Osteoporosis is a major health problem in postmenopausal women. At age 50, half of women will suffer an osteoporotic fracture in their remaining lifetime [1], causing increased disability and mortality [1, 2]. Vitamin D deficiency, defined as a serum 25(OH)D <15 ng/mL, contributes to osteoporosis via decreased calcium absorption (CaAb), secondary hyperparathyroidism (HPT), increased bone resorption and decreased bone mineral density (BMD) [3]. Thus, experts agree that patients with vitamin D deficiency should receive vitamin D therapy [4-7]. 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 [8]. Experts disagree on whether to treat VDI, as the clinical benefits of therapy are uncertain. Some experts [8-11] insist the optimal 25(OH)D level is e30 ng/mL. By contrast, both the Food and Nutrition Board [12] and NIH Evidence Report No. 158 [13] 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 e30 ng/mL. Moreover, secondary HPT, the proposed mechanism by which VDI causes bone loss, occurs in only 10% to 33% of people with VDI [14-17]. As such, people with VDI and normal PTH might not experience clinical benefits from vitamin D therapy. VDI is widespread [15, 18, 19], affecting 26% to 39% of postmenopausal American women with [20] and without [21] 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 CaAb, 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 e30 ng/mL [17], is superior in its effects on study outcomes compared to a low-dose vitamin D regimen that can permit continued VDI [22-25].

Public Health Relevance

One in two women past menopause has mildly low vitamin D levels. We don't know if vitamin D therapy helps these women to have stronger bones that break less easily. We also don't know whether high-dose vitamin D therapy is better than low-dose vitamin D, in its effects on calcium absorption, bone calcium levels and muscle function. We will ask 250 women past menopause with mildly low vitamin D levels to take part in a one year study. One third of women will receive placebo, one-third will receive low-dose vitamin D and one-third will receive a high-dose vitamin D tablet that keeps their blood levels above 30 ng/mL. We will compare the changes in calcium CaAb, bone calcium levels and muscle fitness among women receiving placebo, low-dose vitamin D and high- dose vitamin D. This study will help decide whether vitamin D therapy lessens the risk of osteoporosis in postmenopausal women, and at what vitamin D dose those benefits occur.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Hannah, Judy S
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University of Wisconsin Madison
Internal Medicine/Medicine
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Hanseree, Preaw; Staples, Abigail C; Cryns, Vincent L et al. (2017) Hypocalciuria as a Predictor of Reduced Intestinal Calcium Absorption. J Endocr Soc 1:1179-1187
Weiker, Madelyn K; Nielsen, Birgitte; Waclawik, Andrew J et al. (2017) Muscle Cramps Do Not Improve With Correction of Vitamin D Insufficiency. WMJ 116:200-204
Hansen, Karen E; Johnson, Michael G (2016) Proposed Guidelines for Future Vitamin D Studies--Reply. JAMA Intern Med 176:281-2
Hansen, Karen E; Johnson, Michael G (2016) An update on vitamin D for clinicians. Curr Opin Endocrinol Diabetes Obes 23:440-444
Vreede, Andrew P; Jones, Andrea N; Hansen, Karen E (2015) Can serum isotope levels accurately measure intestinal calcium absorption compared to gold-standard methods? Nutr J 14:73
Hansen, Karen E; Johnson, R Erin; Chambers, Kaitlin R et al. (2015) Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med 175:1612-21
Ramsubeik, Karishma; Keuler, Nicholas S; Davis, Lisa A et al. (2014) Factors associated with calcium absorption in postmenopausal women: a post hoc analysis of dual-isotope studies. J Acad Nutr Diet 114:761-7
Hansen, Karen E; Ney, Denise (2014) A systematic review of bone mineral density and fractures in phenylketonuria. J Inherit Metab Dis 37:875-80
Hansen, Karen E; Bartels, Christie M; Gangnon, Ronald E et al. (2014) An evaluation of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol 20:112-4
Hansen, Karen E; Kleker, Brian; Safdar, Nasia et al. (2014) A systematic review and meta-analysis of glucocorticoid-induced osteoporosis in children. Semin Arthritis Rheum 44:47-54

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