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Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.

Background: Maternal vitamin D status during pregnancy and lactation is a modifiable factor that may influence offspring musculoskeletal outcomes. However, few randomized trials have tested the effects of prenatal or postpartum vitamin D supplementation on offspring bone and muscle development., Objectives: The aim was to examine hypothesized effects of improvements in early-life vitamin D status on childhood musculoskeletal health in Dhaka, Bangladesh., Methods: In a previously completed, double-blind, dose-ranging trial, healthy pregnant women (n = 1300) were recruited at 17-24 weeks' gestation and randomly assigned to a prenatal/postpartum regimen of 0/0, 4200/0, 16,800/0, 28,000/0, or 28,000/28,000 IU cholecalciferol (vitamin D3)/wk until 26 wk postpartum. In this new report, we describe additional follow-up at 4 y of age (n = 642) for longer-term outcomes. Bone mineral content (BMC) and areal bone mineral density (aBMD) were measured by DXA. Grip strength was tested using a hand-held dynamometer. The primary comparison was children of women assigned to 28,000 IU/wk prenatally compared with placebo. Differences are expressed as means and 95% CIs., Results: Total-body-less-head (TBLH) BMC, TBLH aBMD, and grip strength were similar in the combined high-dose prenatal (28,000/0 and 28,000/28,000 IU/wk) compared with placebo groups (mean difference [95% CI] = 0.61 g [-10.90, 12.13], 0.0004 g/cm2 [-0.0089, 0.0097], and 0.02 kg [-0.26, 0.31], respectively). In dose-ranging analyses, TBLH BMC and aBMD, whole-body BMC and aBMD, and grip strength in each of the prenatal vitamin D groups were not significantly different from placebo (P > 0.05 for all comparisons). Only head aBMD was greater in children of women assigned to the 28,000/28,000-IU regimen compared with placebo (mean difference [95% CI] = 0.024 g/cm2 [0.0009, 0.047], P = 0.042); the effect was attenuated upon adjustment for child height, weight, and sex (P = 0.11)., Conclusions: Maternal prenatal, with or without postpartum, vitamin D supplementation does not improve child BMC, aBMD, or grip strength at 4 y of age. The MDIG trial and present follow-up study were registered prospectively at www.clinicaltrials.gov as NCT01924013 and NCT03537443, respectively., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Vitamin D deficiency is common worldwide, contributing to nutritional rickets and osteomalacia which have a major impact on health, growth, and development of infants, children and adolescents. Vitamin D levels are low in breast milk and exclusively breastfed infants are at risk of vitamin D insufficiency or deficiency., Objectives: To determine the effect of vitamin D supplementation given to infants, or lactating mothers, on vitamin D deficiency, bone density and growth in healthy term breastfed infants., Search Methods: We used the standard search strategy of Cochrane Neonatal to 29 May 2020 supplemented by searches of clinical trials databases, conference proceedings, and citations., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs in breastfeeding mother-infant pairs comparing vitamin D supplementation given to infants or lactating mothers compared to placebo or no intervention, or sunlight, or that compare vitamin D supplementation of infants to supplementation of mothers., Data Collection and Analysis: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We used the GRADE approach to assess the certainty of evidence., Main Results: We included 19 studies with 2837 mother-infant pairs assessing vitamin D given to infants (nine studies), to lactating mothers (eight studies), and to infants versus lactating mothers (six studies). No studies compared vitamin D given to infants versus periods of infant sun exposure. Vitamin D supplementation given to infants: vitamin D at 400 IU/day may increase 25-OH vitamin D levels (MD 22.63 nmol/L, 95% CI 17.05 to 28.21; participants = 334; studies = 6; low-certainty) and may reduce the incidence of vitamin D insufficiency (25-OH vitamin D < 50 nmol/L) (RR 0.57, 95% CI 0.41 to 0.80; participants = 274; studies = 4; low-certainty). However, there was insufficient evidence to determine if vitamin D given to the infant reduces the risk of vitamin D deficiency (25-OH vitamin D < 30 nmol/L) up till six months of age (RR 0.41, 95% CI 0.16 to 1.05; participants = 122; studies = 2), affects bone mineral content (BMC), or the incidence of biochemical or radiological rickets (all very-low certainty). We are uncertain about adverse effects including hypercalcaemia. There were no studies of higher doses of infant vitamin D (> 400 IU/day) compared to placebo. Vitamin D supplementation given to lactating mothers: vitamin D supplementation given to lactating mothers may increase infant 25-OH vitamin D levels (MD 24.60 nmol/L, 95% CI 21.59 to 27.60; participants = 597; studies = 