25-hydroxyvitamin D concentration is key to analyzing vitamin D’s effects

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The recent Practice Alert by Dr. Campos-Outcalt, “How to proceed when it comes to vitamin D” (J Fam Pract. 2021;70:289-292) claimed that the value of vitamin D supplements for prevention is nil or still unknown.1 Most of the references cited in support of this statement were centered on randomized controlled trials (RCTs) based on vitamin D dose rather than achieved 25-­hydroxyvitamin D [25(OH)D] concentration. Since the health effects of vitamin D supplementation are correlated with 25(OH)D concentration, the latter should be used to evaluate the results of vitamin D RCTs—a point I made in my 2018 article on the topic.2

For example, in the Vitamin D and Type 2 Diabetes (D2d) Study, in which participants in the treatment arm received 4000 IU/d vitamin D3, there was no reduced rate of progression from prediabetes to diabetes. However, when 25(OH)D concentrations were analyzed for those in the vitamin D arm during the trial, the risk was found to be reduced by 25% (hazard ratio [HR] = 0.75; 95% CI, 0.68-0.82) per 10 ng/mL increase in 25(OH)D.3

There are significant benefits of vitamin D supplementation to achieve a 25(OH)D concentration of 30 to 60 ng/mL for important health outcomes.

Another trial, the Harvard-led VITamin D and OmegA-3 TriaL (VITAL), enrolled more than 25,000 participants, with the treatment arm receiving 2000 IU/d vitamin D3.4 There were no significant reductions in incidence of either cancer or cardiovascular disease for the entire group. The mean baseline 25(OH)D concentration for those for whom values were provided was 31 ng/mL (32.2 ng/mL for White participants, 24.9 ng/mL for Black participants). However, there were ~25% reductions in cancer risk among Black participants (who had lower 25(OH)D concentrations than White participants) and those with a body mass index < 25. A posthoc analysis suggested a possible benefit related to the rate of total cancer deaths.

A recent article reported the results of long-term vitamin D supplementation among Veterans Health Administration patients who had an initial 25(OH)D concentration of < 20 ng/mL.5 For those who were treated with vitamin D and achieved a 25(OH)D concentration of > 30 ng/mL (compared to those who were untreated and had an average concentration of < 20 ng/mL), the risk of myocardial infarction was 27% lower (HR = 0.73; 95% CI, 0.55-0.96) and the risk of all-cause mortality was reduced by 39% (HR = 0.61; 95% CI, 0.56-0.67).

An analysis of SARS-CoV-2 positivity examined data for more than 190,000 patients in the United States who had serum 25(OH)D concentration measurements taken up to 1 year prior to their SARS-CoV-2 test. Positivity rates were 12.5% (95% CI, 12.2%-12.8%) for those with a 25(OH)D concentration < 20 ng/mL vs 5.9% (95% CI, 5.5%-6.4%) for those with a 25(OH)D concentration ≥55 ng/mL.6

Thus, there are significant benefits of vitamin D supplementation to achieve a 25(OH)D concentration of 30 to 60 ng/mL for important health outcomes.


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