Vitamin D Supplementation in Older Women

The prevalence of osteoporosis is high in the United States, with about 10 million people
over the age of 50 already having the disease and another 34 million at risk for developing
it. Development of low-cost and effective strategies is important for preventing
osteoporosis and reducing osteoporotic fractures. A simple inexpensive strategy to prevent
osteoporosis is adequate nutrition with calcium and vitamin D. Serum 25OHD
(25-hydroxyvitamin D) is now accepted as the objective measure of vitamin D nutrition. There
is a growing understanding that serum 25OHD concentrations of at least 30-32 ng/ml are
needed for optimal bone health at which serum parathyroid hormone (PTH) concentrations reach
a minimum.

There are no systematic prospective dose response studies aimed at determining the optimum
amount of vitamin D intake required to maintain optimum serum 25OHD levels in the population
which will help in determining the estimated average requirement (EAR) and recommended
dietary requirement (RDA) for vitamin D. More work to determine the RDA for vitamin D has
been recommended by the Panel on Calcium and Related Nutrients of the Food and Nutrition
Board. This study is aimed at filling the information gap by concentrating on the high risk
group of postmenopausal women. We are testing the theory that increasing serum 25OHD to a
level greater than 30 ng/ml will reduce serum PTH in the high risk group of vitamin D
insufficient postmenopausal women with an adequate intake of calcium. We also believe that
the dose of vitamin D that will achieve this level is approximately 4400IU per day, which is
well above the suggested adequate intake of 400-600 ID recommended for the elderly.

In a one year double blind, randomized prospective clinical trial, we will examine the dose
response effect of supplementation with different doses of vitamin D3 (400, 800, 1600, 2400,
3200, 4000, 4800IU/day) on the primary outcomes of serum 25OHD and PTH in 160 postmenopausal
Caucasian and 160 African American women who have inadequate vitamin D levels in winter. We
expect that the results from this study will add useful and important information about the
RDA for vitamin D for postmenopausal women who are more susceptible to osteoporosis. The
results from this study will also help in designing future clinical trials to study the
effect of vitamin D, for example in preventing fractures, falls, cancer.

The main objective of the current proposal is to study the effect of increasing doses of
vitamin D3 in the high risk group of postmenopausal Caucasian and African American women
with hypovitaminosis D (serum 25OHD <20 ng/ml) in winter in presence of sufficient calcium
intake, in order to determine the Estimated Average Requirement (EAR) that covers 50% and
the Recommended Daily allowance (RDA) covers 97.5% of population for vitamin D. We will use
a serum 25OHD concentration equal >30 ng/ml and normalization of serum PTH as indicators of
adequacy. We expect that the results from this proposal will add important information
helpful in designing future larger clinical trials to determine the recommended dietary
allowance (RDA) for vitamin D in other ethnic groups and designing clinical trials on the
effect of vitamin D on falls and fractures.

We hypothesize that increasing serum 25OHD to a level greater than 30 ng/ml with vitamin D
supplements in 97 percent of the study subjects will reduce serum PTH and bone markers to
premenopausal range. We postulate that the RDA of vitamin D that will achieve a serum 25OHD
of ≥ 30 ng/ml in 97.5% of women during winter is approximately 4400 IU/d and the EAR dose of
vitamin D is between 800-1000 IU.

The specific aims of the proposal are,

1. To examine the dose response effect of vitamin D3, 400, 800, 1600, 2400, 3200, 4000,
and 4800 IU /d in postmenopausal Caucasian and African American women with
hypovitaminosis D (serum 25OHD equal <20 ng/ml) in winter plus an adequate calcium
intake compared to a calcium control group, on serum 25OHD and PTH levels, which
constitute our primary outcome measures.

2. To determine the EAR and RDA for postmenopausal women by establishing the dose of
vitamin D3 that will increase serum 25OHD above 30 ng/ml in 97.5% of study subjects in
winter and reduce serum PTH to the normal premenopausal range.

3. To study the dose response effect of vitamin D3 on calcium absorption,
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) serum calcium, serum bone markers, bone mineral
density (BMD) and falls (only in elderly) (the secondary outcome measures)

4. To establish the long term safety of these doses relating to hypercalcemia and
hypercalciuria

Progress: Caucasian enrollment completed July 2008; African American enrollment completed
May 2009

Inclusion Criteria:

- At least 7 years post-menopause

- Serum 25OHD level 5 ng/ml to 20 ng/ml

- BMI less than or equal to 40 kg/m2

- Willing to discontinue multivitamins that contain vitamin D during the study

Exclusion Criteria:

- Cancer (except basal cell carcinoma) or terminal illness

- Previous hip fracture

- Hemiplegia (paralysis of one side of the body)

- Uncontrolled type I diabetes or fasting blood sugar greater than 140 mg in type II

- Kidney stones more than twice in a lifetime

- Chronic renal failure

- Evidence of chronic liver disease, including alcoholism

- Physical conditions such as severe osteoarthritis, rheumatoid arthritis, heart
failure severe enough to prevent reasonable physical activity

- Previous treatment with bisphosphonates (more that 3 months), PTH or PTH derivatives,
(e.g. Teriparatide or Fluoride) in the last 6 months

- Previous treatment within the last 6 months with calcitonin or estrogen

- Chronic high dose corticosteroid therapy (more than 10 mg per day) for over 6 months
and not within the last 6 months

- Anticonvulsant therapy

- High dose thiazide therapy (more than 37.5 mg)

- 24 hour urine calcium greater than 290 mg on 2 baseline tests

- Serum calcium exceeding upper normal limit on 2 baseline tests

- Bone Mineral Density T-score less than -3.0 for spine or hip