Nanoscale or microscale heterogeneity, i.e., spatial variation in material properties, is emerging as a potentially important contributor to bone fracture resistance because of its putative contribution to tissue-level toughening mechanisms. However, the current understanding of the contribution of heterogeneity of material properties to fracture risk is still in an incipient stage. Several projects relate bone tissue material heterogeneity to fracture incidence.

Bone quality in patients with typical and atypical osteoporotic hip fractures
Key findings: This project builds on a key finding in which we showed that postmenopausal women with fragility fractures who received bisphosphonate treatment for osteoporosis had narrower distributions of bone tissue compositional properties than bisphosphonate-naïve patients. The subset of patients with AFFs had greater mineral content than those with typical fragility fractures.

Next, we extended our prior work to identify spectroscopic and biochemical markers of bone quality in an expanded cohort of patients with AFFs. We demonstrated that women with AFFs had harder, more mineralized cortical bone than those with typical fragility fractures who also used bisphosphonates, and the bone tissue of those who used bisphosphonates had decreased fracture toughness, with lower crack-initiation toughness and less crack deflection at microstructural interfaces after long-term use compared to that of bisphosphonate-naïve patients [Lloyd et al.2017].Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.

Impact Our findings identify key mechanisms by which long-term bisphosphonate treatment reduces the resistance of bone tissue to crack propagation and contribute to atypical fractures. By elucidating these mechanisms, we inform guidelines for timing and duration of treatment for patients at risk for fragility fractures.

Crack paths (in red) in uCT images and SEM images of propagated cracks in cortical bone from patients with differing fracture morphologies and bisphosphonate (BIS) treatment histories (A-D) exemplify reduced crack tortuosity in BIS-treated patients (E) and suggest less deviation at osteonal interfaces (Scale bars: 50 um) [Lloyd et al 2017].

Current and future work We are currently characterizing distributions of material properties in cortical bone from postmenopausal women with and without histories of atypical fractures and bisphosphonate therapy, and we have demonstrated that the most brittle bone (from patients with atypical femoral fractures (AFFs)) had trends in compositional heterogeneity that depended on the length scale of assessment. Our data support the few existing studies that have shown that nanoscale heterogeneity increases toughness by dissipating strain energy, but that larger scale heterogeneity decreases fracture resistance by acting as stress concentrations and suggest that an optimal characteristic length scale of heterogeneity in bone, below 1 µm, may be key to increased fracture resistance.

To further understand the role of long-term bisphosphonate therapy on toughness, we are collaborating with Dr. Ani Ural’s group at Villanova University to generate patient-specific, fracture mechanics-based finite element models of our human patient specimens. Outcomes from the finite element model include crack volume and damage volume. Model inputs can be altered in silico to elucidate the role of the distribution of microstructure and material properties on fracture resistance of bone tissue at the micron scale.

Ani Ural, Villanova University
Robert Ritchie, UC Berkeley
Joseph Lane, Hospital for Special Surgery