25-Hydroxyvitamin D Levels and Mortality

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Retrospective observational study


247,574 individuals of all ages from Copenhagen, Denmark, whose serum 25-hydroxyvitamin D level had been measured by their general practitioner between April 2004 and January 2010

Study Parameters 

Serum 25-hydroxyvitamin D levels and all-cause mortality

Primary Outcome Measures 

The association between serum 25-hydroxyvitamin D levels and all-cause mortality

Key Findings 

During a median follow-up period of 3.07 years, 15,198 subjects (6.1%) died. A reverse J-shaped association between serum 25-hydroxyvitamin D and mortality was observed. A level of 50–60 nmol/L was associated with the lowest mortality. Compared with 50 nmol/L, the hazard ratios (95% confidence intervals) of all-cause mortality at very low (10 nmol/L) and high (140 nmol/L) serum levels of 25-hydroxyvitamin D were 2.13 (2.02–2.24) and 1.42 (1.31–1.53), respectively. After exclusion of subjects who died within 1 year of blood collection, the reverse J-shaped association remained, although the hazard ratios for all-cause mortality at both the highest and lowest levels of 25-hydroxyvitamin D decreased slightly.

Practice Implications 

Observational studies do not prove cause-and-effect. A number of factors other than vitamin D nutritional status influence serum 25-hydroxyvitamin D levels. For example, 25-hydroxyvitamin D is an acute-phase reactant that declines in the serum in response to inflammation.1 In addition, a substantial amount of 25-hydroxylation of vitamin D occurs in the gonads, and serum 25-hydroxyvitamin D levels appear to be influenced by gonadal function.2 Observational studies on 25-hydroxyvitamin D levels and health outcomes may therefore be confounded by differences in levels of testosterone, estrogen, and DHEA, each of which may influence health outcomes. Although less is known about factors that might increase serum 25-hydroxyvitamin D levels, such increases could conceivably occur in response to certain disease states.
Despite these limitations, the results of the present study are consistent with the possibility that both deficiency and excess of vitamin D are harmful. One recent study compared the effect of 800 IU per day and 6,500 IU per day of vitamin D3 on bone mineral density in postmenopausal women. After 1 year of supplementation, bone mineral density increased with both doses, but the increases were nonsignificantly greater with the lower dose than with the higher dose.3
It is clear from the available research that many people could benefit from vitamin D supplementation in doses of 800–1,200 IU per day. However, at present, the safety and efficacy of routinely prescribing much larger doses (such as more than 2,000 IU per day for long periods of time) has not been established.

About the Author

Alan R. Gaby, MD, received his BA from Yale University, his MS in biochemistry from Emory University, and his MD from the University of Maryland. He is the author of the newly released textbook Nutritional Medicine. He is past president of the American Holistic Medical Association and has provided expert testimony to the White House Commission on Complementary and Alternative Medicine regarding the cost-effectiveness of nutritional supplements.


  1.  Reid D, Toole BJ, Knox S, et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr. 2011;93:1006-1011.
  2.  Foresta C, Selice R, Di Mambro A, Strapazzon G. Testiculopathy and vitamin D insufficiency. Lancet. 2010;376:1301.
  3.  Grimnes G, Joakimsen R, Figenschau Y, et al. The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass - a randomized controlled 1-year trial. Osteoporos Int. 2012;23:201-211.