# Comparative Effectiveness and Safety of Denosumab Versus Bisphosphonates in Elderly Patients with Cancer Bone Metastases: A Target Trial Emulation Study

## TL;DR

This study compares Denosumab and bisphosphonates in elderly cancer patients with bone metastases, finding Denosumab more effective in preventing bone-related events and reducing mortality.

## Contribution

The study extends evidence on Denosumab versus bisphosphonates to elderly patients, a vulnerable group previously underrepresented in clinical trials.

## Key findings

- Denosumab was associated with a lower risk of skeletal-related events compared to bisphosphonates in elderly cancer patients.
- Bisphosphonate use was linked to higher all-cause mortality and increased risk of pathological fractures.
- Denosumab had a higher incidence of hypocalcaemia but similar risks for kidney-related events.

## Abstract

Objective: Bone-modifying agents (BMA) are central to the prevention of skeletal-related events (SREs) in patients with cancer bone metastases, yet evidence guiding agent selection in very old patients remains limited. This study aimed to compare the effectiveness and safety of Denosumab versus bisphosphonates in patients aged ≥75 years with solid tumour-related bone metastases using a target trial emulation framework. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to emulate a hypothetical randomised trial. Patients aged ≥75 years with solid tumour-related bone metastases initiating Denosumab or bisphosphonates were included. After 1:1 propensity score matching (PSM), 10,662 patients were analysed in each treatment group. The primary outcome was time to first SRE. Secondary outcomes included individual SRE components, all-cause mortality, and safety events. Results: Among 21,324 matched patients (mean age, 75.6 years), bisphosphonate use was associated with a higher risk of SREs compared with Denosumab (hazard ratio [HR], 1.15; 95% CI, 1.06–1.25). The excess risk was driven by pathological fractures (HR, 1.28; 95% CI, 1.10–1.49), whereas other SRE components did not differ significantly. All-cause mortality was higher among bisphosphonate users (HR, 1.41; 95% CI, 1.33–1.49, p < 0.001). Hypocalcaemia occurred more frequently with Denosumab (5.7% vs. 2.4%), while risks of acute kidney injury and end-stage renal disease (ESRD) were similar. Findings were consistent across sensitivity and subgroup analyses. Conclusions: In patients aged ≥75 years with solid tumour-related bone metastases, Denosumab was associated with lower risks of skeletal-related events—particularly pathological fractures—and reduced all-cause mortality compared with bisphosphonates. These results extend randomised trial evidence to a clinically vulnerable population and support Denosumab as a preferred BMA in older adults.