Factors affecting musculoskeletal disease and predictors of progression

Osteoarthritis (OA) is a significant public health issue, for which there is no cure. OA is a leading cause of pain and disability particularly among the elderly. The societal and economic burden of this disease is only expected to increase with the obesity epidemic and the ageing population. Despite this, factors affecting structural change and the underlying pathogenesis of disease remain unclear. Furthermore, valid and reliable predictors of progression are limited. The OA research area has been advanced significantly by the use of Magnetic Resonance Imaging (MRI). MRI represents a relatively non-invasive, valid and sensitive tool to measure early structural changes at the knee, including cartilage defects and BMLs, as well as articular cartilage volume. The ability to assess early structural change is particularly important, as there is an evolving view of OA as a continuum of disease, from a healthy to a diseased joint and ultimately joint failure. Thus the aim of this thesis was to understand factors affecting musculoskeletal disease, with a particular focus on knee joint structures. This thesis includes healthy populations, to enable the identification of risk factors associated with early structural change. This may be useful for informing disease prevention strategies. In addition, a population with established disease waS examined, in order to identify factors that may slow or reduce the progression of disease. Paper 1 examines the natural history of bone marrow lesions, a potential imaging biomarker, in a population of healthy women over 2 years. Approximately 46% of BMLs present at baseline completely resolved over 2 years. 'Large' BML had the potential to improve, while the majority of 'very large' BMLs remained stable. Approximately 9% of women developed incident BMLs, and there was a trend toward weight being a risk factor for the development of 'very large' BMLs. Papers 2 and 3 contribute to the understanding of the pathogenesis of disease, exploring possible underlying mechanisms for the relationship between obesity and musculoskeletal disease. Paper 2 describes the relationship between components of body composition including fat and muscle mass on knee joint structures in a relatively healthy popUlation. Fat, but not muscle mass was associated with early structural changes including cartilage defects and BMLs. Paper 3 also describes the relationship between body composition and back pathology, an~ther significant musculoskeletal health problem. Similar to those results obtained at the knee, increased fat, but not muscle mass, was asso~iated with back pain and disability~ This suggests that metabolic factors may be important. Paper 4 aims to identify factors affecting patellofemoral joint structure, as this compartment is largely understudied. This paper describes the relationship between the vastus medialis and lateralis muscles, and patellofemoral joint structures including cartilage and bone volume in a healthy population. Vastus medialis cross-sectional area was positively associated with patella cartilage and bone volume, suggesting a beneficial effect on the joint. To further improve the understanding of the pathogenesis of knee OA, paper 5 in this thesis explores the potential role of Bone Mineral Density (BMD) in explaining the well established sex differences in knee cartilage volume. In a relatively healthy population, it was found that the positive relationship between BMD and medial cartilage volume was stronger in men than women. Paper 6 describes the relationship between serum biomarkers of bone metabolism and disease progression in a popUlation with symptomatic and radiographic knee OA. Baseline . biomarkers of bone formation PINP and osteocalcin, and biomarkers of bone resorption, CTX-I and NTX-I were significantly associated with reduced cartilage loss. However, when subjects were divided into subgroups with high or low bone formation markers (based on levels of marker ~mean or < mean for the popUlation, respectively), in the subgroup with high PINP there was a significant association between increasing bone resorption markers CTX-I and NTX-I and reduced cartilage loss. Similarly, in the subgroup with high osteocalcin, there was a significant association between increasing CTX-I and NTX-I and reduced cartilage loss. In contrast, in subgroups with low bone formation markers, no significant associations were obtained. Paper 7 describes the relationship between serum biomarkers of cartilage metabolism and disease progression. The relationship between cartilage biomarkers and cartilage volume loss was not linear across the whole popUlation. In the low (biomarker level < mean), but not high (biomarker ~ mean) COMP subgroup, COMP was significantly associated with a reduced rate of medial cartilage volume loss. Similarly, in the low but not high PIIANP subgroup, vii PUANP was associated with a significantly reduced rate of medial volume cartilage loss. PUANP was associated with a reduced risk of joint replacement. Paper 8 extends this work, to examine a group of adipose derived cytokines, termed adipokines, which may provide a potential metabolic link between obesity and joint damage. Baseline leptin was associated with increased biomarkers of bone formation (osteocalcin and PINP) over 2 years, whilst the soluble leptin receptor sOB-Rb was associated with reduced osteocalcin. Baseline sOB-Rb was associated with reduced cartilage synthesis biomarker (PUANP) and increased cartilage volume loss over 2 years. The results of this thesis contribute to the understanding of the pathogenesis of OA, identification of potential therapeutic targets, and may have tlfe potential to inform more effective prevention strategies. In order to reduce the burden of this disease, further research will be required to build on these findings.