title: Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a genetic disease of Type I collagen and collagen-associated pathways that results in brittle bone behavior characterized by fracture and reduced mechanical properties. Based on previous work in our laboratory showing that raloxifene (RAL) can significantly improve bone mechanical properties through non-cellular mechanisms, we hypothesized that raloxifene would improve the mechanical properties of OI bone. In experiment 1, tibiae from female wild type (WT) and homozygous oim mice were subjected to in vitro soaking in RAL followed by mechanical tests. RAL soaking resulted in significantly higher post-yield displacement (+75% in WT, +472% in oim; p<0.004), with no effect on ultimate load or stiffness, in both WT and oim animals. In experiment 2, eight-week old WT and oim male mice were treated for eight weeks with saline vehicle (VEH) or RAL. Endpoint measures included assessment of in vivo skeletal fractures, bone density/geometry and mechanical properties. In vivo skeletal fractures of the femora, assessed by micro CT imaging, were significantly lower in oim-RAL (20%) compared to oim-VEH (48%, p=0.047). RAL led to significantly higher DXA-based BMD (p<0.01) and CT-based trabecular BV/TV in both WT and oim animals compared to those treated with VEH. Fracture toughness of the femora was lower in oim mice compared to WT and improved with RAL in both genotypes. These results suggest that raloxifene reduces the incidence of fracture in this mouse model of oim. Furthermore, they suggest that raloxifene's effects may be the result of both cellular (increased bone mass) and non-cellular (presumably changes in hydration) mechanisms, raising the possibility of using raloxifene, or related compounds, as a new approach for treating bone fragility associated with OI.
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States.
authors.forename: Alycia G
authors.initials: AG
authors.lastname: Berman
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States; Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wallace
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Bart
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States; Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: matallen@iupui.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D008297:Male; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000150:complications* / Q000000981:diagnostic imaging; D053245:RANK Ligand / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage* / Q000494:pharmacology; D014057:Tomography, X-Ray Computed
chemical_list: D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D020849:Raloxifene Hydrochloride
keywords: Bone mechanical properties; OI; Oim/oim; SERM