In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.
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Skeletal complications from metastases and androgen deprivation therapy are common in prostate cancer survivors.
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New pharmacologic approaches to preventing skeletal related events and other complications in this population are being employed.
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In addition to palliating pain caused by bone metastases in prostate cancer, the well-tolerated radiopharmaceutical Alpharadin appears to prolong life.
Normal bone physiology
Healthy bone is perpetually in a state of turnover, striking a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. Estrogen plays an important role in the regulation of this balance through estrogen receptors on osteoblasts and osteoclasts. In low estrogen states, the balance favors bone resorption rather than formation. Low estrogen levels are likely one of the most significant contributors to the decline of bone mineral density (BMD) in hypogonadal states.
Additional regulatory signaling occurs via the receptor activator of nuclear factor-κB ligand (RANKL) system. RANKL, a member of the tumor necrosis factor superfamily of proteins, is produced by osteoblasts and bone marrow stromal cells. It binds to RANK receptors on osteoclasts and osteoclast precursors to induce differentiation, activation, and survival of osteoclasts. The activation of RANK ultimately causes increased osteoclast activity and bone resorption. The action of osteoprotegerin (OPG), a protein produced by osteoblasts and other stromal tissues, decreases osteoclast activity by OPG binding RANKL, preventing the RANK/RANKL interaction. Relative levels of OPG and RANKL are thought to play a pivotal role in determining the degree to which bone resorption and formation occur.
Pathophysiology of bone metastases
Bone lesions in prostate cancer appear osteoblastic radiographically, but both osteoblast and osteoclast activity is upregulated. Osteoclast activity is enhanced by several mechanisms, including marrow stromal and tumor secretion of stimulatory proteins that act on nearby osteoclasts. Stromal cells produce RANKL and macrophage colony-stimulating factor (M-CSF) receptor, both of which stimulate osteoclast differentiation and activation. Tumor cells also promote osteoclast activity by producing M-CSF and parathyroid hormone–related protein. It has also been proposed that osteoclast activation may be explained almost entirely by the effect of androgen deprivation therapy (ADT), one of the most common treatments for recurrent or metastatic prostate cancer. The mechanism of osteoblast activity promotion is less well defined, but is presumed to be driven by stromal and tumor secretion of osteoblasts-stimulating factors, such as insulinlike growth factor, bone-morphogenic proteins, transforming growth factor-beta, fibroblast growth factors, and others.
Pathophysiology of bone metastases
Bone lesions in prostate cancer appear osteoblastic radiographically, but both osteoblast and osteoclast activity is upregulated. Osteoclast activity is enhanced by several mechanisms, including marrow stromal and tumor secretion of stimulatory proteins that act on nearby osteoclasts. Stromal cells produce RANKL and macrophage colony-stimulating factor (M-CSF) receptor, both of which stimulate osteoclast differentiation and activation. Tumor cells also promote osteoclast activity by producing M-CSF and parathyroid hormone–related protein. It has also been proposed that osteoclast activation may be explained almost entirely by the effect of androgen deprivation therapy (ADT), one of the most common treatments for recurrent or metastatic prostate cancer. The mechanism of osteoblast activity promotion is less well defined, but is presumed to be driven by stromal and tumor secretion of osteoblasts-stimulating factors, such as insulinlike growth factor, bone-morphogenic proteins, transforming growth factor-beta, fibroblast growth factors, and others.
Clinical complications of bone metastases
The most common site of metastatic disease in advanced prostate cancer is bone, especially the bones of the axial skeleton, pelvis, and long bones. Spread to bone occurs via hematogenous dissemination. The biology of bone metastases is complex. Multiple factors appear to contribute to the bone tropism in prostate cancer, including blood flow in the bone marrow, expression of adhesive molecules on cancer cells that bind them to the bone matrix and stroma, and a rich supply of growth factors in the bone microenvironment. There is also a significant amount of reciprocal signaling between osteoblasts, osteoclasts, fibroblasts, and other cells of the bone microenvironment and prostate cancer cells through the secretion of cytokines, proteases, and growth factors that promote prostate cancer cell survival and growth.
