Knee osteoarthritis, its comorbidity and the role of vitamin D

Osteoarthritis (OA) is the most common chronic joint disease. Although disease progression is usually slow, it can ultimately lead to joint failure with pain, stiffness, swelling and disability. Additionally, patients with OA are at significantly higher risk of developing comorbidity than without OA. Coexisting with comorbidity results in increased difficulties in OA management, reduced quality of life and increased disease burden. Up to date of this thesis, OA disease- modifying therapy remains the greatest unmet. Hence, there is an urgency for developing an effective treatment to slow the disease progression and identifying modifiable risk factors for OA comorbidity. This thesis aims to use a mixed approach to investigate multiple aspects of OA, including the effect of vitamin D on the disease and its comorbidity and factors associated with its comorbidity. It is based on the Vitamin D Effects on Osteoarthritis (VIDEO) study, which is a randomised clinical trial and aims to examine the effects of monthly vitamin D supplementation over two years on knee pain and knee structural changes in symptomatic knee OA patients with low vitamin D levels. 413 participants (mean age: 63.2 years; 50% female) with symptomatic knee OA and low 25(OH)D levels (>12.5nmol/L and <60nmol/L) were randomised to treatment and control groups in Hobart and Melbourne. Chapter 4 describes the differences in disease progression and symptoms among people with knee OA by vitamin D status over time, which is a post hoc analysis of the original VIDEO study. Participants who maintained vitamin D sufficiency over two years had decreased loss of tibial cartilage volume, less increase in effusion-synovitis volume and more improvement in knee joint physical function compared with those who did not. This suggests beneficial effects of maintaining vitamin D sufficiency on cartilage loss, effusion-synovitis and physical function in patients with symptomatic knee OA. Chapter 5 investigates whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers over two years in patients with knee OA and vitamin D deficiency. Vitamin D supplementation had no significant effects on changes in serum hs-CRP, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin, compared to placebo. Furthermore, being consistently vitamin D sufficient over two years was also not associated with changes in these biomarkers compared to not being consistently sufficient. These do not suggest vitamin D supplementation and maintaining vitamin D sufficiency may alter systemic inflammation in knee OA patients. Chapter 6 investigates the effect of vitamin D supplementation and maintaining vitamin D sufficiency on depressive symptoms in patients with knee OA patients. Depressive symptoms improved more in the vitamin D treatment group and the participants who maintained vitamin D sufficiency between month 3 and 24 over 24 months, compared to the placebo group and the group which did not maintain sufficient vitamin D, respectively. Although the improvement was small, and the clinical importance was uncertain, vitamin D supplementation and maintaining vitamin D sufficiency could reduce depressive symptoms in patients with knee OA. These suggest that vitamin D supplementation and maintaining adequate vitamin D levels over 24 months may be beneficial for depressive symptoms in patients with knee OA. Chapter 7 describes the temporal relationships between demographic and OA clinical factors, joint symptoms and depression in patients with symptomatic knee OA. The prevalence and the incidence of depression was 25.4% and 11.2%, respectively. The common OA risk factors such as higher BMI, lower education level and having two or more comorbidities were associated with prevalent depression and being female was associated with incident depression in knee OA patients. Also, higher levels of knee pain and physical dysfunction and having multi-site pain were associated with increased risks of both prevalent and incident depression. These findings provide empirical evidence that management of common OA risk factors, chronic pain and joint dysfunction may be beneficial for preventing and managing depression in knee OA patients. Chapter 8 investigates the effect of vitamin D supplementation and maintaining vitamin D sufficiency on foot pain in patients with knee OA patients. In this sample, 51.8% of participants reported they had foot pain in patients with knee OA and vitamin D deficiency. Foot pain improved more in the vitamin D treatment group and the participants who maintained vitamin D sufficiency between month 3 and 24 over 24 months, compared to the placebo group and the group which did not maintain sufficient vitamin D, respectively. These suggest that vitamin D supplementation and maintaining adequate vitamin D levels over 24 months had beneficial effects on foot pain deterioration in OA patients. In summary, this thesis indicates that depression and foot pain are common comorbidities in patients with knee OA. Management of common OA risk factors, chronic pain and joint dysfunction may be beneficial for the prevention and management of depression in knee OA patients. Maintaining vitamin D sufficiency may be beneficial on cartilage loss, effusion-synovitis and physical function in people with symptomatic knee OA. Vitamin D supplementation and maintaining vitamin D sufficiency may not affect systemic inflammation but may have beneficial effects on comorbidities including depression and foot pain in patients with knee OA.