In brief: Eldecalcitol, a long acting active vitamin D3 analogue with lower affinity for vitamin D receptor and resistance to inactivation by vitamin D 24-hydroxylase, causes FGF23 resistance. This leads to complete restoration of renal phosphate transport and NaPi-2a protein levels and improves rachitic bone phenotypes in Hyp mice, a murine model of X-linked hypophosphatemia (XLH).
Comment: FGF23 inhibits phosphate reabsorption in the kidney. Loss-of-function mutations in PHEX gene results in excess circulating FGF23, which impairs renal phosphate reabsorption causing hypophosphatemia, and decreased synthesis of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D. Conventional therapy for XLH consists of multiple daily doses of oral phosphate salts and vitamin D metabolites or analogues as replacement therapy. Recently anti-FGF23 antibody therapy, burosumab, was approved to treat children with XLH.
Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy) vitamin D3] is an active vitamin D3 analog approved for osteoporosis therapy in Japan. It has a biologically longer life and a lower affinity for the vitamin D receptor and is resistant to vitamin D 24-hydroxylase (Cyp24a1; the catabolic enzyme for vitamin D compounds) compared with 1,25-dihydroxyvitamin D. In these contexts, Eldecalcitol has beneficial effects on osteoporotic bone; however, its specific effect on phosphate metabolism and its skeletal effects for hypophosphatemic rickets are unknown.
This study assessed the mechanism of Eldecalcitol on phosphate homeostasis and evaluated the effect of bone growth and mineralization using Hyp mice which, demonstrates clinical features similar to XLH. They found that Eldecalcitol maintains skeletal calcification and adjusts phosphate homeostasis by balancing intestinal phosphate absorption and renal phosphate excretion in WT and Hyp mice. In addition, Eldecalcitol directly facilitated bone development and calcification in hypophosphatemic rickets. However, the mechanism of FGF23 resistance by Eldecalcitol is not known. Eldecalcitol could potentially provide another therapeutic option for patients with XLH.