Laura Armas

Vitamin D3 Is More Potent Than Vitamin D2 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.

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.

Vitamin D3 Distribution and Status in the Body

Objective: To estimate the amount, type, and tissue distribution of vitamin D in the adult body under typical inputs. Methods: Review and reanalysis of published measurements and analysis of tissue samples from growing pigs raised in confinement on diets providing about 2000 IU vitamin D/day. Cholecalciferol and 25-hydroxyvitamin D [25(OH)D] concentration measured by HPLC. Results: Mean serum 25(OH)D in all studies combined was 45 nmol/L. At the level of vitamin D repletion represented by this concentration, total body vitamin D would be 14,665 IU for a 70 kg adult woman. 65% of this total was present as native cholecalciferol and 35% as 25(OH)D. Nearly three-quarters of the cholecalciferol was in fat, while 25(OH)D was more evenly distributed throughout the body (20% in muscle, 30% in serum, 35% in fat, and 15% in all other tissues). At the daily vitamin D consumption rates in these animals total body stores provided only a ∼7-day reserve. Conclusions: At total intakes on the order of 2000 IU/day, an adult has very little vitamin D reserve, despite intakes 10× the current recommendations. Those recommended inputs need to be increased by at least an order of magnitude. Food tables that fail to take into account 25(OH)D content of various meat products lead to underestimation of dietary vitamin D intake.

Trabecular bone histomorphometry in humans with Type 1 Diabetes Mellitus.

Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone microarchitecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex-matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. [1]. Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility.

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.

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.

Older Mayan residents of the western highlands of Guatemala lack sufficient levels of vitamin D

Vitamin D (VitD) levels in older Mayans are currently unknown. Geographic factors, for example, residences in areas receiving ample sunlight at high altitudes and latitudes near the equator, would favor optimum VitD levels, whereas demographic factors, for example, darker skin pigmentation, clothing practices, and older age, would favor low 25-hydroxy-vitamin D, or 25(OH)D, levels. Conjecturing that demographic factors affecting VitD status might outweigh geographic factors in this population, we hypothesized that older Mayans have suboptimal values of 25(OH)D. We also hypothesized that older Mayans in rural areas would have higher VitD levels than would their urban counterparts. Blood samples were collected from 108 healthy older Mayans (mean age, 69 years) from urban (n = 84, 50% male) and rural settings (n = 24, 50% male) during the summer of 2008 in the highlands of Quetzaltenango, Guatemala. We assessed 25(OH)D concentrations by radioimmunoassay in a US-based laboratory. Mean (SD) serum 25(OH)D values were 53.3 (15.0) nmol/L, and lower 25(OH)D values were associated with increasing age (r = -0.58, P = .004). Of all subjects, 3.7% (n = 4) maintained an optimal status of 25(OH)D (>80 nmol/L), 50% (n = 54) had values between 50 and 80 nmol/L, and 46.3% (n = 50) had levels less than 50 nmol/L. Urban subjects had nonsignificantly higher 25(OH)D values (55.0 ± 15.3 nmol/L) than did rural subjects (47.4 ± 12.4 nmol/L, P = .228). Men had significantly higher values (58.2 ± 16.5 nmol/L) than did women (48.4 ± 11.6 nmol/L, P = .001). We conclude that despite residing in an optimal geographic location to receive adequate sunlight exposure, most older Guatemalan Mayans in Quetzaltenango have suboptimal levels of VitD.

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 Ds 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.

Vitamin D Status and Associations in Newborn Formula-Fed Infants during Initial Hospitalization

BACKGROUND Evidence suggests that adequate vitamin D status in infancy plays a role in improving bone health and preventing disease, including type 1 diabetes, infections, and asthma. The objective of this study was to provide newborn hospitalized infants with American Academy of Pediatrics recommendations of 400 IU/day vitamin D-3 and measure the effect on serum 25(OH)D levels. DESIGN This trial was conducted August 2009 to June 2010. Infants were randomized to a control were measured from cord blood, every 7 days, and at discharge. Intact parathyroid hormone was measured at discharge. PARTICIPANTS/SETTING Fifty-two infants <32 weeks gestational age who received formula feedings during their neonatal intensive care unit hospitalization. STATISTICAL ANALYSIS Patient characteristics for each treatment group were summarized using descriptive statistics. The Mann-Whitney test was used to compare continuous variables, and categorical variables were compared using the χ(2) test or Fishers exact test. The Pearson correlation coefficient was used to look at associations between continuous variables. RESULTS The mean cord blood level for all participants was 17.6±7.0 ng/mL. White infants had significantly higher 25(OH)D levels than non-white infants (P=0.0003). The mean 25(OH)D level at discharge of the supplemented group was 23.1±7.0 ng/mL (57.66±17.47 nmol/L), the mean 25(OH)D level of the unsupplemented group was 17.8±4.7 ng/mL (44.43±11.3 nmol/L), (P=0.007). Serum 25(OH)D showed a positive correlation with serum calcium in the first week of life (r=0.44, P=0.003) and negative correlation with parathyroid hormone levels at discharge (r=-0.35, P=0.02). CONCLUSIONS In newborn hospitalized infants, vitamin D-3 supplementation of 400 IU/day increased mean 25(OH)D levels from 17 ng/mL at birth to 23.1 ng/mL at discharge. Lower 25(OH)D levels were correlated with hypocalcemia during the first week of life, and elevated parathyroid hormone levels at discharge.