Patients with advanced prostate cancer are at significant risk of skeletal-related events (SREs) due to a complex interplay between bone health and prostate cancer due to cancer biology and the predilection of prostate cancer to spread to bone, the toxicity of prostate cancer treatments, and shared epidemiology of the two conditions.
Skeletal-related events are used to denote events related to osseous metastases, including pathologic bone fractures, spinal cord compression, orthopedic surgical intervention, and palliative radiation directed at the bone.1 This definition has been widely used in the design of randomized controlled trials and for drug approval. In some circumstances, authors include a change in systemic anti-neoplastic therapy as a result of bony pain in the definition of skeletal-related events. The key to this definition is that skeletal-related events may be clinically manifested due to symptoms or only radiographically detected. Thus, skeletal-related events may or may not be symptomatic. In contrast, symptomatic skeletal-related events (SSEs) is a relatively newer outcome representing a subset of skeletal-related events which symptomatically affect the patient experience. This outcome was first used in the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial,2 wherein symptomatic skeletal-related events were defined as bone-directed radiotherapy to relieve bony pain, new symptomatic pathologic fractures, spinal cord compression, or tumor-related orthopedic surgery. While there is a significant overlap between these conditions, there are important differences that relate to both study design and patient care: namely, detection of SREs requires routine radiographic evaluation to detect asymptomatic skeletal-related events while detection of SSEs can be driven by patient evaluation.
Skeletal related events contribute significantly to the disease-related morbidity and mortality of prostate cancer, in addition to being very costly. A range of lifestyle, nutritional, and pharmaceutical interventions can be undertaken to decrease the risk of skeletal-related events in patients with advanced prostate cancer.
Lifestyle and nutrition-based interventions
These recommendations are not unique to patients with prostate cancer, but rather apply to all men with osteoporosis or decreased bone mineral density to reduce the risk of fractures.
The Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends the following lifestyle interventions:3
- Calcium intake: it is recommended that men with or at risk for osteoporosis consume 1000 to 1200 mg of calcium daily. While dietary sources are preferable, calcium supplementation should be used if dietary calcium intake is inadequate.
- Vitamin D intake: men with low vitamin D levels (< 30 ng/mL or < 75 nmol/L) should receive vitamin D supplementation to raise serum vitamin D levels to at least these levels.
- Exercise: men at risk of osteoporosis are recommended to participate in weight-bearing activities at least three or four times per week, for 30 to 40 minutes per session.
- Alcohol intake: it is recommended that men at risk of osteoporosis reduce their alcohol intake to fewer than three units of alcohol. One unit of alcohol is defined as 10 mL of pure alcohol. This amount could be found in 25 mL of spirits (40% alcohol by volume), one third to one half a pint of beer (5-6% alcohol by volume), or half a standard glass of wine (12% alcohol by volume).
- Smoking cessation: it is recommended that all men at risk of osteoporosis stop smoking.
The American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer similarly endorses preventative therapy in the form of supplemental calcium and vitamin D in men with castration-resistant prostate cancer.4 However, such interventions are likely advisable much earlier in the disease trajectory given the relatively minor risks of these supplements in contrast to the potentially debilitating and costly consequences of skeletal-related events. To this end, the NCCN and the National Osteoporosis Foundation recommend these interventions in all men over the age of 50 years who are receiving androgen deprivation therapy.
In addition to calcium and vitamin D as highlighted above, the American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer endorses pharmacotherapy with denosumab or zoledronic acid in men with castration-resistant prostate cancer.4
While further indications exist, the Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends pharmacologic therapy in men at high risk for fracture based on, but not limited to, the following factors:3
- Men with a history of previous non-traumatic hip or vertebral fracture.
- Men with bone mineral density (T-score) that is 2.5 standard deviations or more below the mean of normal young white men, in the absence of spine or hip fractures.
- Men with a bone mineral density (T-score) from 1.0 to 2.5 standard deviations who also have an increased risk of fracture. In the United States, the suggested criteria for increased risk of fracture are a 10-year risk of any fracture equal to or exceeding 20% or a 10-year risk of hip fracture equal to or exceeding 3%, as determined using the FRAX tool. In other regions, the Guidelines recommend the utilization of region-specific guidelines.
- Men who are receiving long-term glucocorticoid treatment in significant doses defined by the 2010 American Society of Rheumatology as > 7.5 ng per day of prednisone or equivalent.
Pharmaceuticals - bisphosphonates
Bisphosphonates were among the first agents successfully used to prevent skeletal-related events in advanced prostate cancer. They function by reducing bone resorption through a variety of mechanisms including decreased osteoclast differentiation and survival and increased osteoblast survival. To do so, they compete with pyrophosphate for hydroxyapatite crystal binding sites, thus reducing osteoclast adherence to the bone. While there are a number of bisphosphonates used for a variety of clinical indications, zoledronic acid is most commonly used in patients with metastatic prostate cancer due to the Zometa 039 trial which demonstrated a reduction in SREs for patients who received zoledronic acid as compared to placebo.5 Based on these data, zoledronic acid is the only bisphosphonate approved for the prevention of skeletal-related events in men with metastatic prostate cancer.
