Combined Treatment with a C-Type Natriuretic Peptide Analog and Bisphosphonate Enhances Bone Growth in Growing Mice with Osteogenesis Imperfecta: A Pilot Study

Abstract

Osteogenesis imperfecta (OI) is a heterogenous type 1 collagenopathy characterized by recurrent fractures, decreased bone mass, and shorter stature. Bisphosphonates reduce fracture incidence in children with OI but do not improve growth velocity. C-type natriuretic peptide (CNP) is produced in the growth plate (also in the brain and heart) and positively regulates linear bone growth; people with OI have been shown to have a reduced serum level of CNP. This pilot study evaluated whether a CNP analog combined with alendronate (ALN) improves growth and bone mineral density in oim/oim (OIM) mice, a model of moderate-to-severe Type III OI. Two-week-old OIM and WT mice received weekly ALN and one of three CNP regimens: 10 μg/kg three days/week (low), 20 μg/kg three days/week (medium), or 20 μg/kg five days/week (high). Controls received saline. Faxitron images were taken at two, eight, and 14 weeks (sacrifice) to assess fracture incidence and measure femoral length and vertebral height. Microcomputed tomography (micro-CT) was used to assess bone microstructural parameters of the femur ex vivo. The high-dose group had no fractures post-sacrifice; one fracture each was observed in the low and medium dose groups. Femoral length increased in all treated groups, with the high dose group showing the greatest increase (8.2%, significant) in OIM mice. Vertebral height increased in all treated groups; low and high dose groups had greater, comparable increases than the medium group in OIM mice. All treated groups showed increased trabecular bone mineral density (BMD). Cortical tissue mineral density (TMD), BMD, and thickness were also elevated in all treated groups compared to controls. In conclusion, CNP analog adjuvant treatment enhanced linear growth and bone quality without compromising fracture reduction, providing benefits not seen with bisphosphonates alone. These results will inform optimal dosing for future studies. A full murine study is planned to further evaluate therapeutic potential for translation to humans.

Keywords: Antiresorptives; Bone QCT/microCT; Fracture prevention; Growth plate; Injury/fracture healing; Osteogenesis imperfecta; Preclinical Studies; THERAPEUTICS.