Maintaining bone health is important in the management of men with prostate cancer. Patients receiving androgen deprivation therapy are at increased risk for treatment-related osteoporosis, and patients with bone metastases are at increased risk for skeletal morbidity related to debilitating skeletal-related events (SREs). Optimizing bone health in these patients includes lifestyle modifications, calcium/vitamin D supplementation, and osteoclast-targeted agents in select high-risk patients. No agent is approved for the prevention of bone metastases. Novel systemic agents have shown a beneficial effect bone by directly affecting tumor growth. Integration of these anticancer agents with osteoclast-targeted agents warrants further investigation.
Key points
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Patients with prostate cancer are at increased risk of skeletal complications.
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Treatment-related osteoporosis is an established risk for patients receiving androgen deprivation therapy.
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Several agents, including bisphosphonates, receptor activator of nuclear factor-κβ ligand inhibitors, and selective estrogen receptor modulators, have shown benefit in the management of treatment-related osteoporosis.
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Patients with bone metastases from prostate cancer are at increased risk of skeletal-related events (SREs).
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Zoledronic acid and denosumab are effective in preventing SREs in patients with castration-resistant prostate cancer with bone metastases.
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Radium-223, a radiopharmaceutical that targets bone, is effective at preventing SREs and improving survival in patients with metastatic castration-resistant prostate cancer.
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Systemic agents, including abiraterone and enzalutamide, are active in preventing SREs, given efficacy in disease control.
Introduction
Prostate cancer is the most common cancer in men in the United States, with a lifetime risk of 16%, and is the second leading cause of death in this population. Patients on androgen deprivation therapy (ADT) or those with bone metastases are susceptible to skeletal complications. Therefore, optimizing bone health is critical in the management of patients with prostate cancer.
Introduction
Prostate cancer is the most common cancer in men in the United States, with a lifetime risk of 16%, and is the second leading cause of death in this population. Patients on androgen deprivation therapy (ADT) or those with bone metastases are susceptible to skeletal complications. Therefore, optimizing bone health is critical in the management of patients with prostate cancer.
Normal bone physiology
Normal bone remodeling is the process by which bone is renewed to maintain strength and mineral homeostasis. It involves the coordinated actions of osteoclasts, responsible for bone resorption, and osteoblasts, which mediate bone formation ( Fig. 1 ).
The receptor activator of nuclear factor-κβ ligand (RANKL) is a critical cytokine in the remodeling process. RANKL, which is released from osteoblasts and bone marrow stromal cells, binds to RANK receptors on monocyte/macrophage precursor cells, thus promoting osteoclast differentiation, activation, and survival. Subsequently, mature, multinucleated osteoclasts adhere to the bone matrix. They undergo structural changes to form resorption lacunae and export acid and lytic enzymes into the lacunae, which leads to hydroxyapatite decalcification and bone degradation. Osteoprotegerin (OPG), which is secreted from osteoblasts and stromal cells, competitively blocks RANKL binding to its cellular receptor RANK. The RANKL/RANK/OPG regulatory axis results in tight coupling of the process of bone remodeling. Certain hormones, cytokines, and humoral factors influence bone homeostasis. Proresorptive factors include parathyroid hormone (PTH), PTH-related protein (PTHrP), interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF), prostaglandin E 2 , and vitamin D.
Osteoblasts arise from osteoprogenitor cells, which are induced to differentiate under the influence of bone morphogenetic proteins (BMPs), estrogens, calcitonin, transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF). The Wnt signaling pathway and runt-related transcription factor 2 are critical for the initiation of osteoblast differentiation. Mature osteoblasts form the connective tissue matrix, which mineralizes to become bone. Thus, the coupling of osteoclast and osteoblast function maintains bone homeostasis.
Treatment-related osteoporosis
ADT is the mainstay of systemic treatment of prostate cancer. The intended therapeutic effect of ADT is severe hypogonadism, a common cause of osteoporosis in men. Based on retrospective SEER (Surveillance Epidemiology and End Results)/Medicare claims data, in men diagnosed with prostate cancer between 2000 and 2002, approximately 45% were exposed to ADT at some point after their diagnosis. In addition, the prevalence of ADT is increasing in the United States.
Bone mineral density (BMD), a surrogate for fracture risk, decreases in men receiving ADT. A rapid loss of BMD occurs within the first 12 months of therapy. Based on a review of data from clinical trials and retrospective studies, rates of bone loss in the lumbar spine ranged from 2% to 8% and from 1.8% to 6.5% in the femoral neck during the initial 12 months of ADT. Typically, men 50 years and older not receiving ADT lose BMD at a rate of 0.5% per year. BMD continues to decline with ADT treatment beyond 12 months.
