Vitamin D supplementation at 2,000 IU per day did not reduce the risk of major cardiovascular events or invasive cancer in generally healthy adults over five years of follow-up, according to VITAL, a nationwide randomized trial of 25,871 US adults by Manson and colleagues published in the New England Journal of Medicine in 2019. The 2024 clinical practice guideline from the Endocrine Society, led by Marie Demay and published in the Journal of Clinical Endocrinology and Metabolism, integrates this and other trial evidence and reaches a similarly narrowed conclusion: routine vitamin D supplementation and routine testing are not indicated for most healthy adults under 75, though specific populations do benefit from empiric supplementation.
Vitamin D behaves more like a hormone than a vitamin
Vitamin D is the only vitamin the body can synthesize when the skin is exposed to ultraviolet B (UVB) radiation, and it acts primarily through nuclear vitamin D receptors that alter gene expression. That mechanism, shared with steroid hormones and thyroid hormone, is different from the enzymatic cofactor role of most other vitamins. Its established clinical function is enabling intestinal absorption of calcium and phosphate for bone mineralization. Severe deficiency causes rickets in children and osteomalacia in adults.
Deficiency is common but hard to define
Serum 25-hydroxyvitamin D concentration is the standard clinical measure. Thresholds have shifted over the past two decades. The Institute of Medicine (now the National Academy of Medicine) defines deficiency as below 30 nmol/L (12 ng/mL), with 30 to 50 nmol/L considered inadequate for bone health in some individuals. The Endocrine Society previously defined deficiency as below 50 nmol/L (20 ng/mL). Estimates of population prevalence vary accordingly. Lower serum levels are more common at northern latitudes in winter, in people with darker skin (higher melanin reduces UVB conversion), in the elderly (reduced skin synthesis and lower dietary intake), in people with obesity (vitamin D is sequestered in adipose tissue), and in people with malabsorption syndromes.
The randomized evidence for extra-skeletal benefits is thin
Over the past two decades, vitamin D has been implicated in observational studies linking low serum levels to cardiovascular disease, cancer, depression, cognitive decline, autoimmune disease, and infection. Randomized trials at scale have generally not confirmed those observational signals in people without deficiency. The VITAL trial found no reduction in cardiovascular events or cancer at 2,000 IU per day. Similar large trials have found no effect of vitamin D supplementation on fracture prevention in community-dwelling adults (VITAL bone health substudy), depression (VITAL-DEP), cognitive function, or respiratory infection risk at meaningful effect sizes. The pattern is consistent: correcting actual deficiency improves outcomes; supplementing above sufficiency does not appear to provide broad additional protection.
The 2024 Endocrine Society guideline narrowed the recommendations
The Demay guideline replaces the Society’s 2011 vitamin D guideline and takes a much more restrained view. It recommends empiric vitamin D supplementation, meaning supplementation above the Institute of Medicine dietary reference intake without pre-testing 25-hydroxyvitamin D levels, in four specific populations: children and adolescents aged 1 to 18, adults over 75, pregnant women, and adults with high-risk prediabetes. In each case, the recommendation is based on randomized trial evidence of specific outcomes: reduction of nutritional rickets in children, of respiratory tract infections in children, of all-cause mortality in adults over 75, of adverse pregnancy outcomes, and of progression from prediabetes to diabetes. In her comment at the guideline release, Demay said the panel concluded that “healthy populations who may benefit from higher dose vitamin D supplements are those 75 and older, pregnant people, adults with prediabetes, and children and adolescents 18 and younger, but we do not recommend routine testing for vitamin D levels in any of these groups.” For generally healthy adults under 75, the guideline recommends against routine supplementation above the standard dietary reference intake and against routine 25-hydroxyvitamin D testing.
High doses are not benign
Vitamin D toxicity, though rare, is a genuine risk at doses well above the RDA sustained over months. It causes hypercalcemia, kidney stones, and, in severe cases, kidney damage and vascular calcification. The Institute of Medicine set a tolerable upper intake level of 4,000 IU per day for adults. Doses above that without medical indication or monitoring are not evidence-based and carry real risk.
What to actually do
The practical picture is narrower than the supplement industry suggests. For an adult under 75 without malabsorption, without dark skin plus limited sun exposure, and without pregnancy or prediabetes, routine daily vitamin D above the dietary reference intake (600 to 800 IU depending on age) is not evidence-supported. For adults 75 and older, pregnant women, adolescents and children, and people with high-risk prediabetes, low-dose empiric supplementation is reasonable, with 1,000 to 2,000 IU per day covering most needs. For people with malabsorption syndromes, chronic kidney disease, or clinical suspicion of deficiency, testing and physician-guided treatment is appropriate.
What the evidence cannot yet answer
The optimal serum 25-hydroxyvitamin D level for disease prevention outside skeletal health is not established; the Demay guideline notes explicitly that no serum threshold has been shown to predict clinical outcomes in generally healthy people. Whether specific subpopulations, defined by genetics, race, or environmental factors, benefit from targeted supplementation is under investigation. And the observational associations between low vitamin D and diverse chronic diseases have not been reconciled with the null randomized trial findings, which may reflect reverse causation, confounding by outdoor activity, or a threshold effect that only correcting true deficiency can address.
References
- Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. New England Journal of Medicine, 2019; 380: 33-44. DOI: 10.1056/NEJMoa1809944
- Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism, 2024; 109: 1907-1947. DOI: 10.1210/clinem/dgae290
- Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011.
- LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. New England Journal of Medicine, 2022; 387: 299-309. DOI: 10.1056/NEJMoa2202106