Vitamin D Deficiency
Conditions
Keywords
Vitamin D, Cholecalciferol, Parathyroid Hormone, Calcium Absorption, Bone Mineral Density, Muscle Function
Brief summary
The purpose of this study is to answer the following questions: Does vitamin D increase calcium absorption, bone mass and muscle mass and function in women past menopause who have mildly low vitamin D levels? Do these benefits require prescription-strength vitamin D, or is an over the counter vitamin D dose enough?
Detailed description
Osteoporosis is a major health problem in postmenopausal women. At age 50, half of women will suffer an osteoporotic fracture in their remaining lifetime, causing increased disability and mortality. Vitamin D deficiency, defined as a serum 25(OH)D \<15 ng/mL, contributes to osteoporosis via decreased calcium absorption (Ca·Ab), secondary hyperparathyroidism (HPT), increased bone resorption and decreased bone mineral density (BMD). Thus, experts agree that patients with vitamin D deficiency should receive vitamin D therapy. Vitamin D insufficiency (VDI) is a milder form of hypovitaminosis D defined as a 25(OH)D level between 15 and 30 ng/mL regardless of parathyroid hormone (PTH) status. Experts disagree on whether to treat VDI, as the clinical benefits of therapy are uncertain. Some experts insist the optimal 25(OH)D level is ≥30 ng/mL. By contrast, both the Food and Nutrition Board and NIH Evidence Report No. 158 state that insufficient evidence exists to declare the optimal serum 25(OH)D for bone health, despite review of \ 170 studies. Consequently, the Food and Nutrition Board cannot determine a recommended daily allowance for vitamin D. Confusion over the optimal 25(OH)D level results, in part, because previous trials failed to recruit subjects based on initial 25(OH)D levels and/or failed to target or achieve 25(OH)D levels ≥30 ng/mL. Moreover, secondary HPT, the proposed mechanism by which VDI causes bone loss, occurs in only 10% to 33% of people with VDI. As such, people with VDI and normal PTH might not experience clinical benefits from vitamin D therapy. VDI is widespread, affecting 26% to 39% of postmenopausal American women with and without osteoporosis. Therefore, determining the ideal 25(OH)D level for optimal calcium homeostasis and bone health is of utmost clinical and public health importance. Our overall goal, congruent with Healthy People 2010 objective 2-9, is to evaluate the effect of vitamin D therapy on the risk of osteoporosis in postmenopausal women with VDI, as reflected by changes in Ca·Ab, BMD and muscle fitness. Our second goal is to evaluate whether a high-dose vitamin D regimen, chosen to achieve and maintain a 25(OH)D level ≥30 ng/mL, is superior in its effects on study outcomes compared to a low-dose vitamin D regimen that can permit continued VDI. We will conduct a randomized, placebo-controlled double-blind trial of low-dose and high-dose vitamin D in postmenopausal women with vitamin D insufficiency in order to investigate the following aims: 1. To evaluate the effect of vitamin D3 therapy on Ca·Ab in postmenopausal women less than or equal to 75 years old with VDI. Sub-aims include the investigation of subject variables influencing Ca·Ab and 25(OH)D levels at baseline and one month, the accuracy of oral isotope plasma levels for Ca·Ab measurement and the ability of a questionnaire to identify patients with low vitamin D status. 2. To evaluate the effects of vitamin D3 therapy on the 12-month change in BMD and bone turnover in the same trial conducted for Aim 1. Sub-aims include the identification of subject variables significantly influencing change in BMD and an evaluation of the relationship between changes in Ca·Ab and changes in BMD. 3. To evaluate the effect of vitamin D therapy on muscle mass and functional capacity in the same trial conducted for Aim 1. We will measure muscle mass by whole body bone densitometry and assess muscle function using the Timed Up and Go (TUG) Test and the modified Stanford Health Assessment Questionnaire (HAQ) score. Sub-aims include the identification of subject variables significantly influencing muscle outcomes.
Interventions
DIETARY_SUPPLEMENTHigh Dose Vitamin D3
Yellow gel-cap vitamin D3 at 50,000 International Units daily for 15 days then two times a month for 350 days. Daily white placebo pills.
DIETARY_SUPPLEMENTLow Dose Vitamin D3
White gel-cap vitamin D3 at 800 International Units to take orally, daily for 365 days. Intermittent yellow placebo pills.
DIETARY_SUPPLEMENTPlacebo
Yellow gel-cap placebo pills to take orally, daily for 15 days then two times a month for 350 days. White gel-cap placebo pills once daily for 365 days.
