Dose-dependent Effects of Vitamin D on Bone Health

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by University of Calgary
Sponsor:
Collaborator:
Funding Source: Pure North S'Energy Foundation
Information provided by (Responsible Party):
David A. Hanley, MD, FRCPC, University of Calgary
ClinicalTrials.gov Identifier:
NCT01900860
First received: July 2, 2013
Last updated: September 5, 2013
Last verified: September 2013
  Purpose

We propose to conduct a randomized double blind trial of three doses of vitamin D, 400, 4000, and 10,000 International Units (IU) per day, to assess the effect on bone density and architecture as assessed by high resolution peripheral quantitative tomography (HR-pQCT) measurements at the radius and distal tibia, and standard Dual X-ray absorptiometry (DXA). Other measures of bone and calcium metabolism will be assessed. The trial will last as long as three years. Approximately 300 healthy men and women, aged 50-70 years of age, will be recruited, and randomly assigned to one of the three doses of vitamin D. Other outcome variables assessed include quality of life, depression, muscle strength and balance.


Condition Intervention
Age-Related Osteoporosis
Dietary Supplement: Vitamin D

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Randomized Double-blind Study Investigating Dose-dependent Longitudinal Effects of Vitamin D Supplementation on Bone Health

Resource links provided by NLM:


Further study details as provided by University of Calgary:

Primary Outcome Measures:
  • non-invasive assessment of bone strength, as measured by High Resolution peripheral Quantitative Computed Tomography (HR-pQCT) [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: Yes ]
    The primary outcomes of the HR-pQCT scans are morphological parameters such as trabecular thickness (Tb.Th), trabecular number (Tb.N), bone volume ratio (bone volume / trabecular volume (BV/TV) and estimated bone strength from finite element analysis. Change from baseline measured at 6, 12, 24, and 36 months.


Secondary Outcome Measures:
  • Bone Mineral Density as measured by Dual X-ray Absorptiometry [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: Yes ]
    Dual X-ray absorptiometry (DXA) will be used to scan the distal radius, lumbar spine and the proximal femur to obtain an areal (two dimensional) estimate of bone mineral density (aBMD). DXA is the current clinical standard for measuring bone density. From the scan of the lumbar spine and left proximal femur (~ 1 min), aBMD (g/cm2) will be used to determine a subject-specific T-score (aBMD compared to reference mean for a young healthy adult) and this value will be compared to standard World Health Organization criteria to classify each subject as normal (T-score>-1), low bone density (-1 < T > -2.5) or osteoporotic (T score < -2.5). Change from baseline will be assessed at 12, 24 and 36 months.

  • Quality of Life [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: No ]
    SF-36 questionnaire will be administered at baseline and at 12, 24, and 36 months

  • Depression symptoms [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: No ]
    Beck Depression Inventory or PHQ-9 questionnaire will be used (decision not made yet); measured at entry and at 3, 6 and 12 months, then annually. This is not expected to be a safety issue in recruiting healthy volunteers, but obviously could become one.

  • Biochemical markers of calcium and bone metabolism [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: No ]
    In addition to the markers identified as safety measures in "other outcomes" (serum and urine calcium, serum creatinine, etc), we will also obtain serum for measurement of markers of bone turnover: serum C-telopeptide of Type I Collagen (CTX), and Procollagen I N-terminal Propeptide. Measurements taken at baseline and at 3, 6, 12, 24, and 36 months. Still to be arranged: Under-carboxylated osteocalcin and osteocalcin.

