, respectively, and for tibial plateau alignment were 0.88 and 0.88 (22).

Hard-copy films were digitized using a Lumisys Lumiscan laser digitizer (Sunnyvale, CA) with a 100-μm pixel size. The minimum medial tibiofemoral JSW was measured from the digitized images using a computerized edge detection program (24). Bone margins were drawn by the computer independently on the baseline and followup films. A single trained reader then reviewed paired films, side by side but randomly and blinded to chronology, and made manual corrections to the bone margins as needed. Intrareader reliability (root mean square error [RMSE] coefficient of variance percentage [CV%]) of minimum JSW using this method is 2.9% for knees with OA and 5.5% for normal knees (24). On images of the left knee, measurements of midtibial plateau alignment were made using an electronic caliper. In 25 randomly selected right knees, agreement (ICC) between ruler and electronic caliper measurements of tibial plateau alignment was 0.88. In these same knees, intrareader reliability for repeat electronic caliper measurements was 0.96.

MRIs.

Magnetic resonance images were evaluated for cartilage damage by trained readers using the Whole-Organ MRI Score (WORMS) method (25). Using the WORMS method, cartilage damage is scored on a 7-level ordinal scale, assessing the articular surfaces of the medial tibia and femur and the lateral tibia and femur, with anterior, central, and posterior subregions of each plate scored separately, for a total of 10 scores that can be summed for a compartment-specific composite score. A cartilage score of 1 does not represent a change in morphology but rather a change in signal in cartilage of otherwise normal morphology. Scores of 2 and 3 represent similar types of abnormality of the cartilage, involving focal defects without overall thinning. Therefore, to create a scale for evaluation of cartilage morphologic change, as in previous analyses (26, 27), we collapsed the original WORMS values of 0 and 1 to a score of 0, the original values of 2 and 3 were collapsed to a score of 1, and the original values of 4, 5, and 6 were considered to be scores of 2, 3, and 4, respectively, on a modified 0–4-point scale. A compartment was defined as worsening if there was an increase of at least 1 point, reflecting significant morphologic change, in the cartilage score for any of its subregions. Interreader agreement for the WORMS cartilage assessments performed in Health ABC was acceptable, with ICCs of 0.89–0.92 for the medial and lateral tibiofemoral compartments (28).

Statistical analysis.

Analyses of joint space loss were limited to knees with at least 0.5 mm of minimum JSW at baseline according to the computerized measurement, because knees with little or no joint space remaining are not suitable for studies of joint space loss. Joint space loss was calculated by subtracting the followup value of the minimum JSW from the baseline value in the same knee, so that a positive value indicates a decrease in JSW.

A random-effects analysis of variance (ANOVA) model was used to determine the reproducibility of JSW measurements from same-day test–retest knee radiographs (29). The RMSE was calculated from the ANOVA model, with the knee as the explanatory variable and JSW as the dependent variable; the CV% was calculated as (RMSE/mean JSW) × 100. For comparison with other studies, CV% was also calculated using the mean and median of the within-pair SDs. Agreement between measurements was evaluated using the ICC.

The significance of change in the minimum JSW between baseline and followup was evaluated with paired t-tests. Sensitivity to detect joint space loss was expressed as the standardized response mean (SRM), calculated as the mean change in joint space divided by its SD. One-way ANOVA and general linear models (GLMs) were used to assess the association of joint space loss with disease characteristics and positioning indicators. Tests for trend across ordered categoric variables were performed using GLM.

RESULTS

More than one-third of the 80 patients were men, 39% were African American, and 44% had symptoms in only 1 knee at baseline (Table 1). Median followup was 37 months (range 23–47 months). Radiographic knee OA, defined as a K/L grade of ≥2 or definite osteophytes (OARSI atlas grade ≥1), was present in at least 1 knee in 49% of patients at baseline, while in 39% of the patients, symptoms and osteophytes were in the same knee. In 2 right knees and 4 left knees, minimum JSW at baseline was <0.5 mm (computerized measurement), and 1 right knee was replaced during followup; these knees were not further analyzed.

Table 1. Characteristics of the 80 study patients*
  • *

    Except where indicated otherwise, values are the percentage. BMI = body mass index; OA = osteoarthritis.

  • Pain, aching, or stiffness on most days for at least 1 month in the past 12 months, or moderate or worse knee pain for ≥1 activity on the Western Ontario and McMaster Universities Osteoarthritis Index.

