Vitamin D: Evidence-Based Health Benefits and Recommendations for Population Guidelines

Abstract

Vitamin D offers numerous under-recognized health benefits beyond its well-known role in musculoskeletal health. It is vital for extra-renal tissues, prenatal health, brain function, immunity, pregnancy, cancer prevention, and cardiovascular health. Existing guidelines issued by governmental and health organizations are bone-centric and largely overlook the abovementioned extra-skeletal benefits and optimal thresholds for vitamin D. In addition, they rely on randomized controlled trials (RCTs), which seldom show benefits due to high baseline 25-hydroxyvitamin D [25(OH)D] concentrations, moderate supplementation doses, and flawed study designs. This review emphasizes the findings from prospective cohort studies showing that higher 25(OH)D concentrations reduce the risks of major diseases and mortality, including pregnancy and birth outcomes. Serum concentrations > 30 ng/mL (75 nmol/L) significantly lower disease and mortality risks compared to <20 ng/mL. With 25% of the U.S. population and 60% of Central Europeans having levels <20 ng/mL, concentrations should be raised above 30 ng/mL. This is achievable through daily supplementation with 2000 IU/day (50 mcg/day) of vitamin D₃, which prevent diseases and deaths. Furthermore, a daily dose between 4000 and 6000 IU of vitamin D₃ to achieve serum 25(OH)D levels between 40 and 70 ng/mL would provide greater protection against many adverse health outcomes. Future guidelines and recommendations should integrate the findings from observational prospective cohort studies and well-designed RCTs to improve public health and personalized care.

Keywords: COVID-19; Endocrine Society; cancer; cardiovascular disease; chronic kidney disease; chronic lower respiratory diseases; dementia; diabetes mellitus; pregnancy.

Figure 1

The relative risk of major cardiovascular events (MACEs) for low vs. high serum 25(OH)D concentrations (mostly >30 vs. <20 ng/mL) versus the mean follow-up period [37]. The two shortest follow-up period papers were those of de Metrio [55] and Beska [56], which are considered closest to the actual effect of 25(OH)D concentration against MACE. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 2

Plot of relative risk of stroke versus years of follow-up concerning high vs. low 25(OH)D concentrations (mostly >30 vs. <20 ng/mL) [37]. The papers with the two shortest follow-up periods are those of Zittermann et al. [61] and Anderson et al. [62], which are considered closest to the effect of 25(OH)D concentration against stroke. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 3

Odds ratio (OR) for colorectal cancer concerning high vs. low 25(OH)D concentrations against median years to diagnosis for data from men and women used in the study of McCullough et al. [27], as shown in [28]. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 4

Scatter plot of relative risk (RR) against low vs. high 25(OH)D concentrations (mostly <20 vs. >30 ng/mL) for dementia from [38]. The data for the two shortest follow-up periods were from the studies of Littlejohns et al. [115], Kiderman et al. [116], and Van Lent et al. [117], which are considered the most accurate. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 5

Relative risk (RR) for AD against low vs. high 25(OH)D concentrations (mostly <20 vs. >30 ng/mL) according to the mean follow-up period [38]. The two shortest follow-up period data are from the studies of Littlejohns et al. [115] and Melo van Lent et al. [117], which are considered the most accurate. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 6

Calculated serum 25(OH)D concentrations needed to overcome different groups of conditions and disorders and the reported average (percentage) improvements/responses in primary clinical outcomes. The cumulated data from many outcome-based vitamin D-related clinical trials (both observational and RCTs) studies are summarized (Wimalwansa et al., 2024) [12,18]. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024).

Figure 7

The dose–response for vitamin D with the associated health benefits. When the vitamin D [25(OH)D] level reaches sufficiency for a given tissue/system, no further benefits will be obtained (i.e., providing more would not provide additional physiological benefits). The broken red line illustrates that the beneficial effects of vitamin D could continue without causing hypercalcemia when high doses are administered under close medical supervision. Unlike pharmaceutical agents, nutrient response curves are narrower by about half of an order of magnitude (Wimalwansa et al., 2024) [18]. This figure is from an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/, accessed on 10 December 2024). The broken purple line in the upper right corner of Figure 7 represents those with rare indications (i.e., resistance to standard therapy), such as drug-resistant migraine and cluster headaches, psoriasis, asthma, etc. These groups of patients require significantly higher serum 25(OH)D concentrations to be maintained to achieve vital benefits, for example, between 80 and 150 ng/mL [12]. As with the Coimbra protocol, benefits can be obtained without demonstrable adverse effects when appropriately treated under medical supervision. Hypercalcemia generally does not manifest under 150 ng/mL [12].