Summary Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint ...structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes.
Objective
Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was ...undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi).
Methods
We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait‐list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2‐tailed test, with P values less than 0.05 considered significant.
Results
Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was −0.4 mm3 (interquartile range IQR −34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm3 IQR −29.6, 26.4) (P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group.
Conclusion
Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.
Summary Objective To determine how frontal plane lower limb alignment obtained using a new femorotibial angle (FTA) measurement and non-radiographic handheld goniometry, predict femorotibial ...cartilage thickness loss in varus and valgus knees, compared with the gold standard mechanical axis (hip-knee-ankle HKA). Methods 934 Osteoarthritis (OA) Initiative knees with radiographic OA had the above alignment measures and 3T knee MRIs acquired. The new FTA measure was compared to the gold standard, with and without adjusting FTA for the sex-specific varus shift. Changes in medial (MFTC) and lateral femorotibial (LFTC) cartilage thickness were quantified over 1-year and 2-years. Adjusted odds ratios (adjORs) were used to compare how the different alignment measures predict medial and lateral cartilage loss in varus and valgus knees. Results Pearson correlation coefficients between 2-year MFTC/LFTC cartilage loss and alignment measures were small to moderate, and were similar for FTA ( r = 0.28/−0.30) and for HKA ( r = 0.28/−0.29). Using the adjusted FTA measure, varus and valgus predicted MFTC progression (adjOR = 3.73) and LFTC progression (adjOR = 2.55) as well as HKA (adjOR = 3.16 and 2.31) over 1-year, and this relationship was also observed over 2-years. Goniometry was a weak predictor for MFTC and LFTC progression (adjOR1-year = 1.65 and 1.71; adjOR2-year = 0.68 and 1.24). Conclusions After adjustment, the new FTA measure obtained from short (fixed-flexion) knee films was as good as the gold standard in predicting medial and lateral cartilage loss over 1- or 2-years, without need for obtaining long-limb radiographs for determining the mechanical axis. Goniometry and non-adjusted FTA measures, in contrast, were poor predictors of cartilage loss.
Bone marrow lesions (BMLs) contribute to pain and progression of knee OA. Bisphosphonates may be a potential disease-modifier through amelioration of BMLs. We sought to determine the effect of oral ...bisphosphonates on BML volume over 12 months.
Women in the Osteoarthritis Initiative who newly initiated an oral bisphosphonate were propensity-score matched to non-initiators. BML volume was assessed using sagittal turbo spin echo fat-suppressed intermediate-weighted MR images at the index date and 12 months later. A validated semi-automated process was used to segment subchondral OA-related BMLs to determine total volume of BMLs based on number of voxels within the outlined area of interest. Mean change in BML volume over 12 months among bisphosphonate initiators was compared with non-initiators using multiple linear regression.
145 bisphosphonate initiators were identified, who were well-matched to their comparators. The difference in mean change in total BML volume between the two groups, regardless of presence of baseline BMLs, was not significant (P = 0.4, 95% CI -156.6 to +354.2). The proportion of participants with decreased, increased, or unchanged BML volumes over the 12 months were similar in both groups. Among those with baseline BMLs, bisphosphonate initiators had a greater proportion with a decrease in BML volume compared with stable or increased BML volume than non-initiators (P = 0.03).
In this ‘real-world’ setting of women starting bisphosphonates, we found no clear evidence of benefit on BML volume over a 12-month period, though a trend towards a decrease in BML volume was noted.
Knee osteoarthritis (OA) onset and progression has been defined with transitions in Kellgren-Lawrence (KL) grade or Osteoarthritis Research Society International (OARSI) Joint Space Narrowing (JSN) ...grade. We quantitatively describe one-year transitions in KL grade and JSN, using fixed joint space width (fJSW), among knees with or at risk of OA.
Radiographic assessments from the Osteoarthritis Initiative (OAI) were used to identify transitions in KLG and JSN grade between consecutive annual visits. The fJSW was measured in the medial and lateral compartments. The distribution of change in fJSW for KLG and JSN transitions were described, and mean change in fJSW was estimated using mixed models.
KL grade and JSN scores were available for about 20,000 annual transitions from 6047 knees contributed by 3389 participants. Knees that remained stable in KL or OARSI-JSN over 1 year had mean medial fJSW loss between −0.06 and −0.19 mm/year. Transition from KL grade 0 to 1, 0 to 2, and KL 1 to 2 were similar with respect to mean medial fJSW loss (0.18–0.28 mm). Greatest annual changes in medial fJSW corresponded to KL 0 to 3 (1.62 mm), KL 2 to 4 (1.23 mm) and JSN 0 to 2 (1.85 mm).
Anchoring quantitatively measured loss of joint space width to transitions in KL grade and JSN provides reference values based on traditional definitions of knee OA onset and progression.
