ICCBH2015 Oral Communications (1) (22 abstracts)
1Hospital for Special Surgery, New York, New York, USA; 2Temple University, Philadelphia, Pennsylvania, USA; 3University of Michigan, Ann Arbor, Michigan, USA.
Objective: The purpose of this ongoing study was to determine whether osteogenesis imperfecta (OI) patients entering adulthood should continue with bisphosphonate therapy or would benefit from switching to a RANKL blockade therapy. To address this question, we used a mouse model of type-III OI.
Methods: Under IACUC-approval, +/+ and oim/oim mice were treated from 226 weeks (n=20/treatment/genotype) with either 1) saline 24 weeks; 2) saline 12 weeks then RANK-Fc 12 weeks (saline+RANK-Fc); 3) RANK-Fc 24 weeks; 4) ALN 12 weeks then RANK-Fc 12 weeks; or 5) ALN 24 weeks (ALN: 0.21 mg/kg per dose; RANK-Fc 1.5 mg/kg per dose). Groups 3, 4, 5 defined as long-term treatment. Animals were faxitroned at 14 and 26 weeks; fractures were counted in all long bones and five vertebrae into the tail. Femurs and humeri were scanned and evaluated using micro-computed tomography (μCT) and were mechanically tested by three-point bending. Demineralized femurs and tibias were evaluated histologically. Statistics: mixed linear model adjusted for body size; P<0.05 considered significant.
Results: All treatments reduced fracture incidence at 14 and 26 weeks. From 14 to 26 weeks no new fractures occurred in the long-term treatment groups; saline-treated mice averaged 0.9 new fractures and saline+RANK-Fc averaged 0.3 new fractures.
Biomechanics: Saline-treated +/+ mice sustained higher loads, were more ductile, and had a greater work-to-fracture compared to oim/oim mice. Long-term treated +/+ bones were more brittle compared to saline-treatment. No changes were found in oim/oim mice.
μCT: Saline-treated +/+ had greater cortical BV/TV compared to oim/oim. oim/oim long-term treatment increased cortical BV/TV compared to saline-treatment. Trabecular bone mass increased with long-term treatment in +/+ and oim/oim mice due to increased trabecular number and decreased separation.
Conclusion: Both anti-resorptives, in succession or alone, significantly reduced fracture incidence but did not improve mechanical properties in oim/oim. Cortical gains observed by μCT did not correct oim/oim values to +/+. All mechanical improvements in +/+ mice were at the expense of brittleness. The anti-resorptive therapies mainly affected trabecular bone mass in oim/oim, which was not verifiable by three-point bending. Based on observations at the tissue level, reduction in fracture incidence is likely due to enhanced bone mass and corticalization of trabecular bone, an effect that was not sex-, genotype-, or treatment-specific.
Disclosure: We received drug and money for this study from Amgen. Dr Boskey owns stock in Amgen. Dr Raggio sits on the medical board for the Osteogenesis Imperfecta Foundation.