7; low-certainty), may reduce the incidences of vitamin D insufficiency (RR 0.47, 95% CI 0.39 to 0.57; participants = 512; studies = 5; low-certainty), vitamin D deficiency (RR 0.15, 95% CI 0.09 to 0.24; participants = 512; studies = 5; low-certainty) and biochemical rickets (RR 0.06, 95% CI 0.01 to 0.44; participants = 229; studies = 2; low-certainty). The two studies that reported biochemical rickets used maternal dosages of oral D3 60,000 IU/day for 10 days and oral D3 60,000 IU postpartum and at 6, 10, and 14 weeks. However, infant BMC was not reported and there was insufficient evidence to determine if maternal supplementation has an effect on radiological rickets (RR 0.76, 95% CI 0.18 to 3.31; participants = 536; studies = 3; very low-certainty). All studies of maternal supplementation enrolled populations at high risk of vitamin D deficiency. We are uncertain of the effects of maternal supplementation on infant growth and adverse effects including hypercalcaemia. Vitamin D supplementation given to infants compared with supplementation given to lactating mothers: infant vitamin D supplementation compared to lactating mother supplementation may increase infant 25-OH vitamin D levels (MD 14.35 nmol/L, 95% CI 9.64 to 19.06; participants = 269; studies = 4; low-certainty). Infant vitamin D supplementation may reduce the incidence of vitamin D insufficiency (RR 0.61, 95% CI 0.40 to 0.94; participants = 334; studies = 4) and may reduce vitamin D deficiency (RR 0.35, 95% CI 0.17 to 0.72; participants = 334; studies = 4) but the evidence is very uncertain. Infant BMC and radiological rickets were not reported and there was insufficient evidence to determine if maternal supplementation has an effect on infant biochemical rickets. All studies enrolled patient populations at high risk of vitamin D deficiency. Studies compared an infant dose of vitamin D 400 IU/day with varying maternal vitamin D doses from 400 IU/day to > 4000 IU/day. We are uncertain about adverse effects including hypercalcaemia., Authors' Conclusions: For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25-OH vitamin D levels and reduces vitamin D insufficiency, but there was insufficient evidence to assess its effect on vitamin D deficiency and bone health. For higher-risk infants who are breastfeeding, maternal vitamin D supplementation reduces vitamin D insufficiency and vitamin D deficiency, but there was insufficient evidence to determine an effect on bone health. In populations at higher risk of vitamin D deficiency, vitamin D supplementation of infants led to greater increases in infant 25-OH vitamin D levels, reductions in vitamin D insufficiency and vitamin D deficiency compared to supplementation of lactating mothers. However, the evidence is very uncertain for markers of bone health. Maternal higher dose supplementation (≥ 4000 IU/day) produced similar infant 25-OH vitamin D levels as infant supplementation of 400 IU/day. The certainty of evidence was graded as low to very low for all outcomes., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Vitamin D is necessary for the active (transcellular) absorption of calcium and for skeletal health. Inadequate vitamin D in infants leads to increased risks of poor bone mineralization and ultimately rickets. Rickets is uncommon in full-term infants with a much higher risk in very premature infants. However, the primary cause of rickets in premature infants is a deficiency of calcium and phosphorus, not vitamin D. Available research, as well as most guidelines, recommend an intake of 400 IU daily of vitamin D as adequate for bone health in preterm and full-term infants. Higher doses have not been consistently shown to have specific clinical benefits for healthy infants. There are no strong data to support either routine testing of serum 25-hydroxyvitamin D or targeting high serum 25-hydroxyvitamin D levels (e.g., 30 ng/mL) in healthy preterm or full-term infants. Vitamin D is commonly provided to infants via drops for breastfed babies or via infant formula, although alternative dosing approaches exist for breastfed infants, which some families may prefer. These include the use of drops placed on the mother's breast, dissolvable doses, and high maternal doses (approximately 6,400 IU daily). Infant formula contains vitamin D, and most infants will reach an intake from formula of about 400 IU daily within the first 2 months of life if they are consuming routine cow milk-based formula. Although vitamin D toxicity is very uncommon, caution should be used to avoid extremely concentrated high doses found in some commercially available drops. Infants with liver or kidney disease may need special attention to vitamin D intake and status. Further research is needed to define the role of vitamin D in non-bone health outcomes of infants and to identify methods to enhance compliance with current recommendations for vitamin D intake in infants., (© 2020 S. Karger AG, Basel.)

