Understanding osteoarthritis utilising magnetic resonance imaging

Osteoarthritis (OA), whose aetiology remains elusive, is the most common form of musculoskeletal diseases. Its high prevalence, particularly in the elderly, and the resultant physical disability make OA one of the ten most disabling diseases in developed countries. Conventional radiography has been used in the assessment of joint structural change and has provided the basis for much of our understanding in OA. However, its two dimensional nature, indirect measure of the structure of the joint, and poor association with symptoms limit its value. Magnetic resonance imaging (MRI), a non-invasive imaging technique with multiplanar capabilities and unparalleled soft tissue contrast and lack of ionising radiation, has an important role in the evaluation, diagnosis, and monitoring of OA. Based on MRI measurements of the hip and knee, this thesis examines a number of questions relevant to pathogenesis of OA as well as feasibility of MRI methodology in large epidemiological studies. Chapter 1 consists of the literature review in two parts. The first part gives a broad overview of OA while the second part reviews the available literature to date which covers MRI evaluation of articular cartilage morphology. Based on this review, the questions that will be addressed in this thesis are raised. Chapter 2 describes the research questions. Chapter 3 describes the research methodology. Chapter 4 examines the genetic contribution to muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis (ROA), and assesses whether the heritability of the knee structural components is independent of ROA. A sib pair design was utilised. A sagittal TI-weighted fat-suppressed MRI scan of the right knee was performed to determine cartilage volume and bone size. A standing semi-flexed radiograph of the same knee was performed to assess the presence of ROA. Knee pain was assessed by questionnaire and muscle strength by dynamometry. Heritability was estimated using the genetic analysis program SOLAR. A total of 128 subjects (61 males and 67 females with mean age 45 years) from 51 families representing 115 sib pairs took part. Lower limb muscle strength was found to have high heritability (42%, p=0.02) as did knee pain (44%, p=0.07). Heritability estimates for cartilage volume were 65% for medial tibia!, 77% for lateral tibia! and 84% for patellar and for bone size were 85% for medial tibia! bone area, 57% for lateral tibia! bone area and 70% for patella bone volume (all p<0.01). For ROA, heritability was 56% for presence with a large standard error (p=0.23) and 63% for severity (p=0.01). The estimates for tibia! bone areas only were markedly reduced after adjustment for body size while all estimates with the exception of knee pain were independent of ROA. Cartilage and, to a lesser extent, bone sites were largely under independent genetic control with a lesser-shared genetic component. These results suggests that with the exception of prevalent ROA all knee modalities assessed had high heritability most likely reflecting a strong genetic component. Cartilage volume, bone size and muscle strength all have potential for quantitative trait linkage analyses but their exact relevance for osteoarthritis remains uncertain at this time. Chapter 5 presents estimates of the heritability of longitudinal changes in knee cartilage volume, chondral defects, subchondral bone size, and lower limb muscle strength. A sibpair design was utilized. Longitudinal changes in lateral and medial tibia! cartilage volume and bone size as well as progression of chondral defects were determined on serial Tl weighted fat suppressed MRI images. X-ray was performed and scored for individual features of ROA at baseline. Lower limb muscle strength was measured by dynamometry. Heritability was estimated using SOLAR. A total of 128 subjects (61 males, 67 females, mean age 45 years) from 51 families representing 115 sib pairs were followed for a mean of 2.4 years. The adjusted heritability estimates for changes in cartilage volume were 73% for the medial (P<0.01) and 40% for the lateral (P=0.10); the adjusted heritability estimates for changes in bone size were 62% for the lateral (P=0.03) and 20% for the medial (P=0.22); the adjusted heritability estimate for changes in muscle strength was 64% (P=0.01 ). The heritability estimates for progression of chondral defects were 80% for the lateral compartment (P=0.06) and 98% for the medial compartment (P=0.03). These changed little after adjustment for each other and the predominantly mild ROA, with the exception of lateral compartment chondral defects. These results' suggests that early longitudinal changes in knee strnctures of relevance to later OA such as medial tibial cartilage volume, lateral tibial bone size, progression of chondral defects as well as muscle strength have a high heritability, most likely reflecting a strong genetic component and suggesting their potential to be studied in quantitative trait linkage and association analysis. Chapter 6 describes clinical, strnctural and biochemical factors associated with knee pain in younger subjects. A cross-sectional convenience sample of 372 male and female subjects (mean age 45 years, range 26-61) was studied. Knee pain was assessed by questionnaire. Chondral defects, cartilage volume, and bone area of the right knee were determined using TI-weighted fat saturation MRI. X-ray was performed on the same knee for the assessment of radiographic features of OA. The urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II) was measured by ELISA. Height and weight were measured by standard protocols and body mass index (BMI) was calculated. The prevalence of knee pain