Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study

Abstract

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.

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.

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.