In addition to decreased BMD, ADT use in men is associated with an increased risk of clinical osteoporosis-related bone fractures. In a SEER/Medicare claims study of more than 50,000 men diagnosed with prostate cancer, of men surviving at least 5 years after diagnosis, men who received ADT had a significantly higher fracture rate compared with men not receiving ADT (19.4% vs 12.6%; P <.001). The risk of fracture increased with longer duration of therapy. This study included patients with both metastatic and nonmetastatic disease. In another Medicare claims study of more than 11,000 patients, men with nonmetastatic prostate cancer receiving gonadotropin-releasing hormone (GnRH) agonist therapy were more likely to develop fractures than a control group of men with nonmetastatic prostate cancer not receiving GnRH-agonist treatment (relative risk [RR] 1.21; 95% confidence internal [CI] 1.14–1.29; P <.001). Patients receiving less than 1 year of therapy were not at increased fracture risk. Based on retrospective data, there is evidence to suggest that skeletal fracture is an independent negative predictor of survival in patients with prostate cancer (both nonmetastatic and metastatic).
Testosterone and estrogen are essential in regulating bone integrity in men. The direct effect of estrogen on osteocytes, osteoclasts, and osteoblasts leads to inhibition of bone remodeling, decreased bone resorption, and maintenance of bone formation, respectively. In a study examining the relative contributions of testosterone versus estrogen toward regulating bone metabolism in men, estrogen accounted for 70% of the total effect of sex steroids on bone resorption in older men. Based on results from a prospective study, older men with low estradiol were at greater risk for low BMD and increased fracture.
Given that testosterone undergoes peripheral aromatization to form estradiol, men treated with ADT also have low estrogen states. In a prospective study of men initiating ADT for nonmetastatic prostate cancer, there was a 73% decrease in serum estradiol from baseline pretreatment levels to after 48 weeks of treatment. Low estrogen states are associated with an imbalance between bone resorption and formation, resulting in decreased BMD and increased risk of fracture.
Bone metastases in prostate cancer
The skeleton is the most frequent site of metastases in advanced prostate cancer, with estimates of involvement between 80% and 90% in castration-resistant prostate cancer (CRPC). The most common sites of involvement include the vertebral column, pelvis, ribs, long bones, and skull. Although prostate cancer causes radiographically dense osteoblastic lesions, the woven bone produced by osteoblasts is structurally weak. Pain is a common symptom associated with the presence of bone metastases. In addition, patients are at risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for skeletal radiation, need for surgery to the bone, and, in some cases, hypercalcemia. The rate of SREs in patients with bone metastases and CRPC ranges from 40% to 50%.
Bone metastases in prostate cancer promote increased osteoblast and osteoclast activity, as made evident by increased biochemical markers of bone turnover. It is postulated that interactions between tumor cells and the bone microenvironment result in a vicious cycle of bone destruction and aggressive tumor growth ( Fig. 2 ). Production of interleukins, prostaglandins, and parathyroid hormone-related protein (PTH-rP) by tumor cells stimulates osteolysis, leading to the release of factors and cytokines derived from the bone matrix. These factors, including TGF-β and PDGF, induce tumor cell proliferation, leading to propagation of the vicious cycle of tumor growth and bone destruction.
Osteoclast-targeted therapies
Bisphosphonates
Bisphosphonates are stable analogues of a naturally occurring inorganic pyrophosphate ( Fig. 3 ). Bisphosphonates have 2 additional side-chains (R 1 and R 2 ), which are not present on pyrophosphate. In general, a hydroxyl substitution at R 1 enhances the affinity of bisphosphonates for calcium, whereas the presence of a nitrogen atom in R 2 enhances the potency of the compound and determines the mechanism of action. Table 1 highlights the potency of available bisphosphonates based on in vitro assays.
| Agent | Relative Potency |
|---|---|
| Non–Nitrogen-Containing Bisphosphonates | |
| First generation | |
| Etidronate | 1 |
| Clodronate | 10 |
| Nitrogen-Containing Bisphosphonates | |
| Second generation | |
| Alendronate | 100 |
| Pamidronate | 100–1000 |
| Third generation | |
| Neridronate | 100 |
| Risedronate | 1000–10,000 |
| Ibandronate | 1000–10,000 |
| Zoledronate | >10,000 |
Bisphosphonates bind to hydroxyapatite crystals on exposed bone. They are released in the acidic environment of the resorption lacunae and are taken up by osteoclasts via endocytosis. Non-nitrogen–containing bisphosphonates incorporate into adenosine triphosphate and induce osteoclast apoptosis. Nitrogen-containing bisphosphonates induce changes in the cytoskeleton of osteoclasts, including loss of the ruffled border, leading to osteoclast inactivation and apoptosis. This action is mainly the result of inhibition of farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway, which plays a key role in cholesterol biosynthesis. In addition to their inhibitory effect on osteoclasts, bisphosphonates seem to have a beneficial effect on osteoblasts.
