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Background: Serum 25-hydroxyvitamin D [25(OH)D] concentrations can be affected by several environmental and individual factors. It is not clear to what extent genetic influences play a role in determining vitamin D status. Thus far, studies on the heritability of vitamin D have provided conflicting results. Objective: We estimated the heritability of vitamin D concentrations and the effect of season on heritability estimates. Design: We measured serum 25(OH)D concentrations in 510 middle-aged, male twins (310 monozygotic and 200 dizygotic twins) selected from the Vietnam Era Twin Registry. Generalized estimating equations were used to test the association between 25(OH)D and other study factors. Structural equation modeling was used to estimate the heritability of 25(OH)D. Results: The twins' mean ([+ or -]SD) age was 55 [+ or -] 2.8 y. The mean ([+ or -]SD) 25(OH)D concentration was 38.4 [+ or -] 23.3 ng/mL with a substantial seasonal variation (a 6.1-ng/mL lower value during the winter than during the summer, P = 0.003). Approximately 70% of the variation in 25(OH)D concentrations during the winter was explained by genetic factors. However, in the summer, 25(OH)D concentrations were not heritable. During the summer, 53% of the variation in 25(OH)D concentrations was due to shared environmental factors, and 47% of the variation in 25(OH)D concentrations was due to unique environmental factors. Conclusions: Serum 25(OH)D concentrations are highly heritable during the winter season only. In the summer, environmental conditions (eg, sun exposure) prevail over genetic backgrounds in determining serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00017836. Am J Clin Nutr 2010;92: 1393-8. doi: 10.3945/ajcn.2010.30176.

Background: The role of dairy calcium intake and serum vitamin D concentrations in weight loss is controversial. Objective: The objective was to assess the association of dairy calcium intake and serum vitamin D with weight loss. Design: We analyzed data from participants in the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT) [n = 322; mean body mass index (BMI; in kg/[m.sup.2]): 31; mean age: 52 y]. A representative sample (n = 126) was followed for 6 mo for serum vitamin D changes. Results: Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations decreased significantly across the tertiles of baseline BMI (25.6 + 8.0, 24.1 + 8.9, and 22.9 + 6.8 ng/mL, respectively; P for trend = 0.02). Baseline concentrations of vitamin D and dairy calcium intake were not associated with subsequent weight loss. However, in repeated-measures models adjusted for age, sex, baseline BMI, total fat intake, and diet group assignment, higher 6-mo tertile levels of dairy calcium intake (median for tertiles: 156.5, 358.0, and 582.9 mg/d, respectively) and serum 25(OH)D (14.5, 21.2, and 30.2 ng/mL, respectively) were associated with increased weight loss across the 2-y intervention (-3.3, -3.5, and -5.3 kg, respectively, for dairy calcium; P = 0.043; -3.1, -3.8, and -5.6 kg, respectively, for vitamin D; P = 0.013). In a multivariate logistic regression adjusted simultaneously for age, sex, baseline BMI, total fat intake, diet group, vitamin D concentration, and dairy calcium, an increase of 1 SD in dairy calcium intake increased the likelihood of weight loss of >4.5 kg in the preceding 6 mo [odds ratio (OR): 1.45; P = 0.046]. A similar increase was seen for serum 25(OH)D at the 6-mo point (OR: 1.7; P = 0.009). Conclusion: Our study suggests that both higher dairy calcium intake and increased serum vitamin D are related to greater diet-induced weight loss. This trial was registered at clinicaltrials.gov as NCT00160108. doi: 10.3945/ajcn.2010.29355

Background: Vitamin D status is known to be important for bone health but may also affect the development of several chronic diseases, including cancer and cardiovascular diseases, which are 2 major causes of death. Objective: We aimed to examine how vitamin D status relates to overall and cause-specific mortality. Design: The Uppsala Longitudinal Study of Adult Men, a community-based cohort of elderly men (mean age at baseline: 71 y; n = 1194), was used to investigate the association between plasma 25-hydroxyvitamin D [25(OH)D] and mortality. Total plasma 25(OH)D was determined with HPLC atmospheric pressure chemical ionization mass spectrometry. Proportional hazards regression was used to compute hazard ratios (HRs). Results: During follow-up (median: 12.7 y), 584 (49%) participants died. There was a U-shaped association between vitamin D concentrations and total mortality. An approximately 50% higher total mortality rate was observed among men in the lowest 10% (98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations. Cancer mortality was also higher at low plasma concentrations (multivariable-adjusted HR: 2.20; 95% CI: 1.44, 3.38) and at high concentrations (HR: 2.64; 95% CI: 1.46, 4.78). For cardiovascular death, only low (HR: 1.89; 95% CI: 1.21, 2.96) but not high (HR: 1.33; 95% CI: 0.69, 2.54) concentrations indicated higher risk. Conclusions: Both high and low concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality. Low concentrations are associated with cardiovascular mortality. Am J Clin Nutr 2010;92:841-8. doi: 10.3945/ajcn.2010.29749.

