Treatment of X-Linked Hypophosphatemia in Children: History
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Subjects: Pediatrics

The conventional treatment for X-linked hypophosphatemia (XLH), consisting of phosphorus supplementation and a biologically active form of vitamin D (alfacalcidol or calcitriol), is used to treat rickets and leg deformities and promote growth. However, patients’ adult height often remains less than −2 SD. Moreover, adverse events, such as renal calcification and hyperparathyroidism, may occur. The main pathology in XLH is caused by excessive production of fibroblast growth factor 23 (FGF23). Treatment with burosumab, a blocking neutralizing antibody against FGF23, is better than conventional therapy for severe XLH and has no serious, short-term side effects. Thus, treatment with burosumab may be an option for severe XLH. 

  • phosphorus
  • active form of Vitamin D
  • renal calcification
  • fibroblast growth factor 23 (FGF23)
  • burosumab

1. Introduction

Hereditary hypo-phosphatemic disorders caused by elevated fibroblast growth factor-23 (FGF23) includes X-linked hypo-phosphatemic rickets (XLH) and autosomal-dominant hypo-phosphatemic rickets (ADHR) [1,2,3,4]. Osteoblasts and osteocytes produce and secrete FGF23, which binds to KLOTHO-FGF receptor 1 (FGFR1) in the target organs [3,4]. FGF23 suppresses the expression of type 2a and 2c sodium-phosphate cotransporters in renal proximal tubules, inhibiting phosphate reabsorption [3,4]. Moreover, FGF23 downregulates the expression of 1α-hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D to 1, 25 (OH)2 hydroxyvitamin D [3,4]. Thus, the symptoms of XLH and ADHR consist of rickets, short stature, osteo-malacia, bone pain, and dental diseases caused by renal phosphate wasting and low or inappropriately normal 1, 25 (OH)2-hydroxyvitamin D levels [1,2].
The frequency of XLH is 1.7 per 100,000 children [1,2,3]. XLH arises from mutations of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene (Xp22.11), and its inheritance is X-linked dominant [3,4]. Males and females are equally affected, but the clinical severity is often variable even in familial cases [3,4]. The PHEX protein, a protease expressed in osteocytes and odontoblasts, does not degrade FGF23 [3,4]. Although the exact mechanism underlying elevated FGF23 in XLH is not completely understood, it is speculated that the sensing of phosphate in osteocytes may be disturbed [3,4].
The treatment target in X-linked hypophosphatemia (XLH) in childhood is to improve rickets, restore growth, alleviate bone pain, improve physical activity, and maintain dental health [1,2,5,6,7,8,9]. Infants in whom the condition is diagnosed at birth via family screening should be treated as soon as possible, as the outcomes are better the earlier therapy is begun [1,2,10].
The conventional therapy for XLH consists of oral phosphorus supplementation and alfacalcidol or calcitriol [1,2,5,6,7,8,9]. Recently burosumab, an IgG1 monoclonal antibody targeting FGF23, was developed and authorized for use by the European Medicines Agency and Food and Drug Administration [1,2,3,10,11,12], and several studies of its use in the treatment of severe XLH have already been published [13,14,15,16,17].