Sponsors
National Institutes of Health (NIH)
National Institute on Aging (NIA)
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Vitamin D insufficiency, defined as a serum 25(OH)D 16 to 25 ng/mL by high performance liquid chromotography assay * Women ≥ 5 years past the date of last menses or bilateral oophorectomy, or ≥ 60 years old if they had prior hysterectomy without bilateral oophorectomy * Total dietary and supplemental calcium intake \< 600 mg daily but ≤ 1,400 mg daily, based on a food frequency questionnaire
Exclusion criteria
* Women \> 75 years old * Hypercalcemia (serum calcium corrected for albumin \> 10.4 mg/dL) * Nephrolithiasis by medical record or patient report * Inflammatory bowel disease, malabsorption or chronic diarrhea * Stage 3, 4 or 5 Chronic Kidney Disease based on the Modification of Renal Diet (MDRD) formula * Use of bone-active medications within the past 6 months including bisphosphonates, estrogen compounds, calcitonin, teriparatide, oral corticosteroids and anticonvulsants * Allergy or intolerance to orange juice * Allergy or intolerance to sunscreen * Prior adult clinical fragility fracture of the hip, spine or wrist or a T-score below -2.5 at the lumbar spine or femur
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intestinal Calcium Absorption | One Year | Percent of calcium absorbed in the intestinal tract within one day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone Mineral Density | 1 Year | Annualized percent change in bone mineral density at spine, hip, femoral neck, and body |
Other
| Measure | Time frame | Description |
|---|---|---|
| Bone Turnover | 0, 30, 60, 120, 365 days | C-telopeptide (pg/mL) was measured at baseline, 30 days, 60 days, 120 days, 365 days in the subset of subjects who arrived at all study visit fasting since midnight and had phlebotomy prior to 10 am. Data demonstrated outliers and was summarized using the median (25th, 75th interquartile range). |
| Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | 1 Year | We summarized within-arm one-year changes in continuous muscle outcomes using the mean (95% confidence interval). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose Vitamin D Loading Dose: 50,000 International Units vitamin D3 gel-caps (yellow) to take daily for 15 days and placebo gel-caps (white) to take daily for 15 days.
Maintenance Dose: 50,000 International Units vitamin D3 gel-caps (yellow) to take two times a month for 350 days and placebo gel-caps (white) to take daily for 350 days.
High Dose Vitamin D3: Yellow gel-cap vitamin D3 at 50,000 International Units to take orally, daily for 15 days then two times a month for 350 days.
Placebo: White gel-cap placebo pills to take orally, daily for 355 days. | 79 |
| Low Dose Vitamin D Loading Dose: 800 International Units vitamin D3 gel-caps (white) to take daily for 15 days plus placebo gel-caps (yellow) to take daily for 15 days.
Maintenance Dose: 800 International Units vitamin D3 gel-caps (white) to take daily for 350 days plus placebo gel-caps (yellow) to take two times a month for 350 days.
Low Dose Vitamin D3: White gel-cap vitamin D3 at 800 International Units to take orally, daily for 355 days
Placebo: Yellow gel-cap placebo pills to take orally, daily for 15 days then two times a month for 350 days. | 75 |
| Placebo Loading Dose: Placebo gel-caps (yellow) to take daily for 15 days plus placebo gel-caps (white) to take daily for 15 days.
Maintenance Dose: Placebo gel-caps (yellow) to take two times a month for 350 days plus placebo gel-caps (white) to take daily for 350 days.
Placebo: Yellow gel-cap placebo pills to take orally, daily for 15 days then two times a month for 350 days.
Placebo: White gel-cap placebo pills to take orally, daily for 355 days. | 76 |
| Total | 230 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 1 | 3 |
Baseline characteristics
| Characteristic | High Dose Vitamin D | Total | Placebo | Low Dose Vitamin D |
|---|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 5 | 61 years STANDARD_DEVIATION 6 | 61 years STANDARD_DEVIATION 6 | 60 years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 14 Participants | 6 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 73 Participants | 209 Participants | 69 Participants | 67 Participants |
| Region of Enrollment United States | 79 participants | 230 participants | 76 participants | 75 participants |
| Sex: Female, Male Female | 79 Participants | 230 Participants | 76 Participants | 75 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 71 / 79 | 72 / 75 | 69 / 76 |
| serious Total, serious adverse events | 4 / 79 | 7 / 75 | 6 / 76 |
Outcome results
Primary
Intestinal Calcium Absorption
Percent of calcium absorbed in the intestinal tract within one day
Time frame: One Year
Population: 4% of subjects withdrew from the study. Additionally the calcium isotope dose was not recorded in 2 subjects and a urine sample was mishandled in a third. Thus, the number of participants analyzed is less than the number randomized into the trial.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Vitamin D | Intestinal Calcium Absorption | Baseline | 0.200 Total Fractional Calcium Absorption |
| High Dose Vitamin D | Intestinal Calcium Absorption | One Year | 0.206 Total Fractional Calcium Absorption |
