Background/Aim: X-linked hypophosphatemia (XLH) is a rare disease caused by PHEX mutation, leading to elevated FGF23, renal phosphate wasting, hypophosphatemia, insufficient 1,25(OH)2D synthesis. Clinically, it manifests with rickets including leg deformities, poor growth, dental abscesses, craniosynostosis, and hearing loss. Beyond conventional treatment (phosphate supplements + active vitamin D), burosumab is pathogenetic anti-FGF23 therapeutic approach, whose efficacy was demonstrated in clinical trials on 1–12 years-old children affected with XLH. Here, we prospectively assessed the efficacy and safety of burosumab on a large cohort of children in clinical practice, including adolescents ≥ 13 years of age at moment of treatment.
Patients/methods: 57 XLH-children (36 girls/21 boys; 9.1 ± 8.9 years; including 10 adolescents ≥ 13 year-old, 14.5 ± 1.2 years) were switched from conventional therapy to burosumab.
Objectives: The primary end-point was the change from baseline (M0) to 12 months (M12) in the rachitic lesions evaluated through knee MRI by measuring of the maximum width of physis and the transverse extent of widening. The secondary end-points were the changes in biochemical (serum phosphate (sP), TmP/eGFR, ALP, 1,25(OH)2D, PTH), clinical parameters (height-SDS, function evaluated through 6-minutes walking test [6MWT]), incidence of dental-hearing-neurological manifestations and safety (incidence of any adverse events, nephrocalcinosis, hyperparathyroidism). In France, the target sP was > 1.2 mmol/l ( > 3.7 mg/dl).
Results: 1-year treatment with burosumab significantly reduced the disease activity, as shown by reduction of the transverse extent of widening and the maximum width of medial physis by 50% and 44% (M0→M12: 62 ± 34 → 31 ± 20%; 5.5 ± 2.1 → 3.2 ± 1.4 mm, P = 0.00 for all, respectively). This was associated with significant reduction in ALP (M0 → M12: 418 ± 150 → 299 ± 146U/l, P = 0.006) and improvement in physical ability expressed as age-adjusted 6MWT-SDS (M0 → M12: −3.3 ± 1.3 → −2.8 ± 1.3, P = 0.03). As expected, we found a rescue of phosphate wasting (M0→M12:sP 0.73 ± 0.12 → 1.19 ± 0.15 mmol/l, TmP/eGFR 0.62 ± 0.12 → 1.07 ± 0.17) and 1,25(OH)2D synthesis (M0 → M12: 25 ± 15 → 79 ± 22 pg/ml); P = 0.00 for all. There were no significant changes in height-SDS and incidence of complications after 1 year. The most common side effects were bone-muscular-abdominal pain, headache, reactions at sites of injection. Adolescents showed higher baseline PTH levels, however, upon burosumab, PTH reduced overtime (M0 → M6 → M12: PTH 85 ± 43 → 57 ± 27 → 66 ± 39 ng/l, P = 0.7). Secondary hyperparathyroidism in adolescents was associated to a slower restoration of phosphate metabolism.
Conclusion: Our findings on efficacy and safety of burosumab confirm those of clinical trials. Restoration of phosphatemia and endogenous calcitriol synthesis by burosumab leads to healing of rickets, reduction of disease activity and improvement of physical function. XLH-adolescents show slower restoration of phosphate wasting under burosumab likely due to secondary hyperparathyroidism; noteworthy, the use of burosumab seems to control PTH in adolescents.
05 Sep 2020 - 09 Sep 2020