Abstract
Background: Androgen deprivation therapy (ADT) suppresses the production of androgen, and ADT is broadly used for intermediate or higher risk disease including advanced and metastatic cancer. ADT is associated with numerous adverse effects derived from the pharmacological properties. Previous meta-analysis on fracture risk among ADT users possessed limited data without further subgroup analysis. Risk estimation of updated real-world evidence on ADT-related fracture remains unknown.Objectives: To assess the risk of fracture and fracture requiring hospitalization associated with ADT among prostate cancer population on different disease conditions, treatment regimen, dosage level, fracture sites.Methods: The Cochrane Library, PubMed, and Embase databases were systematically screened for eligible cohort studies published from inception to March 2020. Two authors independently reviewed all the included studies. The risks of any fracture and of fracture requiring hospitalization were assessed using a random-effects model, following by leave-one-out, stratified, and sensitivity analyses. The Grading of Recommendations Assessments, Development and Evaluations (GRADE) system was used to grade the certainty of evidence.Results: Sixteen eligible studies were included, and total population was 519,168 men. ADT use is associated with increasing fracture risk (OR, 1.39; 95% CI, 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88). Stratified analysis revealed that high-dose ADT results in an elevated risk of fracture with little statistical heterogeneity, whereas sensitivity analysis restricted to adjust for additional factors indicated increased fracture risks for patients with unknown stage prostate cancer or with no restriction on age with minimal heterogeneity. The GRADE level of evidence was moderate for any fracture and low for fracture requiring hospitalization.Conclusion: Cumulative evidence supports the association of elevated fracture risk with ADT among patients with prostate cancer, including those with different disease conditions, treatment regimens, dose levels, and fracture sites. Further prospective trials with intact information on potential risk factors on fracture under ADT use are warranted to identify the risky population.
Highlights
Prostate cancer is the most common cancer among men, and remains the second leading cause of death in the United States in 2020 (Siegel et al, 2020)
androgen deprivation therapy (ADT) use is associated with increasing fracture risk (OR, 1.39; 95% confidence interval (CI), 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88)
Stratified analysis revealed that high-dose ADT results in an elevated risk of fracture with little statistical heterogeneity, whereas sensitivity analysis restricted to adjust for additional factors indicated increased fracture risks for patients with unknown stage prostate cancer or with no restriction on age with minimal heterogeneity
Summary
Prostate cancer is the most common cancer among men, and remains the second leading cause of death in the United States in 2020 (Siegel et al, 2020). Standard treatments based on health status for localized or locally advanced disease including watchful waiting, active surveillance, radical prostatectomy (RP), and radiotherapy (RT) with or without androgen deprivation therapy (ADT) (Gamat and McNeel, 2017; NCCN, 2020). For hormone-sensitive and castration-resistant metastatic disease, second-generation antiandrogens, docetaxel, radium-223, sipuleucel-T, and poly ADP ribose polymerase (PARP) inhibitors are the treatment options for various patient groups. ADT is an effective treatment for prostate cancer (Gamat and McNeel, 2017; NCCN, 2020), including for those patients receiving RT or RP adjuvant therapy for localized or locally advanced disease or with castration-resistant or hormonesensitive metastatic disease as well as patients with contraindications for or intolerance of radical treatment in very high-risk groups (A M El Batri et al, 2019), improving progression-free, overall survival (Tosco et al, 2019). Risk estimation of updated real-world evidence on ADT-related fracture remains unknown
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