Advantages and disadvantages of intermittent versus daily vitamin D supplementation especially in adults with or at risk of osteoporosis are discussed by the Osteoporosis Research and Information Group (GRIO). The analysis of the literature suggests that intermittent long-term high doses vitamin D supplementation (such as 60,000IU/month or more), may increase the risk of falls, fracture and premature death in certain populations, while daily doses of 800-1000IU with calcium decrease falls and non-vertebral fractures in the elderly with vitamin D deficiency. In patients with or at risk of osteoporosis we hence recommend measuring the 25(OH)D concentration prior to supplementation and to provide vitamin D supplementation (with optimization of calcium intake if needed) to obtain a concentration between 30 and 60ng/mL. We recommend the use of an initial loading dose, especially in those who need a quick repletion of vitamin D store (symptoms of osteomalacia and/or 25(OH)D concentration <12ng/mL, patients eligible for treatment with potent antiresorptive therapy), followed by a maintenance dose. A daily supplementation should be the rule when possible. When daily forms are however not available or not reimbursed, we recommend, like other experts, to continue using intermittent dosing with the smallest available dose (≤50,000IU) and the shortest interval between doses as a stopgap until reimbursement or adequate daily pharmaceutical forms (pills or soft capsules of 1000, 2000IU) are available.

There are conflicting results on the association between maternal vitamin D concentrations during pregnancy and respiratory outcomes for their offspring. However, published studies have mainly focused on the second and third trimesters of pregnancy or on high-risk population. The main objective of this study was to evaluate the association between vitamin D plasma concentrations in the first trimester (T1) of pregnancy and effective specific airway resistance (sReff) for children aged 5 to 6. Secondary objectives were to evaluate this association in the third trimester (T3) and in cord blood as well as the association between vitamin D plasma concentration and interrupter resistance (Rint), bronchiolitis, asthma, and allergen sensitization at the same time points. This multicenter study included 140 children born from women enrolled in the FEPED cohort. Associations between sReff and maternal vitamin D plasma concentration at T1, T3 of pregnancy, and in cord blood were assessed. sReff was analyzed according to in-utero and postnatal exposure to tobacco smoke and the occurrence of an episode of bronchiolitis before 6 months of age. The impact of maternal vitamin D status on the secondary outcomes was similarly assessed. sReff values were not associated with the maternal vitamin D status at T1 and T3, nor asthma status or allergen sensitization. Conclusion: In a cohort of young children, airway resistance and asthma were not associated with early vitamin D deficiency during pregnancy. Trial registration: This study is registered with the ClinicalTrials.gov identifier NCT03229317.

Objectives: Inherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to investigate: 1/ whether IAAMDs was associated with growth, pubertal, bone mineral apparent density (BMAD) or body composition impairments; 2/ associations linking height, amino-acid mixture (AAM), plasma amino-acids and IGF1 concentrations. Design: Retrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD,n = 77), organic aciduria (OA,n = 89), maple syrup urine disease (MSUD,n = 34), or tyrosinaemia type 1 (n = 13). Methods: We collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. Results: Overall final height (n = 69) was below target height (TH): -0.9(1.4) vs. -0.1(0.9) SD, p < 0.001. Final height was <= TH-2SD in 12 (21%) patients. Height <= - 2SD was more frequent during puberty than during early-infancy and pre-puberty: 23.5% vs. 6.9%, p = 0.002; and vs. 10.7%, p < 0.001. Pubertal delay was frequent (26.7%). Height (SD) was positively associated with isoleucine concentration: beta, 0.008; 95%CI, 0.003 to 0.012; p = 0.001. In the pubertal subgroup, height (SD) was lower in patients with vs. without AAM supplementation: -1.22 (1.40) vs. -0.63 (1.46) (p = 0.02). In OA, height and median (IQR) isoleucine and valine concentrations(mu mol/L) during puberty were lower in patients with vs. without AAM supplementation: -1.75 (1.30) vs. -0.33 (1.55) SD, p < 0.001; and 40 (23) vs. 60 (25) (p = 0.02) and 138 (92) vs. 191 (63) (p = 0.01), respectively. No correlation was found with IGF1. Lean-mass index was lower than fat-mass index: -2.03 (1.15) vs. -0.44 (0.89), p < 0.001. Conclusions: In IAAMDs, growth retardation worsened during puberty which was delayed in all disease subgroups. Height seems linked to the disease, AAM composition and lower isoleucine concentration, independently of the GH-IGF1 pathway. We recommend close monitoring of diet during puberty.