2. Conventional Therapy

The conventional therapy for XLH consists of oral phosphorus supplementation and alfacalcidol or calcitriol. Oral phosphorus supplementation compensates for renal phosphate wasting, and alfacalcidol or calcitriol compensates for impaired 1, 25 (OH)2-hydroxyvitamin D production caused by excess fibroblast growth factor 23 (FGF23) [1,2,18].
Oral phosphorus 20–60 mg/kg/day is recommended as the initial dosage, depending on the age of the patient and the severity of the clinical symptoms [1,2]. It may be advisable to begin with a low dosage. However, to avoid gastrointestinal side effects, such as abdominal pain and diarrhea, and hyperparathyroidism, the dosage should not exceed 80 mg/kg/day [1,2]. When phosphorus is administered orally, it is poorly absorbed by the intestinal tract and returns to the original value after a few hours [2]. Therefore, multiple, daily doses of phosphorus are needed. In children, four to six divided doses daily are preferable [2]. The serum phosphate level should not be used to adjust the dosage of phosphorus supplementation [2].
Alfacalcidol or calcitriol is administered with oral phosphorus supplementation to compensate for impaired 1, 25 (OH)2 hydroxyvitamin D production caused by excess FGF23 [1,2,5,6,7,8]. Alfacalcidol and calcitriol increase the absorption of phosphorus from the intestines. Initially, alfacalcidol 0.03–0.05 mg/kg/day should be administered once daily, and calcitriol 0.02–0.03 mg/kg/day could be administered in one or two doses daily [2]. The alfacalcidol and calcitriol dosage are often higher in toddlers and adolescents than in children [1,2,5,6] and should be adjusted so that it does not exceed (0.35 mg/mg) in urinary calcium/creatine [2]. If necessary, water intake is recommended to reduce the urinary calcium concentration [1]. Calculating the dosage should also take into consideration the degree of ALP decrease as well [1,2]. While administering a large amount of alfacalcidol or calcitriol is effective for improving rickets and growth velocity, it can lead to hypercalcemia, increased urinary calcium excretion, and renal calcification [1,2,5,6,7,8]. However, if the dosage is too low, it will be ineffective in improving rickets or the growth velocity. Thus, fine-tuning the alfacalcidol and calcitriol dosage is often difficult.
Three to five phosphorus doses are normally administered. Phosphorus supplementation stimulates the gastrointestinal system and can cause diarrhea [1,2], possibly leading to decreased compliance. Furthermore, alfacalcidol and calcitriol have a relatively narrow therapeutic window, as mentioned previously, and may thus increase urinary calcium excretion. Increased urinary calcium excretion and hyper-phosphaturia lead to nephrocalcinosis and nephrolithiasis [3,4,5,6]. Renal calcification reportedly occurs in 30–70% of patients with XLH [1,32,33,34] as a manifestation of secondary hyperparathyroidism [1,2,8,35,36,37], which is caused by the high dose of oral phosphorus and/or an active form of vitamin D. In addition, FGF23 contributes to the progression of secondary hyperparathyroidism by reducing 1, 25 (OH)2 hydroxyvitamin D synthesis and subsequently decreasing active intestinal calcium transport [1,2,8]. Furthermore, hyperparathyroidism in XLH patients has been reported to cause hypertension [36,37]. According to Alon et al. [36]. eight of 41 patients with XLH aged 20–29 years experienced hypertension during treatment. Secondary and tertiary hyperparathyroidism were observed in all eight of these patients, and nephrocalcinosis was observed in seven patients. Nakamura et al. [37] also reported that six of 22 adult patients with XLH experienced hypertension, and that the average age at hypertension onset was 29 years. All six patients had secondary or tertiary hyperparathyroidism, and two patients had renal dysfunction. Monitoring of blood pressure is necessary for XLH patients with hyperparathyroidism.

3. Burosumab

Recently, burosumab, an anti-FGF23 antibody, was developed as a drug for decreasing excess FGF23 [3,11,12], which is central to the pathology of XLH [1,2,3]. Burosumab is a recombinant immunoglobulin G1 monoclonal antibody that binds intact and fragmented FGF23 at the N-terminal domain [12]. N-terminal antibodies to FGF23 can prevent the interaction of FGF23 and FGF receptor 1c [12]. Blood levels of burosumab peak in seven to 11 days on average, and its half-life in blood is 16 to 19 days [38,39]. The pharmacokinetics are the same for adults and children [39].

Aono et al. [12] reported the effects of antiFGF23 antibody in Hyp mice. The antibodies were administered to 4-week-old mice once a week for one month. As a result, the serum phosphate and 1, 25 (OH)2 hydroxyvitamin D levels increased. Improvement of bone deformities and mineralization were observed. Blocking FGF23 with antibodies can cause a rapid increase in 1, 25 (OH)2 hydroxyvitamin D, leading to hypercalcemia and possible renal calcification. However, in the previously cited study of Hyp mice, no nephrocalcinosis was observed.

A recent, longitudinal study reported that adverse events related to burosumab occurred in 73% of the patients enrolled [16]. The most common adverse event was a reaction at the injection site [13,14,15,16,17], which occurred in about half the patients receiving burosumab but resolved one to two days after the injection. The second most common burosumab-related adverse event was pain in the extremities (10%). One patient experienced two serious adverse events requiring hospitalization (fever and muscle pain at week 48 and headache at week 182) but the therapy was nonetheless continued [16].
The initial burosumab dosage is 0.8 mg/kg administered subcutaneously every two weeks [2]. The dosage should be adjusted so that the fasting serum phosphorus concentration is at the lower end of the normal reference range by age [2]. The fasting phosphate level should be measured 12–14 days after the injection to avoid hyperphosphatemia [2].

This entry is adapted from the peer-reviewed paper 10.3390/endocrines3030042

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