Bone health is a critical concern in managing preterm infants. Key nutrients of importance are calcium, vitamin D, and phosphorus. Although human milk is critical for the health of preterm infants, it is low in these nutrients relative to the needs of the infants during growth. Strategies should be in place to fortify human milk for preterm infants with birth weight <1800 to 2000 g and to ensure adequate mineral intake during hospitalization and after hospital discharge. Biochemical monitoring of very low birth weight infants should be performed during their hospitalization. Vitamin D should be provided at 200 to 400 IU/day both during hospitalization and after discharge from the hospital. Infants with radiologic evidence of rickets should have efforts made to maximize calcium and phosphorus intake by using available commercial products and, if needed, direct supplementation with these minerals.

Vitamin D is a key nutrient for both healthy children and those with chronic illnesses. Understanding its roles in health and disease has become one of the most important issues in the nutritional management of children. Formal guidelines related to nutrient requirements for vitamin D in healthy children, recommending dietary intakes of 400 IU per day for infants and 600 IU per day for children over 1 year of age, were released by the Institute of Medicine in November 2010. However, application of these guidelines to children with acute and chronic illnesses is less clear. In this Review, we consider major illness categories and specific examples of conditions in children that might be affected by vitamin D. This information can be used in developing both model systems of investigation and clinical trials of vitamin D in children with acute and chronic illnesses.

In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.

The importance of vitamin D for ensuring the health of children has long been understood. Over time, however, dietary recommendations for vitamin D intake have varied, with some eras seeing higher levels recommended and some lower. Remarkably, the current recommendations from the Institute of Medicine are not much different from those released with the first edition of the recommended dietary allowances in 1941. The present review examines the evolution of vitamin D recommendations over time and considers the differences and potential consequences related to the various recommendations in effect today. In considering strategies to evaluate the vitamin D status of children and efforts to assure its adequacy, individual caregivers and policy makers need to consider carefully the costs and potential risks of different screening strategies involving blood testing in children and of supplementation. More data on the long-term risks and benefits are needed before widespread screening or supplementation can be advocated., (© 2012 International Life Sciences Institute.)

Background: To evaluate the effects on serum 25(OH)D and bone mineralization of supplementation of breast-fed Hispanic and non-Hispanic Caucasian infants with vitamin D in infants in Houston, Texas., Methods: We measured cord serum 25(OH)D levels, bone mineral content (BMC), bone mineral density (BMD) and their changes over 3 months of life with 400 IU/day of vitamin D3 supplementation., Results: Cord serum 25(OH)D was significantly lower in Hispanic than non-Hispanic Caucasian infants (16.4 ± 6.5 ng/mL, n = 27, vs 22.3 ± 9.4 n = 22, p = 0.013). Among 38 infants who completed a 3 month vitamin D supplementation intervention, provision of 400 IU/day of vitamin D increased final 25(OH)D to a higher level in non-Hispanic Caucasian compared to Hispanic infants. There was no significant relationship between cord serum 25(OH)D and BMC or BMD in the first week of life (n = 49) or after 3 months of vitamin D supplementation., Conclusion: Low cord 25(OH)D levels are seen in Hispanic infants, but their functional significance is uncertain related to bone health in a southern US setting. Daily vitamin D intake of 400 IU during the first months of life appears adequate to increase serum 25(OH)D and support BMC increases despite low initial 25(OH)D levels in some infants., Trial Registration: ClincalTrials.gov NCT00697294.

Purpose of Review: There remains very strong interest in the calcium and vitamin D requirements of adolescents related to bone health. The Institute of Medicine (IOM) released new dietary guidelines in late 2010 for these nutrients. These guidelines were primarily based on literature published in 2009 and earlier and emphasized the role of vitamin D combined with calcium in optimizing bone health. A series of research studies published in 2010 and 2011, mostly not included in the IOM report, have further addressed these issues., Recent Findings: These most recently published data are generally consistent with the IOM report and earlier data in supporting calcium intakes of 1300 mg/day and vitamin D intakes of 600 IU/day for adolescents. However, there is some suggestion that a slightly higher Recommended Dietary Allowance for vitamin D might be considered at some future time., Summary: New dietary guidelines and recent research support increased vitamin D intakes compared with previous recommendations, but not very high doses. Further studies are needed related to high-dose vitamin D intake.

Bone minerals and vitamin D are crucial for infants and small children. Human milk has little vitamin D, and supplemental vitamin D must be given to all infants either via drops or as contained in infant formula or foods. The calcium and phosphorus in human milk are adequate for infants in the first six months of life, with supplemental minerals coming from weaning foods after six months. Long-term benefits to providing bone minerals at greater levels than in human milk have not been shown. There is no evidence to support high-dose bone mineral supplementation or high-dose vitamin D supplementation in infancy, and controlled trials are needed before these can be advocated.

