title: Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate.
abstract: Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
authors.forename: Cory N
authors.initials: CN
authors.lastname: Meixner
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Aref
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
authors.forename: Aryaman
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
authors.forename: Erin M B
authors.initials: EMB
authors.lastname: McNerny
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Brown
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wallace
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA. matallen@iupui.edu.|Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. matallen@iupui.edu.|Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA. matallen@iupui.edu.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA. matallen@iupui.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D005269:Femur / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D020849:Raloxifene Hydrochloride; D000077211:Zoledronic Acid
keywords: Bisphosphonate; Bone quality; Mechanical properties; SERMs