VItamin D Effect on Osteoarthritis Study

NCT ID: NCT01176344

Last Updated: 2015-09-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 413 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2014-12-31

Brief Summary

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

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.

Conditions

Osteoarthritis, Knee

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Vitamin D supplementation

Participants in the intervention arm will receive 50,000 IU (1.25 mg) cholecalciferol capsules given once monthly

Group Type: EXPERIMENTAL

Vitamin D

Intervention Type: DRUG

50,000 IU (1.25 mg) cholecalciferol capsules once monthly for 2 years

Placebo

The control arm will receive identical inert placebo capsules given once monthly.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Inert placebo capsules once monthly for 2 years.

Interventions

Vitamin D

50,000 IU (1.25 mg) cholecalciferol capsules once monthly for 2 years

Intervention Type: DRUG

Placebo

Inert placebo capsules once monthly for 2 years.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age 50-79 years old;

2. 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;

3. Have an American College of Rheumatology (ACR) functional class rating of I, II and III;

4. 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]);

5. Have serum vitamin D level of >12.5 nmol/L and <60 nmol/L;

6. Are able to read, speak and understand English, capable of understanding the study requirements and willing to co-operate with the study instructions;

7. Are able and willing to give informed consent;

8. Are willing and able to give blood samples;

9. Are willing and able to have knee MRIs performed

Exclusion Criteria

1. Have Grade 3 radiographic changes in their knee which is to be investigated;

2. Have severe knee pain (more than 80 mm on a 100-mm visual analogue scale,VAS) in most days of the last month;

3. Have any contra-indications for having MRIs scans performed;

4. 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;

5. Have ever had knee joint replacement;

6. Have anticipated need for knee or hip surgery in the next 2 years;

7. Have any stomach or intestinal condition possibly affecting oral drug absorption;

8. 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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Monash University

OTHER

Sponsor Role: collaborator

Menzies Institute for Medical Research

OTHER

Sponsor Role: lead

Responsible Party

Changhai Ding

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Changhai Ding, MD

Role: PRINCIPAL_INVESTIGATOR

Menzies Research Institute & Monash University

Graeme Jones, MD

Role: PRINCIPAL_INVESTIGATOR

Menzies Institute for Medical Research

Flavia M Cicuttini, PhD

Role: PRINCIPAL_INVESTIGATOR

Monash University

Locations

Menzies Research Institute, University of Tasmania

Hobart, Tasmania, Australia

Department of Epidemiology & Preventive Medicine, Monash University

Melbourne, Victoria, Australia

Countries

Australia

References

Ding C, Cicuttini F, Parameswaran V, Burgess J, Quinn S, Jones G. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum. 2009 May;60(5):1381-9. doi: 10.1002/art.24486.

Reference Type: BACKGROUND

PMID: 19404958 (View on PubMed)

Wang T, Zheng S, Jin X, Cen H, Zhu Z, Han W, Wluka A, Cicuttini F, Cao P, Ding C. Baseline 25-hydroxyvitamin D levels predict the effects of vitamin D supplementation on joint symptoms and cartilage loss in patients with knee osteoarthritis. Rheumatol Adv Pract. 2025 May 27;9(3):rkaf061. doi: 10.1093/rap/rkaf061. eCollection 2025.

Reference Type: DERIVED

PMID: 40677617 (View on PubMed)

Chang J, Chen T, Yan Y, Zhu Z, Han W, Zhao Y, Antony B, Wluka A, Winzenberg T, Cicuttini F, Ding C. Associations between the morphological parameters of proximal tibiofibular joint (PTFJ) and changes in tibiofemoral joint structures in patients with knee osteoarthritis. Arthritis Res Ther. 2022 Jan 27;24(1):34. doi: 10.1186/s13075-022-02719-8.

Reference Type: DERIVED

PMID: 35086561 (View on PubMed)

Zheng S, Tu L, Cicuttini F, Zhu Z, Han W, Antony B, Wluka AE, Winzenberg T, Aitken D, Blizzard L, Jones G, Ding C. Depression in patients with knee osteoarthritis: risk factors and associations with joint symptoms. BMC Musculoskelet Disord. 2021 Jan 7;22(1):40. doi: 10.1186/s12891-020-03875-1.

