New Therapies for Hypophosphatemia-Related to FGF23 Excess

Calcif Tissue Int. 2021 Jan;108(1):143-157. doi: 10.1007/s00223-020-00705-3. Epub 2020 Jun 5.


FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adult
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Child
  • Familial Hypophosphatemic Rickets* / drug therapy
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / genetics*
  • Humans
  • Hypophosphatemia* / drug therapy
  • Osteomalacia
  • Phosphates


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • FGF23 protein, human
  • Phosphates
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • burosumab