  • Kellgren/Lawrence grade ≥2 or definite osteophytes (Osteoarthritis Research Society International grade ≥1).

Age, mean ± SD years73.5 ± 3.1
Male36.4
African American39.0
BMI, mean ± SD kg/m227.8 ± 4.3
Knee symptoms100.0
 1 knee43.8
 Both knees56.2
Radiographic knee OA48.8
 1 knee23.8
 Both knees25.0

Of the 153 knees included in the analysis, 53 (35%) had radiographic OA at baseline. Baseline and followup computerized measurements of minimum medial tibiofemoral JSW were available for 153 knees, and paired manual measurements of JSW were available for 77 right knees. In right knees, there was excellent agreement between the computerized and manual measurements of JSW at baseline (ICC 0.96) and very good agreement for joint space loss over 3 years (ICC 0.79). All subsequent results were for the computerized JSW measurements. Results were nearly identical using manual measurements (data not shown).

For 53 knees with same-day repeat films, the ICC for JSW was 0.98, the RMSE was 0.23 mm, and the RMSE CV was 7.4%. The mean and median within-pair SDs (CVs) were, respectively, 0.15 mm (4.9%) and 0.08 mm (2.6%). Eighty-eight percent of test–retest measurements were within 0.5 mm of each other, and 95% were within 1.0 mm.

The mean ± SD joint space loss over 3 years in all knees was 0.24 ± 0.59 mm (Table 2), with a mean ± SD annual rate of joint space loss of 0.07 ± 0.20 mm. Pseudo-widening (an increase in JSW of ≥0.5 mm over 3 years) occurred in 9 knees (5.9%), while joint space loss of ≥0.5 mm occurred in 44 knees (28.8%). Seven of the 9 instances of pseudo-widening occurred in knees with a normal baseline joint space, defined as a JSW >4.0 mm and joint space narrowing grade 0.

Table 2. Medial tibiofemoral JSW at baseline, and computerized and manual measurements of joint space loss over 3 years*
Measurement methodBoth knees (n = 153)Right knee (n = 77)
  • *

    Except where indicated otherwise, values are the mean ± SD. Manual measurements were obtained in right knees only. JSW = joint space width; SRM = standardized response mean.

  • By paired t-test.

Computerized  
 Baseline JSW, mm3.66 ± 1.253.62 ± 1.31
 Joint space loss, mm0.24 ± 0.590.26 ± 0.57
 SRM0.410.46
 P<0.001<0.001
Manual  
 Baseline JSW, mm3.79 ± 1.40
 Joint space loss, mm0.27 ± 0.50
 SRM0.54
 P<0.001

The value for joint space loss over 3 years and its SRM increased sharply with the degree of baseline medial compartment joint space narrowing (Table 3). Compared with the 73% of knees with normal joint space (grade 0) at baseline, joint space loss was 2.6-fold greater in knees with grade 1 narrowing at baseline and nearly 5-fold greater in knees with grade 2 narrowing (P < 0.001 for trend across the 3 categories). There was a trend for increased joint space loss in knees with grade 2 compared with grade 1 narrowing, but this was not significant. The mean ± SD annual rate of joint space loss in knees that were narrowed at baseline (n = 42) was 0.17 ± 0.23 mm. In knees with K/L grade ≥2 or definite osteophytes (n = 53), the mean ± SD joint space loss over 3 years was 0.43 ± 0.66 mm (P < 0.001; SRM 0.65), significantly (P < 0.01) greater than that in knees without radiographic OA, and annual joint space loss was 0.14 ± 0.22 mm.

Table 3. Baseline medial compartment JSN grade and medial tibiofemoral joint space loss over 3 years*
Baseline JSNJoint space lossSRMP
  • *

    Values are the mean ± SD mm (computerized measurement of joint space loss). JSN = joint space narrowing; SRM = standardized response mean.

  • By paired t-test.

  • P < 0.001, grade ≥1 versus grade 0.

  • §

    P < 0.001 for trend, by increasing grade of JSN; P = 0.15, grade 2 versus grade 1.