The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively reviewed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for ages older than 1 year. For nonskeletal outcomes, including cancer, cardiovascular disease, diabetes, infections, and autoimmune disorders, randomized clinical trials were sparse, and evidence was inconsistent, inconclusive as to causality, and insufficient for Dietary Reference Intake (DRI) development. The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily, respectively, for ages 1 year and older. For vitamin D (assuming minimal sun exposure), the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older, corresponding to serum 25-hydroxyvitamin D (25OHD) levels of 16 ng/mL (40 nmol/L) for EARs and 20 ng/mL (50 nmol/L) or more for RDAs. Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA. Higher serum 25OHD levels were not consistently associated with greater benefit, and for some outcomes U-shaped associations with risks at both low and high levels were observed. The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily, based on calcium excretion or kidney stone formation, and from 1,000 to 4,000 IU daily for vitamin D, based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships. Urgently needed are evidence-based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention., (Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved.)

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1-70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

Nutritional rickets has long been considered a disease caused by vitamin D deficiency, but recent data indicate that inadequate dietary calcium intake is an important cause of rickets, particularly in tropical countries. Children with rickets due to calcium deficiency do not have very low 25(OH)D concentrations, and serum 1,25(OH)(2) D values are markedly elevated. Studies of Nigerian children with rickets demonstrated they have high fractional calcium absorption. A high-phytate diet was demonstrated to increase calcium absorption compared with the fasting state, and enzymatic dephytinization did not significantly improve calcium absorption. When given vitamin D, children with rickets have a marked increase in 1,25(OH)(2) D concentrations without any change in fractional calcium absorption. No positive relationship was found between fractional calcium absorption and serum 25(OH)D concentrations in children on low-calcium diets. More research is needed to understand the interaction between calcium and vitamin D and the role of vitamin D in calcium absorption., (© 2010 International Life Sciences Institute.)

In adults, maximal suppression of serum parathyroid hormone (PTH) has commonly been used to determine the sufficiency of serum 25-hydroxyvitamin D [25(OH)D]. In children and adolescents, the relationship between serum 25(OH)D and PTH is less clear and most studies reporting a relationship are derived from relatively small samples and homogeneous cohorts. Our objective was to determine the relationship between serum 25(OH)D and PTH in children and adolescents from a large and diverse U.S. cohort and to identify a point of inflection of serum 25(OH)D for maximal suppression of serum PTH. Data from 735 participants, ages 7-18 y, were pooled from 3 study sites located in Indiana, Texas, and Massachusetts. A two-phase linear spline was used to model the relationship between serum 25(OH)D and PTH. The value of serum 25(OH)D for maximal suppression of serum PTH was identified as the inflection point of the spline. Before adjustment for site, the inflection point of serum 25(OH)D for maximal suppression of serum PTH was 92.4 nmol/L (95% CI: 62.2, 130.7). After adjusting for site, the point of inflection was poorly defined and the relationship between serum 25(OH)D and PTH appeared to be linear. The lack of an inflection point of serum 25(OH)D for maximal suppression of PTH brings into question the value of using maximal suppression of serum PTH as a basis for determining optimal serum 25(OH)D for healthy children and adolescents.

Context: Increasing serum 25-hydroxyvitamin D (25-OHD) in adults may enhance calcium absorption (Ca-abs). There are few similar pediatric data leading to uncertainty about the optimal target for 25-OHD to maximize Ca-abs., Objective: Our objective was to evaluate the relationship between 25-OHD and Ca-abs in a large cohort of school-age children and adolescents., Design: We evaluated data from 439 Ca-abs measurements performed using dual-tracer stable isotope techniques conducted at our center over a 15-yr period in 251 healthy children, 4.9-16.7 yr of age., Results: Serum 25-OHD ranged from 28 to 197 nmol/liter (mean 85 +/- 2 nmol/liter) (sem). Total Ca-abs (intake times fractional absorption) were significantly correlated to 25-OHD in the whole population (r = 0.16, P = 0.001). This relationship was closer in the 197 studies in early puberty (Tanner 2 or 3, r = 0.35, P < 0.001) and not significant in pre- or late pubertal subjects. For the whole population, fractional Ca-abs adjusted for calcium intake were slightly but significantly higher at 25-OHD of 28-50 nmol/liter (0.344 +/- 0.019) compared with 25-OHD of 50-80 nmol/liter (0.280 +/- 0.014) or 25-OHD greater than 80 nmol/liter (0.297 +/- 0.015, P < 0.01 for each), suggesting adaptation to moderately low 25-OHD values., Conclusion: There is no consistent pattern of relationship between 25-OHD and either fractional or total calcium absorption in school-age children. However, there appears to be a modest calcium absorptive response to higher 25-OHD during early puberty.

