Risk of Fracture During Androgen Deprivation Therapy Among Patients With Prostate Cancer: A Systematic Review and Meta-Analysis of Cohort Studies

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.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group

“…In one meta-analysis, the risk of fracture in patients with PCa was 39% higher in those receiving ADT. 22 BMD reduction occurs rapidly after ADT initiation, within 6 to 12 months, and in a dose-dependent manner. Furthermore, the risk for fracture persists beyond ADT discontinuation.…”

Androgens, brain and androgen deprivation therapy in paraphilic disorders: A narrative review

“…ADT was also associated with increased fracture risk (OR, 1.39; 95% CI, 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88) among patients with prostate cancer, including those with different disease conditions, treatment regimens, dose levels and fracture sites (Wu et al, 2021).…”

Implementing and Evaluating the Impact of BoneRx: A Healthy Bone Prescription for Men with Prostate Cancer Initiating Androgen Deprivation Therapy

“…The initiation of ADT results in rapid and profound hypogonadism, resulting in significant bone and muscle loss, increasing the risk for osteoporosis (OP), falls, and fractures [ 14 , 15 , 16 ]. Men receiving ADT have been shown to have a 5- to 10-fold increased loss of bone mass [ 14 , 17 , 18 ], and the risk of fracture has been reported up to 20% by 5 years of treatment [ 19 , 20 , 21 , 22 ], an at least 50% greater risk of fractures than in healthy controls or men with PCa who are not on ADT [ 20 , 21 , 22 , 23 ]. In a large SEER database study, 58% of men at high risk and 38% of men at low risk for fracture at baseline developed at least one fracture after ADT [ 24 ].…”