When tumors break bones; emerging paradigms in the pathogenesis and prevention of oncologic skeletal fractures

Abstract

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.

Keywords: Neoplasm, Bone fractures, Pathologic, Bone neoplasm, Bone remodeling, Osteolysis, Bone density conservation, Bone resorption