Pharmacological management of X-linked hypophosphataemia

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Abstract

The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.

Original languageEnglish (US)
JournalBritish Journal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Pharmacology
Phosphates
Therapeutics
Antibodies, Monoclonal, Humanized
Endopeptidases
X-Linked Genes
Mutation
Vitamin D
Hormones
Kidney
Bone and Bones
Genes
fibroblast growth factor 23

Keywords

  • burosumab-twza
  • fibroblast growth factor 23
  • PHEX
  • X-linked hypophosphataemia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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title = "Pharmacological management of X-linked hypophosphataemia",
abstract = "The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.",
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