Quantifying the vitamin D economy.

Vitamin D enters the body through multiple routes and in a variety of chemical forms. Utilization varies with input, demand, and genetics. Vitamin D and its metabolites are carried in the blood on a Gc protein that has three principal alleles with differing binding affinities and ethnic prevalences. Three major metabolites are produced, which act via two routes, endocrine and autocrine/paracrine, and in two compartments, extracellular and intracellular. Metabolic consumption is influenced by physiological controls, noxious stimuli, and tissue demand. When administered as a supplement, varying dosing schedules produce major differences in serum metabolite profiles. To understand vitamin D's role in human physiology, it is necessary both to identify the foregoing entities, mechanisms, and pathways and, specifically, to quantify them. This review was performed to delineate the principal entities and transitions involved in the vitamin D economy, summarize the status of present knowledge of the applicable rates and masses, draw inferences about functions that are implicit in these quantifications, and point out implications for the determination of adequacy.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL and incidence of kidney stones.

OBJECTIVES: Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. We used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence. METHODS: The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones. RESULTS: We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3). CONCLUSIONS: We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.

Quantifying the food sources of basal vitamin d input.

Cutaneous synthesis and traditional food sources do not fully account for unsupplemented vitamin D status. Non-traditional food sources may be an undiscovered input. In a cohort of 780 non-supplement-taking adults with a mean serum 25-hydroxyvitamin D [25(OH)D] of 33 (±14)ng/ml we assessed the relationship between vitamin D status and selected food sources. Serum 25(OH)D concentration was adjusted for season, UVB exposures, and body size. These adjusted values were then regressed against multiple food items and combinations. Whole milk cottage cheese, eggs, red meat, and total protein were positively associated with total 25(OH)D and/or 25(OH)D3 (P<0.05 for each), whereas fish and milk intake were not. The slope of the relationship was such that for every intake of 1serving/day, serum 25(OH)D rose by about 2ng/ml for eggs and 1ng/ml for meat and total protein. For every weekly serving of whole milk cottage cheese, serum 25(OH)D rose by about 1ng/ml. While some food sources were significant predictors of vitamin D status, their ability to explain inter-individual variability was limited. Supplementation will likely remain essential to improving vitamin D status on a population level. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Quantifying the non-food sources of basal vitamin D input.

Unsupplemented vitamin D status is determined by cutaneous synthesis and food inputs; however, their relative magnitudes are largely unknown. In a cohort of 780 non-supplement-taking adults with a mean serum 25-hydroxyvitamin D [25(OH)D] of 33 (±14)ng/ml we assessed the relationship between serum 25(OH)D and non-food environmental variables. Serum 25(OH)D concentration was adjusted for seasonal influence (which removed 2% of the total variance) and these adjusted values were regressed against factors involved in cutaneous synthesis. Indoor tanning use, sun exposure, and percent of work performed outdoors were significantly positively associated and body mass index (BMI) was significantly negatively associated with 25(OH)D values (P<0.03 for each). Latitude, gender, and age were not significantly correlated (P>0.10). Season and non-food predictors together explained 13% of the total variance in serum 25(OH)D concentration. Non-traditional food sources need to be investigated as possible vitamin D inputs. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

25-Hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults.

CONTEXT: Guidelines have suggested that obese adults need 2 to 3 times more vitamin D than lean adults to treat vitamin D deficiency, but few studies have evaluated the vitamin D dose response in obese subjects. OBJECTIVE: The purpose of this study was to characterize the pharmacokinetics of 25-hydroxyvitamin D [25(OH)D] response to 3 different doses of vitamin D3 (cholecalciferol) in a group of obese subjects and to quantify the 25(OH)D dose-response relationship. DESIGN, SETTING, INTERVENTION, PATIENTS: This was a randomized, single-blind study of 3 doses of oral vitamin D3 (1000, 5000, or 10,000 IU) given daily to 67 obese subjects for 21 weeks during the winter months. MAIN OUTCOME MEASURES: Serum 25(OH)D levels were measured at baseline and after vitamin D replacement, and 25(OH)D pharmacokinetic parameters were determined, fitting the 25(OH)D concentrations to an exponential model. RESULTS: Mean measured increments in 25(OH)D at week 21 were 12.4 ± 9.7 ng/mL in the 1000 IU/d group, 27.8 ± 10.2 ng/mL in the 5000 IU/d group, and 48.1 ± 19.6 ng/mL in the 10,000 IU/d group. Steady-state increments computed from the model were 20.6 ± 17.1, 35.2 ± 14.6, and 51.3 ± 22.0 ng/mL, respectively. There were no hypercalcuria or hypercalcemia events during the study. CONCLUSION: Our data show that in obese people, the 25(OH)D response to vitamin D3 is directly related to dose and body size with ∼2.5 IU/kg required for every unit increment in 25(OH)D (nanograms per milliliter).

