INTRODUCTION

Vitamin D, first identified as a vitamin early in the 20th century, is now recognized as a prohormone. A unique aspect of vitamin D as a nutrient is that it can be synthesized by the human body through the action of sunlight. These dual sources of vitamin D make it challenging to develop dietary reference intake values.

Vitamin D, also known as calciferol, comprises a group of fat-soluble seco-sterols. The two major forms are vitamin D₂ and vitamin D₃. Vitamin D₂ (ergocalciferol) is largely human-made and added to foods, whereas vitamin D₃ (cholecalciferol) is synthesized in the skin of humans from 7-dehydrocholesterol and is also consumed in the diet via the intake of animal-based foods. Both vitamin D₃ and vitamin D₂ are synthesized commercially and found in dietary supplements or fortified foods. The D₂ and D₃ forms differ only in their side chain structure. The differences do not affect metabolism (i.e., activation), and both forms function as prohormones. When activated, the D₂ and D₃ forms have been reported to exhibit identical responses in the body, and the potency related to the ability to cure vitamin D–deficiency rickets is the same (Fieser and Fieser, 1959; Jones et al., 1998; Jurutka et al., 2001). Experimental animal studies have indicated that vitamin D₂ is less toxic than vitamin D₃, but this has not been demonstrated in humans.

The activation steps involved in converting vitamin D from the diet and cutaneous synthesis are illustrated in Figure 3-1. Vitamin D, in either the D₂ or D₃ form, is considered biologically inactive until it undergoes two enzymatic hydroxylation reactions. The first takes place in the liver, mediated by the 25-hydroxylase (most likely cytochrome P450 2R1 [CYP2R1]) which forms 25-hydroxyvitamin D (hereafter referred to as 25OHD). The second reaction takes place in the kidney, mediated by 1α-hydroxylase (CYP27B1), which converts 25OHD to the biologically active hormone, calcitriol (1,25-dihydroxyvitamin D). The 1α-hydroxylase gene is also expressed in several extra-renal tissues, but its contribution to calcitriol formation in these tissues is unknown. 25OHD, the precursor of calcitriol, is the major circulating form of vitamin D; it circulates bound to a specific plasma carrier protein, vitamin D binding protein (DBP). DBP also transports vitamin D and calcitriol.

FIGURE 3-1

Overview of vitamin D synthesis, intake, and activation.

The renal synthesis of calcitriol is tightly regulated by two counter-acting hormones, with up-regulation via parathyroid hormone (PTH) and down-regulation via fibroblast-like growth factor-23 (FGF23) (Galitzer et al., 2008; Bergwitz and Juppner, 2010). Low serum phosphorus levels stimulate calcitriol synthesis, whereas high serum phosphorus levels inhibit it. Following its synthesis in the kidney, calcitriol binds to DBP to be transported to target organs. The biological actions of calcitriol, involve regulation of gene expression at the transcriptional level, and are mediated through binding to a vitamin D receptor (VDR), located primarily in the nuclei of target cells (Jones et al., 1998; Jurutka et al., 2001). Additional hydroxylation reactions, such as that mediated by CYP24A1, as shown in Figure 3-1, result in more polar metabolites with greatly reduced or no apparent biological activity.

The classical actions of vitamin D—which by itself is inactive—are due to the functions of the active metabolite, calcitriol. These actions take the form of the regulation of serum calcium and phosphate homeostasis and, in turn, the development and maintenance of bone health (DeLuca, 1988; Reichel et al., 1989; Jones et al., 1998). Non-classical functions are less well elucidated. VDRs are found fairly ubiquitously throughout the body in tissues not involved with calcium and phosphate homeostasis, and the presence of VDRs in these tissues implies that calcitriol may play a more general role or that ligands other than calcitriol can activate the VDR. Furthermore, the specific vitamin D–responsive elements (VDREs), considered the hallmark of vitamin D action, are present in a large number of human genes involved in a wide range of classical and non-classical roles, such as the regulation of cell proliferation, cell differentiation, and apoptosis. It has been suggested that calcitriol exerts immunomodulatory and anti-proliferative effects through autocrine and paracrine pathways (Adams and Hewison, 2008). These wide-ranging actions of calcitriol have further been hypothesized to play a potential role in preventive or therapeutic action in cancer (Masuda and Jones, 2006) and chronic conditions such as auto-immune conditions (including type 1 diabetes), cardiovascular disease, and infections (Holick et al., 2007).

Outside of the biological forms of vitamin D, a number of analogues based on the vitamin D structure have been synthesized for use as potential pharmacological agents. These are not, however, dietary or biosynthesized compounds; rather, they are designed for specific applications in research or clinical treatment. Examples of synthetic analogues that have gained importance in clinical medicine are briefly mentioned below.

The term vitamin D is generally used in this report to refer to both the D₂ and D₃ forms as well as their metabolites, although the two forms are distinguished when necessary for clarification (see Box 3-1 for definitions). Vitamin D levels in the diet—from foods and supplements—are expressed in International Units (IU), but may be expressed elsewhere in micrograms (μg). The biological activity of 1 μg of vitamin D is equivalent to 40 IU. Owing to the frequency with which serum 25OHD levels are included in this report text, the levels are expressed only as nanomoles per liter (nmol/L). As shown in Box 3-1, the nanomoles per liter measure can be converted to nanograms per milliliter (ng/mL) by dividing by a factor of 2.5.

BOX 3-1

Terms and Conversions Used in Reference to Vitamin D. Vitamin D—also referred to as calciferol Vitamin D₂—also referred to as ergocalciferol

SOURCES OF VITAMIN D

Synthesis in the Skin

Vitamin D₃ is synthesized in human skin from 7-dehydrocholesterol following exposure to ultraviolet B (UVB) radiation with wavelength 290 to 320 nm.⁵ The process of UVB-mediated conversion of 7-dehydrocholesterol to the previtamin D₃ form and subsequent thermal isomerization to vitamin D₃ occurring in the epidermis is illustrated in Figure 3-2.

FIGURE 3-2

Photochemical events that lead to the production and regulation of vitamin D₃ (cholecalciferol) in the skin. NOTE: DBP = vitamin D binding protein. SOURCE: Holick (1994). Reprinted with permission from the American Journal of Clinical Nutrition (1994, (more...)

The production of vitamin D₃ in skin is a function of the amount of UVB radiation reaching the dermis as well as the availability of 7-dehydrocholesterol (Holick, 1995). As such, the level of synthesis is influenced by a number of factors, as described below in the section entitled “Measures Associated with Vitamin D: Serum 25OHD,” including season of the year, skin pigmentation, latitude, use of sunscreen, clothing, and amount of skin exposed. Age is also a factor, in that synthesis of vitamin D declines with increasing age, due in part to a fall in 7-dehydrocholesterol levels and due in part to alterations in skin morphology (MacLaughlin and Holick, 1985).

Toxic levels of vitamin D do not occur from prolonged sun exposure. Thermal activation of previtamin D₃ in the skin gives rise to multiple non–vitamin D forms, such as lumisterol, tachysterol and others (Holick et al., 1981; Webb et al., 1989), as illustrated in Figure 3-2; this limits the formation of vitamin D₃ itself. Vitamin D₃ can also be converted to nonactive forms.

The absolute percentage of circulating 25OHD that arises from cutaneous synthesis versus oral intake of vitamin D in the free-living North American population cannot be clearly specified. Individuals living at Earth's poles during winter months and submariner crew members with very limited or no measurable UVB exposure have detectable levels of 25OHD in blood, arising from dietary sources and likely from previously synthesized and stored vitamin D. This topic is further explored in the section below that focuses on serum 25OHD.

METABOLISM OF VITAMIN D

Metabolism to the Active Hormonal Form

Vitamin D, regardless of origin, is an inactive prohormone and must first be metabolized to its hormonal form before it can function. Once vitamin D enters the circulation from the skin or from the lymph, it is cleared by the liver or storage tissues within a few hours. The processes that follow are illustrated in Figure 3-3. Vitamin D is converted in the liver to 25OHD, a process carried out by a CYP enzyme that has yet to be fully defined but is likely CYP2R1 (Cheng et al., 2003). The crystal structure of CYP2R1 has been determined with vitamin D in the active site, and the enzyme has been shown to metabolize both vitamin D₂ and vitamin D₃ equally efficiently (Strushkevich et al., 2008). There is little, if any, feedback regulation of this enzyme. A large genome-wide association study of factors that might be determinants of the circulating 25OHD levels identified the human chromosomal 11p15 locus of CYP2R1 as a significant determinant, whereas the loci of the other enzymes purported to have 25-hydroxylase activity (e.g., CYP27A1 and CYP3A4) were not identified (Wang et al., 2010). The other determinants of serum 25OHD besides CYP2R1 have been reported to be DBP (also known as Gc protein), which has six common phenotypes (Laing and Cooke, 2005) as well as 7-dehydrocholesterol reductase and CYP24A1. Increasing intake of vitamin D results in higher blood levels of 25OHD, although perhaps not in a linear manner (Stamp et al., 1977; Clements et al., 1987).

FIGURE 3-3

The metabolism of vitamin D₃ from synthesis/intake to formation of metabolites. The process is the same for vitamin D₂ once it enters the circulation. NOTE: CYP = cytochrome P450 (a large and diverse group of enzymes).

At this point, 25OHD bound to DBP circulates in the blood stream and, when calcitriol is required due to a lack of calcium (or lack of phosphate), 25OHD is 1α-hydroxylated in the kidney to form calcitriol, the active form, by the 1α-hydroxylase enzyme (also known as CYP27B1) (Tanaka and DeLuca, 1983). This metabolic step is very tightly regulated by blood calcium and phosphate levels through PTH and the phosphaturic hormone, FGF23, and constitutes the basis of the vitamin D endocrine system that is central to maintaining calcium and phosphate homeostasis (see discussion below on functions and physiological actions). FGF23 acts by reducing the expression of renal sodium–phosphate transporters and reducing serum calcitriol levels.

Production of the CYP27B1 enzyme is stimulated by PTH, which is secreted in response to a lack of calcium. It is also stimulated by the hypophosphatemic action of FGF23 on renal phosphate excretion, but to a lesser extent. When PTH is suppressed, or FGF23, produced by osteocytes, is stimulated, 1α-hydroxylation is markedly reduced (Liu et al., 2007; Quarles, 2008). Furthermore, calcitriol can act as a suppressor of CYP27B1, although the mechanism is not fully understood.

Calcitriol has its strongest metabolic activity in inducing its own destruction by stimulating the 24-hydroxylase enzyme (now known as CYP24A1; Figure 3-1) (Jones et al., 1998). The enzyme CYP24A1 is found in all target tissues and is induced in response to calcitriol interacting with the VDR. CYP24A1 is largely responsible for the metabolic degradation of calcitriol and its precursor, 25OHD, and its deletion in the mouse results in 50 percent lethality at weaning and an inability to efficiently clear the active form of vitamin D (Masuda et al., 2005). CYP24A1 carries out a series of reactions resulting ultimately in production of calcitroic acid from calcitriol and 1-desoxycalcitroic acid from 24,25(OH)₂D, the major metabolite of 25OHD. These products are excreted through the bile into the feces (Jones et al., 1998); very little is eliminated through the urine (Kumar et al., 1976). The active forms of vitamin D₂ are also catabolized by CYP24A1 into a series of biliary metabolites, somewhat analogous to those of vitamin D₃.