Bisphosphonates have poor oral bioavailability, with absorption of only about 1% of an oral dose ( Table 2 ). Approximately 50% of the absorbed bisphosphonate is rapidly cleared by the kidney, with a half-life of approximately 1 hour, and the remaining 50% is taken up by bone, and may persist there for years.
| Drug | Mechanism of Action | Bioavailability | Half-Life (d) | Clearance | Dose Modification |
|---|---|---|---|---|---|
| Zoledronic acid | Binds to hydroxyapatite crystals on exposed bone | 1% (oral), 100% (IV) | Triphasic | Renal | Yes a |
| Denosumab | Monoclonal antibody to RANKL | 62% (subcutaneous) | 25 | Reticuloendothelial system | No b |
a Dose modification is based on renal function. Trials of zoledronic acid in men with prostate cancer excluded patients with creatinine clearance rate <30 mL/min. Use is not recommended in patients with creatinine clearance rate <30 mL/min or on dialysis given risk of hypocalcemia and worsening renal function.
b No adjustment is necessary when administered every 6 months. Once-monthly dosing has not been evaluated in patients with renal impairment. Patients with creatinine clearance rate <30 mL/min or on dialysis require close monitoring because of increased risk of hypocalcemia.
Therapy with bisphosphonates is associated with adverse side effects, including hypocalcemia, renal impairment, osteonecrosis of the jaw (ONJ), and acute phase reactions. Bisphosphonates with greater potency and those administrated intravenously (IV) have a greater potential for adverse events. Bisphosphonates require dose modification for renal impairment and are not recommended for patients with a creatinine clearance rate less than 30 mL/min, given risk of hypocalcemia and worsening renal failure. ONJ is a well-recognized complication of bisphosphonate treatment. In patients with bone metastases receiving higher doses of IV therapy, the incidence is approximately 1% to 12%. The Southwest Oncology Group is investigating the incidence, risk factors, and outcomes associated with ONJ in a prospective trial seeking to enroll a total of 7200 patients. Risk factors for the development of ONJ include head and neck radiotherapy, periodontal disease, and dental extractions. About 30% of patients treated with IV zoledronic acid are at risk of an acute phase reaction, associated with fevers, myalgias, and nausea, which can occur within the first several days following administration, but diminishes in duration and intensity.
Receptor Activator of Nuclear Factor-κβ Ligand Inhibitors
Denosumab is a fully human monoclonal antibody administered subcutaneously that has high affinity and specificity for RANKL. It mimics the action of OPG by binding RANKL and reducing the activity of osteoclasts. Unlike bisphosphonates, denosumab does not accumulate in bone and has a longer circulatory half-life (>25 days) (see Table 2 ). Although there are no recommendations for dose adjustment for renal insufficiency, patients with severe renal insufficiency are more prone to hypocalcemia. In addition, use of monthly denosumab is not advised when creatinine clearance rate is less than 30 mL/min, given limited studies in this patient population.
Management of treatment-related osteoporosis
Defining Osteoporosis
The definition and diagnosis of osteoporosis in men relies, at least in part, on female standards. The World Health Organization (WHO) recommends using the same classification of BMD to define osteoporosis in men, aged 50 years and older, as in women :
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Normal is defined as a T-score greater than –1.0.
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Osteopenia is defined as a T-score between –1.0 and –2.5.
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Osteoporosis is defined as a T-score of less than or equal to –2.5.
The T-score is reported as the number of standard deviations (SDs) that a patient’s BMD value is higher or lower than the reference value for a healthy 30-year-old adult. Fracture risk increases approximately 2-fold for every SD decrease in BMD.
Who to Consider for Screening and Treatment?
