Study design and subjects.
The Multicenter Osteoarthritis Study (MOST) was a prospective epidemiologic study of individuals ages 50–79 years, in which the goal was to identify risk factors for incident symptomatic knee OA and progressive knee OA. Study subjects either had knee OA or were at high risk of developing the disease. Factors considered to contribute to a high risk of knee OA included being overweight or meeting the criteria for obesity, having knee pain, aching, or stiffness on most of the preceding 30 days, a prior knee injury that made it difficult to walk for at least 1 week, or previous knee surgery. Weight eligibility for MOST was defined as having a body weight higher than the median weight for each age- and sex-specific group based on the data from the Framingham OA Study (9). For example, the body weight cutoff values were as follows: in women, ages 50–59 years, 154 pounds, ages 60–69 years, 151 pounds, and ages 70–79 years, 148 pounds; in men, ages 50–59 years, 194 pounds, ages 60–69 years, 187 pounds, and ages 70–79 years, 182 pounds. For body weight determinations, each subject was weighed without shoes and heavy jewelry and wore a standard gown or lightweight clothing. In addition, each subject's height (without shoes) was measured using a stadiometer.
All MOST subjects were recruited from 2 communities in the US, Birmingham, Alabama and Iowa City, Iowa, through mass mailing of letters and study brochures, supplemented by media and community outreach campaigns. Each center also recruited ethnic minorities according to their representation in the recruitment population. Subjects were excluded from the MOST if they screened positive for rheumatoid arthritis (10), had ankylosing spondylitis, psoriatic arthritis, or reactive arthritis, experienced problems with the kidneys that resulted in the need for hemo- or peritoneal dialysis, had a history of cancer (except for nonmelanoma skin cancer), had undergone bilateral knee replacement surgery, were unable to walk without the help of another person or walker, or were planning to move out of the area in the subsequent 3 years. The study protocol was approved by the institutional review boards at the University of Iowa, University of Alabama, Birmingham, University of California, San Francisco, and Boston University Medical Center.
In the present study we used a subsample of subjects from the parent study. Using a nested case–control study design (11), we investigated knees that were considered eligible for MRI and that had been examined both at baseline and at 15 months' followup. At baseline, all study subjects were asked a question regarding knee pain, as follows: “During the past 30 days, have you had pain, aching, or stiffness in your knee on most days?” This question was posed to subjects both by phone interview and during a clinic visit 1 month thereafter. If the subject answered no regarding the presence of pain, aching, or stiffness in the knee at each of these time points at baseline, that knee was considered eligible for analysis in the current nested case–control study.
At 15 months' followup, this same question regarding knee pain was posed to subjects, both in a phone interview and at a clinic visit. If the subject answered yes to the question at both of these followup time points, the knee with new pain was considered to be a case knee (n = 110). Because this question was intended to identify pain, aching, or stiffness “on most days,” and because the 2 time points were, on average, 1 month apart, we characterized a positive response at both time points as “consistent frequent knee pain.” Furthermore, although our question included the symptoms of stiffness and aching, we labeled a positive response as related to pain. Control knees (n = 220) were selected randomly from among the knees examined by MRI at baseline and for which the subject indicated absence of pain at both baseline time points.
In addition, at the baseline clinic examination, subjects completed surveys on medication use and filled out a questionnaire on symptoms of depression, the Center for Epidemiologic Studies Depression Scale (CES-D) (12). In addition, subjects were weighed (without shoes) on a balance-beam scale to determine the body mass index (BMI), computed as weight (kg)/height (m2). The same survey on medication use was administered at the 15-month visit. Subjects also completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a survey of joint pain, stiffness, and limitation of physical function (13), for each knee at both the baseline and 15-month visits.
MR images were obtained with a 1.0T dedicated MR system (OrthOne; Oni, Wilmington, MA) with a circumferential extremity coil. All MRIs were performed using fat-suppressed, fast spin-echo, proton density–weighted sequences in 2 planes, the sagittal plane (repetition time [TR] 4,800 msec, time to echo [TE] 35 msec, slice thickness 3 mm, interslice gap 0 mm, field of view [FOV] 14 cm, matrix 288 × 192 pixels, number of excitations [NEX] 2) and the axial plane (TR 4,700 msec, TE 13.2 msec, slice thickness 3 mm, interslice gap 0 mm, FOV 14 cm, matrix 288 × 192 pixels, NEX 2), and a STIR sequence in the coronal plane (TR 7,820 msec, TE 14 msec, inversion time 100 msec, slice thickness 3 mm, interslice gap 0 mm, FOV 14 cm, matrix 256 × 256 pixels, NEX 2).
