Impact of burosumab on lower limb alignment in children with X-linked hypophosphatemia

Abstract

Background: Osteotomy and hemiepiphysiodesis are used to treat lower limb deformities in the rare musculoskeletal disease X-linked hypophosphatemia (XLH), but postsurgical complications and malalignment recurrence are possible. This retrospective analysis assessed whether treatment with burosumab, a fully human IgG1 monoclonal antibody to fibroblast growth factor 23 approved for treatment of rickets in XLH, improves lower limb malalignment toward age-specific normal values in children with XLH.

Methods: Children with confirmed XLH received burosumab for 160 weeks in the open-label phase 2 study CL205, or conventional therapy (Pi/D) or burosumab for 64 weeks in the randomized, open-label phase 3 study CL301, with crossover from Pi/D to burosumab through 88 weeks. Full-length, anteroposterior lower limb radiographs were reviewed. The mechanical femoral-tibial angle (MFTA) of lower limbs was measured at baseline and postbaseline. Each MFTA was classified as normal (within 1 standard deviation [SD] of age-specific normal range) or clinically normal (within 2 degrees of normal).

Results: Overall, 116 limbs were included (CL205, n = 26; CL301, n = 90). Varus or valgus limbs were observed at baseline in 21 (80.8%) limbs in CL205 and in 69 (76.7%) limbs in CL301. In CL205, mean (SD) MFTA decreased from 13.0° (6.7°) at baseline to 5.7° (6.0°) at week 64 and 1.0° (4.8°) at week 160. In CL301, mean (SD) MFTA decreased from 15.5° (13.6°) at baseline to 8.5° (10.0°) at week 64 in the burosumab arm, and in the crossover arm, from 9.2° (10.4°) at week 64 to 6.9° (9.4°) at week 88 (after 22 weeks of burosumab). The proportion of normal or clinically normal limbs increased with burosumab in CL205 (baseline to week 160, 19.2% to 58.3%) and in the CL301 burosumab arm (baseline to week 64, 19.6% to 37.0%) but not in the CL301 crossover arm (week 64-88, 34.1% to 33.3%).

Conclusions: In children with XLH, long-term treatment with burosumab is capable of correcting the MFTA of varus and valgus lower limbs to a neutral alignment without requiring surgical intervention.

Key concepts: 1.Treatment with burosumab led to the correction of lower limb angular deformity to neutral alignment in children with X-linked hypophosphatemia (XLH).2.Continued treatment with burosumab for at least 1 year appears to have further positive effects on the correction of lower limb angular deformity in children with XLH.3.Initial treatment with burosumab is indicated in young children with XLH for whom hemiepiphysiodesis is being considered.

Level of evidence: III.

Keywords: Burosumab; Children; Lower limb deformities; Rickets; X-linked hypophosphatemia.

Figure 1

Patient disposition in the CL205 and CL301 studies, extension periods, and the retrospective radiographic analysis. XLH, X-linked hypophosphatemia.

Figure 2

Classification of lower limb MFTA. (A) MFTA normal ranges by age group. The lower and upper limits of the MFTA normal range for each age group were calculated using the mean ± 1 SD reported by Sabharwal and Zhao . (B) Definitions used for classification of lower limb MFTA. At each time point, the MFTA measured for each limb was compared with the normal range of the appropriate age group, with the normal range adjusted for new age at each radiographic measurement. Limbs at each time point were categorized using the following definitions: Normal (an MFTA within 1 SD above or below the age group-specific mean normal hip-knee-ankle angle values reported by Sabharwal and Zhao [29]); Clinically Normal (an MFTA not achieving normal status but was no more than 2 degrees above or no less than 2 degrees below the age group-specific normal range); Valgus (an MFTA below the age group-specific clinically normal range); Varus (an MFTA above the age group-specific clinically normal range); Improved (a valgus MFTA that increased from baseline but remained below the clinically normal range, or a varus MFTA that decreased from baseline but remained above the clinically normal range); No Change (a valgus or varus MFTA that did not change from baseline); Overcorrected (a valgus MFTA that increased from baseline to above the upper clinically normal age group-specific range, or a varus MFTA that decreased from baseline to below the lower clinically normal age group-specific range); or worsened (a valgus MFTA that further decreased from the baseline value, or a varus MFTA that further increased from the baseline value). MFTA, mechanical femorotibial angle; SD, standard deviation.

Figure 3

Baseline MFTA classification by age group. Each circle or square represents an individual lower limb MFTA. MFTA, mechanical femorotibial angle.

Figure 4

Change in MFTA. (A) Summary of MFTA at each study time point in study CL205. (B) Summary of MFTA at each study time point in study CL301. (C) Mean (SD) change from baseline in MFTA (degrees) at each study time point in study CL205. (D) Mean (SD) change from baseline in MFTA (degrees) at each study time point in study CL301. MFTA, mechanical femorotibial angle; SD, standard deviation.

Figure 5

Lower limb radiographs. (A) Study CL205 lower limb radiographs from a 1.6-year-old male at baseline and after 64 and 160 weeks of treatment with burosumab. (B) Study CL205 lower limb radiographs from a 3.7-year-old male at baseline and after 64 and 160 weeks of treatment with burosumab. (C) Study CL301 lower limb radiographs from a 7.2-year-old female at baseline and after 64 and 88 weeks of treatment with burosumab. (D) Study CL301 lower limb radiographs from a 2.1-year-old female at baseline who had 64 weeks of conventional therapy (Pi/D) and then crossed over to burosumab through 88 weeks of treatment. Mechanical femorotibial angle measurements are illustrated in red.