The Influence of Ovariohysterectomy and Bisphosphonate Treatment on the Fatigue Behaviour of Whole-Bone and Bone Tissue

Bisphosphonates are the current front-line therapy for osteoporosis due to their effectiveness at increasing bone density and strength; nonetheless, their long-term use has been associated with rare cases of atypical femoral fracture (AFF). The mechanistic link between bisphosphonates and AFFs is unclear, but it has been hypothesized that the potent antiresorptive mechanism of bisphosphonates impairs fatigue resistance through alterations to bone material properties. The purpose of this thesis was to quantify the influence of high-dose bisphosphonate therapy on the mechanical fatigue properties of bone at different length scales using an ovariohysterectomized (OVH) and a gonad-intact (GDI) rabbit model. A total of 12 OVH and 12 GDI New Zealand White rabbits were treated for six months via subcutaneous injection with 1 ml/kg vehicle saline (VEH) or 0.15 mg/kg alendronate (ALN). Bone mineral density (BMD) and bone mineral content (BMC) were assessed longitudinally via dual-energy x-ray absorptiometry (DXA). After treatment, mechanical testing was used to determine the fatigue life of cortical bone tissue and whole-bone from lower limbs as well as the ultimate strength in lumbar vertebrae. High-resolution imaging and density measurements were performed to evaluate bone composition and microarchitecture, while finite element models were generated to predict whole-bone strain. No differences between treatment groups were observed in microarchitecture, density measurements, strain distributions or fatigue life of bone tissue and whole-bone. Differences between VEH and ALN in the vertebrae of GDI rabbits were not significant but the ALN group in OVH rabbits demonstrated significantly higher vertebrae BMD (p < 0.001), BMC (p = 0.005), and ultimate strength (p = 0.012) in addition to greater total BMD in both the femur (p = 0.002) and the tibia (p = 0.003). To summarize, this study found no detrimental effects of bisphosphonate treatment that could explain the relationship between AFFs and bisphosphonates, but extended treatment durations may be warranted

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Year

Entry

2000

Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. November 2000;27(5):687-694.

2005

Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. March 2005;90(3):1294-1301.

2010

Gourion-Arsiquaud S, Allen MR, Burr DB, Vashishth D, Tang SY, Boskey AL. Bisphosphonate treatment modifies canine bone mineral and matrix properties and their heterogeneity. Bone. March 2010;46(3):666-672.

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.

1997

Yeni YN, Brown CU, Wang Z, Norman TL. The influence of bone morphology on fracture toughness of the human femur and tibia. Bone. November 1997;21(4):453-459.