Grade 0 (n = 111)0.14 ± 0.530.260.010
Grade ≥1 (n = 42)0.50 ± 0.670.75<0.001
 Grade 1 (n = 23)0.36 ± 0.760.470.014
 Grade 2 (n = 19)0.63 ± 0.66§0.95<0.001

In 122 knees with serial MRIs scored for cartilage lesions, those that did not have medial compartment cartilage lesions did not have significant joint space loss, those with baseline lesions that worsened had the highest rate of joint space loss, while knees with baseline lesions that did not worsen had an intermediate rate of joint space loss (P = 0.017 for trend across the 3 categories) (Table 4). The difference in joint space loss between knees with lesions that worsened and those with lesions that did not worsen was not significant. Higher baseline composite cartilage scores and increases in composite cartilage scores during followup were moderately correlated with greater joint space loss (r = −0.33, P = 0.0002 and r = −0.26, P < 0.01, respectively).

Table 4. Medial tibiofemoral compartment MRI scores and joint space loss over 3 years*
Cartilage lesion scoreJoint space lossSRMP
  • *

    Values are the mean ± SD mm (computerized measurement of joint space loss). Cartilage lesion scores are based on the modified Whole-Organ Magnetic Resonance Imaging (MRI) Score method (0–4 scale), where worsening within a compartment is defined as a score increase of ≥1 in any subregion. SRM = standardized response mean.

  • By paired t-test.

  • P = 0.016, baseline grade ≥1 versus grade 0.

  • §

    P = 0.017 for trend across categories (no baseline lesions; versus baseline lesions and no worsening; versus baseline lesions and worsening); P = 0.522 for baseline grade ≥1 with worsening versus baseline grade ≥1 with no worsening.

Baseline grade 0 (n = 56)0.08 ± 0.490.160.253
Baseline grade ≥1 (n = 66)0.34 ± 0.710.48<0.001
 Baseline grade ≥1, no worsening (n = 47)0.30 ± 0.640.470.003
 Baseline grade ≥1, worsening (n = 19)0.42 ± 0.86§0.490.044

There was no significant association of joint space loss with the degree of alignment of the tibial plateau rims at baseline and followup (Table 5). The greatest joint space loss (and SRM value) was observed in knees with parallel alignment at both time points, but only 12% of knees were in this group, and the values were not significantly different from those in knees with nonparallel alignment.

Table 5. Effect of mid–medial compartment tibial plateau rim alignment at baseline (BL) and followup (FU) on medial tibiofemoral joint space loss over 3 years*
Medial tibial rim alignmentJoint space lossSRMP
  • *

    Values are the mean ± SD mm (computerized measurement of joint space loss). Mid–medial compartment tibial rim alignment is defined as the absolute value of the distance between the anterior and posterior rims of the medial tibial plateau at its midpoint. There were no significant differences in joint space loss by category of tibial rim alignment (P ≥ 0.49 for overall analysis of variance, all pairwise comparisons, and tests for trend across the 3 categories; P = 0.20 for aligned [n = 18] versus not aligned [n = 135]). Results were no different after adjustment for baseline joint space narrowing. SRM = standardized response mean.

  • By paired t-tests.

Both BL and FU alignment <1.5 mm (n = 18)0.41 ± 0.700.590.003
Either BL or FU alignment ≥1.5 mm, difference between BL and FU <1.5 mm (n = 93)0.23 ± 0.580.40<0.001
Either BL or FU alignment ≥1.5 mm, difference between BL and FU ≥1.5 mm (n = 42)0.21 ± 0.590.360.028

DISCUSSION

This study evaluated assessment of medial tibiofemoral minimum joint space loss, a primary outcome measure for knee OA, with the nonfluoroscopically guided fixed-flexion radiography protocol, a posteroanterior view that fixes the degree of knee flexion and rotation using a positioning frame and angles the x-ray beam caudally 10 degrees (13). Our results demonstrate the sensitivity of this protocol for detection of joint space loss in a 3-year longitudinal study of knees with OA. We observed a significant decrease in joint space in a sample that included knees with and those without radiographic OA and knees with and those without pain. Knees with radiographic evidence of OA at baseline, either osteophytes or joint space narrowing, and those with MRI evidence of morphologic lesions in cartilage had significantly greater joint space loss than knees without these findings.

We confirmed results of a previous study (30) showing that the short-term test–retest precision for the measurement of JSW for repeat fixed-flexion radiographs acquired in a field setting is comparable with that achieved in similar settings with the fluoroscopically guided semiflexed view (31) and Lyon schuss view (5) radiography protocols and the nonfluoroscopically guided metatarsophalangeal (MTP) protocol (14, 32, 33). Short-term test–retest precision does not differentiate between these alternative knee radiography protocols. Many factors that influence the ability to reproduce radioanatomic positioning of the knee, such as pain, muscle weakness, and ligamentous laxity, can change substantially over the extended time interval needed to detect joint space loss. Therefore, acceptable short-term test–retest precision is an essential but not a sufficient condition for good performance of knee radiography in detecting loss of joint space, and this must be assessed directly in longitudinal studies.

