title: Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA. Jeff.Meganck@caliperls.com
authors.forename: J A
authors.initials: JA
authors.lastname: Meganck
authors.forename: D L
authors.initials: DL
authors.lastname: Begun
authors.forename: J D
authors.initials: JD
authors.lastname: McElderry
authors.forename: A
authors.initials: A
authors.lastname: Swick
authors.forename: K M
authors.initials: KM
authors.lastname: Kozloff
authors.forename: S A
authors.initials: SA
authors.lastname: Goldstein
authors.forename: M D
authors.initials: MD
authors.lastname: Morris
authors.forename: J C
authors.initials: JC
authors.lastname: Marini
authors.forename: M S
authors.initials: MS
authors.lastname: Caird
mesh_terms: D019386:Alendronate / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002146:Bony Callus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D003720:Densitometry; D004195:Disease Models, Animal; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D005838:Genotype; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D013059:Spectrum Analysis, Raman; D055114:X-Ray Microtomography
chemical_list: D019386:Alendronate
keywords: Bisphosphonates; Bone; Fracture repair; Osteogenesis imperfecta; Rodent