Abstract
X-linked hypophosphatemia (XLH) causes significant burden in pediatric patients in spite of maintained treatment with phosphate supplements and vitamin D derivatives. Administration of burosumab has shown promising results in clinical trial but studies assessing its effect in the everyday practice are missing. With this aim, we analyzed the response to one-year treatment with burosumab, injected subcutaneously at 0.8 mg/kg every 2 weeks, in five children (three females) aged from 6 to 16 years, with genetically confirmed XLH. Patients were being treated with phosphate and vitamin D analogs until the beginning of burosumab treatment. In all children, burosumab administration led to normalization of serum phosphate in association with marked increase of tubular reabsorption of phosphate and reduction of elevated serum alkaline phosphatase levels. Baseline height of patients, from −3.56 to −0.46 SD, increased in the three prepubertal children (+0.84, +0.89, and +0.16 SD) during burosumab treatment. Growth improvement was associated with reduction in body mass index (−1.75, −1.47, and −0.17 SD, respectively), suggesting a salutary effect of burosumab on physical activity and body composition. Burosumab was well-tolerated, mild local pain at the injection site and transient and mild headache following the initial doses of burosumab being the only reported undesirable side effects. No patient exhibited hyperphosphatemia, progression of nephrocalcinosis, worsening of metabolic control or developed hyperparathyroidism. Mild elevation of serum PTH present at the beginning of treatment in one patient 4 was not modified by burosumab administration. These results indicate that in the clinical setting, beyond the strict conditions and follow-up of clinical trials, burosumab treatment for 1 year exerts positive effects in pediatric patients with XLH without major adverse events.
Highlights
X-linked hypophosphatemic rickets (XLH) is a monogenic disorder that follows a Mendelian dominant inheritance (OMIM 307800) and it is the most common hereditary form of rickets [1].XLH is caused by loss of function of the gene PHEX [2], a phosphate regulating gene with homologies to endopeptidases, leading to elevated circulating levels of fibroblast growth factor Burosumab in XLH23 (FGF23), renal wasting of phosphate and defective renal production of 1,25-dihydroxyvitamin D [3]. XLH is characterized by a broad phenotypical expression, active lesions of rickets, subsequent bone deformities and disharmonic growth retardation are major manifestations of the disease in the pediatric age
Hypophosphatemia associated to urinary wasting of phosphate, relatively low values of 1,25dihydroxyvitamin D and elevated alkaline phosphatase levels all support the diagnosis of XLH, confirmed by the mutation found in the PHEX gene
Serum phosphate normalized in all patients, in patient 1 after a transient worsening of hypophosphatemia immediately following the first burosumab dose
Summary
X-linked hypophosphatemic rickets (XLH) is a monogenic disorder that follows a Mendelian dominant inheritance (OMIM 307800) and it is the most common hereditary form of rickets [1]. Classical medical treatment of XLH is based on the oral administration of phosphate supplements and 1-hydroxy metabolites of vitamin D, given chronically, at least until the end of body growth [4]. This therapy usually heals the active radiological lesions of rickets and improves growth but does not normalize serum phosphate, does not avoid major clinical manifestations of the disease, does not result in the achievement of a normal final adult height and entails the risk of potential undesirable side effects such as nephrocalcinosis or hyperparathyroidism [5, 6]. All subjects gave written informed consent in accordance with the Declaration of Helsinki
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