Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety

For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 microg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold.     

Dose response to vitamin D supplementation among postmenopausal African American women

BACKGROUND: Reports on the dose response to vitamin D are conflicting, and most data were derived from white men and women. OBJECTIVE: The objective was to determine the response of serum 25-hydroxyvitamin D [25(OH)D] to oral vitamin D(3) supplementation in an African American population. DESIGN: Healthy black postmenopausal women (n = 208) participated in a vitamin D(3) supplementation trial for a period of 3 y. Analyses were done in the vitamin D supplementation arm (n = 104) to quantify the response in serum 25-hydroxyvitamin D concentrations at a steady state vitamin D input. The participants received 20 microg/d (800 IU) oral vitamin D(3) for the initial 2 y and 50 microg/d (2000 IU) for the third year. RESULTS: Supplementation with 20 microg/d (800 IU/d) vitamin D(3) raised the mean serum 25(OH)D concentration from a baseline of 46.9 +/- 20.6 nmol/L to 71.4 +/- 21.5 nmol/L at 3 mo. The mean (+/-SD) concentration of serum 25(OH)D was 87.3 +/- 27.0 nmol/L 3 mo after supplementation increased to 50 microg/d (2000 IU/d). All participants achieved a serum 25(OH)D concentration >35 nmol/L, 95% achieved a concentration >50 nmol/L, but only 60% achieved a concentration >75 nmol/L. All patients had concentrations <153 nmol/L. On the basis of our findings, an algorithm for prescribing vitamin D so that patients reach optimal serum concentrations was developed. The algorithm suggests a dose of 70 microg (2800 IU/d) for those with a concentration >45 nmol/L and a dose of 100 microg (4000 IU/d) for those with a concentration <45 nmol/L. CONCLUSIONS: Supplementation with 50 microg/d (2000 IU/d) oral vitamin D(3) is sufficient to raise serum 25-hydroxyvitamin D concentrations to >50 nmol/L in almost all postmenopausal African American women. However, higher doses were needed to achieve concentrations >75 nmol/L in many women in this population.     

Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies

During pregnancy and lactation, mothers require significant amounts of calcium to pass on to the developing fetus and suckling neonate, respectively. Given the dependence of adult calcium concentrations and bone metabolism on vitamin D, one might anticipate that vitamin D sufficiency would be even more critical during pregnancy and lactation. However, maternal adaptations during pregnancy and lactation and fetal adaptations provide the necessary calcium relatively independently of vitamin D status. It is the vitamin D-deficient or insufficient neonate who is at risk of problems, including hypocalcemia and rickets. Due to poor penetrance of vitamin D and 25-hydroxyvitamin D [25(OH)D] into milk, exclusively breastfed infants are at higher risk of vitamin D deficiency than are formula-fed infants. Dosing recommendations for women during pregnancy and lactation might be best directed toward ensuring that the neonate is vitamin D-sufficient and that this sufficiency is maintained during infancy and beyond. A dose of vitamin D that provides 25(OH)D sufficiency in the mother during pregnancy should provide normal cord blood concentrations of 25(OH)D. Research has shown that during lactation, supplements administered directly to the infant can easily achieve vitamin D sufficiency; the mother needs much higher doses (100 mug or 4000 IU per day) to achieve adult-normal 25(OH)D concentrations in her exclusively breastfed infant. In addition, the relation (if any) of vitamin D insufficiency in the fetus or neonate to long-term nonskeletal outcomes such as type 1 diabetes and other chronic diseases needs to be investigated.     

Can vitamin D supplementation in infancy prevent type 1 diabetes?

Several recent European studies suggested that supplementing infants with vitamin D during their first year might prevent type 1 diabetes. A dose of 50 microg/day was associated with decreased diabetes risk in Finland, but the effectiveness of lower doses was not examined. The recommended dietary intake of vitamin D for U.S. infants is 5 microg/day and the tolerable upper level is 25 microg/day. There is no evidence that intakes between 5 and 25 microg/day would reduce diabetes incidence, but it would seem prudent to ensure that infants reach at least the lower end of this range.     

