title: Differential effects of alendronate treatment on bone from growing osteogenesis imperfecta and wild-type mouse.
abstract: Bisphosphonates have been reported to decrease the number of fractures in children with osteogenesis imperfecta (OI). The current study sought to further explore bisphosphonate-associated bone changes in OI by investigating the effects of alendronate (ALN) treatment on bone mechanical and material properties in osteogenesis imperfecta (oim/oim) and wild-type (+/+) mice treated with 26-73 microg kg(-1) day(-1) of ALN for 8 weeks via subcutaneously implanted pumps. Femoral three-point bend tests to evaluate cortical bone were combined with geometric and material density analysis. Cortical and trabecular architecture of metaphyseal bone were histomorphometrically evaluated and material density assessed by quantitative backscattered electron imaging (qBEI). For the cortical oim/oim bone, which revealed principally inferior biomechanical properties compared to +/+ bone, ALN neither improved cortical strength or any other mechanical property, nor affected cortical width (Ct.Wi.) or material density. In contrast, for the +/+ mice, bone strength was enhanced (+22%, P < 0.05) though coupled with increased brittleness (+28%, P < 0.05). This mechanical improvement was associated with an increase in Ct.Wi. (+17.3%, P = 0.02) and a reduction in heterogeneity of cortical mineralization (Ca(Width), -4%, P = 0.04). In the metaphysis, ALN raised cancellous bone volume (BV/TV) significantly in oim/oim as well as in +/+ mice (+97%, P = 0.008 and +200%, P < 0.0001, respectively). This occurred without any change in either material density or trabecular thickness (Tb.Th.) in the oim/oim mice, while in the +/+ mice, material density increased slightly but significantly (+3%, P = 0.004), and Tb.Th. increased by 77% (P < 0.0001). Taken together, these results illustrate the differential effects of ALN on oim/oim vs. +/+ bone, as well as on specific skeletal sites, i.e., cortical vs. trabecular bone. ALN augmented the mechanical, geometrical, and material properties of +/+ cortical and trabecular bone, while the only observable improvement to the oim/oim bone was increased cancellous bone volume. This suggests that in this mouse model of OI, the previously demonstrated bisphosphonate-associated reduction in fractures is primarily attributable to increased metaphyseal bone mass.
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 4th Med. Department Hanusch Hospital, Kundratstr, 37, A-1120 Vienna, Austria.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Misof
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.forename: Todd
authors.initials: T
authors.lastname: Baldini
authors.forename: Cathleen L
authors.initials: CL
authors.lastname: Raggio
authors.forename: Vivien
authors.initials: V
authors.lastname: Zraick
authors.forename: Leon
authors.initials: L
authors.lastname: Root
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.forename: Peter
authors.initials: P
authors.lastname: Fratzl
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Camacho
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000517:prevention & control; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000503:physiopathology*
chemical_list: D019386:Alendronate