As described above, all naturally occurring vitamin D compounds interact with DBP. Calcitriol and vitamin D have significantly lower affinity for this protein than does 25OHD. Whereas vitamin D has an average lifetime in the body of approximately 2 months, 25OHD has a lifetime of 15 days, and calcitriol has a lifetime measured in hours (Jones et al., 1998). Aside from these key elements in vitamin D metabolism, more than 30 other metabolites have been found, including the 3-epi series of vitamin D compounds (DeLuca and Schnoes, 1983; Siu-Caldera et al., 1999). Their importance seems minimal and need not be discussed here.

Although the route of catabolism between 1α,25(OH)₂D₂ and 1α,25(OH)₂D₃ differs beyond the initial 24-hydroxylation step, because 24-hydroxylation is primarily a deactivation step (Brommage and DeLuca, 1985; Horst et al., 1986; Lohnes and Jones, 1992; Jones et al., 1998), the rate of this initial step should be the important indicator of the loss of biological action. Comparisons of initial rate kinetics of the 24-hydroxylase enzyme (CYP24A1) activity toward 1α,25(OH)₂D₂ and 1α,25(OH)₂D₃ and their precursors suggest that the rates of inactivation by CYP24A1 in vitro are virtually identical (Jones et al., 2009; Urushino et al., 2009). Although side-chain hydroxylation of 1α,25(OH)₂D₂ represents the primary route of metabolism in the target cell, clearance of the metabolic products in vivo is complicated by additional non-specific liver CYPs (e.g., CYP3A4) (Gupta et al., 2004, 2005) that are inducible by 1α,25(OH)₂D₃ in certain extra-hepatic tissues (Thompson et al., 2002) and also Phase II enzymes, including uridine diphosphate-glucuronosyl transferases, which are known to subject vitamin D metabolites to glucuronidation (LeVan et al., 1981; Hashizume et al., 2008). The pharmacokinetic consequence of the sum of these catabolic systems, as shown in studies in rats, is a slightly reduced half-life for 1α,25(OH)₂D₂ compared with 1α,25(OH)₂D₃ (Knutson et al., 1997).

There are reports that vitamin D₂ and vitamin D₃ are differentially susceptible to these non-specific inactivating modifications, such as those occurring in the liver in response to a variety of drugs. These enzymes include the liver and intestinal CYPs that are known to metabolize vitamin D compounds differently, such as CYP27A1, which 25-hydroxylates vitamin D₃ and 24-hydroxylates vitamin D₂ (Guo et al., 1993), and CYP3A4, which 24- and 25-hydroxylates vitamin D₂ substrates more efficiently than vitamin D₃ substrates (Gupta et al., 2004, 2005) and 23R- and 24S-hydroxylates 1α,25(OH)₂D₃ (Xu et al., 2006); the latter enzyme has recently been shown to be selectively induced by 1α,25(OH)₂D in the intestine (Thompson et al., 2002; Xu et al., 2006). Both CYP27A1 and CYP3A4 are known to have significantly lower Michaelis-Menten constants (K_m values) for 25OHD₃ compared with CYP2R1 (Guo et al., 1993; Sawada et al., 2000), in the micromole per liter range; this questions their physiological but not their pharmacological relevance. Recent work (Helvig et al., 2008; Jones et al., 2009) has shown that both human intestinal microsomes and recombinant CYP3A4 protein break down 1α,25(OH)₂D₂ at a significantly faster rate than 1α,25(OH)₂D₃, suggesting that this non-specific CYP might limit vitamin D₂ action preferentially in target cells, where it is expressed and when the substrate is in the pharmacological dose range. The same type of mechanism involving differential induction of non-specific CYPs may underlie the occasional reports of co-administered drug classes, such as anti-convulsants (Christiansen et al., 1975; Tjellesen et al., 1985; Hosseinpour et al., 2007), causing accelerated degradation of one vitamin D form over the other.

FUNCTIONS AND PHYSIOLOGICAL ACTIONS OF VITAMIN D

VITAMIN D ACROSS THE LIFE CYCLE

Overall, vitamin D's role at different life stages is less clearly age-related than that of calcium, and also less well understood, with numerous gaps in basic information. Although some aspects of vitamin D nutrition and physiology have been found to differ with life stage, most of the functions of vitamin D are quite consistent across life stages from infancy and childhood, to adolescence, adulthood, and old age. For all life stages highlighted below, specific studies and conclusions are detailed in Chapter 4.

MEASURES ASSOCIATED WITH VITAMIN D: SERUM 25OHD

Serum 25OHD level is widely considered as a marker of vitamin D nutriture, and consideration of serum 25OHD measures for the purposes of nutrient reference value development has generated notable interest. There is agreement that circulating serum 25OHD levels are currently the best available indicator of the net incoming contributions from cutaneous synthesis and total intake (foods and supplements) (Davis et al., 2007; Brannon et al., 2008; Davis, 2008). Thus, the serum 25OHD level may function as a biomarker of exposure; it is a reflection of the supply of vitamin D to the body and can be a useful adjunct to examining the intake level of vitamin D if the confounders and the measure's variability depending upon a range of variables are kept in mind. However, what is not clearly established is the extent to which 25OHD levels serve as a biomarker of effect. That is, there is some question as to whether levels of 25OHD relate to health outcomes via a causal pathway and can serve as predictors of such outcomes.

Research recommendations in the previous Dietary Reference Intake (DRI) review of vitamin D (IOM, 1997), as well as an Institute of Medicine (IOM) workshop on DRI research needs (IOM, 2007), called for studies to evaluate the intake requirements for vitamin D as related to optimal circulating 25OHD concentrations across life stage and race/ethnicity groups of U.S. and Canadian populations, taking into account variability in UVB radiation exposures. The issue of the role of serum 25OHD concentrations was also identified by the sponsors of this current study on vitamin D and calcium DRIs as central to the development of DRIs for vitamin D (Yetley et al., 2009). Much in the way of this information gap for serum 25OHD concentrations has not yet been addressed. Nonetheless, measures of serum 25OHD are important considerations in developing DRI values for vitamin D intake. The sections below highlight factors affecting serum 25OHD level and methodologies for its measurement. It is important to note that these discussions refer to 25OHD, not to calcitriol (i.e., 1,25-dihydroxyvitamin D). Calcitriol, the active hormonal form of the nutrient, has not been used typically as a measure associated with vitamin D nutriture or as an intermediate related to health outcomes. Calcitriol is not useful as such a measure, for several reasons. Its half-life is short (hours), its formation is not directly regulated by vitamin D intake, its levels are regulated by other factors (such as serum PTH), and, even in the presence of severe vitamin D deficiency the calcitriol level may be normal or even elevated as a result of up-regulation of the 1α-hydroxylase enzyme.

Factors Affecting Serum 25OHD Levels

Dietary Intake (Foods and Supplements)

Available literature demonstrates that serum 25OHD levels increase in response to increased vitamin D intake, although overall it can be concluded that the relationship is non-linear rather than linear. Factors that may affect the relationship between vitamin D intake and serum 25OHD levels are not entirely clear, and the reliability of such measures may be less than desirable. Moreover, there remains debate over the equivalence of vitamins D₂ and D₃ in the diet (Armas et al., 2004; Rapuri et al., 2004; Vieth, 2004), although it has been assumed that they are 25-hydroxylated at similar rates (see previous discussion of functions and physiological actions of vitamin D).

As part of the 2007 Agency for Healthcare Research and Quality (AHRQ) systematic review (Cranney et al., 2007, 2008), referred to hereafter as AHRQ-Ottawa, exploratory meta-regression analysis was conducted of 16 trials in adults, which suggested an association between vitamin D dose and serum 25OHD concentrations. The analysis found that for each additional 100 IU of vitamin D₃, serum 25OHD concentrations rose by 1 to 2 nmol/L. Trials varied in their use of vitamin D₂ or vitamin D₃. A few of the studies reported different effects of vitamin D₂ and vitamin D₃ on serum 25OHD levels. Although the later AHRQ-Tufts analysis (Chung et al., 2009) did not identify newer (compared with AHRQ-Ottawa) randomized controlled trials related to intake of vitamin D and serum 25OHD levels, it did graphically evaluate the net changes in serum 25OHD concentrations against the doses of vitamin D supplementation using data from the trials in adults. The analysis confirmed the relationship between increasing doses of vitamin D and increasing net change in serum 25OHD concentrations in both adults and children, but it also concluded that the dose–response relationships differ depending upon study participants' baseline serum 25OHD levels (≤ 40 vs. > 40 nmol/L) and duration of the supplementation (≤ 3 vs. > 3 months).

In a recent study conducted by Smith et al. (2009), personnel stationed in the Antarctic in winter months (and thus presumed to obtain vitamin D from food and supplements only) were given graded doses of 400, 1,000, or 2,000 IU of vitamin D₃ per day for 5 months. Baseline levels of serum 25OHD rose from approximately 44 nmol/L to 57, 63, and 71 nmol/L, respectively, representing a change in 25OHD levels of 13, 19, or 27 nmol/L. Evident in this study is the continuing fall in 25OHD level in the “no pill” group (to 34 nmol/L) of men who were deprived of sunlight and received approximately 250 to 350 IU of vitamin D (which included foods and any non-study supplements) per day. A possible complicating factor in interpreting these data is that the subjects were consuming diets with a vitamin D content that ranged from 241 to 356 IU/day, in addition to the graded doses of vitamin D from administered supplements, although the amounts of vitamin D obtained from foods (or non-study supplements) were not significantly different between treatment groups. Therefore, any effect of these sources of vitamin D on serum levels would have been consistent between treatment groups.

Another study of serum 25OHD response to total intake under conditions of minimal sun exposure used two populations based in Cork, Ireland (51°N), and Coleraine, Northern Ireland (55°N). The study estimated the dose of vitamin D required to maintain 25OHD levels above certain chosen cutoff values (i.e., 25.0, 37.5, 50.0, and 80.0 nmol/L) during the winter months (Cashman et al., 2008). The researchers found that serum 25OHD levels that ranged between 65.7 and 75.9 nmol/L in late fall fell in all groups receiving 200, 400, and 600 IU of vitamin D₃ per day, as well as in the placebo group, in winter. The decrease in the 600 IU/day group was minimal, from 75.9 to 69.0 nmol/L. Cashman et al. (2008) went on to plot the serum 25OHD levels attained after 5 months versus the estimated total vitamin D intake (approximately 0 to 1,400 IU/day) in 215 individuals, as shown in Figure 3-4. They concluded that, in these two populations at 51°N and 55°N, the wintertime intake required to achieve 25OHD cutoff levels of 37.5, 50.0, and 80.0 nmol/L were 796, 1,120, and 1,644 IU/day, respectively.

FIGURE 3-4

The relationship between serum 25-hydroxyvitamin D concentrations (in late winter 2007) and total vitamin D intake (dietary and supplemental) in 20- to 40-year-old healthy persons (n = 215) living at northern latitudes (51°N and 55°N). (more...)

Importantly, the relationship between vitamin D intake and serum 25OHD response appears not to be linear, given evidence that increasing serum 25OHD level above 50 nmol/L requires more vitamin D intake than does increasing serum 25OHD levels when the starting point is less than 50 nmol/L (Aloia et al., 2008). Factors such as baseline serum 25OHD level in the population may be relevant. Further, there have been reports that the rise in serum 25OHD levels for a given dose tends to stabilize by week 6 (Harris and Dawson-Hughes, 2002; Holick et al., 2008) and that it does not vary with age at least up to 80 years of age (Harris and Dawson-Hughes, 2002; Cashman et al., 2008, 2009).