All-source basal vitamin D inputs are greater than previously thought and cutaneous inputs are smaller.

The magnitude of vitamin D inputs in individuals not taking supplements is unknown; however, there is a great deal of information on quantitative response to varying supplement doses. We reanalyzed individual 25-hydroxyvitamin D [25(OH)D] concentration data from 8 studies involving cholecalciferol supplementation (total sample size = 3000). We extrapolated individual study dose-response curves to zero concentration values for serum 25(OH)D by using both linear and curvilinear approaches and measured seasonal oscillation in the serum 25(OH)D concentration. The total basal input (food plus solar) was calculated to range from a low of 778 iu/d in patients with end-stage renal disease to a high of 2667 iu/d in healthy Caucasian adults. Consistent with expectations, obese individuals had lower baseline, unsupplemented 25(OH)D concentrations and a smaller response to supplements. Similarly, African Americans had both lower baseline concentrations and lower calculated basal, all-source inputs. Seasonal oscillation in 4 studies ranged from 5.20 to 11.4 nmol/L, reflecting a mean cutaneous synthesis of cholecalciferol ranging from 209 to 651 iu/d at the summer peak. We conclude that: 1) all-source, basal vitamin D inputs are approximately an order of magnitude higher than can be explained by traditional food sources; 2) cutaneous, solar input in these cohorts accounts for only 10-25% of unsupplemented input at the summer peak; and 3) the remainder must come from undocumented food sources, possibly in part as preformed 25(OH)D.

Calcium absorption response to cholecalciferol supplementation in hemodialysis.

BACKGROUND AND OBJECTIVES: Recent understanding of extrarenal production of calcitriol has led to the use of more vitamin D supplementation in CKD populations. This paper reports the effect of cholecalciferol supplementation on calcium absorption. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Paired calcium absorption tests were done before and after 12-13 weeks of 20,000 IU weekly cholecalciferol supplementation in 30 participants with stage 5 CKD on hemodialysis. The study was conducted from April to December of 2011. Calcium absorption was tested with a standardized meal containing 300 mg calcium carbonate intrinsically labeled with (45)Ca; 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured. RESULTS: 25-Hydroxyvitamin D rose from 14.2 ng/ml (11.5-18.5) at baseline to 49.3 ng/ml (42.3-58.1) at the end of the study (P<0.001). 1,25-Dihydroxyvitamin D rose from 15.1 (10.5-18.8) pg/ml at baseline to 20.5 (17.0-24.7) pg/ml at the end of the study (P<0.001). The median baseline calcium absorption was 12% (7%-17%) and 12% (7%-16%) at the end of study. CONCLUSIONS: Patients with stage 5 CKD on hemodialysis had very low calcium absorption values at baseline, and cholecalciferol supplementation that raised 25(OH)D levels to 50 ng/ml had no effect on calcium absorption.

Low vitamin D status and suicide: a case-control study of active duty military service members.

OBJECTIVE: Considering that epidemiological studies show that suicide rates in many countries are highest in the spring when vitamin D status is lowest, and that low vitamin D status can affect brain function, we sought to evaluate if a low level of 25-hydroxyvitamin D [25(OH)D] could be a predisposing factor for suicide. METHOD: We conducted a prospective, nested, case-control study using serum samples stored in the Department of Defense Serum Repository. Participants were previously deployed active duty US military personnel (2002-2008) who had a recent archived serum sample available for analysis. Vitamin D status was estimated by measuring 25(OH) D levels in serum samples drawn within 24 months of the suicide. Each verified suicide case (n = 495) was matched to a control (n = 495) by rank, age and sex. We calculated odds ratio of suicide associated with categorical levels (octiles) of 25(OH) D, adjusted by season of serum collection. FINDINGS: More than 30% of all subjects had 25(OH)D values below 20 ng/mL. Although mean serum 25(OH)D concentrations did not differ between suicide cases and controls, risk estimates indicated that subjects in the lowest octile of season-adjusted 25(OH)D (<15.5 ng/mL) had the highest risk of suicide, with subjects in the subsequent higher octiles showing approximately the same level of decreased risk (combined odds ratio compared to lowest octile = 0.49; 95% C.I.: 0.315-0.768). CONCLUSIONS: Low vitamin D status is common in active duty service members. The lowest 25(OH)D levels are associated with an increased risk for suicide. Future studies could determine if additional sunlight exposure and vitamin D supplementation might reduce suicide by increasing 25(OH) D levels.

