ESPEYB15 5 Bone, Growth Plate and Mineral Metabolism New and repurposed therapies (2 abstracts)
5.1 Burosumab Therapy in Children with X-Linked Hypophosphatemia
Carpenter TO , Whyte MP , Imel EA , Boot AM , Hogler W , Linglart A , Padidela R , Van’t Hoff W , Mao M , Chen CY , Skrinar A , Kakkis E , San Martin J & Portale AA
Yale University School of Medicine, New Haven, CT, USA
To read the full abstract: N Engl J Med 2018;378:1987-1998
FGF-23 is the primary regulator of phosphate homeostasis and acts by inhibiting phosphate reabsorption in the kidney (1). Loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog X-linked (PHEX) results in excess circulating FGF-23, which impairs renal phosphate reabsorption causing hypophosphatemia, and decreases the synthesis of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D.
Conventional therapy for XLH consists of multiple daily doses of oral phosphate salts and vitamin D metabolites or analogues as replacement therapy. Frequent and high doses of oral phosphate supplementation causes gastrointestinal symptoms (abdominal pain and diarrhoea) in children and despite frequent administrations it only transiently increases serum phosphorus levels. Consequently, there is incomplete healing of rickets, residual skeletal deformity, and persistent short stature. Transient increases in phosphate cause hyperparathyroidism which is counteracted by simultaneous administration of alfacalcidol or calcitriol, which induces risks of metabolic and endocrine abnormalities such as hypercalciuria and nephrocalcinosis.
Burosumab is a recombinant human IgG1 monoclonal antibody that reduces function of FGF-23. Preliminary data in adults with XLH indicate that it improves phosphate balance (2). In this phase 2 study in children between 5-12 years of age, burosumab increased renal tubular phosphate reabsorption and reduced severity of rickets. The healing of rickets contributed to concurrent improvements in growth and physical activity and a reduction in pain. Burosumab was also safe with very few adverse effects. Effectiveness of burosumab in XLH provides new hope for patients with XLH and suggests that it may be beneficial in other elevated FGF-23 conditions such as tumour induced osteomalacia and renal failure.
1. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF 23. Nat Genet 2000;26:345–348.
2. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, Peacock M, Carpenter TO. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab 2015;100:2565-2573.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
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