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Published on: June 8, 2014
RANKL inhibition improves bone properties in a mouse model of osteogenesis imperfecta
Renee Bargman1, Alice Huang, Adele L Boskey
1NYPH-Weill Cornell Medical Center, New York, New York, USA.
Abstract:
Recently, a new class of agents targeting the receptor activator of nuclear factor-kappaB ligand (RANKL) pathway has been developed for the treatment of osteoporosis and other bone diseases. In the current study, inhibition of the RANKL pathway was evaluated to assess effects on "bone quality" and fracture incidence in an animal model of osteogenesis imperfect (OI), the oim/oim mouse. Juvenile oim/oim ( approximately 6 weeks old) and wildtype (+/+) mice were treated with either a RANKL inhibitor (RANK-Fc) or saline. After treatment, bone density increased significantly in the femurs of both genotypes. Femoral length decreased with RANK-Fc in +/+ mice. Geometric measurements at mid-diaphysis in the oim/oim groups showed increases in the ML periosteal and endosteal diameters and AP cortical thickness in the treated groups. Within +/+ groups, ML cortical thickness and ML femoral periosteal diameter were significantly increased with RANK-Fc. Biomechanical testing revealed increased stiffness in oim/oim and +/+ mice. Total strain was increased with treatment in the +/+ mice. Histologically, RANKL inhibition resulted in retained growth plate cartilage in both genotypes. The average number of fractures sustained by RANK-Fc-treated oim/oim mice was not significantly decreased compared to saline treated oim/oim mice. This preclinical study demonstrated that RANKL inhibition at the current dose improved density and some geometric and biomechanical properties of oim/oim bone, but it did not decrease fracture incidence. Further studies that address commencement of therapy at earlier time points are needed to determine whether this mode of therapy will be clinically useful in OI.
Insights
Receptor activator of nuclear factor-kappaB ligand (RANKL) inhibition improved bone density and quality in osteogenesis imperfect mice but did not reduce fracture incidence. Earlier treatment initiation is needed to assess clinical utility for bone diseases.
Area of Science:
- Orthopedics
- Pharmacology
- Genetics
Background:
- Osteogenesis imperfect (OI) is a genetic disorder characterized by fragile bones.
- Receptor activator of nuclear factor-kappaB ligand (RANKL) pathway is a target for bone disease treatment.
- Current treatments for OI have limitations in improving bone quality and reducing fractures.
Purpose of the Study:
- To evaluate the effects of RANKL inhibition on bone quality and fracture incidence in a mouse model of OI.
- To assess the impact of RANKL inhibition on bone density, geometry, biomechanics, and growth plate in oim/oim mice.
Main Methods:
- Juvenile oim/oim and wildtype mice were treated with a RANKL inhibitor (RANK-Fc) or saline.
- Bone density, femoral length, and mid-diaphyseal geometry were measured.
- Biomechanical testing and histological analysis of growth plates were performed.
- Fracture incidence was recorded in treated and control groups.
Main Results:
- RANKL inhibition increased bone density and stiffness in both oim/oim and wildtype mice.
- Geometric improvements were observed in oim/oim mice, including increased cortical thickness.
- RANKL inhibition preserved growth plate cartilage but did not significantly decrease fracture incidence in oim/oim mice.
Conclusions:
- RANKL inhibition shows potential for improving bone density and biomechanical properties in OI.
- The current therapeutic approach did not reduce fracture incidence, suggesting a need for earlier intervention.
- Further research is required to determine the optimal timing for RANKL inhibition therapy in OI.
