Summary: Current intake recommendations of 200 to 600IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D. Introduction: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk. Methods and results: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000IU vitamin D per day or mean 25(OH)D between 75 and 110nmol/l (30-44ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000IU per day or achieved 25(OH)D up to 643nmol/l. Mean levels of 75 to 110nmol/l were reached in most RCTs with 1,800 to 4,000IU vitamin D per day without risk. Conclusion: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the populatio