Background: Vitamin D sufficiency may be determined by the serum concentration of 25-hydroxyvitamin D [25(OH)D] that results in maximal intestinal calcium absorption efficiency. However, some investigators questioned whether 25(OH)D concentrations above the concentrations associated with rickets or osteomalacia influence calcium absorption. Objective: We determined whether calcium absorption efficiency is related to serum 25(OH)D or serum 1,25-dihydroxyvitamin D [1,25[(OH).sub.2]D] concentrations. Design: We measured calcium absorption efficiency in 492 black and white healthy women (age range: 20-80 y) by the single-isotope method with [sup.45]Ca. Serum 25(OH)D concentrations were measured by a radioreceptor assay. Other relevant measurements included concentrations of serum 1,25[(OH).sub.2]D, serum parathyroid hormone, serum creatinine, and serum estradiol, calcium intake, and bone mineral density. Results: There was no relation between serum 25(OH)D concentrations and calcium absorption efficiency. In development of a multivariate model, the 4 major determinants of calcium absorption efficiency were menopausal status, calcium intake, and serum estradiol and serum 1,25[(OH).sub.2]D concentrations. There was an interaction between serum 25(OH)D and 1,25[(OH).sub.2]D concentrations on calcium absorption efficiency. The relation between calcium absorption and 1,25[(OH).sub.2]D was positive, and this relation was stronger for lower concentrations of 25(OH)D than for higher concentrations of 25(OH)D. Conclusion: The relation of serum 25(OH)D to calcium absorption is not useful as an indicator of vitamin D sufficiency. Am J Clin Nutr 2010;92:835-40. doi: 10.3945/ajcn.2010.29553.

Background: Vitamin D has been added to calcium-fortified orange juice. It is unknown whether vitamin D is as bioavailable from orange juice as it is from supplements. Objectives: The objective was to compare the bioavailability of vitamin [D.sub.2] and vitamin [D.sub.3] from orange juice with that from vitamin [D.sub.2] and vitamin [D.sub.3] supplements. A secondary aim was to determine which form of vitamin D is more bioavailable in orange juice. Design: A randomized, placebo-controlled, double-blind study was conducted in healthy adults aged 18-84 y (15-20/group) who received 1000 IU vitamin [D.sub.3], 1000 IU vitamin [D.sub.2], or placebo in orange juice or capsule for 11 wk at the end of winter. Results: A total of 64% of subjects began the study deficient in vitamin D (ie, 25-hydroxyvitamin D [25(OH)D]) concentrations 0.1). Similarly, no significant difference in serum 25(OH)[D.sub.2] was observed between subjects who consumed vitamin [D.sub.2]--fortified orange juice and vitamin [D.sub.2] capsules (P > 0.1). No significant overall difference in parathyroid hormone concentrations was observed between the groups (P = 0.82). Conclusion: Vitamin [D.sub.2] and vitamin [D.sub.3] are equally bioavailable in orange juice and capsules. doi: 10.3945/ajcn.2009.27972.

Background: It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations. Objective: The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status. Design: A random sample of 3055 postmenopausal women (aged 50-70 y) participating in 3 nested case-control studies of the Women's Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995-2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Women's Health Initiative baseline (1993-1998), were used. Results: More than half of the women (57.1%) had deficient ( Conclusions: Surrogate markers for 25(OH)D concentrations, although somewhat correlated, do not adequately reflect serum vitamin D measures. These markers and predictive models of blood 25(OH)D concentrations should not be given as much weight in epidemiologic studies of cancer risk. doi: 10.3945/ajcn.2009.28908.

Background: To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza. Objective: We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren. Design: From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D3 supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen. Results: Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D3 group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D3 compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006). Conclusion: This study suggests that vitamin D3 supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373. doi: 10.3945/ajcn.2009.29094.

Background: Dietary calcium and vitamin D intakes may be inversely associated with cardiovascular disease (CVD) risk, possibly because of their potential beneficial effects on circulating lipids. Clinical trials that have evaluated the effect of calcium supplementation on lipids are limited by a short follow-up, and data on vitamin D are scarce. Objective: The objective was to evaluate the effect of a longer-term effect (over 5 y) of calcium and vitamin D (CAD) supplementation on changes in the concentrations of several lipids: LDL, HDL, non-HDL, total cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]. Design: The study was conducted in 1259 postmenopausal women in the Calcium plus Vitamin D Trial (1 g elemental Ca as carbonate plus 400 IU vitamin [D.sub.3]/d compared with placebo) of the Women's Health Initiative. Analyses were conducted by intention-to-treat. Repeated measurements on lipids during follow-up were analyzed by linear mixed-effects models. Results: Overall, the change in lipids was relatively small [[less than or equal to ]5% except for Lp(a), which was 20-25%], and there was no significant difference in the mean change of any lipid variable between the active and placebo groups. Conclusions: Our results indicate that CaD supplementation is not associated with lipid changes over 5 y. Existing and future CaD trials should consider evaluating this association for different doses of supplements. This study was registered at clinicaltrials.gov as NCT00000611. Am J Clin Nutr 2010;91:894-9. doi: 10.3945/ajcn.2009.28579.

