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Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

ABSTRACT: Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25-hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n?>?2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50?years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard-disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high-risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3?years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Scragg R

PROVIDER: S-EPMC7839821 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

Scragg Robert R Sluyter John D JD

JBMR plus 20210104 1

Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25-hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (<i>n</i> > 2000 participants in each) o ...[more]

PMID: 33553994

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Project description:BACKGROUND:The extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients. METHODS:We conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 µg vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials. RESULTS:Seven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population. CONCLUSION:Vitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future.

Project description:SummaryThe Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer.IntroductionThis study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality.MethodsWHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS).ResultsAmong women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive.ConclusionThough based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

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Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

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Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

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