Effect of a combination of genistein, polyunsaturated fatty acids and vitamins D3 and K1 on bone mineral density in postmenopausal women: a randomized, placebo-controlled, double-blind pilot study.

PURPOSE: Many postmenopausal women desire non-pharmaceutical alternatives to hormone therapy for protection against osteoporosis. Soybean isoflavones, especially genistein, are being studied for this purpose. This study examined the effects of synthetic genistein in combination with other potential bone-protective dietary molecules on bone mineral density (BMD) in early postmenopausal women. METHODS: In this 6-month double-blind pilot study, 70 subjects were randomized to receive daily either calcium only or the geniVida™ bone blend (GBB), which consisted of genistein (30 mg/days), vitamin D3 (800 IU/days), vitamin K1 (150 µg/days) and polyunsaturated fatty acids (1 g polyunsaturated fatty acids as ethyl ester: eicosapentaenoic acid/docosahexaenoic acid ratio = ~2/1). Markers of bone resorption and formation and BMD at the femoral neck, lumbar spine, Ward's triangle, trochanter and intertrochanter, total hip and whole body were assessed. RESULTS: Subjects supplemented with the GBB (n = 30) maintained femoral neck BMD, whereas in the placebo group (n = 28), BMD significantly decreased (p = 0.007). There was also a significant difference (p < 0.05) in BMD between the groups at Ward's triangle in favor of the GBB group. Bone-specific alkaline phosphatase and N-telopeptide significantly increased in the GBB group in comparison with those in baseline and in the placebo group. The GBB was well tolerated, and there were no significant differences in adverse events between groups. CONCLUSIONS: The GBB may help to prevent osteoporosis and reduce fracture risk, at least at the hip, in postmenopausal women. Larger and longer-term clinical trials are warranted.

A review of calcium supplements and cardiovascular disease risk.

A group of academic and industry experts in the fields of nutrition, cardiology, epidemiology, food science, bone health, and integrative medicine examined the data on the relationship between calcium supplement use and risk of cardiovascular events, with an emphasis on 4 of the Bradford Hill criteria for causal inference: strength, consistency, dose-response, and biological plausibility. Results from 2 epidemiological studies and a meta-analysis of randomized, controlled clinical trials, including a subgroup analysis from the Women's Health Initiative, have prompted concern about a potential association between calcium supplement use and a small increase in the risk of adverse cardiovascular events. However, a number of issues with the studies, such as inadequate compliance with the intervention, use of nontrial calcium supplements, potential bias in event ascertainment, and lack of information on and adjustment for known cardiovascular risk determinants, suggest that bias and confounding cannot be excluded as explanations for the reported associations. Findings from other cohort studies also suggest no detrimental effect of calcium from diet or supplements, with or without vitamin D, on cardiovascular disease risk. In addition, little evidence exists for plausible biological mechanisms to link calcium supplement use with adverse cardiovascular outcomes. The authors do not believe that the evidence presented to date regarding the hypothesized relationship between calcium supplement use and increased cardiovascular disease risk is sufficient to warrant a change in the Institute of Medicine recommendations, which advocate use of supplements to promote optimal bone health in individuals who do not obtain recommended intakes of calcium through dietary sources.

25-Hydroxyvitamin D response to cholecalciferol supplementation in hemodialysis.