Background: Older adults may be more prone to developing vitamin D deficiency than younger adults. Dietary requirements for vitamin D in older adults are based on limited evidence. Objective: The objective was to establish the dietary intake of vitamin D required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above various cutoffs between 25 and 80 nmol/L during wintertime, which accounted for the effect of summer sunshine exposure and diet. Design: A randomized, placebo-controlled, double-blind, 22-wk intervention was conducted in men and women aged [greater than or equal to]64 y (n = 225) at supplemental levels of 0, 5, 10, and 15 [micro]g vitamin [D.sub.3]/d from October 2007 to March 2008. Results: Clear dose-related increments (P < 0.0001) in serum 25(OH)D were observed with increasing supplemental vitamin [D.sub.3] intakes. The slope of the relation between total vitamin D intake and serum 25(OH)D was 1.97 nmol x [L.sup.-1] x [micro]g [intake.sup.-1]. The vitamin D intake that maintained serum 25(OH)D concentrations >25 nmol/L in 97.5% of the sample was 8.6 [micro]g/d. Intakes were 7.9 and 11.4 [micro]g/d in those who reported a minimum of 15 min daily summer sunshine exposure or less, respectively. The intakes required to maintain serum 25(OH)D concentrations of >37.5, >50, and >80 nmol/L in 97.5% of the sample were 17.2, 24.7, and 38.7 [micro]g/d, respectively. Conclusion: To ensure that the vitamin D requirement is met by the vast majority (>97.5%) of adults aged [greater than or equal to]64 y during winter, between 7.9 and 42.8 [micro]g vitamin D/d is required, depending on summer sun exposure and the threshold of adequacy of 25(OH)D. This trial was registered at http://www.controlled-trials.com/ISRCTN20236112 as ISRCTN registration no. ISRCTN20236112.

Background: High blood concentrations of parathyroid hormone and low concentrations of the vitamin D metabolites 25-hydroxyvitamin D [25(OH)D] and calcitriol are considered new cardiovascular disease risk markers. However, there is also evidence that calcitriol increases lipogenesis and decreases lipolysis. Objective: We investigated the effect of vitamin D on weight loss and traditional and nontraditional cardiovascular disease risk markers in overweight subjects. Design: Healthy overweight subjects (n = 200) with mean 25(OH)D concentrations of 30 nmol/L (12 ng/mL) received vitamin D (83 [micro]g/d) or placebo in a double-blind manner for 12 mo while participating in a weight-reduction program. Results: Weight loss was not affected significantly by vitamin D supplementation (-5.7 [+ or -] 5.8 kg) or placebo (-6.4[+ or -] 5.6 kg). However, mean 25(OH)D and calcitriol concentrations increased by 55.5 nmol/L and 40.0 pmol/L, respectively, in the vitamin D group but by only 11.8 nmol/L and 9.3 pmol/L, respectively, in the placebo group (P < 0.001), whereas a more pronounced decrease occurred in the vitamin D group than in the placebo group in blood concentrations of parathyroid hormone (-26.5% compared with -18.7%; P = 0.014), triglycerides (-13.5% compared with +3.0%; P < 0.001), and the inflammation marker tumor necrosis factor-[alpha] (-10.2% compared with -3.2%; P = 0.049). The beneficial biochemical effects were independent of the loss in body weight, fat mass, and sex. However, compared with placebo, vitamin D supplementation also increased LDL-cholesterol concentrations (+5.4% compared with -2.5%; P < 0.001). Conclusions: The results indicate that a vitamin D supplement of 83 [micro]g/d does not adversely affect weight loss and is able to significantly improve several cardiovascular disease risk markers in overweight subjects with inadequate vitamin D status participating in a weight-reduction program. This trial was registered at clinicaltrials.gov as NCT00493012. Am J Clin Nutr 2009;89:1321-7.

Background: In older adults, a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L lowers the risk of fracture. An oral intake of 125 [micro]g (5000 IU) vitamin [D.sub.3]/d may be required to achieve this target. Objective: The objective was to characterize the safety and efficacy of fortifying bread with a biologically meaningful amount of vitamin [D.sub.3]. Design: In a single-arm design, 45 nursing home residents consumed one bun daily that had been fortified with 125 [micro]g (5000 1U) vitamin [D.sub.3] and 320 mg elemental calcium. Results: The initial mean ([+ or -] SD) serum 25(OH)D concentration was 28.5 [+ or -] 10.8 nmol/L. After 12 mo, the 25(OH)D concentration was 125.6 [+ or -] 38.8 nmol/L, and it exceeded 74 nmol/L in 92% of the patients. At every 3-mo follow-up, serum parathyroid hormone was lower than at baseline (P = 0.001). No changes in serum calcium or cases of hypercalcemia were observed at the follow-up assessments. Both mean total urinary calcium and the mean urinary calcium-creatinine ratio increased from baseline at one follow-up time point (P < 0.05). Between baseline and the 12-mo visit, z scores for bone mineral density at the lumbar spine and the hip both increased significantly (P < 0.001). Conclusions: Fortification of bread with much more vitamin D than used previously produced no evident adverse effects on sun-deprived nursing home residents and improved bone density measures. Fortification of bread with 5000 IU vitamin [D.sub.3]/d provided reasonable assurance that vitamin D-deficient older adults attained a serum 25(OH)D concentration greater than the desirable objective of >75 nmol/L. This trial was registered at clinicaltrials.gov as NCT00789503.