Sun Exposure

The cutaneous synthesis of vitamin D, and in turn its contribution to the concentration of serum 25OHD, is initially dependent upon the presence of 7-dehydrocholesterol in the skin. However, many variables can affect the cutaneous synthesis of vitamin D, making it difficult to estimate an average amount of vitamin D and, in turn, serum 25OHD levels that are produced by sun exposure in North America. There is, however, agreement that sun exposure is a significant source of the circulating serum 25OHD in summer for many North Americans, and is notably reduced as a contributor in the winter months. Early work from Webb et al. (1988, 1989) as well as a letter from Holick et al. (1989) have outlined the role of sunlight in regulating cutaneous synthesis of the vitamin and have implicated factors in vitamin D₃ synthesis in the skin to include aging, melanin pigmentation, season of the year, latitude, and use of sunscreen. Matsuoka et al. (1992) has discussed the role of clothing in preventing synthesis.

The 2007 AHRQ-Ottawa systematic review (Cranney et al., 2007) noted that the few available randomized clinical trials conducted between 1982 and the time of the analysis, which focused on the effect of UVB radiation on serum 25OHD level revealed little information about the impact of age, ethnicity, skin pigmentation, BMI, or latitude on serum 25OHD levels. However, UVB exposure increased serum 25OHD levels in vitamin D–deficient and –sufficient subjects with mean increases ranging from 15 to 42 nmol/L.

The difference in seasonal contributions to serum 25OHD level from sun exposure is discussed first. Next, factors affecting the synthesis of vitamin D—and, in turn, the levels of 25OHD in serum—are outlined.

Effect of season on circulating serum 25OHD level Sunlight exposure as a source of cutaneous synthesis of vitamin D is subject to a number of limitations. For example, excess exposure can lead to photo-degradation as a regulatory mechanism to avoid toxicity (Chen et al., 2007). In addition, latitude, time of exposure, and season all affect cutaneous synthesis, depending on the ability of UV rays to stimulate vitamin D production. Differences in seasonal exposure can vary by as much as 6 months at extreme northern and southern latitudes (Lucas et al., 2005; Kull et al., 2009).

A number of studies have examined serum 25OHD levels in different seasons. Van der Mei et al. (2007) compared cross-sectional data from men and women less than 60 years of age living in Australia and concluded that season was a strong determinant of serum 25OHD concentrations. Berry et al. (2009) examined white adults ages 20 to 60 years living in the United Kingdom (UK) at latitude 53°N. In this study, women were found to have higher average serum 25OHD levels than men in both summer and winter (9 and 20 percent higher, respectively). In a study of young adults of diverse ethnic backgrounds living in Toronto, Gozdik et al. (2009) found that in winter, serum 25OHD levels of individuals with East and South Asian backgrounds were significantly lower than those of individuals with European ancestry. Kull et al. (2009) measured seasonal variance of 25OHD levels in adults ages 25 to 70 years living in Estonia in northern Europe, where dairy products are not fortified with vitamin D. During the winter, 73 percent of the study population had 25OHD levels that were below 50 nmol/L, and 8 percent had levels that were below 25 nmol/L, compared with 29 percent and 1 percent, respectively, during the summer. Rapuri et al. (2002) examined white, black, and Hispanic women 65 to 77 years of age in Omaha and reported mean serum 25OHD levels of 68 nmol/L in February and 86 nmol/L in August. These studies, despite variations in age, gender, and ethnicity, all suggest that seasonal change can affect cutaneous vitamin D synthesis. The winter low serum 25OHD concentrations and the summer high serum 25OHD concentrations from these studies are summarized in Table 3-1.

TABLE 3-1

Winter Low 25OHD Levels and Summer High 25OHD Levels Around the World.

Although there are variations in the available data as well as a number of unknowns that may influence such values, they suggest a seasonal change in serum 25OHD concentrations between the winter nadir and the summer zenith of approximately 25 nmol/L. Free-living individuals in the latitudes studied appear to experience an approximately one-third seasonal increase in their circulating serum 25OHD levels as they moved from the winter months to the summer months.

The 25 nmol/L change in serum 25OHD level would appear to be similar in magnitude to change experienced by subjects given 2,000 IU/day in the Antarctic study (Smith et al., 2009). Although these data suggest that average cutaneous synthesis during the summer in northern latitudes equates to 2,000 IU/day, this may be a questionable conclusion given the many variables that come into play, ranging from feedback mechanisms to skin pigmentation to baseline levels of 25OHD. For example, recent work from Olds et al. (2008) suggested a curvilinear relationship between sun exposure and serum 25OHD levels, as well as variation depending upon initial concentrations of 7-dehydrocholesterol levels. At lower doses, vitamin D₃ production rises immediately in response to UV exposure, whereas at higher doses, the rate of production is lower and reaches an earlier plateau.

Effect of skin pigmentation on synthesis The presence of melanin in the epidermal layer is responsible for skin pigmentation. A number of recent studies have reinforced the relationship of skin pigmentation to the capacity to produce vitamin D₃ after UV exposure, but the results are not all consistent. Armas et al. (2007) studied the incremental change in serum 25OHD levels in individuals with average 25OHD baseline levels of 52 nmol/L and with different skin pigmentation who were exposed to different daily doses of 20 to 80 mJ/cm² of UVB light three times per week for 4 weeks on 90 percent of their skin surface area. The work suggested that for individuals at the lighter pigmentation scale,⁷ exposed to similar UVB doses (20 to 80 mJ/cm²) resulted in twice the increase in serum 25OHD concentration compared with individuals at the opposite extreme (i.e., 62 vs. 32 nmol/L change) (Armas et al., 2007) (see modeled representation in Figure 3-5). However, other studies have shown that the response to UV dose is non-linear and dependent on genetic factors (Snellman et al., 2009), duration and dose rate of UV exposure, and baseline serum 25OHD levels (Bogh et al., 2010).

FIGURE 3-5

Three-dimensional scatter-plot of 4-week change in serum 25OHD concentration above baseline expressed as a function of both basic skin lightness (L*) and UVB dose rate. Surface is hyperboloid, plotting equation 1, and was fitted to data using least squares (more...)

Another population study of 237 subjects at a single geographical location (Toronto, 43°N) also explored the effect of skin pigmentation on 25OHD synthesis (Gozdik et al., 2009). The mean serum 25OHD levels in Canadians of European, East Asian, and South Asian ancestry were 71.7, 44.6, and 33.9 nmol/L, respectively, in late fall; and 51.6, 28.1, and 26.5 nmol/L, respectively, in the winter. The authors found that differences between the three subgroups were strongly associated with skin pigmentation as well as amount of time spent outdoors and total vitamin D intake. A recent study of 182 individuals in Denmark, screened in January and February and selected to reflect wide ranges of baseline 25OHD levels and skin pigmentation, found that the increase in 25OHD levels after UVB exposure was inversely correlated with skin pigmentation as well as with baseline 25OHD (Bogh et al., 2010).

A number of small studies have reported serum 25OHD levels to be consistently lower in persons with darker skin pigmentation, and data from NHANES suggest that serum 25OHD levels are highest in whites, lowest in non-Hispanic blacks, and intermediate in Hispanic groups (Looker et al., 2008). Overall, there is considerable evidence that darker skin pigmentation is associated with a smaller increase in serum 25OHD concentration for a given amount of UVB exposure.

Effect of latitude on synthesis Early on, in vitro methods, such as exposure of sealed vials of 7-dehydrocholesterol to UVB radiation under “idealized conditions” at various geographical locations, were used to assess the effect of latitude, time of day, and season on the rate of vitamin D production (Webb et al., 1988). However, this approach cannot completely simulate the in vivo conditions in the body, where many factors serve to regulate this process. Furthermore, although the measurement of vitamin D concentrations in a mixture of irradiation products is analytically simple, vitamin D₃ levels in human serum are rarely used to estimate cutaneous synthesis of the vitamin, in part because of the transient nature of this blood parameter and the difficulty of measuring the low levels in serum (Holick, 1988; Hollis, 2008). Nevertheless, Holick and colleagues used a serum vitamin D₃ assay to augment in vitro methodology and suggested that, at latitudes above 43°N, cutaneous synthesis contributes little serum 25OHD to the system in the winter months between October and March in North America (Webb et al., 1988; Matsuoka et al., 1989).

More recent data may call into question current assumptions about the effect of latitude. In fact, Kimlin et al. (2007), using computer modeling, concluded that it may no longer be correct to assume that vitamin D levels in populations follow latitude gradients. Indeed, the relationship between UVB penetration and latitude is complex, as a result of differences in, for example, the height of the atmosphere (50 percent less at the poles), cloud cover (more intense at the equator than at the poles), and ozone cover. The duration of sunlight in summer versus winter is another factor contributing to the complexity of the relationship. Geophysical surveys have shown that UVB penetration over 24 hours, during the summer months at Canadian north latitudes when there are many hours of sunlight, equals or exceeds UVB penetration at the equator (Lubin et al., 1998). Consequently, there is ample opportunity during the spring, summer, and fall months in the far north for humans (as well as animals that serve as food sources) to form vitamin D₃ and store it in liver and fat. These factors may explain why latitude alone does not consistently predict the average serum 25OHD level of a population.

Effect of sunscreen on synthesis Sunscreens are used to protect the skin from ultraviolet A (UVA) and UVB waveband exposure that is associated with deoxyribonucleic acid (DNA) damage—the same UVB exposure that is needed for vitamin D synthesis. Experimental studies suggest that sunscreens can decrease cutaneous vitamin D synthesis (Misra et al., 2008). However, emerging evidence suggests that although sunscreens are effective, many may not actually be blocking UVB because they are improperly or inadequately applied. Thus, sunscreen use may not actually diminish vitamin D synthesis in real world use, although further study is needed to verify its actual impact (Diehl and Chiu, 2010; Springbett et al., 2010).

Other variables affecting synthesis A number of other variables can impede sun exposure and thus inhibit cutaneous vitamin D synthesis. Clothing is an effective barrier to sun exposure and the UVB waveband, but the effectiveness of sun blocking depends on the thickness or weave of the fabric (Diehl and Chiu, 2010). Likewise, ethnic practices, such as extensive skin coverage with clothing, urban environments that reduce or block sunlight, air pollution, and cloud cover that reduces solar penetration can variously reduce sun exposure. In contrast, high altitude reduces the atmospheric protection against UVB waveband and can increase risk for sun damage as well as increase vitamin D synthesis (Misra et al., 2008). There may be a role for measures of physical activity in affecting vitamin D synthesis, although many covariates may be relevant, and some have suggested that genetics can account for some of the differences in synthesis of serum 25OHD.

Confounders Affecting Serum 25OHD Concentrations

Adiposity Interpreting data on serum 25OHD concentrations in obese and overweight persons is particularly challenging. Data from NHANES showed lower circulating levels of 25OHD among young adult obese non-Hispanic white women compared with their leaner counterparts; the relationship appeared to be weaker among non-Hispanic blacks. Differences in physical activity levels partially explain these differences (Looker, 2005, 2007). However, overweight and obese persons in NHANES also reported lower use of dietary supplements than did leaner persons of the same age or gender group (Radimer et al., 2004; Picciano et al., 2007), suggesting that lower dietary exposures could also contribute to the lower serum 25OHD levels in obese and overweight people.

