Bone health effects of androgen-deprivation therapy and androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer

Abstract

Background Osteoporosis is a skeletal disorder characterized by compromised bone strength, resulting in increased fracture risk. Patients with prostate cancer may have multiple risk factors contributing to bone fragility: advanced age, hypogonadism, and long-term use of androgen-deprivation therapy. Despite absence of metastatic disease, patients with nonmetastatic castrate-resistant prostate cancer receiving newer androgen receptor inhibitors can experience decreased bone mineral density. A systematic approach to bone health care has been hampered by a simplistic view that does not account for heterogeneity among prostate cancer patients or treatments they receive. This review aims to raise awareness in oncology and urology communities regarding the complexity of bone health, and to provide a framework for management strategies for patients with nonmetastatic castrate-resistant prostate cancer receiving androgen receptor inhibitor treatment. Methods We searched peer-reviewed literature on the PubMed database using key words “androgen-deprivation therapy,” “androgen receptor inhibitors,” “bone,” “bone complications,” and “nonmetastatic prostate cancer” from 2000 to present. Results We discuss how androgen inhibition affects bone health in patients with nonmetastatic castrate-resistant prostate cancer. We present data from phase 3 trials on the three approved androgen receptor inhibitors with regard to effects on bone. Finally, we present management strategies for maintenance of bone health. Conclusions In patients with nonmetastatic castrate-resistant prostate cancer, aging, and antiandrogen therapy contribute to bone fragility. Newer androgen receptor inhibitors were associated with falls or fractures in a small subset of patients. Management guidelines include regular assessment of bone density, nutritional guidance, and use of antiresorptive bone health agents when warranted.

Effects of Exercise During Radiation Therapy on Physical Function and Treatment-Related Side Effects in Men With Prostate Cancer: A Systematic Review and Meta-Analysis

“…In particular a decline in musculoskeletal fitness secondary to loss of lean mass with ageing and accelerated by ADT is thought to contribute to a reduced physical reserve capacity that may be prevented or even reversed by targeted resistance training [31]. Moreover, exercise has been shown to reduce the rate of falls in older people [32] and is an important strategy in osteoporosis management [33], thus reducing the risk of fractures, a concern particularly relevant for men treated with ADT [34]. In addition, poorer outcomes on physical performance tests have been associated with treatment-related complications and reduced survival in cancer patients [35].…”

Multidisciplinary Consensus on the Prevention and Treatment of Osteoporosis and Fragility Fractures in Patients with Prostate Cancer Receiving Androgen-Deprivation Therapy

“…Additional second-line AR antagonists hormonal treatments (enzalutamide, apalutamide, or darolutamide), CYP17A inhibition to further decrease androgen biosynthesis with abiraterone acetate and/or chemotherapy are frequently the 3 therapeutic mainstays during the CRPC stage [ 21 ]. A group of patients with substantial risk of osteoporosis and osteoporotic fractures are those with CRPC in the absence of clinically detectable metastatic disease, This group is referred to as non-metastatic CRPC [ 22 ], and represents about 2%–8% of the total PCa population [ 23 ]. Prescription of novel and more potent AR inhibitors in this population, in addition to prior long-term use of ADT, results in longer exposure times and consequently higher risk of osteoporotic fractures [ 22 ].…”

“…A group of patients with substantial risk of osteoporosis and osteoporotic fractures are those with CRPC in the absence of clinically detectable metastatic disease, This group is referred to as non-metastatic CRPC [ 22 ], and represents about 2%–8% of the total PCa population [ 23 ]. Prescription of novel and more potent AR inhibitors in this population, in addition to prior long-term use of ADT, results in longer exposure times and consequently higher risk of osteoporotic fractures [ 22 ].…”

“…These new antihormonal therapies are now being utilized earlier in the treatment of PCa. Therefore, patients with PCa are receiving more potent treatments and longer durations of intensified ADT, which increase further their risk of bone loss and fractures [ 22 ].…”

Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids

“…Standard-of-care APDTs, such as enzalutamide, can be helpful initially to prolong life; however, the majority of patients with bone metastases inevitably develop castration resistance [ 12 , 13 ]. As a result, many CRPC patients with bone metastases experience significant morbidity, including debilitating fractures and severe bone pain [ 14 , 15 ]. In addition, neuroendocrine PCa is emerging as a particularly aggressive, therapy-resistant metastatic PCa in patients treated with APDT [ 1 , 2 , 3 , 4 , 5 , 16 ].…”