Measurements of the Vitamin D Metabolome in the Calgary Vitamin D Study: Relationship of Vitamin D Metabolites to Bone Loss.

In a 36-month randomized controlled trial examining the effect of high-dose vitamin D3 on radial and tibial total bone mineral density (TtBMD), measured by high-resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with dual-energy X-ray absorptiometry T-scores > -2.5 without vitamin D deficiency) were randomized to receive 400 IU (N = 109), 4000 IU (N = 100), or 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24, and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D3 ; 24,25-(OH)2 D3 ; 1,25-(OH)2 D3 ; and 1,24,25-(OH)3 D3 ]. The relationship between peak values in vitamin D metabolites and changes in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D3 , 24,25-(OH)2 D3 and 1,24,25-(OH)3 D3 , but no dose-related change in plasma 1,25-(OH)2 D3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH)3 D3 (-0.05, 95% confidence interval [CI] -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D3 (female: -0.01, 95% CI -0.12, -0.07; male: -0.04, 95% CI -0.06, -0.01, p = 0.001) and 24,25-(OH)2 D3 (female: -0.75, 95% CI -0.98, -0.52; male: -0.35, 95% CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D3 (-0.03, 95% CI -0.05, -0.01, p < 0.001), 24,25-(OH)2 D3 (-0.30, 95% CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH)3 D3 (-0.03, 95% CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH)2 D3 may be responsible for the bone loss seen in the Calgary Vitamin D Study. Although plasma 1,25-(OH)2 D3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH)3 D3 prevented the detection of a dose-related rise in plasma 1,25-(OH)2 D3 . © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Response to High-Dose Vitamin D Supplementation Is Specific to Imaging Modality and Skeletal Site.

High-dose vitamin D supplementation (4000 or 10,000 IU/d) in vitamin D-sufficient individuals results in a dose-dependent decrease in radius and tibia total bone mineral density (Tt.BMD) compared with 400 IU/d. This exploratory analysis examined whether the response to high-dose vitamin D supplementation depends on imaging modality and skeletal site. Participants were aged 55 to 70 years, not osteoporotic, with serum 25(OH)D 30 to 125 nM. Participants' radius and tibia were scanned on high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure Tt.BMD, trabecular bone volume fraction (Tb.BV/TV), trabecular separation (Tb.Sp), cortical thickness (Ct.Th), and finite element analysis (FEA) estimated failure load. Three-dimensional image registration was used. Dual-energy X-ray absorptiometry (DXA) scans of the hip, spine, and radius measured areal BMD (aBMD) and trabecular bone score (TBS). Constrained linear mixed-effects models determined treatment group-by-time and treatment group-by-time-by-sex interactions. The treatment group-by-time interaction previously observed for radial Tt.BMD was observed at both ultradistal (UD, p < 0.001) and 33% (p < 0.001) aBMD sites. However, the treatment group-by-time-by-sex interaction observed for radial Tt.BMD was not observed with aBMD at either the UD or 33% site, and the 4000 and 400 groups did not differ. Registered radial FEA results mirrored Tt.BMD. An increase in Tb.Sp and decrease in Ct.Th underpinned dose-dependent changes in radial BMD and strength. We observed no effects in DXA-based aBMD at the hip or spine or TBS. At the tibia, we observed a time-by-treatment group effect for Tb.BV/TV. Given that DXA measures at the radius did not detect sex differences or differences between the 4000 and 400 groups, HR-pQCT at the radius may be more sensitive for examining bone changes after vitamin D supplementation. Although DXA did not reveal treatment effects at the hip or spine, whether that is a true skeletal site difference or a lack of modality sensitivity remains unclear. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Adverse Effects of High-Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males.

