Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

CONTEXT: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. OBJECTIVE AND METHODS: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. RESULTS: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. CONCLUSION: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.

Vitamin D and acute and severe illness - a mechanistic and pharmacokinetic perspective.

The coronavirus disease 2019 (COVID-19) pandemic has generated high interest in factors modulating risk of infection, disease severity and recovery. Vitamin D has garnered interest since it is known to modulate immune function and vitamin D deficiency is associated with increased risk of respiratory infections and adverse health outcomes in severely ill patients. There are no population representative data on the direct relationship between vitamin D status and severe acute respiratory syndrome coronavirus 2 infection risk and severity of COVID-19. Data from intervention studies are limited to four studies. Here we summarise findings regarding vitamin D status and metabolism and their alterations during severe illness, relevant to COVID-19 patients. Further, we summarise vitamin D intervention studies with respiratory disease outcomes and in critically ill patients and provide an overview of relevant patient and population guidelines. Vitamin D deficiency is highly prevalent in hospitalised patients, particularly when critically ill, including those with COVID-19. Acute and critical illness leads to pronounced changes in vitamin D metabolism and status, suggestive of increased requirements. This needs to be considered in the interpretation of potential links between vitamin D status and disease risk and severity and for patient management. There is some evidence that vitamin D supplementation decreases the risk of respiratory tract infections, while supplementation of intensive care unit patients has shown little effect on disease severity or length of treatment. Considering the high prevalence of deficiency and low risks associated with supplementation, pro-actively applying current population and patient management guidelines to prevent, monitor and correct vitamin D deficiency is appropriate.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Vitamin D Supplementation for Patients with Chronic Kidney Disease: A Systematic Review and Meta-analyses of Trials Investigating the Response to Supplementation and an Overview of Guidelines.

A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US population guidelines) and this contributes to the development of CKD-mineral bone disease (CKD-MBD). Gaps in the evidence-base for the management of vitamin D status in relation to CKD-MBD are hindering the formulation of comprehensive guidelines. We conducted a systemic review of 22 RCTs with different forms of vitamin D or analogues with CKD-MBD related outcomes and meta-analyses for parathyroid hormone (PTH). We provide a comprehensive overview of current guidelines for the management of vitamin D status for pre-dialysis CKD patients. Vitamin D supplementation had an inconsistent effect on PTH concentrations and meta-analysis showed non- significant reduction (P = 0.08) whereas calcifediol, calcitriol and paricalcitol consistently reduced PTH. An increase in Fibroblast Growth Factor 23 (FGF23) with analogue administration was found in all 3 studies reporting FGF23, but was unaltered in 4 studies with vitamin D or calcifediol. Few RCTS reported markers of bone metabolism and variations in the range of markers prevented direct comparisons. Guidelines for CKD stages G1-G3a follow general population recommendations. For the correction of deficiency general or CKD-specific patient guidelines provide recommendations. Calcitriol or analogues administration is restricted to stages G3b-G5 and depends on patient characteristics. In conclusion, the effect of vitamin D supplementation in CKD patients was inconsistent between studies. Calcifediol and analogues consistently suppressed PTH, but the increase in FGF23 with calcitriol analogues warrants caution.

Vitamin D Status Increases During Pregnancy and in Response to Vitamin D Supplementation in Rural Gambian Women.

BACKGROUND: Vitamin D is important to maternal, fetal, and infant health, but quality data on vitamin D status in low- and middle-income countries and response to cholecalciferol supplementation in pregnancy are sparse. OBJECTIVE: We characterized vitamin D status and vitamin D metabolite change across pregnancy and in response to cholecalciferol supplementation in rural Gambia. METHODS: This study was a secondary analysis of samples collected in a 4-arm trial of maternal nutritional supplementation [iron folic acid (FeFol); multiple micronutrients (MMN); protein energy (PE) as lipid-based supplement; PE + MMN]; MMN included 10 µg/d cholecalciferol. Plasma 25-hydroxycholecalciferol [25(OH)D3], 24,25-dihydroxycholecalciferol [24,25(OH)2D3], and C3-epimer-25-hydroxycholecalciferol [3-epi-25(OH)D3] were measured by LC-MS/MS in 863 women [aged 30 ± 7 y (mean ± SD)] in early pregnancy (presupplementation) and late pregnancy, (gestational age 14 ± 3 and 30 ± 1 wk). Changes in 25(OH)D3 and vitamin D metabolite concentrations and associations with pregnancy stage and maternal age and anthropometry were tested. RESULTS: Early pregnancy 25(OH)D3 concentration was 70 ± 15 nmol/L and increased according to pregnancy stage (82 ± 18 and 87 ± 17 nmol/L in the FeFol and PE-arms) and to cholecalciferol supplementation (95 ± 19 and 90 ± 20 nmol/L in the MMN and PE + MMN-arms) (P < 0.0001). There was no difference between supplemented groups. Early pregnancy 25(OH)D3 was positively associated with maternal age and gestational age. Change in 25(OH)D3 was negatively associated with late pregnancy, but not early pregnancy, triceps skinfold thickness. The pattern of change of 24,25(OH)2D3 mirrored that of 25(OH)D3 and appeared to flatten as pregnancy progressed, whereas 3-epi-25(OH)D3 concentration increased across pregnancy. CONCLUSION: This study provides important data on the vitamin D status of a large cohort of healthy pregnant women in rural Africa. Without supplementation, vitamin D status increased during pregnancy, demonstrating that pregnancy stage should be considered when assessing vitamin D status. Nutritionally relevant cholecalciferol supplementation further increased vitamin D status. These data are relevant to the development of fortification and supplementation policies in pregnant women in West Africa.

