Efficacy of Using Zoledronate for Prevention of Craniofacial Fractures in Mice with Osteogenesis Imperfecta

Date

2024-03-21

ORCID

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

Osteogenesis imperfecta (OI) is a genetic disorder of type I collagen that results in increased bone fragility, increased fracture rates, and abnormalities of the limbs, vertebral column, and craniofacial skeleton. Long-lasting bisphosphonate drugs, like zoledronate, are used in children with OI to increase bone mineral density and prevent skeletal fractures. Zoledronate increases osteoclast apoptosis, thus reducing relative rates of bone resorption and increasing formation rates. Previous experimental research on the efficacy of zoledronate has focused largely on the postcranial skeleton (e.g. limbs). The goal of this study is to investigate if zoledronate reduces the rate of craniofacial fractures in mice with osteogenesis imperfecta. We hypothesize that mice treated with zoledronate will have fewer skeletal fractures of the skull compared to untreated mice.

Mice with OI (OIM, B6C3Fe a/a-Col1a2oim/oim) and unaffected littermates (wild-type, WT) were randomly assigned into either control (C) or zoledronate (ZOL) treatment groups (n=5/genotype/group). Mice treated with zoledronate received subcutaneous injections of the drug (80 µg/kg) at 4, 8, and 12 weeks of age. The craniofacial skeleton of all mice was imaged with a micro-CT scanner (20 µm3 voxels) every 4 weeks from 4-16 weeks. 3D models of the craniofacial skeleton were generated in 3D Slicer software, and analyzed for incidence and location of fractures.

At 8 weeks, no fractures were observed in WT-C or WT-ZOL mice. However, fractures were observed in both groups of OIM mice. 80% (4/5 per group) of OIM-C and OIM-ZOL mice had skeletal fractures, and the remaining 20% (1/5 per group) had fractured incisors. All skeletal fractures were observed along the zygomatic arch, proximal to the attachment site of the masseter muscle. Both unilateral and bilateral zygomatic fractures were observed.

Preliminary data indicates that a single treatment with zoledronate at 4 weeks of age does not reduce the incidence of craniofacial fractures in mice with OI. Additional data is needed to assess if zoledronate improves fracture healing or bone quality outcomes (e.g. BMD) in the craniofacial skeleton, as has been demonstrated in limb bones. Additionally, the prevalence of fractures proximal to skeletal attachment sites for feeding muscles suggestions that muscle-bone interactions are a key component for understanding the origin of facial fractures in this model. Previous work has shown that long-term use of bisphosphonates like zoledronate may have negative outcomes for the craniofacial skeleton, including delayed bone formation, altered dental eruption, and osteonecrosis of the jaw (ONJ). This study suggests that craniofacial health is an important consideration, distinct from postcranial health, when planning interventions for patients with OI.

Description

Keywords

Citation

Rights

License