Heritable and acquired disorders of phosphate metabolism: Etiologies involving FGF23 and current therapeutics

Abstract

Phosphate is critical for many cellular processes and structural functions, including as a key molecule for nucleic acid synthesis and energy metabolism, as well as hydroxyapatite formation in bone. Therefore it is critical to maintain tight regulation of systemic phosphate levels. Based upon its broad biological importance, disruption of normal phosphate homeostasis has detrimental effects on skeletal integrity and overall health. Investigating heritable diseases of altered phosphate metabolism has led to key discoveries underlying the regulation and systemic actions of the phosphaturic hormone Fibroblast growth factor-23 (FGF23). Both molecular and clinical studies have revealed novel targets for the development and optimization of therapies for disorders of phosphate handling. This review will focus upon the bridge between genetic discoveries involving disorders of altered FGF23 bioactivity, as well as describe how these findings have translated into pharmacologic application.

Keywords: FGF-23; Genetics; Hyperphosphatemia; Hypophosphatemia; Klotho; Tumoral calcinosis.

Figure 1

FGF23 regulatory systems. FGF23 is produced in bone and secreted into the circulation, potentially in response to increased phosphate (Pi), 1,25D, and PTH. FGF23 acts in the kidney through αKlotho to decrease Npt2a and Npt2c expression and decrease 1,25D production, resulting in hypophosphatemia. 1,25D acts in the intestine to increase calcium (Ca) and Pi absorption. FGF23 acts in the parathyroid glands to reduce PTH. Hypophosphatemia and reduced 1,25D complete the feedback loop and inhibit FGF23 production.

Figure 2

Emerging therapeutics for heritable hypophosphatemias. The genetic discovery of the underlying pathogenesis of diseases associated with gain of FGF23 bioactivity has resulted in new therapeutic approaches. In theory, all of the heritable and acquired disorders of elevated iFGF23, including ADHR, XLH, TIO, ENS, KLOTHO translocation, and ARHR1–3 may benefit from anti-FGF23 therapy (KRN23). In anemic ADHR patients, iron supplementation may reduce serum FGF23. The blue boxes indicate diseases under evaluation or recruiting clinical trials (www.clinicaltrials.gov), with KRN23 for XLH, ENS, and TIO; and iron supplementation for ADHR.

Figure 3

Emerging therapeutics for heritable hyperphosphatemias. Treatments for hfTC currently lag behind those for the genetic hypophosphatemias and are often combination therapies of phosphate binders and low phosphate diet to attempt to reduce serum phosphate that occurs from lack of iFGF23 production or loss of KL signaling. In FGF23- and GALNT3-hfTC, patients have benefited from topical sodium thiosulfate as well as the carbonic anhydrase inhibitor acetazolamide to reduce calcification burden.