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2023-01-10 | Phosphatonins: From Discovery to Therapeutics.
Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment. A focused literature search of PubMed was conducted. Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults. The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.
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2021-07-28 | New Therapies for Hypophosphatemia-Related to FGF23 Excess.
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.
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