Only limited aspects of the transfer of calcium across the placenta to the fetus are known. Clinical outcome studies suggest that bone mineral mass in newborn infants is related to maternal size and dairy intake. Available data indicate that vitamin D deficiency may also limit in utero fetal bone mineral accumulation. Recent data suggest that maternal vitamin D status affects long-term childhood bone status. At present, no strong evidence exists showing that improving maternal calcium or vitamin D status has a long-term positive effect on childhood bone mass. In premature infants, clinical rickets and fractures are common. In utero rates of calcium accretion during the third trimester cannot be readily achieved. The use of fortifiers designed for human-milk-fed infants or specially designed high-mineral-containing formulas allows for bone mineral accretion at or near in utero rates. Recent data have shown that physical therapy programs, judiciously used, in combination with adequate mineral content, can enhance bone mineral mass in preterm infants. There is little evidence for the use of high doses of vitamin D in the management of premature infants. After hospital discharge, continuation of a relatively high mineral intake has been shown to enhance bone mineral acquisition. Future research should include evaluations of the role of maternal vitamin D supplementation on fetal and infant bone mass, the mineral needs of infants weighing <800 g or <25 wk gestation, and the optimal discharge management of premature infants who are at risk of low bone mass.

Background: Evidence suggests that vitamin D status in adults, as assessed by serum 25-hydroxyvitamin D (25-OHD), is positively associated with calcium absorption fraction and inversely associated with serum PTH. Few comparable pediatric data exist., Objectives: The objective of this study was to evaluate the relationships among vitamin D status, PTH, and calcium absorption in midpubertal boys and girls., Methods: Calcium absorption was measured as part of an evaluation of the effects of prebiotics (inulin-type fructans) using a stable isotope method in 93 young adolescents, 12.7 +/- 1.0 yr of age, receiving diets averaging approximately 900 mg/d calcium., Results: A significant positive relation to calcium absorption was found for serum 1,25-dihydroxyvitamin D (P = 0.048) and PTH (P = 0.007), but not for 25-OHD (P = 0.77). PTH was significantly inversely related to 25-OHD and was positively related to serum 1,25-dihydroxyvitamin D and osteocalcin. PTH was marginally significantly inversely related to lumbar spinal, but not whole body, bone mineral density., Conclusions: These data suggest that in adolescents, especially in the presence of vitamin D insufficiency, PTH secretion increases to adapt to higher rates of bone formation associated with growth. This results in higher serum 1,25(OH)2D concentrations and increased calcium absorption results. Vitamin D status, as reflected by the serum 25-OHD level, is not closely related to calcium absorption. Whether adaptation to low serum 25-OHD is adequate under physiologically stressful situations, including those leading to very low serum 25-OHD levels, is unknown.

Provision of the bone minerals and vitamin D as fortificants in food or as dietary supplements designed for older infants and toddlers in Latin America is likely to be beneficial and safe. Currently available data are inadequate to establish the precise amounts of these nutrients that would be required for such a supplement. These amounts would vary according to the local base diet. However, reasonable estimates can be made on the basis of current dietary recommendations as well as existing data on bioavailability and customary intake. The strongest case can be made for calcium and vitamin D supplementation. Because excessive dietary calcium can reduce zinc absorption as a result of interactive effects within the intestine, an appropriate ratio of calcium to zinc should be used, even if this means adding zinc as a fortificant or supplement. Magnesium supplementation may be appropriate in some circumstances but it cannot be routinely advocated at present. It is unlikely that phosphorus supplementation is needed for most population groups because of the relatively high usual dietary phosphorus intakes, primarily from phosphate salts added to carbonated beverages and as food preservatives.

