Dose Response to Vitamin D Supplementation in Postmenopausal Women

Abstract

Vitamin D supplementation is widely recommended in adults, although no interventional trials have established a relationship between supplementation and medical outcomes. No randomized controlled studies have evaluated the relationship between doses of vitamin D and serum 25-(OH)D. Vitamin D insufficiency was defined by the World Health Organization in 2003 as a 25-(OH)D level of 50 nM or less in the presence of adequate calcium intake. This randomized, placebo-controlled clinical trial was designed to establish the dose of vitamin D3 required to increase serum 25-(OH)D levels to 75 nM and normalize serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency. The study estimated the dosage of vitamin D3 that met the recommended dietary allowance (RDA; defined as meeting the needs of 97.5% of the population). The trial was conducted at a medical center in the United States between 2007 and 2008. The study subjects, 163 healthy postmenopausal white women with vitamin D insufficiency, were randomly assigned to receive a once-daily dose of placebo or vitamin D3 (400, 800, 1600, 2400, 3200, 4000, or 4800 IU) and were observed for 1 year. Calcium supplements were administered daily to maintain the total daily calcium intake between 1200 and 1400 mg. Primary outcomes were levels of serum 25-(OH)D and PTH after 6 months and 1 year. The mean baseline 25-(OH)D level in the placebo was estimated to be 39 nM. The dose-response was curvilinear; serum 25-(OH)D increased with higher dosages of vitamin D3 and tended to plateau at approximately 112 nM in subjects receiving more than 3200 IU/d of vitamin D3. The RDA of vitamin D3 needed to obtain a 25-(OH)D level greater than 50 nM was 800 IU/d. A previously described mixed-effects model predicted that 600 IU of vitamin D3 daily would achieve the same response. The serum 25-(OH)D level in obese women (body mass index ≥ 30 kg/m2) was 17.8 nM lower than that in normal-weight women (body mass index < 25 kg/m2). At 12 months, serum PTH levels decreased with increasing vitamin D3 doses (P = 0.012). With respect to the safety of high doses of vitamin D and calcium, depending on the study criteria, 2.8% to 9% of subjects had an episode of hypercalcemia and 12% to 33% had an episode of hypercalciuria; adverse events were unrelated to dose. Because the study was conducted in healthy postmenopausal white women, the findings may not be generalizable to women in other age groups or those with some comorbid conditions. These findings show that the dosage of vitamin D needed to increase serum 25-(OH)D levels to greater than 50 nM in 97.5% of women is 800 IU/d. However, a model from a previous study predicts the same response with a vitamin D3 dosage of 600 IU/d.