Gene-vegetarianism interactions in calcium, estimated glomerular filtration rate, and testosterone identified in genome-wide analysis across 30 biomarkers.

We examined the associations of vegetarianism with metabolic biomarkers using traditional and genetic epidemiology. First, we addressed inconsistencies in self-reported vegetarianism among UK Biobank participants by utilizing data from two dietary surveys to find a cohort of strict European vegetarians (N = 2,312). Vegetarians were matched 1:4 with nonvegetarians for non-genetic association analyses, revealing significant effects of vegetarianism in 15 of 30 biomarkers. Cholesterol measures plus vitamin D were significantly lower in vegetarians, while triglycerides were higher. A genome-wide association study revealed no genome-wide significant (GWS; 5×10-8) associations with vegetarian behavior. We performed genome-wide gene-vegetarianism interaction analyses for the biomarkers, and detected a GWS interaction impacting calcium at rs72952628 (P = 4.47×10-8). rs72952628 is in MMAA, a B12 metabolic pathway gene; B12 has major deficiency potential in vegetarians. Gene-based interaction tests revealed two significant genes, RNF168 in testosterone (P = 1.45×10-6) and DOCK4 in estimated glomerular filtration rate (eGFR) (P = 6.76×10-7), which have previously been associated with testicular and renal traits, respectively. These nutrigenetic findings indicate genotype can modify the associations between vegetarianism and health outcomes.

Intratumoral vitamin D signaling and lethal prostate cancer.

High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.

The effect of an acute bout of exercise on circulating vitamin D metabolite concentrations: a randomised crossover study in healthy adults.

The effect of acute exercise on circulating concentrations of vitamin D metabolites is unclear. To address this knowledge gap, we examined the effect of a bout of treadmill-based exercise versus rest on circulating concentrations of 25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and vitamin D2 and D3 in healthy men and women. Thirty-three healthy adults (14 females, 41 (15) years, body mass index 26.2 (3.7) kg/m2, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ 36.2 (9.2) ml/kg/min; mean (SD)) completed two laboratory visits involving 60 min of moderate-intensity treadmill exercise (60% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ ) versus 60 min of seated rest, both in an overnight fasted-state, as part of a randomised crossover design. Venous blood samples were drawn at baseline, immediately (0 h), 1 h and 24 h after the exercise or rest-period. There was a significant time × trial interaction effect for total circulating 25(OH)D (P = 0.0148), 25(OH)D3 (P = 0.0127) and 1,25(OH)2D3 (P = 0.0226). Immediately post-exercise, 25(OH)D, 25(OH)D3 and 1,25(OH)2D3 concentrations were significantly elevated compared to the control resting condition, and 1,25(OH) 2D3 remained significantly elevated 1 h later. Circulating albumin, vitamin D binding protein, calcium and parathyroid hormone were elevated immediately post-exercise. Thus, an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. KEY POINTS: Observational studies suggest that acute exercise might change circulating concentrations of vitamin D metabolites, but this has not been investigated using randomised crossover studies and using robust analytical procedures. In this study, we used a randomised crossover design to examine the effect of a bout of treadmill-based exercise (vs. rest) on circulating concentrations of a wide range of vitamin D metabolites in healthy humans. We show that an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. These findings indicate that regular exercise could lead to transient but regular windows of enhanced vitamin D biological action.

Effect of Daily Vitamin D Supplementation on Risk of Upper Respiratory Infection in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. RESULTS: Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI}, .86-1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI, .28-1.30]). Statistical power to assess effect modification in other subgroups was limited. CONCLUSIONS: In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259.

Predicted 25-hydroxyvitamin D over the adult lifetime and the risk of ovarian cancer.

The evidence from previous studies of serum 25-hydroxyvitamin D (25(OH)D) and ovarian cancer risk is not conclusive. However, the 25(OH)D levels were generally only measured in late adulthood, which may not capture the etiologically relevant exposure periods. We investigated predicted 25(OH)D over the adult lifetime in relation to ovarian cancer risk in a population-based case-control study conducted from 2011 to 2016 in Montreal, Canada (n = 490 cases and 896 controls). Predicted 25(OH)D was computed using previously validated regression models. Unconditional multivariable logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% CIs for average predicted 25(OH)D over the adult lifetime and ovarian cancer risk. In addition, the relative importance of different periods of past 25(OH)D exposure was explored using a weighted cumulative exposure (WCE) model. For each 20-nmol/L increase in average predicted 25(OH)D over the adult lifetime, the aOR (95% CI) was 0.73 (0.55-0.96). In WCE analyses, the inverse association was strongest for exposures 5 to 20 years and 35 to 55 years prior to diagnosis, with aORs (95% CIs) of 0.82 (0.69-0.94) and 0.79 (0.66-1.02), respectively, for each 20-nmol/L increase in predicted 25(OH)D. These results support an inverse association between 25(OH)D levels in adulthood and ovarian cancer risk. This article is part of a Special Collection on Gynecological Cancers.