Both pathologic fractures directly related to metastatic lesions and treatment-related benign osteoporotic fractures occur commonly in men with prostate cancer. Up to 22% of men with metastatic castrate-resistant prostate cancer (CRPC) experience pathologic fractures during the course of their disease because of weakened bone integrity in the area of metastasis. Benign osteoporotic fractures occur owing to the treatment-related decline of BMD that can result in osteoporosis and increase an individual’s risk of fracture. Several large retrospective database analyses of men with nonmetastatic prostate cancer demonstrated that men treated with ADT have a significantly higher rate of fracture that those who were not, and the risk increases over time as BMD falls.
Bone metastases are also associated with the development of additional skeletal complications. Both pain and weakness can develop from bone or nerve involvement with metastases. Hypocalcemia and subsequent secondary hyperparathyroidism occur owing to increased osteoblast activity in metastatic deposits.
Treatment-related osteoporosis
ADT, via bilateral orchiectomies or through administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists, is the cornerstone of systemic treatment for prostate cancer. The goal of ADT is to dramatically lower serum testosterone, typically lower than 20 ng/dL, or less than 5% of baseline values. Because of peripheral aromatization of testosterone to estradiol, reducing serum testosterone causes estradiol levels to fall. Estradiol levels decline to lower than 20% of baseline values, reaching levels as low as or lower than those of postmenopausal women.
ADT is widely used, both in subgroups of men with prostate cancer who clearly have improved overall survival with ADT, and in those in whom a survival benefit has not been demonstrated. One group that appears to benefit from treatment with ADT is men with metastatic disease who have an improved overall survival and quality of life with treatment. Men undergoing treatment with radiation for high-risk localized disease or locally advanced prostate cancer experience prolonged survival with the addition of ADT. Finally, there is evidence that men who have positive lymph nodes after radical prostatectomy have improved overall survival when treated with ADT. Although there is no evidence of improved overall survival in men with a prostate-specific antigen (PSA)-only relapse, this population is frequently treated with ADT alone or in combination with salvage radiation.
The major causes of osteoporosis in men are use of steroids, alcohol use, or hypogonadism. The intended therapeutic effect of ADT is marked hypogonadism. Consistent with the important role of gonadal steroids in normal bone metabolism in men, ADT decreases BMD and is associated with greater fracture risk. Within 6 to 9 months of initiating ADT, BMD falls. BMD continues to decline during treatment at a rate of 2% to 3% per year. This is substantially faster than typical age-related decline in men of 0.5% to 1.0%.
ADT is also associated with an increased fracture rate. Within 5 years of initiating therapy with ADT, the incidence of fracture approaches 20%. Several large retrospective analyses found that men treated with ADT experience a 21% to 45% relative increase in fracture risk as compared with men not treated with ADT. Additionally, a Surveillance Epidemiology and End Results (SEER) Medicare analysis of more than 50,000 men with prostate cancer found a fracture rate of 19.4% in men treated with ADT, whereas the rate of fracture in men not undergoing treatment was 12.6% ( P <.001). A second analysis of Medicare data from the same year included 4000 men with nonmetastatic prostate cancer and reported a relative risk of fracture of 1.21 among men treated with ADT as compared with those who were not (95% confidence interval [CI], 1.14–1.29, P <.01).
Mechanisms of treatment-related bone loss
ADT decreases BMD through several mechanisms. Both testosterone and estrogen are important for maintaining normal bone homeostasis, and ADT causes a significant decline in both testosterone and estrogen. When serum testosterone is low, less testosterone is available to undergo peripheral aromatization to estradiol. Low estrogen states are associated with increased bone resorption. In healthy men, studies demonstrate a decline in BMD when estradiol levels are low, and an inverse relationship between fracture risk and estradiol levels.
ADT also affects the rate of bone turnover and skeletal sensitivity to parathyroid hormone. Serum markers of osteoblast activity, like bone-specific alkaline phosphatase and osteocalcin, and markers of osteoclast activity, such as N-telopeptide, increase in men treated with ADT. These markers generally increase within 6 to 12 weeks of initiating therapy with ADT, and plateau approximately 6 months after starting therapy. ADT also increases skeletal sensitivity to parathyroid hormone.
Osteoclast-targeted therapy
Two osteoclast-targeted therapies have been studied in men with prostate cancer. Bisphosphonates are used to prevent skeletal-related events (SREs) in metastatic CRPC. SREs are a group of skeletal complications associated with malignancy. The term typically encompasses the following outcomes: pathologic fractures, cord compression, and the use of surgery or radiation to treat unstable or painful metastatic lesions in bone. Some studies also include the development of hypercalcemia or hypocalcemia in the definition. Denosumab, a fully humanized monoclonal antibody targeting RANKL, has been approved to prevent SREs in metastatic solid tumors, including CRPC, and to increase BMD in men at risk for ADT-associated bone loss.
