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

Abstract

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.

Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURES

This work was supported in part by a grant from Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Financial conflicts of interest to disclose: Shi-Ming Tu served on an Advisory Board sponsored by the Novartis Pharmaceuticals Corporation. The other authors have no conflicts of interest to disclose.

Published by Elsevier Inc.

Figures

Fig. 1

Diagram of the mevalonate pathway demonstrates sites of synergistic inhibition for statins and bisphosphanates. Inhibiting prenylated proteins, indicated at the bottom right, eventually inhibits the Rho and RAS intracellular cascades, which contribute to cell cycle arrest and induction of apoptosis, respectively.

Fig. 2

Graphs illustrate the median serum concentrations of the bone-specific biomarkers over the course of the study, by both patient (relatively thinner lines) and group (relatively thicker lines). Solid lines represent patients who did not experience a skeletal event during the study (Group A), whereas dashed lines represent patients who experienced a skeletal event (Group B). Notice the differences in the changes in median deoxypyridinoline (DPD) and N-telopeptide (NTX) levels between the different patients and groups and the relative lack of these changes in the median bone-specific alkaline phosphatase (BSAP) levels (P = 0.03, 0.02, and 0.66, respectively).

Fig. 3

The patients’ serum cholesterol concentrations were measured every 2 months. Graphs illustrate the changes in cholesterol over the course of the study. Notice that only 2 patients (numbers 1 and 5) had a concentration > 200 mg/dL when they discontinued from the study; this resulted from only 2 measurements having been taken because of their short study participation. Note also that in the case of 1 patient (number 3), the concentration increased to > 200 mg/dL but subsequently decreased and stayed below that level. The remainder of the patients’ cholesterol concentrations both started and stayed at