VItamin D Effect on Osteoarthritis Study

Study Overview
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Brief Summary
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Observational evidence suggests that vitamin D deficiency may have a role in the causes of osteoarthritis (OA) and there are biologically plausible mechanisms to explain this. There is, however, no evidence which shows that intervening with vitamin D supplementation can slow the progression of OA. This study is to determine if vitamin D supplementation can reduce knee pain and slow knee cartilage loss in OA patients comparing with a placebo. Use of MRI will provide sensitive measures of knee OA changes.

Detailed Description
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Osteoarthritis (OA) is the most common joint disorder in the world. In 2004, OA was estimated to affect over 1.6 million Australians, with total costs of $1.4 billion. OA is the most frequent reason for joint replacement, at a cost of about $1 billion each year. Conventional treatment is palliative and costly, and currently there are no effective medical remedies for OA. These facts have led to 2000-2010 being labelled the Bone and Joint decade, and musculoskeletal disorders being recognised as a National Health Priority. The primary task for OA management should be to identify modifiable risk factors. Vitamin D deficiency is very common in older people and has been linked with osteoporosis and falls in both older women and men. Emerging data suggests that it also plays an important role in the pathogenesis of knee OA. Firstly, vitamin D may have direct effects on chondrocytes in osteoarthritic cartilage; secondly, chronic vitamin D inadequacy in adults has adverse effects on calcium metabolism, osteoblast activity, matrix ossification and bone density, and thus could impair the ability of bone to respond optimally to pathophysiological processes in OA; and thirdly, low vitamin D levels are associated with loss of muscle strength and muscle mass in older men and women, which may be associated with an increased risk of knee OA. Some observational studies have shown that vitamin D insufficiency is associated with the progression and development of radiographic knee or hip OA. Recently we have demonstrated that baseline serum levels of 25-hydroxy-vitamin D(25-(OH)D) predicts change in cartilage volume in older adults over 2 years, and increases in vitamin D levels are associated with a further protective association. This suggests that vitamin D supplementation may enhance cartilage and bone health, and thus prevent disease progression in patients with knee OA. The aim of this study is to compare the effects of vitamin D supplementation versus placebo on knee pain and knee structural changes in patients with symptomatic knee osteoarthritis over a 2- year period. The proposed study design is a randomised, placebo-controlled, double-blind clinical trial. We will recruit 400 subjects (50-79 years old, having relatively good health and serum vitamin D level of <60 and >12.5 nmol/L) with symptomatic knee OA for at least 6 months using a combined strategy in Southern Tasmania and Melbourne. Participants in the intervention arm (n=200) will receive 50,000 IU (1.25 mg) cholecalciferol tablets given once monthly, whilst those in the control arm (n=200) will receive an identical inert placebo. All participants will be provided recommended standard of care. Knee structural changes including knee cartilage volume, cartilage defects, tibial bone area, bone marrow lesions, and meniscal pathology (assessed by MRI), and knee pain at baseline and 2 years later will be determined as outcome measures. Other explanatory factors, such as serum vitamin D levels, height, weight, physical activity, and smoking will also be determined through study period. Significance: Observational evidence suggests that vitamin D deficiency may have a role in the progression of OA and there are biologically plausible mechanisms to explain this. However, randomized controlled trials using a sensitive method are required to determine whether intervening with vitamin D supplementation can in fact slow the progression of this disease. In this study, the randomized, placebo-controlled, double-blind design, and the use of MRI to provide sensitive and precise measures of knee structural change will ensure a rigorous evaluation of the impact of vitamin D supplementation on knee OA. It will be the first long term clinical trial to determine comprehensively the effects on knee structural changes (cartilage, bone) utilizing the pioneering MRI techniques and limb muscle strength assessment. This study builds upon previous clinical and epidemiological studies that supports the objectives of the Bone and Joint Decade organization and addresses a National Health Priority Area.

Official Title
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Does Vitamin D Supplementation Prevent Progression of Knee Osteoarthritis? A Randomised Controlled Trial

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: Vitamin D
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 50-79 years old; Men and women with symptomatic knee osteoarthritis (OA) with a pain visual analogue scale (VAS) of at least 20 mm in most days of the last month; Have an American College of Rheumatology (ACR) functional class rating of I, II and III; Have relatively good health (0-2 according to the investigator's global assessment of disease status on a 5-point Likert scale, range 0 [very well] to 4 [very poor]); Have serum vitamin D level of >12.5 nmol/L and <60 nmol/L; Are able to read, speak and understand English, capable of understanding the study requirements and willing to co-operate with the study instructions; Are able and willing to give informed consent; Are willing and able to give blood samples; Are willing and able to have knee MRIs performed Exclusion Criteria: Have Grade 3 radiographic changes in their knee which is to be investigated; Have severe knee pain (more than 80 mm on a 100-mm visual analogue scale,VAS) in most days of the last month; Have any contra-indications for having MRIs scans performed; Have had significant trauma to the knees including arthroscopy or significant injury to ligaments or menisci of the knee within 1 year preceding the screening visit; Have ever had knee joint replacement; Have anticipated need for knee or hip surgery in the next 2 years; Have any stomach or intestinal condition possibly affecting oral drug absorption; Have any clinically significant condition(s) such as (but not limited to) rheumatoid arthritis, psoriatic arthritis, lupus, active cancer, cardiac or renal function impairment or hypersensitivity to vitamin D that in the opinion of the investigator may compromise their safety or compliance, interfere with evaluation or preclude completion of the study.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D supplementation<br>Participants in the intervention arm will receive 50,000 IU (1.25 mg) cholecalciferol capsules given once monthly | Drug: Vitamin D<br>* 50,000 IU (1.25 mg) cholecalciferol capsules once monthly for 2 years<br>|
| Placebo Comparator: Placebo<br>The control arm will receive identical inert placebo capsules given once monthly. | Drug: Placebo<br>* Inert placebo capsules once monthly for 2 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loss of knee cartilage volume | Cartilage volume will be assessed using magnetic resonance imaging (MRI) | Over 2 years (Cartilage volume will be assessed at baseline and 2 years later) | 
| Change in knee pain | Assessed using WOMAC | Over 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of knee cartilage defects | Knee cartilage defects will be measured using MRI. | Over 2 years (Cartilahe defects will be measured at baseline and 2 years later) | 
| Change in bone marrow lesions | Assessed using MRI | Over 2 years | 
| Change in knee pain | Assessed using VAS | Over 2 years | 
| Change in physical function | Assessed using WOMAC function | Over 2 years | 
| Change in joint effusion | Assessed using MRI | Over 2 years | 
| Central blood pressure | Radial applanation tonometry | one year | 
| Aortic stiffness | Carotid to femoral pulse wave velocity | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D supplementation, Osteoarthritis, Knee, Randomised clinical trial (RCT), Cartilage, MRI