Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials

Context: The addition of androgen receptor signalling inhibitors (ARSIs) to standard androgen deprivation therapy (ADT) has improved survival outcomes in patients with advanced prostate cancer (PCa). Advanced PCa patients have a higher incidence of osteoporosis, compounded by rapid bone density loss upon commencement of ADT resulting in an increased fracture risk. The effect of treatment intensification with ARSIs on fall and fracture risk is unclear. Objective: To assess the risk of falls and fractures in men with PCa treated with ARSIs. Evidence acquisition: A systematic review of EMBASE, MEDLINE, The Cochrane Library, and The Health Technology Assessment Database for randomised control trials between 1990 and June 2023 was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses guidance. Risk ratios were estimated for the incidence of fracture and fall events. Subgroup analyses by grade of event and disease state were conducted. Evidence synthesis: Twenty-three studies were eligible for inclusion. Fracture outcomes were reported in 17 studies (N N = 18 811) and fall outcomes in 16 studies (N N = 16 537). A pooled analysis demonstrated that ARSIs increased the risk of fractures (relative risk [RR] 2.32, 95% confidence interval [CI] 2.00-2.71; p < 0.01) and falls (RR 2.22, 95% CI 1.81- 2.72; p < 0.01) compared with control. A subgroup analysis demonstrated an increased risk of both fractures (RR 2.13,95% CI 1.70-2.67; p < 0.01) and falls (RR 2.19,95% CI 1.53- 3.12; p < 0.0001) in metastatic hormone-sensitive PCa patients, and an increased risk of fractures in the nonmetastatic (RR 2.27, 95% CI 1.60-3.20; p < 0.00001) and metastatic castrate-resistant (RR 2.85, 95% CI 2.16-3.76; p <0.00001) settings. The key limitations include an inability to distinguish fragility from pathological fractures and potential for a competing risk bias. Conclusions: Addition of an ARSI to standard ADT significantly increases the risk of fractures and falls in men with prostate cancer.