Pilot trial of bone-targeted therapy combining zoledronate with fluvastatin or atorvastatin for patients with metastatic renal cell carcinoma

Background: The biological rationale for this study came from the observation that bisphosphonates and statins affect bone metastasis in different ways and thus combination therapy may provide synergistic benefit. This pilot trial evaluated the efficacy and safety of combining a bisphosphonate and a statin in patients with RCC metastatic to bone. Methods: Patients with RCC and bone metastasis received zoledronate and fluvastatin or atorvastatin. Patients were monitored clinically and by imaging for skeletal events. Concentrations of the bone resorption markers deoxypyridinoline (DPD) and N-telopeptide (NTX) and the bone formation marker bone-specific alkaline phosphatase (BSAP) were monitored for changes during treatment. Results: Eleven patients were enrolled and followed for a median of 6 months. The median time to first skeletal-related event for all patients was 9.0 months. Seven (63%) patients experienced skeletal events with a median time to first skeletal-related event of 4.0 months (range, 3-18 months); 4 patients (36%) experiences no skeletal events for a median of 12 months of follow-up (range, 2-28 months); 4 patients (36%) demonstrated treatment responses with development of sclerosis in lytic bone lesions. Differences in the median changes in biomarker levels between patients who had skeletal events and those who did not were statistically significant for DPD and NTX (P =.03 and.01, respectively) but not for BSAP (P =.4). The regimen was well tolerated, with few adverse reactions related to the study drugs. Conclusion: Although the use of bone-targeting therapy combining zoledronate and fluvastatin or atorvastatin affected certain bone biomarkers and provided bone response in several patients with RCC and bone metastasis, we could not demonstrate a statistically significant improvement in time to skeletal events.