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

Universitas Indonesia35 enrolled

Overview

This randomised, double-blind, placebo-controlled pilot trial evaluated the therapeutic response of zoledronic acid combined with simvastatin in women with breast cancer and confirmed bone metastases. Participants were randomized to receive zoledronic acid plus simvastatin 40 mg daily or zoledronic acid plus placebo for six treatment cycles. Clinical response, bone scan response, bone turnover biomarkers, and treatment-related safety and tolerability were evaluated. The study was designed as a pilot trial and was not powered to establish definitive efficacy.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

SimvastatinDRUG

Simvastatin 40 mg was administered orally once daily at night for six treatment cycles, with each cycle separated by three weeks, in combination with zoledronic acid

PlaceboDRUG

An identical placebo tablet was administered orally once daily at night for six treatment cycles, with each cycle separated by three weeks, in combination with zoledronic acid.

Zoledronic Acid (Zometa)DRUG

Zoledronic acid 4 mg was administered as an intravenous infusion over 15 minutes for six treatment cycles, with each cycle separated by three weeks.

Eligibility

Sex: FEMALEMin age: 19 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Change in Serum DKK-1 Level

Change in serum Dkk-1 concentration from baseline to the end of treatment following six treatment cycles

Time frame: Baseline to the end of Cycle 6 (each cycle is 21 days)

Secondary Outcomes

Change in VAS pain Score

Pain was assessed using the Visual Analog Scale (VAS), ranging from 0 to 10, with higher scores indicating greater pain.

Time frame: Baseline, end of Cycle 3, and end of Cycle 6 (each cycle is 21 days)

Bone Scan Response

Bone scan response categorized as responsive, stable disease, or progressive disease.

Time frame: At the end of Cycle 6 (each cycle is 21 days)

Change in serum TRAcP-5b level

Change in serum TRACP-5b concentration from baseline to the end of treatment.

Time frame: Baseline to the end of Cycle 6 (each cycle is 21 days)

Safety and Tolerability

Incidence and severity of treatment-related adverse events during the study, including hematological, non-hematological, musculoskeletal, renal, bisphosphonate-related, and statin-associated toxicities. Adverse events were graded according to CTCAE version 4.03.

Time frame: Throughout the six treatment cycles (each cycle is 21 days)