FGF23, Hypophosphatemia, and Emerging Treatments

Erik A Imel, Andrew Biggin, Aaron Schindeler, Craig F Munns, Erik A Imel, Andrew Biggin, Aaron Schindeler, Craig F Munns

Abstract

FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation and 24-hydroxylation in the renal proximal tubules. The most common FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23-mediated forms of hypophosphatemia are characterized by phosphaturia and low or low-normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23-mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor-induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23-mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: BUROSUMAB; FGF23; KLOTHO; XLH; X‐LINKED HYPOPHOSPHATEMIA.

Figures

Figure 1
Figure 1
A now 14‐year‐old female with XLH (PHEX:c.[151C>T];[=] p.[Gln51*]) diagnosed at 7 months of age. (A) Radiograph of left hand and wrist at diagnosis with rachitic changes of distal radius and ulna and lacey appearance of bone. (B) Radiograph of right knee at 18 months old while treated with phosphate and calcitriol. There is fraying and splaying at the metaphyses and early cupping noted at the distal femur as well as the proximal tibia and fibula. (C) At 14 years old, she was managed with phosphate and calcitriol. She had short stature, normal ALP, and mild elevation in PTH. Symptoms included persistent ankle pain and waddling gait. There was also lateral bowing of both femora and tibias with widening of the proximal tibial growth plate. (D) Left hand radiograph at age 14 years showing widening of the proximal radius and ulna growth plates with evidence of rachitic changes.