| Low Dose Vitamin D | Intestinal Calcium Absorption | Baseline | 0.217 Total Fractional Calcium Absorption |
| Low Dose Vitamin D | Intestinal Calcium Absorption | One Year | 0.172 Total Fractional Calcium Absorption |
| Placebo | Intestinal Calcium Absorption | Baseline | 0.183 Total Fractional Calcium Absorption |
| Placebo | Intestinal Calcium Absorption | One Year | 0.174 Total Fractional Calcium Absorption |
Secondary
Bone Mineral Density
Annualized percent change in bone mineral density at spine, hip, femoral neck, and body
Time frame: 1 Year
Population: Annual changes in bone mineral density were analyzed for subjects who completed the study. 9 subjects (4%) withdrew from the study, all for personal reasons. Thus, number of participants analyzed is 4% less than number of subjects randomized.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| High Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in BMD at Spine | -0.3 Percent Change in Bone Mineral Density |
| High Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Total Hip BMD | -0.2 Percent Change in Bone Mineral Density |
| High Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Femoral Neck BMD | -0.3 Percent Change in Bone Mineral Density |
| High Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Total Body BMD | -0.4 Percent Change in Bone Mineral Density |
| Low Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Total Body BMD | -0.5 Percent Change in Bone Mineral Density |
| Low Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in BMD at Spine | 0.0 Percent Change in Bone Mineral Density |
| Low Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Femoral Neck BMD | -0.9 Percent Change in Bone Mineral Density |
| Low Dose Vitamin D | Bone Mineral Density | Annualized Percent Change in Total Hip BMD | -0.5 Percent Change in Bone Mineral Density |
| Placebo | Bone Mineral Density | Annualized Percent Change in Total Body BMD | -0.5 Percent Change in Bone Mineral Density |
| Placebo | Bone Mineral Density | Annualized Percent Change in Total Hip BMD | -0.9 Percent Change in Bone Mineral Density |
| Placebo | Bone Mineral Density | Annualized Percent Change in Femoral Neck BMD | -0.8 Percent Change in Bone Mineral Density |
| Placebo | Bone Mineral Density | Annualized Percent Change in BMD at Spine | 0.2 Percent Change in Bone Mineral Density |
Other Pre-specified
Bone Turnover
C-telopeptide (pg/mL) was measured at baseline, 30 days, 60 days, 120 days, 365 days in the subset of subjects who arrived at all study visit fasting since midnight and had phlebotomy prior to 10 am. Data demonstrated outliers and was summarized using the median (25th, 75th interquartile range).
Time frame: 0, 30, 60, 120, 365 days
Population: Bone turnover markers were analyzed in duplicate for the subset of subjects who arrived at all study visit fasting since midnight and had phlebotomy prior to 10 am.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 120 days | 1 pg/mL |
| High Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 60 days | 0 pg/mL |
| High Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at Baseline | 81 pg/mL |
| High Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 30 days | 2 pg/mL |
| High Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 365 days | 2 pg/mL |
| Low Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 60 days | -1 pg/mL |
| Low Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at Baseline | 97 pg/mL |
| Low Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 30 days | 1 pg/mL |
| Low Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 120 days | -1 pg/mL |
| Low Dose Vitamin D | Bone Turnover | C-telopeptide (pg/mL) at 365 days | 0 pg/mL |
| Placebo | Bone Turnover | C-telopeptide (pg/mL) at 365 days | 0 pg/mL |
| Placebo | Bone Turnover | C-telopeptide (pg/mL) at 120 days | -2 pg/mL |
| Placebo | Bone Turnover | C-telopeptide (pg/mL) at Baseline | 98 pg/mL |
| Placebo | Bone Turnover | C-telopeptide (pg/mL) at 60 days | -1 pg/mL |
| Placebo | Bone Turnover | C-telopeptide (pg/mL) at 30 days | 0 pg/mL |
Other Pre-specified
Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test
We summarized within-arm one-year changes in continuous muscle outcomes using the mean (95% confidence interval).
Time frame: 1 Year
Population: 4% of subjects withdrew from the study and muscle tests were not conducted in four additional subjects who sustained injury or reported leg pain during a study visit. Thus the number analyzed is less than the number randomized into the trial.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| High Dose Vitamin D | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Timed Up and Go Test (seconds) | -0.38 seconds |
| High Dose Vitamin D | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Five Sit-to-Stand Test (sec) | -1.04 seconds |
| Low Dose Vitamin D | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Timed Up and Go Test (seconds) | -0.44 seconds |
| Low Dose Vitamin D | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Five Sit-to-Stand Test (sec) | -0.98 seconds |
| Placebo | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Timed Up and Go Test (seconds) | -0.35 seconds |
| Placebo | Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test | One Year Change in Five Sit-to-Stand Test (sec) | -0.55 seconds |