  • Balance and grip strength [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: No ]
    The balance tests include standing with (a) two feet on the force platform with eyes open, (b) two feet on the force platform with eyes closed, (c) two feet on a foam pad with eyes open, and (d) two feet on a foam pad with eyes closed. All tests will be performed 5 times, and a blindfold will be used for all eyes-closed assessments. The total testing time is approximately 15 minutes. Measurements done at baseline and at 12, 24 and 36 months


Other Outcome Measures:
  • changes in parameters of calcium metabolism [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: Yes ]
    The main concern in safety of vitamin D consumption is the avoidance of toxicity in the form of hypercalcemia or renal damage, related to hypercalcemia and hypercalciuria. Two of the doses in this study are generally accepted as safe. The 10,000 IU daily dose exceeds the recommended upper limit of safe, unsupervised vitamin D intake, hence, this trial includes regular clinical laboratory testing of parameters of calcium metabolism, including serum and urine calcium, parathyroid hormone, 25OH-Vitamin D. Measurements will be done at baseline, 3, 6, 12, 24, and 36 months

  • Parameters of glucose metabolism [ Time Frame: Particiants will be followed from baseline up to 36 months ] [ Designated as safety issue: No ]
    Hemoglobin A1C, and fasting glucose, and the osteocalcin measurements will address some of the potential effects of vitamin D on glucose metabolism. A full assessment of the effects of vitamin D on diabetes and glucose metabolism is beyond the scope of this proposal, but because these parameters are very easily obtained measurements they will be examined at baseline, 3, 6 , 12, 24 and 36 months.


Estimated Enrollment: 300
Study Start Date: August 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: vitamin D 10,000 IU
Subjects in this arm receive 10,000 IU Vitamin D p.o. (as 5 drops of a blinded vitamin D solution) per day. Duration: 3 years
Dietary Supplement: Vitamin D
Three different doses of vitamin D will be administered in a double-blinded fashion. The three doses are 400, 4000, or 10,000 IU/day
Other Name: Vitamin D3, Cholecalciferol
Active Comparator: Vitamin D 4000 IU
Subjects in this arm receive 4,000 IU Vitamin D p.o. (as 5 drops of a blinded vitamin D solution) per day. Duration: 3 years
Dietary Supplement: Vitamin D
Three different doses of vitamin D will be administered in a double-blinded fashion. The three doses are 400, 4000, or 10,000 IU/day
Other Name: Vitamin D3, Cholecalciferol
Active Comparator: Vitamin D 400 IU
Subjects in this arm receive 400 IU Vitamin D p.o. (as 5 drops of a blinded vitamin D solution) per day. Duration: 3 years
Dietary Supplement: Vitamin D
Three different doses of vitamin D will be administered in a double-blinded fashion. The three doses are 400, 4000, or 10,000 IU/day
Other Name: Vitamin D3, Cholecalciferol

Detailed Description:

Hypotheses being tested:

  1. It is hypothesized that vitamin D, in a dose-dependent manner, will suppress parathyroid hormone action, resulting in less bone turnover, and decreased cortical porosity, leading to improved bone strength as assessed by finite element analysis.
  2. It is hypothesized that vitamin D, in a dose-dependent manner, will increase bone density in the central skeleton (spine, hip), as measured by the current standard method of dual X-ray absorptiometry (DXA).
  3. It is hypothesized that vitamin D, in a dose-dependent manner, will have an impact on quality of life, including indices of depression, as measured by the SF-36 questionnaire and an appropriate index of depression.

Outcomes:

Primary outcome:

  • bone strength as measured by HR-pQCT, including an assessment of the relative contribution of trabecular and cortical bone.

Secondary outcomes:

  • bone mineral density as measured by DXA
  • parameters of calcium metabolism, including biochemical markers of bone turnover and DNA to examine possible variations in the genes that control vitamin D metabolism.
  • quality of life score
  • depression scale score
  • balance, grip strength.
  • fasting glucose and Hemoglobin A1C will also be measured.
  • Safety will be assessed during the scheduled follow-up visits by obtaining history of adverse events, as well as measurements of serum and urine parameters of mineral metabolism as described below.

INTERVENTION DRUG: Vitamin D3 in one of three doses Rationale: For adults under age 70 years, the recent Institute of Medicine (IOM) report recommends a total intake of 600 IU vitamin D/day will provide all the vitamin D needed for bone health, and since the typical Canadian diet contains between 200 and 300 units of vitamin D, the subjects in the lowest dose arm of our study will receive 400 IU/day. The other two groups will receive 10,000 IU and 4,000 IU, respectively. The 10,000 IU dose is the tolerable upper intake level (TUL) recommended by Hathcock et al (Am J Clin Nutr 2007) and 4,000 IU is the IOM's recommended TUL.

