Growth pattern in children with X-linked hypophosphatemia treated with burosumab and growth hormone

Abstract

Background: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.

Results: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)₂D increased dramatically under burosumab therapy.

Conclusion: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

Keywords: Burosumab; Children; Growth; Recombinant human growth hormone; X-linked hypophosphatemia (XLH).

Fig. 1

Study design and groups. B-1: 1 year before burosumab initiation, B0: initiation of burosumab therapy, B1: 1 year after burosumab initiation, GH0: initiation of rhGH therapy, GH-1: 1 year before rhGH initiation, GH1: 1 year after rhGH initiation

Fig. 2

Individual changes in height SDS in group 1. Solid black lines correspond to girls and dashed black lines to boys. The solid red lines mark 0 and − 2 SDS

Fig. 3

Individual changes in height SDS in group 2. Black and grey lines correspond to prepubertal and pubertal participants, respectively. The solid red lines mark 0 and − 2 SDS

Fig. 4

Individual growth pattern in patients treated with rhGH and burosumab. P: percentile

Fig. 5

Distribution of serum IGF-I levels in the pubertal group 2 population. Normal ranges depended on the Tanner stage. II: 198–551 ng/ml, III: 238–672 ng/ml, IV: 318–870 ng/ml, V: 302–774 ng/ml

Fig. 6

Individual changes in serum phosphate and alkaline phosphatase. Black and grey lines correspond to prepubertal and pubertal participants, respectively. Dashed lines show the lower limit of normal for serum phosphate (1.0–1.85 mmol/L) and the upper limit of normal for alkaline phosphatase: in black and grey for the prepubertal (50–390 IU/L) and pubertal (131–424 IU/L) populations, respectively

Fig. 7

Individual changes in TmP/GFR. Black and grey lines correspond to prepubertal and pubertal participants, respectively. Dashed black lines show the lower limit of normal (1.15–2.44 mmol/L)