CONTEXT:Serum calcium is frequently measured during the neonatal period, and it is known to be influenced by the vitamin D status. OBJECTIVE:We hypothesized that the 25-hydroxyvitamin D (25OHD) concentration may influence the lower limit of the serum calcium normal range in neonates. METHODS:We included in our prospective cohort study 1002 mother-newborn pair recruited from April 2012 to July 2014, in 2 centers located in the neighborhoods of Paris, France, whose serum calcium was measured at 3 days of life. We established, after exclusion of outliers, a 95% CI for serum calcium (i) in our whole population of 1002 neonates; (ii) in neonates with a cord blood 25OHD concentration ≥ 30 nmol/L; and (iii) in those with a 25OHD ≥ 50 nmol/L. RESULTS:The mean serum total calcium was 2.46 ± 0.13 nmol/L (95% CI: 2.19-2.72 mmol/L), 2.47 ± 0.25 mmol/L (95% CI: 2.22-2.72 mmol/L), and 2.50 ± 0.25 mmol/L (95% CI: 2.25-2.75 mmol/L) in the whole group, in the 514 neonates with 25OHD ≥ 30 nmol/L, and in the 202 neonates with 25OHD ≥ 50 nmol/L respectively. The lower limit of the 95% range was significantly higher in neonates with 25 OHD ≥ 30 nmol/L (P < 0.05) and ≥ 50 nmol/L (P < .001) than in the entire cohort. CONCLUSION:We show that the lower limit of the normal serum calcium range is higher in groups with a higher 25OHD than in unselected subjects. We propose that the reference range for serum calcium in neonates is 2.25 to 2.75 mmol/L.

Vitamin D is important for growth and bone health. It stimulates the absorption of calcium and phosphate, controls the secretion of parathyroid hormone, is involved in the renal absorption of calcium in the distal tubule, and exerts complex effects on bone which may be anabolic or catabolic depending on the needs, and stimulates the secretion of FGF23 by osteocytes. Vitamin D is hydroxylated in the liver to make 25-hydroxyvitamin D (25OHD), and then in the kidney to make 1,25-dihydroxyvitamin D (1,25OH2D or calcitriol), the active vitamin D metabolite which binds to a nuclear receptor, the VDR, in target tissues that are reached through the bloodsteam. According to this mechanism, calcitriol can clearly be considered as a true hormone. It must also be remembered that vitamin D and/or 25OHD may penetrate in many tissues where they are activated into calcitriol which binds locally in the VDR present in these tissues to exert intracrine effects. (c) 2023 Published by Elsevier Masson SAS on behalf of Soci & eacute;t & eacute; fran & ccedil;aise de nutrition.

INTRODUCTION:Serum calcium rapidly declines at birth because of the sudden interruption of the maternal-fetal calcium influx. Several factors are known to influence serum calcium in the first days of life, including circulating concentrations of maternal vitamin D. Objective was to establish the normal range variations of neonatal serum calcium according to the current French vitamin D supplementation during pregnancy, i.e., 100,000 IU of cholecalciferol during the third trimester. METHODS:We included in our prospective cohort study 1,002 mother-newborn dyads recruited from April 2012 to July 2014 in two centers located in the neighborhoods of Paris, France. RESULTS:Total serum calcium at 3 days of life in neonates varied from 2.06 mmol/L to 2.73 mmol/L [2.5 and 97.5 percentiles], with a mean of 2.45 mmol/L. Serum calcium was similar between babies born from vitamin D-supplemented mothers and those born from non-supplemented ones. In univariate and multivariable analyses, we demonstrated the importance of maternal and cord blood 25(OH)D concentrations for newborn serum calcium maintenance. CONCLUSION:We established that the expected serum calcium in neonates ranges between 2.06 mmol/L and 2.73 mmol/L which is significantly wider than the adult range. This finding should help physicians in the diagnosis of hypo- or hypercalcemia. In addition, our study supports the importance of vitamin D supplementation and 25(OH)D status for neonatal serum calcium maintenance.

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.

OBJECTIVE:This study was undertaken to assess the effect of treatment of vitamin D deficiency in drug-resistant epilepsy. METHODS:We conducted a multicenter, double-blind, placebo-controlled, randomized clinical trial, including patients aged ≥15 years with drug-resistant focal or generalized epilepsy. Patients with 25-hydroxyvitamin D (25[OH]D) < 30 ng/mL were randomized to an experimental group (EG) receiving vitamin D3 (cholecalciferol, 100 000 IU, five doses in 3 months) or a control group (CG) receiving matched placebo. During the open-label study, EG patients received 100 000 IU/month for 6 months, whereas CG patients received five doses in 3 months then 1/month for 3 months. Monitoring included seizure frequency (SF), 25(OH)D, calcium, albumin, creatinine assays, and standardized scales for fatigue, anxiety-depression, and quality of life (Modified Fatigue Impact Scale [M-FIS], Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy [QOLIE-31]) at 3, 6, and 12 months. The primary efficacy outcome was the percentage of SF reduction compared to the reference period and CG at 3 months. Secondary outcomes were SF and bilateral tonic-clonic seizure (BTCS) reduction, scale score changes, and correlations with 25(OH)D during the follow-up. RESULTS:Eighty-eight patients were enrolled in the study (56 females, aged 17-74 years), with median baseline SF per 3 months = 16.5 and ≥2 antiseizure medications in 88.6%. In 75 patients (85%), 25(OH)D was <30 ng/mL; 40 of them were randomly assigned to EG and 34 to CG. After the 3-month blinded period, SF reduction did not significantly differ between groups. However, during the open-label period, SF significantly decreased (30% median SF reduction, 33% responder rate at 12 months). BTCSs were reduced by 52%. M-FIS and QOLIE-31 scores were significantly improved at the whole group level. SF reduction correlated with 25(OH)D > 30 ng/mL for >6 months. SIGNIFICANCE:Despite no proven effect after the 3-month blinded period, the open-label study suggests that long-term vitamin D3 supplementation with optimal 25(OH)D may reduce SF and BTCSs, with a positive effect on fatigue and quality of life. These findings need to be confirmed by further long-term studies. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT03475225 (03-22-2018).

