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Abstract Context Vitamin D is classically recognized as a regulator of calcium and phosphorus metabolism. Recent advances in the measurement of vitamin D metabolites, diagnosis of vitamin D deficiency, and clinical observations have led to an appreciation that along with its role in skeletal metabolism, vitamin D may well have an important role in nonclassical settings. Measurement of the circulating form of vitamin D that best describes total body stores, namely 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented. Likewise, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative. Moreover, the target concentrations of 25-hydroxyvitamin D to address a number of putative links between vitamin D inadequacy and nonskeletal diseases are further areas of uncertainty. Setting To address these issues, an international conference on “Controversies in Vitamin D” was held in Pisa, Italy, in June 2017. Three main topics were addressed: (i) vitamin D assays and the definition of hypovitaminosis D; (ii) skeletal and extraskeletal effects of vitamin D; (iii) therapeutics of vitamin D. Results This report provides a summary of the deliberations of the expert panels of the conference. Conclusions Despite great advances in our appreciation of vitamin D metabolism, measurements, biological actions on classical and nonclassical tissues, and therapeutics, all of which this report summarizes, much more work remains to be done so that our knowledge base can become even more secure. This summary statement reports the deliberations and conclusions of an international conference on “Controversies in Vitamin D.”

24,25-Dihydroxyvitamin D [24,25(OH)2D] in serum may be both a nuisance and nutritionally valuable. We investigated the impact of 24,25(OH)2D3 on the performance of commercially available immunoassays for serum total 25-hydroxyvitamin D [25(OH)D] using (a) serum from a nationally representative sample of adults, (b) serum from a spiking experiment, and (c) data from the UK Vitamin D External Quality Assurance Scheme (DEQAS). We also investigated the utility of the serum ratio of 24,25(OH)2D3 to 25(OH)D as an index of inactivation and of response to vitamin D supplementation using randomized controlled trial (RCT) data. Measurement of 24,25(OH)2D in sera by a LC-MS/MS method allowed for an investigation of its impact on immunoassay-derived serum 25(OH)D values as well as its clinical utility. We report data from a nationally representative sample of adults, a recent vitamin D RCT in older adults, and DEQAS. 24,25(OH)2D3 contributed to the positive bias observed in some immunoassays relative to LC-MS/MS-derived estimates for total 25(OH)D. A spiking experiment showed that the degree of cross-reactivity with 24,25(OH)2D was high and may underpin this positive bias. Adjustment for 24,25(OH)2D3 concentration brought estimates closer to true values. Data from the vitamin D RCT showed that the ratio of 24,25(OH)2D3 to 25(OH)D was associated with serum 25(OH)D3 and with response of serum 25(OH)D to vitamin D supplementation. Our findings highlight that the effect of 24,25(OH)2D3 in serum is a double-edged sword-an interferent for some immunoassays, yet potentially informative of nutritional status.

Abstract Background There is controversy regarding the potential influence of vitamin D deficiency, exposure to environmental tobacco smoke, BCG vaccination, season, and body habitus on susceptibility to Mycobacterium tuberculosis (MTB) infection. Methods We conducted a cross-sectional analysis to identify determinants of a positive QuantiFERON-TB Gold (QFT) assay result in children aged 6–13 years attending 18 schools in Ulaanbaatar, Mongolia. Data relating to potential risk factors for MTB infection were collected by questionnaire, physical examination, and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios (RRs) were calculated with adjustment for potential confounders, and population attributable fractions (PAFs) were calculated for modifiable risk factors identified. Results Nine hundred forty-six of 9810 (9.6%) participants had a positive QFT result. QFT positivity was independently associated with household exposure to pulmonary tuberculosis (adjusted RR [aRR], 4.75 [95% confidence interval {CI}, 4.13–5.46, P < .001]; PAF, 13.1% [95% CI, 11.1%–15.0%]), vitamin D deficiency (aRR, 1.23 [95% CI, 1.08–1.40], P = .002; PAF, 5.7% [95% CI, 1.9%–9.3%]), exposure to environmental tobacco smoke (1 indoor smoker, aRR, 1.19 [95% CI, 1.04–1.35]; ≥2 indoor smokers, aRR, 1.30 [95% CI, 1.02–1.64]; P for trend = .006; PAF, 7.2% [95% CI, 2.2%–12.0%]), and increasing age (aRR per additional year, 1.14 [95% CI, 1.10–1.19], P < .001). No statistically significant independent association was seen for presence of a BCG scar, season of sampling, or body mass index. Conclusions Vitamin D deficiency and exposure to environmental tobacco smoke are potentially modifiable risk factors for MTB infection. This large community-based study of risk factors for QuantiFERON positivity in Mongolian schoolchildren reports that household exposure to an index case of pulmonary tuberculosis, vitamin D deficiency, passive smoking, and increasing age are risk factors for Mycobacterium tuberculosis infection in childhood.

An interlaboratory comparison study was conducted by the Vitamin D Standardization Program (VDSP) to assess the performance of ligand binding assays (Part 2) for the determination of serum total 25-hydroxyvitamin D [25(OH)D]. Fifty single-donor samples were assigned target values for concentrations of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], 3-epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3], and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] using isotope dilution liquid chromatography–tandem mass spectrometry (ID LC-MS/MS). VDSP Intercomparison Study 2 Part 2 includes results from 17 laboratories using 32 ligand binding assays. Assay performance was evaluated using mean % bias compared to the assigned target values and using linear regression analysis of the test assay mean results and the target values. Only 50% of the ligand binding assays achieved the VDSP criterion of mean % bias ≤ |± 5%|. For the 13 unique ligand binding assays evaluated in this study, only 4 assays were consistently within ± 5% mean bias and 4 assays were consistently outside ± 5% mean bias regardless of the laboratory performing the assay. Based on multivariable regression analysis using the concentrations of individual vitamin D metabolites in the 50 single-donor samples, most assays underestimate 25(OH)D2 and several assays (Abbott, bioMérieux, DiaSorin, IDS-EIA, and IDS-iSYS) may have cross-reactivity from 24R,25(OH)2D3. The results of this interlaboratory study represent the most comprehensive comparison of 25(OH)D ligand binding assays published to date and is the only study to assess the impact of 24R,25(OH)2D3 content using results from a reference measurement procedure.

Background Comparability of 25-hydroxyvitamin D (25(OH)D) measurements is hampered by method-related differences in measurement values. International standardization of laboratory assays has been suggested to solve this problem. Methods As part of the European Commission–funded project ‘Food-based solutions for optimal vitamin D nutrition and health through the life cycle’ (ODIN), original measurements of serum 25(OH)D of three German national health surveys conducted between 1998 and 2011 have been standardized retrospectively. In these representative population-based samples including persons aged between 1 and 79 years, the original 25(OH)D values were compared with those after standardization. Mean values and prevalences of vitamin D deficiency, insufficiency, and sufficiency (25(OH)D levels < 30, 30- < 50, and > =50 nmol/l, respectively) were calculated by sex and age groups based on original and standardized 25(OH)D data. Results In comparison to the original 25(OH)D levels, the standardized levels showed higher means overall and in age- and sex-specific analyses. After standardization, the prevalence of vitamin D deficiency was lower in all surveys while the prevalence of vitamin D sufficiency was higher. Nevertheless, even after standardization ~ 15% of adults and 12.5% of children had serum 25(OH)D levels < 30 nmol/l. Thus, the proportion of deficient vitamin D levels in the German population is still considerable. Conclusions The use of standardization of 25(OH)D levels has a substantial impact on estimates of the vitamin D status in Germany. Since clinical diagnostic, therapeutic and public health decision-making require valid and comparable data, standardization and calibration of commercial, clinical and research laboratory assays for 25(OH)D measurement should become common practice. Until then, researchers, health practitioners and policy makers should be aware of the peculiarities of the measurement methods when comparing and interpreting 25(OH)D levels.

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

The prevalence of obesity is increasing, and there is evidence that obesity, in particular abdominal obesity as a marker of insulin resistance, is negatively associated with pulmonary function. The mechanism for this association and the best marker of abdominal adiposity in relation to pulmonary function is not known. We assessed the association between pulmonary function and weight, body mass index (BMI), waist circumference, waist/hip ratio, and abdominal height as markers of adiposity and body fat distribution. We used multiple linear regression to analyze the association of pulmonary function (ie, FEV1 and FVC) [with maneuvers performed in the sitting position] with overall adiposity markers (ie, weight and BMI) and abdominal adiposity markers, stratified by gender, and adjusted for height, age, race, smoking, and other covariates. A random sample of individuals (n = 2,153) from the general population living in western New York state, 35 to 79 years of age. In women, abdominal height and waist circumference were negatively associated with FEV1 percent predicted, while all five adiposity markers were negatively associated with FVC percent predicted. In men, all overall and abdominal adiposity markers were inversely associated with FEV1 percent predicted and FVC percent predicted. These results suggest that abdominal adiposity is a better predictor of pulmonary function than weight or BMI, and investigators should consider it when investigating the determinants of pulmonary function.

