Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: PAIN AND ANALGESIC USE ASSOCIATED WITH SREs IN PATIENTS WITH ADVANCED BREAST CANCER AND BONE METASTASES TREATED WITH BONE-MODIFYING AGENTS: A RETROSPECTIVE OBSERVATIONAL STUDY

Abstract Background Bone metastases (BM) are common in patients with metastatic breast cancer, often leading to skeletal-related events (SREs) and significant bone pain, which compromise patient quality of life and increase healthcare burdens. Zoledronic acid (ZA) and denosumab (Dmab) are widely used antiresorptive agents for managing BM, yet limited real-world data are available on their long-term analgesic efficacy and effectiveness in SRE prevention over extended treatment periods. Purpose This retrospective observational study assesses the impact of 24 consecutive administrations of ZA or Dmab on SRE incidence and pain management in breast cancer patients with skeletal metastases in a clinical setting. Patients and Method From January 2008, 364 patients with BM due to breast cancer received subcutaneous Dmab 120 mg (n = 170) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 194) once every 4 weeks for at least 24 administrations. Daily supplemental calcium and vitamin D were strongly recommended. Endpoints were: (I) time to first on-study SRE (defined as pathological fractures, spinal cord compression, and hypercalcemia of malignancy); (II) assessments of serious adverse event incidence (i.e. osteonecrosis of the jaw (ONJ) and hypocalcaemia); (III) pain intensity (measured by NRS, the shift thought the three steps of the World Health Organization (WHO) analgesic ladder, and opioid requirements (expressed in mg of oral morphine equivalents (OME, mg/day). Results The cumulative incidence of the first skeletal event was equal to 28.9% (24.2%, 33.7% 95% CI) in the ZA group as well as in the Dmab group. ZA and Dmab were equally well tolerated. No ONJ occurred during the treatment time in both groups. Patients treated with Dmab showed a higher probability of belonging to the 0 step of the WHO analgesic ladder and lower probability of belonging at higher step compared to those treated with ZA. Mean NRS score for the Dmab group was 1.82 (1.52, 2.10 95% CI) compared to 2.20 (1.91, 2.48 95% CI) in the ZA group. Dmab group assumed an average of 0.42 meq (0.039, 1.09 95% CI) compared to 3.71 meq (1.69, 8.91 95% CI) in the ZA. Conclusion This study supports Dmab’s potential for improved long-term analgesic outcomes compared to ZA in real-world clinical practice, though both drugs effectively reduce SREs. Further research is warranted to confirm these findings and optimize therapeutic strategies for pain and SRE management in metastatic breast cancer. Keywords Bone metastases (BM), Skeletal-related events (SREs), Bone pain, Bone-modifying agents (BMAs), Zoledronic acid (ZA), Denosumab (Dmab)