Effectiveness and safety of bone protective interventions to mitigate bone loss and skeletal fractures experienced by patients with non-metastatic breast cancer: a systematic review and meta-analysis

Cancer treatment-induced bone loss (CTIBL) and skeletal fractures are potential consequences of anticancer therapies used in the treatment of non-metastatic breast cancer (BC). This systematic review and meta-analysis aim to synthesise the available evidence regarding the effectiveness and safety of bone protective interventions in the mitigation of CTIBL and skeletal fractures. Multiple databases including MEDLINE/PubMed, Embase and Cochrane, clinical trial registries and grey literature were systematically searched for experimental and observational studies, investigating the use of bisphosphonates, denosumab, calcium or vitamin D supplementation. Outcomes of interest were change in bone mineral density (BMD), the incidence of skeletal fractures, change in bone turnover markers, the incidence of adverse events (AEs), the presence of aromatase inhibitor musculoskeletal symptoms and quality of life. A total of 88 studies were included in our systematic review and meta-analysis, with sample sizes ranging from 11 to 4819 participants. For change in BMD outcomes able to be meta-analysed, bisphosphonates demonstrated a significant benefit compared to controls (pooled mean difference estimate; lumbar spine: 4.17, p = 0.0; total hip: 1.81, p = 0.034; femoral neck: 2.35, p = 0.001). Incidence of skeletal fractures significantly decreased with bisphosphonates compared to controls (pooled relative risk estimate; 0.77, p < 0.001). Denosumab demonstrated similar effects on BMD and skeletal fracture incidence; however, meta-analysis was not possible due to the lack of randomised controlled trials. Osteonecrosis of the jaw represents the most concerning AE with bisphosphonates. Considering the effectiveness and safety, and the level of evidence available, bisphosphonates present as the preferred bone protective intervention for the management of bone health in patients with non-metastatic BC.