Vitamin D Measurement, the Debates Continue, New Analytes Have Emerged, Developments Have Variable Outcomes.

The demand for measurement of vitamin D metabolites for clinical diagnosis and to advance our understanding of the role of vitamin D in human health has significantly increased in the last decade. New developments in technologies employed have enabled the separation and quantification of additional metabolites and interferences. Also, developments of immunoassays have changed the landscape. Programmes and materials for assay standardisation, harmonisation and the expansion of the vitamin D external quality assurance scheme (DEQAS) with the provision of target values as measured by a reference measurement procedure have improved standardisation, quality assurance and comparability of measurements. In this article, we describe developments in the measurement of the commonly analysed vitamin D metabolites in clinical and research practice. We describe current analytical approaches, discuss differences between assays, their origin, and how these may be influenced by physiological and experimental conditions. The value of measuring metabolites beyond 25 hydroxyvitamin D (25(OH)D), the marker of vitamin D status, in routine clinical practice is not yet confirmed. Here we provide an overview of the value and application of the measurement of 1,25 dihydroxyvitamin D, 24,25 dihydroxyvitamin D and free 25OHD in the diagnosis of patients with abnormalities in vitamin D metabolism and for research purposes.

Late Pregnancy Vitamin D Deficiency is Associated with Doubled Odds of Birth Asphyxia and Emergency Caesarean Section: A Prospective Cohort Study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the associations between maternal vitamin D status in late pregnancy and emergency caesarean section (EMCS) and birth asphyxia, in a population based sample of women in Sweden. METHODS: Pregnant women were recruited at the antenatal care in Sweden and 1832 women were included after exclusion of miscarriages, terminated pregnancies and missing data on vitamin D status. Mode of delivery was retrieved from medical records. EMCS was defined as caesarean section after onset of labour. Birth asphyxia was defined as either 5 min Apgar score < 7 or arterial umbilical cord pH < 7.1. Serum was sampled in the third trimester of pregnancy (T3) and 25-hydroxyvitamin D (25OHD) was analysed by liquid chromatography tandem mass spectrometry. Vitamin D deficiency was defined as 25OHD < 30 nmol/L, and associations were studied using logistic regression analysis and expressed as adjusted odds ratios (AOR). RESULTS: In total, 141 (7.7%) women had an EMCS and 58 (3.2%) children were born with birth asphyxia. Vitamin D deficiency was only associated with higher odds of EMCS in women without epidural anaesthesia (AOR = 2.01, p = 0.044). Vitamin D deficiency was also associated with higher odds of birth asphyxia (AOR = 2.22, p = 0.044). CONCLUSIONS FOR PRACTICE: In this Swedish prospective population-based cohort study, vitamin D deficiency in late pregnancy was associated with doubled odds of birth asphyxia and with EMCS in deliveries not aided by epidural anaesthesia. Prevention of vitamin D deficiency among pregnant women may reduce the incidence of EMCS and birth asphyxia. The mechanism behind the findings require further investigation.

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study.

BACKGROUND: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. METHODS: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57-58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. RESULTS: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. CONCLUSIONS: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy.

Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition.

The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25-hydroxyvitamin D (p = .049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.

Effects of vitamin D supplementation on endothelial function: a systematic review and meta-analysis of randomised clinical trials.

BACKGROUND: In addition to regulating calcium homoeostasis and bone health, vitamin D influences vascular and metabolic processes including endothelial function (EF) and insulin signalling. This systematic review and meta-analysis of randomised clinical trials (RCTs) were conducted to investigate the effect of vitamin D supplementation on EF and to examine whether the effect size was modified by health status, study duration, dose, route of vitamin D administration, vitamin D status (baseline and post-intervention), body mass index (BMI), age and type of vitamin D. METHODS: We searched the Medline, Embase, Cochrane Library and Scopus databases from inception until March 2015 for studies meeting the following criteria: (1) RCT with adult participants, (2) vitamin D administration alone, (3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography, applanation tonometry and laser Doppler. RESULTS: Sixteen articles reporting data for 1177 participants were included. Study duration ranged from 4 to 52 weeks. The effect of vitamin D on EF was not significant (SMD: 0.08, 95 % CI -0.06, 0.22, p = 0.28). Subgroup analysis showed a significant improvement of EF in diabetic subjects (SMD: 0.31, 95 % CI 0.05, 0.57, p = 0.02). A non-significant trend was found for diastolic blood pressure (ß = 0.02; p = 0.07) and BMI (ß = 0.05; p = 0.06). CONCLUSIONS: Vitamin D supplementation did not improve EF. The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function. This remains to be tested in future studies.

Sequences of Regressions Distinguish Nonmechanical from Mechanical Associations between Metabolic Factors, Body Composition, and Bone in Healthy Postmenopausal Women.

BACKGROUND: There is increasing recognition of complex interrelations between the endocrine functions of bone and fat tissues or organs. OBJECTIVE: The objective was to describe nonmechanical and mechanical links between metabolic factors, body composition, and bone with the use of graphical Markov models. METHODS: Seventy postmenopausal women with a mean ± SD age of 62.3 ± 3.7 y and body mass index (in kg/m2) of 24.9 ± 3.8 were recruited. Bone outcomes were peripheral quantitative computed tomography measures of the distal and diaphyseal tibia, cross-sectional area (CSA), volumetric bone mineral density (vBMD), and cortical CSA. Biomarkers of osteoblast and adipocyte function were plasma concentrations of leptin, adiponectin, osteocalcin, undercarboxylated osteocalcin (UCOC), and phylloquinone. Body composition measurements were lean and percent fat mass, which were derived with the use of a 4-compartment model. Sequences of Regressions, a subclass of graphical Markov models, were used to describe the direct (nonmechanical) and indirect (mechanical) interrelations between metabolic factors and bone by simultaneously modeling multiple bone outcomes and their relation with biomarker outcomes with lean mass, percent fat mass, and height as intermediate explanatory variables. RESULTS: The graphical Markov models showed both direct and indirect associations linking plasma leptin and adiponectin concentrations with CSA and vBMD. At the distal tibia, lean mass, height, and adiponectin-UCOC interaction were directly explanatory of CSA (R2 = 0.45); at the diaphysis, lean mass, percent fat mass, leptin, osteocalcin, and age-adiponectin interaction were directly explanatory of CSA (R2 = 0.49). The regression models exploring direct associations for vBMD were much weaker, with R2 = 0.15 and 0.18 at the distal and diaphyseal sites, respectively. Lean mass and UCOC were associated, and the global Markov property of the graph indicated that this association was explained by osteocalcin. CONCLUSIONS: This study, to our knowledge, offers a novel approach to the description of the complex physiological interrelations between adiponectin, leptin, and osteocalcin and the musculoskeletal system. There may be benefits to jointly targeting both systems to improve bone health.

Early renal impairment affects hormonal regulators of calcium and bone metabolism and Wnt signalling and the response to vitamin D supplementation in healthy older adults.