Sequestration of vitamin D into fat likely also plays a significant role in reducing the amount that can be presented to the liver for 25-hydroxylation. As noted previously, vitamin D is absorbed with fat as part of chylomicrons and is taken up first by peripheral tissues that express lipoprotein lipase, especially adipose tissue and skeletal muscle. This pathway predicts that increased adiposity should lead to lower serum 25OHD levels and, conversely, that weight loss should reduce peripheral sequestration and enable higher 25OHD levels. Consistent with this, not only does increasing adiposity correlate with lower 25OHD levels, but also a few studies of modest weight loss have found the circulating 25OHD levels to increase despite no increased intake of vitamin D from diet or sunlight exposure (Riedt et al., 2005; Reinehr et al., 2007; Zittermann et al., 2009; Tzotzas et al., 2010). The measured increase in serum 25OHD levels in overweight and obese individuals was about 1.5 nmol/L for a 100 IU/day vitamin D intake over 12 months (Sneve et al., 2008; Zittermann et al., 2009). Others found that obese subjects show a lower rise in serum 25OHD levels in response to both oral vitamin D intake and UVB exposure (Wortsman et al., 2000) or in a retrospective analysis in response to 700 IU/day vitamin D₃ supplementation (Blum et al., 2008). It is interesting that in severely obese individuals after malabsorptive gastric bypass surgery, vitamin D supplementation resulted in a marked rise in serum 25OHD level of approximately 3 nmol/100 IU intake when the dose was 800 to 2,000 IU/day, but only a 1 nmol/L rise when intake was increased to 5,000 IU/day (Goldner et al., 2009).

African American ancestry Serum 25OHD levels are lower in African Americans compared with light-skinned population groups (Looker et al., 2008), yet the risk for fracture is lower for African Americans than for other ethnic groups (Aloia, 2008). It should be noted, however, that there is a wide range of variability among individuals of any race or ethnicity (Aloia, 2008). Serum 25OHD levels in African Americans and whites have been shown to be similarly responsive to vitamin D supplementation at 40°N latitude (equivalent to Philadelphia or Indianapolis), increasing by 1 to 2 nmol/L per 100 IU/day at a dose of 3,440 IU/day (Aloia et al., 2008), although at doses below 2,000 IU/day, serum 25OHD levels do not increase above 50 nmol/L in African American girls (Talwar et al., 2007). The significance of maintaining a higher serum 25OHD level in African Americans is not understood at this time because of a lack of evidence on extra-skeletal effects of vitamin D.

Size and frequency of dose Dosing of vitamin D daily, weekly, or monthly has been tested, and there are reports of annual dosing as well. The results of a study by Chel et al. (2008) suggested that daily (600 IU/day) and weekly doses of vitamin D will increase serum 25OHD levels more than monthly doses, but Ish-Shalom et al. (2008) using a dose of 1,500 IU/day found no difference due to timing of the doses. Ish-Shalom et al. (2008) suggested that the attenuated response to monthly dose in the Chel et al. (2008) study may have been due to poor compliance with a powdered monthly supplement compared with pills used for their daily and weekly doses. An alternative explanation is that only a lower (Chel et al., 2008) and not a higher (Ish-Shalom et al., 2008) dose is influenced by timing of the vitamin D supplement. Thus far, studies suggest that weekly and daily dosing give similar serum 25OHD responses.

MEASURES ASSOCIATED WITH VITAMIN D: PARATHYROID HORMONE

PTH, which, as described above, plays a role in vitamin D metabolism, is also a known marker for bone resorption, based upon the bone manifestations of secondary hyperparathyroidism—increased bone turnover, increased rates of bone loss, osteoporosis, and increased risk of fractures. Serum PTH level has thus been explored and suggested as a measure indicative of adequate vitamin D nutriture, notably on the basis of the level of serum 25OHD at which serum PTH level rises or, alternatively, the level of serum 25OHD at which serum PTH level no longer declines. This measure is discussed more fully in Chapter 4.

