Different effects of moderate tibial loading and Yoda1 on breast cancer-induced osteolysis in aged mice.

Elderly breast cancer patients and survivors are at high risk of bone loss but experience obstacles to harness the known benefits of exercise due to aging, cancer, and cancer treatment. Previously, we and others showed that moderate mechanical loading suppressed breast cancer-induced osteolysis in young adult mice. To overcome the mechano-transduction deficits in aged skeletons, we recently tested a dual therapy combining mechanical and Yoda1 activation of mechanosensitive Piezo1 channels. We found that the dual therapy was more effective in mitigating bone loss due to aging and doxorubicin in mature mice than the individual interventions. In the present study, we further tested the hypothesis that dual therapy combining moderate tibial loading and Yoda1 protects aged skeleton from breast cancer-induced osteolysis better than individual treatments. Aged female C57BL/6 J mice (∼74-week-old) receiving Py8119 breast cancer cells in both tibiae were assigned to the four experimental groups (n = 5-8 per group) to examine the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles per day, 5 days/week), individually or combined on bone structural integrity. At the end of 4 weeks' experiments, the dual therapy group had the lowest incidence of osteolytic perforation (56 %) compared to the non-treated group (80 %), loading only group (70 %), and Yoda1 only group (100 %). The relative drop of cortical polar moment of inertia (Ct.pMOI), calculated as [(Week 4- Week 0)/Week 0, %], were analyzed at the proximal end, mid-diaphysis, and tibial-fibular junction of the tibia. The average values over the three locations were - 12.7 %, -3.2 %, -24.0 %, -4.2 % for the non-treated, loading only, Yoda1 only, and dual therapy groups, respectively. Furthermore, the % of samples with decreased Ct.pMOI (indication of structural deterioration) was suppressed in the dual therapy group (33 %), compared with nontreated (100 %), loading only (80 %), and Yoda1 only (100 %) groups. Each treatment differentially affected the osteoclast activity, tumor proliferation, and apoptosis of osteocytes, marrow cells and tumor cells, revealing the complex interactions of bone, tumor, and mechanical stimulations. In summary, the dual therapy resulted in skeletal benefits comparable to or slightly better than loading only treatment. However, the exacerbated bone loss and cortical perforation associated with Yoda1 call for further investigation on safe and effective treatments of skeletal damages caused by metastatic breast cancers.