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Serum 25-Hydroxyvitamin D Concentration and Risk for Major Clinical Disease Events in a Community-Based Population of Older Adults: A Cohort Study

Ian H. de Boer, MD, MS; Gregory Levin, MS; Cassianne Robinson-Cohen, MS; Mary L. Biggs, PhD; Andy N. Hoofnagle, MD, PhD; David S. Siscovick, MD, MPH; and Bryan Kestenbaum, MD, MS
[+] Article, Author, and Disclosure Information

From the University of Washington, Seattle, Washington.

Grant Support: By the National Heart, Lung, and Blood Institute (contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant HL080295), with additional contribution from the National Institute of Neurologic Disorders and Stroke. Additional support was provided by the National Institute on Aging (AG-023629, AG-15928, AG-20098, and AG-027058); the National Heart, Lung, and Blood Institute (grants R01HL084443 and R01HL096875); and the National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK088762). A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2074.

Reproducible Research Statement:Study protocol and statistical code: Available from Dr. de Boer (e-mail, mailto:deboer@u.washington.edu). Data set: Not available.

Requests for Single Reprints: Ian H. de Boer, MD, MS, Box 359606, 325 9th Avenue, Seattle, WA 98104; e-mail, mailto:deboer@u.washington.edu.

Current Author Addresses: Drs. de Boer and Kestenbaum and Ms. Robinson-Cohen: Kidney Research Institute, Box 359606, 325 9th Avenue, Seattle, WA 98104.

Mr. Levin: Department of Biostatistics, Box 357232, 1959 Northeast Pacific Street, Seattle, WA 98195.

Dr. Biggs: Collaborative Health Studies Coordinating Center, Building 29, Suite 310, 6200 Northeast 74th Street, Seattle, WA 98115.

Dr. Hoofnagle: Department of Laboratory Medicine, Box 357110, 1959 Northeast Pacific Street, Seattle, WA 98195.

Dr. Siscovick: Cardiovascular Health Research Unit, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101.

Author Contributions: Conception and design: I.H. de Boer, G. Levin, B. Kestenbaum.

Analysis and interpretation of the data: I.H. de Boer, G. Levin, C. Robinson-Cohen, A.N. Hoofnagle, D.S. Siscovick, B. Kestenbaum.

Drafting of the article: I.H. de Boer, G. Levin, C. Robinson-Cohen.

Critical revision of the article for important intellectual content: G. Levin, C. Robinson-Cohen, M.L. Biggs, A.N. Hoofnagle, D.S. Siscovick, B. Kestenbaum.

Final approval of the article: I.H. de Boer, C. Robinson-Cohen, M.L. Biggs, A.N. Hoofnagle, D.S. Siscovick, B. Kestenbaum.

Statistical expertise: G. Levin, C. Robinson-Cohen, A.N. Hoofnagle.

Obtaining of funding: I.H. de Boer, B. Kestenbaum.

Collection and assembly of data: G. Levin, M.L. Biggs, A.N. Hoofnagle, D.S. Siscovick.

Ann Intern Med. 2012;156(9):627-634. doi:10.7326/0003-4819-156-9-201205010-00004
Text Size: A A A

Background: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.

Objective: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.

Design: Cohort study.

Setting: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.

Participants: 1621 white older adults.

Measurements: Serum 25-(OH)D concentration (using a high-performance liquid chromatography–tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.

Results: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of −0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.

Limitation: The observational study was restricted to white participants.

Conclusion: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.

Primary Funding Source: National Institutes of Health.


Grahic Jump Location
Figure 1.

Box plot of 25-(OH)D concentration by season, showing the 25th, 50th, and 75th percentiles of distributions, with outliers not shown.

Mean 25-(OH)D was 56 nmol/L (SD, 24), 63 nmol/L (SD, 24), 74 nmol/L (SD, 25), and 69 nmol/L (SD, 26) (22 ng/mL [SD, 10], 25 ng/mL [SD, 10], 30 ng/mL [SD, 10], and 28 ng/mL [SD, 11]) in winter (January–March), spring (April–June), summer (July–September), and autumn (October–December), respectively. 25-(OH)D = 25-hydroxyvitamin D.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Association of season-specific 25-(OH)D Z score with the risk for incident myocardial infarction, cancer, hip fracture, or death (composite outcome) among 1621 participants in the Cardiovascular Health Study, evaluated using a penalized spline.

Proportional hazards model adjusts for age, sex, clinical site, body mass index, physical activity, and smoking. The shaded area represents Z score less than −0.54 (29th percentile of the normal distribution), which best discriminated risk for the composite outcome. The x-axis is displayed as season-specific Z score (uppermost x-axis, reflecting the primary method of analysis) and as corresponding season-specific absolute 25-(OH)D concentrations (lower 4 axes). 25-(OH)D = 25-hydroxyvitamin D.

Grahic Jump Location




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Submit a Comment/Letter
Optimal serum 25-hydroxyvitamin D concentrations are higher than threshold concentrations
Posted on May 9, 2012
William B., Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center, San Francisco, CA
Conflict of Interest: None Declared

To the Editor: The paper by de Boer et al. (1) reported that the serum 25-hydroxyvitamin D [25(OH)D] threshold for incidence of major disease varied from 43 to 61 nmol/L depending on season. These values are consistent with the recommendation of the Institute of Medicine (Ref. 1 in 1). However, it is noted that the serum 25(OH)D concentration-disease outcome relations found in other studies (2,3) are similar to that in Figure 2 in Ref. 1, i.e., rapid changes below 50 nmol/L with optimal concentrations between 75 and 100 nmol/L. Thus, threshold concentrations and optimal concentrations are not synonymous.

One of the problems with studies such as in Ref. (1) is that a single serum 25(OH)D concentration from the time of enrollment in the cohort is used as the measure of vitamin D status. As the follow-up time increases, absolute and relative serum 25(OH)D concentrations vary. An analysis finds that the regression coefficients for 25(OH)D concentrations measured at two times decrease at a rate of 0.02/year (4). Significant decreases results in findings regarding all-cause mortality rate (4) and cancer incidence (5) result from these changes. The median follow-up time in Ref. 1 was 11 years.

Inspection of the 25(OH)D concentration-breast cancer incidence relations determined from observational studies used in Ref. 5, it is seen that for case-control studies (no follow-up time), odds ratios decrease monotonically with increasing serum 25(OH)D concentrations with the lower bound of the highest quintile ranging from 60 to 150 nmol/L. For one cohort study with a 2.7-year follow-up time, the bound of the highest tertile was 84 nmol/L. For three cohort studies with 3.9- to 6.5-year follow-up periods, there were no trends for two studies and a monotonic decrease above 72 nmol/L in one study. Thus, the longer the follow-up time, the less likely the study is to find beneficial effects of higher serum 25(OH)D concentration for breast cancer incidence.

To overcome the limitation of a single serum 25(OH)D concentration with a long follow-up time, it is recommended that such studies arrange for blood draws every two-to-three years.

Disclosure I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).


1. de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle AN, Siscovick DS, Kestenbaum B. Serum 25-hydroxyvitamin d concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. Ann Intern Med. 2012;156:627-34.

2. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011;65:1016-26.

3. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: A meta- analysis of prospective cohort studies. Am J Clin Nutr. 2012;95:91-100.

4. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermato-Endocrinology. 2012;4(2) epub http://www.landesbioscience.com/journals/dermatoendocrinology/article/20514/

5. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25- hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermato-Endocrinology. 2011;3:199-204.

Conflict of Interest:

None declared

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Vitamin D Levels and Risk for Major Clinical Disease Events

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