Background: Persons with limited exposure to ultraviolet B light, including space travelers, may not receive enough vitamin D. Recent studies indicate that optimal serum 25-hydroxyvitamin D [25(OH)D] should be [greater than or equal to] 80 nmol/L. Objective: This study was designed to evaluate the effectiveness of 3 doses of vitamin D to raise and maintain 25(OH)D to a concentration >80 nmol/L in persons with limited ultraviolet B light exposure. Design: This was a 5-mo, prospective, randomized, double-blind study of vitamin D supplementation. It was conducted during winter in Antarctica at the McMurdo Station, when ultraviolet B radiation levels are essentially zero. The 55 subjects were randomly divided into 3 groups for vitamin D supplementation: 2000 IU/d (n = 18), 1000 IU/d (n = 19), and 400 IU/d (n = 18). An additional 7 subjects did not take supplements or took supplements of their own choosing. Blood samples were collected about every 2 mo during the winter. Results: About 5 mo after supplementation started, 25(OH)D increased to 71 [+ or -] 23 nmol/L in the 2000-IU/d group, 63 [+ or -] 25 nmol/L in the 1000-IU/d group, and 57 [+ or -] 15 nmol/L in the 400-IU/d group and decreased to 34 [+ or -] 12 nmol/L in the group not taking supplements. Conclusions: These data will enable us to provide space crews with evidence-based recommendations for vitamin D supplementation. The findings also have implications for other persons with limited ultraviolet light exposure, including polar workers and the elderly.

Recent Institute of Medicine (IOM) reviews of the process for deriving Dietary Reference Intakes (DRIs) suggest that determining the need for a new nutrient review should be evaluated against criteria set a priori. After selecting the criterion of significant new and relevant research, a working group of US and Canadian government scientists used results from a systematic review and 2 conferences on vitamin D and health to evaluate whether significant new and relevant scientific evidence had become available since the 1997 IOM publication of the DRIs for vitamin D. This working group concluded that there appears to be new research meeting the criteria for 4 key DRI questions. The new research is of larger quantity and quality for the elderly than for other groups, but overall 1) adds to the bone-related and status evidence available to the 1997 DRI Committee for several of the life-stage groups, 2) identifies new outcomes with respect to risk of falls and performance measures in the elderly and potential adverse effects, and 3) provides additional information on dose-response relations between intakes and circulating 25-hydroxyvitamin D concentrations and between 25-hydroxyvitamin D concentrations and several health outcomes (ie, bone-related outcomes for all ages and risk of falls and performance measures in older adults). Members of the working group concluded that significant new and relevant research was available for reviewing the existing DRIs for vitamin D while leaving the decision of whether the new research will result in changes to the current DRIs to a future IOM-convened DRI committee.

Background: Multiple sclerosis (MS) risk is determined by both genes and environment. One of the most striking features of MS is its geographic distribution, particularly the pattern of high MS frequency in areas with low sunlight exposure, the main inducer of vitamin D synthesis. Recent epidemiologic, experimental, and clinical evidence support an effect for low environmental supplies of vitamin D in mediating an increased susceptibility to MS. Objectives: We 1) examined the association of serum 25-hydroxy-vitaminD [25(OH)D] concentrations and MS status and 2) assessed the genetic contribution to serum 25(OH)D concentrations and tested for its association with genetic variants in 2 candidate genes [vitamin D receptor and 1-[alpha]-hydroxylase (CYP27B1)]. Design: We used a twin study approach, comprising adult pairs identified from the longitudinal population-based Canadian Collaborative Project on Genetic Susceptibility to MS. Monozygotic (MZ; n = 40) and dizygotic (DZ; n = 59) pairs, both concordant and discordant for MS, were studied. End-of-winter serum 25(OH)D concentrations were measured by radioimmunoassay, and genotypes were assessed by single nucleotide polymorphism (SNP) assay. Results: Serum concentrations of 25(OH)D were highly correlated in MS-concordant pairs (r = 0.83, P < 0.001), but they were not significantly associated with having the disease (P = 0.4) when analyzed by logistic regression. Intraclass correlation for 25(OH)D concentration was significantly greater in MZ pairs (MZ, r: 0.71 > DZ r: 0.32, P = 0.006). Significant associations of 2 CYP27B1 SNP variants and 25(OH)D concentrations were observed. Conclusion: The findings indicate important genetic influences on regulation of seasonal circulating 25(OH)D concentrations in MS twins.

A diversity of scientific literature supports a role for vitamin D in decreasing colorectal cancer incidence, but the available evidence provides only limited support for an inverse association between vitamin D status and the risk of other types of cancer. We need additional studies analyzing the dose-response relation between vitamin D status and cancer risk, the optimal level of 25-hydroxyvitamin D, the length of time required to observe an effect, and the time period of life when exposure is most relevant. Studies of vitamin D receptor polymorphisms have found that not all polymorphisms have the same association with cancer, and the cancer site could further dictate which polymorphisms might be most important; this indicates a need for more research on gene-environment interactions. Several dietary components and the balance between energy intake and expenditure influence vitamin D metabolism. These studies show that scientists need to identify confounders and modifiers of the biological response to vitamin D, including dietary factors, lifestyle factors such as exercise, and race or ethnicity. Transgenic and knockout animals are powerful tools for identifying the molecular targets of bioactive food components. Scientists should therefore make increased use of these models to identify molecular targets for vitamin D. Many research gaps relate to the need to develop predictive, validated, and sensitive biomarkers, including biomarkers that researchers can use to reliably evaluate intake or exposure to vitamin D, assess one or more specific biological effects that are linked to cancer, and effectively predict individual susceptibility as a function of nutrient-nutrient interactions and genetics.

