title: Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD).
abstract: The etiology of Adynamic Bone Disease (ABD) is poorly understood but the hallmark of ABD is a lack of bone turnover. ABD occurs in renal osteodystrophy (ROD) and is suspected to occur in elderly patients on long-term anti-resorptive therapy. A major clinical concern of ABD is diminished bone quality and an increased fracture risk. To our knowledge, experimental animal models for ABD other than ROD-ABD have not been developed or studied. The objectives of this study were to develop a mouse model of ABD without the complications of renal ablation, and to characterize changes in bone quality in ABD relative to controls. To re-create the adynamic bone condition, 4-month old female Col2.3Δtk mice were treated with ganciclovir to specifically ablate osteoblasts, and pamidronate was used to inhibit osteoclastic resorption. Four groups of animals were used to characterize bone quality in ABD: Normal bone controls, No Formation controls, No Resorption controls, and an Adynamic group. After a 6-week treatment period, the animals were sacrificed and the bones were harvested for analyses. Bone quality assessments were conducted using established techniques including bone histology, quantitative backscattered electron imaging (qBEI), dual energy X-ray absorptiometry (DXA), microcomputed tomography (microCT), and biomechanical testing. Histomorphometry confirmed osteoblast-related hallmarks of ABD in our mouse model. Bone formation was near complete suppression in the No Formation and Adynamic specimens. Inhibition of bone resorption in the Adynamic group was confirmed by tartrate-resistant acid phosphatase (TRAP) stain. Normal bone mineral density and architecture were maintained in the Adynamic group, whereas the No Formation group showed a reduction in bone mineral content and trabecular thickness relative to the Adynamic group. As expected, the No Formation group had a more hypomineralized profile and the Adynamic group had a higher mean mineralization profile that is similar to suppressed bone turnover in human. This data confirms successful replication of the adynamic bone condition in a mouse without the complication of renal ablation. Our approach is the first model of ABD that uses pharmacological manipulation in a transgenic mouse to mimic the bone cellular dynamics observed in the human ABD condition. We plan to use our mouse model to investigate the adynamic bone condition in aging and to study changes to bone quality and fracture risk as a consequence of over-suppressed bone turnover.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Adeline H
authors.initials: AH
authors.lastname: Ng
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Willett
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address: grynpas@lunenfeld.on.ca.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Grynpas
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001847:Bone Diseases / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005265:Femoral Neck Fractures / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D015203:Reproducibility of Results; D013131:Spine / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D055114:X-Ray Microtomography
keywords: Adynamic bone disease; Biomechanics; Bone quality; Low bone turnover; Mouse model