High Vitamin D Not Harmful, Whites Most Susceptible to Low Levels

High vitamin D levels that exceed recommended ranges — an increasingly common trend in the population — show no association with all-cause mortality, while the better-known risks of vitamin D deficiency appear notably stronger in whites than any other race or ethnicity, according to new research.

"Given the rapid increase in the incidence of serum 25-hydroxyvitamin D (25 [OH]D) values greater than 50 ng/mL in the population, our finding is reassuring that all-cause mortality was not increased in this group," say Daniel V. Dudenkov, MD, of the Mayo Clinic, in Rochester, Minnesota, and colleagues, in their study, published online May 2 in Mayo Clinic Proceedings.

The finding of racial differences in mortality risk with vitamin D deficiencies is new, they add.

"A novel finding of our study was the significant interaction of race/ethnicity and serum 25(OH)D in the relationship with all-cause mortality. Despite a strong association between 25(OH)D concentrations of less than 20 ng/mL and all-cause mortality in whites, this relationship was absent in patients of other race/ethnicity, even at very low 25(OH)D values."

Concerns of J-Shaped Association With Mortality and Vitamin D Allayed?

Whereas the potential health risks of low 25(OH)D levels, including greater cardiovascular disease, cancer, and respiratory deaths, have been well documented, concerns about health effects at the opposite end of the spectrum — high vitamin D levels — have been raised more recently, including in a study that described a "reverse J-shaped" association of all-cause and cardiovascular disease mortality with 25(OH)D values greater than 50 to 60 ng/mL (J Clin Endocrinol Metab. 2012;97:2644-2652).

That research was especially notable in light of findings from another study by Dudenkov and colleagues that showed a significant increase in the incidence of high 25(OH)D values, greater than 50 ng/mL, in the population between 2002 and 2011 (Mayo Clin Proc. 2015;90:577-586). That study, importantly, did not show an increase in acute clinical toxicity with high vitamin D levels.

Nevertheless, in response to the concern, an Institute of Medicine committee that formulated dietary reference intakes for vitamin D recommends a tolerable upper intake level of 4000 IU, which corresponds to a serum 25(OH)D concentration of approximately 50 ng/mL.

Meanwhile, recommendations on the lower level generally consider serum 25(OH)D values below 20 ng/mL to indicate vitamin D deficiency.

Commenting on the current study for Medscape Medical News, Michael F. Holick, MD, PhD, of the Section of Endocrinology, Nutrition, and Diabetes at Boston University, Massachusetts, underscored the importance of the finding that higher vitamin D is not associated with increased mortality. He noted that the results confirm those reported in a meta-analysis of 32 studies (Am J Public Health. 2014;104:e43-50), which showed the maximum health benefit in terms of mortality were seen with 25(OH)D levels greater than 30 ng/mL, and even above 70 ng/mL.

"The [meta-analysis] concluded that there is no evidence that increasing your vitamin D status increases the risk for mortality, and in fact it continues to provide benefit. The current study now confirms that observation," Holick said.

Strong Association of Mortality With Low Vitamin D, but Only in Whites

In this latest study, Dudenkov and colleagues evaluated data on individuals from Olmsted County, Minnesota, enrolled in the Rochester Epidemiology Project between 2005 and 2011 and followed until their last visit or death.

The 11,022 participants had a mean baseline 25(OH)D of 30.0 ± 12.9 ng/mL. They were a mean age of 54.3 years, 77.1% were women, and 87.6% were white.

Of the total cohort, the proportions of patients with 25(OH)D levels of less than 12, 12 to 19, 20 to 50, and greater than 50 ng/mL were 5.8%, 14.6%, 74.5%, and 5.1%, respectively. Among patients of "other race/ethnicity", a greater proportion had levels in the lower 25(OH)D ranges than whites.

After a median follow-up of 4.8 years, there were 723 deaths (123 cancer-related, 125 circulatory-related, 159 respiratory-related, and 316 other).

Researchers found no increased risk of all-cause mortality among patients with 25(OH)D above the "high" level of 50 ng/mL, compared with recommended levels of between 20 and 50 ng/mL.

After adjustment in a multivariate analysis, a significant interaction was seen between the effect of 25(OH)D and race/ethnicity on mortality (P < .001).

In white patients, adjusted hazard ratios (HRs) for 25(OH)D values of less than 12, 12 to 19, 20 to 50, and greater than 50 ng/mL were 2.5 (95% CI, 2.2 - 2.9), 1.4 (95% CI, 1.2 - 1.6), 1.0 (referent), and 1.0 (95% CI, 0.81 - 1.3), respectively.

In patients of other race/ethnicity, adjusted HRs were 1.9 (95% CI, 1.5 - 2.3), 1.7 (95% CI, 1.1 - 2.6), 1.5 (95% CI, 1.0 - 2.0), and 2.1 (95% CI, 0.77 - 5.5), compared with the reference group (whites with 25(OH)D values of 20 to 50 ng/mL).

"We found a strong association between 25(OH)D concentrations of less than 20 ng/mL and all-cause mortality," the authors say, noting however a "significant interaction by race/ethnicity, with no association for patients of other race/ethnicity, even at very low 25(OH)D values (< 12 ng/mL)."

A "Vitamin D Paradox" Previously Described in Blacks

Whereas vitamin D deficiency can result from a variety of causes, ranging from dietary to physiological effects of disease, high 25(OH)D values above 50 ng/mL are typically the result of supplementation, either in osteoporosis treatment or because the patient is at risk for vitamin D deficiency, the authors explain.

Although low levels may not have a causative effect on increasing mortality, vitamin D can be important in helping to prevent mortality from various illnesses, they add.

"The effects of vitamin D and its metabolites on inflammation, cellular proliferation, genetic regulation, calcium homeostasis, and immune modulation could have a salutary effect in a variety of diseases that contribute to mortality."

And individuals who are not white are known to have lower 25(OH)D concentrations in general.

However, an effect known as the "vitamin D paradox" has shown that African Americans in fact tend to have a lower risk of osteoporosis despite having lower 25(OH)D levels, the authors go on to explain.

Blacks have been shown to be at lower risk of other effects of low vitamin D, they add.

"Unlike whites, low 25(OH)D values have not been associated with fracture risk in blacks," and concentrations below 15 ng/mL have been associated with a higher risk of fatal stroke in whites but not blacks, after adjustment for covariates.

A key limitation of the current study, however, is that a relatively low percentage of participants were nonwhite, and women were over-represented.

Holick agrees: "Only 12% of the total study population were black, so the numbers are relatively small."

"Typically, doctors are aware that blacks are more at risk of vitamin D deficiency than their white patients, so it's also likely that those patients were being treated for vitamin D deficiency," he added. "That may have therefore skewed the numbers and made things more difficult to interpret."

Nevertheless, he concluded that, considering the research to date overall, the study "confirms that you can definitely have higher levels of vitamin D in the range recommended by the Endocrine Society Practice Guidelines, which recommend a preferred range of 40 to 60 ng/mL, and even suggest that levels up to 100 ng/mL are perfectly safe."

The authors and Holick have reported no relevant financial relationships.

Mayo Clinic Proceedings. Published online May 2, 2018. Abstract

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