Low vitamin D status in Europe: moving from evidence to sound public health policies.

There is no doubt that interest in vitamin D has burgeoned over the past few decades. Between 1995 and 2015, annual peer-reviewed, vitamin D–related publications have quadrupled (1). Over this same period, media coverage of vitamin D–related topics has also increased exponentially. Enthusiasm in the research, clinical, and lay communities about this unique prohormone is likely related to its touted pleiotropic effects (based largely on observational research) and the seductive simplicity with which “better” vitamin D status is theoretically achievable. However, controversy exists over the most appropriate threshold for defining optimal vitamin D status (2, 3), as well as the most effective strategies to improve vitamin D status in the general population. In this issue of the Journal, Cashman et al. (4) report serum 25-hydroxyvitamin D [25(OH)D] concentrations from.55,000 adults and children in more than a dozen different studies from many countries within the European Union (EU). The investigators found that 13% of individuals had 25(OH)D concentrations ,30 nmol/L and 40% had concentrations ,50 nmol/L. All measurements were performed by using liquid chromatography–mass spectrometry and in accordance with Vitamin D Standardization Program (VDSP) protocols (5). Interestingly, 11 of the cohorts included in the present study had previously measured 25(OH)D levels, and reanalysis using VDSP protocols resulted in significant differences in the estimated prevalence of low vitamin D status. These results not only emphasize the importance of standardizing 25(OH)D testing but also highlight the potential impracticality of public health policies that encourage universal 25(OH)D testing, which may use laboratory assay methodologies of variable quality. However, converting to and maintaining VDSP standards in all clinical laboratories throughout the EU would be an expensive undertaking and may not be the most cost-effective means of addressing the pandemic of low vitamin D status or of improving general population health. Although 1,25-dihydroxyvitamin D is the most biologically active form of vitamin D, it has a relatively short half-life and is tightly regulated in humans. Indeed, 1,25-dihydroxyvitamin D concentrations are not consistently associated with disease states that are thought to be modifiable through vitamin D supplementation. On the other hand, circulating 25(OH)D, the most abundant vitamin D metabolite, is widely accepted as the best indicator of vitamin D exposure, and numerous epidemiologic studies have shown inverse associations of 25(OH)D concentrations with various diseases (6). However, randomized controlled trials of vitamin D supplementation have yielded mixed results to date, suggesting that the association between “low” 25(OH)D concentrations and disease outcomes may not always be causal. Current evidence suggests that the bioavailable component of 25(OH)D may be a better marker of vitamin D status (7). 25(OH)D is predominantly (;88%), and tightly, bound to vitamin D binding protein (DBP); the remaining ;12% is loosely bound to albumin, and only 0.03% of 25(OH)D is found in its free form (8). Bioavailable 25(OH)D refers to the free and albumin-bound 25(OH)D and is thought to represent the mobile pool of vitamin D that is available for autocrine and paracrine activity in times of metabolic demand. Moreover, polymorphisms in the DBP gene and in the vitamin D receptor likely have a strong influence on individual need for vitamin D and on the response to supplementation (9). Taken together, emerging evidence suggests that simply measuring total 25(OH)D concentrations may not be the most informative or biologically relevant assessment of vitamin D status. However, until future research can establish the physiologic significance of bioavailable 25(OH)D and the contributions of vitamin D–related gene polymorphisms to human health, it appears reasonable to make recommendations for vitamin supplementation in the general population on the basis of achieving targeted 25(OH)D concentrations. The optimal 25(OH)D concentration for maximizing the health benefits of vitamin D is a hotly debated topic, but there is general consensus that concentrations $50 nmol/L are desirable in the general population (based primarily on bone health outcomes). And although the Recommended Dietary Allowance (RDA) for