Study design
The Osteoarthritis Initiative (OAI) is a multicentre, prospective observational cohort study of 4,796 subjects, designed to identify biomarkers and risk factors for KOA incidence and progression [18]. The OAI was approved by the institutional review board of the University of California, San Francisco, as well as each OAI Clinical Center, all patients provided informed consent [18]. OAI participants were 45-79 years of age at enrolment and had (or were at risk of) symptomatic KOA in at least one knee. Clinical data, 3Tesla MR images (Siemens Magnetom Trio, Erlangen, Germany; quadrature transmit-receive knee coils from USA Instruments, Aurora, OH, USA) and radiographs of the knee were acquired at annual visits [18,19,20].
To be eligible as a case for the current study, total or unicompartmental medial KR had to be confirmed by radiography or by hospital records at the 36-month (M), 48M, or 60M follow-up visit. Further, 3T MR images for which quantitative cartilage analysis [21, 22] had been performed, had to be available for the annual visit before KR (T0) and the annual visit two years before T0 (T-2) (Fig. 1). KRs detected at the 12M or 24M follow-up visit were not included, due to an insufficient longitudinal observation period before KR. If both knees of one participant were reported as replaced at the same, or different time points, both knees were included in the analyses. Only knees with baseline Kellgren-Lawrence grade (KLG) ≤2 were included to ensure rapid and clinically relevant progression of KOA [21, 22]. Knees with lateral Osteoarthritis Society International JSN grades >0 were excluded from the analyses, since lateral compartment JSN increases the risk of lateral progression, potentially masking progression in the medial compartment [12].
Quantitative joint space width measures
Weight-bearing, posterior-anterior fixed-flexion (10°) radiographs were acquired from OAI participants at each annual visit [18, 23]. Semi-automated radiographic JSW measurements were performed for the majority of these knees [9, 10] (Fig. 2). In the current study, we analysed medial compartment mJSW and medial compartment fixed-location JSW at 22.5% of the mediolateral width of the distal femur [medial fixed-location (medf)JSW, Fig. 2] [9] as this measure has been previously shown to display greater sensitivity to change in KOA [10, 24] and a stronger relationship with subsequent KR than mJSW [2].
Quantitative cartilage thickness measures
MR images from a sagittal double echo steady state sequence with water excitation (DESSwe, 0.7mm slice thickness; interpolated in-plane resolution 0.37mm × 0.37mm) [19] were used for segmenting the femorotibial cartilages at the T-2 and T0 visits [22] (Fig. 3a). Total subchondral bone area and the cartilage joint surface area of the medial tibia (MT) and the central (weight-bearing) medial femoral condyle (cMF) were manually traced by experienced readers, as described previously [22]. The analysis, conducted with blinding to acquisition order, relied on custom software (Chondrometrics GmbH, Ainring, Germany). Quality control readings were performed by an expert reader. The mean cartilage thickness was computed for MT and cMF, for the total medial femorotibial compartment (MFTC=MT+cMF), and for a combined central femorotibial subregion (cMFTC) (Fig. 3b) [25, 26].
Quantitative meniscal measures
Coronal multi-planar reconstructions (1.5mm slice thickness; interpolated in-plane resolution 0.37mm × 0.37mm) were derived from the near isotropic sagittal DESSwe MR images. The medial tibial plateau area (i.e. the area of cartilage surface including denuded areas of subchondral bone) and the surfaces of the medial meniscus (tibial, femoral and external area) were segmented at T-2 and T0 from the coronally reconstructed images obtained, which were previously used for the cartilage thickness measurements (with blinding to acquisition order, Fig. 4a). The segmentations were performed by a PhD (M.R.), who was first formally trained in quantitative meniscus analysis; all segmentations done in this study were quality controlled by an expert reader (K.E.) with >5 years of experience in quantitative meniscus analysis. Each case (two time points, two menisci) required approximately 2.5 h, including quality control readings and potential corrections following quality control. Measures of meniscal morphology included mean and maximal meniscal thickness and width, and meniscal volume (Fig. 4b-c) [13]. Measures of meniscal position relative to the tibial plateau encompassed the tibial plateau area covered by the meniscus (absolute/percent), the tibial meniscal surface area not covering the tibial plateau (absolute/percent), mean and maximal extrusion distance and overlap distance between the meniscus and the medial tibial plateau area (Fig. 4b) [13].
Statistical analysis
Paired t-tests were used to determine whether significant changes in JSW, cartilage and meniscal parameters occurred between T-2 and T0. The bootstrap method [27] (1000 replications, BCa method, simple sampling), that renders P values relatively robust against non-normally distributed data, was applied to use the same statistical approach for all variables, even in the case of non-normal distribution. The Wilcoxon signed-rank test was additionally used to confirm the results for non-normally distributed variables. Sensitivity to change of the parameters was assessed using the standardized response mean (SRM=mean change/standard deviation of change).
Bivariate correlation coefficients (r; Pearson; two-sided; bootstrapping as above) between the 2-year change in JSW parameters (mJSW, medfJSW) and the two-year change in meniscal and cartilage measures were assessed.
Multiple linear regression analyses were performed to examine the association of meniscal and cartilage measures with JSW change based on a hierarchical approach, the variables being predefined manually by the study team: Step 1 forced cMFTC cartilage thickness (Fig. 3b) into the model, because this cartilage parameter has previously displayed high sensitivity to change in medial KOA [21]. Please note that in correlation analyses cMFTC cartilage thickness also displayed the strongest coefficient between JSW change amongst the cartilage measures (Table 1). Step 2 allowed the model to include one positional (tibial meniscal surface area not covering the tibial plateau; Fig. 4b) and two morphological (maximal thickness, mean width; Fig. 4b-c) meniscal measures in a stepwise fashion. The specific meniscal measures were chosen based on their high correlation with JSW parameters and their responsiveness (SRM), and so that different meniscal properties were represented in the model. In step 3, the model was allowed to include age (at T-2) and body weight change (from T-2 to T0) in a stepwise manner to compensate for possible confounding. The Akaike information criterion (AIC) permitted comparison of the models at the different stages. For statistical comparison of the model steps, analysis-of-variance was performed. For exploratory purposes the models were also calculated based on a second approach, which exchanged step 1 and 2 in their order. p values of < 0.05 were considered significant, no correction was performed for multiple testing due to the exploratory nature of this study.
Table 1 Joint space width, cartilage and medial meniscal parameters at 2 years prior to knee replacement (T-2) and respective 2-year change (T-2→T0).
All statistical analyses, except for the AIC (Stata V14.2, StataCorp, TX, USA), were done using SPSS 23 (IBM Corporation, Armonk, NY, USA).