Summer Apostalo

Background: Breast cancer metastasizes to bone in approximately 70% of patients with advanced disease, causing osteolytic destruction, pathologic fractures, hypercalcemia, and significant morbidity.¹,² A central driver of osteolysis is the RANK/RANKL/OPG signaling axis, which regulates osteoclast differentiation and fuels a self-amplifying “vicious cycle” between tumor expansion and bone resorption.³ Current anti-resorptive therapies such as bisphosphonates and denosumab reduce skeletal complications but do not eliminate metastatic disease, and the molecular mechanisms governing each stage of progression—and why single-pathway blockade so often fails in advanced disease—remain incompletely understood.⁴

Objective: In this narrative review, we examine a stage-specific mechanistic model of osteolytic breast cancer bone metastasis, focusing on how the bone microenvironment drives early niche formation, dormancy programming, myeloid remodeling, RANKL-independent osteoclastogenesis, and immune evasion across disease progression.

Search Methods: A literature search was conducted using PubMed from 2017 to 2025 with the following MeSH terms and keywords: “breast cancer bone metastasis,” “RANKL,” “osteoclastogenesis,” “bone marrow niche,” “TGF-beta,” “IL-11,” “Siglec-15,” “mesenchymal stem cell extracellular vesicles,” and “bone microenvironment.”

Results: Five primary studies were reviewed. Gkikopoulou et al. demonstrated in a human RANKL-overexpressing transgenic (TgRANKL) mouse model that elevated RANKL signaling increased skeletal metastasis burden and osteolytic damage.⁵ Treatment with prophylactic denosumab reduced both osteolysis and metastatic progression, whereas delayed treatment reduced bone destruction but did not significantly decrease tumor burden, indicating that RANKL is critical during early niche formation but insufficient as a sole target once disease is established.⁵ Sandiford et al. showed that bone marrow mesenchymal stem cell–derived extracellular vesicles (MSC-EVs) actively programmed disseminated breast cancer cells into dormancy in the perivascular niche, with naïve EVs inducing quiescence and DNA repair signaling, and primed EVs driving further dedifferentiation into cancer stem cell–like cells through Wnt/β-catenin signaling.⁶ The results demonstrated that tumor cells with fewer initial cancer stem cell characteristics were most susceptible to this reprogramming, creating a protected reservoir resistant to conventional therapy.⁶ Buenrostro et al. found that early TGF-β neutralization reduced osteolytic lesion area by approximately 50% and tumor burden by approximately two-fold.⁷ Critically, myeloid-specific TGF-β receptor knockout reproduced this protective effect while tumor-specific knockout did not, demonstrating that TGF-β promotes osteolysis through myeloid cell intermediaries rather than direct tumor cell effects.⁷ Liang et al. identified IL-11 as a mediator of RANKL-independent osteoclastogenesis, showing that bone-metastatic breast cancer cells drove osteoclast formation through JAK1/STAT3/c-Myc signaling even without RANKL.⁸ STAT3 inhibition with AG-490 reduced both bone destruction and tumor growth in vivo, confirming this pathway as therapeutically targetable.⁸ Wang et al. demonstrated that Siglec-15, upregulated on osteoclasts and macrophages in the metastatic niche, simultaneously promoted osteoclast formation and suppressed CD8⁺ T-cell activity while increasing T-cell exhaustion markers (PD-1, TIM-3, LAG-3).⁹ Anti-Siglec-15 treatment reduced tumor burden, preserved trabecular bone, restored T-cell proliferation, and blocked secondary metastatic spread from bone to lung.⁹

Conclusion: Together, these findings support a stage-specific model in which early osteolytic disease is RANKL-dependent, while progression is sustained by other mechanisms including stromal dormancy programming, TGF-β–driven myeloid remodeling, RANKL-independent IL-11/STAT3 osteoclastogenesis, and Siglec-15–mediated immune suppression. Because each stage introduces reinforcing mechanisms, single-pathway therapy is unlikely to control established disease. This framework explains why early anti-resorptive therapy outperforms delayed treatment and supports the development of stage-matched combinatorial strategies. Future research should investigate early RANKL blockade in high-risk patients, TGF-β inhibition combined with radiotherapy to limit post-treatment rebound osteolysis, JAK/STAT pathway inhibitors for RANKL-refractory disease, and anti-Siglec-15 agents to simultaneously address bone destruction and restore anti-tumor immunity in bone-predominant metastatic breast cancer.

Works Cited

1. Pang L, Gan C, Xu J, et al. Bone metastasis of breast cancer: molecular mechanisms and therapeutic strategies. Cancers (Basel). 2022;14(23):5727. doi:10.3390/cancers14235727
2. Wang M, Xia F, Wei Y, Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res. 2020;8(1):30. doi:10.1038/s41413-020-00105-1
3. Zhang Y, Liang D. The RANK/RANKL/OPG system and tumor bone metastasis: potential mechanisms and therapeutic strategies. Front Endocrinol (Lausanne). 2022;13:1063815. doi:10.3389/fendo.2022.1063815
4. Liu Y, Chen H, Chen T, Qiu G, Han Y. The emerging role of osteoclasts in the treatment of bone metastases: rationale and recent clinical evidence. Front Oncol. 2024;14:1445025. doi:10.3389/fonc.2024.1445025
5. Gkikopoulou E, Syrigos C-C, Mantogiannakou I, et al. RANKL drives bone metastasis in mammary cancer: protective effects of anti-resorptive treatments. Int J Mol Sci. 2025;26(11):4990. doi:10.3390/ijms26114990
6. Sandiford OA, Donnelly RJ, El-Far MH, et al. Mesenchymal stem cell–secreted extracellular vesicles instruct stepwise dedifferentiation of breast cancer cells into dormancy at the bone marrow perivascular region. Cancer Res. 2021;81(6):1567-1582. doi:10.1158/0008-5472.CAN-20-2434
7. Buenrostro D, Kwakwa KA, Putnam NE, et al. Early TGF-β inhibition in mice reduces the incidence of breast cancer induced bone disease in a myeloid dependent manner. Bone. 2018;113:77-88. doi:10.1016/j.bone.2018.05.008
8. Liang M, Ma Q, Ding N, et al. IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis. Cell Death Dis. 2019;10(5):353. doi:10.1038/s41419-019-1594-1
9. Wang Y, Xu Z, Wu KL, et al. Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis. Proc Natl Acad Sci U S A. 2024;121(5):e2312929121. doi:10.1073/pnas.2312929121