Dose-dependent Effects of Vitamin D on Bone Health

Study Overview
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Brief Summary
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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.

Detailed Description
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Hypotheses being tested: 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. 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). 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.

Official Title
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Randomized Double-blind Study Investigating Dose-dependent Longitudinal Effects of Vitamin D Supplementation on Bone Health

Conditions
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Age-Related Osteoporosis

Intervention / Treatment
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* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: vitamin D 10,000 IU<br>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<br>* 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<br>* Other names: Vitamin D3, Cholecalciferol;|
| Active Comparator: Vitamin D 4000 IU<br>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<br>* 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<br>* Other names: Vitamin D3, Cholecalciferol;|
| Active Comparator: Vitamin D 400 IU<br>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<br>* 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<br>* Other names: Vitamin D3, Cholecalciferol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Bone Mineral Density (Tt.BMD) at the distal radius and tibia, as measured by High Resolution peripheral Quantitative Tomography (HR-pQCT) | Unlike the measurement of bone density by DXA (a secondary outcome, see below), which estimates bone density based on assumptions of the depth of a 2-dimensional image of bone, HR-pQCT measurement of Tt.BMD provides a true volume based density measurement. HR-pQCT also provides a much higher resolution image of the region of interest than the image derived from a DXA measurement. Units of this measurement are milligrams hydroxyapatite per cubic centimetre (mg HA/cm3). The analysis will examine change in Tt.BMD at distal radius and tibia from baseline to measurements at 6, 12, 24, and 36 months. | Participants will be followed from baseline up to 36 months | 
| Bone strength, as estimated by Finite Element Analysis of High Resolution peripheral Quantitative Computed Tomography (HR-pQCT) measurements at the distal radius and tibia | HR-pQCT scans provide the ability to measure a true volumetric density of the bone region of interest and to study microarchitecture of both trabecular and cortical bone, from which an assessment of strength by Finite Element Analysis (FEA) can be determined: briefly, a 3-dimensional computer model of bone can be constructed from the HR-pQCT data, and subjected to strength testing. FEA software (FAIM, version 6.0, Numerics88 Solutions, Calgary, Canada) is used to estimate failure load (N) based on 2 % of the elements exceeding 7,000 μstrain. The analysis examines change from baseline measured at 6, 12, 24, and 36 months. | Participants will be followed from baseline up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortical bone density (Ct.BMD) of bone as measured by HR-pQCT | Cortical density (Ct.BMD) is a morphological parameter of microarchitecture of bone, and is measured in mg HA/cm3 | From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months. | 
| Cortical Porosity (Ct.Po) of bone as measured by HR-pQCT | Cortical Porosityis a morphological parameter of microarchitecture of bone, and is measured in percent. | From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months. | 
| Trabecular bone density (Tb.BMD) of bone as measured by HR-pQCT | Trabecular density (Tb.BMD) is a morphological parameter of microarchitecture of bone, and is measured in mg HA/cm3 Trabecular density (Tb.BMD) is a morphological parameter of microarchitecture of bone, and is measured in mg HA/cm3 | From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months. | 
| Trabecular number (Tb.N) as measured by HR-pQCT | Trabecular number (Tb.N) is a morphological parameter of microarchitecture of bone, and is measured as mean number of trabeculae per unit of length (mm) | From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months. | 
| Bone Mineral Density as measured by Dual X-ray Absorptiometry | 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. | Participants will be followed from baseline up to 36 months | 
| Quality of Life (Mental Health Component) | Vitamin D deficiency has been associated with depression. We propose to examine whether our Vitamin D intervention has an effect on depression or other aspects of mental health. The SF-36 questionnaire will be administered at baseline and at 12, 24, and 36 months. This will be used to assess subjects' perception of their Quality of Life, specifically the Mental Health Component, and whether the intervention (Vitamin D dose assignment) is associated with changes in the SF-36 scores for Mental Health Component change over the course of the study. | Participants will be followed from baseline up to 36 months | 
| Depression symptoms | PHQ-9 questionnaire will be used to assess any effect the Vitamin D intervention might have on depression symptoms. The PHQ-9 analog scale score will be 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. | Participants will be followed from baseline up to 36 months | 
| Biochemical markers of calcium and bone metabolism | 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. | Participants will be followed from baseline up to 36 months | 
| Balance and grip strength | 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 3 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 | Participants will be followed from baseline up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, Bone quality, Bone density, calcium metabolism, High resolution peripheral quantitative computed tomography, Dual X-ray absorptiometry, Quality of life