Bisphosphonates
Bisphosphonates prevent bone resorption through several mechanisms, including decreased osteoclast differentiation and survival and increased osteoblast survival. Bisphosphonate molecules are structurally similar to native pyrophosphate molecules that normally adhere to hydroxyapatite crystal-binding sites. The molecules attach to binding sites located in areas of bone resorption, reducing osteoclast activity by preventing their adherence to the bone surface and the formation of the ruffled border. Bisphosphonates impair osteoclast progenitor differentiation and survival via their effects on osteoblasts.
Bisphosphonates vary by the R2 group attached to their common structural backbone. The R2 group determines the potency of the molecule, with nitrogen-containing bisphosphonates like pamidronate, alendronate, and zoledronic acid being significantly more potent than simple bisphosphonates like clodronate and etidronate, which are non-nitrogenous. Among the nitrogen-containing bisphosphonates, those that contain secondary or tertiary amino groups, such as zoledronic acid, are significantly more potent than other compounds. Zoledronic acid is estimated to be at least 100 times more potent than pamidronate and more than 1000 times as potent as etidronate in vitro.
Several bisphosphonates are currently used in patients with cancer. Indications include hypercalcemia, low BMD, and metastatic lesions in bone. As early as the 1990s, evidence demonstrated that pamidronate decreased the risk of skeletal complications in individuals with metastatic breast cancer and multiple myeloma. Pamidronate was subsequently approved for use in these populations in 1995. Zoledronic acid was approved to prevent skeletal complications in multiple myeloma and in any solid tumor with bone metastases in 2002. The study that specifically led to its approval in metastatic prostate cancer, Zometa 039, demonstrated a reduction in SRE as compared with placebo.
Denosumab
As described previously, bone exists in state of continuous remodeling, striking a balance between osteoclast resorption and osteoblast formation of new bone. The RANKL/RANK system plays a key role in achieving this balance. Currently, the only available therapy that targets this system is denosumab, a fully human monoclonal antibody directed at RANKL. The drug mimics the action of OPG by binding RANKL and reducing osteoclast action. It has a half-life of more than 30 days, does not accumulate in bone, like bisphosphonates, and can be used in patients with renal insufficiency. Similar to bisphosphonates, treatment with denosumab carries a small risk of developing osteonecrosis of the jaw.
Denosumab has been studied to prevent the development of osteoporosis and reduce the risk of fracture in postmenopausal women. In the fracture-prevention trial, 7868 postmenopausal women with osteoporosis were randomized to receive placebo or twice-yearly denosumab. Women in the denosumab group developed fewer new vertebral fractures, nonvertebral fractures, and hip fractures than those in the placebo group during the 36-month follow-up period (relative decreased risk of vertebral fractures 68%, nonvertebral fractures 20%, and hip fractures 40%). Denosumab was approved by the Food and Drug Administration (FDA) to treat postmenopausal women with osteoporosis based on this study.
Denosumab was also studied in women with breast cancer who were being treated with aromatase inhibitors. Aromatase inhibitors are associated with a decline in BMD in women owing to the inhibition of peripheral tissue estrogen production. A recent study demonstrated that denosumab prevents the loss of BMD at the lumbar spine in women with breast cancer being treated with aromatase inhibitors as compared with placebo (BMD increased by 5.5% and 7.6% at 12 and 24 months, respectively [ P <.0001 at both time points]).
Clinical uses of osteoclast-targeted therapies in prostate cancer
Prevention of Therapy-related Fragility Fractures
Several medications have been evaluated for prevention of fragility fractures, the most clinically relevant end point in this population ( Table 1 ). Denosumab, the fully human monoclonal antibody against RANKL, has been approved to prevent treatment-related fragility fractures in men treated with ADT. Toremifene, a selective estrogen receptor modulator (SERM) has been studied in this setting, but has not been approved for use because of an unacceptable risk-benefit ratio. Multiple bisphosphonates, including alendronate, pamidronate, zoledronic acid, and neridronate, have been evaluated to prevent a decline in BMD, but those studies were not powered to evaluate fracture prevention.
