We characterized associations of NIST-verified serum 25-(OH)D concentration with risk for adverse clinical events that are pathophysiologically relevant to pleiotropic vitamin D actions in a community-based population. The association of 25-(OH)D with a composite clinical outcome of hip fracture, MI, cancer, and death varied by season, supporting use of season-specific 25-(OH)D thresholds. In our study population, threshold 25-(OH)D concentrations optimally associated with risk for the composite outcome were 43 nmol/L (17 ng/mL) in winter months, 50 nmol/L (20 ng/mL) in spring months, 61 nmol/L (24 ng/mL) in summer months, and 55 nmol/L (22 ng/mL) in autumn months.
The IOM recently evaluated the clinical application of 25-(OH)D testing in the context of vitamin D supplementation (1
). In reviewing available data, it concluded that inadequate vitamin D can contribute to bone disease, vitamin D supplementation can decrease risk for bone disease in at-risk populations, and 25-(OH)D concentration less than 50 nmol/L (20 ng/mL) identifies persons at increased risk. The proposed threshold of 50 nmol/L (20 ng/mL) was lower than that of 75 nmol/L (30 ng/mL) recommended by many professional societies and vitamin D researchers (12
). The IOM noted a lack of high-quality data about the effects of vitamin D supplementation on risk for nonbone health outcomes, including MI, cancer, and death, and it did not, therefore, base its estimate of target 25-(OH)D concentration on these outcomes. These findings were echoed in an updated clinical practice summary on vitamin D deficiency (3
In comparison with existing literature and recommendations, we have 2 principal findings. First, 25-(OH)D thresholds associated with risk for diverse major clinical disease events in our work center close to the 50 nmol/L (20 ng/mL) recommended by the IOM for bone health. We agree with the IOM’s conclusions that high-quality intervention studies are needed to test whether vitamin D deficiency is causally related to nonbone outcomes in humans. Until these data are available, the finding of a similar 25-(OH)D threshold for risk for major clinical disease events to that recommended by the IOM for bone health is reassuring and supports generally targeting 50 nmol/L (20 ng/mL) over 75 nmol/L (30 ng/mL) when 25-(OH)D testing is clinically indicated.
In our study, 30.5% of participants had a 25-(OH)D concentration less than the season-specific threshold centered near 50 nmol/L (20 ng/mL). This proportion is congruent with the prevalence of 25-(OH)D concentrations less than 50 nmol/L (20 ng/mL) in other populations and emphasizes the large number of people at risk for potential complications of low 25-(OH)D concentration (34
). However, the distinction between 50 and 75 nmol/L (20 and 30 ng/mL) is important because more than 40% of the U.S. population has concentrations between 50 and 75 nmol/L (20 and 30 ng/mL) (34
). Our estimate of the 25-(OH)D threshold that best discriminates risk for clinical disease events was generated with some statistical uncertainty, but a threshold as high as 75 nmol/L (30 ng/mL) was unlikely to be congruent with our data.
Second, our data suggest that season-specific targets are most appropriate for 25-(OH)D concentration. Variation in 25-(OH)D concentration within persons and populations over the calendar year is well-known to be large relative to mean concentration (16
). This is probably due to seasonal variation in exposure to ultraviolet light. As a result, clinical decisions about initiation and dose of year-long vitamin D supplementation are likely to be heavily influenced by time of ascertainment, which is often arbitrary. Combined with this background knowledge, our results that demonstrated heterogeneity of the 25-(OH)D–composite outcome association by season and a trend toward improved classification of risk using season-specific 25-(OH)D thresholds suggest that season-specific targets for 25-(OH)D concentration are more appropriate than the static targets previously recommended when the need for year-long vitamin D supplementation is being considered (1
We examined a composite end point of clinical disease events that plausibly reflect net pleiotropic vitamin D actions, are supported by existing literature, and have a quantifiable time of onset, understanding that this may include 1 or more outcomes that are not causally related to 25-(OH)D and may omit some important vitamin D–related effects. Associations of low season-specific 25-(OH)D concentration with the composite outcome and each of its components were of similar magnitude, enabling this approach. Statistical significance using the standard α
level of 0.05 was achieved only for the composite outcome and for death. However, this study was not powered to detect associations with individual composite outcome components, and statistical confidence is likely to be inflated by testing inference in the same data set in which threshold 25-(OH)D concentrations were derived. Moreover, the primary goal of this study was to study the pattern of the 25-(OH)D–composite outcome relationship, not its existence, which has been demonstrated in previous studies (5
Strengths of this study include the use of a community-based population of older adults, who are often targeted for 25-(OH)D testing; the use of NIST-verified 25-(OH)D concentration, which has not, to our knowledge, been previously applied to large epidemiologic studies; and the ascertainment of clinical outcomes directly relevant to both bone and nonbone vitamin D actions over long-term follow-up. Limitations include the inclusion of only older adults; the availability of only white participants in sufficient numbers to rigorously evaluate relationships of 25-(OH)D with study outcomes; the availability of only one 25-(OH)D measurement per participant, which may bias magnitudes of association toward the null; and the inability of available statistical methods to precisely determine optimal threshold concentrations with statistical confidence. Most important, this study is observational. Ultimately, optimal 25-(OH)D concentrations should be defined as the baseline 25-(OH)D concentrations above which vitamin D supplementation does not improve relevant clinical outcomes in large, diverse, randomized clinical trials.
In conclusion, we found that “optimal” concentrations of 25-(OH)D, gauged by associations with major clinical disease events, centered near 50 nmol/L (20 ng/mL), the level recently recommended by the IOM for bone health. We further report that the association of 25-(OH)D with clinical health events varies by season and suggest that season-specific targets for 25-(OH)D concentration are more appropriate than static targets when considering potential implications for long-term health.