Zurich Multiple Endpoint Vitamin D Trial in Knee OA Patients

Role of Vitamin D in Secondary Prevention of Knee Osteoarthritis: A Double-blind Randomized Controlled Trial

This is a 2-year double-blind randomized controlled trial in 287 community-dwelling individuals age 60 years or older undergoing uni-lateral total knee replacement due to severe OA of the knee.We compare an oral dose of 2000 IU vitamin D3 per day to 800 IU. The primary endpoints are pain and disability related to rehabilitation of the operated knee,and related to the expected high prevalence of OA in the contra-lateral knee. Secondary endpoints are change in 25(OH)D levels, muscle strength, balance, lower extremity function, the rate of falls, bone density and bone quality, bone metabolism, general pain, fall-related fractures, body composition, blood-pressure, major cardiovascular events, blood glucose-insulin levels, executive cognitive function, rate of upper respiratory tract infections / all infections, tooth loss, dental health, health care utilization, number and size of facial skin keratosis, and radiographic progression of the non-operated knee. Pain and disability will be assessed by the pain and function subscales of the Western Ontario- McMaster Universities Osteoarthritis Index (WOMAC). Randomization will be stratified by WOMAC function prior to surgery, radiological evidence for OA in the contra-lateral knee, and hospital. Clinical visits will take place at baseline (6-8 weeks after TKR), at 6, 12, 18 and 24 months of treatment. In addition, all individuals will receive a phone call every 2 month to assess adverse outcomes and compliance to treatment, supported by a hotline for immediate report of adverse events.

Statistical power: We expect more than 80% power with 200 participants completing their 24 month follow-up, and 260 participants completing their 12 month follow-up.

This is a trial with medicinal product.

Study Overview

• Status: Completed
• Conditions: Knee Osteoarthritis
• Intervention / Treatment: Dietary supplement: Vitamin D3 (cholecalciferol)

• Study Type: Interventional
• Enrollment (Actual): 273
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • ZH
    • Zurich, ZH, Switzerland, 8091
      • University Hospital Zurich, Centre on Aging and Mobility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unilateral knee replacement due to knee osteoarthritis
• Age 60+ years
• German language skills
• community dwelling

Exclusion Criteria:

• Bi-lateral knee replacement or hip replacement planned in the trial period, or in the previous 6 months
• Chronic steroid intake
• Serum calcium corrected for serum albumin > 2.6 mmol/l
• GFR < 30 ml/min
• Severe visual or hearing impairment
• Inflammatory arthritis
• Malabsorption
• High alcohol intake
• Sarcoidosis, primary hyperparathyroidism
• History of kidney stones, lymphoma
• Chemotherapy for cancer in the previous 12 months
• Hemiplegia
• Morbus Parkinson
• Unable to walk 3 meters prior to surgery
• Bisphosphonate, parathyroid hormone , fluoride or calcitonine therapy in the last 6 months
• Zolendronate in the last year
• M. Paget (Ostitis deformans)
• Vitamin D3 intake more than 800IU/d over more than 1 month
• stay on a sunny location for more than 6 weeks per year
• heart failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1: 2000 IU D3/day; 2000 IU vitamin D3 taken orally each day for 2 years	Dietary supplement: Vitamin D3 (cholecalciferol); the intervention is a dietary supplement comparing the current standard (800 IU) to the current safe upper limit (2000 IU)
ACTIVE_COMPARATOR: 2: 800 IU D3 / day; 800 IU vitamin D3 taken orally each day for 2 years	Dietary supplement: Vitamin D3 (cholecalciferol); the intervention is a dietary supplement comparing the current standard (800 IU) to the current safe upper limit (2000 IU)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
pain and function of the operated and non-operated knee	0, 6,12,18, 24 months
rate of falls	0, 24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
strength, balance, function, physical activity	0,6,12,18,24 months
bone density, bone quality	0, 24 months
body composition	0, 24 months
blood pressure	0,12,24 months
number of teeth	0, 24 months
cost, health care utilization	0,6,12,18,24 months
facial skin keratosis (number and size)	0, 24 months
cognitive function	0, 24 months
depression, mental health	0,12,24 months
fasting blood glucose - insulin levels	0,12,24
Number of upper respiratory infections and number of any infections	0, 6,12,28,24
bone metabolism	0,6,12,18,24
radiographic progression of the non-operated knee	0, 24 months
general pain	0,6,12,18,24 months
Quality of life	0,6,12,18,24

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: Boston University; Tufts University; Harvard School of Public Health (HSPH)
• Investigators: Principal Investigator: Heike Bischoff-Ferrari, MD, MPH, University Hospital Zurich, Centre on Aging and Mobility

Publications and helpful links

General Publications

• Abderhalden LA, Meyer S, Dawson-Hughes B, Orav EJ, Meyer U, de Godoi Rezende Costa Molino C, Theiler R, Stahelin HB, Ruschitzka F, Egli A, Forman JP, Willett WC, Bischoff-Ferrari HA. Effect of daily 2000 IU versus 800 IU vitamin D on blood pressure among adults age 60 years and older: a randomized clinical trial. Am J Clin Nutr. 2020 Sep 1;112(3):527-537. doi: 10.1093/ajcn/nqaa145.
• Freystaetter G, Fischer K, Orav EJ, Egli A, Theiler R, Munzer T, Felson DT, Bischoff-Ferrari HA. Total Serum Testosterone and Western Ontario and McMaster Universities Osteoarthritis Index Pain and Function Among Older Men and Women With Severe Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2020 Nov;72(11):1511-1518. doi: 10.1002/acr.24074.
• Schietzel S, Fischer K, Brugger P, Orav EJ, Renerts K, Gagesch M, Freystaetter G, Stahelin HB, Egli A, Bischoff-Ferrari HA. Effect of 2000 IU compared with 800 IU vitamin D on cognitive performance among adults age 60 years and older: a randomized controlled trial. Am J Clin Nutr. 2019 Jul 1;110(1):246-253. doi: 10.1093/ajcn/nqz081.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: January 10, 2008
• First Submitted That Met QC Criteria: January 23, 2008
• First Posted (ESTIMATE): January 24, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): October 28, 2014
• Last Update Submitted That Met QC Criteria: October 27, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: PP00B-114864; 2007DR4347 (OTHER: Swiss Agency for Therapeutic Products (Swissmedic))