BACKGROUND AND OBJECTIVES: Recent understanding of extrarenal production of calcitriol has led to the exploration of native vitamin D treatment in dialysis patients. This paper reports the pharmacokinetics of 25-hydroxyvitamin D response to 10,333 IU cholecalciferol given weekly in subjects on chronic dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, double-blind, placebo-controlled trial of 15 weeks of oral cholecalciferol in subjects with stage 5 CKD requiring maintenance hemodialysis was conducted from November of 2007 to March of 2010. The time course of serum 25-hydroxyvitamin D was measured over the course of treatment. Additionally, blood was drawn at baseline and last visit for calcium, phosphorus, calcitriol, and parathyroid hormone levels. RESULTS: The median (interquartile range) baseline 25-hydroxyvitamin D level was 13.3 (11.1-16.2) ng/ml for the treatment group and 15.2 (10.7-19.9) ng/ml for the placebo group. 25-hydroxyvitamin D steady state levels rose by 23.6 (19.2-29.9) ng/ml in the treatment group, and there was no change in the placebo group. Calcitriol levels also increased significantly in the treatment group. There were no significant changes in levels of calcium, albumin, phosphorus, and parathyroid hormone in either group. CONCLUSIONS: Cholecalciferol (10,333 IU) given weekly in patients on chronic hemodialysis produces a steady state in 25-hydroxyvitamin D of approximately 24 ng/ml.

Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity.

Vitamin D status is known to be poor in obese individuals; there is no consensus as to the reason. Cross-sectional study of the relation between serum 25-hydroxyvitamin D (25(OH)D) concentration and body size in the baseline data from unsupplemented adults entering two study cohorts in our research unit, N = 686. Regression analyses of body size variables against serum 25(OH)D concentration, using both linear and hyperbolic models. The fit to a hyperbolic model of 25(OH)D against body weight completely removed the obesity-related component of inter-individual variability in serum 25(OH)D concentration. The hyperbolic fit using total body weight was significantly better than any linear model, and specifically better than any using BMI. Dilution of ingested or cutaneously synthesized vitamin D in the large fat mass of obese patients fully explains their typically low vitamin D status. There is no evidence for sequestration of supplemental or endogenous cholecalciferol. Vitamin D replacement therapy needs to be adjusted for body size if desired serum 25(OH)D concentrations are to be achieved.

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.

OBJECTIVE: The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. PARTICIPANTS: The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D(2) or vitamin D(3) was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention.

BACKGROUND: Studies indicate that intake of vitamin D in the range from 1,100 to 4,000 IU/d and a serum 25-hydroxyvitamin D concentration [25(OH)D] from 60-80 ng/ml may be needed to reduce cancer risk. Few community-based studies allow estimation of the dose-response relationship between oral intake of vitamin D and corresponding serum 25(OH)D in the range above 1,000 IU/d. MATERIALS AND METHODS: A descriptive study of serum 25(OH)D concentration and self-reported vitamin D intake in a community-based cohort (n = 3,667, mean age 51.3 ± 13.4 y). RESULTS: Serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion, with no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml). Unsupplemented all-source input was estimated at 3,300 IU/d. The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d. CONCLUSION: Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.

Why the IOM recommendations for vitamin D are deficient.

The IOM recommendations for vitamin D fail in a major way on logic, on science, and on effective public health guidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model for development of nutritional policy.

Vitamin D(3) is more potent than vitamin D(2) in humans.

BACKGROUND: Current unitage for the calciferols suggests that equimolar quantities of vitamins D(2) (D2) and D(3) (D3) are biologically equivalent. Published studies yield mixed results. OBJECTIVE: The aim of the study was to compare the potencies of D2 and D3. DESIGN: The trial used a single-blind, randomized design in 33 healthy adults. Calciferols were dosed at 50,000 IU/wk for 12 wk. Principal outcome variables were area under the curve for incremental total 25-hydroxyvitamin D [25(OH)D] and change in calciferol content of sc fat. RESULTS: Incremental mean (sd) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml (516) for the D2-treated group and 2136 (606) for the D3 (P < 0.001). Mean (sd) steady-state 25(OH)D increments showed similar differences: 24 ng/ml for D2 (10.3) and 45 ng/ml (16.2) for D3 (P <0.001). Subcutaneous fat content of D2 rose by 50 µg/kg in the D2-treated group, and D3 content rose by 104 µg/kg in the D3-treated group. Total calciferol in fat rose by only 33 ng/kg in the D2-treated, whereas it rose by 104 µg/kg in the D3-treated group. Extrapolating to total body fat D3, storage amounted to just 17% of the administered dose. CONCLUSION: D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2. For neither was there evidence of sequestration in fat, as had been postulated for doses in this range. Given its greater potency and lower cost, D3 should be the preferred treatment option when correcting vitamin D deficiency.