High-dose vitamin D to attenuate bone loss in patients with prostate cancer on androgen deprivation therapy: A phase 2 RCT.

BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.

Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation.

BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

BACKGROUND: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). METHODS: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1ß, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. RESULTS: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1ß and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1ß: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). CONCLUSIONS: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Effects of probiotic and vitamin D co-supplementation on clinical symptoms, mental health, and inflammation in adult patients with migraine headache: a randomized, triple-blinded, placebo-controlled trial.

BACKGROUND: Migraine headache is a major public health problem. Routine medications for migraine treatment are not useful in treating all patients and may have some side effects. The present study aimed to investigate the effect of vitamin D and probiotic co-supplementation on clinical characteristics of migraine, daily functioning, mental health outcomes, and serum levels of high-sensitivity C-reactive protein (hs-CRP). METHODS: In this randomized, triple-blinded, placebo-controlled trial, patients aged 18 to 55 years diagnosed with migraine based on the International Classification of Headache Disorders-3 (ICHD-3) were randomized to either vitamin D (50,000 IU every 2 weeks) plus probiotic (4.5 × 1011 CFU per day) or placebo for 12 weeks. The Headache Impact Test (HIT-6) and Depression, Anxiety, and Stress Scale (DASS) questionnaires were administered to patients at baseline and after 12 weeks. In addition, the frequency, duration, and severity of migraine headaches per month were assessed using a self-administered 30-day headache diary at baseline and the end of the intervention. Anthropometric indices, blood pressure, and serum levels of 25-hydroxy vitamin D and hs-CRP were also examined at first and the end of the study. RESULTS: Seventy-two migraine patients with a mean age of 37.46 ± 8.32 years were included in this trial. Probiotic and vitamin D co-supplementation compared to placebo resulted in a significant increase in serum levels of vitamin D (+ 12.86 ± 1.64 vs. + 1.12 ± 0.80 ng/mL, P < 0.001). The between-group analysis in the adjusted model showed a significantly greater reduction in migraine headache frequency (- 3.17 ± 0.84 vs. - 1.25 ± 0.34; P = 0.031) and severity (- 1.55 ± 0.35 vs. + 0.67 ± 0.29; P = 0.017) in the probiotic and vitamin D group than the placebo group. No significant difference was found between the two arms of the intervention regarding the change in headache duration, hs-CRP, scores of DASS, and HIT-6 questionnaires (P > 0.05). CONCLUSIONS: This trial showed that probiotic and vitamin D co-supplementation for 12 weeks has beneficial effects on migraine headache characteristics. Further research is needed to confirm this finding.

Vitamin D: Analytical Advances, Clinical Impact, and Ongoing Debates on Health Perspectives.

BACKGROUND: Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected to conclude when the outcomes of high-dose supplementation randomized controlled trials were available. Skepticism arose with inconclusive results from these trials. CONTENT: This review begins with an exploration of vitamin D metabolism, followed by a detailed description of the measurement of vitamin D metabolites and the crucial role of standardization. Subsequent sections focus on the association of vitamin D with bone health and explore the extra-skeletal effects. The review concludes with a comprehensive discussion on the definition of vitamin D status and its implications for supplementation. SUMMARY: Despite standardization efforts, assay variations and challenges still exist, especially in specific patient groups. Vitamin D supplementation has a significant impact on bone metabolism and optimal vitamin D status improves the efficacy of antiresorptive drugs such as bisphosphonates. The extra-skeletal effects of vitamin D remain debated, but may include potential benefits in conditions such as respiratory infections and cancer mortality, particularly in deficient individuals. The definition of vitamin D sufficiency is nuanced, especially when variations in population groups and analytical methods are taken into account. Despite ongoing debates and recent mega-trials tempering enthusiasm, vitamin D remains a complex and essential element in human health. Further research is needed to clarify its role in various health outcomes and guide supplementation strategies.

Vitamin D Metabolites Before and After Kidney Transplantation in Patients Who Are Anephric.