Reference Type: DERIVED

PMID: 33413273 (View on PubMed)

Tu L, Zheng S, Cicuttini F, Jin X, Han W, Zhu Z, Antony B, Winzenberg T, Jones G, Gu J, Wluka AE, Ding C. Effects of Vitamin D Supplementation on Disabling Foot Pain in Patients With Symptomatic Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2021 Jun;73(6):781-787. doi: 10.1002/acr.24371.

Reference Type: DERIVED

PMID: 32623812 (View on PubMed)

Cuellar WA, Blizzard L, Hides JA, Callisaya ML, Jones G, Cicuttini F, Wluka AE, Ding C, Winzenberg TM. Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial. J Cachexia Sarcopenia Muscle. 2019 Feb;10(1):177-187. doi: 10.1002/jcsm.12364. Epub 2018 Nov 22.

Reference Type: DERIVED

PMID: 30565892 (View on PubMed)

Wang X, Jin X, Blizzard L, Antony B, Han W, Zhu Z, Cicuttini F, Wluka AE, Winzenberg T, Jones G, Ding C. Associations Between Knee Effusion-synovitis and Joint Structural Changes in Patients with Knee Osteoarthritis. J Rheumatol. 2017 Nov;44(11):1644-1651. doi: 10.3899/jrheum.161596. Epub 2017 Sep 1.

Reference Type: DERIVED

PMID: 28864651 (View on PubMed)

Zhu Z, Otahal P, Wang B, Jin X, Laslett LL, Wluka AE, Antony B, Han W, Wang X, Winzenberg T, Cicuttini F, Jones G, Ding C. Cross-sectional and longitudinal associations between serum inflammatory cytokines and knee bone marrow lesions in patients with knee osteoarthritis. Osteoarthritis Cartilage. 2017 Apr;25(4):499-505. doi: 10.1016/j.joca.2016.10.024. Epub 2016 Nov 9.

Reference Type: DERIVED

PMID: 27836676 (View on PubMed)

Jin X, Jones G, Cicuttini F, Wluka A, Zhu Z, Han W, Antony B, Wang X, Winzenberg T, Blizzard L, Ding C. Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2016 Mar 8;315(10):1005-13. doi: 10.1001/jama.2016.1961.

Reference Type: DERIVED

PMID: 26954409 (View on PubMed)

Zhu Z, Jin X, Wang B, Wluka A, Antony B, Laslett LL, Winzenberg T, Cicuttini F, Jones G, Ding C. Cross-Sectional and Longitudinal Associations Between Serum Levels of High-Sensitivity C-Reactive Protein, Knee Bone Marrow Lesions, and Knee Pain in Patients With Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2016 Oct;68(10):1471-7. doi: 10.1002/acr.22834. Epub 2016 Sep 6.

Reference Type: DERIVED

PMID: 26748954 (View on PubMed)

Veloudi P, Blizzard CL, Ding CH, Cicuttini FM, Jin X, Wluka AE, Winzenberg T, Jones G, Sharman JE. Effect of Vitamin D Supplementation on Aortic Stiffness and Arterial Hemodynamics in People With Osteoarthritis and Vitamin D Deficiency. J Am Coll Cardiol. 2015 Dec 15;66(23):2679-2681. doi: 10.1016/j.jacc.2015.10.007. No abstract available.

Reference Type: DERIVED

PMID: 26670070 (View on PubMed)

Cao Y, Jones G, Cicuttini F, Winzenberg T, Wluka A, Sharman J, Nguo K, Ding C. Vitamin D supplementation in the management of knee osteoarthritis: study protocol for a randomized controlled trial. Trials. 2012 Aug 6;13:131. doi: 10.1186/1745-6215-13-131.

Reference Type: DERIVED

PMID: 22867111 (View on PubMed)

Other Identifiers

VIDEO605501

Identifier Type: -

Identifier Source: org_study_id