ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2020) 70 AEP184 | DOI: 10.1530/endoabs.70.AEP184

Free 25-hydroxyvitamin D, but not free 1.25-dihydroxyvitamin D, predicts all-cause mortality in ageing men

Leen Antonio1,2, Marian Dejaeger3,4, Roger Bouillon1,2, Frederick Wu5, Terence O’Neill6, Stephen Pye6, Ilpo Huhtaniemi7, Giulia Rastrelli8, Gianni Forti8, Felipe Casanueva9, Jolanta Slowikowska-Hilczer10, Margus Punab11, Jos Tournoy4,12 & Dirk Vanderschueren1,2

1KULeuven, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium; 2University Hospitals Leuven, Department of Endocrinology, Leuven, Belgium; 3KULeuven, Department of Public Health and Primary Care, Belgium; 4University Hospitals Leuven, Department of Geriatrics, Leuven, Belgium; 5The University of Manchester, Andrology Research Unit, Centre for Endocrinology & Diabetes, Institute of Human Development, Manchester, United Kingdom; 6The University of Manchester, Centre for Epidemiology Versus Arthritis, Manchester, United Kingdom; 7Imperial College London, Department of Metabolism, Digestion and Reproduction, London, United Kingdom; 8University of Florence, Andrology Unit, Florence, Italy; 9Universidad de Santiago de Compostela, Department of Medicine, Santiago de Compostela, Spain; 10Medical University of Łódź, Department of Andrology and Reproductive Endocrinology, Łódź, Poland; 11Tartu University, Andrology Unit, Tartu, Estonia; 12KULeuven, Department of Public Health and Primary Care, Leuven, Belgium

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.