REFERENCES

1. Aasheim ET, Bjorkman S, Sovik TT, Engstrom M, Hanvold SE, Mala T, Olbers T, Bohmer T. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. American Journal of Clinical Nutrition. 2009;90(1):15–22. [PubMed: 19439456]
2. Abrams SA, Griffin IJ, Hawthorne KM, Gunn SK, Gundberg CM, Carpenter TO. Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents. Journal of Clinical Endocrinology and Metabolism. 2005;90(10):5576–81. [PMC free article: PMC1283091] [PubMed: 16076940]
3. Adams JS, Modlin RL, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. Journal of Clinical Endocrinology and Metabolism. 1989;69(2):457–60. [PubMed: 2502557]
4. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. National Clinical Practice Endocrinology Metabolism. 2008;4(2):80–90. [PMC free article: PMC2678245] [PubMed: 18212810]
5. Aksnes L, Aarskog D. Plasma concentrations of vitamin D metabolites in puberty: effect of sexual maturation and implications for growth. Journal of Clinical Endocrinology and Metabolism. 1982;55(1):94–101. [PubMed: 6978890]
6. Aloia JF. African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox. American Journal of Clinical Nutrition. 2008;88(2):545S–50S. [PMC free article: PMC2777641] [PubMed: 18689399]
7. Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, Pollack S, Yeh JK. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. American Journal of Clinical Nutrition. 2008;87(6):1952–8. [PubMed: 18541590]
8. Armas LA, Hollis BW, Heaney RP. Vitamin D₂ is much less effective than vitamin D3 in humans. Journal of Clinical Endocrinology and Metabolism. 2004;89(11):5387–91. [PubMed: 15531486]
9. Armas LA, Dowell S, Akhter M, Duthuluru S, Huerter C, Hollis BW, Lund R, Heaney RP. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. Journal of the American Academy of Dermatology. 2007;57(4):588–93. [PubMed: 17637484]
10. Bachrach S, Fisher J, Parks JS. An outbreak of vitamin D deficiency rickets in a susceptible population. Pediatrics. 1979;64(6):871–7. [PubMed: 574626]
11. Bao BY, Yao J, Lee YF. 1alpha, 25-dihydroxyvitamin D₃ suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis. 2006;27(9):1883–93. [PubMed: 16624828]
12. Beer TM, Myrthue A. Calcitriol in cancer treatment: from the lab to the clinic. Moleecular Cancer Therapy. 2004;3(3):373–81. [PubMed: 15026558]
13. Belsey R, Deluca HF, Potts JT Jr. Competitive binding assay for vitamin D and 25-OH vitamin D. Journal of Clinical Endocrinology and Metabolism. 1971;33(3):554–7. [PubMed: 4328344]
14. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annual Review of Medicine. 2010;61:91–104. [PMC free article: PMC4777331] [PubMed: 20059333]
15. Berry JL, Webb AR, Kift R, Durkin M, Vail A, O'Brien SJ, Rhodes LE. Should we, in the U.K. be taking vitamin D supplements during the winter?. Presented at 14th Workshop on Vitamin D; October 4-8, 2009; Brugge, Belgium. 2009.
16. Bises G, Kallay E, Weiland T, Wrba F, Wenzl E, Bonner E, Kriwanek S, Obrist P, Cross HS. 25-hydroxyvitamin D₃-1alpha-hydroxylase expression in normal and malignant human colon. Journal of Histochemistry and Cytochemistry. 2004;52(7):985–9. [PubMed: 15208365]
17. Blomstrand R, Forsgren L. Intestinal absorption and esterification of vitamin D₃-1,2-3H in man. Acta Chemica Scandinavica. 1967;21(6):1662–3. [PubMed: 4293764]
18. Blum M, Dallal GE, Dawson-Hughes B. Body size and serum 25 hydroxy vitamin D response to oral supplements in healthy older adults. Journal of the American College of Nutrition. 2008;27(2):274–9. [PMC free article: PMC2729752] [PubMed: 18689559]
19. Blunt JW, DeLuca HF, Schnoes HK. 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry. 1968;7(10):3317–22. [PubMed: 4300699]
20. Bogh MK, Schmedes AV, Philipsen PA, Thieden E, Wulf HC. Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation. Journal of Investigative Dermatology. 2010;130(2):546–53. [PubMed: 19812604]
21. Brannon PM, Yetley EA, Bailey RL, Picciano MF. Vitamin D and health in the 21st century: an update. Proceedings of a conference held September 2007 in Bethesda, Maryland, USA. American Journal of Clinical Nutrition. 2008;88(2):483S–592S. [PubMed: 18788091]
22. Brommage R, DeLuca HF. Evidence that 1,25-dihydroxyvitamin D₃ is the physiologically active metabolite of vitamin D₃. Endocrine Reviews. 1985;6(4):491–511. [PubMed: 3000754]
23. Bruno C, Fulford AD, Potts JR, McClintock R, Jones R, Cacucci BM, Gupta CE, Peacock M, Considine RV. Serum markers of bone turnover are increased at six and 18 months after Roux-en-Y bariatric surgery: correlation with the reduction in leptin. Journal of Clinical Endocrinology and Metabolism. 2010;95(1):159–66. [PMC free article: PMC2805478] [PubMed: 19858320]
24. Byrdwell WC. Analysis of vitamin D in food control materials and fortified foods. Presented at the Committee to Review Dietary Reference Intakes for Vitamin D and Calcium Information-gathering Workshop; March 26, 2009; Washington, DC. 2009.
25. Campbell MJ, Elstner E, Holden S, Uskokovic M, Koeffler HP. Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D₃ analogue involves the induction of p21waf1, p27kip1 and E-cadherin. Journal of Molecular Endocrinology. 1997;19(1):15–27. [PubMed: 9278857]
26. Carter GD, Carter R, Jones J, Berry J. How accurate are assays for 25-hydroxyvitamin D? Data from the international vitamin D external quality assessment scheme. Clinical Chemistry. 2004;50(11):2195–7. [PubMed: 15375018]
27. Carter GD. 25-hydroxyvitamin D assays: the quest for accuracy. Clinical Chemistry. 2009;55(7):1300–2. [PubMed: 19423731]
28. Carter GD, Jones JC. Use of a common standard improves the performance of liquid chromatography-tandem mass spectrometry methods for serum 25-hydroxyvitamin-D. Annals of Clinical Biochemistry. 2009;46(Pt 1):79–81. [PubMed: 19103962]
29. Carter GD, Berry JL, Gunter E, Jones G, Jones JC, Makin HL, Sufi S, Wheeler MJ. Proficiency testing of 25-hydroxyvitamin D (25-OHD) assays. Journal of Steroid Biochemistry and Molecular Biology. 2010;121(1-2):176–9. [PubMed: 20302938]
30. Cashman KD, Hill TR, Lucey AJ, Taylor N, Seamans KM, Muldowney S, Fitzgerald AP, Flynn A, Barnes MS, Horigan G, Bonham MP, Duffy EM, Strain JJ, Wallace JM, Kiely M. Estimation of the dietary requirement for vitamin D in healthy adults. American Journal of Clinical Nutrition. 2008;88(6):1535–42. [PubMed: 19064513]
31. Cashman KD, Wallace JM, Horigan G, Hill TR, Barnes MS, Lucey AJ, Bonham MP, Taylor N, Duffy EM, Seamans K, Muldowney S, Fitzgerald AP, Flynn A, Strain JJ, Kiely M. Estimation of the dietary requirement for vitamin D in free-living adults ≥64 y of age. American Journal of Clinical Nutrition. 2009;89(5):1366–74. [PubMed: 19297462]
32. Chel V, Wijnhoven HA, Smit JH, Ooms M, Lips P. Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporosis International. 2008;19(5):663–71. [PMC free article: PMC2277446] [PubMed: 17874029]
33. Chen PS Jr, Bosmann HB. Effect of vitamins D2 and D3 on serum calcium and phosphorus in rachitic chicks. Journal of Nutrition. 1964;83:133–9. [PubMed: 14171311]
34. Chen TC, Shao A, Heath H 3rd, Holick MF. An update on the vitamin D content of fortified milk from the United States and Canada. New England Journal of Medicine. 1993;329(20):1507. [PubMed: 8413473]
35. Chen TC, Chimeh F, Lu Z, Mathieu J, Person KS, Zhang A, Kohn N, Martinello S, Berkowitz R, Holick MF. Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Archives of Biochemistry and Biophysics. 2007;460(2):213–7. [PMC free article: PMC2698590] [PubMed: 17254541]
36. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. Journal of Biological Chemistry. 2003;278(39):38084–93. [PMC free article: PMC4450819] [PubMed: 12867411]
37. Christiansen C, Rodbro P, Munck O. Actions of vitamins D₂ and D₃ and 25-OHD₃ in anticonvulsant osteomalacia. British Medical Journal. 1975;2(5967):363–5. [PMC free article: PMC1673157] [PubMed: 165857]
38. Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and calcium: a systematic review of health outcomes, Evidence Report No. 183 (Prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.). Rockville, MD: Agency for Healthcare Research and Quality; 2009. AHRQ Publication No. 09-E015.
39. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, Adams PH. Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clinical Science (London). 1987;73(6):659–64. [PubMed: 3690980]
40. Compston JE, Merrett AL, Hammett FG, Magill P. Comparison of the appearance of radiolabelled vitamin D₃ and 25-hydroxy-vitamin D₃ in the chylomicron fraction of plasma after oral administration in man. Clinical Science (London). 1981;60(2):241–3. [PubMed: 6263539]
41. Cranney A, Horsley T, O'Donnell S, Weiler HA, Puil L, Ooi DS, Atkinson SA, Ward LM, Moher D, Hanley DA, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V. Effectiveness and safety of vitamin D in relation to bone health, Evidence Report/Technology Assessment No. 158 (Prepared by the University of Ottawa Evidence-based Practice Center [UO-EPC] under Contract No. 290-02-0021). Rockville, MD: Agency for Healthcare Research and Quality; 2007. AHRQ Publication No. 07-E013.
42. Cranney A, Weiler HA, O'Donnell S, Puil L. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. American Journal of Clinical Nutrition. 2008;88(2):513S–9S. [PubMed: 18689393]
43. Davis CD, Hartmuller V, Freedman DM, Hartge P, Picciano MF, Swanson CA, Milner JA. Vitamin D and cancer: current dilemmas and future needs. Nutrition Reviews. 2007;65(8 Pt 2):S71–4. [PubMed: 17867373]
44. Davis CD. Vitamin D and cancer: current dilemmas and future research needs. American Journal of Clinical Nutrition. 2008;88(2):565S–9S. [PubMed: 18689403]
45. Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Reviews Cancer. 2007;7(9):684–700. [PubMed: 17721433]
46. DeLuca HF. Vitamin D: the vitamin and the hormone. Federation Proceedings. 1974;33(11):2211–9. [PubMed: 4372106]
47. Deluca HF. Vitamin D-resistant rickets. A prototype of nutritional management of a genetic disorder. Current Concepts in Nutrition. 1979;8:3–32. [PubMed: 230941]
48. Deluca HF. The transformation of a vitamin into a hormone: the vitamin D story. Harvey lectures. 1979;75:333–79. [PubMed: 400608]
49. DeLuca HF, Schnoes HK. Vitamin D: recent advances. Annual Review of Biochemistry. 1983;52:411–39. [PubMed: 6311080]
50. DeLuca HF. The vitamin D story: a collaborative effort of basic science and clinical medicine. FASEB Journal. 1988;2(3):224–36. [PubMed: 3280376]
51. DeLuca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB Journal. 2001;15(14):2579–85. [PubMed: 11726533]
52. Deluca HF. Vitamin D toxicity. Paper prepared for the Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Washington, DC. 2009.
53. DeLucia MC, Mitnick ME, Carpenter TO. Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants. Journal of Clinical Endocrinology and Metabolism. 2003;88(8):3539–45. [PubMed: 12915633]
54. Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced by the active metabolite of vitamin D₃ and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Research. 2000;60(8):2304–12. [PubMed: 10786699]
55. Diehl JW, Chiu MW. Effects of ambient sunlight and photoprotection on vitamin D status. Dermatologic Therapy. 2010;23(1):48–60. [PubMed: 20136908]
56. Diesing D, Cordes T, Fischer D, Diedrich K, Friedrich M. Vitamin D—metabolism in the human breast cancer cell line MCF-7. Anticancer Research. 2006;26(4A):2755–9. [PubMed: 16886688]
57. Drescher D, Deluca HF, Imrie MH. On the site of discrimination of chicks against vitamin D. Archives of Biochemistry and Biophysics. 1969;130(1):657–61. [PubMed: 4305169]
58. Faulkner H, Hussein A, Foran M, Szijarto L. A survey of vitamin A and D contents of fortified fluid milk in Ontario. Journal of Dairy Science. 2000;83(6):1210–6. [PubMed: 10877385]
59. FDA (Food and Drug Administration). Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Food Labeling Regulations. Federal Register. 2009;74(201):53743–6.
60. Fieser LF, Fieser M. Vitamin D. New York: Reinhold; 1959. pp. 90–168.
61. Fleet JC, Gliniak C, Zhang Z, Xue Y, Smith KB, McReedy R, Adedokon SA. Serum metabolite profiles and target tissue gene expression define the effect of cholecalciferol intake on calcium metabolism in rats and mice. Journal of Nutrition. 2008;138(6):1114–20. [PMC free article: PMC2542586] [PubMed: 18492843]
62. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. New England Journal of Medicine. 1973;289(16):817–22. [PubMed: 4357855]
63. Galitzer H, Ben-Dov I, Lavi-Moshayoff V, Naveh-Many T, Silver J. Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion. Current Opinion in Nephrology and Hypertension. 2008;17(4):363–7. [PubMed: 18660671]
64. Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proceedings of the National Academy of Sciences of the United States of America. 1972;69(7):1673–6. [PMC free article: PMC426775] [PubMed: 4340153]
65. Gartner LM, Greer FR. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics. 2003;111(4 Pt 1):908–10. [PubMed: 12671133]
66. Gaschott T, Stein J. Short-chain fatty acids and colon cancer cells: the vitamin D receptor—butyrate connection. Recent Results in Cancer Research. 2003;164:247–57. [PubMed: 12899527]
67. Gehrer S, Kern B, Peters T, Christoffel-Courtin C, Peterli R. Fewer nutrient deficiencies after laparoscopic sleeve gastrectomy (LSG) than after laparoscopic Roux-Y-gastric bypass (LRYGB)—a prospective study. Obesity Surgery. 2010;20(4):447–53. [PubMed: 20101473]
68. Glendenning P, Taranto M, Noble JM, Musk AA, Hammond C, Goldswain PR, Fraser WD, Vasikaran SD. Current assays overestimate 25-hydroxyvitamin D₃ and underestimate 25-hydroxyvitamin D₂ compared with HPLC: need for assay-specific decision limits and metabolite-specific assays. Annals of Clinical Biochemistry. 2006;43(Pt 1):23–30. [PubMed: 16390606]
69. Goldner WS, Stoner JA, Lyden E, Thompson J, Taylor K, Larson L, Erickson J, McBride C. Finding the optimal dose of vitamin D following Roux-en-Y gastric bypass: a prospective, randomized pilot clinical trial. Obesity Surgery. 2009;19(2):173–9. [PubMed: 18795378]
70. Gozdik A, Barta JL, Wu H, Cole D, Vieth R, Whiting S, Parra E. Seasonal changes in vitamin D status in healthy young adults of different ancestry in the greater Toronto area. Presented at the 14th Workshop on Vitamin D; October 4-8, 2009; Brugge, Belgium. 2009.
71. Guo YD, Strugnell S, Back DW, Jones G. Substrate specificity of the liver mitochondrial cytochrome P-450, CYP-27, towards vitamin D and its analogs. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:8668–72. [PMC free article: PMC47419] [PubMed: 7690968]
72. Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH. CYP3A4 is a human microsomal vitamin D 25-hydroxylase. Journal of Bone and Mineral Research. 2004;19(4):680–8. [PubMed: 15005856]
73. Gupta RP, He YA, Patrick KS, Halpert JR, Bell NH. CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):1210–9. [PubMed: 15546903]
74. Haddad JG Jr, Hahn TJ. Natural and synthetic sources of circulating 25-hydroxyvitamin D in man. Nature. 1973;244(5417):515–7. [PubMed: 4621128]
75. Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J. Human plasma transport of vitamin D after its endogenous synthesis. Journal of Clinical Investigation. 1993;91(6):2552–5. [PMC free article: PMC443317] [PubMed: 8390483]
76. Harris SS, Dawson-Hughes B. Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D₃. Journal of the American College of Nutrition. 2002;21(4):357–62. [PubMed: 12166534]