Perinatal vitamin D and calcium status of northern Canadian mothers and their newborn infants

OBJECTIVE: This study was undertaken to examine the vitamin D and calcium status of mothers and their newborns. METHODS: The intakes of vitamin D and calcium were determined prenatally in 121 women including 33 Caucasians, 51 Inuits, and 37 Native Indians, living in the Inuvik zone of the Northwest Territories. Plasma concentrations of 25-(OH)-D and calcium were also measured in mothers as well as in their offspring at delivery. RESULTS: The daily mean vitamin D intake of native mothers, including Inuits and Indians, with (8.1+/-5.5 microg) and without supplements (3.4+/-2.5 microg) was significantly lower than that of non-native mothers (13.2+/-5.9 microg and 5.8+/-4.3 microg, respectively). According to the predicted prevalence of low vitamin D intake, there existed a higher risk of vitamin D deficiency without supplementation in both native (88.6% vs 48.4%) and non-native (63.5% vs. 15.1%) mothers. The trend for calcium intakes with and without supplementation was similar to vitamin D intake. At the point of delivery, the plasma levels of 25-(OH)-D were lower in native mothers (50.1 19.3 nmol/L) and their offspring (34.2+/-13.1 nmol/L) than their counterparts (59.8+/-29.4 nmol/L and 41.4+/-23.5 nmol/L, respectively). Its plasma levels in newborn infants averaged only 67% of their mothers. None of these infants showed clinical evidence of vitamin D deficiency. In fact, their plasma calcium levels were significantly higher than their mothers. CONCLUSIONS: Plasma 25-(OH)-D concentrations of 60 to 70% of maternal levels may represent a "normal" range for newborn infants. However, a supplementation in native northern Canadian mothers during pregnancy and in their neonates during infancy may have a role to play in the prevention of vitamin D deficiency.     

西安地区新生儿维生素D水平及影响因素分析

目的调查西安地区(北纬34°)新生儿维生素D水平,并分析其影响因素。方法选取2018年10月至2019年10月在西安交通大学第一附属医院新生儿科住院,生后48小时内入院且生命体征平稳的161例新生儿为研究对象。检测新生儿生后48小时内血清25-羟维生素D[25(OH)D]水平,并分析性别、胎龄、出生季节,母亲年龄、分娩方式、妊娠胎数,以及母亲孕晚期维生素D补充剂量对新生儿血清25(OH)D水平的影响。结果新生儿血清25(OH)D平均水平为12.20(9.10,17.30)ng/mL,维生素D缺乏、不足和充足的发生率分别为65.84%、15.53%和18.63%。单胎新生儿血清25(OH)D水平显著高于双胎新生儿(Z=-1.967,P<0.05)。秋季出生的新生儿血清25(OH)D水平显著高于春季出生的新生儿(H=-2.726,P<0.05)。与母亲孕晚期补充维生素D剂量<600IU/d相比,母亲孕晚期补充维生素D剂量≥600IU/d新生儿血清25(OH)D水平显著增高(Z=-3.968,P<0.05),维生素D缺乏发生率显著降低(χ^2=8.003,P<0.017)。经Logistic回归分析显示,母亲孕晚期补充维生素D剂量<600IU/d是新生儿维生素D缺乏的危险因素(OR=2.481,95%CI:1.023~6.008,P<0.001)。结论西安地区新生儿维生素D缺乏发生率较高;胎数、出生季节和母亲孕期维生素D补充剂量是新生儿维生素D水平的影响因素。     

25-Hydroxyvitamin D: functional outcomes in infants and young children

Vitamin D deficiency occurs in the United States in exclusively breastfed infants who have high levels of skin pigmentation, inadequate vitamin D supplementation, and insufficient sunlight exposure. I review serum 25-hydroxyvitamin D [25(OH)D] concentrations and functional outcomes of vitamin deficiency in young children and breastfed and nonbreastfed infants. These outcomes include the presence or absence of vitamin D deficiency rickets, bone mineral content, and serum parathyroid hormone concentration. Daily vitamin D supplements of 400 IU/L keep serum 25(OH)D concentrations higher than 50 nmol/L and prevent rickets in infants and young children. The available evidence is not sufficient to support the use of bone mineral content or parathyroid hormone concentrations in infants and young children as functional outcomes to define deficient or sufficient levels of 25(OH)D. I therefore propose a research agenda to establish the functional definitions of vitamin D sufficiency or deficiency in infants and young children.     