The performance of the fixed-flexion view radiography protocol in terms of the rate of medial tibiofemoral joint space loss and sensitivity to change (SRM) in knees with OA was within the range seen in longitudinal studies of 12 months or longer using fluoroscopically assisted radiography protocols in knees with OA (Table 6). Because both joint space loss and the SRM value may increase with duration of followup, the most informative comparison with our findings is the 30-month study using the fluoroscopically assisted semiflexed view protocol (15). To our knowledge, there are no studies of at least 12 months duration using other nonfluoroscopically assisted flexed-knee radiography protocols that demonstrate a loss of joint space. However, without the benefit of a head-to-head comparison between different protocols used in the same knees over the same time interval, it is not possible to definitively compare their performance. Differences in patient characteristics, duration of followup, and other factors between studies that use different radiography protocols may confound differences in the rate and variability of joint space loss observed with different protocols.

Table 6. Joint space loss in OA knees from studies using fluoroscopically guided radiography protocols and knees from the present study*
Protocol (ref.)OA definitionNo. of kneesMonths of followupJoint space lossSRM
  • *

    Except where indicated otherwise, values are the mean ± SD mm. OA = osteoarthritis; SRM = standardized response mean; fluoro = fluoroscopically guided; ACR = American College of Rheumatology criteria.

Fluoro Lyon schuss (16)Clinical/ACR73120.19 ± 0.480.40
Fluoro semiflexed (17)Clinical/ACR85120.12 ± 0.420.29
Fluoro semiflexed (31)Radiographic52140.09 ± 0.310.19
Fluoro Lyon schuss (11)Clinical/ACR58240.24 ± 0.500.48
Fluoro semiflexed (15)Radiographic180300.45 ± 0.700.64
Non-fluoro fixed-flexion (present study)Radiographic53360.43 ± 0.660.65

Our study supports the construct validity of assessing joint space loss with the fixed-flexion view radiography protocol, by demonstrating the association of joint space loss with several factors with which it should be related. First, in this sample from the general population, the rate of joint space loss and SRM value were substantially greater in knees with baseline osteophytes (34% of knees) or in knees with joint space narrowing (29% of knees) compared with knees without these findings, and both joint space loss and its SRM value increased with the severity of baseline joint space narrowing. Second, to further validate the radiographically determined estimates of structural progression, we examined the relationship between joint space loss and MRI-based measures of cartilage morphologic lesions. The rate of joint space loss and SRM value were associated with the presence of cartilage lesions and with worsening of cartilage lesion scores during the study.

Radioanatomic positioning of the knee and its variability between exams is an important factor in determining the ability of a radiography protocol to assess knee OA progression (7–9). Conventional standing radiographs obtained with the knees in full extension do not provide reproducible measurements of JSW nor necessarily accurate depictions of cartilage thickness (2, 5, 8, 11, 34). In the fully extended knee, interposition of the meniscus and contact between bony prominences of the articulation may cause apparent JSW to be discrepant with cartilage thickness (3). In addition, femoral cartilage loss in OA varies in the anteroposterior direction (4, 6). Changes in the degree of knee extension attained may alter the area of the femoral condyle in contact at the load-bearing axis of the knee as well as the effect of the meniscus and bony prominences, potentially resulting in changes in JSW despite no corresponding change in cartilage thickness.

In nonfluoroscopically guided fixed-flexion and MTP (12) views and fluoroscopically positioned semiflexed (8) and Lyon schuss views (5), the knees are positioned in flexion in a manner designed to be reproducible over time. The approach to this varies, as does the resulting degree of knee flexion. The protocols for fixed-flexion and Lyon schuss views use variants of a positioning frame to attempt to standardize and reproduce knee flexion, and for these views the amount of flexion attained averages ∼25–30 degrees (5, 13). The protocol for MTP views attempts to achieve this by positioning the feet and knees in a standardized location relative to the cassette (or x-ray detector), with resulting knee flexion reported to average ∼7–10 degrees (12, 35). The protocol for semiflexed views, in contrast, attempts to standardize and reproduce both knee flexion and the sectional plane of the joint space imaged, by having the patient flex and extend the knee under fluoroscopic guidance until the anterior and posterior rims of the medial tibial plateau appear to be parallel with the x-ray beam, resulting in average flexion of 5–7 degrees (3, 8). Due to biologic variability in the inclination of the tibial plateau (36, 37), the amount of knee flexion needed to align the tibial rims varies from knee to knee and includes minimal or no flexion.

