This study was conducted as part of the Offspring study, a population-based study that began in Southern Tasmania in June 2000. Matched sampling was used to recruit the study participants (mean-age 47 (28–63) years; 57 % females). Half of the participants were the adult offspring of patients (only one parent) who had a knee replacement performed for idiopathic knee OA at any Hobart hospital from 1996 to 2000 [9]. The diagnosis was confirmed by reference to the medical records of the orthopaedic surgeons and the original radiographs when possible. The other half were age and sex matched controls, randomly selected from the population with no history of knee OA in either parent. This study includes data from the first (visit-2) and second (visit-3) follow-up visits at approximately two and ten years respectively, as we did not have the correct MRI sequence to score meniscal tears at baseline.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. The Southern Tasmanian Health and Medical Human Research Ethics Committee approved the protocol, and written informed consent was obtained from all participants.
Participants were excluded if they had a contraindication to MRI (including metal sutures, presence of shrapnel, iron filing in eye, or claustrophobia). Participants were also excluded if they had undergone a knee replacement surgery or did so after the commencement of the study. Knee pain and knee injury were not a basis for exclusion.
Knee pain
Knee pain was assessed by self-administered questionnaire using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at both visits [10]. Five categories of pain (walking on flat surface, going up or down stairs, at night, sitting or lying, and standing upright) were assessed separately with a 10-point scale from 0 (no pain) to 10 (most severe pain). Each category was summed to create a total pain score (range 0 to 50). Furthermore, the five categories were clinically categorized into weight-bearing pain (including walking on flat surface, going up or down stairs and standing) and non-weight-bearing pain (including pain at night and sitting or lying).
Knee joint injury
History of knee joint injury was assessed using a self-administered questionnaire [11] which included the following questions:
“Have you ever had a previous knee injury which resulted in non-weight bearing treatment for 24 h or more?”
“If yes, then which knee?”
“Please provide further details about the injury”
Magnetic resonance imaging
MRI of the right knee was performed as described previously [12, 13]. Knees were imaged in the sagittal plane on a 1.5-T whole-body magnetic resonance unit (Picker International, USA) using a commercial transmit-receive extremity coil. The following image sequence was used: (1) a T1-weighted fat-suppressed 3D gradient-recalled acquisition in the steady state, flip angle 55°, repetition time 58 msec, echo time 12 msec, field of view 16 cm, 60 partitions, 512 × 512–pixel matrix, slice thickness of 1.5 mm without an interslice-gap; and (2) a T2-weighted fat saturation 2D fast spin echo, flip angle 90°, repetition time 3067 ms, echo time 112 ms, field of view 16 cm, 15 partitions, 256 × 256 matrix, slice thickness of 4 mm with an interslice gap of 0.5–1.0 mm.
Meniscal tears
Meniscal tears were assessed by a trained observer (musculoskeletal radiologist with several years of experience) on T2-weighted fat saturated (side by side) MR images at visit-2 and 3 of the study as previously described [14]. The proportion of the menisci affected by a tear was scored separately (0–2 scale; 0 = absence of a tear, 1 = simple tear of different types: longitudinal, oblique, radial or horizontal, 2 = macerated tear signifying loss > 50 % area of meniscal tissue) at the anterior, middle, and posterior horns. Anterior, middle and posterior scores were summed to create medial and lateral meniscal tear scores. The intra- and inter-observer correlation coefficient (expressed as intraclass correlation coefficient (ICC)) ranged from 0.86 to 0.96 [15].
Meniscal extrusion
The extent of meniscal extrusion on the medial or lateral edges of the tibial femoral joint space, not including the osteophytes, was evaluated at visit-2 and 3 for the anterior, body, and posterior horns of the menisci on T1-weighted gradient echo MR images, as previously described [15]. A score from 0 to 2 was used (0 = no extrusion, 1 = partial meniscal extrusion, and 2 = complete meniscal extrusion with no contact with the joint space). The scores of anterior, body and posterior horns of medial or lateral menisci were summed to create a total meniscal extrusion score for each of the medial and lateral tibiofemoral compartments which had a possible range from 0 to 6. The intra- and inter-observer correlation coefficient ranged from 0.85 to 0.92 for meniscal extrusion [14].