Two musculoskeletal radiologists (AG and FR), who were blinded to the case/control status and clinical data, read the MR images for evidence of BMLs and effusions, according to the Whole-Organ MRI Score (WORMS) (14). Using the WORMS, BMLs were scored 0–3 based on the size, or volume, of the lesion in each of 5 subregions of the medial and lateral compartments and in 4 subregions of the patellofemoral compartment. Similarly, effusion volume was scored 0–3. The MR images were read as paired images from both the baseline and followup visits. In addition, bone attrition was scored 0–3 for each subregion, with results expressed as the maximal score for a compartment. Periarticular lesions (e.g., anserine bursitis) have also been cross-sectionally associated with knee pain (15); however, no change in these lesions was observed in our subjects' knees.
Given that the results of previous studies (5, 6) have suggested that the size of BMLs is associated with pain, we focused on the change in size, or volume, of the lesion as our measure of BML change. We summed the BML score for all 5 subregions of the medial compartment (score range 0–3 in each subregion; across all 5 subregions, score range 0–15), all 5 subregions of the lateral compartment (score range 0–15), and all 4 subregions of the patellofemoral compartment (score range 0–12). This yielded 3 BML scores for each knee.
In each knee compartment, change was defined as change in the BML score from baseline to followup. Interreader agreement for this change score was an intraclass correlation coefficient (ICC) of 0.93 (P < 0.001). Given the compartment-specific nature of OA and the likelihood that a compartment would develop new or worse disease, we focused on change in BML score in each compartment. For each subject, we thus obtained 3 compartment-specific BML change scores, and of these 3 scores, we focused on the change score that showed the maximal unit increase; we have previously used this compartment-specific approach for scoring of BMLs to identify a strong relationship between BMLs and knee malalignment (16). In a sensitivity analysis, we summed all of the BML scores for the whole knee and created a global knee change score by subtracting the baseline score from the followup score. Results were the same as those obtained using the compartment-specific approach.
At baseline, all subjects underwent weight-bearing, posteroanterior (PA), fixed-flexion radiographic evaluation of the knee using the protocol described by Peterfy et al (17). Body weight was equally distributed between the 2 legs, and the big toes of the feet and the front of the thighs were placed in contact with the front plate of the plexiglass frame. The external rotation of the feet was fixed at 10 degrees, using a V-shaped foot angulation support on the frame. The central radiographic beam was directed to the midpoint between the back of the knees, at a caudal angle of ∼10 degrees, to allow the anterior and posterior lips of the medial tibial plateau to be optimally superimposed (film-focus distance 183 cm).
A musculoskeletal radiologist (PA) and a rheumatologist (DTF), who were experienced in reading study films and were blinded to both the case/control status and clinical data, graded all of the PA radiographs according to the Kellgren/Lawrence (K/L) scale of radiographic knee OA (18). Radiographic OA was considered present if knees were assessed a K/L grade ≥2.
Full-limb radiographs of both legs were obtained at baseline, using the method of Sharma et al (19). The mechanical axis was defined as the angle formed by the intersection of a line from the center of the head of the femur to the center of the tibial spines, and a second line from the center of the talus to the center of the tibial spines. The interobserver ICC for determination of the mechanical axis was 0.99 (P < 0.0001).
To test the frequency of change in BMLs in the case knees as compared with the control knees, we used a chi-square test, both comparing knees and comparing subjects (given the occurrence of 8 cases in which both the left and the right knee of a subject were affected). We used multiple logistic regression with generalized estimating equations (to adjust for the correlation of knees) to evaluate the relationship between an increase in BML score and incident knee pain, in models adjusted for age, sex, race (white versus African American), BMI, CES-D score, baseline quadriceps strength, K/L grade, effusion score, baseline BML score, and change in effusion score, and with or without adjustment for mechanical knee alignment. Additional analyses in which we examined change in pain medication use (including use of nonsteroidal antiinflammatory drugs) as a covariate yielded similar findings, as did additional analyses in which we adjusted for the presence or absence of bone attrition (a rare finding in the knees studied). All P values (2-tailed) were calculated using SAS for Windows, version 9.1 (SAS Institute, Cary, NC). P values less than or equal to 0.05 were considered significant.