References

    1. Korsensky L, Ron D Regulation of FGF signaling: Recent insights from studying positive and negative modulators. Semin Cell Dev Biol. 2016;53:101–114.
    1. Brewer JR, Mazot P, Soriano P Genetic insights into the mechanisms of Fgf signaling. Genes Dev. 2016;30(7):751–771.
    1. Ornitz DM, Itoh N The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev: Dev Biol. 2015;4(3):215–266.
    1. Kinoshita S, Kawai M The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. Vitam Horm. 2016;101:151–174.
    1. Bergwitz C, Juppner H Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Am J Nephrol. 2010;31(3):230–238. 10.1159/000274483. Epub 2010 Jan 6
    1. Berndt T, Kumar R Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda). 2009;24:17–25.
    1. Quarles LD Endocrine functions of bone in mineral metabolism regulation. Electrolyte Blood Press. 2008;6(2):68–76. 10.5049/EBP.2008.6.2.68. Epub Dec 31
    1. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770–774.
    1. Chen G, Liu Y, Goetz R, et al. alpha‐Klotho is a non‐enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018;553(7689):461–466.
    1. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF‐23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429–435.
    1. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor‐independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol. 2005;289(5):F1088–F1095.
    1. Kuro OM, Moe OW FGF23‐alphaKlotho as a paradigm for a kidney‐bone network. Bone. 2017;100:4–18.
    1. Kuro OM The FGF23 and Klotho system beyond mineral metabolism. Clin Exp Nephrol. 2017;21(Suppl 1):64–69. 10.1007/s10157-016-1357-6. Epub 2016 Nov 12
    1. Bai XY, Miao D, Goltzman D, Karaplis AC The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem. 2003;278(11):9843–9849.
    1. Kolek OI, Hines ER, Jones MD, et al. 1alpha,25‐Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal‐gastrointestinal‐skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005;289(6):G1036–G1042.
    1. Nishi H, Nii‐Kono T, Nakanishi S, et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor‐23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract. 2005;101(2):c94–c99.
    1. Ben‐Dov IZ, Galitzer H, Lavi‐Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117(12):4003–4008.
    1. Larsson T, Marsell R, Schipani E, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145(7):3087–3094.
    1. Carpenter TO, Mitnick MA, Ellison A, Smith C, Insogna KL Nocturnal hyperparathyroidism: a frequent feature of X‐linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78(6):1378–1383.
    1. Olauson H, Larsson TE FGF23 and Klotho in chronic kidney disease. Curr Opin Nephrol Hypertens. 2013;22(4):397–404.
    1. Kaludjerovic J, Komaba H, Sato T, et al. Klotho expression in long bones regulates FGF23 production during renal failure. FASEB J. 2017;31(5):2050–2064.
    1. Lafage‐Proust MH Does the downregulation of the FGF23 signaling pathway in hyperplastic parathyroid glands contribute to refractory secondary hyperparathyroidism in CKD patients? Kidney Int. 2010;77(5):390–392.
    1. Yokota H, Pires A, Raposo JF, Ferreira HG Model‐Based Analysis of FGF23 Regulation in Chronic Kidney Disease. Gene Regul Syst Bio. 2010;4:53–60.
    1. Shalhoub V, Shatzen EM, Ward SC, et al. FGF23 neutralization improves chronic kidney disease‐associated hyperparathyroidism yet increases mortality. J Clin Invest. 2012;122(7):2543–2553.
    1. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–4408.
    1. Liu ES, Thoonen R, Petit E, et al. Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH. Endocrinology. 2018;159(5):2165–2172.
    1. Slavic S, Ford K, Modert M, et al. Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload. Sci Rep. 2017;7(1):11298.
    1. Takashi Y, Kinoshita Y, Hori M, Ito N, Taguchi M, Fukumoto S Patients with FGF23‐related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy. Endocr Res. 2017;42(2):132–137.
    1. Grieff M, Mumm S, Waeltz P, et al. Expression and cloning of the human X‐linked hypophosphatemia gene cDNA. Biochem Biophys Res Commun. 1997;231(3):635–639.
    1. Whyte MP, Schranck FW, Armamento‐Villareal R X‐linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children. J Clin Endocrinol Metab. 1996;81(11):4075–4080.
    1. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL A clinician's guide to X‐linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381–1388.
    1. Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E Early treatment improves growth and biochemical and radiographic outcome in X‐linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88(8):3591–3597.
    1. Harrison HE, Harrison HC, Lifshitz F, Johnson AD Growth disturbance in hereditary hypophosphatemia. Am J Dis Child. 1966;112(4):290–297.
    1. Gjorup H, Kjaer I, Sonnesen L, et al. Craniofacial morphology in patients with hypophosphatemic rickets: a cephalometric study focusing on differences between bone of cartilaginous and intramembranous origin. Am J Med Genet A. 2011;155A(11):2654–2660.
    1. Vega RA, Opalak C, Harshbarger RJ, et al. Hypophosphatemic rickets and craniosynostosis: a multicenter case series. J Neurosurg Pediatr. 2016;17(6):694–700.
    1. Zivicnjak M, Schnabel D, Billing H, et al. Age‐related stature and linear body segments in children with X‐linked hypophosphatemic rickets. Pediatr Nephrol. 2011;26(2):223–231.
