Effect of ADT and ARPI on Bone Loss of Patients with Prostate Cancer

Prostate cancer is the second most common malignancy in men worldwide and ranks fifth in cancer mortality among men. In developed countries in Europe and America, it has the highest incidence rate. In recent years, with the development of the social economy, increased life expectancy, changes in lifestyle, and improvements in the level of medical and health care, the incidence of prostate cancer in China is gradually rising, posing a serious threat to the life safety of men. In China, more than half of the patients with newly diagnosed prostate cancer have advanced metastatic disease. The skeleton is the most common site of metastasis in these patients. Metastatic lesions may cause pathological fractures and spinal cord compression. Patients with extensive bone metastasis are prone to fatigue, weight loss, anemia, and in severe cases, even systemic organ failure. Hormonal therapy based on ADT remains the main treatment for advanced prostate cancer, with the goal of reducing or eliminating the promoting effect of androgens on cancer cell growth. While ADT treatment benefits patients with metastatic prostate cancer, it also leads to numerous side effects, such as cardiovascular diseases, changes in body composition, decreased bone mineral density (BMD), hot flashes, gynecomastia, cognitive decline, fatigue, anemia, and sexual dysfunction. ADT treatment can affect the number and function of osteoblasts and osteoclasts through various pathways, disrupting the balance of bone remodeling and leading to cancer treatment-induced bone loss. Under normal conditions, testosterone can be converted to estradiol via aromatase and bind to the estrogen receptors on the surface of osteoclasts, indirectly regulating these cells. With increasing age, the bioactivity of both testosterone and estrogen declines in normal men, resulting in low-turnover bone metabolic changes and a bone loss rate of 0.5% to 1% per year. In patients undergoing ADT, the levels of testosterone and estrogen decrease more significantly, and the number of osteoclasts increases markedly. Moreover, ADT treatment can reduce muscle mass and increase fat, leading to sarcopenic obesity, which is accompanied by chronic low-grade inflammation throughout the body and disrupts bone homeostasis. ADT may also lower the levels of circulating vitamin D, which not only affects bone mineralization but also has adverse effects on skeletal muscle and prostate cancer itself. Studies have shown that after 12 months of ADT treatment, the median lumbar spine BMD in patients decreased by an average of 3.6%, higher than that in untreated elderly men (0.5% to 1%). The BLADE study (NCT03202381) confirmed that long-term ADT treatment with either Gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists significantly reduces bone quality. In fact, bone loss caused by ADT treatment can also lead to skeletal-related events (SREs), represented by pathological fractures, bone radiotherapy, bone surgery, and spinal cord compression. ARPIs play a crucial role in the treatment of prostate cancer. Prostate cancer cells often rely on androgens for growth, and ARPIs work by blocking the androgen receptor pathway, thereby inhibiting the proliferation of cancer cells. These inhibitors, such as abiraterone, enzalutamide, and apalutamide, have significantly improved outcomes for patients with advanced prostate cancer, including those with metastatic castration-resistant prostate cancer (mCRPC). By reducing the levels of androgens or blocking their effects, ARPIs may also negatively impact bone quality in patients with prostate cancer. These agents, by reducing androgen levels, may lead to decreased BMD and increased fracture risk. The impact of combining ADT with ARPIs on bone quality remains unclear. While clinical trial data on ARPIs in nonmetastatic castration-resistant prostate cancer (nmCRPC) have shown mixed results regarding bone health. Further research is needed to fully understand the combined effects of ADT and ARPIs on bone quality. It is essential to gain a deeper understanding of the patterns of osteoporosis to provide most effective bone-protective therapies to prevent the occurrence of SREs.