title: Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli.
abstract: Long-term warfarin use has been reported to increase fracture risk of rib and vertebra but not hip in elderly patients, but the mechanisms remain unknown. We hypothesized that warfarin would impair bone material quality but could not weaken bone strength under conditions with higher mechanical stimuli. To test this hypothesis, rats were randomized to vehicle or warfarin group at 4 weeks of age and subsequently weight matched into a sedentary or jumping exercise group at 12 weeks of age. At 6 months of age, osteocalcin content, bone mineral density (BMD), mineral size, material properties, morphological parameters, and biomechanical properties of cortical bones were evaluated. In order to seek evidence for a common mechanism of action, effects of nucleation rate of mineral crystals on their rigidity were also investigated using computer simulation. In humeral cortical bones, warfarin did not change BMD, but markedly decreased osteocalcin content, diminished mineral size, and impaired material hardness. Consistent with these results, our computer-simulation model showed that osteocalcin-induced delay of mineral crystal nucleation decreased mineral formation rate, increased mean and distribution of mineral sizes, and strengthened mineral rigidity. In tibial cortical bones, warfarin decreased material ultimate stress; however, under jumping exercise, warfarin increased cross-sectional total and bone areas of these tibiae and completely maintained their biomechanical properties including work to failure. Collectively, our findings suggest that long-term warfarin therapy weakens rib and vertebra by impairing cortical bone material quality due to a marked decrease in osteocalcin content but could not reduce hip strength through compensatory adaptation of cortical bone structure to higher mechanical stimuli.
authors.affiliation: Department of Orthopaedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Yamaguchi 755-8505, Japan. tsugiyama@rvc.ac.uk
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takaki
authors.forename: Kenya
authors.initials: K
authors.lastname: Sakanaka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sadamaru
authors.forename: Koji
authors.initials: K
authors.lastname: Mori
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kato
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Taguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects*; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003198:Computer Simulation; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D005260:Female; D050723:Fractures, Bone / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009068:Movement; D015675:Osteocalcin / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012306:Risk; D013314:Stress, Mechanical; D013997:Time Factors; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D015675:Osteocalcin; D014859:Warfarin