Bone and renal metabolism are regulated by common factors and there is extensive cross-talk between these organs (the 'renal-bone-axis'). Ageing is associated with physiological changes including reduced bone mass, renal function and tissue sensitivity to regulatory hormones, impacting the renal-bone axis. We aimed to investigate the influence of estimated Glomerular Filtration Rate (eGFR) on plasma concentrations of vitamin D metabolites, Wnt signalling and bone metabolism in a dose ranging vitamin D3 RCT (12,000 IU, 24,000 IU, 48,000 IU/month for 1 year; n = 379, >70 y) with a baseline eGFR > 30 mL/min/1.73 m2. Participants were categorised on basis of eGFR (≥60 or mL/min/1.73 m2) based on 5 commonly used algorithms for eGFR. Differences between eGFR categories were tested with ANCOVA. Before supplementation commenced, a lower eGFR was associated with significantly higher concentrations of c-terminal and intact Fibroblast Growth Factor-23 (cFGF23; iFGF23), intact Parathyroid Hormone (iPTH) and Sclerostin (SOST) and lower Klotho, 1,25-dihydroxy Vitamin D (1,25(OH)2D) and Dickkopf-related Protein 1 (DKK1) concentrations. Differences between eGFR groups in 25-hydroxy Vitamin D (25(OH)D), 24,25-dihydroxy Vitamin D (24,25(OH)2D) and iPTH were only detected with eGFR based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification in Diet for Renal Disease (MDRD-4) algorithms. Differences in Bone Mineral Density and Content (BMD; BMC) and bone turnover markers were detected only with Cockcroft-Gault (CG). Pre- and post- supplementation comparisons showed differences in the response to supplementation by eGFR group. Plasma 25(OH)D, 24,25(OH)2D, 1,25(OH)2D and DKK1 increased and iPTH and C-terminal telopeptide (CTX) decreased in both groups. Plasma iFGF23, bone specific alkaline phosphatase (BAP) and Procollagen 1 intact N-terminal Propeptide (PINP) increased and phosphate decreased only in the group with eGFR ≥ 60 mL/min/1.73 m2. Findings were largely consistent across all eGFR algorithms. Post-supplementation, cFGF23, iFGF23, iPTH and SOST remained significantly higher in the lower eGFR group. Plasma 1,25(OH)2D and Klotho did no longer differ between eGFR groups. This was found for all eGFR algorithms, with the exception of iPTH and iFGF23, which were not significantly different with eGFR based on CG. Differences in BMD and BMC were detected with CKD-EPI-creatinine and MDRD-4 but not GC. This study showed that even a moderate decline in eGFR is associated with alterations in vitamin D metabolism, Wnt signalling and bone turnover markers. Renal function influenced the response to vitamin D supplementation. Supplementation increased Vitamin D metabolites in the group with moderate renal impairment to concentrations comparable to those found in the group with normal renal function. However, although CTX decreased, an increase in bone formation markers was not found in the group with eGFR 60 mL/min/1.73 m2. In conclusion, vitamin D supplementation had beneficial effects on markers of the renal-bone axis in older people with both normal and impaired renal function.

3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1.

Loss-of-function mutations in the CYP24A1 protein-coding region causing reduced 25 hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D (1,25(OH)2 D) catabolism have been observed in some cases of infantile hypercalcemia type 1 (HCINF1), which can manifest as nephrocalcinosis, hypercalcemia and adult-onset hypercalciuria, and renal stone formation. Some cases present with apparent CYP24A1 phenotypes but do not exhibit pathogenic mutations. Here, we assessed the molecular mechanisms driving apparent HCINF1 where there was a lack of CYP24A1 mutation. We obtained blood samples from 47 patients with either a single abnormality of no obvious cause or a combination of hypercalcemia, hypercalciuria, and nephrolithiasis as part of our metabolic and stone clinics. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine serum vitamin D metabolites and direct sequencing to confirm CYP24A1 genotype. Six patients presented with profiles characteristic of altered CYP24A1 function but lacked protein-coding mutations in CYP24A1. Analysis upstream and downstream of the coding sequence showed single nucleotide variants (SNVs) in the CYP24A1 3' untranslated region (UTR). Bioinformatics approaches revealed that these 3' UTR abnormalities did not result in microRNA silencing but altered the CYP24A1 messenger RNA (mRNA) secondary structure, which negatively impacted translation. Our experiments showed that mRNA misfolding driven by these 3' UTR sequence-dependent structural elements was associated with normal 25OHD but abnormal 1,25(OH)2 D catabolism. Using CRISPR-Cas9 gene editing, we developed an in vitro mutant model for future CYP24A1 studies. Our results form a basis for future studies investigating structure-function relationships and novel CYP24A1 mutations producing a semifunctional protein. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Plasma appearance and disappearance of an oral dose of 25-hydroxyvitamin D2 in healthy adults.

25-Hydroxyvitamin D (25(OH)D) half-life is a potential biomarker for investigating vitamin D metabolism and requirements. We performed a pilot study to assess the approach and practical feasibility of measuring 25(OH)D half-life after an oral dose. A total of twelve healthy Gambian men aged 18-23 years were divided into two groups to investigate the rate and timing of (1) absorption and (2) plasma disappearance after an 80 nmol oral dose of 25(OH)D2. Fasting blood samples were collected at baseline and, in the first group, every 2 h post-dose for 12 h, at 24 h, 48 h and on day 15. In the second group, fasting blood samples were collected on days 3, 4, 5, 6, 9, 12, 15, 18 and 21. Urine was collected for 2 h after the first morning void at baseline and on day 15. 25(OH)D2 plasma concentration was measured by ultra-performance liquid chromatography-tandem MS/MS and corrected for baseline. Biomarkers of vitamin D, Ca and P metabolism were measured at baseline and on day 15. The peak plasma concentration of 25(OH)D2 was 9·6 (sd 0·9) nmol/l at 4·4 (sd 1·8) h. The terminal slope of 25(OH)D2 disappearance was identified to commence from day 6. The terminal half-life of plasma 25(OH)D2 was 13·4 (sd 2·7) d. There were no significant differences in plasma 25(OH)D3, total 1,25(OH)2D, parathyroid hormone, P, Ca and ionised Ca and urinary Ca and P between baseline and day 15 and between the two groups. The present study provides data on the plasma response to oral 25(OH)D2 that will underpin and contribute to the further development of studies to investigate 25(OH)D half-life.

