1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Abstract

T he identification in the year 2000 of mutations in fibroblast growth factor 23 (FGF23) as the genetic cause of autosomal dominant hypophosphatemic rickets (ADHR) was a seminal discovery in the field of bone and mineral homeostasis.(1)Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), (2) tumor-induced osteomalacia (TIO), (3) fibrous dysplasia of bone, (4) autosomal recessive hypophosphatemic rickets (ARHR), (5) cutaneous skeletal hypophosphatemia syndrome (CSHS), (6) familial tumoral calcinosis, (7) and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25-dihydroxyvitamin D 3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation. (8) The fact that PTH, like FGF23, is also important in regulating phosphate and vitamin D homeostasis invokes the existence of an FGF23-Vitamin D-PTH axis that is key to many important aspects of bone and mineral biology. It is a complicated axis that involves the interaction of multiple receptors, a coreceptor, Klotho, (9) and multiple disparate but interacting signaling and enzymatic pathways. (10,11) Unraveling, in a hierarchical fashion, the roles of these complicated, intersecting, and overlapping pathways is important for both understanding mineral homeostasis physiology, and for the treatment of phosphate disorders. This has proved a significant challenge. Although a large number of very informative mouse models have been developed to understand and query this axis, at times the complexity of these models introduces potential confounders that are difficult to control for, and yield results inconsistent with observed human physiology. Thus, it is often difficult to understand and contextualize the findings and apply them to human mineral physiology and pathophysiology. The number of clinical studies conducted in this area is limited, and often focused on renal failure cohorts, the physiology of which differs significantly from those with normal renal function.Although a complete understanding of the FGF23-Vitamin D-PTH axis is lacking, there are a number of findings that are generally accepted to be true. These include: (1) FGF23 directly inhibits phosphate reabsorption and the generation of active vitamin D, 1,25-dihydroxyvitamin D 3 (1,25-D) at the level of the proximal renal tubule leading to a lowering of blood phosphate and 1,25-D levels (8) ; (2) in a classical feedback fashion, increases in blood phosphate and 1,25-D increase FGF23 levels (12,13) ; and (3) frank or relative FGF23-mediated reductions in serum 1,25-D lead to a compensatory increase in PTH, especially evident in the more severe forms of FGF23 excess such as TIO and renal failure. (14,15) The phosphaturic effects of increased PTH exacerbate the phosphate-lowering effects of FGF23 in patients with intact renal function such as TIO and XLH (reviewed in Blau and Collins (11) ). As for the hierarchic...

Dental manifestations and treatment of hypophosphatemic rickets: A case report and review of literature

“…Treatment initiation is recommended as soon as diagnosis is established [ 17 ]. Conventional treatment with oral phosphate supplements and active vitamin D (calcitriol or alfacalcidol), has been proposed for decades [ 3 , 18 , 19 ]. This kind of therapy has been shown to result in the positive outcomes of decrease in bone pain, normalization of alkaline phosphatase level, increase in growth velocity, straightening of legs and improving dental mineralization [ 3 , 13 , 20 , 21 ].…”

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

“…Hypophosphatemic myopathy is currently treated with Pi supplementation 30,59 . However, Pi supplements are poorly tolerated and can cause intestinal symptoms, renal calcifications and secondary hyperparathyroidism 67 . Insights gained from smPit1 −/− ; smPit2 −/− and three allele knockout mice suggest, that optimizing AMPK and ERK1/2 signaling and modification of XPR1 and PIC/SLC25A3 activity may offer alternative strategies for the treatment of hypophosphatemic myopathy.…”