In the present large, community-based study of older adults, the serum 25(OH)D concentration varied in a sinusoidal pattern throughout the calendar year, and the extent of this variation (peak-trough difference = 9.6 ng/mL) was large compared with the annual mean concentration (25.1 ng/mL). As a result, use of single 25(OH)D measurements without accounting for time of collection led to misclassification of estimated long-term vitamin D exposure, particularly when 25(OH)D was measured during summer or winter months. The main implication of these findings is that analytic approaches that accurately account for collection time, perhaps based on the sinusoidal model presented here, might more accurately inform clinical decisions regarding year-long vitamin D supplementation and reduce bias when the 25(OH)D concentration is used to assess health risk in clinical research studies.
In many prior epidemiology studies, investigators have observed seasonal variation in 25(OH)D concentrations (5
). Sherman et al. (5
) and Bolland et al. (6
) suggested that this variation might be best captured using a sine function. The present work builds on those observations by demonstrating the robust nature of a cosinor model in a large, community-based population with racial diversity by using this model to demonstrate clinical characteristics that affect seasonal variation in 25(OH)D concentration and by applying this model to complementary circulating makers of mineral metabolism.
As in other studies, the mean levels of 25(OH)D varied by age, race, sex, geographic location, BMI, presence of diabetes mellitus, and physical activity level (4
). In addition, the extent of seasonal variation in 25(OH)D varied by age, sex, geographic location, and physical activity level but not by race or BMI. Thus, younger participants, men, and participants who reported more physical activity had higher mean 25(OH)D concentrations throughout the calendar year (upward shift of the 25(OH)D sine wave) and greater seasonal variation in 25(OH)D (larger peak-trough difference), and participants in more northern study sites had larger seasonal 25(OH)D variations. Across these clinical characteristics, differences in 25(OH)D were accentuated during summer compared with winter. This pattern can be fully explained by differences in ultraviolet light exposure.
In contrast, black participants (compared with white participants) and more obese participants had lower 25(OH)D concentrations throughout the calendar year (downward shift of the 25(OH)D sine wave) but no statistically significant differences in seasonal variation in 25(OH)D (roughly parallel 25(OH)D sine waves over the calendar year). Skin pigmentation directly affects the amount of vitamin D produced in skin upon a given dose of ultraviolet radiation (23
). As a result, we expected seasonal 25(OH)D variation to be smaller among black participants because of a smaller increase in summer vitamin D synthesis. Lack of a racial difference in seasonal 25(OH)D variation is thus a pertinent negative finding that should be confirmed or disproved in future studies. In particular, the relatively few black participants in whom 25(OH)D was measured during summer might have limited our ability to detect a racial difference in seasonal variation in the present study. More obese persons were previously observed to have less seasonal variation in 25(OH)D concentration, perhaps because of adipose tissue buffering of circulating levels or decreased summer sunlight exposure (6
). In the present study, a BMI of 30 or higher was associated with slightly less 25(OH)D variation, but this difference was small and not statistically significant.
Classification of 25(OH)D status differed using single measured 25(OH)D concentrations compared with estimated annual mean 25(OH)D concentrations. This approach posits that mean long-term 25(OH)D exposure is most relevant for health (10
). It is also possible that the yearly 25(OH)D concentration nadir affects health, and comparing single measured 25(OH)D concentrations and estimated annual nadir 25(OH)D concentrations results in even more differential classification of 25(OH)D status (6
). Thus, whether mean or nadir 25(OH)D concentrations are important, seasonal variation meaningfully impacts classification. The Institute of Medicine recently called for additional study of non-bone vitamin D actions to advise public health policy regarding vitamin D supplementation and fortification (1
). Accurate classification of 25(OH)D concentration is important for such studies.
Mean serum concentrations of PTH and BAP varied in a sinusoidal fashion reciprocal to 25(OH)D concentration. PTH secretion is suppressed by vitamin D, and the elevated PTH concentration is often viewed as a marker of vitamin D insufficiency (9
). BAP is secreted from osteoblasts and is a biomarker of bone turnover. Insufficient vitamin D is a known risk factor for osteoporosis, which is characterized by high bone turnover. Therefore, reciprocal relations with PTH and BAP suggest that seasonal changes in 25(OH)D may have biologic effects.
The present study confirmed that PTH concentrations tend to be higher for people who are older and/or black and/or who have lower GFRs (5
). Mean annual PTH concentrations were higher among women, and the seasonal PTH variation was greater in men, which could be explained by differences in mean 25(OH)D and 25(OH)D variation, respectively. BAP concentrations were higher for participants who were female, black, and/or obese. These associations may reflect increased bone turnover related to lower 25(OH)D levels.
Common genetic polymorphisms previously associated with 25(OH)D concentration in a large meta-analysis (19
) were strongly associated with the annual mean 25(OH)D concentration but not with the amount of seasonal variation in 25(OH)D concentration. Based on biologic action, genetic variability in 7-dehydrocholesterol reductase, which is involved in cutaneous vitamin D synthesis, may have been expected to influence seasonal variation in 25(OH)D. Our results suggest that examined genetic polymorphisms affect vitamin D metabolism downstream from cutaneous vitamin D synthesis and, thus, the association with annual mean but not the amount of seasonal variation.
The main limitation of the present study is that variation in 25(OH)D and other biomarkers was assessed in cross-sectional analyses rather than by using multiple longitudinal measurements within individuals. Estimates of seasonal 25(OH)D variation relative to mean 25(OH)D concentrations from this study are still likely to be valid because mean seasonal 25(OH)D variation on the population level is likely to be equal or similar to the mean seasonal 25(OH)D variation of the individuals who comprise it. However, this study is unable to estimate the specific distribution of seasonal 25(OH)D variation for individuals. To validate any approach estimating year-long 25(OH)D exposure for an individual, investigators should first measure seasonal variation in 25(OH)D within individuals over time. It would also be useful to test whether randomly timed measurements of 25(OH)D concentration, season-specific 25(OH)D measurements, or a validated estimate of year-long 25(OH)D exposure most closely associates with adverse health outcomes. In addition, the present study included only older adults from 4 US communities, which limited external validity. Further limitations include no available information on dietary or supplemental sources of vitamin D and no direct measure of sun exposure; this analysis used physical activity as a maker for sun exposure, but not all physical activities occur outdoors, and use of sun protection varies widely.
The present study represents a first step toward more accurately classifying long-term vitamin D sufficiency. Ultimately, it may be useful to develop and validate equations that estimate year-long 25(OH)D exposure from single 25(OH)D measurements to better guide decisions for vitamin D supplementation in clinical practice and to reduce misclassification bias in clinical research. Further studies that seek to improve classification of vitamin D status can draw upon the cosinor model developed in this study and should take into account the clinical characteristics observed to be related to 25(OH)D concentration and its seasonal variation.