The National Comprehensive Cancer Network guidelines recommend screening and treatment of osteoporosis in men with prostate cancer according to the National Osteoporosis Foundation (NOF) guidelines for the general population ( Table 3 ). In the past, BMD was the primary factor used to assess fracture risk, although most fractures occurred in men with BMD measurements not in the osteoporotic range. Given that there was a need for more sensitive risk determination, in 2008 the WHO introduced the Fracture Risk Assessment Tool (FRAX), which estimates the 10-year probability of hip fracture and major osteoporotic fracture for untreated patients between ages 40 and 90 years using clinical risk factors for fracture and femoral neck BMD if available ( http://www.shef.ac.uk/FRAX/ ). The FRAX algorithm is integrated into the NOF recommendations for treatment. Application of the NOF treatment guidelines to men in MrOS (Osteoporotic Fractures in Men Study) estimated that 34% of US white men aged 65 years and older and 49% of men aged 75 years and older would be recommended for treatment. In a study of 363 men receiving ADT for prostate cancer, the FRAX algorithm without BMD assessment estimated that 51.2% of men met criteria for pharmacologic intervention. The FRAX algorithm with BMD assessment estimated that 15% of men met criteria for pharmacologic intervention. Although the FRAX algorithm uses epidemiologic data from the general population, it is still a reasonable strategy to determine fracture risk in men receiving ADT for prostate cancer. To monitor effectiveness of treatment, the NOF recommends baseline BMD assessment with repeat testing every 2 years, recognizing that more frequent testing may be warranted in certain clinical situations.
| Screening recommendations | All men age 70 y or older |
| Adults who have a fracture after age 50 y | |
| Adults with a condition or taking a medicine associated with low bone mass or bone loss | |
| Anyone being considered for pharmacologic therapy for osteoporosis | |
| Anyone being treated for osteoporosis, to monitor treatment effect | |
| Men ≥50 y of age presenting with the following should be considered for treatment | Hip or vertebral fracture (both clinical or radiological) |
| T-score ≤–2.5 at the femoral neck or spine after evaluation to exclude secondary causes | |
| Low bone mass as defined by T-score between –1.0 and –2.5 at the femoral neck or spine and 10-y probability of a hip fracture ≥3% or a 10-y probability of a major osteoporosis-related fracture ≥20% based on the US-adapted WHO/FRAX algorithm ( http://www.shef.ac.uk/FRAX/ ) |
Pharmacologic Interventions for Treatment-Related Osteoporosis
Several agents including bisphosphonates, RANKL inhibitors, and selective estrogen receptor modulators (SERMs) have shown benefit in the management of treatment-related osteoporosis ( Table 4 ). The efficacy of bisphosphonates has been shown in small studies that reported improvement in BMD; however, these studies were not powered to assess fracture risk. Denosumab and toremifene have both been evaluated in phase 3 trials and showed improved BMD and decreased fracture risk. Despite efficacy of these treatments, the optimal agent, schedule, and duration of therapy remain in question.
| Trial | Number of Patients | Population | Treatment | Primary End Point | Outcome |
|---|---|---|---|---|---|
| Denosumab HALT 138 | 1468 | Men with nonmetastatic prostate cancer treated with ADT at high risk of fracture (age ≥70 y, low BMD, or history of osteoporotic fracture) | Denosumab 60 mg subcutaneous every 6 mo vs placebo × 2 y | Percent change in BMD at lumbar spine at 24 mo | Improvement in BMD at all sites and decreased incidence of new vertebral fractures (1.5% vs 3.9%; P = .006) |
| Toremifene | 1284 | Men with nonmetastatic prostate cancer treated with ADT at high risk of fracture (age ≥70 y or low BMD) | Toremifene 80 mg orally daily vs placebo × 2 y | Incidence of new vertebral fractures | Improvement in BMD at all sites and decreased incidence of new vertebral fractures (2.5% vs 4.9%; P = .05) |
Bisphosphonates
Although multiple bisphosphonates including neridronate (Nerixia), alendronate (Fosamax), pamidronate (Aredia), and zoledronic acid have been shown to decrease bone turnover and improve BMD in men receiving ADT, none has reported statistically significant improvement in the rates of fragility fractures. These were smaller studies designed to primarily evaluate BMD as a surrogate end point. In a meta-analysis of 2634 men with prostate cancer (including both nonmetastatic and metastatic disease), treatment with bisphosphonate therapy had a substantial effect in preventing fractures (RR 0.80; P = .005) and osteoporosis (RR 0.39; P <.00001). Given limited clinical data in men with ADT-associated bone loss, there still exists significant controversy regarding choice of agent, dose, and schedule. Compared with what is typically used for the prevention of SREs in patients with metastatic disease, dosing is appreciably less for the management of treatment-related osteoporosis.