Pharmaceuticals - denosumab
Denosumab is another agent which targets osteoclast activity. Bone exists in homeostasis between formation (driven by osteoblasts) and resorption (driven by osteoclasts). This homeostasis is regulated by the RANK (receptor activator of nuclear factor κB)/RANK-ligand system. Denosumab is a fully human monoclonal antibody that targets the RANK-ligand by mimicking OPG. Denosumab was first examined in postmenopausal women to prevent the development of osteoporosis and reduce the risk of fracture. Subsequently, denosumab was examined in women with breast cancer. Most relevantly, the Denosumab Protocol 20050103 compared denosumab and zoledronic acid in 1901 men with castrate-resistant prostate cancer.6 After a median follow-up of approximately one year, patients receiving denosumab had a significantly prolonged time to first-SRE (3.6 months incremental benefit, hazard ratio 0.82, 95% confidence interval 0.71 to 0.95). As a result of these data, denosumab was approved for the prevention of SREs in patients with metastatic solid tumors.
Pharmaceuticals – radio-isotopes
In addition to these osteoclast targeting agents, radio-isotopes may be used in the prevention of skeletal-related events. While beta-emitting particles (strontium-89 and samarium-153) may be used in the palliation of disease-related bony pain, they don’t have proven benefit in the prevention of SREs. In contrast, the alpha-emitting particle radium-223 has proven both palliative benefit as well as improvements in time to first SRE and overall survival. In the pivotal ALSYMPCA trial, 922 men with castrate-resistant prostate cancer and at least two symptomatic bony metastases who had either previously received or were unfit to receive docetaxel were randomized to radium-223 or placebo. Patients receiving radium-223 had significant improvements in time to first SRE (incremental benefit 5.2 months) as well as overall survival (incremental benefit in median survival of 2.8 months).2
Approach to preventing skeletal-related events
Philosophically, there are a number of times in the natural history of prostate cancer where a clinician may intervene to reduce the risk of prostate cancer related skeletal-related events. These relate to the complex interplay between prostate cancer and bone disease.
First, treatment may be directed at reducing or preventing fragility fractures due to prostate cancer-related therapy. In this disease space, lifestyle and nutrition-based interventions are paramount and are recommended by AUA guidelines as well as the National Comprehensive Cancer Network (NCCN). Pharmacologic interventions, including the use of osteoclast targeting therapies (bisphosphonates and RANK-ligand inhibitors), should be considered in this setting for patients at increased risk of fragility related fracture. Denosumab is FDA approved for this indication on the basis of the HALT 138 trial which found an increase in bone mineral density and a decrease in vertebral fractures among men receiving ADT for non-metastatic hormone-sensitive prostate cancer who receiving denosumab versus placebo.
Second, treatment may be directed at preventing bone metastases. In this disease space, bone-targeting agents including bisphosphonates and denosumab have been examined. The MRC PR04 trial demonstrated no benefit to clodronate in metastasis-free survival. Unfortunately, the Zometa 704 trial assessing the role of zoledronic acid in men with non-metastatic castration-resistant prostate cancer failed to accrue. However, the ZEUS trial accrued 1393 men with high-risk localized prostate cancer. Treatment with zoledronic acid failed to demonstrate an improvement in bone metastasis compared to placebo.7 The Denosumab Protocol 20050147 randomized men with high-risk nonmetastatic castrate-resistant prostate cancer to denosumab or placebo. Men receiving denosumab had prolonged metastasis-free survival (incremental benefit of 4.2 months).8
However, other approaches utilizing the suppression of the androgen axis in patients with non-metastatic castration-resistant prostate cancer (enzalutamide, apalutamide, and darolutamide) have demonstrated improvements in metastasis-free survival. While not a primary endpoint of these studies, it would be anticipated that delaying metastasis may improve skeletal-related events in these patients.
Third, we may seek to prevent skeletal-related events in men with known metastatic prostate cancer. This applies whether these men are in the castrate-sensitive or castrate-resistant disease space and it is here that the bulk of the evidence for prevention of SREs lies. In men with castrate-sensitive disease, CALGB 90202 demonstrated no improvement in skeletal-related events with the administration of zoledronic acid while castrate-sensitive rather than delayed initiation at the time of castration resistance.9 In contrast, there is significant evidence for the role of bone targeting agents in men with castrate-resistant disease. As previously mentioned, Zometa 039 demonstrated improvements in SREs for men receiving zoledronic acid compared with a placebo. Interestingly, CGP 032 and INT 05 failed to demonstrate a benefit to pamidronate. Thus, zoledronic acid is the only bisphosphonate approved in this space. The Denosumab Protocol 20050103 demonstrated an improvement in time to first SRE, as previously mentioned. Further, radio-isotope therapy using radium-223 was demonstrated in ALSYMPCA to improve time to first SRE in men with castrate-resistant prostate cancer and at least two symptomatic bony metastases.
Christopher J.D. Wallis, MD PhD, Urologic Oncology Fellow and Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee
Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md