Combined treatment with a C-type natriuretic peptide analog and bisphosphonate enhances bone growth in growing mice
Jack E Mulcrone1, Ketsia Seide1, Jonathan Chacko1
1Hospital for Special Surgery, HSS Research Institute, New York, NY 10021, United States.
Insights
This study shows that combining a C-type natriuretic peptide (CNP) analog with alendronate (ALN) improved growth and bone density in Osteogenesis Imperfecta (OI) mice. This combination therapy offers benefits beyond bisphosphonates alone for OI treatment.
Area of Science:
- Biochemistry
- Genetics
- Orthopedics
Background:
- Osteogenesis imperfecta (OI) is a genetic disorder affecting collagen, leading to brittle bones and impaired growth.
- Current treatments like bisphosphonates reduce fractures but don't enhance linear growth.
- Reduced serum levels of C-type natriuretic peptide (CNP) are observed in OI patients.
Purpose of the Study:
- To evaluate the efficacy of a CNP analog combined with alendronate (ALN) in improving growth and bone mineral density in a mouse model of Osteogenesis Imperfecta (OIM).
Main Methods:
- OIM mice received weekly ALN and varying regimens of a CNP analog.
- Fracture incidence, femoral length, and vertebral height were assessed.
- Microcomputed tomography (micro-CT) analyzed bone microstructural parameters.
Main Results:
- The high-dose CNP analog group showed no fractures and significant increases in femoral length (8.2%) in OIM mice.
- All treatment groups exhibited increased vertebral height and improved bone mineral density (trabecular and cortical).
- Combined therapy enhanced linear growth and bone quality without compromising fracture reduction.
Conclusions:
- CNP analog adjuvant therapy, combined with ALN, promotes linear growth and improves bone quality in OIM mice.
- This combination therapy offers potential benefits not achieved with bisphosphonates alone.
- Results support further investigation for potential human translation in Osteogenesis Imperfecta treatment.
Abstract:
Osteogenesis imperfecta (OI) is a heterogeneous type 1 collagenopathy characterized by recurrent fractures, decreased bone mass, and short 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 it positively regulates linear bone growth; people with OI have been shown to have reduced serum levels of CNP. This pilot study evaluated whether a CNP analog combined with alendronate (ALN) improves growth and BMD in oim/oim (OIM) mice, a model of moderate-to-severe Type III OI. Two-wk-old OIM and WT mice received weekly ALN and 1 of 3 CNP regimens: 10 μg/kg 3 d/wk (low), 20 μg/kg 3 d/wk (medium), or 20 μg/kg 5 d/wk (high). Controls received saline. Faxitron images were taken at 2, 8, and 14 wk (sacrifice) to assess fracture incidence and measure femoral length and vertebral height. MicroCT was used to assess bone microstructural parameters of the femur ex vivo. The high-dose group had no fractures post-sacrifice, while 1 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% and significant) in OIM mice. Vertebral height increased in all treated groups; low and high dose groups had greater and comparable increases than the medium group in OIM mice. All treated groups showed increased trabecular BMD. Cortical tissue mineral density, BMD, and thickness were also elevated in all treated groups compared to the 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 the therapeutic potential for translation to humans.
