Improved palliative management of established metastatic osseous lesions has resulted in marked increases both in survival times and in the incidence of metastatic lesions and subsequent pathologic fractures. The assessment and treatment of established osseous metastases is thus an increasingly important aspect of the clinical management of cancer patients. However, there are currently available only the most qualitative of clinical guidelines for assessing the increased fracture risk associated with metastatic lesions and thus for determining the appropriate time for prophylactic stabilization of impending fractures. We have in the previous funding period explored the biomechanics of diaphyseal osseous metastatic lesions and demonstrated far more severe strength losses (up to 85%) than had been previously thought to occur with bone defects corresponding to established clinical guidelines for prophylactic stabilization of impending fractures. We have also developed the first preliminary guidelines for increased fracture risk associated with lytic lesions of the proximal femur and shown that planar radiographs cannot provide sufficiently detailed information on lesion geometry to make informed assessments of fracture risk. We now propose to extend our studies to intertrochanteric lesions of the femur and to the vertebrae. We will continue to use a combination of mathematical modeling based on the finite element method and in-vitro testing to establish key features of lesion geometry and loading which incur marked increases in fracture risk. We will also pursue preliminary observations that the mechanical properties of cortical and trabecular bone are severely degraded in areas immediately adjacent to osseous metastases and that this factor can have marked influences on bone strength. And finally, to begin to build stronger links to the clinical community, we will undertake a limited prospective study of patients with metastatic lesions to the femoral shaft, proximal femur, and vertebral body. Collaborating orthopaedists and radiation therapists will order QCT scans according to our protocols and provide us with CT tapes to determine actual lesion geometries for comparison with our idealized models. We will also attempt to develop quantitative techniques to estimate local bone mechanical properties around typical lesions. Based on these findings, we hope to provide an integrated set of clinical guidelines which may be used to estimate fracture risk associated with metastatic defects of diaphyseal bone, the proximal femur, and the vertebral body. We will then design a controlled prospective clinical trail of these guidelines to be tested as part of a subsequent renewal application.

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National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Beth Israel Deaconess Medical Center
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Leong, Natalie L; Anderson, Megan E; Gebhardt, Mark C et al. (2010) Computed tomography-based structural analysis for predicting fracture risk in children with benign skeletal neoplasms: comparison of specificity with that of plain radiographs. J Bone Joint Surg Am 92:1827-33
Snyder, Brian D; Hauser-Kara, Diana A; Hipp, John A et al. (2006) Predicting fracture through benign skeletal lesions with quantitative computed tomography. J Bone Joint Surg Am 88:55-70
Hong, James; Cabe, Greg D; Tedrow, John R et al. (2004) Failure of trabecular bone with simulated lytic defects can be predicted non-invasively by structural analysis. J Orthop Res 22:479-86
Hong, J; Hipp, J A; Mulkern, R V et al. (2000) Magnetic resonance imaging measurements of bone density and cross-sectional geometry. Calcif Tissue Int 66:74-8
Windhagen, H; Hipp, J A; Hayes, W C (2000) Postfracture instability of vertebrae with simulated defects can be predicted from computed tomography data. Spine (Phila Pa 1976) 25:1775-81
Whealan, K M; Kwak, S D; Tedrow, J R et al. (2000) Noninvasive imaging predicts failure load of the spine with simulated osteolytic defects. J Bone Joint Surg Am 82:1240-51
Michaeli, D A; Inoue, K; Hayes, W C et al. (1999) Density predicts the activity-dependent failure load of proximal femora with defects. Skeletal Radiol 28:90-5
Windhagen, H J; Hipp, J A; Silva, M J et al. (1997) Predicting failure of thoracic vertebrae with simulated and actual metastatic defects. Clin Orthop Relat Res :313-9
Hipp, J A; Jansujwicz, A; Simmons, C A et al. (1996) Trabecular bone morphology from micro-magnetic resonance imaging. J Bone Miner Res 11:286-97
Cheal, E J; Hipp, J A; Hayes, W C (1993) Evaluation of finite element analysis for prediction of the strength reduction due to metastatic lesions in the femoral neck. J Biomech 26:251-64

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