    1. Boukpessi T, Hoac B, Coyac BR, et al. Osteopontin and the dento‐osseous pathobiology of X‐linked hypophosphatemia. Bone. 2017;95:151–161.
    1. Chaussain‐Miller C, Sinding C, Wolikow M, Lasfargues JJ, Godeau G, Garabedian M Dental abnormalities in patients with familial hypophosphatemic vitamin D‐resistant rickets: prevention by early treatment with 1‐hydroxyvitamin D. J Pediatr. 2003;142(3):324–331.
    1. Fong H, Chu EY, Tompkins KA, et al. Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse. J Periodontol. 2009;80(8):1348–1354.
    1. Connor J, Olear EA, Insogna KL, et al. Conventional Therapy in Adults With X‐Linked Hypophosphatemia: Effects on Enthesopathy and Dental Disease. J Clin Endocrinol Metab. 2015;100(10):3625–3632.
    1. Biosse Duplan M, Coyac BR, Bardet C, et al. Phosphate and Vitamin D Prevent Periodontitis in X‐Linked Hypophosphatemia. J Dent Res. 2017;96(4):388–395.
    1. Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP X‐linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine (Baltimore). 1989;68(6):336–352.
    1. Insogna KL, Briot K, Imel EA, et al. A Randomized, Double‐Blind, Placebo‐Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti‐FGF23 Antibody, in Adults With X‐Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018;33(8):1383–1393.
    1. Veilleux LN, Cheung M, Ben Amor M, Rauch F Abnormalities in muscle density and muscle function in hypophosphatemic rickets. J Clin Endocrinol Metab. 2012;97(8):E1492–E1498.
    1. Levy‐Litan V, Hershkovitz E, Avizov L, et al. Autosomal‐recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86(2):273–278.
    1. Rutsch F, Ruf N, Vaingankar S, et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat Genet. 2003;34(4):379–381.
    1. Ferreira C, Ziegler S, Gahl WA, et al. In: Generalized Arterial Calcification of Infancy. Seattle (WA): GeneReviews(R) 2014, pp. 1993–2019.
    1. Rafaelsen SH, Raeder H, Fagerheim AK, et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23‐related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28(6):1378–1385.
    1. Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor‐23 (Fgf23) knock‐in mice. Proc Natl Acad Sci U S A. 2011;108(46):E1146–E1155.
    1. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96(11):3541–3549.
    1. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94(7):2332–2337.
    1. Linglart A, Biosse‐Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13–R30.
    1. Kapelari K, Kohle J, Kotzot D, Hogler W Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. J Clin Endocrinol Metab. 2015;100(9):3388–92.
    1. Imel EA, Liu Z, Coffman M, Acton D, Econs MJ Oral Iron Therapy Normalizes Fibroblast Growth Factor 23 (FGF23) in Patients with Autosomal Dominant Hypophosphatemic Rickets. J Bone Miner Res. 2018;33:S1–S56. (LB‐1170).
    1. Schober HC, Kneitz C, Fieber F, Hesse K, Schroeder H Selective blood sampling for FGF‐23 in tumor‐induced osteomalacia. Endocrinol Diabetes Metab Case Rep. 2017;2017 10.1530/EDM-17-0006
    1. Imel EA, Peacock M, Pitukcheewanont P, et al. Sensitivity of fibroblast growth factor 23 measurements in tumor‐induced osteomalacia. Clin Calcium. 2006;16(4):542–546.
    1. Lee JC, Su SY, Changou CA, et al. Characterization of FN1‐FGFR1 and novel FN1‐FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. 2016;29(11):1335–1346.
    1. Drezner MK Tumor‐induced osteomalacia. Rev Endocr Metab Disord. 2001;2(2):175–186.
    1. Florenzano P, Gafni RI, Collins MT Tumor‐induced osteomalacia. Bone Rep. 2017;7:90–97.
    1. Kobayashi K, Imanishi Y, Koshiyama H, et al. Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci. 2006;78(20):2295–2301.
    1. Agopiantz M, Journeau P, Lebon‐Labich B, et al. McCune‐Albright syndrome, natural history and multidisciplinary management in a series of 14 pediatric cases. Ann Endocrinol (Paris). 2016;77(1):7–13.
    1. Hart ES, Kelly MH, Brillante B, et al. Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J Bone Miner Res. 2007;22(9):1468–1474.
    1. Kushchayeva YS, Kushchayev SV, Glushko TY, et al. Fibrous dysplasia for radiologists: beyond ground glass bone matrix. Insights Imaging. 2018;9(6):1035–1056.
    1. Riminucci M, Collins MT, Fedarko NS, et al. FGF‐23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112(5):683–692.
    1. Plotkin H, Rauch F, Zeitlin L, Munns C, Travers R, Glorieux FH Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab. 2003;88(10):4569–4575.
    1. Ovejero D, Lim YH, Boyce AM, et al. Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. Osteoporos Int. 2016;27(12):3615–3626.
    1. Lim YH, Ovejero D, Sugarman JS, et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Nephrol Dial Transplant. 2014;29(2):437–441. 10.1093/ndt/gft382. Epub 2013 Sep 5
    1. Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio MS, Given KS Elevated fibroblast growth factor‐23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A. 2005;134(3):233–236.
    1. Imel EA, White KE Pharmacological management of X‐linked hypophosphataemia. Br J Clin Pharmacol. 2018. 10.111/BCP.13763
    1. Yavropoulou MP, Kotsa K, Gotzamani Psarrakou A, et al. Cinacalcet in hyperparathyroidism secondary to X‐linked hypophosphatemic rickets: case report and brief literature review. Hormones (Athens). 2010;9(3):274–278.