The degree of knee flexion typically achieved with a given protocol may influence sensitivity to joint space loss, since a more posterior region of the femoral condyle corresponds to the region of peak load on the femoral cartilage during walking and stair climbing and of early cartilage loss in OA (4, 5, 6). Despite the potential importance of this variable, no study has compared the amount, variability, and reproducibility of knee flexion attained with different protocols when used in the same knees or examined their effects on sensitivity to change.

The fixed-flexion protocol does not attempt to align the x-ray beam with the tibial plateau rims of each knee, as is done in the 2 fluoroscopy protocols, but rather fixes the angulation of the tibia using the positioning frame and sets the x-ray beam at a constant 10-degree caudal angle, based on fluoroscopy studies showing that a mean beam angle of 9–11 degrees caudal is required to align the mid–medial tibial plateau rims with fixed-flexion positioning (13, 36). As a result, the x-ray beam is aligned in parallel with the tibial plateau in some knees but not in others. As expected, fixed flexion did not achieve parallel alignment of the tibial plateau in a high proportion of knees in this study but did achieve consistent alignment over 3 years to an extent similar to that seen in some studies with fluoroscopically guided positioning (11, 22, 36).

Some studies have shown that sensitivity to joint space loss is greater in knees with serial radiographs that show parallel alignment of the tibial plateau rims compared with other knees with serial radiographs, acquired with the same protocol, that do not exhibit parallel alignment (11, 16). Although we observed a trend for increased joint space loss in knees with parallel compared with nonparallel alignment, the difference was not statistically significant, and there was a small number of knees with parallel alignment on both films. It is possible that varying the beam angle under fluoroscopic guidance (as is done in the Lyon schuss protocol) to achieve parallel alignment in a larger number of knees would have provided greater sensitivity to joint space loss in our subjects. Head-to-head comparison studies are needed to determine the independent effect of parallel alignment of the tibial plateau rims. Such information will facilitate weighing all the advantages and disadvantages of the alternative protocols, including radiation exposure from fluoroscopy, training and quality assurance burdens, the need for magnification correction of JSW, and costs (3).

Our study has several strengths. The radiographs were obtained in the field setting of a multicenter study with an intensity of radiographer training and ongoing quality assurance that is attainable in most studies; therefore, our results should be generalizable to typical uses of this protocol in clinical research settings. Our study included knees with and knees without OA at baseline, and our results are relevant to both clinical studies of knee OA and epidemiologic studies of the general population. Independent computerized and manual measurements of joint space width gave nearly identical results.

Our study also has features that limit its generalizability. We included knees with less baseline minimum joint space (from 0.5 mm to <2.0 mm) compared with that in many clinical trials of knee OA, which typically require minimum joint space of at least 2.0 mm. The duration of followup was 3 years, and no interim radiographs were obtained; our results may not apply to shorter periods of followup. Our results also may not apply to unilateral radiographs acquired using the fixed-flexion view, due to differences in centering of the x-ray beam (13). The number of knees with OA in our study is relatively small, although it is comparable with that in several studies evaluating the sensitivity of other methods (11, 16, 33); a larger sample would provide more precise estimates of joint space loss. Finally, our study was not a head-to-head comparison of alternative protocols, which is the only way to definitively compare their performance.

In conclusion, fixed-flexion knee radiography provides a sensitive and valid measure of joint space loss in long-term (3-year) longitudinal studies of knee OA, without the use of fluoroscopy to aid in knee positioning.

AUTHOR CONTRIBUTIONS

Dr. Nevitt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Nevitt, Peterfy, Felson, Duryea, Woodworth, Harris.

Acquisition of data. Nevitt, Guermazi, Kwoh, Harris.

Analysis and interpretation of data. Nevitt, Peterfy, Guermazi, Duryea, Woodworth, Chen, Kwoh.

Manuscript preparation. Nevitt, Peterfy, Guermazi, Felson, Duryea, Woodworth, Kwoh, Harris.

Statistical analysis. Chen.

Acknowledgements

We thank Burton Sack, MD, Boston University.

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