This study demonstrates that the risk of sustaining a fragility fracture is almost 4 times higher in patients that started with ADT treatment following PCa diagnosis, and the risk is already higher within the first 6 months of ADT use. Furthermore, this study showed that the risk of sustaining any fracture (both fragility and malignancy-related) is fivefold in patients that started with ADT treatment. Our findings regarding the overall fracture risk are in line with those reported in several epidemiological studies that showed an association between ADT and an increased fracture risk. A recently published meta-analysis of 16 studies with a total population of 519,168 men with PCa by Wu et al. [25] also showed that ADT use was associated with an increased fracture risk (OR 1.39; 95% CI 1.26–1.52). The primary outcome in this study was “any fracture” and included studies with fragility fractures as well as malignancy-related fractures but the authors did not perform stratified analyses for fragility fractures and malignancy-related fractures respectively. The authors concluded that although ADT is associated with an increased risk of any fracture and the risk is positively correlated with the duration of ADT, heterogeneity in study populations (e.g., age, disease stage, and treatment duration) contribute to outcomes with low to moderate certainty of evidence [25].

As in our study, a large Swedish registry study by Wallander et al. [10] reported an increased risk of fragility fractures of (HR 1.40, 95% CI 1.28–1.53) in men treated with ADT compared to PCa patients without ADT and patients without PCa. However, the men treated with ADT included in this study were older compared to our study (82 years ± 7.0 vs 70.5 ± 8.3), and this study reported a statistical interaction between age and risk of fracture. In comparison to these previous studies, our results distinguish between malignancy-related and fragility fractures by manually reviewing all radiology reports, additionally, our analyses were adjusted for age and stage of disease. According to our results, the patients with PCa on ADT treatment represent a group with a high risk of fractures, especially fragility fractures (HR 3.62, 95% CI 1.57–8.32). This was also found by Lee et al. [11] with a comparable design and approach to our study, involving 741 Chinese PCa patients. They found that ADT was significantly associated with risk of fragility fractures (HR 3.60, 95% CI 1.41–9.23) [11] which is very similar to the findings in our study. The findings in these previous studies and in our study emphasize that although there are geographical variations in peak bone mass and skeletal geometry, as well as lifestyle and environmental factors associated with fracture risk, ADT use is associated with an increased fracture risk of fragility fractures among patients with divers ethnologically characteristics.

Regarding ADT exposure, Shahinian et al. [7] showed a dose-dependent increase of the risk (RR 1.45, 95% CI 1.36 to 1.56) of any fracture during the first year of PCa with an administration of > 9 doses of ADT. Wu et al. [25] found an increased risk of “any fracture” with increased dosages in their analyses, with ORs of 1.08 in low, 1.20 in medium, and 1.54 in high dosage. However, no sensitivity analysis could be conducted for this stratification because the included studies were adjusted for more than 4 factors. Moreover, in our study we also found an increased risk of all fractures and especially of fragility fractures in men treated with ADT even when exposed less than 6 months. We believe that a possible explanation for this observation, which is not in line with the studies by Shahinian et al. [7] and Wu et al. [25], could possibly be explained by the different inclusion criteria and methods used in those studies as compared to the present study. Wu et al. [25] and Shahinian et al. [7] only included patients who survived the first 5 years after the prostate cancer diagnosis, and did not suffer from a fracture during the first 12 months. Furthermore, they performed a time-fixed analysis which was stratified by the total received ADT doses within the first year after diagnosis. This finding, however, emphasizes that preventive strategies have to be implemented at the time of ADT treatment initiation, even in patients who receive short-term (neo) adjuvant curative treatment in conjunction with radiotherapy.

This study has several strengths and limitations. We used real-world data including longitudinal information on ADT prescription as well as radiographically confirmed fractures. Further with respect to the fractures, we were able to distinguish malignancy-related fractures from fragility fractures. Additionally, by initiating follow-up from the point of diagnosis and treatment, which enabled the timely observation of fracture risk. The limitations of our study are the single-center observational design with a relatively small sample size and number of events (fractures). Due to the finding that there were no patients that sustained a malignancy-related fracture in the no-ADT users, the association between ADT stratified by recency and duration and malignancy-related fractures could not be studied. Furthermore, due to the nature of our data collection, which is based on real-world data, we were unable to present a comprehensive analysis on body mass index or comorbidities associated with fracture risk because we only had partial information at baseline or during follow up. Nonetheless, our study found a higher risk of fragility fractures that are significant risks to the PCa patient, as these fractures have been proven to have a major impact of their mortality risk and quality of life [8, 27]. In many patients with PCa, there is anxiety around treatment and fear of complications and disease progression [28]. In those who are at high risk of fractures, improving preventive strategies are important to optimally benefit from ADT. In general, the overall survival of men with PCa on ADT should be aimed for without compromising quality of life due to fractures, with a timely start of preventive strategies. However, fracture prevention in PCa patients on ADT is not well implemented; there are low rates of diagnostic testing, low rates of education and diet and lifestyle guidance, and low rates of pharmacological management to reduce fracture risk [29]. Actively and systematically screened and treated PCa patients on ADT had a 72% lower hip fracture rate compared to a non-screened control group [30]. A known highly effective approach for systematically screening fracture risk in patients is through Fracture Liaison Services (FLS). FLSs have demonstrated a reduction in both subsequent fractures and mortality according to Vranken et al. [31]. Moreover, the professionals engaged in FLSs have extensive expertise and experience in fracture prevention which could potentially be applied to prevent fragility fractures in patients with PCa on ADT thereby offering the opportunity to improve patient care.