77. Hashizume T, Xu Y, Mohutsky MA, Alberts J, Hadden C, Kalhorn TF, Isoherranen N, Shuhart MC, Thummel KE. Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1alpha,25-dihydroxyvitamin D₃ conjugation. Biochemical Pharmacology. 2008;75(5):1240–50. [PMC free article: PMC2664830] [PubMed: 18177842]
78. Hay AW, Watson G. The binding of 25-hydroxycholecalciferol and 25-hydroxyergocalciferol to receptor proteins in a New World and an Old World primate. Comparative Biochemistry and Physiology. B: Comparative Biochemistry. 1977;56(2):131–4. [PubMed: 401479]
79. Helvig C, Cuerrier D, Kharebov A, Ireland B, Kim J, Ryder K, Petkovich M. Comparison of 1,25-dihydroxyvitamin D2 and calcitriol effects in an adenine-induced model of CKD reveals differential control over serum calcium and phosphate. Journal of Bone and Mineral Research. 2008;23((S357))
80. Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, Modlin RL, Adams JS. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. Journal of Steroid Biochemistry and Molecular Biology. 2007;103(3-5):316–21. [PubMed: 17368179]
81. Holick MF, MacLaughlin JA, Doppelt SH. Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science. 1981;211(4482):590–3. [PubMed: 6256855]
82. Holick MF. Skin: site of the synthesis of vitamin D and a target tissue for the active form, 1,25-dihydroxyvitamin D₃. Annals of the New York Academy of Sciences. 1988;548:14–26. [PubMed: 2854716]
83. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet. 1989;334(8671):1104–5. [PubMed: 2572832]
84. Holick MF, Shao Q, Liu WW, Chen TC. The vitamin D content of fortified milk and infant formula. New England Journal of Medicine. 1992;326(18):1178–81. [PubMed: 1313548]
85. Holick M. McCollum Award Lecture, 1994: vitamin D—new horizons for the 21st century. American Journal of Clinical Nutrition. 1994;60(4):619–630. [PubMed: 8092101]
86. Holick MF. Vitamin D: photobiology, metabolism, and clinical applications, Endocrinology. 3rd. DeGroot LJ, Besser M, Burger HG, et al., editors. Philadelphia, PA: W. B. Saunders; 1995.
87. Holick MF. Vitamin D: photobiology, metabolism, mechanism of action, and clinical application, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3rd. Favus MJ, editor. Philadelphia, PA: Lippincott-Raven; 1996. pp. 74–81.
88. Holick MF. Vitamin D and sunlight: strategies for cancer prevention and other health benefits. Clinical Journal of the American Society of Nephrology. 2008;3(5):1548–54. [PMC free article: PMC4571149] [PubMed: 18550652]
89. Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD. Vitamin D₂ is as effective as vitamin D₃ in maintaining circulating concentrations of 25-hydroxyvitamin D. Journal of Clinical Endocrinology and Metabolism. 2008;93(3):677–81. [PMC free article: PMC2266966] [PubMed: 18089691]
90. Hollis BW, Roos BA, Draper HH, Lambert PW. Vitamin D and its metabolites in human and bovine milk. Journal of Nutrition. 1981;111(7):1240–8. [PubMed: 6788913]
91. Hollis BW, Napoli JL. Improved radioimmunoassay for vitamin D and its use in assessing vitamin D status. Clinical Chemistry. 1985;31(11):1815–9. [PubMed: 4053351]
92. Hollis BW. Measuring 25-hydroxyvitamin D in a clinical environment: challenges and needs. American Journal of Clinical Nutrition. 2008;88(2):507S–10S. [PubMed: 18689391]
93. Horst RL, Shepard RM, Jorgensen NA, DeLuca HF. The determination of the vitamin D metabolites on a single plasma sample: changes during parturition in dairy cows. Archives of Biochemistry and Biophysics. 1979;192(2):512–23. [PubMed: 434838]
94. Horst RL, Reinhardt TA, Ramberg CF, Koszewski NJ, Napoli JL. 24-hydroxylation of 1,25-dihydroxyergocalciferol. An unambiguous deactivation process. Journal of Biological Chemistry. 1986;261(20):9250–6. [PubMed: 3013880]
95. Hosseinpour F, Ellfolk M, Norlin M, Wikvall K. Phenobarbital suppresses vitamin D₃ 25-hydroxylase expression: a potential new mechanism for drug-induced osteomalacia. Biochemical and Biophysical Research Communications. 2007;357(3):603–7. [PubMed: 17445763]
96. Hunt RD, Garcia FG, Walsh RJ. A comparison of the toxicity of ergocalciferol and cholecalciferol in rhesus monkeys (Macaca mulatta). Journal of Nutrition. 1972;102(8):975–86. [PubMed: 4340673]
97. IOM (Institute of Medicine). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997. [PubMed: 23115811]
98. IOM. Dietary Reference Intakes Research Synthesis: Workshop Summary. Washington, DC: The National Academies Press; 2007.
99. Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL, Vieth R. Comparison of daily, weekly, and monthly vitamin D₃ in ethanol dosing protocols for two months in elderly hip fracture patients. Journal of Clinical Endocrinology and Metabolism. 2008;93(9):3430–5. [PubMed: 18544622]
100. James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D₃ and its analogues on induction of apoptosis in breast cancer cells. Journal of Steroid Biochemistry and Molecular Biology. 1996;58(4):395–401. [PubMed: 8903423]
101. James WP, Avenell A, Broom J, Whitehead J. A one-year trial to assess the value of orlistat in the management of obesity. International Journal of Obesity and Related Metabolic Disorders. 1997;21(Suppl 3):S24–30. [PubMed: 9225173]
102. Jiang F, Bao J, Li P, Nicosia SV, Bai W. Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D₃ through the down-regulation of telomerase. Journal of Biological Chemistry. 2004;279(51):53213–21. [PubMed: 15485861]
103. Johnson JL, Mistry VV, Vukovich MD, Hogie-Lorenzen T, Hollis BW, Specker BL. Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly. Journal of Dairy Science. 2005;88(7):2295–301. [PubMed: 15956292]
104. Jones G, Schnoes HK, DeLuca HF. Isolation and identification of 1,25-dihydroxyvitamin D₂. Biochemistry. 1975;14(6):1250–6. [PubMed: 1078978]
105. Jones G. Assay of vitamins D₂ and D₃, and 25-hydroxyvitamins D₂ and D₃ in human plasma by high-performance liquid chromatography. Clinical Chemistry. 1978;24(2):287–98. [PubMed: 203413]
106. Jones G, Rosenthal A, Segev D, Mazur Y, Frolow F, Halfon Y, Rabinovich D, Shakked Z. Isolation and identification of 24,25-dihydroxyvitamin D₂ using the perfused rat kidney. Biochemistry. 1979;18(6):1094–11. [PubMed: 311655]
107. Jones G, Byrnes B, Palma F, Segev D, Mazur Y. Displacement potency of vitamin D₂ analogs in competitive protein-binding assays for 25-hydroxyvitamin D₃, 24,25-dihydroxyvitamin D₃, and 1,25-dihydroxyvitamin D₃. Journal of Clinical Endocrinology and Metabolism. 1980;50(4):773–5. [PubMed: 6965943]
108. Jones G, Schnoes HK, Levan L, Deluca HF. Isolation and identification of 24-hydroxyvitamin D₂ and 24,25-dihydroxyvitamin D₂. Archives of Biochemistry and Biophysics. 1980;202(2):450–7. [PubMed: 6970013]
109. Jones G, Vriezen D, Lohnes D, Palda V, Edwards NS. Side-chain hydroxylation of vitamin D₃ and its physiological implications. Steroids. 1987;49(1-3):29–53. [PubMed: 2842896]
110. Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiological Reviews. 1998;78(4):1193–231. [PubMed: 9790574]
111. Jones G, Makin HL. Vitamin Ds: metabolites and analogs, Modern Chromatographic Analysis of Vitamins. 3rd. de Leenheer AP, Lambert WE, Van Bocxlaer JF, editors. New York: Marcel Dekker; 2000.
112. Jones G. Pharmacokinetics of vitamin D toxicity. American Journal of Clinical Nutrition. 2008;88(2):582S–6S. [PubMed: 18689406]
113. Jones G, Byford V, Helvig C, Petkovich M. Differential disposition of vitamin D₂ does not involve CYP24A1. Presented at 14th International Vitamin D Workshop; October 4-8, 2009; Brugge, Belgium. 2009.
114. Jongen MJ, Van Ginkel FC, van der Vijgh WJ, Kuiper S, Netelenbos JC, Lips P. An international comparison of vitamin D metabolite measurements. Clinical Chemistry. 1984;30(3):399–403. [PubMed: 6607788]
115. Jongen M, van der Vijgh WJ, Netelenbos JC, Postma GJ, Lips P. Pharmacokinetics of 24,25-dihydroxyvitamin D₃ in humans. Hormone and Metabolic Research. 1989;21(10):577–80. [PubMed: 2807147]
116. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Reviews in Endocrinology and Metabloic Disorders. 2001;2(2):203–16. [PubMed: 11705326]
117. Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K, Homma T, Nikaido T, Furihata K. Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D₃ on the proliferation of pancreatic cancer cell lines. Gastroenterology. 1996;110(5):1605–13. [PubMed: 8613068]
118. Kimlin MG, Olds WJ, Moore MR. Location and vitamin D synthesis: is the hypothesis validated by geophysical data? Journal of Photochemistry and Photobiology. B, Biology. 2007;86(3):234–9. [PubMed: 17142054]
119. Knutson JC, LeVan LW, Valliere CR, Bishop CW. Pharmacokinetics and systemic effect on calcium homeostasis of 1 alpha,24-dihydroxyvitamin D₂ in rats. Comparison with 1 alpha,25-dihydroxyvitamin D₂, calcitriol, and calcipotriol. Biochemical Pharmacology. 1997;53(6):829–37. [PubMed: 9113104]
120. Koga M, Eisman JA, Sutherland RL. Regulation of epidermal growth factor receptor levels by 1,25-dihydroxyvitamin D₃ in human breast cancer cells. Cancer Research. 1988;48(10):2734–9. [PubMed: 2834048]
121. Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocrine Reviews. 1997;18(6):832–72. [PubMed: 9408745]
122. Kovalenko PL, Zhang Z, Cui M, Clinton SK, Fleet JC. 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1. BMC Genomics. 2010;11:26. [PMC free article: PMC2820456] [PubMed: 20070897]
123. Kull M Jr, Kallikorm R, Tamm A, Lember M. Seasonal variance of 25-(OH) vitamin D in the general population of Estonia, a Northern European country. BMC Public Health. 2009;9:22. [PMC free article: PMC2632995] [PubMed: 19152676]
124. Kumagai T, Shih LY, Hughes SV, Desmond JC, O'Kelly J, Hewison M, Koeffler HP. 19-Nor-l,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Research. 2005;65(6):2488–97. [PubMed: 15781666]
125. Kumar R, Harnden D, DeLuca HF. Metabolism of 1,25-dihydroxyvitamin D₃: evidence for side-chain oxidation. Biochemistry. 1976;15(11):2420–3. [PubMed: 1276151]
126. Laing CJ, Cooke NE. Chapter 8: Vitamin D binding protein, Vitamin D. 2nd. Feldman D, Pike JW, Glorieux FH, editors. Burlington MA: Elsevier Academic Press; 2005.
127. Leerbeck E, Sondergaard H. The total content of vitamin D in human milk and cow's milk. British Journal of Nutrition. 1980;44(1):7–12. [PubMed: 7426605]
128. Lensmeyer GL, Wiebe DA, Binkley N, Drezner MK. HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. Clinical Chemistry. 2006;52(6):1120–6. [PubMed: 16574756]
129. LeVan LW, Schnoes HK, DeLuca HF. Isolation and identification of 25-hydroxyvitamin D₂ 25-glucuronide: a biliary metabolite of vitamin D₂ in the chick. Biochemistry. 1981;20(1):222–6. [PubMed: 6970592]
130. Li P, Li C, Zhao X, Zhang X, Nicosia SV, Bai W. p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. Journal of Biological Chemistry. 2004;279(24):25260–7. [PubMed: 15075339]
131. Liel Y, Edwards J, Shary J, Spicer KM, Gordon L, Bell NH. The effects of race and body habitus on bone mineral density of the radius, hip, and spine in premenopausal women. Journal of Clinical Endocrinology and Metabolism. 1988;66(6):1247–50. [PubMed: 3372686]
132. Lips P. Vitamin D physiology. Progress in Biophysics and Molecular Biology. 2006;92(1):4–8. [PubMed: 16563471]
133. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–3. [PubMed: 16497887]
134. Liu S, Gupta A, Quarles LD. Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Current Opinion in Nephrology and Hypertension. 2007;16(4):329–35. [PubMed: 17565275]
135. Liu N, Nguyen L, Chun RF, Lagishetty V, Ren S, Wu S, Hollis B, DeLuca HF, Adams JS, Hewison M. Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology. 2008;149(10):4799–808. [PMC free article: PMC2582909] [PubMed: 18535110]
136. Lohnes D, Jones G. Further metabolism of 1α,25-dihydroxyvitamin D3 in target cells. Proceedings of the First International Congress on Vitamins and Biofactors in Life Science. Journal Nutritional Science and Vitaminology (Special Issue). 1992:75–78. [PubMed: 1297826]
137. Looker AC. Body fat and vitamin D status in black versus white women. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):635–40. [PubMed: 15546897]
138. Looker AC. Do body fat and exercise modulate vitamin D status? Nutrition Reviews. 2007;65(8 Pt 2):S124–6. [PubMed: 17867388]
139. Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. American Journal of Clinical Nutrition. 2008;88(6):1519–27. [PMC free article: PMC2745830] [PubMed: 19064511]
140. Lubin D, Jensen EH, Gies HP. Global surface ultraviolet radiation climatology from TOMS and ERBE data. Journal of Geophysical Research. 1998;103(D20):26061–91.
141. Lucas JA, Bolland MJ, Grey AB, Ames RW, Mason BH, Horne AM, Gamble GD, Reid IR. Determinants of vitamin D status in older women living in a subtropical climate. Osteoporosis International. 2005;16(12):1641–8. [PubMed: 16027959]
142. Ma JF, Nonn L, Campbell MJ, Hewison M, Feldman D, Peehl DM. Mechanisms of decreased vitamin D 1alpha-hydroxylase activity in prostate cancer cells. Molecular and Cellular Endocrinology. 2004;221(1-2):67–74. [PubMed: 15223133]
143. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D₃. Journal of Clinical Investigation. 1985;76(4):1536–8. [PMC free article: PMC424123] [PubMed: 2997282]
144. Mahdy T, Atia S, Farid M, Adulatif A. Effect of Roux-en Y gastric bypass on bone metabolism in patients with morbid obesity: Mansoura experiences. Obesity Surgery. 2008;18(12):1526–31. [PubMed: 18716852]
145. Makin HLJ, Jones G, Kaufman M, Calverley MJ. Chapter 11: Analysis of vitamins D, their metabolites and analogs, Steroid Analysis. Makin HLJ, Gower DB, editors. New York: Springer; 2010.
146. Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE. 1 Alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circulation Research. 2000;87(3):214–20. [PubMed: 10926872]
147. Martinez ME, Del Campo MT, Sanchez-Cabezudo MJ, Balaguer G, Rodriguez-Carmona A, Selgas R. Effect of oral calcidiol treatment on its serum levels and peritoneal losses. Peritoneal Dialysis International. 1995;15(1):65–70. [PubMed: 7734564]
148. Masuda S, Byford V, Arabian A, Sakai Y, Demay MB, St-Arnaud R, Jones G. Altered pharmacokinetics of 1alpha,25-dihydroxyvitamin D₃ and 25-hydroxyvitamin D₃ in the blood and tissues of the 25-hydroxyvitamin D-24-hydroxylase (Cyp24a1) null mouse. Endocrinology. 2005;146(2):825–34. [PubMed: 15498883]
149. Masuda S, Jones G. Promise of vitamin D analogues in the treatment of hyper-proliferative conditions. Molecular Cancer Therapeutics. 2006;5(4):797–808. [PubMed: 16648549]
150. Matsuoka LY, Wortsman J, Haddad JG, Hollis BW. In vivo threshold for cutaneous synthesis of vitamin D₃. Journal of Laboratory and Clinical Medicine. 1989;114(3):301–5. [PubMed: 2549141]
151. McDuffie JR, Calis KA, Booth SL, Uwaifo GI, Yanovski JA. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002;22(7):814–22. [PubMed: 12126214]
152. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417. [PubMed: 18676559]
153. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Research. 2005;65(17):7917–25. [PubMed: 16140963]
154. Morris JF, Peacock M. Assay of plasma 25-hydroxy vitamin D. Clinica Chimica Acta. 1976;72(3):383–91. [PubMed: 975590]
155. Mulligan GB, Licata A. Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. Journal of Bone and Mineral Research. 2010;25(4):928–30. [PubMed: 20200983]
156. Murphy SC, Whited LJ, Rosenberry LC, Hammond BH, Bandler DK, Boor KJ. Fluid milk vitamin fortification compliance in New York State. Journal of Dairy Science. 2001;84(12):2813–20. [PubMed: 11814039]
157. Olds WJ, McKinley AR, Moore MR, Kimlin MG. In vitro model of vitamin D3 (cholecalciferol) synthesis by UV radiation: dose-response relationships. Journal of Photochemistry and Photobiology. B, Biology. 2008;93(2):88–93. [PubMed: 18755599]
