title: The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta.
abstract: Currently, the standard treatment for osteogenesis imperfecta (OI) is bisphosphonate therapy. Recent studies, however, have shown delayed healing of osteotomies in a subset of OI patients treated with such agents. The current study sought to determine the effects of another therapy, RANKL inhibition, on bone healing and bone strength in the growing oim/oim mouse, a model of moderate to severe OI. Mice [73 oim/oim and 69 wild-type (WT)] were injected twice weekly with either soluble murine RANK (RANK-Fc) (1.5 mg/kg) or saline beginning at 6 weeks of age. At 8 weeks of age, the animals underwent transverse mid-diaphyseal osteotomies of the right femur. Therapy was continued until sacrifice at 2, 3, 4, or 6 weeks postfracture. At 6 weeks post-fracture, greater callus area (6.59 +/- 3.78 mm(2) vs. 2.67 +/- 2.05 mm(2), p = 0.003) and increased radiographic intensity (mineral density) (0.48 +/- 0.14 vs. 0.30 +/- 0.80, p = 0.005) were found in the RANK-Fc versus saline oim/oim group, indicating a delay in callus remodeling. Despite this delay, mechanical tests at 6 weeks postfracture revealed no significant differences in whole bone properties of stiffness and failure moment. Further, RANKL inhibition resulted in a greater failure moment and greater work to failure for the nonfractured contralateral WT bones compared to the nonfractured saline WT bones. Together, these results demonstrate that RANKL inhibition does not adversely affect the mechanical properties of healing bone in the oim/oim mice, and is associated with increased strength in intact bone in the WT mice.
authors.affiliation: Research Division, Hospital for Special Surgery, 535 E. 70th Street, New York, New York 10021, USA.
authors.forename: Demetris
authors.initials: D
authors.lastname: Delos
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Ricciardi
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Myers
authors.forename: Mathias P G
authors.initials: MP
authors.lastname: Bostrom
authors.forename: Nancy Pleshko
authors.initials: NP
authors.lastname: Camacho
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017102:Fracture Healing; D006720:Homozygote; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D013314:Stress, Mechanical
chemical_list: D053245:RANK Ligand