New knowledge of the biological and clinical importance of the steroid hormone l[alpha],25-dihydroxyvitamin [D.sub.3] [1[alpha],25[(OH).sub.2][D.sub.3]] and its receptor, the vitamin D receptor (VDR), has resulted in significant contributions to good bone health. However, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clinical knowledge is not being translated into better human health. Over the past several decades, the biological sphere of influence of vitamin [D.sub.3], as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis (intestine, bone, kidney, and parathyroid). Now, research has shown that the pluripotent steroid hormone 1[alpha],25[(OH).sub.2][D.sub.3] initiates the physiologic responses of [greater than or equal to] 36 cell types that possess the VDR. In addition to the kidney's endocrine production of circulating 1[alpha],25[(OH).sub.2][D.sub.3], researchers have found a paracrine production of this steroid hormone in [greater than or equal to] 10 extrarenal organs. This article identifies the fundamentals of the vitamin D endocrine system, including its potential for contributions to good health in 5 physiologic arenas in which investigators have clearly documented new biological actions of 1[alpha],25[(OH).sub.2][D.sub.3] through the VDR. As a consequence, the nutritional guidelines for vitamin [D.sub.3] intake (defined by serum hydroxyvitamin [D.sub.3] concentrations) should be reevaluated, taking into account the contributions to good health that all 36 VDR target organs can provide.

The purpose of this review is to summarize the peer-reviewed literature in relation to sunlight exposure assessment and the validity of using sunlight exposure questionnaires to quantify vitamin D status. There is greater variability in personal ultraviolet (UV) light exposure as the result of personal behavior than as the result of ambient UV light exposure. Although statistically significant, the correlation coefficients for the relation between personal report of sun exposure and ambient UV light measured by dosimetry (assessment of radiation dose) are relatively low. Moreover, the few studies to assess the relation between sunlight measures and serum 25-hydroxyvitamin D show low correlations. These low correlations may not be surprising given that personal factors like melanin content in skin and age also influence cutaneous synthesis of vitamin D. In summary, sunlight exposure questionnaires currently provide imprecise estimates of vitamin D status. Research should be directed to develop more objective, nonintrusive, and economical measures of sunlight exposure to quantify personal vitamin D status. KEY WORDS Sunlight, environmental exposure, vitamin D, film dosimetry, ultraviolet rays, questionnaires

In the past quarter century, more than 50 metabolites of vitamin D have been described. To date, only a few of these have been quantified in blood, but this has widened our understanding of the pathologic role that altered vitamin D metabolism plays in the development of diseases of calcium homeostasis. Currently, awareness is growing of the prevalence of vitamin D insufficiency in the general population in association with an increased risk of several diseases. However, for many researchers, it is not clear which vitamin D metabolites should be quantified and what the information gained from such an analysis tells us. Only 2 metabolites, namely, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)[sub.2]D], have received the greatest attention. Of these, the need for measuring serum 1,25(OH)[sub.2]D is limited, and this metabolite should therefore not be considered as part of the standard vitamin D testing regimen. On the other hand, serum 25(OH)D provides the single best assessment of vitamin D status and thus should be the only vitamin D assay typically performed. Currently, numerous formats exist for measuring serum 25(OH)D concentrations, each with its own advantages and disadvantages. This article reviews the currently available methods for serum 25(OH)D quantitation and considers important issues such as whether both the [D.sub.2] and the [D.sub.3] forms of the vitamin should be assayed, whether total or free concentrations are most important, and what measures should be taken to ensure the fidelity of the measurements.

Specific data on vitamin D2 and vitamin D3 are needed to enable the assessment of vitamin D dietary intake. These forms of the vitamin can occur in foods, both naturally or from fortification. The Nutrient Data Laboratory at the Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture collaborated with vitamin D experts in an analytic project with 2 major goals: 1) to review and develop methods for analyzing a variety of food items for vitamin D content and 2) to sample and analyze foods considered to be major contributors of vitamin D. During 2007, analysts from up to 6 laboratories compared methods, made modifications in some cases, and validated results with quality-control samples of similar food types in preparation for the analysis of sampled foods. The Nutrient Data Laboratory has prioritized foods for analysis and has identified the following as important contributors of vitamin D: finfish and shellfish, naturally occurring sources, and fortified foods such as milk, calcium-fortified orange juice, breakfast cereals, American cheese, margarines, and yogurt. A nationwide multistage sampling plan was designed and conducted to select and procure representative sample units of all such foods. After analysis of these food samples and review of the results, acceptable values for vitamin [D.sub.2] and [D.sub.3] will be disseminated in the National Nutrient Database for Standard Reference (Internet: http://www.ars.usda.gov/nutrientdata).

In the past decade, research on the relation between vitamin D exposure and disease in population-based studies has increased exponentially. These studies have involved measurement of vitamin D exposure by means of several methods: blood assays, self-reported dietary and supplemental intakes, and sunlight exposure questionnaires or diaries. As with all exposure measurements, researchers must consider the validity of their assessment tools for capturing vitamin D exposure. The purpose of this article is to summarize our current understanding of the various approaches to measuring vitamin D status within populations as reviewed at the 2007 Experimental Biology symposium, 'Assessment of Vitamin D in PopulationBased Studies.' In summary, serum 25-hydroxyvitamin D is the accepted biomarker for short-term vitamin D status, but estimates of long-term dietary and supplemental intakes of vitamin D and longterm sunlight exposure may be the most logistically feasible indicators of lifetime vitamin D exposure in population-based studies. Also discussed are issues investigators should consider when analyzing relations between vitamin D exposure and disease outcomes in population-based studies as well as research avenues that need further exploration. The best method for assessing vitamin D status in population-based studies will depend primarily on the research question asked and the critical window of vitamin D exposure hypothesized to be most important.

