The Role of Bisphosphonate and Simvastatin Combination on Therapeutic Response in Breast Cancer With Bone Metastasis Via Dicckopf-1 Pathway

This was a prospective, single-center, randomized, double-blind, placebo-controlled pilot trial involving women with breast cancer and confirmed bone metastases. Participants were randomized to receive either zoledronic acid (ZA) in combination with simvastatin 40 mg daily or ZA with placebo for six treatment cycles.

Zoledronic acid 4 mg was administered by intravenous infusion over 15 minutes. Simvastatin 40 mg or an identical placebo tablet was administered orally once daily at night. Each treatment cycle was separated by three weeks.

Placebo tablets were prepared by the hospital pharmacy to be identical in appearance, size, and colour to simvastatin tablets. Treatment allocation was concealed from both patients and investigators throughout the study. Patient adherence to the oral medication was monitored using self-reported patient diaries reviewed at each clinic visit.

Clinical efficacy was assessed using the Visual Analog Scale (VAS) pain score. Radio-imaging efficacy was evaluated using bone scintigraphy according to the MD Anderson criteria. Biological efficacy was assessed by measuring serum Dkk-1 and TRACP-5b at baseline and after the sixth treatment cycle. Safety and tolerability were evaluated throughout treatment using clinical and laboratory assessments, with adverse events graded according to CTCAE version 4.03.

As a pilot trial, the study was not powered to establish definitive efficacy. The estimates were intended to inform the design and sample size of a future adequately powered trial.

Inclusion criteria

• Women diagnosed with breast cancer with confirmed bone metastasis based on bone scan.
• Previously received systemic chemotherapy.
• Scheduled to initiate bisphosphonate therapy as part of standard oncologic management.
• Age >18 years.
• ECOG performance status ≤1.
• Written informed consent.
• Serum creatinine ≤1.5 times normal range.
• ALT ≤2 times normal range or total bilirubin ≤1.5 times normal range.

Exclusion criteria

• Pregnancy or lactation.
• Prior or ongoing simvastatin or other statin treatment.
• Known hypersensitivity to bisphosphonates.
• Allergy to statins.