This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

It is well-recognized that young women with untreated premature ovarian failure (POF) are at increased risk of osteoporosis and bone fracture. Large, randomized trials have demonstrated that hormone replacement therapy with estrogen/progesterone in postmenopausal women can dramatically improve bone mineral density (BMD) and reduce fracture risk; however, there are little data on the effect of hormone replacement in young women with POF. At present, young women with POF are given either combined hormone replacement treatment or physiologic SSR (pSSR) consisting of combined transdermal estradiol and vaginal progesterone replacement regimens.This open-label, randomized controlled crossover pilot trial was designed to determine whether a regimen of pSSR could improve skeletal health among young women with POF caused by a variety of reasons. A total of 34 patients were randomized to receive a 4-week cycle of either pSSR (transdermal estradiol 100 g daily for week 1 and 150 g for weeks 2-4, with progesterone 200 mg twice daily for weeks 3-4) or standard hormone replacement therapy (sHRT) (oral ethinyl estradiol 30 g and norethisterone 1.5 mg daily for weeks 1-3, followed by 7 "pill-free" days for 12 months). Dual-energy x-ray absorptiometry was used to measure BMD at baseline and after each 12-month treatment period. During the study period, blood samples were collected for hormonal measurements and for markers of bone formation (bone alkaline phosphatase and procollagen type I aminoterminal propeptide) and bone resorption (CrossLaps [cross-linked C-terminal telopeptide of type I collagen]) before and after each washout period, and at 3, 6, and 12 months. Of the 34 women, 18 (mean age 27; range, 19-39 years) completed the study. LH (luteinizing hormone) and FSH (follicle-stimulating hormone) were decreased to a similar extent by both pSSR and sHRT. Treatment with pSSR increased the mean baseline lumbar spine BMD z-score by ϩ0.17 (95% confidence interval: ϩ0.07 to ϩ0.27; P ϭ 0.003), whereas there was no significant increase in response to sHRT (ϩ0.07, with a 95% confidence interval: Ϫ0.03 to ϩ0.18; P ϭ 0.2). During pSSR, the increment in lumbar spine BMD z-score was positively associated with estradiol (r ϭ ϩ0.49; P ϭ 0.04) and inversely associated with FSH (r ϭ Ϫ0.65; P ϭ 0.004). Both bone alkaline phosphatase and procollagen type I amino-terminal propeptide were increased significantly by pSSR ( ANOVA P Ͻ 0.001). In contrast, both of these bone formation markers were decreased by sHRT (P Ͻ 0.01). The bone resorption marker, CrossLaps, was suppressed by both regimens (P Ͻ 0.001). GYNECOLOGYVolume 66, Number 6 OBSTETRICAL AND GYNECOLOGICAL SURVEY

The important reactions that occur to the vitamin D molecule and the important reactions involved in the expression of the final active form of vitamin D are reviewed in a critical manner. After an overview of the metabolism of vitamin D to its active form and to its metabolic degradation products, the molecular understanding of the 1alpha-hydroxylation reaction and the 24-hydroxylation reaction of the vitamin D hormone is presented. Furthermore, the role of vitamin D in maintenance of serum calcium is reviewed at the physiological level and at the molecular level whenever possible. Of particular importance is the regulation of the parathyroid gland by the vitamin D hormone. A third section describes the known molecular events involved in the action of 1alpha,25-dihydroxyvitamin D3 on its target cells. This includes reviewing what is now known concerning the overall mechanism of transcriptional regulation by vitamin D. It describes the vitamin D receptors that have been cloned and identified and describes the coactivators and retinoid X receptors required for the function of vitamin D in its genomic actions. The presence of receptor in previously uncharted target organs of vitamin D action has led to a study of the possible function of vitamin D in these organs. A good example of a new function described for 1alpha,25-dihydroxyvitamin D3 is that found in the parathyroid gland. This is also true for the role of vitamin D hormone in skin, the immune system, a possible role in the pancreas, i.e., in the islet cells, and a possible role in female reproduction. This review also raises the intriguing question of whether vitamin D plays an important role in embryonic development, since vitamin D deficiency does not prohibit development, nor does vitamin D receptor knockout. The final section reviews some interesting analogs of the vitamin D hormone and their possible uses. The review ends with possible ideas with regard to future directions of vitamin D drug design.

Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin.

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The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

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In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.