Systemic factors, structural biomarkers and vitamin D treatment in knee osteoarthritis

Osteoarthritis (OA) is a multifactorial disease of the joints and is a leading cause of pain and disability in older adults. The knee is the most common joint affected by OA. Up to the date of this thesis, there are no approved disease-modifying treatments available for knee OA. Therefore, there is an urgent need for identifying modifiable risk factors for this disease. This thesis aims to use a mixed approach to investigate multiple aspects of the disease, including the roles of systemic risk factors in knee OA, the effects of vitamin D supplementation on disease progression, as well as the predictive values of magnetic resonance imaging (MRI) biomarkers for knee replacement. Chapter 4 systematically reviews 32 studies on the relationship between serum C-reactive protein levels measured by a high sensitivity method (hs-CRP) and OA, as well as the correlation between circulating CRP levels and OA phenotypes. Serum hs-CRP levels in OA were modestly but statistically significantly higher than controls. The levels were significantly associated with pain and decreased physical function, but not radiographic OA. This suggests low-grade systemic inflammation may play a greater role in symptoms rather than radiographic changes in OA. Chapter 5 describes the longitudinal relationship between adiposity and change in knee pain. Data from a population-based sample of older adults show that body mass index (BMI) is the most consistent correlate of knee pain. Fat mass is associated with non-weight-bearing knee pain suggesting systemic mechanisms are involved. Chapter 6 investigates the effects of vitamin D supplementation versus placebo on knee pain and knee cartilage volume in symptomatic knee OA patients with low vitamin D levels in a randomized clinical trial. Compared with placebo, vitamin D supplementation did not result in significant differences in change in MRI-measured tibial cartilage volume or knee pain score over 2 years. There were no significant differences in changes of tibiofemoral cartilage defects or bone marrow lesions; however, fewer of those receiving vitamin D had increases in bone marrow lesions.These findings do not support the use of vitamin D supplementation for preventing tibial cartilage loss or improving knee pain in patients with knee OA. Chapter 7 describes the longitudinal associations between serum levels of estrogen, progesterone and testosterone and MRI knee structural changes in both males and females with symptomatic knee OA. For women, progesterone was associated with cartilage volume and estradiol levels were inversely associated with grades of bone marrow lesions (BMLs), while estradiol, progesterone and testosterone were inversely associated with effusion-synovitis volume. No consistent associations were observed for men. This suggests endogenous sex hormones may be protective for joint structural changes in women but not men, which may contribute to observed sex differences in knee OA. Chapter 8 describes the independent association of MRI markers and total knee replacement (TKR) over 10.7 years in older adults from a general population. MRI markers studied included cartilage defects, BMLs, effusion-synovitis and meniscal pathologies. Cartilage defects, BMLs and meniscal tears, but not effusion-synovitis or meniscal extrusion in the right knee were independent predictors of TKR in either knee over 10.7 years. The presence of multiple pathologies increased the risk of TKR, suggesting that MRI structural markers are good predictors of rapid knee OA progression in the general population. In conclusion, this series of studies indicate that knee OA is a complex disease that is associated with systematic factors such as low-grade inflammation, adiposity and sex hormones. Vitamin D supplementation does not significantly prevent knee cartilage loss and knee pain in patients with symptomatic knee OA. MRI structural markers are good predictors of endstage knee OA in the general population. Future study should continue to validate the utility of using a panel of MRI biomarkers in predicting clinical endpoints. When developing disease-modifying OA drugs (DMOADS), systemic and metabolic inflammation should be a potential treatment target. Further investigation is needed to examine the effects of exogenous hormone replacement therapy on MRI structural changes in women