Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL)

LeBoff, Meryl S.; Chou, Sharon H.; Murata, Elle M; Donlon, Catherine M.; Cook, Nancy R.; Mora, Samia; Lee, I-Min; Kotler, Gregory; Bubes, Vadim; Buring, Julie E.; Manson, JoAnn E.

doi:10.1002/jbmr.3958

Cited by 78 publications

(83 citation statements)

References 54 publications

(65 reference statements)

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“…(20) Similarly, no vitamin D supplementation and sex effects were observed using peripheral quantitative computed tomography (pQCT) in the VITAL Trial. (20) In normal aging populations, age-by-sex-by-time interactions have been reported for TtBMD using pQCT at the tibia, where females had a steeper rate of decline than males. (22) That finding is supported by HR-pQCT studies where age-by-sex interactions were observed at the radius and tibia for total and cortical volumetric BMD but not trabecular BMD, (7) consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

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

Burt

Billington

Rose

et al. 2020

Journal of Bone and Mineral Research

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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).

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Section: Discussionmentioning

confidence: 99%

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

Burt

Billington

Rose

et al. 2020

Journal of Bone and Mineral Research

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“…In the endothelium, vitamin D modulates macrophage and T lymphocyte activity, and it exerts anti-inflammatory and antibacterial activities [126,127]. Vitamin D supplements show extensive benefits if the population has vitamin D deficiency [128][129][130][131][132]. In CKD patients, uremic toxins contribute to the inflammatory response and lead to immune dysregulation.…”

Section: Vitamin D Supplement Is Beneficial In Ecs and Adipose Tissuementioning

confidence: 99%

Sirtuin-1 and Its Relevance in Vascular Calcification

Liao

Hou

et al. 2020

IJMS

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Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

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“…We recently found that vitamin D 3 supplementation compared to placebo did not affect bone density or structure in the VITamin D and OmegA-3 TriaL (VITAL). However, in exploratory analyses, in adults with lower baseline free, but not total, 25(OH)D levels, supplemental vitamin D had a benefit on bone density ( 17 ). There are no large RCTs or primary prevention trials of supplemental vitamin D that assess the role of free 25(OH)D levels in predicting the risk of falls.…”

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confidence: 99%

VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population

LeBoff

Murata

Cook

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting. Objective The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk. Design VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median). Setting This is a nationwide study. Participants Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study. Interventions Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design. Main Outcome Measures Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit. Results Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points. Conclusion Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

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Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL)

Cited by 78 publications

References 54 publications

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

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

Sirtuin-1 and Its Relevance in Vascular Calcification

VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population

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