for safety) as well as through a measure of interest, serum 25OHD concentration. The median serum 25OHD concentration 1 month after dose for study participants was 120 nmol/L. By 3 months, the median value was approximately 90 nmol/L. One other study (Smith et al., 2007) also reported an increase in fracture associated with vitamin D treatment. Participants were 75 years of age or older (4,354 men and 5,086 women) and received an annual injection of 300,000 IU as ergocalciferol or placebo. In men, treatment had no effect on fractures. However, women treated with vitamin D had increased risk of fractures classified as non-vertebral (HR = 1.21), hip/femur (HR = 1.80), and hip/femur/wrist/forearm (HR = 1.59). No effect on falls was observed; however, falls were a secondary outcome and ascertainment was based on 6-month recall. Baseline serum 25OHD levels and changes in serum 25OHD levels were very similar to the results from Sanders et al. (2010). Another common feature was that calcium supplements were not given.
A recent study reported by Cauley et al. (2009) indicated that in contrast to white and American Indian women, black women and possibly Asian women appeared to be at greater risk of fracture with higher serum 25OHD levels (≥ 75 nmol/L).
Despite the limitations of the evidence, there is a notable congruence across different health indicators—all-cause mortality, some cancers, CVD risk, fractures and falls—for adverse outcomes associated with serum 25OHD levels ranging from about 75 to 120 nmol/L. The U-shaped curve, or possibly a reverse-J-shaped curve, for risk does indeed emerge, with adverse effects reported at either end of the serum 25OHD concentration span. Data for associated intakes of vitamin D are limited.
The committee’s approach was to consider whether it was reasonable to use these findings as a basis for adjusting data on the toxicity of vitamin D, discussed above. In doing so, it was aware of recent criticisms related to taking into account these so-called U-shaped serum 25OHD response curves for elucidating levels of vitamin D that may cause adverse effects (e.g., Grant, 2010). However, although these data may be characterized as emerging and in need of further study before firm conclusions can be made, they are not reflective of flawed studies nor are they readily dismissed by other literature. Further, in the absence of data to demonstrate benefit at such serum 25OHD levels, a cautious approach is justified and appropriate given the purpose of the UL. In the committee’s view, these emerging relationships do not have to be definitively proven in order to justify a cautious approach that is most likely to ensure safety, and in the absence of data to demonstrate benefit from the higher intake level or higher