Total Duration of Breastfeeding,Vitamin D Supplementation,and Serum Levels of 25-Hydroxyvitamin D

Objectives. To determine the association between total breastfeeding duration and serum 25-hydroxyvitamin D (25-OHD) and to explore whether vitamin D supplementation influences this association.Methods. We conducted a cross-sectional study of healthy children between September 2011 and August 2013 through the TARGet Kids! primary health care research network. Of the 4533 eligible children, we included only the 2508 who had 25-OHD measured. We assessed adjusted associations of total breastfeeding duration (in months) with serum 25-OHD and in supplemented versus nonsupplemented children, with the odds of 25-OHD less than 20 nanograms per milliliter.Results. Each 1-month increase in total breastfeeding duration was associated with a 0.12 nanograms per milliliter lower median serum 25-OHD (95% confidence interval [CI] = –0.21 ng/mL, –0.02 ng/mL) among children who were not supplemented. The odds of serum 25-OHD less than 20 nanograms per milliliter increased by 6% (odds ratio [OR] = 1.06; 95% CI = 1.03, 1.10) for every 1-month increase in total breastfeeding duration among nonsupplemented children. The interaction between vitamin D supplementation, duration of breastfeeding, and median serum 25-OHD was statistically significant (P = .04).Conclusions. Breastfed children who were not supplemented, particularly those breastfed more than 1 year, appear to have lower vitamin D status. Vitamin D supplementation may mitigate this risk. These findings support recommendations for supplementation during breastfeeding of any duration.Vitamin D is a fat-soluble steroid that has numerous biological actions that affect health.1–4 In infants and young children, very low vitamin D intake can lead to rickets.5–8 Exclusively breastfed infants who are not supplemented with vitamin D are at increased risk for developing rickets because of the limited transfer of vitamin D in breast milk.9,10 Although previous research supports the association between exclusive breastfeeding and low serum vitamin D levels in children,11,12 little is known about the effect of total duration of breastfeeding, including the period of nonexclusive breastfeeding, on vitamin D status.Guidelines for vitamin D supplementation during breastfeeding beyond the first year of life vary throughout the world. The American Academy of Pediatrics recommends, “Any breastfeeding infant, regardless of whether he or she is being supplemented with formula, should be supplemented with 400 IU of vitamin D.”10^(p1146) The Committee on Nutrition of the French Society of Pediatrics also suggests continuous vitamin D supplementation beyond the first year of life,13 irrespective of breastfeeding status, and the Canadian Pediatric Society recommends, “400 IU/day for all infants during the first year.”14 An improved understanding of the relationship between breastfeeding beyond the first year of life, vitamin D supplementation, and vitamin D stores may assist with reducing variation in professional recommendations, current practice, and optimizing vitamin D status during breastfeeding beyond the first year.We examined whether total duration of breastfeeding is associated with infant serum 25-hydroxyvitamin D (25-OHD) concentration in a cohort of healthy urban North American children. Our secondary objective was to explore how vitamin D supplementation influences the relationship between total duration of breastfeeding and 25-OHD.     

Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis

The purpose of this review is to put into perspective the many health benefits of vitamin D and the role of vitamin D deficiency in increasing the risk of many common and serious diseases, including some common cancers, type 1 diabetes, cardiovascular disease, and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of vitamin D(3) in the skin, is important in preventing many chronic diseases. Because very few foods naturally contain vitamin D, sunlight supplies most of our vitamin D requirement. 25-Hydroxyvitamin D [25(OH)D] is the metabolite that should be measured in the blood to determine vitamin D status. Vitamin D deficiency is prevalent in infants who are solely breastfed and who do not receive vitamin D supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. Vitamin D deficiency is often misdiagnosed as fibromyalgia. A new dietary source of vitamin D is orange juice fortified with vitamin D. Studies in both human and animal models add strength to the hypothesis that the unrecognized epidemic of vitamin D deficiency worldwide is a contributing factor of many chronic debilitating diseases. Greater awareness of the insidious consequences of vitamin D deficiency is needed. Annual measurement of serum 25(OH)D is a reasonable approach to monitoring for vitamin D deficiency. The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1000 IU vitamin D/d is required to maintain a healthy concentration of 25(OH)D in the blood.     