Background: A high prevalence of vitamin D insufficiency has been found in the general population and in patients with chronic kidney disease. Objective: The aim was to examine vitamin D status and determinants and metabolic correlates of serum 25-hydroxyvitamin D in a population of adult Danish kidney transplant patients. Design: This was a cross-sectional study of 173 adult kidney transplant patients with a mean ([+ or -] SD) age of 53.4 [+ or -] 11.7 y and a median graft age of 7.4 y (interquartile range: 3.3-12.7 y). Serum concentrations of intact parathyroid hormone (S-PTH), 25-hydroxy-vitamin D [S-25(OH)D], and 1,25-dihydroxyvitamin D [S-1,25[(OH).sub.2]D] were measured. Dietary and supplementary intake of vitamin D, avoidance of solar ultraviolet B exposure, and selected lifestyle factors were assessed in a subgroup (n = 97). Results: Fifty-one percent of the patients had vitamin D insufficiency [S-25(OH)D 40-75 nmol/L], and an additional 29% had moderate-to-severe vitamin D deficiency [S-25(OH)D [less than or equal to] 39 nmol/ L]. In multiple regression analysis, sun avoidance (negative association) and vitamin D supplementation (positive association) were independent determinants of S-25(OH)D concentrations. Low S-25(OH)D concentrations were associated with 1) increased S-PTH concentrations (P = 0.0002), independently of S- 1,25[(OH).sub.2]D concentrations, and 2) decreased S- 1,25[(OH).sub.2]D concentrations (P = 0.002), independently of graft function. Conclusions: Hypovitaminosis D is common among Danish kidney transplant patients and is associated with reduced concentrations of S-1,25[(OH).sub.2]D and increased S-PTH concentrations. Sun avoidance and vitamin D supplementation are important determinants of vitamin D status. The observed hypovitaminosis D might be corrected by intensified routine vitamin D supplementation as opposed to the current supplementation practice. KEY WORDS Kidney transplantation, hypovitaminosis D, prevalence, sun exposure, vitamin D intake, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone

Background: Reports on the dose response to vitamin D are conflicting, and most data were derived from white men and women. Objective: The objective was to determine the response of serum 25-hydroxyvitamin D [25(OH)D] to oral vitamin [D.sub.3] supplementation in an African American population. Design: Healthy black postmenopausal women (n = 208) participated in a vitamin [D.sub.3] supplementation trial for a period of 3 y. Analyses were done in the vitamin D supplementation arm (n = 104) to quantify the response in serum 25-hydroxyvitamin D concentrations at a steady state vitamin D input. The participants received 20 [micro]g/d (800 IU) oral vitamin [D.sub.3] for the initial 2 y and 50 [micro]g/d (2000 IU) for the third year. Results: Supplementation with 20 [micro]g/d (800 IU/d) vitamin [D.sub.3] raised the mean serum 25(OH)D concentration from a baseline of 46.9 [+ or -] 20.6 nmol/L to 71.4 [+ or -] 21.5 nmol/L at 3 too. The mean ([+ or -] SD) concentration of serum 25(OH)D was 87.3 [+ or -] 27.0 nmol/L 3 mo after supplementation increased to 50 [micro]g/d (2000 IU/d). All participants achieved a serum 25(OH)D concentration >35 nmol/L, 95% achieved a concentration >50 nmol/L, but only 60% achieved a concentration >75 nmol/L. All patients had concentrations 45 nmol/L and a dose of 100/xg (4000 IU/d) for those with a concentration Conclusions: Supplementation with 50 [micro]/d (2000 IU/d) oral vitamin [D.sub.3] is sufficient to raise serum 25-hydroxyvitamin D concentrations to >50 nmol/L in almost all postmenopausal African American women. However, higher doses were needed to achieve concentrations >75 nmol/L in many women in this population. KEY WORDS Ethnicity, vitamin D, 25-hydroxyvitamin D, osteoporosis, vitamin D deficiency, African Americans

Background: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation. Objective: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL. Design: Serum vitamin D concentrations were measured in 2160 women aged 18-79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method. Results: Age was negatively correlated with LTL (r = -0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation. Conclusion: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. KEY WORDS Vitamin D, telomere length, inflammation, aging

