Eric Johnson and Sumati Gupta are Oncologists, and Katerina Butler is a Clinical Oncology Pharmacist; all at George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, Utah. Eric Johnson is a Clinical Fellow and Sumati Gupta is an Assistant Professor, both at Huntsman Cancer Institute at the University of Utah in Salt Lake City. Correspondence: Eric Johnson (eric.johnson@hci.utah.edu)
Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.
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Background: The veteran population has an increasingly high number of patients who have either survived, are currently living with, or are being treated for prostate cancer. Survivorship concerns related to the treatment of this disease is a relevant topic in the Veterans Health Administration, given the longevity of life with localized disease treatment and the fairly durable therapies for metastatic disease. Long-term androgen deprivation therapy (ADT) forms the backbone of treatment for advanced and metastatic castration-sensitive prostate cancer.
Observations: The potential bone-health complications resulting from treatment with ADT should be recognized as many patients live for prolonged periods with stable or controlled disease. It is well established that prolonged ADT can lead to significant bone loss and increased fracture risk, which increases all-cause mortality and disability. Bone-remodeling agents, such as bisphosphonates and receptor-activated nuclear factor κ -B ligand inhibitors, are recommended to reduce the risk of fragility fractures in patients at high risk due to diminished bone density while on hormone deprivation therapy for hormone-naive prostate cancer. These agents are also indicated at a higher dose to prevent complications from bone metastases in castration-resistant prostate cancer with bone metastases.
Conclusions: This article reviews recent studies on bone health in men with prostate cancer and presents an evidence-based algorithm for bone-health monitoring during treatment and recommended interventions.
Prostate cancer (PC) is the most commonly and newly diagnosed nonskin cancer and the second leading cause of cancer death in men in the United States. About 191,930 cases and about 33,330 deaths from PC were expected for the year 2020.1 About 1 in 41 men will die of PC. Most men diagnosed with PC are aged > 65 years and do not die of their disease. The 5-year survival rate of localized and regional disease is nearly 100%, and disease with distant metastases is 31%. As a result, more than 3.1 million men in the United States who have been diagnosed with PC are still alive today.1 Among veterans, there is a substantial population living with PC. Skolarus and Hawley reported in 2014 that an estimated 200,000 veterans with PC were survivors and 12,000 were newly diagnosed.2
In PC, skeletal strength can be affected by several factors, such as aging, malnutrition, androgen-deprivation therapy (ADT), and bone metastasis.3,4 In fact, most men can live the rest of their life with PC by using strategies to monitor and treat it, once it shows either radiographic or chemical signs of progression.5 ADT is the standard of care to treat hormone-sensitive PC, which is associated with significant skeletal-related adverse effects (AEs).6,7
Men undergoing ADT are 4 times more likely to develop substantial bone deficiency, Shahinian and colleagues found that in men surviving 5 years after PC diagnosis, 19.4% of those who received ADT had a fracture compared with 12% in men who did not (P < .001). The authors established a significant relation between the number of doses of gonadotropin-releasing hormone given in the first 12 months and the risk of fracture.8 Of those who progressed to metastatic disease, the first metastatic nonnodal site is most commonly to the bone.9 Advanced PC is characterized by increased bone turnover, which further raises concerns for bone health and patient performance.10
Skeletal-related events (SREs) include pathologic fracture, spinal cord compression, palliative radiation, or surgery to bone, and change in antineoplastic therapy secondary to bone pain. The concept of bone health refers to the prevention, diagnosis, and treatment of idiopathic, pathogenic, and treatment-related bone loss and delay or prevention of SREs.6,11 Guidelines and expert groups have recommended screening for osteoporosis at the start of ADT with bone mineral density testing, ensuring adequate calcium and vitamin D intake, modifying lifestyle behaviors (smoking cessation, alcohol moderation, and regular exercise), and prescribing bisphosphonates or receptor-activated nuclear factor κ-B ligand inhibitor, denosumab, for men with osteoporosis or who are at general high-fracture risk.12,13 The overuse of these medications results in undue cost to patients as well as AEs, such as osteonecrosis of the jaw (ONJ), hypocalcemia, and bone/joint pains.14-17 There are evidence-based guidelines for appropriate use of bisphosphonates and denosumab for delay and prevention of SREs in the setting of advanced PC.18 These doses also typically differ in frequency to those of osteoporosis.19 We summarize the evidence and guidance for health care providers who care for patients with PC at various stages and complications from both disease-related and treatment-related comorbidities.
Bone-Strengthening Agents
Overall, there is evidence to support the use of bone-strengthening agents in patients with osteopenia/osteoporosis in the prevention of SREs with significant risk factors for progressive bone demineralization, such as lifestyle factors and, in particular, treatments such as ADT. Bone-remodeling agents for treatment of bony metastasis have been shown to provide therapeutic advantage only in limited instances in the castration-resistant PC (CRPC) setting. Hence, in patients with hormone-sensitive PC due to medication-related AEs, treatment with bone-strengthening agents is indicated only if the patient has a significant preexisting risk for fracture from osteopenia/osteoporosis (Table). The Figure depicts an algorithm for the management of bone health in men with PC who are being treated with ADT.
Denosumab and bisphosphonates have an established role in preventing SREs in metastatic CRPC.20 The choice of denosumab or a bisphosphonate typically varies based on the indication, possible AEs, and cost of therapy. There are multiple studies involving initiation of these agents at various stages of disease to improve both time to progression as well as management of SREs. There is a lack of evidence that bisphosphonates prevent metastatic-bone lesions in castration-sensitive PC; therefore, prophylactic use of this agent is not recommended in patients unless they have significant bone demineralization.21,22