婴幼儿期维生素D补充与一年级小学生超重肥胖的纵向关联

  目的  调查婴幼儿期维生素D补充状况及其对学龄初期超重肥胖的影响,为儿童肥胖的早期预防提供新思路。  方法  以8 744名上海市闵行区2019年9月1日入学,且于2019年10月8日至2020年1月17日进行了常规体检的小学一年级学生为研究对象,由专业医务人员按标准的方法和仪器测量儿童的身高、体重并计算体质量指数(BMI),以BMI界定超重肥胖,并回溯收集其出生记录与婴幼儿期维生素D补充、婴幼儿期喂养记录。采用非条件Logistic回归模型,拟合婴幼儿期维生素D补充对学龄初期超重肥胖的影响,并进一步根据出生后1,4,6月龄内是否纯母乳喂养进行分层分析。  结果  上海市闵行区一年级学生中,超重肥胖率为32.5%(2 843名);出生后1,2,4,6月龄内的婴儿维生素D补充率分别为20.2%,49.7%,66.3%,72.7%,有83.2%的婴幼儿在出生后3年内补充了维生素D。出生后1月龄内补充过维生素D的婴幼儿,学龄初期发生超重肥胖的风险降低(OR=0.82, 95%CI=0.68~0.98);分层分析结果显示,此保护作用在1,4,6月龄内为纯母乳喂养的婴儿中尤其明显[OR(95%CI)=0.76(0.61~0.97),0.76(0.59~0.99),0.69(0.49~0.98),P值均 < 0.05]。  结论  婴幼儿期维生素D补充率有待提高,婴幼儿期维生素D补充尤其对纯母乳喂养儿有降低学龄初期超重肥胖风险的作用。     

High-dose vitamin D supplements are not associated with linear growth in a large Finnish cohort

High vitamin D intake in childhood has been suggested to have an adverse influence on linear growth. In Finland, in the mid-1960s the official recommendation for infant vitamin D supplementation was 2000 IU/d (50 μg/d). We investigated whether high-dose vitamin D supplementation in infancy was associated with subsequent growth in height. We used data from a prospective population-based birth cohort study including all children due to be born in the 2 northernmost provinces in Finland in 1966 (12,058 live-births, coverage 96%). Information on each participant's height was collected at birth and ages 1, 14, and 31 y, as were possible confounding factors (data for analyses available from 10,060 singletons). Information on the frequency and dose of vitamin D supplementation was collected in 1967 when participants were 1 y of age. A weak association was found between frequency of vitamin D supplementation with greater height at age 1 y (P = 0.005), which was explained by birth characteristics and maternal and social factors (adjusted P = 0.34). Neither frequency nor dose of vitamin D supplementation was associated with height at 14 or 31 y (P > 0.13). To conclude, contrary to proposed evidence suggesting that vitamin D has a negative influence on growth rate at a dosage of ~2000 IU/d, supplementation at this level in the Northern Finland Birth Cohort was not associated with reduced height at any age studied.     

Optimal Vitamin D Supplementation Doses that Minimize the Risk for Both Low and High Serum 25-Hydroxyvitamin D Concentrations in the General Population

The Recommended Dietary Allowance (RDA) is the nutrient intake considered to be sufficient to meet the requirements of 97.5% of the population. Recent reports revealed a statistical error in the calculation of the RDA for vitamin D opening the question of what the recommendation should be. We took a dual approach to answer this question: (1) we aggregated 108 published estimates on vitamin D supplementation and vitamin D status; and (2) we analyzed 13,987 observations of program participants. The aggregation of published data revealed that 2909 IU of vitamin D per day is needed to achieve serum 25-hydroxyvitamin D (25(OH)D) concentrations of 50 nmol/L or more in 97.5% of healthy individuals. For normal weight, overweight and obese program participants this was 3094, 4450 and 7248 IU respectively. These supplementation doses would also result in 2.5% of normal weight, overweight and obese participants having 25(OH)D concentrations above 210, 200 and 214 nmol/L respectively. As these concentrations are high, an approach that minimizes the risk for both low and high concentrations seems desirable. With this approach we estimated, for example, that doses of 1885, 2802 and 6235 IU per day are required for normal weight, overweight and obese individuals respectively to achieve natural 25(OH)D concentrations (defined as 58 to 171 nmol/L). In conclusion, the large extent of variability in 25(OH)D concentrations makes a RDA for vitamin D neither desirable nor feasible. We therefore propose recommendations be articulated in the form of an optimal intake that minimizes the risk for both low and high serum 25(OH)D concentrations. This contribution includes body weight specific recommendations for optimal intakes for various combinations of lower and upper 25(OH)D concentration targets.     

Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration

BACKGROUND: Indirect evidence suggests that optimal vitamin D status is achieved with a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L. OBJECTIVE: We aimed to determine the intake of vitamin D(3) needed to raise serum 25(OH)D to >75 nmol/L. DESIGN: The design was a 6-mo, prospective, randomized, double-blinded, double-dummy, placebo-controlled study of vitamin D(3) supplementation. Serum 25(OH)D was measured by radioimmunoassay. Vitamin D(3) intake was adjusted every 2 mo by use of an algorithm based on serum 25(OH)D concentration. RESULTS: A total of 138 subjects entered the study. After 2 dose adjustments, almost all active subjects attained concentrations of 25(OH)D >75 nmol/L, and no subjects exceeded 220 nmol/L. The mean (+/-SD) slope at 9 wk [defined as 25(OH)D change/baseline dose] was 0.66 +/- 0.35 (nmol/L)/(microg/d) and did not differ statistically between blacks and whites. The mean daily dose was 86 microg (3440 IU). The use of computer simulations to obtain the most participants within the range of 75-220 nmol/L predicted an optimal daily dose of 115 microg/d (4600 IU). No hypercalcemia or hypercalciuria was observed. CONCLUSIONS: Determination of the intake required to attain serum 25(OH)D concentrations >75 nmol/L must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations. Projection of the dose-response curves observed in this convenience sample onto the population of the third National Health and Nutrition Examination Survey suggests a dose of 95 microg/d (3800 IU) for those above a 25(OH)D threshold of 55 nmol/L and a dose of 125 microg/d (5000 IU) for those below that threshold.     

Monitored Supplementation of Vitamin D in Preterm Infants: A Randomized Controlled Trial

Appropriate supplementation of vitamin D can affect infections, allergy, and mental and behavioral development. This study aimed to assess the effectiveness of monitored vitamin D supplementation in a population of preterm infants. 109 preterm infants (24 0/7–32 6/7 weeks of gestation) were randomized to receive 500 IU vitamin D standard therapy (n = 55; approximately 800–1000 IU from combined sources) or monitored therapy (n = 54; with an option of dose modification). 25-hydroxyvitamin D [25(OH)D] concentrations were measured at birth, 4 weeks of age, and 35, 40, and 52 ± 2 weeks of post-conceptional age (PCA). Vitamin D supplementation was discontinued in 23% of infants subjected to standard treatment due to increased potentially toxic 25(OH)D concentrations (>90 ng/mL) at 40 weeks of PCA. A significantly higher infants’ percentage in the monitored group had safe vitamin D levels (20–80 ng/mL) at 52 weeks of PCA (p = 0.017). We observed increased vitamin D levels and abnormal ultrasound findings in five infants. Biochemical markers of vitamin D toxicity were observed in two patients at 52 weeks of PCA in the control group. Inadequate and excessive amounts of vitamin D can lead to serious health problems. Supplementation with 800–1000 IU of vitamin D prevents deficiency and should be monitored to avoid overdose.     

25-Hydroxyvitamin D and vitamin D in human milk: effects of supplementation and season

Breast-milk 25-hydroxyvitamin D (25-[OH]D) and vitamin D were measured in mothers supplemented with 2000 or 1000 IU (50 or 25 micrograms) of vitamin D/d or with no supplementation. Fore- and hindmilk samples were collected at two stages of lactation (8 and 15 or 20 wk after delivery) and at different seasons. Season affected the levels of 25-(OH)D and vitamin D. The 25-(OH)D levels were higher in hind- than in foremilk. Supplementation had no effect on vitamin D levels. Milk 25-(OH)D levels of mothers receiving either 1000 or 2000 IU (25 or 50 micrograms) vitamin D/d were significantly higher than those of unsupplemented mothers in February and April. In theory, supplementation with 2000 IU (50 micrograms) vitamin D should have increased the calculated antirachitic activity of the milk in winter to the levels of unsupplemented mothers in September; however, responses varied widely among individuals.     