We summarize here lessons learned from studies on skeletal and extra-skeletal functions of vitamin D in hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients with a mutant, nonfunctioning vitamin D receptor (VDR). During childhood, HVDRR patients are dependent on intestinal VDR, demonstrate low intestinal fraction calcium absorption, and have a bone calcium accretion rate that leads to hypocalcemia and rickets. After puberty, there is recovery in intestinal calcium absorption and in bone calcium accretion and structure. HVDRR monocytes and lymphocytes show impairment in the expression of antimicrobial proteins and demonstrate a proinflammatory cytokine profile. However, HVDRR patients do not exhibit increased rates of infections or inflammatory diseases. Vitamin D deficiency is associated with asthmatic exacerbations. Surprisingly, HVDRR patients do not usually develop asthma. They have normal allergic tests and lung functions and are protected against provoked bronchial hyperactivity. HVDRR patients have decreased IL-5 levels in their exhaled breath condensate. Given that IL-5 is a key cytokine in the development of airway inflammation and hyperactivity and that VDR is important for IL-5 generation, it is plausible that low lung IL-5 protects HVDRR patients from asthma. Vitamin D metabolites have suppressive effects on the renin angiotensin system. However, no HVDRR patient showed hypertension or echocardiographic pathology, and their renin angiotensin metabolites were normal. The VDR is expressed throughout the reproductive system, suggesting a role in reproduction. However, the reproductive history of HVDRR patients is normal despite the lack of a normal VDR. HVDRR patients provide a unique opportunity to study the role of the VDR and the role of vitamin D in various human systems. [ABSTRACT FROM AUTHOR]

Skeletal mineralization is initiated in utero and continues throughout childhood and adolescence. During these key periods of the life cycle, calcium retention must increase significantly to provide sufficient mineral for bone deposition and skeletal growth. Stable calcium isotopes have served as a fundamental tool to non‐invasively characterize the dynamic changes in calcium physiology that occur from infancy through adolescence. These approaches have helped define the dynamics of calcium absorption and utilization in healthy children and in children with chronic diseases. As data in this area have accumulated, new areas of emphasis are beginning to characterize the determinants of variability in mineral retention, the genetic determinants of bone turnover and calcium flux and the impact of the gut microbiome on whole body and niche specific calcium dynamics. Advances in these areas will help define calcium utilization in paediatric populations and provide information that may be useful in maximizing bone acquisition across this critical phase of the life cycle. Stable calcium isotopes can be utilized to characterize normal calcium absorption and utilization in healthy children and evaluate possible alterations in calcium dynamics that occur in children with chronic diseases. Using the dual stable isotope approach, one stable isotope of calcium is ingested orally and a second stable isotope of calcium is given intravenously. The cumulative excretion of the oral to the intravenous calcium tracer in a 24 h urine pool provides a measure of fractional calcium absorption. Rates of bone calcium deposition can be determined by following the clearance of the intravenous tracer in serum and urine for 120 h or more post‐dosing. The amount of calcium secreted into the gastrointestinal tract daily (endogenous faecal calcium secretion) can be quantified with this approach and has been found to roughly equal the amount of calcium lost per day in urine (∼1.5 mg kg−1 day−1). Paediatric diseases that impair gut integrity can increase endogenous faecal calcium secretion, as has been shown for children with cystic fibrosis. Urinary calcium losses may increase when renal function is compromised (as occurs in children with renal disease) or may increase due to interactions with other dietary factors (such as sodium intake) or be associated with other metabolic abnormalities (glycosylated haemoglobin is correlated to urinary calcium excretion in children with juvenile diabetes). Evaluating overall calcium balance provides an estimation of the net amount of calcium available for bone calcium accretion in children and the degree to which calcium is gained or lost by the paediatric skeleton. [ABSTRACT FROM AUTHOR]

Vitamin D is an essential nutrient for bone health and may influence the risks of respiratory illness, adverse pregnancy outcomes, and chronic diseases of adulthood. Because many countries have a relatively low supply of foods rich in vitamin D and inadequate exposure to natural ultraviolet B (UVB) radiation from sunlight, an important proportion of the global population is at risk of vitamin D deficiency. There is general agreement that the minimum serum/plasma 25‐hydroxyvitamin D concentration (25(OH)D) that protects against vitamin D deficiency–related bone disease is approximately 30 nmol/L; therefore, this threshold is suitable to define vitamin D deficiency in population surveys. However, efforts to assess the vitamin D status of populations in low‐ and middle‐income countries have been hampered by limited availability of population‐representative 25(OH)D data, particularly among population subgroups most vulnerable to the skeletal and potential extraskeletal consequences of low vitamin D status, namely exclusively breastfed infants, children, adolescents, pregnant and lactating women, and the elderly. In the absence of 25(OH)D data, identification of communities that would benefit from public health interventions to improve vitamin D status may require proxy indicators of the population risk of vitamin D deficiency, such as the prevalence of rickets or metrics of usual UVB exposure. If a high prevalence of vitamin D deficiency is identified (>20% prevalence of 25(OH)D < 30 nmol/L) or the risk for vitamin D deficiency is determined to be high based on proxy indicators (e.g., prevalence of rickets >1%), food fortification and/or targeted vitamin D supplementation policies can be implemented to reduce the burden of vitamin D deficiency–related conditions in vulnerable populations. Here we report the outcome of a working group convened in January and March 2017 by the Sackler Institute for Nutrition Science at the New York Academy of Sciences and the Bill & Melinda Gates Foundation to assess the global prevalence and disease burden of vitamin D deficiency, and population‐based strategies to improve vitamin D status, particularly in low‐ and middle‐income countries. The working group aimed to examine definitions of vitamin D deficiency based on biomarkers and correlations with disease or health outcomes. [ABSTRACT FROM AUTHOR]

