French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation

Abstract

Androgen-deprivation therapy (ADT) in patients with prostate cancer can be achieved surgically or chemically, notably by prescribing LHRH analogs. Major bone loss occurs rapidly in both cases, due to the decrease in testosterone levels, and can increase the fracture risk. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on a literature review, about osteoporosis prevention and treatment in patients on ADT. The following scientific societies contributed to the work: Société française de rhumatologie (SFR), Groupe de recherche et d’information sur les ostéoporoses (GRIO), Groupe européen d’études des métastases osseuses (GEMO), Association francophone pour les soins de support (AFSOS), Association française d’urologie (AFU), Société française de radiothérapie oncologique (SFRO). Medication prescription and reimbursement modalities in France were taken into account. The recommendations state that a fracture-risk evaluation and interventions targeting risk factors for fractures should be provided to all patients on ADT. Those patients with a history of severe osteoporotic fracture and/or a T-score < −2.5 should receive osteoporosis therapy. Patients whose T-score is between −1.5 and −2.5 should be treated if they exhibit at least two other risk factors among the following: age ≥ 75 years, history of non-severe fracture after 50 years of age, body mass index < 19 kg/m², at least three comorbidities (e.g., cardiovascular disease, depression, Parkinson's disease, and dementia), current glucocorticoid therapy, and repeated falls. When the decision is difficult, FRAX® score determination and an assessment by a bone disease specialist may be helpful. When osteoporosis therapy is not indicated, general measures should be applied, and bone mineral density measured again after 12–24 months. The anti-tumor effects of bisphosphonates and denosumab fall outside the scope of these recommendations.

Introduction

Data collected in 2015 indicate that prostate cancer is by far the most common malignancy in males in continental France, with 53,913 new diagnoses per year, compared to 30,401 for lung cancer and 23,535 for colorectal cancer. The number of deaths due to cancer in males in continental France in 2015 was estimated at 84,041, with lung cancer being the leading cause (20,990 deaths), followed by colorectal cancer (9337 deaths) then by prostate cancer (8713 deaths) [1].

The treatment of localized prostate cancer depends on the risk of recurrence as determined based on the D’Amico risk classification [2], [3] (Table 1). The main treatment tools are radical prostatectomy, radiotherapy, and pharmacological androgen-deprivation therapy (PADT, also known as chemical castration). PADT is used chiefly in patients who are at intermediate and high risk according to the D’Amico risk classification, have metastases, or experience a biochemical recurrence.

PADT is more widely used than surgical orchiectomy and usually consists in administering an analog of luteinizing hormone-releasing hormone (LHRH), which binds to the pituitary LHRH receptors, thereby diminishing the production of LH and FSH and causing a drop in testosterone levels. A peripheral antiandrogen is given concomitantly for about 1 month to avoid initial transient stimulation of the pituitary with a flare-up of testosterone levels. In some situations, such as a risk of spinal cord compression, LHRH antagonists that directly block the pituitary LHRH receptors are given, as they cause no flare-up effect. Finally, peripheral antiandrogens can be used for PADT (Table 2).

The duration of PADT in patients with localized prostate cancer varies according to the level of risk, from about 6 months if the risk is intermediate [4], [5] to 18–36 months if the risk is high [6], [7]. In patients with metastatic disease, PADT can be given intermittently or continuously [8], [9], [10]. In the event of PADT resistance, continuous LHRH therapy is combined with second-generation hormone therapy (e.g., abiraterone [10] or enzalutamide [11]) or with cancer chemotherapy (e.g., docetaxel [12] or cabazitaxel [13]). Metabolic radiotherapy can also be used in patients with metastatic prostate cancer. In recent studies, radium–223 dichloride (Xofigo®, formerly Alpharadin®) increased the overall survival of patients with bone metastases from prostate cancer [14].

The most common adverse effects of PADT can be categorized as clinical (hot flashes, mastodynia, decreased size of the external genitalia, decreased libido, weight gain) and metabolic (insulin resistance, metabolic syndrome, dyslipidemia), increased risk of coronary artery disease, loss of muscle mass, and decreased hemoglobin levels) [15]. In addition, the decrease in testosterone levels induced by surgical or chemical castration causes major and rapid bone loss that predominantly affects the trabecular bone. Consequently, the fracture risk may increase, depending on patient age. Peripheral antiandrogens have no effects on bone, as they do not decrease the testosterone levels when used alone [15].