Summary Objective To develop and validate a new and improved software method to rapidly determine femur–tibia angle (FTA). Methods Three readers, two skilled and one unskilled, without any formal ...medical training, measured FTA in 142 subjects from the Osteoarthritis Initiative (OAI). The reader reliability was assessed using the intra-class correlation coefficient (ICC), root mean square standard deviation (RMSSD), and Bland–Altman plots, comparing the existing and new FTA methods. Gender-specific linear regression assessed the relationship of FTA with the hip–knee–ankle angle (HKA). Results The ICC (RMSSD) for intra- and inter-reader reproducibility of the existing FTA method was 0.96 (0.77°) and 0.92 (1.38°), respectively, and for the new technique was 0.98 (0.25°) and 0.98 (0.37°), with similar results for all three readers. Bland–Altman 95% limits of agreement were greater than ±2° for the existing, and ±1° for the new method. The r -value for the relation of FTA to HKA was 0.68 and 0.72 for the existing and new methods, respectively. Varus (HKA ≤ −2°)/neutral (−2° < HKA < 2°)/valgus (HKA ≥ 2°) alignment based on predicted HKA agreed moderately with measured HKA (weighted kappa = 0.53), and had moderate sensitivity (73%) and specificity (84%) for varus malalignment. The new FTA was related to HKA using a linear equation with a slope of 0.98 and an offset of 4.0°. Conclusions Since it is largely automated and uses unambiguous anatomical landmarks, the new method is highly reproducible and can be made on a standard posteroanterior (PA) knee radiograph by a relatively unskilled reader.
Radiographic joint space width (JSW) has been a standard for measuring knee osteoarthritis (OA) structural change. Limitations in the responsiveness of this approach might be overcome by instead ...measuring 3D JSW on weight-bearing CT (WBCT). This study compared the responsiveness of 3D JSW measurements using WBCT with the responsiveness of radiographic 2D JSW.
Standing, fixed-flexion knee radiographs (XR) and WBCT were acquired ancillary to the 144- and 168-month Multicenter Osteoarthritis Study visits. Tibiofemoral JSW was measured on both XR and WBCT. Responsiveness to change was defined by the standardized response mean (SRM) for change in JSW (1) at predetermined mediolateral locations (JSWx) on both modalities and (2) in the following subregions measured on WBCT images: central medial and lateral femur (CMF/CLF) and tibia (CMT/CLT), and anterior and posterior tibia (AMT/ALT, PMT/MLT).
Baseline and 24-month follow-up JSWx measurements were completed for 265 participants (58.1% women). Responsiveness of 3D JSWx for medial tibiofemoral compartment on coronal WBCT (SRM range: −0.18, −0.24) exceeded that for 2D JSWx (−0.10, −0.16). Responsiveness of 3D JSW subregional mean (−0.06, −0.36) and maximal (−1.14, −1.75) CMF and CMT and maximal CLF/CLT 3D JSW changes were statistically significantly greater in comparison with respective medial and lateral 2D JSWx (P ≤ 0.002).
Subregional 3D JSW on WBCT is substantially more responsive to 24-month changes in tibiofemoral joint structure compared to radiographic measurements. Use of subregional 3D JSW on WBCT could enable improved detection of OA structural progression over a 24-month duration in comparison with measurements made on XR.
3D Magnetic resonance imaging (MRI) scans are generally used for quantitative cartilage measurements in knee osteoarthritis. However, a great deal of MRI data is from 2D scans, often thought to be ...unsuitable for quantitative cartilage assessment. The goal of our study was to demonstrate that mLACS, a modified version of the Local Area Cartilage Segmentation (LACS) method, could be used to measure cartilage volume on 2D MRI images.
We studied 301 randomly selected subjects from the OA Biomarkers Consortium FNIH Study, a nested case-control study within the Osteoarthritis Initiative (OAI). The study comprised four subgroups based on radiographic and pain progression. We compared mLACS applied to 2D TSE scans to LACS on 3D DESS data. The Pearson's correlation coefficient was used to establish agreement between LACS and mLACS, standardized response means (SRMs) for responsiveness, and intra-class correlation coefficients (ICCs) to measure reader precision. Logistic regression in a case/control analysis was used to compare the clinical validity between the two methods.
We found R2 = 0.76 for the correlation between LACS and mLACs. For LACS, the responsiveness was SRM = 0.49 compared to 0.39 for mLACS. The odds ratios (OR) for the primary case/control analyses were 1.62 for LACS and 1.78 for mLACS. The intra and inter reader reproducibility values for mLACS were ICC = 0.90 and 0.86, respectively.
This study has demonstrated that a reproducible, responsive, and clinically valid quantitative measurement of cartilage volume can be made using 2D TSE scans with a modest loss of responsiveness compared to 3D scans.
Summary Objective Large studies of knee osteoarthritis (KOA) require well-characterized efficient methods to assess progression. We previously developed the local-area cartilage segmentation (LACS) ...software method, to measure cartilage volume on magnetic resonance imaging (MRI) scans. The present study further validates this method in a larger patient cohort and assesses predictive validity in a case–control study. Method The OA Biomarkers Consortium FNIH Project, a case–control study of KOA progression nested within the Osteoarthritis Initiative (OAI), includes 600 subjects in four subgroups based on radiographic and pain progression. Our software tool measured change in medial femoral cartilage volume in a central weight-bearing region. Different sized regions of cartilage were assessed to explore their sensitivity to change. The readings were performed on MRI scans at the baseline and 24-month visits. We used standard response means (SRM) for responsiveness and logistic regression for predictive validity. Results Cartilage volume change was associated strongly with radiographic progression (odds ratios (OR) = 4.66; 95% confidence intervals (CI) = 2.85–7.62). OR were significant but of lesser magnitude for the combined radiographic and pain progression outcome (OR = 1.70; 95% CI = 1.40–2.07). For the full 600 subjects, the standardized response mean (SRM) was −0.51 for the largest segmented area. Smaller areas of cartilage segmentation were also able to predict the case–control status. The average reader time for the largest area was less than 20 min per scan. Smaller areas could be assessed with less reader time. Conclusion We demonstrated that the LACS method is fast, responsive, and associated with radiographic and pain progression, and is appropriate for existing and future large studies of KOA.
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