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Title: Is there a reverse J-shaped association between 25-Hydroxyvitamin D and all-cause mortality? Results from the US Nationally Representative NHANES

Author
item SEMPOS, CHRISTOPHER - National Institutes Of Health (NIH)
item DURAZO-ARVIZU, RAMON - Loyola University - Illinois
item DAWSON-HUGHES, BESS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item YETLEY, ELIZABETH - National Institutes Of Health (NIH)
item LOOKER, ANNE - National Center For Health Statistics
item SCHLEICHER, ROSEMARY - National Center For Environmental Health
item CAO, GUICHAN - Loyola University - Illinois
item BURT, VICKI - National Center For Health Statistics
item KRAMER, HOLLY - Loyola University - Illinois
item BAILEY, REGAN - National Institutes Of Health (NIH)
item DWYER, JOHANNA - National Institutes Of Health (NIH)
item ZHANG, CINDY - National Center For Health Statistics
item WILGER, JAIME - National Center For Health Statistics
item ROVNER, ALISHA - National Institutes Of Health (NIH)
item COATES, PAUL - National Institutes Of Health (NIH)
item PICCIANO, MARY FRANCES - National Institutes Of Health (NIH)

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/25/2013
Publication Date: 7/1/2013
Citation: Sempos, C., Durazo-Arvizu, R., Dawson-Hughes, B., Yetley, E., Looker, A., Schleicher, R., Cao, G., Burt, V., Kramer, H., Bailey, R., Dwyer, J., Zhang, C., Wilger, J., Rovner, A., Coates, P., Picciano, M. 2013. Is there a reverse J-shaped association between 25-Hydroxyvitamin D and all-cause mortality? Results from the US Nationally Representative NHANES. Journal of Clinical Endocrinology and Metabolism. 98(7):3001-3009.

Interpretive Summary: Large population and clinical studies have implicated vitamin D as a potential risk factor for a number of chronic and infectious diseases. In several studies of vitamin D levels in [measured in blood as serum 25-hydroxyvitamin D (25OHD)] and mortality, it appears that risk of mortality may be higher at both low and high 25OH D levels, and lower in the mid range. These studies have been limited by the small number of participants with high levels of 25OHD and thus the upswing in mortality at high 25OHD levels is uncertain. In this paper, we analyze National Health and Nutrition Examination Survey III (NHANES III) data with an extended follow-up period of 15 years in order to examine the association between 25OHD and all-cause mortality. Over the 15 years (1991-2006), there were 15,099 participants and 3,784 deaths. Serum 25OHD levels under 60 nmol/L and above 120 nmol/L were both associated with increased risk of mortality. Further study is needed to determine whether low and high 25OHD levels cause mortality or result from other illnesses that cause mortality.

Technical Abstract: The concentration or threshold of 25-Hydroxyvitamin D [25(OH)D] needed to maximally suppress intact serum parathyroid hormone (iPTH) has been suggested as a measure of optimal vitamin D status. Depending upon the definition of maximal suppression of iPTH and the two-phase regression approach used, two distinct clusters for a single 25(OH)D threshold have been reported, i.e. 16-20 ng/ml (40-50 nmol/L) and 30-32 ng/ml (75-80 nmol/L). To rationalize the apparently disparate results, we compared the thresholds from several regression models including a three-phase one to estimate simultaneously two thresholds before and after adjusting for possible confounding for age, body mass index (BMI), glomerular filtration rate (GFR), dietary calcium and season (April-September vs. October – March) within a single data set, i.e. data from the Tufts University STOP/IT study site consisting of 387 men (n=181) and women (n=206) ages 65-87y. Mean levels (+/- SD) of plasma 25(OH)D and serum iPTH were 22.1 +/- 7.44 ng/mL (55.25 +/- 18.6 nmol/L) and 36.6 +/- 16.03 pg/mL, respectively. The three-phase model identified two thresholds of 12 ng/ml (30 nmol/L) and 28 ng/ml (70 nmol/L); similar results were found from the two-phase models evaluated, i.e. 13-20 and 27-30 ng/mL (32.5-50 and 67.5-75 nmol/L) and with previous results. Adjusting for confounding didn’t change the results substantially. Accordingly, the three-phase model appears to be superior to the two-phase approach as it simultaneously estimates the two threshold clusters found from the two-phase approaches along with estimating confidence limits. If replicated, it may be of both clinical and public health significance.