Breast cancer often metastasizes to bone and causes osteolytic lesions. Dynamic changes in the bone microenvironment are rarely studied but are hypothesized to influence the establishment and progression of bone metastatic lesions. Here, we developed an experimental bone metastasis mouse model to detect and characterize breast cancer cell homing and the onset of early bone metastasis. We studied the dissemination of cancer cells to (intact) bones, their proliferative state and direct microenvironment, using 3D light-sheet fluorescence microscopy (LSFM) and multiscale correlative tissue characterization. We show that cancer cells home in all bone compartments using intact bones, with a preference for small clusters in the bone marrow and larger clusters in the periosteum. We developed an image analysis tool to detect and track early bone osteolytic lesions, quantifying their onset, location and growth. Osteolytic lesions were only detected in the metaphysis and were classified as three different types depending on location. Surprisingly, we observed altered bone (re)modeling with increased new bone formation in animals without detectable osteolytic lesions. Our study suggests an early systemic effect of breast cancer cells in the bone microenvironment and provides novel insights of the structural and biophysical changes during the early phase of metastasis.