title: Does suppression of bone turnover impair mechanical properties by allowing microdamage accumulation?
abstract: One plausible purpose of bone turnover is to repair bone microdamage. We hypothesized that suppression of bone turnover impairs bone quality by allowing accumulation of microdamage. We investigated the effect of high-dose etidronate (EHDP) on bone's mechanical properties and microdamage accumulation. Skeletally mature beagles, 1-2 years old at the beginning of the study, were treated with daily injections of vehicle or EHDP at 0.5 mg/kg per day or 5.0 mg/kg per day for 1 year. X-rays were taken at baseline and monthly from 7 to 12 months. Bones were taken upon sacrifice and biomechanical tests, histomorphometry, and microdamage analyses were performed. Fractures of ribs and/or thoracic spinous processes were found in 10 of 11 dogs treated with the higher dose EHDP. Only one fracture of a thoracic spinous process was found in dogs treated with the lower dose EHDP, and no fractures were found in the vehicle controls. Biomechanical tests showed reduced mechanical strength in ribs and lumbar vertebrae, but not in the femoral diaphysis or thoracic spinous process in the higher dose EHDP group. Histomorphometric measurements showed a significant reduction of cancellous bone turnover in both EHDP-treated groups compared with controls. In dogs treated with the higher dose EHDP, activation frequency was reduced to zero in both cortical and cancellous bone. Osteoid volume increased significantly, especially in trabecular bone, resulting in reduced mineralized bone volume in the higher dose EHDP group. Microcrack numerical density (Cr.Dn) increased significantly only in the lumbar vertebral body in the higher dose EHDP group, but not in the rib or thoracic spinous process where fractures occurred. These findings show that suppression of bone turnover using high doses of EHDP is associated with fractures of the ribs and spinous processes in dogs. This is most likely the result of excessive amounts of unmineralized bone produced by the inhibition of mineralization at these high doses, rather than by the accumulation of microdamage.
authors.affiliation: Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis 46285, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hirano
authors.forename: C H
authors.initials: CH
authors.lastname: Turner
authors.forename: M R
authors.initials: MR
authors.lastname: Forwood
authors.forename: C C
authors.initials: CC
authors.lastname: Johnston
authors.forename: D B
authors.initials: DB
authors.lastname: Burr
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology*; D001842:Bone and Bones / Q000473:pathology* / Q000502:physiology*; D004285:Dogs; D004548:Elasticity / Q000187:drug effects; D012968:Etidronic Acid / Q000494:pharmacology*; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced
chemical_list: D012968:Etidronic Acid