was 35% in this sample. Chondral defect scores (particularly femoral and patellar but not tibial) were significantly associated with knee pain in a dose response fashion (all p <0.01). Cartilage volume and bone area were not associated with knee pain in multivariable analysis in this sample. Urinary CTX-II was higher in subjects with knee pain (p = 0.04), but this became non-significant after adjustment for BMI and osteophytes (both of which were significant) suggesting potential mechanisms of effect. These results suggest that knee pain is significantly associated with non-full thickness chondral defects (particularly femoral and patellar), osteophytes, CTX-II, and obesity but not other factors. MRI and biochemical measures can add to radiographs in defining unexplained knee pain in younger subjects. Chapter 7 describes the association between chondral defects, bone marrow lesions, knee and hip ROA and knee pain in older adults. Knee pain was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). TI and T2 weighted fat saturation MRI scans were performed on the right knee to assess chondral defects and subchondral bone marrow lesions. X-ray was performed on the right knee and hip and scored for ROA. BMI and knee extension strength were measured. A total of 500 randomly selected male and female subjects (mean age 63 years, range 50-79) took part. The prevalence of knee pam was 48%. In multivariable analysis, prevalent knee pain was significantly associated with bone marrow lesions (Odds ratio (OR) 1.44/compartment, 95% confidence interval (Cl) 1.04 - 2.00), medial tibial chondral defects (OR grade 3 vs.<3 2.32, 95% Cl 1.02 - 5.28; OR grade 4 vs.<3 4.93, 95% Cl 1.07 - 22.7), hip joint space narrowing (JSN)(OR 1.36/unit, 95% Cl 1.07 - 1.73), BMI (OR l.08/kg/m2, 95% Cl 1.03 -1.13), and knee extension strength (OR 0.96/kg, 95% Cl 0.94 - 0.98) but not knee ROA. These variables were also associated with more severe knee pain. In addition, there was a dose response association between knee pain and number of sites having grade 3 or 4 chondral defects (OR 1.39/site, 95% Cl 1.12-1.73) with 100% subjects having knee pain if all five sites had these defects. In conclusion, knee pain in older adults is independently associated with both full and non-full thickness medial tibial chondral defects, bone marrow lesions, BMI, and knee extension strength but not knee ROA. The association between hip ROA and knee pain indicates that referred pain from the hip needs to be considered in unexplained knee pain. Chapter 8 compares associations between anthropometric and lifestyle factors and femoral head cartilage volume/thickness and radiographic features of OA and provides evidence of construct validity for :MRI assessment of femoral cartilage volume and thickness. A cross sectional sample of 151 randomly selected subjects (79 male, 72 female, mean age 63 years) from the Tasmanian Older Adult Cohort Study took part. A sagittal TI-weighted fat saturation MRI scan of the right hip was performed to determine femoral head cartilage volume, thickness, and size. A weight bearing anterior-posterior pelvic radiograph was performed and scored for ROA in the same joint. Other factors measured were height, weight, leg strength, serum vitamin D levels and bone mineral density. Hip cartilage volume was significantly associated with female sex (regression coefficient {3= -0.44 ml, 95% Cl -0.87, -0.01), BMI ({3= -0.05 ml/k:g/m2, 95% Cl -0.08, -0.02), and femoral head size (3 = O.l 7ml/cm2 , 95% Cl 0.10, 0.25) while hip cartilage thickness was only significantly associated with femoral head size ({3=-0.03ml/cm2, 95% Cr-0.05, -0.01). Female sex was significantly associated with total ROA score ({3=0.95, 95% er 0.2, 1.7) and JSN ({3=0.69, 95% er 0.04, 1.34) but not with osteophytes. Hip radiographic JSN especially axial JSN but not osteophytes was significantly associated with hip cartilage volume ((3 = -0.24, p<0.01) and thickness ((3 = -0.34, p<0.001). fu conclusion, femoral head cartilage volume and thickness have modest but significant construct validity when correlated with radiographs. Furthermore, the generally stronger associations with volume compared to ROA suggest that MRI may be superior at identifying risk factors for hip OA. Chapter 9 examines the optimal sampling of 1.5 mm thick slices of MRI scan to estimate knee cartilage volume in males and females for cross-sectional and longitudinal studies. A total of 150 subjects had a sagittal TI-weighted fat suppressed MRI scan of the right knee at a partition thickness of 1.5 mm to determine their cartilage volume. Fifty subjects had both baseline and 2-year follow up MRI scans. Lateral, medial tibial and patellar cartilage volumes were calculated with different samples from 1.5 mm thick slices by extracting one in two, one in three, and one in four to compare to cartilage volume and its rate of change. Measurement reliability was assessed by means of the intraclass correlation coefficient (ICC) and Bland & Altman plots. Compared to the whole sample of l .5mm thick slices, measuring every second to fourth slice led to very little under or over estimation in cartilage volume and its annual change. At all sites and subgroups, measuring every second slice had less than 1 % mean difference in cartilage volume and its annual rate of change with all ICCs >0.98. In conclusion, sampling alternate 1.5 mm thick MRI slices is sufficient for knee cartilage volume measurement in cross-sectional and longitudinal epidemiological studies with little increase in measurement error. This approach will lead to a substantial decrease in post-scan processing time. Chapter 10 summaries the findings of this thesis and describes the future direction of the research