Background: Vitamin D is produced endogenously after sun exposure but can also be obtained from natural food sources, food fortification, and dietary supplements. Objective: We aimed to determine the vitamin D status of women (61-86 y old) living in central Sweden (latitude 60[degrees]) during winter and its relation with vitamin D intake and exposure to ultraviolet B radiation. Design: In a cross-sectional study, we assessed the vitamin D status (serum 25 -hydroxyvitamin D [25 (OH)D]) of 116 women by using an enzyme immunoassay. The women completed questionnaires coveting food habits, use of dietary supplements, and sun-related behavior. Results: In a multiple linear regression model, the main determinants of serum 25(OH)D concentrations ([bar.x] [+ or -] SD: 69 [+ or -] 23 mmol/L) were dietary vitamin D (6.0 [+ or -] 1.8 [micro]g/d), travel to a sunny location during winter within the previous 6 mo (26%), and the use of dietary supplements (16%). There was no association between serum 25(OH)D status during the winter and age, time spent outdoors, the use of sunscreen, or skin type. Serum 25(OH)D concentrations increased by 25.5 nmol/L with 2-3 servings (130 g/wk) fatty fish/wk, by 6.2 nmol/L with the daily intake of 300 g vitamin D-fortified reduced-fat dairy products, by 11.0 nmol/L with regular use of vitamin D supplements, and by 14.5 nmol/L with a sun vacation during winter. Among nonsupplement users without a wintertime sun vacation, 2-3 servings fatty fish/wk increased serum vitamin D concentrations by 45%. Conclusion: Fatty fish, vitamin D-fortified reduced-fat dairy products, regular supplement use, and taking a sun vacation are important predictors for serum concentrations of 25(OH)D during winter at a latitude of 60[degrees]. Am J Clin Nutr 2007;86:1399-404. KEY WORDS Vitamin D status, ultraviolet B radiation exposure, 25-hydroxyvitamin D, 25(OH)D, vitamin D intake, dietary vitamin D, vitamin D fortification, vitamin D supplements

Background: Vitamin [D.sub.3] may have therapeutic potential in several diseases, including multiple sclerosis. High doses of vitamin [D.sub.3] may be required for therapeutic efficacy, and yet tolerability--in the present context, defined as the serum concentration of 25-hydroxyvitamin D [25(OH)D] that does not cause hypercalcemia--remains poorly characterized. Objective: The objective of the study was to characterize the calcemic response to specific serum 25(OH)D concentrations. Design: In a 28-wk protocol, 12 patients in an active phase of multiple sclerosis were given 1200 mg elemental Ca/d along with progressively increasing doses of vitamin [D.sub.3]: from 700 to 7000 [micro]g/wk (from 28 000 to 280 000 IU/wk). Results: Mean ([+ or -] SD) serum concentrations of 25(OH)D initially were 78 [+ or -] 35 nmol/L and rose to 386 [+ or -] 157 nmol/L (P < 0.001). Serum calcium concentrations and the urinary ratio of calcium to creatinine neither increased in mean values nor exceeded reference values for any participant (2.1-2.6 mmol/L and < 1.0, respectively). Liver enzymes, serum creatinine, electrolytes, serum protein, and parathyroid hormone did not change according to Bonferroni repeated-measures statistics, although parathyroid hormone did decline significantly according to the paired t test. Disease progression and activity were not affected, but the number of gadolinium-enhancing lesions per patient (assessed with a nuclear magnetic brain scan) decreased from the initial mean of 1.75 to the end-of-study mean of 0.83 (P = 0.03). Conclusions: Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin. KEY WORDS Vitamin D, safety, 25-hydroxyvitamin D, 25(OH)D, multiple sclerosis

Background: Low-energy fractures of the hip, forearm, shoulder, and spine are known consequences of osteoporosis. Objective: We evaluated the effect of I y of treatment with calcium and vitamin D on bone mineral density (BMD) and bone markers in patients with a recent low-energy fracture. Design: In a double-blinded design, patients with fracture of the hip (lower-extremity fracture, or LEF) or upper extremity (UEF) were randomly assigned to receive 3000 mg calcium carbonate [+ or -] 1400 IU cholecalciferol or placebo (200IU cholecalciferol). BMD of the hip (HBMD) and lumbar spine (LBMD) were evaluated by dual-energy X-ray absorptiometry, and physical performance was assessed by the timed Up & Go test. Serum concentrations of 25-hydroxycholecalciferol, parathyroid hormone (PTH), telepeptide of type I collagen (ICTP), osteocalcin, and N-terminal propeptide of collagen type I were measured. Results: A total of 122 patients were included (84% women; [bar.x] [+ or -] SD age: 70 [+ or -] 11 y); 68% completed the study. In an intention-to-treat analysis, LBMD increased in the intervention group and decreased in the placebo group, and the difference between the groups was significant after 12 too: 0.931 [+ or -] 0.211 compared with 0.848 [+ or -] 0.194 (P < 0.05). No significant change was shown for HBMD. The effect of treatment was more pronounced in patients aged Conclusions: A l-y intervention with calcium and vitamin D reduced bone turnover, significantly increased BMD in patients younger than 70 y, and decreased bone loss in older patients. The effect of treatment was related to physical performance. KEY WORDS Bone markers, bone mineral density, calcium, immobility, low-energy fracture, hip fracture, shoulder fracture, forearm fracture, vitamin D

Recent evidence suggests that vitamin D intakes above current recommendations may be associated with better health outcomes. However, optimal serum concentrations of 25-hydroxyvitamin D [25(OH)D] have not been defined. This review summarizes evidence from studies that evaluated thresholds for serum 25(OH)D concentrations in relation to bone mineral density (BMD), lower-extremity function, dental health, and risk of falls, fractures, and colorectal cancer. For all endpoints, the most advantageous serum concentrations of 25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L (36-40 ng/mL). In most persons, these concentrations could not be reached with the currently recommended intakes of 200 and 600 IU vitamin D/d for younger and older adults, respectively. A comparison of vitamin D intakes with achieved serum concentrations of 25(OH)D for the purpose of estimating optimal intakes led us to suggest that, for bone health in younger adults and all studied outcomes in older adults, an increase in the currently recommended intake of vitamin D is warranted. An intake for all adults of [greater than or equal to]1000 IU (40/[micro]g) vitamin D (cholecalciferol)/d is needed to bring vitamin D concentrations in no less than 50% of the population up to 75 nmol/L. The implications of higher doses for the entire adult population should be addressed in future studies. KEY WORDS 25-Hydroxyvitamin D, vitamin D intake, bone density, lower-extremity strength, colorectal cancer

