High-dose Vitamin D and Non-Skeletal Health

After several decades of failed vitamin D trials, recent successes in vitamin D studies published since 2024 have demonstrated that high-dose vitamin D therapy and elevated serum 25-hydroxyvitamin D are necessary to demonstrate vitamin D's non-skeletal outcomes in clinical trials. In this review article, we focus on recent randomized controlled trials (RCTs) and large population studies to demonstrate the non-skeletal functions of vitamin D. Diseases and pathologic states covered in this review include prediabetes, type 1 diabetes, type 2 diabetes, multiple sclerosis, atherosclerotic vascular disease, longevity and telomere length preservation. These well-designed randomized controlled trials, large population studies, and long-term studies conclusively demonstrate the strong efficacy and safety of high-dose vitamin D supplementation for non-skeletal health. This review article analyzes these recent studies in light of the 2024 Endocrine Society Guidelines on Vitamin D, which were based on earlier studies. This is particularly important, as these studies indicate that the non-skeletal functions of vitamin D are elicited at a much higher serum concentration of 25-hydroxyvitamin D of 40-60 mg/dL, in contrast to the lower threshold of 20 ng/mL concentration advocated by the Endocrine Society.