158. Park EA. The therapy of rickets. JAMA. 1940;94:370–9.
159. Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, Adorini L. 1,25-Dihydroxyvitamin D₃ selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. Journal of Immunology. 2007;178(1):145–53. [PubMed: 17182549]
160. Phinney KW. Methods development and standard reference materials for 25(OH) D. Presented at the Committee to Review Dietary Reference Intakes for Vitamin D and Calcium Information-gathering Workshop; August 4, 2009; Washington, DC. 2009.
161. Picciano MF, Dwyer JT, Radimer KL, Wilson DH, Fisher KD, Thomas PR, Yetley EA, Moshfegh AJ, Levy PS, Nielsen SJ, Marriott BM. Dietary supplement use among infants, children, and adolescents in the United States, 1999-2002. Archives of Pediatrics and Adolescent Medicine. 2007;161(10):978–85. [PubMed: 17909142]
162. Pike JW, Shevde NK, Hollis BW, Cooke NE, Zella LA. Vitamin D—binding protein influences total circulating levels of 1,25-dihydroxyvitamin D-3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149(7):3656–67. [PMC free article: PMC2453093] [PubMed: 18372326]
163. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. Journal of Clinical Investigation. 2008;118(12):3820–8. [PMC free article: PMC2586800] [PubMed: 19033649]
164. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. American Journal of Epidemiology. 2004;160(4):339–49. [PubMed: 15286019]
165. Rapuri PB, Kinyamu HK, Gallagher JC, Haynatzka V. Seasonal changes in calciotropic hormones, bone markers, and bone mineral density in elderly women. Journal of Clinical Endocrinology and Metabolism. 2002;87(5):2024–32. [PubMed: 11994336]
166. Rapuri PB, Gallagher JC, Haynatzki G. Effect of vitamins D₂ and D₃ supplement use on serum 25OHD concentration in elderly women in summer and winter. Calcified Tissue International. 2004;74(2):150–6. [PubMed: 14648011]
167. Reeve LE, Chesney RW, DeLuca HF. Vitamin D of human milk: identification of biologically active forms. American Journal of Clinical Nutrition. 1982;36(1):122–6. [PubMed: 7091022]
168. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. New England Journal of Medicine. 1989;320(15):980–91. [PubMed: 2648151]
169. Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. European Journal of Endocrinology/European Federation of Endocrine Societies. 2007;157(2):225–32. [PubMed: 17656603]
170. Reinhardt TA, Ramberg CF, Horst RL. Comparison of receptor binding, biological activity, and in vivo tracer kinetics for 1,25-dihydroxyvitamin D₃, 1,25-dihydroxyvitamin D₂, and its 24 epimer. Archives of Biochemistry and Biophysics. 1989;273(1):64–71. [PubMed: 2547343]
171. Riedt CS, Cifuentes M, Stahl T, Chowdhury HA, Schlussel Y, Shapses SA. Overweight postmenopausal women lose bone with moderate weight reduction and 1 g/day calcium intake. Journal of Bone and Mineral Research. 2005;20(3):455–63. [PMC free article: PMC4042194] [PubMed: 15746990]
172. Riedt CS, Brolin RE, Sherrell RM, Field MP, Shapses SA. True fractional calcium absorption is decreased after Roux-en-Y gastric bypass surgery. Obesity (Silver Spring). 2006;14(11):1940–8. [PMC free article: PMC4016232] [PubMed: 17135609]
173. Roborgh JR, de Man T. The hypercalcemic activity of dihydrotachysterol-2 and dihydrotachysterol-3 and of the vitamins D₂ and D₃: comparative experiments on rats. Biochemical Pharmacology. 1959;2:1–6. [PubMed: 14438012]
174. Roborgh JR, de Man T. The hypercalcemic activity of dihydrotachysterol-2 and dihydrotachysterol-3 and of the vitamins D₂ and D₃ after intravenous injection of the aqueous preparations. 2. Comparative experiments on rats. Biochemical Pharmacology. 1960;3:277–82. [PubMed: 14438012]
175. Rosenstreich SJ, Rich C, Volwiler W. Deposition in and release of vitamin D₃ from body fat: evidence for a storage site in the rat. Journal of Clinical Investigation. 1971;50(3):679–87. [PMC free article: PMC291976] [PubMed: 4322721]
176. Roth HJ, Schmidt-Gayk H, Weber H, Niederau C. Accuracy and clinical implications of seven 25-hydroxyvitamin D methods compared with liquid chromatography-tandem mass spectrometry as a reference. Annals of Clinical Biochemistry. 2008;45(Pt 2):153–9. [PubMed: 18325178]
177. Sawada N, Sakaki T, Ohta M, Inouye K. Metabolism of vitamin D(3) by human CYP27A1. Biochemical and Biophysical Research Communications. 2000;273(3):977–84. [PubMed: 10891358]
178. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. Journal of Clinical Investigation. 1986;78(5):1296–301. [PMC free article: PMC423816] [PubMed: 3771798]
179. Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. Journal of Clinical Endocrinology and Metabolism. 2006;91(8):3055–61. [PubMed: 16720650]
180. Siu-Caldera ML, Sekimoto H, Peleg S, Nguyen C, Kissmeyer AM, Binderup L, Weiskopf A, Vouros P, Uskokovic MR, Reddy GS. Enhanced biological activity of 1alpha,25-dihydroxy-20-epi-vitamin D₃, the C-20 epimer of 1alpha,25-dihydroxyvitamin D₃, is in part due to its metabolism into stable intermediary metabolites with significant biological activity. Journal of Steroid Biochemistry and Molecular Biology. 1999;71(3-4):111–21. [PubMed: 10659699]
181. Sjoden G, Smith C, Lindgren U, DeLuca HF. 1 alpha-hydroxyvitamin D₂ is less toxic than 1 alpha-hydroxyvitamin D₃ in the rat. Proceedings of the Society for Experimental Biology and Medicine. 1985;178(3):432–6. [PubMed: 3871952]
182. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. Journal of Clinical Investigation. 1984;74(6):2136–43. [PMC free article: PMC425405] [PubMed: 6549016]
183. Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during Antarctic winter. American Journal of Clinical Nutrition. 2009;89(4):1092–8. [PubMed: 19225122]
184. Snellman G, Melhus H, Gedeborg R, Olofsson S, Wolk A, Pedersen NL, Michaelsson K. Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study. PLoS ONE [Electronic Resource] 2009;4(11):e7747. [PMC free article: PMC2774516] [PubMed: 19915719]
185. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. European Journal of Endocrinology/European Federation of Endocrine Societies. 2008;159(6):675–84. [PubMed: 19056900]
186. Specker BL, Valanis B, Hertzberg V, Edwards N, Tsang RC. Sunshine exposure and serum 25-hydroxyvitamin D concentrations in exclusively breast-fed infants. Journal of Pediatrics. 1985;107(3):372–6. [PubMed: 3839846]
187. Springbett P, Buglass S, Young AR. Photoprotection and vitamin D status. Journal of Photochemistry and Photobiology B: Biology. 2010;101(2):160–8. [PubMed: 20444619]
188. Stamp TC, Haddad JG Jr, Exton-Smith AN, Reuben A, Twigg CA. Assay of vitamin D and its metabolites. Annals of Clinical Biochemistry. 1976;13(6):571–7. [PubMed: 189668]
189. Stamp TC, Haddad JG, Twigg CA. Comparison of oral 25-hydroxycholecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet. 1977;1(8026):1341–3. [PubMed: 69059]
190. Steenbock H, Black A. Fat-soluble vitamins. Journal of Biological Chemistry. 1924;61(2):405–22.
191. Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D₃. Journal of Molecular Biology. 2008;380(1):95–106. [PubMed: 18511070]
192. Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. Journal of the American Society of Nephrology. 2010;21(2):353–61. [PMC free article: PMC2834546] [PubMed: 20007751]
193. Suda T, DeLuca HF, Schnoes HK, Blunt JW. The isolation and identification of 25-hydroxyergocalciferol. Biochemistry. 1969;8(9):3515–20. [PubMed: 5307049]
194. Suda T, Takahashi N, Abe E. Role of vitamin D in bone resorption. Journal of Cellular Biochemistry. 1992;49(1):53–8. [PubMed: 1644855]
195. Sundaram S, Chaudhry M, Reardon D, Gupta M, Gewirtz DA. The vitamin D₃ analog EB 1089 enhances the antiproliferative and apoptotic effects of adriamycin in MCF-7 breast tumor cells. Breast Cancer Research and Treatment. 2000;63(1):1–10. [PubMed: 11079153]
196. Sutton RA, Wong NL, Dirks JH. Effects of parathyroid hormone on sodium and calcium transport in the dog nephron. Clinical Science and Molecular Medicine. 1976;51(4):345–51. [PubMed: 971575]
197. Talwar SA, Aloia JF, Pollack S, Yeh JK. Dose response to vitamin D supplementation among postmenopausal African American women. American Journal of Clinical Nutrition. 2007;86(6):1657–62. [PMC free article: PMC2581841] [PubMed: 18065583]
198. Tanaka Y, DeLuca HF. Stimulation of 1,25-dihydroxyvitamin D₃ production by 1,25-dihydroxyvitamin D₃ in the hypocalcaemic rat. Biochemical Journal. 1983;214(3):893–7. [PMC free article: PMC1152329] [PubMed: 6312966]
199. Tanner JT, Smith J, Defibaugh P, Angyal G, Villalobos M, Bueno MP, McGarrahan ET, Wehr HM, Muniz JF, Hollis BW, et al. Survey of vitamin content of fortified milk. Journal—Association of Official Analytical Chemists. 1988;71(3):607–10. [PubMed: 3391970]
200. Thompson GR, Lewis B, Booth CC. Absorption of vitamin D3-3H in control subjects and patients with intestinal malabsorption. Journal of Clinical Investigation. 1966;45(1):94–102. [PMC free article: PMC292670] [PubMed: 4285212]
201. Thompson PD, Jurutka PW, Whitfield GK, Myskowski SM, Eichhorst KR, Dominguez CE, Haussler CA, Haussler MR. Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochemical and Biophysical Research Communications. 2002;299(5):730–8. [PubMed: 12470639]
202. Tjellesen L, Gotfredsen A, Christiansen C. Different actions of vitamin D₂ and D₃ on bone metabolism in patients treated with phenobarbitone/phenytoin. Calcified Tissue International. 1985;37(3):218–22. [PubMed: 2990641]
203. Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D₂. American Journal of Clinical Nutrition. 1998;68(4):854–8. [PubMed: 9771862]
204. Trump DL, Deeb KK, Johnson CS. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. Cancer Journal. 2010;16(1):1–9. [PMC free article: PMC2857702] [PubMed: 20164683]
205. Turner M, Barre PE, Benjamin A, Goltzman D, Gascon-Barre M. Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy? Mineral and Electrolyte Metabolism. 1988;14(4):246–52. [PubMed: 3211093]
206. Tzotzas T, Papadopoulou FG, Tziomalos K, Karras S, Gastaris K, Perros P, Krassas GE. Rising serum 25-hydroxy-vitamin D levels after weight loss in obese women correlate with improvement in insulin resistance. Journal of Clinical Endocrinology and Metabolism. 2010;95(9):4251–7. [PubMed: 20534751]
207. Urushino N, Yasuda K, Ikushiro S, Kamakura M, Ohta M, Sakaki T. Metabolism of 1alpha,25-dihydroxyvitamin D₂ by human CYP24A1. Biochemical and Biophysical Research Communications. 2009;384(2):144–8. [PubMed: 19393625]
208. Valderas JP, Velasco S, Solari S, Liberona Y, Viviani P, Maiz A, Escalona A, Gonzalez G. Increase of bone resorption and the parathyroid hormone in postmenopausal women in the long-term after Roux-en-Y gastric bypass. Obesity Surgery. 2009;19(8):1132–8. [PubMed: 19517199]
209. van der Mei IA, Ponsonby AL, Engelsen O, Pasco JA, McGrath JJ, Eyles DW, Blizzard L, Dwyer T, Lucas R, Jones G. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environmental Health Perspectives. 2007;115(8):1132–9. [PMC free article: PMC1940076] [PubMed: 17687438]
210. van Dijk CE, de Boer MR, Koppes LL, Roos JC, Lips P, Twisk JW. Positive association between the course of vitamin D intake and bone mineral density at 36 years in men. Bone. 2009;44(3):437–41. [PubMed: 19061980]
211. Vieth R. The mechanisms of vitamin D toxicity. Bone and Mineral. 1990;11(3):267–72. [PubMed: 2085680]
212. Vieth R. Why the optimal requirement for vitamin D₃ is probably much higher than what is officially recommended for adults. Journal of Steroid Biochemistry and Molecular Biology. 2004;89-90(1-5):575–9. [PubMed: 15225842]
213. Wang L, Flanagan JN, Whitlatch LW, Jamieson DP, Holick MF, Chen TC. Regulation of 25-hydroxyvitamin D-1alpha-hydroxylase by epidermal growth factor in prostate cells. Journal of Steroid Biochemistry and Molecular Biology. 2004;89-90(1-5):127–30. [PubMed: 15225759]
214. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376(9736):180–8. [PMC free article: PMC3086761] [PubMed: 20541252]
215. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. Canadian Medical Association Journal. 2007;177(2):161–6. [PMC free article: PMC1913133] [PubMed: 17600035]
216. Wastney ME, Ng J, Smith D, Martin BR, Peacock M, Weaver CM. Differences in calcium kinetics between adolescent girls and young women. American Journal of Physiology. 1996;271(1 Pt 2):R208–16. [PubMed: 8760222]
217. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D₃: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D₃ synthesis in human skin. Journal of Clinical Endocrinology and Metabolism. 1988;67(2):373–8. [PubMed: 2839537]
218. Webb AR, DeCosta BR, Holick MF. Sunlight regulates the cutaneous production of vitamin D₃ by causing its photodegradation. Journal of Clinical Endocrinology and Metabolism. 1989;68(5):882–7. [PubMed: 2541158]
219. Weber F. Absorption mechanisms for fat-soluble vitamins and the effect of other food constituents. Progress in Clinical and Biological Research. 1981;77:119–35. [PubMed: 7038701]
220. Weber F. Absorption of fat-soluble vitamins. International Journal for Vitamin and Nutrition Research. 1983;(Suppl 25):55–65. [PubMed: 6317601]
221. Weber K, Goldberg M, Stangassinger M, Erben RG. 1Alpha-hydroxyvitamin D₂ is less toxic but not bone selective relative to 1alpha-hydroxyvitamin D₃ in ovariectomized rats. Journal of Bone and Mineral Research. 2001;16(4):639–51. [PubMed: 11315991]
222. Willnow T, Nykjaer A. Chapter 10: Endocytic pathways for 25-(OH) vitamin D₃, Vitamin D. 2nd. Feldman D, Pike JW, Glorieux F, editors. Burlington, MA: Elsevier; 2005.
223. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. American Journal of Clinical Nutrition. 2000;72(3):690–3. [PubMed: 10966885]
224. Xie SP, James SY, Colston KW. Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. Journal of Endocrinology. 1997;154(3):495–504. [PubMed: 9379127]
225. Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, Kalhorn TF, Watkins PB, Schuetz EG, Thummel KE. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Molecular Pharmacology. 2006;69(1):56–65. [PubMed: 16207822]
226. Yamamoto M, Kawanobe Y, Takahashi H, Shimazawa E, Kimura S, Ogata E. Vitamin D deficiency and renal calcium transport in the rat. Journal of Clinical Investigation. 1984;74(2):507–13. [PMC free article: PMC370503] [PubMed: 6086715]
227. Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, Kashiwagi K, Toriyabe T, Kawabata M, Miyazono K, Kato S. Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators. Science. 1999;283(5406):1317–21. [PubMed: 10037600]
228. Yasuda H, Higashio K, Suda T. Vitamin D and osteoclastogenesis, Vitamin D. Feldman D, Pike JW, Glorieux FH, editors. Vol. 1. San Diego, CA: Elsevier Academic Press; 2005. pp. 665–85.
229. Yetley EA. Assessing the vitamin D status of the US population. American Journal of Clinical Nutrition. 2008;88(2):558S–64S. [PubMed: 18689402]
230. Yetley EA, Brule D, Cheney MC, Davis CD, Esslinger KA, Fischer PW, Friedl KE, Greene-Finestone LS, Guenther PM, Klurfeld DM, L'Abbe MR, McMurry KY, Starke-Reed PE, Trumbo PR. Dietary reference intakes for vitamin D: justification for a review of the 1997 values. American Journal of Clinical Nutrition. 2009;89(3):719–27. [PMC free article: PMC2667666] [PubMed: 19176741]
231. Zinser GM, Welsh J. Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D₃ receptor null mice. Molecular Endocrinology. 2004;18(9):2208–23. [PubMed: 15178742]
232. Zittermann A, Frisch S, Berthold HK, Gotting C, Kuhn J, Kleesiek K, Stehle P, Koertke H, Koerfer R. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. American Journal of Clinical Nutrition. 2009;89(5):1321–7. [PubMed: 19321573]

