Approximately 16% of men with prostate cancer in the United Kingdom have metastatic disease at diagnosis,¹ with bone being the most common site of spread.² Progression of bone metastases can lead to skeletal events including pathological fracture, spinal cord compression, or significant bone pain, and the incidence of skeletal related events is high (44% at 5 years).³ Androgen deprivation therapy (ADT), the mainstay treatment for metastatic prostate cancer, leads to disruption of bone remodeling, resulting in rapid and progressive bone density loss^4,5 occurring within 12 months of starting treatment.^6,7 Coupled with a higher incidence of osteoporosis at diagnosis compared with age-matched controls,⁸ men with locally advanced and metastatic prostate cancer on long-term ADT have a significantly increased risk of fracture.⁹ In addition to the effects on bone health, ADT leads to decreased muscle mass and increased visceral and subcutaneous fat, contributing to the metabolic syndrome.^10,11 Effects on body composition occur early, typically within 3 to 12 months of starting ADT.¹² Loss of muscle mass, termed sarcopenia, increases the risk of fall and fracture¹³ and is an independent risk factor for cancer-specific survival in men with metastatic prostate cancer.¹⁴

Recent treatment advances have led to significant survival improvements with the addition of androgen receptor signaling inhibitors to ADT for men with metastatic prostate cancer.^15-18 A meta-analysis of data from 14 randomized clinical trials involving 17,411 patients demonstrated an increased risk of both fractures and falls in men with prostate cancer treated with the addition of an androgen receptor signaling inhibitor compared to their respective control.¹⁹

Clinical guidelines currently recommend bone protection, including bisphosphonates and the receptor activator of nuclear factor kappa-B ligand inhibitor denosumab, only to men at increased risk of fracture determined by bone density assessment using dual-energy x-ray absorptiometry or fracture risk assessment tools including FRAX.²⁰ Both of these methods have significant limitations in predicting risk of fracture in men with metastatic bone disease on long-term ADT.²¹ Recent data from the STAMPEDE trial highlight the high cumulative incidence of clinical fractures in men with newly diagnosed metastatic disease and the significant risk reduction with the addition of zoledronic acid, albeit with a dose that was higher than would typically be used for osteoporosis (4 mg 3-weekly for 6 doses then 4-weekly for 2 years vs 5 mg once/twice yearly). However, data from the CALBG 90202 trial failed to show a significant reduction in skeletal related events with use of early zoledronic acid in patients with metastatic hormone-sensitive prostate cancer.²² There is good evidence that denosumab prevents bone density loss and reduces the risk of vertebral fractures in men with prostate cancer.²³ An important consideration with denosumab is the risk of rebound vertebral fractures following discontinuation.²⁴ Patients on zoledronic acid or denosumab should undergo regular dental checks due to risk of jaw osteonecrosis, which is more common at higher doses.²⁵ Calcium and vitamin D supplementation are encouraged for all patients on lifelong ADT, along with regular weight-bearing exercise. However, these methods alone are unlikely to be sufficient on their own.²⁶ The STAMINA trial, currently recruiting in the United Kingdom, is evaluating the effectiveness of long-term supervised exercise in men on ADT.²⁷

Metformin may also help to mitigate the deleterious side effects of ADT along with potential anticancer effects: This is under evaluation in the STAMPEDE trial’s metformin comparison and in its associated metabolic substudy, which recently closed recruitment.²⁸ Alternative approaches to ADT using transdermal estrogen have shown promising results in preserving bone density compared with luteinizing hormone-releasing hormone agonists.²⁹ Data from these studies and others are awaited.

In summary, patients with metastatic prostate cancer are now living longer and, consequently, they have a higher risk of skeletal complications, including fracture. Clinicians should advise patients about the known musculoskeletal side effects of ADT. Bone-protective agents should be considered for patients starting long-term ADT to help limit bone density loss. New data from STAMPEDE have shown significant fracture risk reduction by adding zoledronic acid to ADT. However, more data are needed to determine the optimum dose and schedule of bone protection agents, weighing this against potential toxicities. Focusing on survivorship rather than just survival, it is important to explore the role of alternative treatments and strategies which may help mitigate the unwanted toxicities associated with long-term ADT.