Nickan Research Institute Journal of Parathyroid Disease 2345-6558 14 1 2026 01 01 When tumors break bones; emerging paradigms in the pathogenesis and prevention of oncologic skeletal fractures e13312 e13312 10.34172/jpd.2025.13312 EN Sina Salem Ahim https://orcid.org/0009-0008-2452-434X Zahra Ganjali https://orcid.org/0009-0004-0171-0503 Reyhaneh Hassanshahi https://orcid.org/0009-0003-1689-9639 Zahed Karimi https://orcid.org/0000-0002-2304-6779 Mobin Forghan https://orcid.org/0009-0002-9100-9854 Amir Alilou https://orcid.org/0009-0003-5208-4664 Amin Norouzbeygi https://orcid.org/0000-0001-9728-5740 Hojjat Eghbali Jelodar https://orcid.org/0009-0008-6949-0374 Journal Article 10.34172/jpd.2025.13312 2025 10 07 2025 12 02 Oncologic skeletal fractures or pathologic fractures resulting from tumor-induced bone destruction represent a devastating complication of both primary bone cancers and metastatic disease, profoundly impairing patient quality of life and survival. Traditionally viewed as mechanical failures secondary to osteolytic or osteoblastic lesions, emerging paradigms now recognize these fractures as the culmination of complex, dynamic interactions between tumor cells and the bone microenvironment. Recent advances highlight the role of tumor-secreted factors, which dysregulate normal bone remodeling by takeover of osteoclast and osteoblast activity, leading to structural weakening long before radiographic changes appear. Moreover, the concept of the vicious cycle between tumor growth and bone resorption has been expanded to include immune modulation, angiogenesis, and neural signaling within the skeletal niche. Novel imaging modalities and biomechanical modeling now enable earlier detection of at-risk bone, while biomarkers offer promise for risk stratification. Therapeutically, beyond bisphosphonates and denosumab, emerging strategies target specific molecular pathways like TGF-β, Wnt, CXCR4 to disrupt tumor-bone crosstalk and preserve skeletal integrity. Additionally, prophylactic stabilization guided by fracture risk assessment tools is increasingly personalized. Meanwhile, prevention, rather than reaction, is becoming the cornerstone of management, emphasizing collaboration among oncologists, orthopedic surgeons, radiologists, and bone biologists.