Background: The maximal calcium absorption in response to vitamin D has been proposed as a biomarker for vitamin D sufficiency. Objective: The objective was to determine whether there is a threshold beyond which increasing doses of vitamin D, or concentrations of serum 25-hydroxyvitamin D [25(OH)D], no longer increase calcium absorption. Design: This was a placebo-controlled, dose-response, randomized, double-blind study of the effect of vitamin D on calcium absorption in healthy postmenopausal women. Seventy-six healthy postmenopausal women were randomly assigned to placebo or 800 IU (20 mg), 2000 IU (50 µg), or 4000 IU (100 µg) vitamin D3 for 8 wk. The technique of dual isotopes of stable calcium was used with a calcium carrier to measure calcium absorption at baseline and after 8 wk. Results: Seventy-one women with a mean ± SD age of 58.8 ± 4.9 y completed the study. The mean calcium intake was 1142 6 509 mg/d and serum 25(OH)D was 63 ± 14 nmol/L at baseline. A statistically significant linear trend of an increase in calcium absorption adjusted for age and body mass index with increasing vitamin D3 dose or serum 25(OH)D concentration was observed. A 6.7% absolute increase in calcium absorption was found in the highest vitamin D3 group (100 µg). No evidence of nonlinearity was observed in the dose-response curve. Conclusions: No evidence of a threshold of calcium absorption was found with a serum 25(OH)D range from 40 to 130 nmol/L. Calcium absorption in this range is not a useful biomarker to determine nutritional recommendations for vitamin D. This trial was registered at clinicaltrials. gov as NCT01119378. [ABSTRACT FROM AUTHOR]

Osteopenia and rickets remain a problem for high-risk infants, especially preterm infants <1500 g birthweight (very low birth weight, VLBW). The primary cause of osteopenia in VLBW infants is a low intake of calcium and phosphorus compared to requirements for the rapidly growing skeleton. Human milk is a relatively low mineral containing substance and cannot meet the bone mineral needs of very low birth weight infants. As such, most VLBW infants need additional bone minerals and in many neonatal care units these are provided as part of human milk fortificants or specialized infant formulas. In some nurseries, these are given to all infants < 1800-2000 g birthweight. Management of full-term infants who are small for gestational age at birth is less clear, but in general bone mineral content is associated more with body size than gestational age and supplementation is often provided to these infants. Although all infants, including preterm ones need a source of vitamin D, the benefits of providing high doses of vitamin D to healthy preterm neonates is unproven. Some evidence indicates that most calcium absorption is non-vitamin D dependent in the first weeks of life in both preterm and term infants. However, after achieving full feeds in the preterm infant, it is prudent to provide vitamin D at amounts comparable to that used in full-term infants. Higher doses increase serum 25-hydroxyvitamin D levels more rapidly, but evidence is inconclusive as to the relative benefits vs possible risks of higher doses. In healthy full-term infants, although vitamin D provision via supplement drops to the breastfed infant, high dose maternal supplementation to the lactating mother or infant formula is generally recommended, the current evidence only strongly supports its use in identified at-risk infants. [ABSTRACT FROM AUTHOR]

Background: The effects of vitamin D supplementation in healthy prepubertal children on physiologic outcomes have not been investigated. Objective: The objective was to evaluate the effects of supplementation with 1000 IU vitamin D3/d on calcium absorption. Design: In a double-blind, placebo-controlled trial, we randomly assigned 64 children to 1000 IU vitamin D3/d (n = 32) or placebo (n = 32) for 8 wk. Stable isotopes were used to assess calcium absorption. The main outcome measure was calcium absorption before and after supplementation. Results: All of the data are shown as means ± SDs. At baseline, vitamin D intake was 221 ±79 1U/d and calcium intake was 830 ± 197 mg/d. Baseline serum 25-hydroxyvitamin D [25(OH)D] was not significantly correlated with fractional or total calcium absorption. After 8 wk, with baseline values used as a covariate, no differences were seen in fractional or total calcium absorption based on supplementation group (P = 0.75 and 0.36, respectively). Supplemented children had a significant increase in 25(OH)D concentrations (from 27.7 ± 7.4 to 36.0 ± 10.3 ng/mL; P < 0.0001) and a decrease in parathyroid hormone (from 21.4 ± 10.4 to 12.9 ± 7.1 pg/mL; P < 0.001); no significant changes in the placebo group were observed. No adverse side effects were noted in either group. Conclusions: Vitamin D3 supplementation at 1000 IU/d increases 25(OH)D and decreases parathyroid hormone in children with average vitamin D intakes below the dietary recommendations of the Institute of Medicine. However, no significant effects of this change on calcium absorption occurred. This trial was registered at clinicaltrials.gov as NCT 00868738. [ABSTRACT FROM AUTHOR]

