Addition of an androgen receptor pathway inhibitor (ARPI) to androgen deprivation therapy (ADT) (ADT + ARPI, i.e., maximal androgen blockade, MAB) improves survival outcomes compared to ADT monotherapy in patients with prostate cancer (PC). It is known that ADT increases the risk of fractures in patients with PC, but it is unclear if this risk is higher with MAB. The aim of this study is to conduct a systematic review and meta-analysis to determine if MAB increases the incidence of fractures compared to ADT alone, and if the incidence of fractures was influenced by the type of ARPI.

Clinical trials assessing MAB versus ADT alone in patients with PC were identified using the PubMed/Medline and Cochrane library databases. The pooled odds ratio of developing fractures with MAB versus ADT alone was calculated for each type of ARPI in selected studies by random-effects modeling. The number of patients receiving bone-protecting agent (BPA) was also evaluated.

We identified 17 studies comprising 16162 patients for the systematic review and meta-analysis (9240 patients treated with MAB, 6922 patients treated with ADT alone). Each type of ADT + ARPI resulted in a statistically significant increased risk of fractures compared to ADT alone (pooled OR ranging from 1.5 to 2.4). There was no difference in the magnitude of the risk of fractures among the different ARPIs. Only 7 studies reported the number of patients treated with a BPA.

In our meta-analysis, MAB resulted in a statistically significant increase in fracture risk compared to ADT alone, regardless of the type of ARPI. Since long-term MAB represents the standard of care in various settings of PC, the use of a BPA should be generally recommended. Dosing and frequency of BPA need to be adapted according to the specific PC setting.