Background: Recent studies show a wide prevalence of hypovitaminosis D in Asian Indians. Objective: The objective was to assess the functional significance of 25-hydroxyvitamin D [25(OH)D] deficiency, vitamin D receptor (VDR) gene, and parathyroid hormone (PTH) gene polymorphisms in relation to bone mineral density (BMD) in urban Asian Indians. Design: Serum total calcium, inorganic phosphorus, alkaline phosphatase, 25(OH)D, intact PTH, and BMD at lumbar spine, proximal femur, and forearm were measured in 105 adult subjects. The genotyping related to VDR (BsmI, FokI, and Taq1) and PTH (BstBI and DralI) gene single-nucleotide polymorphisms was carried out by polymerase chain reaction--restriction fragment length potymorphism analysis. Results: The mean serum 25(OH)D concentration in the whole cohort was 9.8 [+ or -] 6.0 ng/mL, which was inversely related with serum intact PTH values (P = 0.042). Ninety-nine (94.3%) of the 105 subjects had vitamin D deficiency with 25(OH)D concentrations < 20 ng/mL. The age- and body mass index (BMI)--adjusted BMD value at the hip was higher in subjects with serum 25(OH)D values > 9.0 ng/mL than in those with values [less than or equal to] 9.0 ng/mL (0.893 [+ or -] 0.114 compared with 0.839 [+ or -]0.112 g/[cm.sup.2], respectively; P = 0.001). The mean forearm and spine BMD values in subjects with TT (VDR, TaqI) or bb (PTH, BstBI) genotypes were significantly higher than the values in subjects with Tt genotype and BB or Bb genotype, respectively. Conclusion: Functionally significant 25(OH)D deficiency affecting BMD at the hip region is prevalent in urban Asian Indians. However, variation in BMD at the spine and forearm is related to VDR and PTH gene polymorphisms rather than to vitamin D status, at least in this hypovitaminotic D population. KEY WORDS Hypovitaminosis D, VDR, PTH, polymorphism, Asian Indians

Concerns about vitamin D have resurfaced in medical and scientific literature because the prevalence of vitamin D deficiency in the United States, particularly among darkly pigmented persons, has increased. The primary goals of this review were to discuss past and current literature and to reassess the dietary reference intake for vitamin D in adults, with particular focus on women during pregnancy and lactation. The appropriate dose of vitamin D during pregnancy and lactation is unknown, although it appears to be greater than the current dietary reference intake of 200-400 IU/d (5-10 [micro]g/d). Doses of [less than or equal to] 10 000 IU vitamin D/d (250 [micro]g/d) for up to 5 mo do not elevate circulating 25-hydroxyvitamin D to concentrations > 90 ng/mL, whereas doses < 1000 IU/d appear, in many cases, to be inadequate for maintaining normal circulating 25-hydroxyvitamin D concentrations of between 15 and 80 ng/mL. Vitamin D plays no etiologic role in cardiac valvular disease, such as that observed in Williams syndrome, and, as such, animal models involving vitamin D intoxication that show an effect on cardiac disease are flawed and offer no insight into normal human physiology. Higher doses of vitamin D are necessary for a large segment of Americans to achieve concentrations equivalent to those in persons who live and work in sun-rich environments. Further studies are necessary to determine optimal vitamin D intakes for pregnant and lactating women as a function of latitude and race. KEY WORDS Vitamin D, cholecalciferol, calcifediol, pregnancy, breast milk, lactation

Background: Short trials of calcium supplementation show that it reduces loss of bone density in postmenopausal women; longer observational studies do not generally find a lower risk of hip fracture with higher-calcium diets. Fewer studies have focused on vitamin D in preventing postmenopausal osteoporosis or fractures. Objective: We assessed relations between postmenopausal hip fracture risk and calcium, vitamin D, and milk consumption. Design: In an 18-y prospective analysis in 72 337 postmenopausal women, dietary intake and nutritional supplement use were assessed at baseline in 1980 and updated several times during follow-up. We identified 603 incident hip fractures resulting from low or moderate trauma. Relative risks (RRs) from proportional hazards models were controlled for other dietary and nondietary factors. Results: Women consuming [greater than or equal to] 12.5 [micro]g vitamin D/d from food plus supplements had a 37% lower risk of hip fracture (RR = 0.63; 95% CI: 0.42, 0.94) than did women consuming < 3.5 [micro]g/d. Total calcium intake was not associated with hip fracture risk (RR = 0.96; 95% CI: 0.68, 1.34 for [greater than or equal to] 1200 compared with < 600 mg/d). Milk consumption was also not associated with a lower risk of hip fracture (P for trend = 0.21). Conclusions: An adequate vitamin D intake is associated with a lower risk of osteoporotic hip fractures in postmenopausal women. Neither milk nor a high-calcium diet appears to reduce risk. Because women commonly consume less than the recommended intake of vitamin D, supplement use or dark fish consumption may be prudent. KEY WORDS Calcium, vitamin D, milk, diet, hip fracture, osteoporosis, postmenopausal women