Material properties of trans-iliac bone biopsies, as assessed by nanoindentation (NI), in patients with and without atypical femur fractures (AFF) on long-term bisphosphonate (BP) therapy for low bone density: Preliminary results of a prospective nested case-controlled study

Objective & Background: AFFs are now a well-established complication of long-term BP therapy, but its pathogenesis still remains unclear. Although severe suppression of bone turnover (SSBT), as we initial proposed as a major contributor, many patients with SSBT as defined may not develop AFF. Accordingly, we studied the material properties of iliac bone biopsy specimens by NI in 20 women (10 with and 10 without AFF matched for age and race). Methods: Nanoindentation data were analyzed using a mixed model ANOVA (SAS 9.4) for 20 subjects, 10 subjects with atypical femur fractures, and 10 without atypical fractures. The model was fit to using either elastic modulus, contact hardness, or resistance to plastic deformation as a function of bone type (cortical - 1, or trabecular -2), femur fracture (no fracture - 0, or fracture - 1) and all first order interactions between bone type and fracture. Post hoc analysis of the least squared means were analyzed and statistically significant differences we reported if p≤0.05. Results: Cortical bone with atypical femur fractures has a higher elastic modulus (is stiffer) than cortical bone without atypical fractures (ECB=17.49±0.16 GPa, ECB=16.56±0.15 GPa p=0.0005). This result suggests that bone with an atypical fracture has a higher level of mineralization, which implies that it has not been recently remodeled and therefore more likely to accumulate microdamage that would contribute to failure. Furthermore, for bone with an atypical femur fracture, the trabecular bone had a significantly lower elastic modulus than that of cortical bone (ETB=16.19±0.17 GPa, ECB=17.49±0.16 GPa p=0.0001). The trabecular bone with a fracture had the lowest mean value elastic modulus that we tested. This result suggests that the trabecular bone in the fracture case may not provide sufficient internal structural rigidity to accommodate applied loads, thus contributing to the overall failure of the bone. For bone with atypical fractures, cortical bone resistance to plastic deformation was significantly less than trabecular bone (HCB=1.97 ± 0.028 GPa, HTB =2.19±0.030 GPa p\u3c0.0001). This result further suggests that the integrity of the cortical bone has been compromised by microdamage, which may contribute to the atypical fracture of the bone. Conclusions: For bone that exhibits atypical femur fractures, the primary damage at the microstructural level appears to be associated with microdamage accumulation within the cortical tissue as evidenced by changes in the elastic modulus and decreased resistance to plastic deformation. In general, the trabecular bone does not appear to be as strongly affected by microdamage