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High dose dietary vitamin D₃ increases bone mass and strength in mice.

ABSTRACT: Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldwide to maintain optimal bone health, but the most appropriate level of supplementation remains controversial. This study aimed to determine the effects of varying doses of dietary vitamin D₃ on the mechanical properties and morphology of growing bone. Eight-week-old female mice were supplied with one of 3 diets, each containing a different dose of vitamin D₃: 1000 IU/kg (control), 8000 IU/kg or 20,000 IU/kg. Mice had ad libitum access to the specialty diet for 4 weeks before they were culled and their tibiae collected for further analysis. The collected tibia underwent three-point bending and reference-point indentation from which their mechanical properties were determined, and cortical and trabecular morphology determined by micro computed tomography. Dietary supplementation with 20,000 IU/kg vitamin D₃ resulted in greater ductility (~ 200%) and toughness (~ 150%) compared to the 1000 IU/kg control. The 20,000 IU/kg diet was also associated with significantly greater trabecular bone volume fraction and trabecular number. The 8000 IU/kg diet had no significant effect on trabecular bone mass. We conclude that vitamin D₃ supplementation of 20,000 IU/kg during early adulthood leads to tougher bone that is more ductile and less brittle than that of mice supplied with standard levels of dietary vitamin D₃ (1000 IU/kg) or 8000 IU/kg. This suggests that dietary vitamin D₃ supplementation may increase bone health by improving bone material strength and supports the use of vitamin D₃ supplementation, during adolescence, for achieving a higher peak bone mass in adulthood and thereby preventing osteoporosis.

SUBMITTER: Williamson L

PROVIDER: S-EPMC5365305 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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High dose dietary vitamin D3 increases bone mass and strength in mice.

Williamson Liam L Hayes Alan A Hanson Erik D ED Pivonka Peter P Sims Natalie A NA Gooi Jonathan H JH

Bone reports 20170210

Vitamin D plays a critical role in skeletal homeostasis. Vitamin D supplementation is used worldwide to maintain optimal bone health, but the most appropriate level of supplementation remains controversial. This study aimed to determine the effects of varying doses of dietary vitamin D3 on the mechanical properties and morphology of growing bone. Eight-week-old female mice were supplied with one of 3 diets, each containing a different dose of vitamin D3: 1000 IU/kg (control ...[more]

PMID: 28377981

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Project description: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.

Project description:Exercise has long-lasting benefits to bone health that may help prevent fractures by increasing bone mass, bone strength, and tissue quality. Long-term exercise of 6-12 weeks in rodents increases bone mass and bone strength. However, in growing mice, a short-term exercise program of 3 weeks can limit increases in bone mass and structural strength, compared to non-exercised controls. Short-term exercise can, however, increase tissue strength, suggesting that exercise may create competition for minerals that favors initially improving tissue-level properties over structural-level properties. It was therefore hypothesized that adding calcium and phosphorus supplements to the diet may prevent decreases in bone mass and structural strength during a short-term exercise program, while leading to greater bone mass and structural strength than exercise alone after a long-term exercise program. A short-term exercise experiment was done for 3 weeks, and a long-term exercise experiment was done for 8 weeks. For each experiment, male 16-week old C57BL/6 mice were assigned to 4 weight-matched groups-exercise and non-exercise groups fed a control or mineral-supplemented diet. Exercise consisted of treadmill running at 12 m/min, 30 min/day for 7 days/week. After 3 weeks, exercised mice fed the supplemented diet had significantly increased tibial tissue mineral content (TMC) and cross-sectional area over exercised mice fed the control diet. After 8 weeks, tibial TMC, cross-sectional area, yield force, and ultimate force were greater from the combined treatments than from either exercise or supplemented diet alone. Serum markers of bone formation (PINP) and resorption (CTX) were both decreased by exercise on day 2. In exercised mice, day 2 PINP was significantly positively correlated with day 2 serum Ca, a correlation that was weaker and negative in non-exercised mice. Increasing dietary mineral consumption during an exercise program increases bone mass after 3 weeks and increases structural strength after 8 weeks, making bones best able to resist fracture.

Project description:BackgroundVitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.ResultsA total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.ConclusionsEarly administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

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High dose dietary vitamin D₃ increases bone mass and strength in mice.

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High dose dietary vitamin D<sub>3</sub> increases bone mass and strength in mice.

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