Non-Destructive Evaluation of the Effects of Combined Bisphosphonate and Photodynamic Therapy on Bone Strain in Metastatic Vertebrae Using Image Registration

Abstract

Skeletal metastases most frequently affect the vertebral column and may lead to severe consequences including fracture. Clinical management of skeletal metastases often utilizes a multimodal treatment approach, including bisphosphonates (BPs). Previous work has demonstrated the synergistic potential of photodynamic therapy (PDT) in combination with BP in treating osteolytic disease through structural, histologic, and destructive mechanical testing analyses. Recent work has developed and validated image-based methods that may be used to non-destructively determine mechanical stability in whole bones, and enable their use for additional (i.e. histologic) analysis. In this work we use an intensity-based 3D image registration technique to compare the strain patterns throughout untreated control and BP + PDT treated rnu/rnu rat spinal motion segments with osteolytic metastases. It was hypothesized that the combination treatment will reduce average and maximum strain values and restore the pattern of strain to that of healthy vertebrae. Mean, median, and 90th percentile strains in the control group were significantly higher than the treatment group. High strain areas in both groups were observed around the endplates; in the control group, large areas of high strains were also observed around the lesions and adjacent to the dorsal wall. Absence of high strains adjacent to the dorsal wall (similar to healthy vertebrae) may correspond to a reduced risk of burst fracture following BP + PDT therapy. This study demonstrates the application of non-destructive image analysis to quantify the positive mechanical effects of combined BP + PDT treatment in the metastatic spine.

Can micro-imaging based analysis methods quantify structural integrity of rat vertebrae with and without metastatic involvement?

“…Each subregion was similarly divided for two more iterations to yield the final level of analysis (Hojjat et al, 2011). The final registration yielded an overall deformation field, which was used to calculate the strain in each image block (Hardisty and Whyne, 2009;Hojjat et al, 2011). The axial strain values calculated from spatial displacement of the mCT voxels were quantified through the calculation of mean, median, 10th percentile, and 90th percentile strains, with negative values corresponding to compression.…”

“…L1-L3 vertebral motion segments were then dissected for further analysis. (Hojjat et al, 2011). Static axial loading was applied to achieve sufficient deformation to produce detectable strain in the L2 vertebra (based on the image registration algorithm (Hardisty and Whyne, 2009)) without causing fracture (45 N to 65 N based on qualitative assessment of the level of metastatic destruction visible within the unloaded scans).…”

“…The deformable registration initially divided the unloaded scan into 8 regions, which were registered to corresponding regions in the loaded scan using an affine transform (allowing translation, rotation, scaling and shearing). Each subregion was similarly divided for two more iterations to yield the final level of analysis (Hojjat et al, 2011). The final registration yielded an overall deformation field, which was used to calculate the strain in each image block (Hardisty and Whyne, 2009;Hojjat et al, 2011).…”

“…Spinal metastases can present as osteolytic, osteoblastic or with a mixed osteolytic/osteoblastic pattern of involvement. Non-invasive quantitative evaluation of the effect of osteolytic spinal metastases on biomechanical stability has been conducted through image-based strain measurement (Hardisty and Whyne, 2009;Hardisty et al, 2010;Hojjat et al, 2011), structural rigidity analyses (Snyder et al, 2009;Entezari et al, 2011;Cory et al, 2010) and continuum-level finite element (FE) modeling (Hardisty and Whyne, 2009;Whyne et al, 2003;Eswaran et al, 2007;Ito et al, 2002;Kim et al, 2007;O'Reilly and Whyne, 2008). However, to date, limited work has been completed to directly compare these analytical tools or been applied to vertebrae with more complex mixed metastatic disease.…”

Animal Cancer Models of Skeletal Metastasis

“…Blocking RANKL has been shown to inhibit breast and prostate cancer-induced osteoclastogenesis and tumor development, growth and progression in bone 14. Bisphosphonates have also been shown to potently inhibit osteoclast-mediated bone resorption and can reduce skeletal tumor burden and inhibit the formation of bone metastases in vivo, as well as demonstrating clinical application in the treatment of patients with osteolytic bone metastases 31,34,38,39. Photodynamic therapy, which causes oxygen toxicity and tumor cell necrosis by light activation of an administered photosensitizer accumulated in tumor tissue, has been shown to inhibit tumor growth in several rat models of human breast cancer vertebral metastases, with additional improvement in the structural integrity of vertebral bone when used in conjunction with bisphosphonates 38–40…”