Browsing by Author "Whittier, Danielle Elizabeth Wein"

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    The assessment of fragility fracture risk using HR-pQCT as a novel tool for diagnosis of osteoporosis
    (2021-08) Whittier, Danielle Elizabeth Wein; Boyd, Steven Kyle; Schneider, Prism Steorra; Manske, Sarah Lynn; Edwards, William Brent; Forkert, Nils Daniel; Hallgrimsson, Benedikt; Jepsen, Karl
    Osteoporosis is a systemic skeletal disease, characterized by reduced bone density and deterioration of bone microarchitecture, leading to increased fracture risk. However, current diagnosis using dual-energy X-ray absorptiometry (DXA) only accounts for density and consequently fails to capture most individuals who fracture. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a medical imaging modality capable of characterizing three-dimensional bone microarchitecture at peripheral skeletal sites, and has demonstrated that bone microarchitecture can improve prediction of fracture risk. However, to date the improvement is modest, as interpretation of the interaction between fracture and the numerous parameters provided by HR-pQCT is complex. The objective of this dissertation was to elucidate the key microarchitectural characteristics that underpin bone fragility, and use these insights to improve assessment of fracture risk with HR-pQCT. First, reference data in the form of centile curves was established for HR-pQCT parameters using a population-based cohort (n=1,236, age 18–90 years), and a new intuitive parameter called void space was developed to capture localized regions of bone loss in HR-pQCT images. In a separate prospective multi-center cohort (n=5,873, age 40–90 years), unsupervised machine learning was implemented to identify common groupings (i.e., phenotypes) of bone microarchitecture in older adults. Three phenotypes were identified and characterized as low density, structurally impaired, and healthy bone, where the low density phenotype had the strongest association with incident osteoporotic fractures (hazard ratio = 3.28). Using the same cohort, a fracture risk assessment tool, called µFRAC, was developed using supervised machine learning methods to provide a 5-year risk of major osteoporotic fracture based on HR-pQCT parameters, and was demonstrated to significantly outperform DXA in predicting fracture risk. Finally, a new retrospective cohort of patients with fragility fractures at the hip (n=108, age 56–96 years) was used to characterize bone fragility. Hip fracture patients were significantly associated with the low density phenotype and had bone void spaces that were 2–3 times larger than controls. Together, these findings provide insight into the characteristics of bone that lead to osteoporotic fractures and introduces tools that enable insightful interpretation of HR-pQCT data for clinical use.
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    The Influence of Ovariohysterectomy and Bisphosphonate Treatment on the Fatigue Behaviour of Whole-Bone and Bone Tissue
    (2024-04-07) Angulo Castro, Ana Gloria; Edwards, William Brent; Manske, Sarah Lynn; Krawetz, Roman; Whittier, Danielle Elizabeth Wein
    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.