Initiation of bisphosphonate therapy in bisphosphonate-naïve patients is known to be associated with radiological changes such as increased bone density in both osteolytic and osteoblastic metastases. It is not known, however, whether switching from a second-generation bisphosphonate to a more potent agent is associated with similar changes. This study aimed to prospectively explore radiological changes, as assessed by thoracolumbar CT scanning, in patients switching from an early generation bisphosphonate (i.e., oral clodronate or intravenous pamidronate) to intravenous zoledronic acid. Patients with progressive bone metastases despite use of an earlier generation bisphosphonate were switched to zoledronic acid as part of a study to evaluate the palliative benefit of this intervention. Quantitative computed tomography (QCT) scanning of the thoracolumbar spine was carried out at baseline, and repeated 4 months after commencing zoledronic acid. The effect of this change of therapy was explored in terms of bone density, as well as volume of osteolytic and osteoblastic disease. Fifteen patients were assessed. Switching of bisphosphonate therapy was associated with a significant increase in bone density, and an increase in osteoblastic volume. There was an insignificant trend towards reduced osteolytic volume. In conclusion, switching from early generation bisphosphonates to a more potent agent is associated with radiological changes similar to those seen when commencing a bisphosphonate in treatment-naïve patients. This is consistent with the observed palliative benefit. The use of QCT may be of benefit in the monitoring of bone metastases.