Relationship of Pathogenic Mutations and Responses to Zoledronic Acid in a Cohort of Osteogenesis Imperfecta Children

Abstract

Context: Osteogenesis imperfecta (OI) is a rare, heterogeneous, genetic disorder characterized by bone fragility and recurrent fractures. Bisphosphonates (BPs) are the most commonly used medications for OI, but their efficacy has great variability.

Objective: We investigated the relationship of pathogenic gene mutations and responses to zoledronic acid (ZOL) in a large cohort of children with OI.

Methods: Children with OI who received ZOL treatment were included and were followed up for at least 1 year. Bone mineral density (BMD) and serum levels of β-isomerized carboxy-telopeptide of type I collagen (β-CTX, bone resorption marker) were measured at baseline and during follow-up. Causative mutations of OI were identified using next-generation sequencing and Sanger sequencing.

Results: 201 children with OI were included. They had initiated ZOL treatment at a median age of 5 years, with mutations identified in 11 genes. After 3 years of treatment, the increase in femoral neck BMD Z-score in patients with OI with autosomal dominant (AD) inheritance was greater than that in patients with autosomal recessive or X-linked inheritance (non-AD) (4.5 ± 2.9 vs 2.0 ± 1.0, P < .001). Collagen structural defects were negatively correlated with the increase in femoral neck BMD Z-score. Patients with collagen structural defects had higher incidence of new fractures (35.1% vs 18.4%, relative risk 0.52, P = .044) and less decline in β-CTX level than those with collagen quantitative reduction. Increase in lumbar spine BMD and change in height Z-score was not associated with the genotype of children with OI.

Conclusion: Patients with OI with non-AD inheritance or with pathogenic mutations leading to collagen structural defects may have relatively poor responses to ZOL treatment, which is possibly associated with their more severe phenotypes. New therapeutic agents are worth developing in these patients.

Keywords: osteogenesis imperfecta; pathogenic mutation; responses to treatment; zoledronic acid.