Breast cancer (BC) bone metastasis poses significant clinical challenges, including bone loss, fractures, and pain. It is well documented that increased mechanical stimuli increases bone volume and has been shown to provide anti-tumorigenic properties. Here, we investigate how soluble factors from irradiated breast cancer affects osteocytes’ mechanoresponse, representing a common patient scenario. Using a proteomic profiler, we identified potential therapeutic targets MMP-9, Galectin-3, VEGF, Cathepsin B, IL-8, DKK-1, ENPP-2, and Cathepsin B as differentially expressed radiation-induced proteins in MDA-MB-231 and ZR-75-1 cells. These proteins relate to bone remodeling pathways, although not significantly expressed. We also found breast cancer soluble factors, are affecting the apoptotic rate of osteocytes with mixed results regarding the effect on osteocytes’ mechanoresponse. Gene expression analysis revealed the impact on osteocyte’s mechanoresponse under irradiated tumor conditioned media (ITCM). Mechanical loading under 2 Gy MDA-MB-231 ITCM did not result in a significant increase in OPG expression, contrasting with the observations in the 0 Gy ITCM condition. For ZR-75-1 2 Gy ITCM, RANKL expression significantly increased under mechanical loading compared to the loaded control. In conclusion, our findings show that radiation induced soluble factors derived from distinct clinical subtypes of breast cancer, impair osteocyte mechanoresponse.