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As reviewed in a recent Biotics Research Forum, an abstract recently presented at the American Heart Association’s Scientific Sessions suggests that personalized dosing of vitamin D may reduce the risk of heart attacks among people with cardiovascular disease. While not yet peer-reviewed, what is notable in this trial (in addition to the substantial risk reduction) is that a fixed dose of vitamin D was not used. Rather, the TARGET-D trial personalized doses to achieve specific blood levels of 25-OH vitamin D (25-OHD). Other trials suggest there may also be advantages to daily dosing rather than large boluses, genetic and other modifiers, etc., meriting a general review of the evidence related to vitamin D dosing.
Several studies suggest that daily to weekly supplementation has clinical benefits, while large monthly or annual dosing either has no benefit or carries some degree of harm. For example, a 2025 systematic review and meta-analysis published in The Lancet, Diabetes & Endocrinology found no overall benefit of vitamin D supplementation compared to placebo for the risk of acute respiratory infections (ARI). This analysis comprised 46 randomized and controlled clinical trials, involving over 64,000 participants. A closer examination of the results revealed statistically significant protection with vitamin D for specific subsets. Regarding dosing frequency, a daily dose was associated with a 16% lower risk of ARI, whereas no protective benefit was observed for either weekly or monthly dosing. Additionally, dosing of 400-1000 IU was associated with a 30% lower risk for ARI, while higher and lower doses were not associated with benefit (none were targeted to a specific 25-OHD level).
High boluses of vitamin D have also been linked to harm in some studies. JAMA, for example, published the results of a double-blind clinical trial that found that among older community-dwelling women, an annual dose of 500,000 IU cholecalciferol (D3) given annually for 3 to 5 years was associated with an increase in both falls and fractures. Similarly, JAMA Internal Medicine published the results of a one-year clinical trial which found that compared to monthly dosing of 24,000 IU vitamin D3, a higher dose of 60,000 D3 did not improve lower extremity function, and was associated with an increase in fall risk (with similar results for a group receiving 24,000 IU D3 in addition to 300 μg of calcifediol (active D, i.e., 25-OH vitamin D). When combined with calcium, daily doses of vitamin D have been shown to lower fracture rates and fall incidence in several (but not all) clinical trials, without evidence of harm.
There may be other modifiers of vitamin D’s effectiveness. Genetic polymorphisms are likely to play a role; for example, in 2023, JAMA Oncology published a secondary analysis of a randomized and controlled trial, which suggests that people with variants in the vitamin D binding protein (DBP) gene are more likely to benefit from vitamin D supplementation. In this trial, over 1,600 people who were recently diagnosed with a colorectal adenoma were given either vitamin D, calcium, both, or a placebo and followed for 3-5 years. People with at least one A allele in the rs4588 SNP (coding for the DBP2 isoform) had a lower risk of recurrence with either calcium or vitamin D supplementation, with the lowest risk observed for the combination (24% lower than placebo). Additionally, this risk was 43% lower among people with two A alleles (homozygotes) in this SNP, while people with the CC genotype had no statistical benefit with either supplement. DPB is a vitamin D carrier protein, and the DBP2 isoform is associated with lower levels of 25-OHD. Additional data from the same trial also found that vitamin D effectiveness was influenced by other genes, such as the vitamin D receptor gene.
BMI-based effectiveness of vitamin D supplementation may also be worth evaluating. In 2023, JAMA Network Open published an analysis from VITAL (Vitamin D and Omega-3 Trial), which found that the effects of vitamin D supplementation on serum vitamin D-related biomarkers (including free and bioavailable vitamin D, 25-OHD, etc.) were blunted among people with overweight or obesity. Varying effects on 25-OHD levels with body weight have been observed previously, and a Mendelian randomization published in PLoS One suggests that a higher BMI leads to a lower 25-OHD, with the reverse phenomenon (a lower 25-OHD leading to a higher BMI) is likely to only be a small effect. An analysis of over 17,000 healthy volunteers also published in PLoS One suggests that vitamin D supplementation should be 2-3 times higher for people with obesity and 1.5 times higher for people with overweight.
While there have been many disappointing trials evaluating vitamin D supplementation, it remains difficult to generalize. Were the doses chosen in the trials appropriate and reflective of differences in BMI and/or genetic variants? Were the doses targeted to a specific 25-OHD or a fixed dose, with the latter likely to have inconsistent effects on the target population? Hopefully, more trials like the TARGET-D study are implemented, and include an analysis of some of the variables related to vitamin D efficacy.
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