Nephrocalcinosis tendency does not worsen under burosumab treatment for X-linked hypophosphatemic rickets: a multicenter pediatric study

Abstract

Background: X-linked hypophosphatemic rickets (XLH) is associated with uninhibited FGF23 activity, which leads to phosphaturia, hypophosphatemia and depressed active vitamin D (1,25OH2D) levels. Conventional treatment with phosphate supplements and vitamin D analogs may lead to hypercalciuria (HC), nephrocalcinosis (NC) and hyperparathyroidism. We investigated the effects of burosumab treatment, an anti-FGF23 monoclonal antibody recently approved for XLH, on these complications.

Methods: This retrospective study included children with XLH who were treated with burosumab for at least one year at one of three referral centers. Clinical and biochemical potential treatment outcomes were regularly followed, including multiple urine calcium measurements and NC severity score (0 = no NC, 3 = worse NC).

Results: Twenty-six (13 male) children aged 7.6 ± 3.9 years were followed for 27.5 ± 9.6 months. Mean serum phosphate levels rapidly increased from 2.67 ± 0.61 at baseline to 3.57 ± 0.53 mg/dL after 3 months (p < 0.001) and remained stable thereafter. Concomitant decreases were observed in phosphaturia, serum alkaline phosphatase and parathyroid hormone. HC (U-Ca/Cr > 0.2 mg/mg) was detected in 2/26 (7.7%) patients before burosumab initiation, resolved in one and persisted, albeit improved, in the second. Two patients were newly diagnosed with HC, 15 and 3 months after therapy, which persisted in one of them despite dose reduction attempts. Seven patients had NC at baseline (mean score: 1.8 ± 0.34), but none showed deterioration or developed new NC.

Conclusion: In children with XLH treated with burosumab, HC was an infrequent side effect and preexisting NC did not worsen.

Keywords: FGF23; XLH; burosumab; hypercalciuria; nephrocalcinosis.

Figure 1

Changes in laboratory parameters during the course of burosumab therapy. Error bars represent the mean and 95% confidence interval values at different times points of serum phosphate (a), serum alkaline phosphatase (b), total reabsorption of phosphate (%) (c), and parathyroid hormone (PTH) (d), before, at baseline, and during the 36 months after the initiation of burosumab therapy. The horizontal broken line shows the lower (a,b) and upper (c,d) limits of normal for each laboratory value. All the values improved, with statistical significance, compared to baseline (a–c), and compared to pretreatment (d). The number of patients (n) assessed at each time point appears below the X axis in each graph.

Figure 2

Mean urinary calcium to creatinine ratio during follow-up.

Figure 3

Spot urine calcium/creatinine (Ca/Cr) ratio values of each of the 26 included patients, before and after the initiation of burosumab treatment. The broken horizontal line shows the upper limit of normal Ca/Cr ratio (0.2 mg/mg). For details see the results section.

Figure 4

Bar chart of NC scores for each of the 26 patients, measured before (black column) and at the last follow up (red column) after burosumab treatment. The arrows represent the patients with hypercalciuria before (red arrows) and after (blue arrows) burosumab initiation. The figure inserts show examples of grade 3 medullary NC in the right and left kidneys of one patient. US, ultrasound.