Parathyroid Hormone (1-34) Signaling for Bone Health in Breast Cancer Survivorship and Metastasis

Osteoporosis, fragility fractures, and pathologic fractures are increasingly recognized as long-term complications in cancer survivors. Women are more susceptible to bone loss than men, and breast cancer is the most common malignancy in women. In this population, bone health is a critical concern due to both therapy-induced bone loss and a high propensity for skeletal metastasis. Antiresorptive agents are widely used; however, their known adverse effects and limited capacity to rapidly reduce fracture risk in high-risk individuals have led to growing support for the early use of osteoanabolic therapies. Among these, intermittent administration of parathyroid hormone [PTH (1-34)] has demonstrated clinical efficacy in reducing fracture risk by activating the PTH 1 receptor in osteoblasts. However, its safety and mechanistic relevance in the context of breast cancer remain poorly understood. This review outlines the osteoblast-specific signaling pathways of PTH (1-34) and includes our recent research that identified p21-activated kinase 4 as a downstream effector linking canonical cyclic adenosine monophosphate-protein kinase A signaling to Wnt/β-catenin activation. Additionally, it explores the potential implications of PTH (1-34) in the context of breast cancer-related bone metastasis.