Calcium economy in human pregnancy and lactation.

Pregnancy and lactation are times of additional demand for Ca. Ca is transferred across the placenta for fetal skeletal mineralisation, and supplied to the mammary gland for secretion into breast milk. In theory, these additional maternal requirements could be met through mobilisation of Ca from the skeleton, increased intestinal Ca absorption efficiency, enhanced renal Ca retention or greater dietary Ca intake. The extent to which any or all of these apply, the underpinning biological mechanisms and the possible consequences for maternal and infant bone health in the short and long term are the focus of the present review. The complexities in the methodological aspects of interpreting the literature in this area are highlighted and the inter-individual variation in the response to pregnancy and lactation is reviewed. In summary, human pregnancy and lactation are associated with changes in Ca and bone metabolism that support the transfer of Ca between mother and child. The changes generally appear to be independent of maternal Ca supply in populations where Ca intakes are close to current recommendations. Evidence suggests that the processes are physiological in humans and that they provide sufficient Ca for fetal growth and breast-milk production, without relying on an increase in dietary Ca intake or compromising long-term maternal bone health. Further research is needed to determine the limitations of the maternal response to the Ca demands of pregnancy and lactation, especially among mothers with marginal and low dietary Ca intake, and to define vitamin D adequacy for reproductive women.

Vitamin D Supplementation for 12 Months in Older Adults Alters Regulators of Bone Metabolism but Does Not Change Wnt Signaling Pathway Markers.

Vitamin D status and supplementation regulates bone metabolism and may modulate Wnt signaling. We studied the response of hormonal regulators of bone metabolism, markers of Wnt signaling and bone turnover and bone mineral density (BMD) and bone mineral content (BMC) in a randomized vitamin D intervention trial (12,000 IU, 24,000 IU, 48,000 IU/mo for 1 year; men and women aged >70 years; n = 379; ISRCTN35648481). Associations with total and free 25(OH)D concentrations were analyzed by linear regression. Baseline vitamin D status was (mean ± SD) 25(OH)D: 40.0 ± 20.1 nmol/L. Supplementation dose-dependently increased total and free 25(OH)D concentrations and decreased plasma phosphate and parathyroid hormone (PTH) (all p < 0.05). The procollagen 1 intact N-terminal (PINP)/C-terminal telopeptide (CTX) ratio, C-terminal fibroblast growth factor-23 (cFGF23), and intact FGF23 (iFGF23) significantly increased with no between-group differences, whereas Klotho was unchanged. 1,25(OH)2D and PINP significantly increased in the 24 IU and 48,000 IU groups. Sclerostin (SOST), osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), BMD, BMC, and CTX remained unchanged. Subgroup analyses with baseline 25(OH)D <25 nmol/L (n = 94) provided similar results. Baseline total and free 25(OH)D concentrations were positively associated with 1,25(OH)2D, 24,25(OH)2D (p < 0.001), vitamin D binding protein (DBP) (p < 0.05), BMD, and BMC (p < 0.05). Associations with PTH (p <0.001), cFGF23 (p < 0.01), and BAP (p < 0.05) were negative. After supplementation, total and free 25(OH)D concentrations remained positively associated only with 24,25(OH)2D (p < 0.001) and DBP (p < 0.001) and negatively with estimated glomerular filtration rate (eGFR) (p < 0.01). PTH and SOST were significantly associated only with free 25(OH)D. There were no significant relationships with BMD and BMC after supplementation. The decrease in PTH and increase in PINP/CTX ratio suggest a protective effect of supplementation on bone metabolism, although no significant effect on BMD or pronounced changes in regulators of Wnt signaling were found. The increase in FGF23 warrants caution because of its negative association with skeletal and cardiovascular health. Associations of total and free 25(OH)D with biomarkers were similar and known positive associations between vitamin D status and BMD were confirmed. The change in associations after supplementation might suggest a threshold effect. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.