Response to systemic therapy in breast cancer patients with lytic skeletal metastases manifests as a shift from increased bone resorption to new bone formation. We hypothesized that dual-energy x-ray absorptiometry (DXA) could be used to prospectively quantitate changes in bone mineral density (BMD) in metastatic skeletal lesions in breast cancer patients receiving systemic therapy. Nine metastatic breast cancer patients with one or more assessable lytic skeletal metastases receiving systemic therapy were prospectively evaluated with DXA, skeletal radiographs, computed tomography (CT), and radionuclide bone scans at baseline (t = 0 months, 2 months, and 6 months). The median (range) percentage change in BMD in skeletal lesions among patients responding to systemic therapy was 10.7% (0.1-21.85), 5.0% (-1.3-23.8), and 16.7% (-2.0-50.8) at 0-2, 2-6, and 0-6 months, respectively. Changes in BMD between 0-2, and 0-6 months were significant (Wilcoxin signed rank test; p = 0.013 and p = 0.017, respectively). The percentage change in BMD skeletal lesions between 0-2 and 2-6 months correlated with the changes imaged on skeletal x-rays (Spearman rank order correlation coefficient [Rs] = 0.511, p = 0.011) and CTs (Rs = 0.416, p = 0.046) but less so with bone scans (Rs = 0.293, p = 0.189). It is technically feasible to use DXA to prospectively monitor changes in lytic skeletal metastases in breast cancer patients receiving systemic therapy. The BMD of skeletal metastases increases in patients responding to treatment and was significantly correlated with the changes imaged on skeletal x-rays and CTs. Additional studies of DXA to evaluate response in skeletal metastasis are warranted.