Bone anabolic agents mitigate bone loss in a model of breast cancer bone metastasis

Bone metastasis remains an issue in advanced breast cancer patients due to the lack of treatments to repair the bone. Transforming growth factor-β (TGF-β) plays a key role in producing osteolytic factors that stimulate bone resorption. Losartan, an FDA approved anti-hypertensive drug, has been shown to inhibit TGF-β and increase bone mass in immunocompetent mice. SD-208, a TGF-βR1 kinase inhibitor has been shown to have bone anabolic effects in immunocompetent mice. However, the effects of losartan and SD-208 on bone in the breast cancer bone metastasis remain undetermined.
The aim of this study was to assess whether losartan or SD-208 can limit/repair lytic bone lesions in models of breast cancer bone metastasis. Two cell types were ultilised: human osteosarcoma cells (SAOS-2) and human triple negative breast cancer (MDA-MB-231 LU2+GFP+). To assess bone anabolic effects of losartan and SD-208, an alkaline phosphatase assay or alizarin red assay were conducted using SAOS-2 cells. A model of breast cancer bone metastasis was established to monitor the development of lytic bone lesions and tumour growth, following intracardiac injection of breast cancer cells (MDA-MB-231 LU2+GFP+) into immunocompromised BALB/c nude mice. The model was then used to assess the effect of losartan and SD-208 on bone with matastatic breast cancer. Losartan and SD-208 were able to increase alkaline phosphatase activity and mineralisation in vitro. In tumour-free mice, losartan and SD-208 increased trabecular bone volume and number compared to vehicle. In the model of breast cancer bone metastasis, losartan and SD-208 reduced tumour induced bone loss compared to vehicle. Losartan and SD-208 were able to mitigate bone loss induced by breast cancer bone metastasis, but not able to completely repair bone lesions. Finally, losartan and SD-208 have the potential to be used in combination with bisphosphonates and chemotherapies in the treatment of breast cancer bone metastasis and other bone-related diseases.