Three years of high-dose vitamin D supplementation (400 IU, 4000 IU, 10,000 IU) in healthy vitamin D-sufficient individuals aged 55 to 70 years (serum 25(OH)D 30-125 nmol/L at baseline), resulted in a negative dose-response relationship for bone density and strength. This study examined whether response differed between males and females. A total of 311 participants (53% male) were randomized to 400 IU (male = 61, female = 48), 4000 IU (male = 51, female = 49), or 10,000 IU (male = 53, female = 49) daily vitamin D3 . Participants were scanned with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD (TtBMD) at baseline, 6, 12, 24, and 36 months. Finite element analysis estimated bone strength. Balance, physical function, and clinical biochemistry parameters were also assessed. Constrained linear mixed effects models determined time-by-treatment group-by-sex interactions. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L (400 IU); 81.3, 115.3, and 132.2 (4000 IU); and 78.4, 188.0, and 144.4 (10,000 IU), respectively. There were significant time-by-treatment group-by-sex interactions for TtBMD at the radius (p = .002) and tibia (p = .005). Treatment with 4000 IU or 10,000 IU compared to 400 IU resulted in TtBMD losses in females, but this was not observed with males. After 3 years, females lost 1.8% (400 IU), 3.8% (4000 IU), and 5.5% (10,000 IU), whereas males lost 0.9% (400 IU), 1.3% (4000 IU), and 1.9% (10,000 IU) at the radius. At the tibia, losses in TtBMD were smaller, but followed a similar trend. There were no significant bone strength interactions. Vitamin D supplementation with 4000 IU or 10,000 IU, compared with 400 IU daily, resulted in greater losses of TtBMD over 3 years in healthy vitamin D-sufficient females, but not males. These results are clinically relevant, because vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention. Our findings do not support a benefit of high-dose vitamin D supplementation for bone health, and raise the possibility of harm for females. © 2020 American Society for Bone and Mineral Research (ASBMR).

Postural Balance Effects Associated with 400, 4000 or 10,000 IU Vitamin D3 Daily for Three Years: A Secondary Analysis of a Randomized Clinical Trial.

Vitamin D supplementation is proposed as a fall prevention strategy, as it may improve neuromuscular function. We examined whether three years of vitamin D supplementation (400, 4000 or 10,000 IU daily) affects postural sway in older adults. Three hundred and seventy-three non-osteoporotic, vitamin D-sufficient, community-dwelling healthy adults, aged 55-70 years, were randomized to 400 (n = 124), 4000 (n = 125) or 10,000 (n = 124) IU daily vitamin D3 for three years. Sway index was assessed at baseline, 12-, 24- and 36-months using the Biosway machine. We tested participants under four conditions: eyes open or eyes closed with firm (EOFI, ECFI) or foam (EOFO, ECFO) surfaces. Secondary assessments examined sway in the anterior-posterior (AP) and medio-lateral (ML) directions. Linear mixed effects models compared sway between supplementation groups across time. Postural sway under EOFO and ECFO conditions significantly improved in all supplementation groups over time. Postural sway did not differ between supplementation groups at any time under any testing conditions in normal, AP or ML directions (p > 0.05 for all). Our findings suggest that high dose (4000 or 10,000 IU) vitamin D supplementation neither benefit nor impair balance compared with 400 IU daily in non-osteoporotic, vitamin D-sufficient, healthy older adults.

Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial.

CONTEXT: More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown. OBJECTIVE: The objective of this work is to establish whether vitamin D doses up to 10 000 IU/day are safe and well tolerated. DESIGN: The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial. SETTING: A single-center study was conducted at the University of Calgary, Canada. PARTICIPANTS: Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L. INTERVENTIONS: Participants were randomly assigned 1:1:1 to vitamin D3 400, 4 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day. MAIN OUTCOME MEASURES: In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression. RESULTS: Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms. CONCLUSIONS: The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.

Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial.

Importance: Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day. Objective: To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength. Design, Setting, and Participants: Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. Interventions: Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. Main Outcomes and Measures: Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. Results: Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (-3.9 mg HA/cm3 [95% CI, -6.5 to -1.3]) and 10 000 IU group (-7.5 mg HA/cm3 [95% CI, -10.1 to -5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of -1.2% (400 IU group), -2.4% (4000 IU group), and -3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were -1.8 mg HA/cm3 (95% CI, -3.7 to 0.1) in the 4000 IU group and -4.1 mg HA/cm3 in the 10 000 IU group (95% CI, -6.0 to -2.2), with mean percent change values of -0.4% (400 IU), -1.0% (4000 IU), and -1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12). Conclusions and Relevance: Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful. Trial Registration: ClinicalTrials.gov Identifier: NCT01900860.

Methods and procedures for: A randomized double-blind study investigating dose-dependent longitudinal effects of vitamin D supplementation on bone health.

The optimum dose of vitamin D and corresponding serum 25-hydroxyvitamin D (25OHD) concentration for bone health is still debated and some health practitioners are recommending doses well above the Canada/USA recommended Dietary Reference Intake (DRI). We designed a three-year randomized double-blind clinical trial investigating whether there are dose-dependent effects of vitamin D supplementation above the Dietary Reference Intake (DRI) on bone health. The primary aims of this study are to assess, whether supplementation of vitamin D3 increases 1) volumetric bone mineral density measured by high-resolution peripheral quantitative computed tomography (HR-pQCT); 2) bone strength assessed by finite element analysis, and 3) areal bone mineral density by dual X-ray absorptiometry (DXA). Secondary aims are to understand whether vitamin D3 supplementation improves parameters of bone microarchitecture, balance, physical function and quality of life. Participants are men and women aged 55-70 years, with women at least 5-years post-menopause. The intervention is daily vitamin D3 supplementation doses of 400, 4000 or 10,000 IU. Participants not achieving adequate dietary calcium intake are provided with calcium supplementation, up to a maximum supplemental dose of 600 mg elemental calcium per day. Results from this three-year study will provide evidence whether daily vitamin D3 supplementation with adequate calcium intake can affect bone density, bone microarchitecture and bone strength in men and women. Furthermore, the safety of high dose daily vitamin D3 supplementation will be explored.

The High Prevalence of Vitamin D Insufficiency in Cord Blood in Calgary, Alberta (APrON-D Study).

OBJECTIVE: Vitamin D is important in promoting healthy pregnancy and fetal development. We undertook this study to measure 25-hydroxyvitamin D in maternal and cord blood and to identify maternal factors related to vitamin D status in Calgary. METHODS: Blood samples collected at the time of delivery from the Alberta Pregnancy Outcomes and Nutrition study cohort (ApronStudy.ca) participants were processed for plasma and assayed using liquid chromatography mass spectrometry methodology for 25(OH)D3. RESULTS: Ninety-two pairs of maternal and cord blood samples were obtained. The prevalence of 25(OH)D3 insufficiency-25(OH)D3 <75 nmol/L-was 38% and 80% in women and neonates, respectively. Vitamin D supplementation was the only clinical factor associated with 25(OH)D3 sufficiency, and the odds of sufficiency were 3.75 (95% CI 1.00 to 14.07) higher for women and 5.27 (95% CI 1.37 to 20.27) when over 2000 IU/day were used. CONCLUSION: Using liquid chromatography mass spectrometry, we demonstrated a very high prevalence of vitamin D insufficiency in cord blood and that the use of high dose vitamin D was associated with greater odds of sufficiency in pregnant women and cord blood in Alberta.

The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial.

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013-March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812.

The Current Recommended Vitamin D Intake Guideline for Diet and Supplements During Pregnancy Is Not Adequate to Achieve Vitamin D Sufficiency for Most Pregnant Women.

BACKGROUND: The aims of this study were to determine if pregnant women consumed the recommended vitamin D through diet alone or through diet and supplements, and if they achieved the current reference range vitamin D status when their reported dietary intake met the current recommendations. METHODS: Data and banked blood samples collected in second trimester from a subset of 537 women in the APrON (Alberta Pregnant Outcomes and Nutrition) study cohort were examined. Frozen collected plasma were assayed using LC-MS/MS (liquid chromatography-tandem mass spectrometry) to determine 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3 concentrations. Dietary data were obtained from questionnaires including a Supplement Intake Questionnaire and a 24-hour recall of the previous day's diet. RESULTS: Participants were 87% Caucasian; mean (SD) age of 31.3 (4.3); BMI 25.8 (4.7); 58% were primiparous; 90% had education beyond high school; 80% had a family income higher than CAN $70,000/year. 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3) were identified in all of the 537 plasma samples;3-epi-25(OH)D3 contributed 5% of the total vitamin D. The median (IQR) total 25(OH)D (D2+D3) was 92.7 (30.4) nmol/L and 20% of women had 25(OH)D concentration < 75 nmol/L. The median (IQR) reported vitamin D intake from diet and supplements was 600 (472) IU/day. There was a significant relationship between maternal reported dietary vitamin D intake (diet and supplement) and 25(OH)D and 3-epi-25(OH)D3 concentrations in an adjusted linear regression model. CONCLUSIONS: We demonstrated the current RDA (600 IU/ day) may not be adequate to achieve vitamin D status >75 nmol/L in some pregnant women who are residing in higher latitudes (Calgary, 51°N) in Alberta, Canada and the current vitamin D recommendations for Canadian pregnant women need to be re-evaluated.

Plasma 3-Epi-25-Hydroxycholecalciferol Can Alter the Assessment of Vitamin D Status Using the Current Reference Ranges for Pregnant Women and Their Newborns.

