The mechanisms underlying reprogramming of growth factor signaling and metabolic pathways during bone metastasis of breast cancer are not clear. The Runt-related transcription factor (Runx2) regulates cell signaling during mammary epithelial morphogenesis and promotes invasion; therefore, we investigated its role in cell growth and metabolic signaling in bone-seeking breast cancer cells. We performed systemic inoculation of control or Runx2 knockdown invasive MDA-MB-231 cells in NOD/SCID mice, and compared parental and bone-derived variants for phenotypic and molecular alterations. The Runx2 knockdown showed early (0-2 weeks) inhibition of metastatic spread but late (4-6 weeks) outgrowth, suggesting Runx2-dependent bi-phasic response and reprogramming of metastatic cells. The late-stage tumor outgrowth of bone-derived Runx2 knockdown cells was associated with increased insulin-like growth factor- 1Rβ (IGF-1Rβ) levels. Interestingly, glucose uptake and glycolysis were reduced in the bone-derived Runx2 knockdown cells that could be further reduced by extracellular-regulated protein kinase (Erk1/2) inhibition. Furthermore, the Runx2 knockdown cells displayed activation of AMP-activated protein kinase (AMPKα), the sensor of cellular metabolism. Importantly, the Runx2 knockdown in bone-derived cells resulted in increased sensitivity to both Erk1/2 inhibition and AMPKα activation by PD184161 and metformin, respectively, despite increased IGF-1Rβ and AMPKα levels. Our results reveal that Runx2 promotes metastatic spread of mammary tumor cells. The growth of late-stage tumor cells can be targeted by Runx2 knockdown in combination with Mek-Erk1/2 inhibition and metformin treatment.