Calcium intake:

All subjects will have adequate calcium intake as defined by the Institute of Medicine (total of 1200 mg/day). A brief dietary history will be taken and subjects will be instructed to take an appropriate dose of supplemental calcium if their daily intake is less than 1200 mg/day (the IOM's Recommended Daily Allowance for this study population).

Interim analysis (with maintenance of blinding of subjects and investigators as to treatment arm):

  • planned at and of years 1 and 2, as well as the final analysis at year 3.
  Eligibility

Ages Eligible for Study:   55 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy women and men between 55 and 70 years of age; women will be at least 5 years post-menopause. Presence of a chronic illness does not exclude participation if the condition is stable and managed by a physician.
  • Baseline lumbar spine and total hip bone mineral density (BMD) T-score above 2.5 as assessed using dual x-ray absorptiometry (DXA).

Exclusion Criteria:

  • A serum 25-[OH] vitamin D (25OHD) of <30 nmol/L (<12 ng/mL) or >100 nmol/L (40 ng/mL).
  • Hypercalcemia (serum calcium >2.55 mmol/L), hypocalcemia (serum calcium <2.10 mmol/L) or eGFR <30 mL/min.
  • Surgical cure of Primary Hyperparathyroidism within the last year.
  • Active kidney stone disease (recurrent stones, recent kidney stone [within last 2 years])
  • Known hypersensitivity or allergy to Vitamin D
  • Serum creatinine, AST, ALT, PTH, calcium, or alkaline phosphatase greater than 1.5 times the upper limit of normal at the screening visit
  • BMD exclusions:

    1. High 10-year risk for osteoporotic fracture, as defined by the Canadian Association of Radiologists/Osteoporosis Canada calculator, or the World Health Organization's FRAX calculator.
    2. DXA T-score below or equal to -2.5 SD.
  • Have taken bone active osteoporosis prescription drugs in the past 2 years (bisphosphonates) or 1 year (other osteoporosis prescription therapies).
  • Any medical condition that would prevent participation in a clinical trial for a full three years.
  • Medications such as prednisone >2.5 mg daily (or equivalent); other bone active medications such as tamoxifen or aromatase inhibitors for breast cancer, or androgen deprivation therapy of prostate cancer.
  • Disorders known to affect vitamin D metabolism such as sarcoidosis or renal failure or malabsorption disorders (e.g. pancreatic insufficiency or celiac disease).
  • Regular (monthly or more frequent) use of tanning salons.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01900860

Contacts
Contact: David A. Hanley, MD, FRCPC 403-955-8327 dahanley@ucalgary.ca
Contact: Steven K. Boyd, PhD 403-220-3664 skboyd@ucalgary.ca

Locations
Canada, Alberta
The University of Calgary Recruiting
Calgary, Alberta, Canada, T2N 4Z6
Contact: Sharon Gaudet, RN, MSc    403-220-8292    gaudet@ucalgary.ca   
Principal Investigator: David A Hanley, MD, FRCPC         
Sponsors and Collaborators
University of Calgary
Funding Source: Pure North S'Energy Foundation
Investigators
Principal Investigator: David A Hanley, MD, FRCPC The University of Calgary
Principal Investigator: Steven K Boyd, PhD The University of Calgary
  More Information

No publications provided

Responsible Party: David A. Hanley, MD, FRCPC, Professor, Department of Medicine, University of Calgary
ClinicalTrials.gov Identifier: NCT01900860     History of Changes
Other Study ID Numbers: 20130101
Study First Received: July 2, 2013
Last Updated: September 5, 2013
Health Authority: Canada: Health Canada

Keywords provided by University of Calgary:
Vitamin D
Bone quality
Bone density
calcium metabolism
High resolution peripheral quantitative computed tomography
Dual X-ray absorptiometry
Quality of life

Additional relevant MeSH terms:
Vitamin D
Ergocalciferols
Osteoporosis
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Cholecalciferol
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on August 28, 2014