Background: Nutritional rickets is common in Nigerian children and responds to calcium supplementation. Low dietary calcium intakes are also common in Nigerian children with and without rickets. Objective: The objective was to assess intestinal calcium absorption in Nigerian children with rickets. Design: Calcium absorption was assessed in 15 children with active rickets (2-8 y of age) and in 15 age- and sex-matched children without rickets by using a dual-tracer stable-isotope method. The children with rickets were supplemented with calcium for 6 mo; calcium absorption was reevaluated 12 mo after the baseline study. Fractional calcium absorption could be determined in 10 children with rickets and in 10 children without rickets. Results: The children with and without rickets had dietary calcium intakes of ≈200 mg/d. Compared with the control children, the children with rickets had lower serum 25-hydroxyvitamin D and calcium concentrations and greater 1,25-dihydroxyvitamin D and parathyroid hormone concentrations. In fact, there were 15 rachitic and 15 control children in the study. Mean (±SD) fractional calcium absorption did not differ between those with (61±20%) and without (63 ± 13%) rickets (P = 0.47). Calcium absorption was not associated with serum concentrations of calcium, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or parathyroid hormone. Mean fractional calcium absorption was significantly greater after (81 ± 10%) than before (61 ± 20%) calcium supplementation for the treatment of rickets (P = 0.035). Conclusions: In Nigerian children with rickets, the capacity to absorb calcium is not impaired; however, fractional calcium absorption increases after the resolution of active disease. Calcium absorption may be inadequate to meet the skeletal demands of children with rickets during the active phase of the disease, despite being similar to that of control children. [ABSTRACT FROM AUTHOR]

Nutritional rickets, an ancient disease that was thought to have been cured in the early part of the 20th century, has made an unexpected comeback in recent years throughout the world. Although the frequency of its occurrence is poorly documented, increasing case reports of rickets are apparently related to low dietary intake of vitamin D and calcium and decreased sunshine exposure. Greater awareness of this problem is needed, as are further data regarding vitamin D status and incidence of rickets among infants and toddlers. Routine provision of supplemental vitamin D to all breastfed infants remains controversial, but may become more widely recommended. Key Words: rickets, vitamin D, calcium, sunshine. [ABSTRACT FROM AUTHOR]

To assess the possibility of ethnic differences in mineral metabolism in prepubertal children, we compared measures of calcium metabolism in 7- and 8-y-old Mexican-American (MA) and non-Hispanic Caucasian (CAU) girls (n = 38) living in southeastern Texas. We found similar fractional calcium absorption, urinary calcium excretion, calcium kinetic values and total-body bone mineral content in the MA and CAU girls. In contrast, parathyroid hormone (PTH) concentrations were greater in MA girls (4.01 +/- 0.47 vs. 1. 96 +/- 0.50 pmol/L, P = 0.005) than in CAU girls. Serum 25-hydroxyvitamin D concentrations were lower in MA girls (68.9 +/- 7.7 vs. 109.4 +/- 8.4 nmol/L, P = 0.001) than in CAU girls, but 1, 25-dihydroxyvitamin D concentrations did not differ between groups. Seasonal variability was seen for 25-hydroxyvitamin D concentrations in girls of both ethnic groups, but values in all of the girls were >30 nmol/L (12 ng/mL). We conclude the following: 1) greater PTH levels in MA girls than CAU girls are present without evidence of vitamin D deficiency; and 2) differences in 25-hydroxyvitamin D and PTH concentrations between MA and CAU girls do not have a large effect on calcium absorption, excretion or bone calcium kinetics. These data do not provide evidence for adjusting dietary recommendations for mineral or vitamin D intake by MA girls. [ABSTRACT FROM AUTHOR]

The article discusses two studies published in the current issue that highlight the relationship between vitamin D status and critical illnesses in children admitted to pediatric intensive care units (PICUs) in the U.S. and Canada. Neither study found an association between vitamin D status and medical or surgical diagnosis, only the study by McNally and colleagues found an association between low vitamin D levels and the presence of septic shock.