Investigation of a Rabbit Ulnar Loading Model for Atypical Fractures in Cortical Bone During Long-Term Bisphosphonate Treatment

Bisphosphonates are the most common pharmaceutical used to reduce fracture risk in postmenopausal women suffering from osteoporosis, but long-term bisphosphonate treatment has been associated with a rare adverse effect, atypical femoral fractures (AFFs). There is currently no suitable animal model to study the underlying pathophysiological mechanisms of AFFs, which remain unknown. Therefore, the objective of this project was to investigate a rabbit ulnar loading model for AFFs in cortical bone during long-term bisphosphonate treatment. The fatigue life and mechanical degradation of rabbit ulnae were measured during ex vivo loading of whole forelimbs in order to determine allowable limits for in vivo fatigue loading regimens. Post-fatigue mechanical testing of whole ulnae was determined to be impractical for use in the model due to the number of animals required and low sensitivity to fatigue damage. Therefore, a novel method was developed for measuring the plane strain fracture toughness of small animal bones at multiple locations along the diaphysis using arc-shaped tension specimens. This test method was able to produce highly repeatable measurements in replicates (coefficient of variation < 15%) and detect differences in fracture toughness due to small differences in tissue mineral density. Finally, an in vivo rabbit ulnar loading model was implemented to study AFFs in cortical bone during long-term bisphosphonate treatment. Several low body mass rabbits suffered displaced fractures during ulnar loading and were thus removed from the study. Treatment groups included a sham (control) and ovariectomized rabbits which were administered either vehicle (saline), a clinical dose, or a high dose of bisphosphonate (alendronate) over one year. Differences in tissue mineral density and fracture toughness between treatment groups were not statistically significant. Preliminary results from histology indicated that periosteal bone formation was stimulated in all treatment groups immediately following in vivo ulnar loading and returned to negligible basal levels within three months, as expected. Interestingly, intracortical remodeling (labelled osteons) was increased immediately following in vivo ulnar loading in the vehicle treatment group and not in the bisphosphonate treatment groups, but further analysis is needed.

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Year

Entry

2010

Burghardt AJ, Kazakia GJ, Sode M, de Papp AE, Link TM, Majumdar S. A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover. J Bone Miner Res. December 2010;25(12):2558-2571.

2008

Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW III. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. November 2008;43(5):798-812.

1995

Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC, Lombardi A, Shah RV, Hirsch LJ, Karpf DB; Group, Alendronate Phase III Osteoporosis Treatment Study. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. NEJM. November 30, 1995;333(22):1437-1443.

2010

Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MCH, Weinstein RS, Whyte M. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. November 2010;25(11):2267-2294.

1990

Burr DB, Milgrom C, Boyd RD, Higgins WL, Robin G, Radin EL. Experimental stress fractures of the tibia: biological and mechanical aetiology in rabbits. J Bone Joint Surg. May 1990;72B(3):370-375.