RATIONALE & OBJECTIVE: Kidneys are vital for vitamin D metabolism, and disruptions in both production and catabolism occur in chronic kidney disease. Although vitamin D activation occurs in numerous tissues, the kidneys are the most relevant source of circulating active vitamin D. This study investigates extrarenal vitamin D activation and the impact of kidney transplantation on vitamin D metabolism in patients who are anephric. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Adult patients with previous bilateral nephrectomy (anephric) not receiving active vitamin D therapy evaluated at the time of (N=38) and 1 year after (n=25) kidney transplantation. ANALYTICAL APPROACH: Chromatography with tandem mass spectrometry was used to measure vitamin D metabolites. Activity of CYP24A1 [24,25(OH)2D/25(OH)D] and CYP27B1 [1α,25(OH)2D/25(OH)D] is expressed as metabolic ratios. Differences between time points were evaluated by paired t-test or Wilcoxon matched-pairs signed-rank test. RESULTS: At time of transplantation, 1α,25(OH)2D was detectable in all patients (4-36pg/mL). There was a linear relationship between 25(OH)D and 1α,25(OH)2D levels (r=0.58, P<0.001), with 25(OH)D explaining 34% of the variation in 1α,25(OH)2D levels. There were no associations between 1α,25(OH)2D and biointact parathyroid hormone (PTH) or fibroblast growth factor 23 (FGF-23). One year after transplantation, 1α,25(OH)2D levels recovered (+205%), and CYP27B1 activity increased (+352%). Measures of vitamin D catabolism, 24,25(OH)2D and CYP24A1 activity increased 3- to 5-fold. Also, at 12 months after transplantation, 1α,25(OH)2D was positively correlated with PTH (ρ=0.603, P=0.04) but not with levels of 25(OH)D or FGF-23. LIMITATIONS: Retrospective, observational study design with a small cohort size. CONCLUSIONS: Low-normal levels of 1α,25(OH)2D was demonstrated in anephric patients, indicating production outside the kidneys. This extrarenal CYP27B1 activity may be more substrate driven than hormonally regulated. Kidney transplantation seems to restore kidney CYP27B1 and CYP24A1 activity, as evaluated by vitamin D metabolic ratios, resulting in both increased vitamin D production and catabolism. These findings may have implications for vitamin D supplementation strategies in the setting of kidney failure and transplantation. PLAIN-LANGUAGE SUMMARY: Vitamin D activation occurs in multiple tissues, but the kidneys are considered the only relevant source of circulating levels. This study investigates vitamin D activation outside the kidneys by measuring vitamin D metabolites in 38 patients without kidneys. Active vitamin D was detectable in all patients, indicating production outside of the kidneys. There was a strong relationship between active and precursor vitamin D levels, but no association with mineral metabolism hormones, indicating that vitamin D production was more substrate dependent than hormonally regulated. One year after kidney transplantation, active vitamin D levels increased 2-fold and breakdown products increased 3-fold, indicating that production and degradation of the hormone recovers after kidney transplantation. These findings are relevant for future research into vitamin D supplementation in kidney failure.

Plasma vitamin D levels are correlated with the pathogenesis of human T-cell leukemia virus type 1-associated diseases.

The active form of vitamin D (VD) exerts hormonal effects by regulating the expression of genes involved in T-cell activity, cell differentiation, and proliferation. Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of life-threatening diseases, adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy (HAM). Among ATL patients, hypercalcemia is one of the most serious complications due to bone resorption. In this study, wild-type mice administered UV-irradiated HTLV-1-infected cells showed up to 47% decrease of plasma VD level compared with untreated mice. To clarify the effect of HTLV-1 on plasma VD level, 315 samples registered in nationwide cohort study on ATL onset were measured. The VD level in HAM (14.98 ± 8.5 ng/mL) was significantly lower than those in asymptomatic carriers and ATL (p < 0.05). Upon comparing the VD levels in ATL stratified by disease subtypes, acute ATL showed a lower level (15.81 ± 12.0 ng/mL) than chronic and smoldering types (p < 0.05). In the longitudinal observation, VD levels were significantly higher in untreated spontaneous remission cases than in ATL progression cases, in which the VD levels decreased approximately 40% after onset. In cases of relapse after transplantation, the plasma VD level dropped to 38.7% of the pre-relapse level, while in cases of complete remission, the VD level increased with improvement of the performance status. Taken together, these results suggest that plasma VD level is a potential indicator for the onset and relapse of HTLV-1-associated diseases.

Associations Between Early-Pregnancy Vitamin D Status and Postpartum Depressive and Anxiety Symptoms.

OBJECTIVE: Maternal postpartum depressive and anxiety symptoms are risk factors for subsequent maternal and child mental health problems. Little is known about the potential role of antepartum vitamin D and C-reactive protein (CRP) in the etiology of maternal postpartum affective symptoms. We investigated associations between antepartum vitamin D status and postpartum depressive and anxiety symptoms and whether antepartum CRP mediated these associations. METHODS: In 2483 participants of the Amsterdam Born Children and their Development prospective cohort, maternal serum vitamin D and CRP were measured at a median of 13 weeks' gestation. Vitamin D status was defined as deficient (≤29.9 nM), insufficient (30-49.9 nM), sufficient (50-79.9 nM), or normal (≥80 nM). Maternal depressive symptoms (Center for Epidemiologic Studies-Depression) and anxiety (State-Trait Anxiety Inventory) were assessed 3 months postpartum. RESULTS: After adjustments for confounders, vitamin D deficiency was only associated with increased postpartum anxiety symptoms ( B = 0.17, 95% confidence interval [CI] = 0.03-0.30, p = .017) compared to normal vitamin D levels (≥80 nM). In women not taking vitamin D supplementation ( n = 2303), vitamin D deficiency was associated with increased postpartum depressive and anxiety symptoms ( B = 0.14, 95% CI = 0.03-0.28, p = .045; and B = 0.17, 95% CI = 0.03-0.32, p = .015). Antepartum CRP did not mediate these links. CONCLUSIONS: We found some evidence that antepartum vitamin D deficiency was associated with increased postpartum affective symptoms, especially in women not taking vitamin D supplementation. Clinical trials should determine whether vitamin D supplementation can reduce the risk for postpartum affective disorders.

Optimisation of vitamin D status in global populations.

Vitamin D is important for musculoskeletal health. Concentrations of 25-hydroxyvitamin D, the most commonly measured metabolite, vary markedly around the world and are influenced by many factors including sun exposure, skin pigmentation, covering, season and supplement use. Whilst overt vitamin D deficiency with biochemical consequences presents an increased risk of severe sequelae such as rickets, osteomalacia or cardiomyopathy and usually warrants prompt replacement treatment, the role of vitamin D supplementation in the population presents a different set of considerations. Here the issue is to keep, on average, the population at a level whereby the risk of adverse health outcomes in the population is minimised. This position paper, which complements recently published work from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, addresses key considerations regarding vitamin D assessment and intervention from the population perspective. This position paper, on behalf of the International Osteoporosis Foundation Vitamin D Working Group, summarises the burden and possible amelioration of vitamin D deficiency in global populations. It addresses key issues including screening, supplementation and food fortification.

Prevalence of low vitamin D levels among older US Asian and Pacific Islander adults.

While US Asian and Pacific Islander adults have lower 25-hydroxyvitamin D (25(OH)D) levels than White adults, ethnic subgroup data remain limited. In a large California population, the adjusted prevalence of 25(OH)D < 20 ng/mL (50 nmol/L) was 1.5- to 2.7-fold higher for Asian/Pacific Islander compared to White adults, with substantial variation by ethnicity. PURPOSE: US Asian and Pacific Islander (PI) adults generally have lower 25-hydroxyvitamin D [25(OH)D] levels than non-Hispanic White (NHW) adults, but subgroup data remain limited. We compared sex- and ethnicity-specific prevalence of low 25(OH)D among older Asian/PI and NHW adults. METHODS: Data from 102,556 Asian/PI and 381,724 NHW adults aged 50-89 years with measured 25(OH)D in 2012-2019 and body mass index (BMI, within ± 1 year) were examined in a California healthcare system. Low 25(OH)D < 20 ng/mL (50 nmol/L) was examined by race and ethnicity. Covariates included age, smoking, BMI, and season of measurement. Modified Poisson regression was used to estimate prevalence ratios (aPR), adjusting for covariates. RESULTS: Among 31,287 Asian/PI men and 71,269 Asian/PI women, the prevalence of low 25(OH)D was 22.6% and 14.7%, respectively, significantly higher than observed for 122,162 NHW men (12.3%) and 259,562 NHW women (9.9%). Within Asian/PI subgroups, low 25(OH)D prevalence ranged from 17 to 18% (Korean, Japanese, Filipino), 22 to 24% (Chinese, Vietnamese), 28% (South Asian), and 35% (Native Hawaiian/PI) among men and 11 to 14% (Japanese, Filipina, Chinese, Korean), 17 to 18% (South Asian, Vietnamese), and 26% (Native Hawaiian/PI) among women. The corresponding aPRs (NHW reference) for men and women were as follows: Native Hawaiian/PI, 2.70 and 2.34; South Asian, 2.56 and 2.07; Vietnamese, 2.17 and 2.31; Chinese, 2.04 and 1.89; Korean, 1.60 and 1.85; Filipino, 1.58 and 1.52; and Japanese, 1.58 and 1.49 (p < 0.001). CONCLUSION: In a large US healthcare population of older Asian/PI adults, low 25(OH)D prevalence was 1.5- to 2.7-fold higher for Asian/PI compared to NHW adults, with substantial variation by sex and ethnicity.

Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies.

BACKGROUND: Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma. METHODS: A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies. RESULTS: We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (ß (95% CI)= - 0.33 (-0.65 to - 0.01); I2 = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D. CONCLUSION: Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.

Prediabetes and insulin resistance: effect of vitamin D.

PURPOSE OF REVIEW: The impact of vitamin D on improving insulin resistance in prediabetes remains controversial. The purpose of this review is to examine whether vitamin D supplementation improves insulin resistance in adults with prediabetes, and if so, to identify the mechanisms and the specific populations. RECENT FINDINGS: Global prevalence of prediabetes is increasing, and prevention is a critical issue because these people with prediabetes will develop type 2 diabetes soon, which will put pressure on healthcare costs. Recent evidence on the effectiveness of vitamin D administration in improving insulin resistance and preventing the onset of type 2 diabetes in adults with prediabetes has been accumulating. The 2024 updated clinical practice guideline of the American Diabetes Association states that vitamin D administration to patients with prediabetes potentially benefits type 2 diabetes incidence in specific populations. There are also reports that vitamin D administration improves insulin resistance via increased serum osteocalcin levels, a marker of bone turnover. SUMMARY: Vitamin D is likely to improve insulin resistance, which is already present at the time of prediabetes. However, the effectiveness may vary depending on ethnic differences and blood vitamin D levels at the start of administration.

Predictive value of Vitamin D levels in pregnant women on gestational length and neonatal weight in China: a population-based retrospective study.

BACKGROUND: Vitamin D deficiency, a common occurrence among pregnant women, is an emerging public health concern worldwide. According to research, prenatal vitamin D deficiency is associated with various complications. This study assessed the vitamin D status of pregnant women in Yanbian, Jilin Province, as well as the correlation and predictive value of their vitamin D levels in relation to gestational length (weeks) and fetal weight, aiming to provide a basis for clinical diagnosis and treatment. METHODS: We conducted a population-based retrospective study involving 510 pregnant women from August 2019 to October 2022. Blood samples were collected at 16-20 weeks of gestation for the detection of serum vitamin D levels. Statistical analyses were performed using SPSS 28.0 and R 4.1.0 software. Multifactorial logistic regression analysis was employed to establish whether each variable was a risk factor for deliveries at ≤ 38 gestational weeks and low fetal weight. These results were used to construct a risk prediction model, and the model's predictive efficacy was evaluated. Results or differences with p < 0.05 were considered statistically significant. RESULTS: Multifactorial logistic regression analysis revealed that vitamin D ≤ 14.7 ng/mL(OR: 1.611; 95% CI: 1.120-2.318; P = 0.010), Bone Mineral Density (BMD) T-value ≤-1(OR: 1.540; 95%CI: 1.067-2.223; P = 0.021), and gestational hypertension(OR: 7.173; 95% CI: 1.482-34.724; P = 0.014) were the independent risk factors for deliveries at ≤ 38 gestational weeks. Additionally, vitamin D ≤ 14.7 ng/mL(OR: 1.610; 95%CI: 1.123-2.307; P = 0.009), BMD T-value ≤ -1(OR: 1.560; 95%CI: 1.085-2.243; P = 0.016), and gestational hypertension(OR: 4.262; 95% CI: 1.058-17.167; P = 0.041) were the independent risk factors for low fetal weight (< 3400 g). CONCLUSION: This study revealed that low vitamin D levels are an independent risk factor for a short gestational length and low fetal weight. Prenatal low BMD T-value and comorbid hypertensive disorders were also found to increase the risk of a short gestational length and low fetal weight.

Cholesterol Interference in the Assessment of Vitamin D Status: A Canadian Health Measures Survey Biobank Project.

