Regulation of Renal and Extrarenal Calcitriol Synthesis and Its Clinical Implications

There is evidence that calcitriol is the only biologically active vitamin D metabolite. This review summarizes data on the regulation of renal and extrarenal synthesis of calcitriol by nutritional, physiologic, mechanical, genetic, and disease-related factors. Relatively low circulating calcitriol due to low substrate availability, i.e. low circulating 25-hydroxyvitamin D, has been reported in nutritional rickets, osteomalacia, obesity, and preeclampsia. In these situations, vitamin D supplementation can increase circulating calcitriol and, together with calcium, prevent rickets/osteomalacia and reduce the risk of preeclampsia and obesity-related type 2 diabetes mellitus. Correction of low circulating calcitriol due to mechanical unloading/immobilization by vitamin D supplementation is, however, not effective in preventing osteoporotic fractures. Circulating calcitriol is also low in diseases such as cardiac and renal failure. Both illnesses share some other similarities regarding dysregulated calcium/phosphate metabolism including elevated parathyroid hormone and fibroblast growth factor-23, suggesting similar treatment strategies. Genetic disorders of vitamin D metabolism are rare and can affect circulating calcitriol differently. Calcitriol synthesis in immune cells is obviously not primarily dependent on circulating 25-hydroxyvitamin D, which challenges the use of vitamin D for infection prevention. Since various factors can differently influence calcitriol regulation, more personalized preventive/therapeutic strategies of targeting calcitriol synthesis are necessary.