Vitamin D(3) and vitamin K(1) supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin

OBJECTIVE: Improvement of vitamin D and K status of about 60 -y-old postmenopausal Dutch women. DESIGN: In a randomized study postmenopausal women with normal (T-score >-1; n=96) and low (T-score< or =-1; n=45) bone mineral density (BMD) of the lumbar spine, were supplemented with 350-400 IU vitamin D(3), 80 microg vitamins K(1) vitamins K(1)+D(3), or placebo for 1 y. Serum 25-hydroxyvitamin D [25(OH)D] and percentage carboxylated osteocalcin (%carbOC) were measured at baseline and after 3, 6 and 12 months. RESULTS: Baseline %carbOC of the entire study population was positively correlated with BMD of the lumbar spine and femoral neck. Correspondingly, women with low BMD had lower %carbOC at baseline than women with normal BMD but this difference disappeared after 1 y of supplementation with vitamin K(1) ((mean+/-s.d.) 68+/-11% (95% CI, 64. 5-71.2%) vs 72+/-6% (95% CI, 70.1-72.9%), respectively). One year of supplementation with vitamin D(3) showed maximum increases in 25(OH)D of 33+/-29% (95% CI, 24.8-41.8%) and 68+/-58% (95% CI, 50.1-84.6%) in women with normal and low BMD, respectively. During winter, however, a 29% decline in maximum 25(OH)D levels was not prevented in women with low BMD. CONCLUSION: Daily supplementation of Dutch postmenopausal women with >400 IU vitamin D(3) is indicated to prevent a winter decline in 25(OH)D and to control serum parathyroid hormone levels. Daily supplementation with 80 microg vitamin K(1) seems to be necessary to reach premenopausal %carbOC levels. A stimulatory effect of calcium and/or vitamin D on %carbOC cannot be excluded. European Journal of Clinical Nutrition (2000) 54, 626-631.     

Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D

It has been more than 3 decades since the first assay assessing circulating 25-hydroxyvitamin D [25(OH)D] in human subjects was performed and led to the definition of "normal" nutritional vitamin D status, i.e., vitamin D sufficiency. Sampling human subjects, who appear to be free from disease, and assessing "normal" circulating 25(OH)D levels based on a Gaussian distribution of these values is now considered to be a grossly inaccurate method of identifying the normal range. Several factors contribute to the inaccuracy of this approach, including race, lifestyle habits, sunscreen usage, age, latitude, and inappropriately low dietary intake recommendations for vitamin D. The current adult recommendations for vitamin D, 200-600 IU/d, are very inadequate when one considers that a 10-15 min whole-body exposure to peak summer sun will generate and release up to 20,000 IU vitamin D-3 into the circulation. We are now able to better identify sufficient circulating 25(OH)D levels through the use of specific biomarkers that appropriately increase or decrease with changes in 25(OH)D levels; these include intact parathyroid hormone, calcium absorption, and bone mineral density. Using these functional indicators, several studies have more accurately defined vitamin D deficiency as circulating levels of 25(OH)D < or = 80 nmol or 32 microg/L. Recent studies reveal that current dietary recommendations for adults are not sufficient to maintain circulating 25(OH)D levels at or above this level, especially in pregnancy and lactation.     

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes

Recent evidence suggests that vitamin D intakes above current recommendations may be associated with better health outcomes. However, optimal serum concentrations of 25-hydroxyvitamin D [25(OH)D] have not been defined. This review summarizes evidence from studies that evaluated thresholds for serum 25(OH)D concentrations in relation to bone mineral density (BMD), lower-extremity function, dental health, and risk of falls, fractures, and colorectal cancer. For all endpoints, the most advantageous serum concentrations of 25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L (36-40 ng/mL). In most persons, these concentrations could not be reached with the currently recommended intakes of 200 and 600 IU vitamin D/d for younger and older adults, respectively. A comparison of vitamin D intakes with achieved serum concentrations of 25(OH)D for the purpose of estimating optimal intakes led us to suggest that, for bone health in younger adults and all studied outcomes in older adults, an increase in the currently recommended intake of vitamin D is warranted. An intake for all adults of > or =1000 IU (25 microg) [corrected] vitamin D (cholecalciferol)/d is needed to bring vitamin D concentrations in no less than 50% of the population up to 75 nmol/L. The implications of higher doses for the entire adult population should be addressed in future studies.     

Risk assessment for vitamin D

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 microg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.