All knees were evaluated for the presence of meniscal extrusion regardless of whether they had a meniscal tear or not.
Cartilage volume
Tibial and femoral cartilage volume was assessed on T1-weighted gradient echo MR images using Osiris (University of Geneva, Switzerland) and Cartiscope (ArthroLab, Montreal, Canada) software respectively at visit-2 and 3, as previously described [12, 15]. The coefficient of variation (CV) for intra-observer repeatability ranged from 2.0–2.2 % for both tibial and femoral cartilage volume measurements [16, 17]. Total cartilage volume was calculated as: tibial + femoral cartilage volume.
Cartilage defects
Cartilage defects were assessed on T1-weighted gradient echo MR images on a 0–4 scale (0 = normal; 1 = focal blistering/signal changes; 2 = <50 % thickness loss; 3= > 50 % thickness loss; 4 = full thickness defect) at visit-2 and 3, as previously described [18]. Intraobserver reliability ranged from ICC of 0.89–0.90 [18]. Interobserver reliability was assessed in 50 MR images and yielded an ICC of 0.85–0.90 [18].
Bone marrow lesions
BMLs were assessed on T2-weighted fat saturated MR images at visit-2 and 3 and were defined as areas of increased signal adjacent to the subchondral bone [10]. One trained observer scored the BMLs by measuring the maximum area of the lesion in a specific compartment. The observer manually selected the MRI slice with the greatest BML size. The BML with the highest score was used if more than one lesion was present at the same site. The ICC for intra-observer reliability, assessed on 40 MR images, was 0.97.
Effusion
Effusion was assessed in the supra-patellar pouch on T2-weighted fat saturated MR images at visit-2 and 3 on a 0–3 scale [19]. Grade-0 signified absence of fluid over the upper margin of the patella in a sagittal image; Grade-1 signified some fluid above the upper margin of the patella but the length of the fluid column shorter than that of the patella; Grade-2 signified a fluid column above the upper margin of patella longer than the length of the patella; Grade-3 signified a fluid column above the upper margin of patella longer than the length of the patella with a thickness of ≥ 1 cm. Intra-observer reliability was assessed in 50 MR images and yielded an ICC of 0.89–0.98. Pathological effusion was defined as any effusion score ≥2.
Radiography
A standing anteroposterior semiflexed view of the right knee (at 15° flexion) was performed in all participants at baseline and 10 years. Radiographs were scored individually for osteophytes and joint space narrowing, as described previously [16]. Each of the following four features was scored on a scale from 0 to 3 (0 = normal and 3 = severe): medial joint space narrowing (JSN), lateral JSN, medial osteophytes (femoral and tibial combined) and lateral osteophytes (femoral and tibial combined). Each score was arrived at by consensus with two readers simultaneously assessing the radiograph with immediate reference to the Osteoarthritis Research Society International (OARSI) atlas [20]. A non-zero score in either joint space narrowing or osteophytosis was regarded as evidence of radiographic osteoarthritis (ROA). Reproducibility was assessed in 50 radiographs, two weeks apart, and yielded an ICC of 0.99 for osteophytes and 0.98 for JSN.
Readers for all the scans were either musculoskeletal radiologists with several years of experience in OA research or health professionals trained by musculoskeletal radiologists. Readers were not blinded to the chronological sequence of the radiographs and MRI scans.
Statistical analysis
Change in all MRI structures and leg strength was calculated as: Visit-3 score – Visit-2 score.
T-test and Chi-square tests were used to describe the baseline characteristics of the participants with or without any change in mean meniscal tear score. T-test was further used to compare change in meniscal score between offspring and control groups. Poisson regression analysis was used to examine the predictors of change in meniscal tears and the association between change in meniscal tears and change in meniscal extrusion. Linear regression analysis was used to describe the association between change in meniscal tears and change in pain, cartilage volume loss and change in BMLs. Multivariable analyses were adjusted for demographics, body mass index (BMI), offspring-control status and knee structures (global knee structural factors known to be associated with the presence of meniscal tears or knee pain). Further analysis was performed to explore any offspring-control interaction in the multivariable models for all the above mentioned associations.
A P-value of less than 0.05 (two-tailed) was considered statistically significant. All statistical analyses were performed on Intercooled Stata 12.0 for windows (StataCorp LP).
