Timing of bone-modifying agents after bone metastasis diagnosis and time to first skeletal-related event: A systematic review and study-level correlation analysis

Abstract

Introduction

Bone-modifying agents (BMAs) effectively prevent skeletal-related events (SREs) in bone metastases (BMs). While early BMA use is recommended upon BM diagnosis, its benefits and optimal timing remain unclear. This study investigated whether early BMA initiation after BM diagnosis delays SRE onset by analyzing pooled data from placebo-controlled trials.

Methods

Randomized controlled trials in which a BMA or placebo was administered after BM diagnosis were extracted. For each trial's BMA and placebo arms, the waiting period from BM diagnosis to BMA initiation and the effective period from BMA initiation to SRE onset were investigated. The hazard ratio (HR) for the SRE-free period relative to the placebo period was calculated. A waiting period of ≤6 months was defined as the early initiation group, whereas that of >6 months was the delayed initiation group. The HRs were meta-analyzed.

Results

Data from 17 studies were analyzed. Early initiation of BMAs showed a trend toward a longer duration of efficacy compared with delayed initiation (+5.5 versus [vs.] + 3.2 months, p = 0.056). However, the pooled HR demonstrated efficacy at both initiation timepoints (0.62 [0.56–0.69] vs. 0.73 [0.60–0.83]).

Conclusions

Although early initiation of a BMA after BM diagnosis is recommended, its efficacy—specifically whether it prolongs the time to SRE onset—remains unclear.