Footnotes

1

Available online at http://laws​.justice.gc​.ca/PDF/Regulation/C/C​.R.C.,_c._870.pdf (accessed July 23, 2010).

2

USDA National Nutrient Database for Standard Reference Release 23. NBD No. 01107. Milk, human, mature, fluid. Available online at http://www​.ars.usda.gov/Services/docs​.htm?docid=8964 (accessed August 3, 2010).

3

USDA National Nutrient Database for Standard Reference Release 23. NBD No. 03946. Infant formula, ROSS, SIMILAC LACTOSE FREE ADVANCE, ready-to-feed, with ARA and DHA; and NDB no. 03815. Infant formula, MEAD JOHNSON, ENFAMIL LIPIL, with iron, ready-to-feed, with ARA and DHA. Available online at http://www​.ars.usda.gov/main/site_main​.htm?modecode​=12-35-45-00 (accessed April 28, 2010).

4

Available online at http://www​.nal.usda.gov​/fnic/foodcomp/search/ (accessed March 16, 2010).

5

The chemical processes that lead to the formation of vitamin D₃ from its precursor are non-enzymatic and can take place ex vivo and in organic solvents, as well as in vivo. Therefore, vitamin D₃ can also be synthesized commercially.

6

Available online at http://www​.hc-sc.gc.ca​/fn-an/nutrition/infant-nourisson​/vita_d_supp-eng.php (accessed September 1, 2010).

7

L*=70; the lightest skin tone of northern Europeans.

8

Available online at http://www​.deqas.org/ (accessed March 9, 2010).

9

Available online at http://ts​.nist.gov/measurementservices​/referencematerials​/index.cfm (accessed March 15, 2010).

10

Available online at http://www​.cdc.gov/nchs​/data/nhanes/nhanes3​/VitaminD_analyticnote.pdf (accessed March 17, 2010).

11

DiaSorin Radio-immunoassay (RIA) (Stillwater, MN).

12

DiaSorin Liaison (Stillwater, MN).