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Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial.
Chandler, PD, Chen, WY, Ajala, ON, Hazra, A, Cook, N, Bubes, V, Lee, IM, Giovannucci, EL, Willett, W, Buring, JE, et al
JAMA network open. 2020;(11):e2025850
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Abstract
IMPORTANCE Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways. OBJECTIVE To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index. DESIGN, SETTING, AND PARTICIPANTS VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017. INTERVENTIONS Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements. MAIN OUTCOMES AND MEASURES For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations. RESULTS Among 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01169259.
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Impact of vitamin D supplementation on inflammatory markers in African Americans: results of a four-arm, randomized, placebo-controlled trial.
Chandler, PD, Scott, JB, Drake, BF, Ng, K, Manson, JE, Rifai, N, Chan, AT, Bennett, GG, Hollis, BW, Giovannucci, EL, et al
Cancer prevention research (Philadelphia, Pa.). 2014;(2):218-25
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African Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [25(OH)D]. The effect of vitamin D3 (cholecalciferol) supplementation on inflammatory markers is uncertain. We conducted a randomized, double-blind, placebo-controlled trial of supplemental oral vitamin D (placebo, 1,000, 2,000, or 4,000 IU/day of vitamin D3 orally for 3 months) in 328 African Americans (median age, 51 years) of public housing communities in Boston, MA, who were enrolled over three consecutive winter periods (2007-2010). Change from 0 to 3 months of plasma levels of 25(OH)D, high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, IL-10, and soluble TNF-α receptor type 2 (sTNF-R2) in 292 (89%) participants were measured. Overall, no statistically significant changes in CRP, IL-6, IL-10, and sTNF-R2 were observed after the vitamin D supplementation period. Baseline CRP was significantly inversely associated with the baseline 25(OH)D level (P < 0.001) in unadjusted and adjusted models. An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP (month 3-month 0; P for interaction = 0.04). Within an unselected population of African Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers. This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index. Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African Americans.
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Effect of vitamin D supplementation on blood pressure in blacks.
Forman, JP, Scott, JB, Ng, K, Drake, BF, Suarez, EG, Hayden, DL, Bennett, GG, Chandler, PD, Hollis, BW, Emmons, KM, et al
Hypertension (Dallas, Tex. : 1979). 2013;(4):779-85
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Abstract
Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, -0.66 mm Hg for 1000 U/d, -3.4 mm Hg for 2000 U/d, and -4.0 mm Hg for 4000 U/d of cholecalciferol (-1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.
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Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial.
Ding, EL, Mehta, S, Fawzi, WW, Giovannucci, EL
International journal of cancer. 2008;(8):1690-4
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Abstract
Although calcium and vitamin-D intake were consistently shown to be inversely associated with colorectal cancer risk in several large prospective studies and protective against adenoma and cancer in multiple randomized trials, the Women's Health Initiative (WHI) of calcium and low-dose vitamin-D supplementation trial found no overall effects on colorectal cancer. However, the previous report did not recognize an important biologic interaction with estrogen therapy. We investigated the treatment interaction of estrogen with calcium and vitamin-D on risk of colorectal cancer via a reanalysis of primary data results from the WHI calcium and vitamin-D supplementation trial (1,000 mg elemental calcium, 400 IU of vitamin-D3, or placebo), reanalyzing results from women concurrently randomized to estrogen interventions and placebo. Results indicate that concurrent estrogen therapy was a strong effect modifier of calcium and vitamin-D supplementation on colorectal cancer risk. While calcium plus vitamin-D supplementation among women concurrently assigned to estrogen therapies suggested increased risk (Hazard Ratio = 1.50, 95% CI: 0.96-2.33), among women concurrently assigned to placebos arms of the estrogen trials, calcium plus vitamin-D indicated suggestive benefits (HR = 0.71, 95% CI: 0.46-1.09) (p-for-estrogen-interaction = 0.018). Consistent interaction was also found by reported estrogen use (p interaction = 0.037). Results indicate contrasting effects of calcium and vitamin-D by concurrent estrogen therapy on colorectal cancer risk. Although further clinical and mechanistic studies are warranted, the potential clinical implications of the apparent interaction of estrogen therapy with calcium and vitamin-D supplementation should be recognized. Important biological mechanisms related to the key membrane receptor megalin and estrogen-dependent protein calbindin are discussed.