title: Higher doses of bisphosphonates further improve bone mass, architecture, and strength but not the tissue material properties in aged rats.
abstract: We report the results of a series of experiments designed to determine the effects of ibandronate (Ibn) and risedronate (Ris) on a number of bone quality parameters in aged osteopenic rats to explain how bone material and bone mass may be affected by the dose of bisphosphonates (BP) and contribute to their anti-fracture efficacy. Eighteen-month old female rats underwent either ovariectomy or sham surgery. The ovariectomized (OVX) groups were left untreated for 2 months to develop osteopenia. Treatments started at 20 months of age as follows: sham and OVX control (treated with saline), OVX + risedronate 30 and 90 (30 or 90 microg/kg/dose), and OVX + ibandronate 30 and 90 (30 or 90 microg/kg/dose). The treatments were given monthly for 4 months by subcutaneous injection. At sacrifice at 24 months of age the 4th lumbar vertebra was used for microCT scans (bone mass, architecture, and degree of mineralization of bone, DMB) and histomorphometry, and the 6th lumbar vertebra, tibia, and femur were collected for biomechanical testing to determine bone structural and material strength, cortical fracture toughness, and tissue elastic modulus. The compression testing of the vertebral bodies (LVB6) was simulated using finite-element analysis (FEA) to also estimate the bone structural stiffness. Both Ibn and Ris dose-dependently increased bone mass and improved vertebral bone microarchitecture and mechanical properties compared to OVX control. Estimates of vertebral maximum stress from FEA were correlated with vertebral maximum load (r=0.5, p<0.001) and maximum stress (r=0.4, p<0.005) measured experimentally. Tibial bone bending modulus and cortical strength increased compared to OVX with both BP but no dose-dependent effect was observed. DMB and elastic modulus of trabecular bone were improved with Ibn 30 compared to OVX but were not affected in other BP-treated groups. DMB of tibial cortical bone showed no change with BP treatments. The fracture toughness examined in midshaft femurs did not change with BP even with the higher doses. In summary, the anti-fracture efficacy of BP is largely due to their preservation of bone mass and while the higher doses further improve the bone structural properties do not improve the localized bone material characteristics such as tissue strength, elastic modulus, and cortical toughness.
authors.affiliation: Department of Internal Medicine, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahnazari
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: WeiWei
authors.initials: W
authors.lastname: Dai
authors.forename: Bob
authors.initials: B
authors.lastname: Wang
authors.forename: Sophi S
authors.initials: SS
authors.lastname: Ionova-Martin
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ritchie
authors.forename: Daniel
authors.initials: D
authors.lastname: Heeren
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Burghardt
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Nicolella
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kimiecik
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D019245:Compressive Strength / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D020342:Finite Element Analysis; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates