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; Bryan Kestenbaum, MD, MS
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:email@example.com). 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:firstname.lastname@example.org.
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.
de Boer I., Levin G., Robinson-Cohen C., Biggs M., Hoofnagle A., Siscovick D., 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;156:627-634. doi: 10.7326/0003-4819-156-9-201205010-00004
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Published: Ann Intern Med. 2012;156(9):627-634.
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.
To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.
The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.
1621 white older adults.
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.
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.
The observational study was restricted to white participants.
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.
National Institutes of Health.
William B., Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center, San Francisco, CA
May 9, 2012
Optimal serum 25-hydroxyvitamin D concentrations are higher than threshold concentrations
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.
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