Background: Total 25 hydroxyvitamin D (25(OH)D) and total 1.25 dihydroxyvitamin D (1.25(OH)2D) are associated with all-cause mortality. The free hormone hypothesis postulates that only the free vitamin D fraction can exert its biological function. Recently some studies suggested that free 25(OH)D levels might be a better predictor for clinical outcomes, including mortality.
Objective: To study the association between total and free 25(OH)D and 1.25(OH)2D with all-cause mortality in a prospective cohort of community-dwelling European men.
Methods: 1970 community-dwelling men, aged 40–79, participated in the European Male Ageing Study (EMAS) between 2003–2005. In 5 of 8 EMAS centres, survival status was available until 1 April 2018. Total 25(OH)D levels were measured by radioimmunoassay and recalibrated to NIST standard reference material. Total 1 25(OH)2D was measured by mass spectrometry and vitamin D binding protein (DBP) by immunodiffusion. Free 25(OH)D and free 1.25(OH)2D were calculated from the total hormone and DBP concentration. Vitamin D measurements and DBP were divided into quintiles. Cox proportional hazard models were used to study the association between vitamin D status and all-cause mortality. Because of the wide age range at inclusion, age was used as time scale instead of years since inclusion adjusting for age. Results were expressed as hazard ratios (HR) with 95% confidence intervals, adjusted for centre, BMI, smoking and self-reported health.
Results: 524 (26.6%) men died during a mean follow-up of 12.3 ± 3.4 years. Men who died had a higher BMI (P = 0.002) and lower physical activity level (P < 0001), but there was no difference in smoking status. 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) had increased mortality risk (HR compared to men in the highest quintile (HR 1.83 (95% CI 1.34–2.50); P < 0.001 and 1.41 (1.04–.90); P < 0.05 respectively). Likewise, 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 (HR 1.91 (1.34–2.73); P < 0.001 for the lowest quintile). However, mortality risk was similar for across all free 1.25(OH)2D and DBP quintiles.
Conclusions: Low total 25(OH)D levels and low total 1.25(OH)2D levels in community-dwelling middle-aged and elderly men have an increased future mortality risk. However, only low free 25(OH)D but not free 1.25(OH)2D levels predict all-cause mortality. Vitamin D deficiency is associated with a negative impact on general health and is predictive of a higher mortality risk.
05 Sep 2020 - 09 Sep 2020