Treatment of Vitamin D Insufficiency

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.

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