Clinical trial NCT01900860: Dose-dependent Effects of Vitamin D on Bone Health
Official title: Randomized Double-blind Study Investigating Dose-dependent Longitudinal Effects of Vitamin D Supplementation on Bone Health
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Age-Related Osteoporosis
Keywords: Vitamin D
Bone quality
Bone density
calcium metabolism
High resolution peripheral quantitative computed tomography
Dual X-ray absorptiometry
Quality of life
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: Pure North S'Energy Foundation
First posted: 2013-07-17
Enrollment: 311
Sex: ALL
Minimum age (years): 55
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility 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 \>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.

Primary outcomes:
measure: Total Bone Mineral Density (Tt.BMD) at the distal radius and tibia, as measured by High Resolution peripheral Quantitative Tomography (HR-pQCT)
timeFrame: Participants will be followed from baseline up to 36 months
measure: Bone strength, as estimated by Finite Element Analysis of High Resolution peripheral Quantitative Computed Tomography (HR-pQCT) measurements at the distal radius and tibia
timeFrame: Participants will be followed from baseline up to 36 months
Secondary outcomes:
measure: Cortical bone density (Ct.BMD) of bone as measured by HR-pQCT
timeFrame: From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months.
measure: Cortical Porosity (Ct.Po) of bone as measured by HR-pQCT
timeFrame: From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months.
measure: Trabecular bone density (Tb.BMD) of bone as measured by HR-pQCT
timeFrame: From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months.
measure: Trabecular number (Tb.N) as measured by HR-pQCT
timeFrame: From baseline to 36 months - measured at 0, 6, 12, 24, and 36 months.
measure: Bone Mineral Density as measured by Dual X-ray Absorptiometry
timeFrame: Participants will be followed from baseline up to 36 months
measure: Quality of Life (Mental Health Component)
timeFrame: Participants will be followed from baseline up to 36 months
measure: Depression symptoms
timeFrame: Participants will be followed from baseline up to 36 months
measure: Biochemical markers of calcium and bone metabolism
timeFrame: Participants will be followed from baseline up to 36 months
measure: Balance and grip strength
timeFrame: Participants will be followed from baseline up to 36 months
Other outcomes:
measure: Safety: changes in parameters of calcium metabolism
timeFrame: Participants will be followed from baseline up to 36 months
measure: Safety: Parameters of glucose metabolism
timeFrame: Participants will be followed from baseline up to 36 months
measure: Safety: Peripheral Vascular Calcification, as assessed by HR-pQCT at the distal radius and tibia
timeFrame: Participants imaging studies will be followed from baseline up to 36 months
Locations:
city: Calgary
country: Canada
facility: The University of Calgary
state: Alberta
Study officials:
affiliation: The University of Calgary
name: David A Hanley, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Calgary
name: Steven K Boyd, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burt LA, Gaudet S, Kan M, Rose MS, Billington EO, Boyd SK, Hanley DA. Methods and procedures for: A randomized double-blind study investigating dose-dependent longitudinal effects of vitamin D supplementation on bone health. Contemp Clin Trials. 2018 Apr;67:68-73. doi: 10.1016/j.cct.2018.02.009. Epub 2018 Feb 20.
citation: Burt LA, Billington EO, Rose MS, Kremer R, Hanley DA, Boyd SK. Adverse Effects of High-Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males. J Bone Miner Res. 2020 Dec;35(12):2404-2414. doi: 10.1002/jbmr.4152. Epub 2020 Sep 16.
citation: Billington EO, Burt LA, Plett R, Rose MS, Boyd SK, Hanley DA. Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial. Osteoporos Int. 2020 Nov;31(11):2141-2150. doi: 10.1007/s00198-020-05500-2. Epub 2020 Jun 15.
citation: Billington EO, Burt LA, Rose MS, Davison EM, Gaudet S, Kan M, Boyd SK, Hanley DA. Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz212. doi: 10.1210/clinem/dgz212.
citation: Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):736-745. doi: 10.1001/jama.2019.11889.