Aspen Pham

Background: Breast cancer is a highly prevalent malignancy globally, with bone representing the most frequent site of distant metastasis, occurring in up to 70% of advanced cases. Bone metastases trigger severe skeletal-related events such as osteolytic lesions, pathological fractures, hypercalcemia, and spinal cord compression which drastically degrade quality of life and worsen prognosis. The bone microenvironment provides a fertile niche for tumor growth, driven by specialized vasculature and a vicious cycle between tumor and bone cells. Parathyroid hormone-related protein (PTHrP), secreted by breast cancer cells, drives osteolytic destruction. Conversely, parathyroid hormone (PTH) and its receptor (PTH1R) modulate metastatic behavior in opposing, context-dependent ways. Current therapies like bisphosphonates and denosumab slow skeletal progression but fail to eliminate metastatic disease, highlighting the need for novel molecular strategies.

Objective & Methods: This narrative review explores the mechanisms by which PTH and PTHrP signaling contribute to breast cancer bone metastases, focusing on type H vasculature, G-CSF-mediated vascular remodeling, PTH1R signaling in osteoblasts and tumor cells, and PTHrP’s role in epithelial-to-mesenchymal transition.

Search Methods: A literature search was conducted using the PubMed database for articles published between 2018 and 2025 using the following MeSH terms and keywords: “breast cancer”, “bone metastases”, “parathyroid hormone”, “PTHrP”, “PTH1R”, “type H vessels”.

Results & Discussion: 3D imaging reveals that mammary tumor cells preferentially colonize type H vascular niches in the bone marrow. These vessels, marked by endomucin and CD31 co-expression, connect arteries to sinusoids and supply critical nutrients supporting tumor survival.³ Tumor-derived G-CSF drives this pathological vascular remodeling and angiogenesis independently of immune cells. Consequently, blocking G-CSF receptor signaling significantly reduces early-stage metastatic progression.³

Intermittent PTH administration reduced bone metastases in mouse models, but this effect required intact PTH1R signaling in both osteoblasts and breast cancer cells. In contrast, PTH pretreatment that expanded osteoblast populations increased overall skeletal tumor burden and redistributed metastases to additional skeletal sites, suggesting that PTH’s anabolic effects can inadvertently enhance metastatic colonization.⁴

PTHrP promotes progression by inducing EMT, enhancing cancer stem cell characteristics, and supporting tumor cell invasiveness. Ablation of PTHrP in triple-negative breast cancer (TNBC) cells caused mesenchymal-to-epithelial transition (MET), reducing motility. In vivo, anti-PTHrP monoclonal antibodies reduced established bone lesions without causing osteoporotic changes in healthy bone.⁵ Furthermore, bone-targeted PTH antagonists engineered peptides combining PTHrP antagonist sequences with a collagen-binding domain significantly reduced tumor burden and osteolytic destruction in preclinical models. These antagonists induced apoptosis in breast cancer cells and inhibited cAMP accumulation in osteosarcoma cells without toxicity to normal cells.¹

Conclusion: PTH and PTHrP signaling play complex, context-dependent roles in bone metastases. While intermittent PTH can reduce metastases through PTH1R-mediated niche remodeling, its anabolic effects may promote tumor growth. PTHrP consistently drives metastatic aggressiveness via EMT induction. Bone-targeted PTHrP antagonists and anti-PTHrP antibodies represent promising strategies to selectively disrupt the tumor-bone cycle with minimal off-target effects.^1,5 Future research should focus on combination strategies targeting both vascular niche remodeling and PTHrP signaling.

Works Cited

1. Anbalagan M, Ponnapakkam T, Zou B, et al. Bone Targeted Parathyroid Hormone Antagonists for Prevention of Breast Cancer Bone Metastases. Cancers (Basel). 2025;17(17):2933. doi:10.3390/cancers17172933
2. Swami S, Zhu H, Nisco A, et al. Parathyroid hormone 1 receptor signaling mediates breast cancer metastases to bone in mice. JCI Insight. 2023;8(5):e157390. doi:10.1172/jci.insight.157390
3. Yip RKH, Rimes JS, Capaldo BD, et al. Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastases. Nat Commun. 2021;12:6920. doi:10.1038/s41467-021-26556-6
4. Brown HK, Ottewell PD, Evans CA, et al. Parathyroid Hormone (PTH) Increases Skeletal Tumour Growth and Alters Tumour Distribution in an In Vivo Model of Breast Cancer. Int J Mol Sci. 2018;19(10):2920. doi:10.3390/ijms19102920
5. Li J, Camirand A, Zakikhani M, et al. Parathyroid hormone-related protein inhibition blocks triple-negative breast cancer expansion in bone through epithelial to mesenchymal transition reversal. JBMR Plus. 2022;6(6):e10587. doi:10.1002/jbm4.10587