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Here, we demonstrate that osteolytic, osteosclerotic, and mixed bone metastasis uniquely modify human vertebral bone architecture and quality, affecting vertebral strength and stiffness. Multivariable analysis showed bone metastasis type dominates vertebral strength and stiffness changes, with neither age nor gender having an independent effect. In osteolytic vertebrae, bone architecture rarefaction, lower tissue mineral content and connectivity, and accumulation of advanced glycation end-products (AGEs) affected low vertebral strength and stiffness. In osteosclerotic vertebrae, high trabecular number and thickness but low AGEs, suggesting a high degree of bone remodeling, yielded high vertebral strength. Our study found that bone metastasis from prostate and breast primary cancers differentially impacted the osteosclerotic bone microenvironment, yielding altered bone architecture and accumulation of AGEs. These findings indicate that therapeutic approaches should target the restoration of bone structural integrity. \u00a9 2022 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4539","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T04:09:26Z","timestamp":1646626166000},"page":"896-907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Influence of Metastatic Bone Lesion Type and Tumor Origin on Human Vertebral Bone Architecture, Matrix Quality, and Mechanical Properties"],"prefix":"10.1093","volume":"37","author":[{"given":"Stacyann","family":"Bailey","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Institute for Applied Life Sciences, University of Massachusetts Amherst Amherst MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc 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