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

The 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. Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), fibrous dysplasia of bone, autosomal recessive hypophosphatemic rickets (ARHR), cutaneous skeletal hypophosphatemia syndrome (CSHS), familial tumoral calcinosis, and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25dihydroxyvitamin D3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation. 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, and multiple disparate but interacting signaling and enzymatic pathways. 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 D3 (1,25-D) at the level of the proximal renal tubule leading to a lowering of blood phosphate and 1,25-D levels; (2) in a classical feedback fashion, increases in blood phosphate and 1,25-D increase FGF23 levels; 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. 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). As for the hierarchical relationship between FGF23 and PTH, FGF23’s suppressive effect on 1a-hydroxylase is more potent than PTH’s stimulatory effect. For example, 1,25-D levels are suppressed in TIO and renal insufficiency, despite normal or high PTH, a phenomenon that can be reversed with blockade of FGF23 signaling. However, it may be that PTH signaling is needed for the full phosphaturic action of FGF23 because PTH-deficient patients with hypoparathyroidism have elevated blood phosphate in the setting of elevated FGF23. In this issue of the Journal of Bone and Mineral Research, Liu and colleagues undertake a straightforward, interesting, and potentially clinically relevant approach to the study and treatment of the hypmouse, the animal model for XLH. The hyp mouse was the first genetic animal model employed to study disorders of FGF23. Of note, the hypmouse was discovered both before the discovery of FGF23 and the identification of the responsible gene. Based on similarities in inheritance pattern and phenotype, the hyp mouse was recognized as an animal model for XLH, and the cause in both species eventually identified as mutations in the gene phosphate-regulating endopeptidase homolog, X-linked PHEX (originally called PEX), which encodes a transmembrane endopeptidase. The precise mechanism by which PHEX regulates FGF23 is not known, but it is clear that Phexmutations in hypmice result in a defect in extracellular phosphate sensing, leading to an increase in FGF23 levels as blood phosphate increases, an observation also seen in patients with XLH. Regardless of a lack of understanding of the precise mechanism of the underlying pathophysiology, the hyp mouse remains a good model for