One in nine women develop breast cancer and one in eleven men develop prostate cancer. At autopsy 84 percent of these cancer patients have skeletal metastases. Pathologic fracture occurs in 30 percent of skeletal metastases causing intractable pain, loss of function and other morbidities. It is difficult for physicians to predict whether the metastatic tumor has weakened the bone sufficiently to lead to fracture. Current radiographic guidelines for estimating fracture risk are poorly defined and not specific. Structural rigidity measured using quantitative computed tomography (QCT) has been validated in controlled laboratory experiments for predicting bone fracture, and it appears to be sensitive and specific. We propose to use this new technique to predict fracture risk among prostate and breast cancer patients with skeletal metastases, and test whether it is more specific than and as sensitive as current clinical guidelines. To compare specificity, a prospective, observational study will be conducted: fracture risk will be assessed when subjects enroll in the study, and they will be subsequently followed to observe the occurrence of fracture while receiving standard clinical care. To compare sensitivity, a case-control study will be conducted to compare the structural rigidities of subjects who fracture to those who do not. To determine if increased bone structural rigidity is related to improved functional performance among cancer patients with skeletal metastases, a validated, site specific, functional outcomes instrument will be administered to each patient, and correlated with the bone structural rigidity measured by QCT. Since bone formation and destruction by tumor cells appears to be mediated by osteoblasts and osteoclasts, our analysis assumes that the density-modulus relationships determined for normal bone are applicable metastatic bone. This assumption will be tested on biopsy specimens from skeletal metastases in patients that fracture and require surgery. The specimens will be imaged using micro-computed tomography to measure apparent bone density and mechanically tested measure elastic modulus. The elastic modulus of the osteoblastic tissue itself will also be measured using nano-indentation testing. Finally, parametric analysis will be performed on existing, validated finite element models of femurs by systematically varying size, location and material properties of the tumor, and the results will be correlated to the results predicted by structural analysis. Therefore, the proposed studies will clinically and analytically establish efficacy of structural rigidity measured from QCT in predicting risk of pathologic fracture. With better fracture prediction, physicians will be able to plan treatments accordingly, preventing morbidities associated with bone fracture among breast and prostate cancer patients.
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