Low Free 25(OH)D Vitamin D Is Best Predictor of Mortality

Becky McCall

September 21, 2020

Low levels of free 25 hydroxyvitamin D [25(OH)D] predicted all-cause mortality in a large study of middle-aged and elderly men that explored the optimal way to measure vitamin D levels when determining likelihood of death.

The findings were recently presented as a poster at the virtual European Congress of Endocrinology 2020 meeting.

"We found vitamin D deficiency is associated with a higher risk of all-cause mortality, and specifically, we found that free 25(OH)D, but not free 1.25(OH)2D, is predictive of all-cause mortality," said lead author Leen Antonio, MD, from University Hospitals, Leuven, Belgium.

The total amount of these vitamin D metabolites is most often used to assess a patient's vitamin D status; 25(OH)D is the prohormone that is converted to 1.25(OH)2D. The latter is considered the "active" form of vitamin D in the body.

Men with the lowest free 25(OH)D levels (<4.43 ng/L) had a 91% increased risk for all-cause mortality compared to those with the very highest amount of free 25(OH)D, reported Antonio.

"Both the total and the free 25(OH)D are predictive of all-cause mortality, but free 25(OH)D is a stronger predictor," she explained.

Total 25(OH)D is easily measured. Levels are assessed routinely in clinical practice; free 25(OH)D is more of a research tool at present, she added.

Most studies focus on the total amount of 25(OH)D and relate this measure to age-related disease and mortality, Antonio explained. The biologically active fraction is unbound and represents less than 1% of all vitamin D metabolites. The current study aimed to assess whether the total or the free fraction was the most important for predicting subsequent mortality.

"As 1.25-dihydroxyvitamin D is the active form of vitamin D in our body, it was possible it could have been a stronger predictor for disease and mortality," Antonio pointed out.

This did not turn out to be the case, however.

Asked to comment on the findings, Harpreet S. Bajaj, MD, said the work calls into question the purported causal association between vitamin D and mortality.

"If the true active form of vitamin D ― ie, the free 1.25(OH)2D measured in this study ― does not predict all-cause mortality, the question is whether the association of total, or even the free 25(OH)D, with health outcomes is a true association, or is it affected by confounding with obesity, comorbidities, sun exposure, etc, needs to be investigated further," noted Bajaj, of the Leadership Sinai Center for Diabetes, Mount Sinai Hospital, Toronto, Canada.

Vitamin D Metabolites and All-Cause Death

Food and sunlight provide 25(OH)D, which is metabolized to 1.25(OH)2D, the most biologically active form that exerts the effects of vitamin D on the body. Vitamin D deficiency is common in Europe, especially among elderly people, and has been associated with a higher risk of developing many age-related diseases, such as cardiovascular disease, cancer, and osteoporosis.

To study the association between total and free 25(OH)D and 1.25(OH)2D with all-cause mortality, data were drawn for the period 2003 to 2005 from the European Male Ageing Study, which included 1970 community-dwelling men aged 40 to 79. Antonio pointed out that the study strengths include the broad age range, the large number of participants, and the 12-year follow-up.

The levels of total and free metabolites of vitamin D were measured and compared with the men's current health status. Adjustments were made for potentially confounding factors, which included age, body mass index, smoking status, and self-reported health.

Vitamin D measurements and binding protein measurements were divided into quintiles. Hazard ratios (HRs) were generated so as to study the association between vitamin D status and all-cause mortality.

For amounts of total metabolites, men in the lowest total 25(OH)D and the lowest total 1.25(OH)2D quintile (cutoff, <9.3 μg/L and <46 ng/L, respectively) were both found to be at increased risk for mortality.

In comparison with men in the highest quintile, the HRs were 1.83 (P < .001) and 1.41 (P < .05), (1.04 – 1.90), respectively .

In comparison with men in the highest quintile, the HRs were 1.83 (P < .001) and 1.41 (P < .05) (1.04 – 1.90), respectively.

With respect to amounts of free metabolites, men in the lowest three free 25(OH)D quintiles (levels <4.43 ng/L) had a higher mortality risk compared to men in the highest quintile, with an HR of 1.91 (P < .001) for the lowest quintile.

A total of 524 men (26.6%) died during a mean follow-up of 12.3 ± 3.4 years. These men had higher BMI (P = .002) and lower levels of physical activity (P < .001). There was no difference in smoking status.

Antonio and Bajaj have disclosed no relevant financial relationships.

European Congress of Endocrinology 2020 : Abstract 1044.

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