BACKGROUND: Matrix effects are a known problem with immunoassays measuring serum 25-hydroxyvitamin D [25(OH)D]. OBJECTIVES: To determine if the inverse association between serum 25(OH)D and serum cholesterol concentrations is a function of assay method: Diasorin Liaison 25(OH) Vitamin D Total Assay (Liaison Total Assay), an immunoassay, compared with liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Canadian Health Measures Survey data and biobank serum (White males aged 20-79 y, n = 392) were evaluated for bias in serum 25(OH)D using Bland-Altman plots. Differences in serum 25(OH)D (Liaison Total Assay - LC-MS/MS) were compared among non-HDL-cholesterol <4.2 (n = 295) compared with ≥4.2 (n = 97) mmol/L and total cholesterol groups <5.2 (n = 256) compared with ≥5.2 (n = 136) mmol/L, and associations tested between 25(OH)D and non-HDL-cholesterol or total cholesterol concentrations, using regression. RESULTS: Serum 25(OH)D measured using Liaison Total Assay ranged from 10.7 to 137.0 nmol/L and 14.4 to 137.9 nmol/L by LC-MS/MS. Liaison Total Assay - LC-MS/MS showed a negative bias of 5.5 (95% limits of agreement -23.8, 12.7) nmol/L. Differences in 25(OH)D were -4.0 ± 9.0 (±SD) nmol/L if non-HDL-cholesterol was <4.2 mmol/L and -10.2 ± 8.7 nmol/L if ≥4.2 mmol/L (P < 0.0001). Differences in 25(OH)D, if total cholesterol was <5.2 mmol/L, were -3.4 ± 8.6 nmol/L and -9.6 ± 9.3 nmol/L if ≥5.2 mmol/L (P < 0.0001). Serum non-HDL-cholesterol (beta -3.17, P = 0.0014) and total cholesterol (beta -2.77, P = 0.0046) were inversely associated with Liaison Total Assay 25(OH)D (adjusted for age, fasting, and body mass index), but not with LC-MS/MS measured 25(OH)D. Interference by these lipoproteins was not eliminated by standardization of the Liaison Total Assay. Similar associations were observed with triglycerides as for the lipoproteins. CONCLUSIONS: Total cholesterol inversely associates with 25(OH)D, which is likely due to elevated non-HDL-cholesterol lipoprotein or triglyceride interference with the Liaison Total Assay. This is important as elevated cholesterol is common, and an underestimation of vitamin D status could be an unnecessary cause for concern.

The Relationship Between Vitamin D Intake and Serum 25-hydroxyvitamin D in Young Children: A Meta-Regression to Inform WHO/FAO Vitamin D Intake Recommendations.

BACKGROUND: This work was commissioned by the World Health Organization and Food and Agriculture Organization to inform their update on the vitamin D requirements for children aged <4 y. OBJECTIVES: The objective of this work was to undertake multilevel and multivariable dose-response modeling of serum 25-hydroxyvitamin D (25OHD) to total vitamin D intake in children aged <4 y with the goal of deriving updated vitamin D requirements for young children. METHODS: Systematically identified randomized controlled trials among healthy children from 2 wk up to 3.9 y of age provided with daily vitamin D supplements or vitamin D-fortified foods were included. Linear and nonlinear random effects multilevel meta-regression models with and without covariates were fitted and compared. Interindividual variability was included by simulating the individual serum 25OHD responses. The percentage of individuals reaching set minimal and maximal serum 25OHD thresholds was calculated and used to derive vitamin D requirements. RESULTS: A total of 31 trials with 186 data points from North America, Europe, Asia, and Australasia/Oceania, with latitudes ranging from 61°N to 38°S, and with participants of likely mostly light or medium skin pigmentation, were included. In 29 studies the children received vitamin D supplements and in 2 studies the children received vitamin D-fortified milk with or without supplements. The dose-response relationship between vitamin D intake and serum 25OHD was best fitted with the unadjusted quadratic model. Adding additional covariates, such as age, did not significantly improve the model. At a vitamin D intake of 10 µg/d, 97.3% of the individuals were predicted to achieve a minimal serum 25OHD threshold of 28 nmol/L. At a vitamin D intake of 35 µg/d, 1.4% of the individuals predicted to reach a maximal serum 25OHD threshold of 200 nmol/L. CONCLUSIONS: In conclusion, this paper details the methodological steps taken to derive vitamin D requirements in children aged <4 y, including the addition of an interindividual variability component.