BACKGROUND: Vitamin D is critical for healthy pregnancies and normal fetal development. It is important to accurately ascertain vitamin D status in mothers and their newborns to establish the optimal vitamin D concentration during pregnancy. There are many different metabolites and epimers of vitamin D in peripheral blood and controversy as to the importance of epimers in estimating vitamin D status in maternal and infant health. OBJECTIVES: We undertook this study to measure 25-hydroxyvitamin D metabolites and epimers and their relations in maternal and cord blood and to evaluate the impact of the inclusion of epimers on assessing vitamin D status. METHODS: We performed a substudy in a longitudinal cohort of pregnant women and their infants in Alberta, Canada [APrON (Alberta Pregnancy Outcomes and Nutrition) Study]. Maternal and cord blood plasma collected at the time of newborn delivery was stored at -70°C until testing and assayed for 25-hydroxyergocalciferol [25(OH)D2], 25-hydroxycholecalciferol [25(OH)D3], and 3-epi-25-hydroxycholecalciferol [3-epi-25(OH)D3] by using LC-tandem mass spectrometry. The effect of 3-epi-25(OH)D3 on estimates of vitamin D adequacy was explored by using McNemar's chi-square test at both recommended thresholds of 50 and 75 nmol/L. RESULTS: Ninety-two pairs of maternal and cord blood samples were obtained. 3-Epi-25(OH)D3 was detected in all samples, comprising 6.0% and 7.8% of 25(OH)D3 in maternal and cord blood, respectively. Positive correlations were found between 25(OH)D3 and 3-epi-25(OH)D3 for both maternal and cord blood (maternal blood: r = 0.34, P = 0.01; cord blood: r = 0.44, P = 0.01). In addition, regression analysis showed a significant association between vitamin D supplementation and 3-epi-25(OH)D3 in maternal and cord blood (ß: 0.423; 95% CI: 0.173, 0.672). When 3-epi-25(OH)D3 was not included in plasma vitamin D estimations, 38% of women and 80% of neonates were classified as having an insufficient concentration (<75 nmol/L); however, with 3-epi-25(OH)D3 included, the estimates of insufficiency were significantly lower: 33% and 73% for women and neonates, respectively. CONCLUSIONS: Using LC-MS/MS we showed the presence of 3-epi-25(OH)D3 in all samples of pregnant women and their cord blood, and when the 3-epimer was included in the estimation of status the prevalence of vitamin D insufficiency (<75 nmol/L) was significantly lower. Our data suggest that the high use of dietary supplements in this group of women contributes to 3-epi-25(OH)D3 concentrations in both maternal and cord blood. Further research on the role of the epimers in characterizing vitamin D status in pregnancy and infancy is imperative.

The VITAH trial VITamin D supplementation and cardiac Autonomic tone in Hemodialysis: a blinded, randomized controlled trial.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have a high rate of mortality and specifically an increased risk of sudden cardiac death (SCD). Impaired cardiac autonomic tone is associated with elevated risk of SCD. Moreover, patients with ESKD are often vitamin D deficient, which we have shown may be linked to autonomic dysfunction in humans. To date, it is not known whether vitamin D supplementation normalizes cardiac autonomic function in the high-risk ESKD population. The VITamin D supplementation and cardiac Autonomic tone in Hemodialysis (VITAH) randomized trial will determine whether intensive vitamin D supplementation therapies improve cardiac autonomic tone to a greater extent than conventional vitamin D supplementation regimens in ESKD patients requiring chronic hemodialysis. METHODS/DESIGN: A total of 60 subjects with ESKD requiring thrice weekly chronic hemodialysis will be enrolled in this 2x2 crossover, blinded, randomized controlled trial. Following a 4-week washout period from any prior vitamin D therapy, subjects are randomized 1:1 to intensive versus standard vitamin D therapy for 6 weeks, followed by a 12-week washout period, and finally the remaining treatment arm for 6 weeks. Intensive vitamin D treatment includes alfacalcidiol (activated vitamin D) 0.25 mcg orally with each dialysis session combined with ergocalciferol (nutritional vitamin D) 50 000 IU orally once per week and placebo the remaining two dialysis days for 6 weeks. The standard vitamin D treatment includes alfacalcidiol 0.25 mcg orally combined with placebo each dialysis session per week for 6 weeks. Cardiac autonomic tone is measured via 24 h Holter monitor assessments on the first dialysis day of the week every 6 weeks throughout the study period. The primary outcome is change in the low frequency: high frequency heart rate variability (HRV) ratio during the first 12 h of the Holter recording at 6 weeks versus baseline. Secondary outcomes include additional measures of HRV. The safety of intensive versus conventional vitamin D supplementation is also assessed. DISCUSSION: VITAH will determine whether an intensive vitamin D supplementation regimen will improve cardiac autonomic tone compared to conventional vitamin D supplementation and will assess the safety of these two supplementation regimens in ESKD patients receiving chronic hemodialysis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812.

Clinical review: Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis.