    1. Raeder H, Shaw N, Netelenbos C, Bjerknes R A case of X‐linked hypophosphatemic rickets: complications and the therapeutic use of cinacalcet. Eur J Endocrinol. 2008;159(Suppl 1):S101–S105.
    1. Alon US, Levy‐Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clinical journal of the American Society of Nephrology: CJASN. 2008;3(3):658–664.
    1. Rhee Y, Bivi N, Farrow E, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor‐23 in vitro and in vivo. Bone. 2011;49(4):636–643.
    1. Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT Cinacalcet in the management of tumor‐induced osteomalacia. J Bone Miner Res. 2007;22(6):931–937.
    1. Alon US, Jarka D, Monachino PJ, Sebestyen VanSickle J, Srivastava T Cinacalcet as an alternative to phosphate therapy in X‐linked hypophosphataemic rickets. Clin Endocrinol (Oxf). 2017;87(1):114–116.
    1. Eddy MC, McAlister WH, Whyte MP X‐linked hypophosphatemia: normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2‐induced renal azotemia. Bone. 1997;21(6):515–520.
    1. Nakamura Y, Takagi M, Takeda R, Miyai K, Hasegawa Y Hypertension is a characteristic complication of X‐linked hypophosphatemia. Endocr J. 2017;64(3):283–289.
    1. Zivicnjak M, Schnabel D, Staude H, et al. Three‐year growth hormone treatment in short children with X‐linked hypophosphatemic rickets: effects on linear growth and body disproportion. J Clin Endocrinol Metab. 2011;96(12):E2097–E2105.
    1. Meyerhoff N, Haffner D, Staude H, et al. Effects of growth hormone treatment on adult height in severely short children with X‐linked hypophosphatemic rickets. Pediatr Nephrol. 2018;33(3):447–456.
    1. Liu ES, Carpenter TO, Gundberg CM, Simpson CA, Insogna KL Calcitonin administration in X‐linked hypophosphatemia. N Engl J Med. 2011;364(17):1678–1680.
    1. Nesbitt T, Lobaugh B, Drezner MK Calcitonin stimulation of renal 25‐hydroxyvitamin D‐1 alpha‐hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X‐linked hypophosphatemia. J Clin Invest. 1987;79(1):15–19.
    1. Econs MJ, Lobaugh B, Drezner MK Normal calcitonin stimulation of serum calcitriol in patients with X‐linked hypophosphatemic rickets. J Clin Endocrinol Metab. 1992;75(2):408–411.
    1. Sullivan R, Abraham A, Simpson C, et al. Three‐Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X‐linked Hypophosphatemia. Calcif Tissue Int. 2018;102(6):666–670.
    1. Yuan B, Feng JQ, Bowman S, et al. Hexa‐D‐arginine treatment increases 7B2*PC2 activity in hyp‐mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res. 2013;28(1):56–72.
    1. Wohrle S, Henninger C, Bonny O, et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23‐mediated hypophosphatemic rickets. Nephrol Dial Transplant. 2013;28(2):352–359. 10.1093/ndt/gfs460. Epub 2012 Nov 4
    1. Yamazaki Y, Tamada T, Kasai N, et al. Anti‐FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res. 2008;23(9):1509–1518.
    1. Aono Y, Yamazaki Y, Yasutake J, et al. Therapeutic effects of anti‐FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009;24(11):1879–1888.
    1. Carpenter TO, Imel EA, Ruppe MD, et al. Randomized trial of the anti‐FGF23 antibody KRN23 in X‐linked hypophosphatemia. J Clin Invest. 2014;124(4):1587–1597.
    1. Imel EA, Zhang X, Ruppe MD, et al. Prolonged Correction of Serum Phosphorus in Adults With X‐Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab. 2015;100(7):2565–2573.
    1. Zhang X, Peyret T, Gosselin NH, Marier JF, Imel EA, Carpenter TO Population pharmacokinetic and pharmacodynamic analyses from a 4‐month intradose escalation and its subsequent 12‐month dose titration studies for a human monoclonal anti‐FGF23 antibody (KRN23) in adults with X‐linked hypophosphatemia. J Clin Pharmacol. 2016;56(4):429–438.
    1. Zhang X, Imel EA, Ruppe MD, et al. Pharmacokinetics and pharmacodynamics of a human monoclonal anti‐FGF23 antibody (KRN23) in the first multiple ascending‐dose trial treating adults with X‐linked hypophosphatemia. J Clin Pharmacol. 2016;56(2):176–185.
    1. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab Therapy in Children with X‐Linked Hypophosphatemia. N Engl J Med. 2018;378(21):1987–98.
    1. Yuan B, Xing Y, Horst RL, Drezner MK Evidence for abnormal translational regulation of renal 25‐hydroxyvitamin D‐1alpha‐hydroxylase activity in the hyp‐mouse. Endocrinology. 2004;145(8):3804–3812.
    1. Chong WH, Andreopoulou P, Chen CC, et al. Tumor localization and biochemical response to cure in tumor‐induced osteomalacia. Kidney Int. 2013;83(6):1159–1168. 10.038/ki.2013.3. Epub Feb 6
    1. Ranch D, Zhang MY, Portale AA, Perwad F Fibroblast growth factor 23 regulates renal 1,25‐dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res. 2011;26(8):1883–1890.
    1. Zhang MY, Ranch D, Pereira RC, Armbrecht HJ, Portale AA, Perwad F Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology. 2012;153(4):1806–1816.
    1. Ruppe MD, Zhang X, Imel EA, et al. Effect of four monthly doses of a human monoclonal anti‐FGF23 antibody (KRN23) on quality of life in X‐linked hypophosphatemia. Bone Rep. 2016;5:158–162.
    1. Whyte MP, Carpenter TO, Gottesman GS, et al. Efficacy and safety of burosumab in children aged 1‐4 years with X‐linked hypophosphataemia: a multicentre, open‐label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7:189–199.

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