Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta

• Overall Objective: To test the hypothesis that oral vitamin D supplementation at higher than currently prescribed doses has a beneficial effect on the skeleton of young patients with osteogenesis imperfecta (OI).
• Specific Aims: 1. To determine whether 12 months of high-dose vitamin D supplementation, compared to standard-dose vitamin D supplementation, increases areal bone mineral density z-scores at the lumbar spine. 2. To examine the effectiveness of high-dose vitamin D supplementation to increase trabecular and cortical bone mineral density at the radius. 3. To examine whether high-dose vitamin D supplementation has an effect on physiological determinants of bone mass (parathyroid hormone, activity of bone metabolism, muscle function).
• Background: In a preliminary cross-sectional study of 282 OI patients we observed an inverse relationship between serum 25-hydroxyvitamin D and parathyroid hormone levels and a positive relationship between circulating levels of 25-hydroxyvitamin D and lumbar spine areal bone mineral density z-scores. This suggested that high-dose vitamin D supplementation would have a beneficial effect on bone density. Most OI patients currently receive oral vitamin D supplementation of 400 International Units per day, but doses of 2000 International Units per day are safe and have been shown to be beneficial in studies on healthy adolescents.
• Study Design: This is a parallel-group double-blind randomized controlled trial of 12 months duration on 60 children and adolescents aged 6 to 19 years with a clinical diagnosis of OI. One group of 30 participants will be randomized to receive vitamin D3 at a dose of 2000 international units per day ('high-dose group'). The other group of 30 participants will be randomized to receive vitamin D3 at a dose of 400 international units per day ('standard-dose group'). Randomization will be stratified according to pubertal status and bisphosphonate treatment status.
• Clinical Relevance: The proposed study aims at direct improvements in the care of OI patients. If a simple and low-cost 'intervention' such as high-dose vitamin D supplementation can be shown to be effective in relieving some of the disease burden associated with OI, the benefit to OI patients worldwide would be substantial.

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Dietary supplement: standard-dose vitamin D (400IU per day); Dietary supplement: high-dose vitamin D (2000 IU per day)

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3G1A6
      • Shriners Hospitals for Children-Canada

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of OI of any type.

Exclusion Criteria:

• Any condition that renders bone density measurements at the lumbar spine impossible. An example for this is prior spinal fusion surgery.
• Bisphosphonate therapy for less than two years duration.
• Use of medication, other than bisphosphonates, known to affect bone metabolism or 25OHD serum concentrations. Examples are anti-epileptics, active vitamin D metabolites, corticosteroids and thyroid hormones.
• Liver and renal disease known to interfere with vitamin D metabolism.
• Any other disorder of calcium and phosphate metabolism (apart from vitamin D deficiency) that might interfere with PTH.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: standard-dose vitamin D; one group of 30 participants will be randomized to receive vitamin D3 at a dose of 400 international units per day ('standard-dose group').	Dietary supplement: standard-dose vitamin D (400IU per day)
Experimental: high-dose vitamin D; One group of 30 participants will be randomized to receive vitamin D3 at a dose of 2000 international units per day ('high-dose group').	Dietary supplement: high-dose vitamin D (2000 IU per day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in areal bone mineral density z-score of the lumbar spine	LS-aBMD z-score will be used as the primary outcome.The lumbar spine is the standard site of measurement both in the clinical follow up of OI patients .	at baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in trabecular and cortical volumetric bone mineral density z-scores at the radius, as measured by pQCT, relative to baseline.	Trabecular bone is analyzed at the distal radial metaphysis ('4% site'). Cortical bone is analyzed at the radial diaphysis ('65% site').	at baseline and at 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage change in lower extremity muscle power per body weight, as measured by jumping mechanography, relative to baseline.	A countermovement jump to maximal height ('single two-legged jump') will be evaluated. In patients who are unable to jump, the heel-rise test will be used to determine muscle power.	baseline and 12 months

Collaborators and Investigators

• Sponsor: Louis-Nicolas Veilleux Ph.D.

Publications and helpful links

General Publications

• Plante L, Veilleux LN, Glorieux FH, Weiler H, Rauch F. Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial. Bone. 2016 May;86:36-42. doi: 10.1016/j.bone.2016.02.013. Epub 2016 Feb 24.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: October 21, 2012
• First Submitted That Met QC Criteria: October 21, 2012
• First Posted (Estimate): October 24, 2012

Study Record Updates

• Last Update Posted (Estimate): September 9, 2014
• Last Update Submitted That Met QC Criteria: September 8, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: bone density; muscle function; osteogenesis imperfecta; high-dose vitamin D
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: A02-M14-12A