CONTEXT: Observational studies report consistent associations between low vitamin D concentration and increased glycemia and risk of type 2 diabetes, but results of randomized controlled trials (RCTs) are mixed. OBJECTIVE: The objective of the study was to systematically review RCTs that report on the effects of vitamin D supplementation on glucose homeostasis or diabetes prevention. DATA SOURCES: Sources of data for the study were MEDLINE, EMBASE, SCOPUS, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment, and Science Citation Index from inception to June 2013. STUDY SELECTION: Study selection was trials that compared vitamin D3 supplementation with placebo or a non-vitamin D supplement in adults with normal glucose tolerance, prediabetes, or type 2 diabetes. DATA EXTRACTION AND SYNTHESIS: Two reviewers collected data and assessed trial quality using the Cochrane Risk of Bias tool. Random-effects models were used to estimate mean differences (MDs) and odds ratios. The main outcomes of interest were homeostasis model assessment of insulin resistance, homeostasis model assessment of ß-cell function, hemoglobin A1c levels, fasting blood glucose, incident diabetes, and adverse events. DATA SYNTHESIS: Thirty-five trials (43 407 patients) with variable risk of bias were included. Vitamin D had no significant effects on insulin resistance [homeostasis model assessment of insulin resistance: MD -0.04; 95% confidence interval (CI) -0.30 to 0.22, I-squared statistic (I(2)) = 45%], insulin secretion (homeostasis model of ß-cell function: MD 1.64; 95% CI -25.94 to 29.22, I(2) = 40%), or hemoglobin A1c (MD -0.05%; 95% CI -0.12 to 0.03, I(2) = 55%) compared with controls. Four RCTs reported on the progression to new diabetes and found no effect of vitamin D (odds ratio 1.02; 95% CI 0.94 to 1.10, I(2) = 0%). Adverse events were rare, and there was no evidence of publication bias. CONCLUSIONS: Evidence from available trials shows no effect of vitamin D3 supplementation on glucose homeostasis or diabetes prevention. Definitive conclusions may be limited in the context of the moderate degree of heterogeneity, variable risk of bias, and short-term follow-up duration of the available evidence to date.

Does a high dietary acid content cause bone loss, and can bone loss be prevented with an alkaline diet?

A popular concept in nutrition and lay literature is that of the role of a diet high in acid or protein in the pathogenesis of osteoporosis. A diet rich in fruit and vegetable intake is thought to enhance bone health as the result of its greater potassium and lower "acidic" content than a diet rich in animal protein and sodium. Consequently, there have been a number of studies of diet manipulation to enhance potassium and "alkaline" content of the diet to improve bone density or other parameters of bone health. Although acid loading or an acidic diet featuring a high protein intake may be associated with an increase in calciuria, the evidence supporting a role of these variables in the development of osteoporosis is not consistent. Similarly, intervention studies with a more alkaline diet or use of supplements of potassium citrate or bicarbonate have not consistently shown a bone health benefit. In the elderly, inadequate protein intake is a greater problem for bone health than protein excess.

Calcium and vitamin D intake and mortality: results from the Canadian Multicentre Osteoporosis Study (CaMos).

CONTEXT: Calcium and vitamin D are recommended for bone health, but there are concerns about adverse risks. Some clinical studies suggest that calcium intake may be cardioprotective, whereas others report increased risk associated with calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have been associated with increased mortality. OBJECTIVE: The purpose of this study was to determine the association between total calcium and vitamin D intake and mortality and heterogeneity by source of intake. DESIGN: The Canadian Multicentre Osteoporosis Study cohort is a population-based longitudinal cohort with a 10-year follow-up (1995-2007). SETTING: This study included randomly selected community-dwelling men and women. PARTICIPANTS: A total of 9033 participants with nonmissing calcium and vitamin D intake data and follow-up were studied. EXPOSURE: Total calcium intake (dairy, nondairy food, and supplements) and total vitamin D intake (milk, yogurt, and supplements) were recorded. OUTCOME: The outcome variable was all-cause mortality. RESULTS: There were 1160 deaths during the 10-year period. For women only, we found a possible benefit of higher total calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01) per 500-mg increase in daily calcium intake and no evidence of heterogeneity by source; use of calcium supplements was also associated with reduced mortality, with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs nonusers with statistically significant reductions remaining among those with doses up to 1000 mg/d. These associations were not modified by levels of concurrent vitamin D intake. No definitive associations were found among men. CONCLUSIONS: Calcium supplements, up to 1000 mg/d, and increased dietary intake of calcium may be associated with reduced risk of mortality in women. We found no evidence of mortality benefit or harm associated with vitamin D intake.