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Cited by 535Vitamin D Research StudiesNutrition and Health StudiesBone health and osteoporosis research

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The health effects of vitamin D supplementation: evidence from human studies

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Bouillon, Roger, Manousaki, Despoina, Rosen, Cliff, Trajanoska, Katerina, Rivadeneira, Fernando, Richards, J. Brent·2022·Nature Reviews Endocrinology
DOI 10.1038/s41574-021-00593-zPMC PMC8609267
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Abstract

Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.

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  • Supplementation effects depend strongly on baseline vitamin D status, assay standardization, dose, formulation, adherence, and population context.

    “supplementation effects depend strongly on baseline status, assay standardization, dose, formulation, adherence, and population context [1,2,3,4,5,6].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [5]

    The safety-outcomes section reports different results by baseline vitamin D status and dose, while the T2DM section describes findings by adherence and participant characteristics. The review therefore supports much of the claim, but our copy does not establish that supplementation effects depend on assay standardization or formulation; assay standardization appears only in a cited reference title. No page numbers were available in the indexed passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Vitamin D supplementation effects depend on baseline 25(OH)D status, dose, formulation, adherence, duration, body composition, and whether participants are deficient or already replete at baseline.

    “Vitamin D supplementation effects depend on baseline 25(OH)D status, dose, formulation, adherence, duration, body composition, and whether participants are deficient or already replete at baseline [3,4,5,6].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [5]

    The T2DM section reports post hoc differences by baseline deficiency, BMI and adherence, while the safety-outcomes section reports different effects at high doses and with intermittent boluses. The Conclusions distinguish deficient from vitamin D-replete people. The review lists trial durations but does not establish that effects depend on duration, and the passages found do not establish an effect of formulation; the T2DM subgroup findings are also more tentative than the claim suggests. No page numbers are available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The present results are consistent with the broader vitamin D trial literature, where extra-skeletal effects often appear weaker in randomized evidence than in observational studies.

    “The present results are consistent with the broader vitamin D trial literature, where extra-skeletal effects often appear weaker in randomized evidence than in observational studies [3,4,5,6].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [5]

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Metadata

Authors
Bouillon, R., Manousaki, D., Rosen, C., Trajanoska, K., Rivadeneira, F., & Richards, J. B.
Affiliations
  • KU Leuven (BE)
  • CHU Sainte-Justine Research Center (CA)
  • Erasmus MC (NL)
  • Jewish General Hospital (CA)
Corresponding author
Bouillon, Roger
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2021-11-23
Volume
18
Issue
2
Pages
96-110
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/s41574-021-00593-z
PMC
PMC8609267
OpenAlex
W3217758006
Cited by
535
References
9
Citations by year
2026: 83 · 2025: 123 · 2024: 135 · 2023: 118 · 2022: 75 · 2021: 1
FWCI
14.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutrition and Health Studies
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
vitamin D supplementation, vitamin D deficiency, 25-hydroxyvitamin D, rickets prevention, cancer prevention, cardiovascular events, falls, type 2 diabetes, multiple sclerosis, Mendelian randomization, VITAL trial, bone health
MeSH terms
Aged, Child, Diabetes Mellitus, Type 2, Humans, Infant, Rickets, Vitamin D, Vitamin D Deficiency, Dietary Supplements

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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