Receptor activator of nuclear factor-κβ ligand inhibitors
The Denosumab HALT (Hormone Ablation Bone Loss Trial) 138 study, a multicenter, double-blind, randomized, placebo-controlled trial, enrolled 1468 men receiving ADT at increased risk of fracture given age 70 years or older, low BMD defined as a T-score less than –1, or a history of an osteoporotic fracture. Patients were randomly assigned to treatment with denosumab 60 mg subcutaneously every 6 months for 24 months or placebo. The primary end point was percent change in BMD at the lumbar spine at 24 months. A secondary end point included incidence of new vertebral fractures. The study reported statistically significant increased BMD at the lumbar spine (6.7% difference between groups), total hip (4.8% difference between groups), femoral neck (3.9% difference between groups), and distal third of the radius (5.5% difference between groups) at 24 months. In addition, patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9%; P = .006). The rates of adverse events were similar between the 2 groups. There was 1 person with hypocalcemia in the treatment arm and zero in the placebo arm. There were no documented cases of ONJ in either group.
SERMs
SERMs have shown benefit in men treated with ADT for prostate cancer secondary to their agonist activity at the estrogen receptor in bone. In a phase 3, international, double-blind, randomized, placebo-controlled trial, 1284 men with nonmetastatic prostate cancer treated with ADT were randomized to toremifene (Fareston) or placebo for 2 years. Patients were at high risk for fracture given age 70 years or older or osteopenia. The primary end point was incidence of new vertebral fractures. Men treated with toremifene had significantly fewer new vertebral fractures compared with placebo (2.5% vs 4.9%; RR 0.50; P = .05). In addition, toremifene significantly increased BMD at the lumbar spine, hip, and femoral neck compared with placebo ( P <.0001). Treatment with toremifene was associated with an increased rate of venous thromboembolic events compared with placebo (2.6% vs 1.1%, respectively).
Calcium and Vitamin D Supplementation
Providing adequate calcium and vitamin D is recommended by the NOF. A meta-analysis of 11 trials, mostly in postmenopausal women, comparing calcium (500–1200 mg daily) plus vitamin D (300–1100 units daily) with placebo showed that combined supplementation reduced the risk of total fractures (RR 0.88; 95% CI 0.78–0.99).
The NOF recommends at least 1200 mg daily of calcium for those older than 50 years. Calcium supplements are available in 2 formulations, including calcium carbonate, which requires gastric acid for optimal absorption, and calcium citrate, which does not require gastric acid for absorption and is recommended for patients receiving proton pump inhibitors.
The NOF recommends at least 1000 IU units daily of vitamin D. All patients to be initiated on ADT should also be tested for vitamin D deficiency via measurement of serum 25-hydroxy vitamin D (25-OH-D). Vitamin D supplements are available as ergocalciferol (D 2 ) or cholechalciferol (D 3 ). There is controversy regarding the choice of agent for supplementation. In a meta-analysis of 7 randomized trials evaluating serum 25-OH-D concentrations after supplementation with D 2 versus D 3 , D 3 was more efficacious at increasing serum 25-OH-D than D 2 , with the greatest difference seen for weekly or monthly rather than daily dosing. Those with significant vitamin D deficiency (defined as 25-OH-D <20 ng/mL) should be aggressively repleted with vitamin D, typically 50,000 IU weekly for 8 weeks.
Lifestyle Modifications
Lifestyle modifications are important in men receiving ADT for prostate cancer. These modifications include smoking cessation, moderating alcohol and caffeine consumption, and regular weight-bearing exercises and resistance training. Fall prevention is also critical in reducing fracture risk. Counseling patients on these modifications is essential in the care of men with prostate cancer treated with ADT and recommended interventions should be individualized.
Summary
Treatment-related osteoporosis can lead to increased morbidity in men treated with ADT for prostate cancer. Initial approaches for men receiving treatment with ADT include education regarding lifestyle modifications to decrease fracture risk and supplementation with calcium and vitamin D. The NOF screening and treatment guidelines (see Table 3 ), which use the FRAX algorithm and BMD assessments, can be used to inform screening and use of pharmacologic agents in patients with high fracture risk. For men who warrant treatment, consensus is lacking regarding the appropriate treatment agent, dose, schedule, and duration of therapy. Denosumab is the only commercially available agent shown to increase bone mass and prevent fracture in high-risk men receiving ADT for prostate cancer. Other pharmacologic agents to consider include bisphosphonates, such as zoledronic acid and alendronate. Repeat BMD assessment is recommended every 2 years, although more frequent testing may be warranted in selected individuals.
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