Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data

Abstract

Asfotase alfa is an enzyme replacement therapy approved for treatment of patients with pediatric-onset hypophosphatasia (HPP), a rare, inherited, systemic disease causing impaired skeletal mineralization, short stature, and reduced physical function in children. The role of dual X-ray absorptiometry (DXA) in the assessment of children with HPP has been insufficiently explored. This post hoc analysis included pooled DXA data from 2 open-label, multicenter studies in 19 children with HPP. The study population was aged ≥5 to <18 years and had received asfotase alfa for ≤6.6 years at enrollment (male: 79%; median age at enrollment: 10.4 y [range: 5.9-16.7]; treatment duration: 6.3 y [range: 0.1-6.6]. Baseline height Z-scores indicated short stature (median [min, max]: -1.26 [-6.6, 0]); mean [SD]: -2.30 [1.97]), thus requiring height adjustment of DXA Z-scores. At Baseline, few patients had height-adjusted bone mineral density (BMD_ht) Z-scores of -2 or less for whole body (n = 3) or lumbar spine (n = 5). In treated patients, mean whole body and lumbar spine BMD_htZ-scores did not change over time, but whole body and lumbar spine height- adjusted bone mineral content (BMC_ht) Z-scores increased significantly from Baseline to Last Assessment (P ≤ 0.0056). Improvements in Radiographic Global Impression of Change (RGI-C) scale scores correlated significantly with increases in whole body and lumbar spine BMC_htZ-scores (P < 0.05) but not BMD_htZ-Scores. Improvements in Rickets Severity Score (RSS) correlated significantly with increases in lumbar spine BMD_htZ-scores and whole body BMC_ht Z-scores (P < 0.05). No significant correlations were observed between any DXA and bone histomorphometry measure. These findings suggest that DXA BMD Z-scores, which are commonly used in clinical practice, have limited utility in assessing deficient bone mineralization in patients with HPP. Although BMC_htZ-scores increased significantly over time with asfotase alfa therapy, the lack of significant changes in more than one DXA parameter suggests that this tool may not be useful in everyday clinical practice. Furthermore, the use of BMC as an independent metric is not typical or recommended by guidelines. Complementary measures, such as skeletal radiographs supplemented with age-appropriate functional assessments, should be considered.

Trial registration: ClinicalTrials.gov NCT00952484 NCT01203826 NCT01163149.

Keywords: Bone mineral content; Bone mineral density; Metabolic bone disease; Tissue-nonspecific alkaline phosphatase.