Faculty Bibliography

Purpose: Osteoarthritis (OA) is a slowly-progressing disease, and imaging biomarkers of cartilage structure have failed to detect short-term (< 6 months) change. An imaging biomarker of cartilage quality (i.e., tissue composition and function) such as magnetic resonance transverse relaxation time of hyaline cartilage water protons (T₂), may be more a responsive biomarker of OA progression. T₂ is a proxy for disorder and hydration, and is easily measured without a contrast agent, but there are few data on variability of this marker over time in OA. The purpose of this study was to determine the short-term (1 week) reproducibility of cartilage T₂ and thickness obtained from an anatomically-corresponded regional analysis using statistical shape modelling. Method: We conducted a multi-centre, non-randomized study at 4 sites with a sample at risk of medial tibiofemoral progression including women, BMI>=25 kg/m², symptomatic radiographic evidence of medial tibiofemoral OA (K&L grade 2-3, medial JSN>= lateral JSN), varus malalignment >=-2degree (anatomic axis), and pain. As part of a larger study, eligible participants had MRI scans of the same knee at baseline and 1 week. The OAI protocol for the index knee was deployed on 3T Siemens Trio systems. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the DESSwe MR images using EndPoint (Imorphics). Anatomically corresponding regions of interest were identified on each image by fitting a bone model, and mean cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. Voxelwise transverse relaxation rates were calculated from a linear least-squares fit of the log of the signal values against echo time. Mean T₂ values were also recorded in each region from the 50% most exochondral and 50% most endochondral voxels. Coefficients of Variation (CoV) were calculated. Results:The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m², with 8 index knees graded as K&L =2 and 21 as K&L=3. Anatomical mal-alignment ranged from -1.9degree to 6.3degree, with mean 0.9degree, where varus mal-alignment is measured in the positive direction. 28 subjects provided data for reproducibility of ThCtAB and 20 for T₂. (Table presented) Conclusion: T₂ can be measured reproducibly in an OA population in multicentre studies and with similar variability to a cartilage structural assessment. These results support further evaluation of T₂ as a candidate biomarker of cartilage composition for assessing interventions

Purpose: To assess whether variability in caudal X-ray beam angulation (CBA) improves alignment of the medial tibial plateau (MTP) versus a fixed 10degree CBA, using non-fluoroscopic fixed-flexion knee radiographs. Methods: 133 subjects with knee OA underwent fixed-flexion AP X-ray examinations as part of a longitudinal study. We performed a cross sectional substudy in which 90 subjects were imaged with a 10degree CBA (Method 1) and 43 subjects were imaged using different CBAs (choosing from 5degree, 10degree, 15degree) determined by a trained radiology technician, depending on MTP alignment assessed in real time (Method 2). After reading a blinded training set of radiographs, an experienced radiologist, who was blinded to patients and method used, read the x-rays for MTP alignment quality using a 1-5 scale (1, 2=good, 3=acceptable, 4= poor, 5= unacceptable), and for Kellgren-Lawrence (KL) grade. Results: Method 1 subjects (10degree angulation): MTP alignment quality was scored as good or acceptable 62% and 69% of the time for the right and left knees, respectively. Method 2 subjects (variable angulation): Variable angulation resulted in good or acceptable MTP alignment quality on at least one x-ray 86% and 88% of the time for right and left knees, respectively. When CBA was changed, MTP alignment quality changed 84% of the time for the right knee and 77% of the time for the left knee in subjects who had at least 2 radiographs (n=43). The KL grade changed 28% and 46% of the time in the right and left knees, respectively, when MTP alignment quality changed in the same knee. The KL grade changed 38% and 36% of the time in the right and left knees, respectively, when there was no change in MTP alignment quality but there was a change in CBA. A change in CBA resulted in MTP alignment quality change in bilateral knees 66% of the time, of which this change was in the same direction (improved vs worsened) 86% of the time. Using a CBA of 10degree resulted in improved (over other angulations) MTP alignment quality 53% and 50% of the time for the right and left knees, respectively. Using a CBA of 10degree resulted in worsened MTP alignment 33% and 22% of the time for right and left knees, respectively. Conclusion: While fixed 10degree CBA in fixed-flexion radiographs results in acceptable or good MTP alignment quality the majority of the time, variable CBA improves this frequency in knee OA subjects. Changes in CBA often change the MTP alignment quality, usually in the same direction in both knees, and sometimes change the KL grade. More studies are needed to determine the optimal CBA for non-fluoroscopic fixed-flexion protocols and all radiographic knee OA studies should report the specific techniques used, including CBA

While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints-bone and synovium-also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly-and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents

Osteoarthritis (OA) is often a progressive and disabling disease resulting from a combination of risk factors, including age, genetics, trauma, and knee alignment, as well as an imbalance of physiologic processes resulting in inflammatory cascades on a molecular level. The synovium, bone, and cartilage are each involved in the pathophysiological mechanisms that lead to progressive joint degeneration, and, thus, also serve as targets for therapies. Efforts to identify disease-modifying osteoarthritis drugs (DMOADs) have been hampered by several factors, but the focus has now shifted toward the validation of chemical and imaging biomarkers that should aid in DMOAD development. In this review, we summarize current pathological mechanisms occurring in the individual but interconnected compartments of OA joints, as well as discuss related therapeutic interventions that are currently available or on the horizon