Dose-dependent Effects of Vitamin D on Bone Health
Dose-dependent Effects of Vitamin D on Bone Health
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.
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 outcomes:

 -  (1) bone density and (2) strength as measured by HR-pQCT

 Secondary outcomes:

 -  HR-pQCT assessment of bone microarchitecture, examining the relative contribution of
 trabecular and cortical bone. We have chosen four parameters for statistical analysis,
 and have listed them as secondary outcome variables in the section below: cortical
 density, cortical porosity, trabecular density and trabecular number.

 -  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.
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 >125 nmol/L (50 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.