Denosumab versus zoledronic acid in metastatic breast cancer: A retrospective observational analysis of 24-dose regimens on analgesia and skeletal-related event prevention

Abstract

Background: Based on available data in the literature, current evidence supporting the analgesic role of antiresorptive drugs is weak. This study compared the efficacy of zoledronic acid (ZA) and denosumab (Dmab) in reducing bone pain and first Skeletal Related Events (SREs) in real world setting.

Methods: A retrospective observational cohort study was conducted in patients with female breast cancer-related bone metastases at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, from January 2008 to January 2023. Patients were included if they had undergone at least 24 consecutive administrations of ZA or Dmab. The primary endpoint was the analgesic effect, evaluated in terms of average pain intensity, analgesic drug use (Word Health Organization analgesic ladder), and daily opioid doses (oral morphine equivalent, OME) assessed at 3, 6, 12, 18, and 24 months, analyzed by Bayesian longitudinal mixed-effects models. Secondary endpoints included first SREs and radiotherapy/surgery incidence.

Results: Among 364 patients (194 ZA, 170 Dmab), Dmab demonstrated a significant analgesic advantage. Dmab group showed an 89 % lower likelihood of increasing one analgesic ladder step, a mean reduction of 0.4 points on the numerical rating scale (95 % CI, -0.7, -0.1), and lower daily OME doses (0.77 mg vs. 6.2 mg for ZA). At 12 and 24 months, ZA and Dmab showed similar cumulative incidences of SREs and radiotherapy/surgery (p = 0.601 and p = 0.923).

Conclusions: Dmab showed consistent superior effect than ZA in reducing bone pain in metastatic BC, yet both treatments delivered similar protection against SREs and the need for radiotherapy or surgery.

Keywords: Bone metastases; Bone pain; Breast cancer; Denosumab; Skeletal-related events; Zoledronic acid.

Fig. 1

Flowchart for real-world evidence study.

Fig. 2

Trend pattern of pain measurements across 0–24-month period stratified by treatment regimen. A) changes over time in the WHO analgesic scale (Step 1 non opioid, Step 2 weak opioids, Step 3 Strong opioids, percentage); B) average pain level (NRS value, mean); C) average OME dose (mean in mg). The blue represents the population treated with Zoledronic Acid, and the red represents the population treated with Denosumab. The vertical error bar in B and C represents the 95 %CI. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Results of the Bayesian Mixed Effect Models and marginal effect of treatment regimen on pain Estimates from the three Bayesian models for each of the pain metrics: (A–B) analgesic use based on the WHO Scale, (C–D) average pain level during the previous week according to NRS, (E–F) average opioid dose in mg OME expressed as log1p. For each pain metric, the figures on the left display the Odds Ratios (WHO analgesic scale) or the coefficient estimates (for the NRS score and opioid dosage in mg OME), while the figures on the right represent the treatment marginal effect.

Fig. 4

Cumulative incidence curves of the first skeletal event and the competitive events Cumulative incidence curves of the first SRE (A) and radiotherapy or bone surgery (B), and 95 % CI, stratified for Treatment.