Clinical trials indicate that a sizable proportion of adults have multiple borderline coronary risk factors and may benefit from treatment. To estimate the relative and absolute contributions of borderline and elevated risk factors to the population burden of coronary heart disease (CHD) events. A prospective cohort study and a national cross-sectional survey. The Framingham Study and the Third National Health and Nutrition Examination Survey (NHANES III). White non-Hispanic persons in the Framingham Study and in NHANES III who were between 35 to 74 years of age and had no CHD. Occurrence of first CHD events according to 5 major CHD risk factors: blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, glucose intolerance, and smoking. Three categories-optimal, borderline, and elevated-were defined for each risk factor per national guidelines. Sex-specific 10-year CHD event rates from the Framingham Study were applied to numbers of at-risk individuals estimated from NHANES III and the 2000 U.S. Census. Twenty-six percent of men and 41% of women had at least 1 borderline risk factor in NHANES III. According to estimates, more than 90% of CHD events will occur in individuals with at least 1 elevated risk factor, and approximately 8% will occur in people with only borderline levels of multiple risk factors. Absolute 10-year CHD risk exceeded 10% in men older than age 45 years who had 1 elevated risk factor and 4 or more borderline risk factors and in those who had at least 2 elevated risk factors. In women, absolute CHD risk exceeded 10% only in those older than age 55 years who had at least 3 elevated risk factors. The generalizability of the findings to persons of other ethnic backgrounds is unknown. Borderline CHD risk factors alone account for a small proportion of CHD events.

Aim: To make quantitative estimates of the burden of disease attributable to alcohol in the year 2000 on a global basis. Design: Secondary data analysis. Measurements: Two dimensions of alcohol exposure were included: average volume of alcohol consumption and patterns of drinking. There were also two main outcome measures: mortality, i.e. the number of deaths, and disability-adjusted life years (DALYs), i.e. the number of years of life lost to premature mortality or to disability. All estimates were prepared separately by sex, age group and WHO region. Findings: Alcohol causes a considerable disease burden: 3.2% of the global deaths and 4.0% of the global DALYs in the year 2000 could be attributed to this exposure. There were marked differences by sex and region for both outcomes. In addition, there were differences by disease category and type of outcome; in particular, unintentional injuries contributed most to alcohol-attributable mortality burden while neuropsychiatric diseases contributed most to alcohol-attributable disease burden. Discussion/Conclusions: The underlying assumptions are discussed and reasons are given as to why the estimates should still be considered conservative despite the considerable burden attributable to alcohol globally.

Summary Vitamin D status has long been related to falls risk. In this planned secondary analysis of a vitamin supplementation trial in postmenopausal women, standardized 25-hydroxyvitamin D concentration up to 60 ng/mL was not associated with increased falls. Women with 25(OH)D ≥ 60 ng/mL had higher odds of ≥ 2 falls. Purpose Falls are common and cause fractures. High circulating 25(OH)D may increase falls risk; thus, recent guidance recommends 25(OH)D not exceed 50 ng/mL. Prior falls studies have not reported standardized 25(OH)D (s25D) data. The purpose of this planned secondary analysis of a 4-year calcium/vitamin D supplementation trial was to evaluate the association of s25D with falls. Methods This study recruited 2,303 postmenopausal women. The analytic dataset consisted of pooled concatenated data from years 2–4 (N Total  = 5,732). Serum 25(OH)D was measured annually and subsequently retrospectively standardized using Vitamin D Standardization Program methods. Falls were recorded by diary. Incidence for ≥ 1 fall and ≥ 2 falls was assessed by s25D group (≤ 20, 20- < 30, 30- < 40, 40- < 50, 50- < 60 and ≥ 60 ng/mL) using multivariable logistic regression. Results Mean (SD) baseline s25D was 32.6 ng/mL (8.3) with no difference between supplement and placebo groups. s25D increased to 41.3 ng/mL at year 2 in the supplement group then remained stable. By s25D group, incidence for ≥ 1 fall varied from 22–32% (p = 0.19). For ≥ 2 falls incidence varied (p = 0.03) from 6% (< 20 ng/mL) to 17% (≥ 60 ng/mL.) There was no significant association between s25D and ≥ 1 fall. Those with s25D ≥ 60 ng/mL had a higher adjusted odds of ≥ 2 falls (OR = 1.99 ± 1.2–3.3) compared to women with s25D of 30- < 40 ng/mL. Conclusion s25D up to 60 ng/mL was not associated with greater risk for ≥ 1 or ≥ 2 falls. Women with a s25D ≥ 60 ng/mL were at higher odds for ≥ 2 falls, however this group included only ~ 2% of study observations; therefore, confirmation in other cohorts is necessary.