La vitamine D est très importante pour la croissance et la santé osseuse. Elle stimule l’absorption intestinale du calcium et des phosphates, contrôle la sécrétion de parathormone, participe à la réabsorption du calcium dans le tubule distal rénal, et exerce des effets complexes sur l’os, anaboliques ou cataboliques suivant les besoins, et y stimule la sécrétion du FGF23 par les ostéocytes. Elle doit être transformée au niveau hépatique en 25-hydroxy vitamine D (25OHD) puis au niveau rénal en 1,25-dihydroxy vitamine D (1,25OH2D) ou calcitriol pour devenir pleinement active en se liant à un récepteur, le VDR, présent dans des tissus cibles qu’elle atteint via la circulation sanguine. Dans ce mécanisme, le calcitriol répond parfaitement à la définition d’une hormone et la vitamine D peut donc être considérée plutôt comme une « pré-pro-hormone » que comme une vitamine. Il ne faut pas négliger le fait que la vitamine D et/ou la 25OHD peuvent pénétrer dans de très nombreux tissus non impliqués dans le métabolisme phosphocalcique où elles sont activées en calcitriol qui se lie au récepteur local pour y exercer des effets que l’on qualifiera d’intracrine.

This file contains supplementary figures showing prostate tumor kinetics (Fig S1) and histology (Fig S2) for the two mouse models, the validation of regimens (Fig S3 and S4), the effects of diets (Fig S5) and aging (Fig S6) on cancer hallmarks, and the results of cell studies complementary to main Figures 3 and 4.

This file contains the legends for the 7 supplementary figures

This file contains the list of antibodies (Table S1), and the sequences of primers (Table S2) and siRNAs (Table S3)

Precise determination of circulating parathyroid hormone (PTH) concentration is crucial to diagnose and manage various disease conditions, including the chronic kidney disease-mineral and bone disorder. However, the lack of standardization in PTH assays is challenging for clinicians, potentially leading to medical errors because the different assays do not provide equivalent results and use different reference ranges. Here, we aimed to evaluate the impact of recalibrating PTH immunoassays by means of a recently developed LC-MS/MS method as the reference. Utilizing a large panel of pooled plasma samples with PTH concentrations determined by the LC-MS/MS method calibrated with the World Health Organization (WHO) 95/ 646 International Standard, five PTH immunoassays were recalibrated. The robustness of this standardization was evaluated over time using different sets of samples. The recalibration successfully reduced inter -assay variability with harmonization of PTH measurements across different assays. By recalibrating the assays based on the WHO 95/ 646 International Standard, we demonstrated the feasibility for standardizing PTH measurement results and adopting common reference ranges for PTH assays, facilitating a more consistent interpretation of PTH values. The recalibration process aligns PTH results obtained from various immunoassays with the LC-MS/MS method, providing more consistent and reliable measurements. Thus, establishing true standardization across all PTH assays is crucial to ensure consistent interpretation and clinical decision -making.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha klotho production, and elevated fibroblast growth factor 23 (FGF23) levels. Altogether, these factors contribute firstly to secondary hyperparathyroidism, and ultimately, to micro- and macrostructural bone changes, which lead to low bone mineral density and an increased risk of fracture. A vitamin D deficiency is common in CKD patients, and low circulating 25(OH)D levels are invariably associated with high serum parathyroid hormone (PTH) levels as well as with bone mineralization defects, such as osteomalacia in case of severe forms. It is also associated with a variety of non-skeletal diseases, including cardiovascular disease, diabetes mellitus, multiple sclerosis, cancer, and reduced immunological response. Current international guidelines recommend supplementing CKD patients with nutritional vitamin D as in the general population; however, there is no randomized clinical trial (RCT) evaluating the effect of vitamin D (or vitamin D+calcium) supplementation on the risk of fracture in the setting of CKD. It is also unknown what level of circulating 25(OH)D would be sufficient to prevent bone abnormalities and fractures in these patients. The impact of vitamin D supplementation on other surrogate endpoints, including bone mineral density and bone-related circulating biomarkers (PTH, FGF23, bone-specific alkaline phosphatase, sclerostin) has been evaluated in several RTCs; however, the results were not always translated into an improvement in long-term outcomes, such as reduced fracture risk. This review provides a brief and comprehensive update on CKD-related bone fragility and the use of natural vitamin D supplementation in these patients.