| Study | N | Study Population | Arms | Outcome |
|---|---|---|---|---|
| Denosumab Halt 138 | 1468 | Men with nonmetastatic prostate cancer being treated with a GnRH agonist and at high risk of fracture. | Denosumab 60 mg subcutaneously every 6 mo vs placebo for 3 y | Denosumab was associated with a significant increase in BMD ( P <.001) and a decrease in the incidence of vertebral fractures (RR 0.38 as compared with placebo, P = .006). |
| Toremifene protocol G300203 | 1294 | Men with nonmetastatic prostate cancer being treated with ADT who were at high risk of fracture. | Toremifene 80 mg orally daily vs placebo | Toremifene was associated with a 50% reduction in the relative risk of new vertebral fracture and an increase in bone mineral density ( P = .05). Elevated risk of thromboembolic events in the toremifene arm. |
The National Comprehensive Cancer Network and National Osteoporosis Foundation (NOF) created guidelines for the treatment of secondary osteoporosis associated with ADT and fracture prevention. These guidelines suggest that all men older than 50 years who are being treated with ADT should be treated with calcium (1200 mg per day) and vitamin D (1000 IU per day). They also recommend additional pharmacologic therapy for fracture prevention for any individual with a 10-year probability of hip fracture of 3% or more or a 20-year probability of major osteoporotic fracture of 20% or more.
An individual’s 10-year probability of fracture depends on multiple factors besides BMD. BMD is routinely used as a surrogate end point for fracture in clinical trials, but most fractures occur in men whose BMD is not in the osteoporotic range. A man’s risk of fracture increases by approximately 30-fold between the ages of 50 and 90, and the decline of BMD with age accounts for only a 4-fold increase in risk of fracture. To address this, the NOF recommends using the World Health Organization (WHO)/Fracture Risk Assessment (FRAX) computer-based tool to calculate the 10-year probability of hip or major osteoporotic fracture. This population-specific assessment is based on various easily obtained clinical factors in addition to BMD, and it can be calculated without BMD data if that is not available.
In clinical practice, more individuals meet criteria for pharmacologic management of therapy-related osteoporosis than would be expected based on the WHO definition of osteoporosis alone (T-score of <–2.5 alone). One recent study applied FRAX to 363 patients with nonmetastatic prostate cancer being treated with ADT in an academic practice. In that cohort, 51.2% met criteria for pharmacologic treatment. Age played a major role in the risk stratification, with 3.3% of men younger than 70 years and 99.8% of men 80 years or older meeting criteria.
Denosumab HALT 138
Denosumab was studied in a phase 3, multicenter, double-blind, randomized-controlled trial evaluating whether it could prevent osteoporosis and reduce the rate of fracture in men treated with ADT (see Table 1 ). Men in the study were treated with a GnRH agonist for nonmetastatic hormone-sensitive prostate cancer, and were at high risk of fracture based on low baseline BMD, age older than 70 years, or previous fragility fracture. A total of 1468 subjects were randomized to receive denosumab or placebo subcutaneously every 6 months, and BMD was evaluated at 24 and 36 months. The primary end point in the study was the change in lumbar spine BMD, and incidence of new vertebral fracture was included as a secondary end point.
The trial found that there was both an increase in BMD and a decrease in the rate of clinical fracture in men treated with denosumab as compared with placebo. At 24 months, there was a 5.6% increase in lumbar spine BMD in the group treated with denosumab as compared with a 1.0% decrease in BMD in the placebo group ( P <.001). Significant differences in BMD were evident in some patients as soon as 1 month after treatment. At 36 months, the denosumab group had significantly fewer vertebral fractures, with an incidence of 1.5% in the denosumab group and 3.9% in the placebo group (relative risk 0.38, P = .006).
Subgroup analyses revealed that denosumab improved BMD at all skeletal sites in all subgroups. The men with the most pronounced improvement in BMD were those with the highest markers of bone turnover (serum C-telopeptide and tartrate-resistant alkaline phosphatase). Adverse events were not significantly different between the 2 groups.
Based on the results of this trial, denosumab was recently approved by the FDA for fracture prevention in men receiving ADT.
Toremifene Protocol G300203
Selective estrogen receptor modulators (SERMs), including raloxifene and toremifene, have been studied to prevent therapy-related fragility fractures in men treated with ADT, but are not approved for use in men with prostate cancer.
Toremifene was evaluated in a recently reported multicenter, international phase III study of 1294 men with nonmetastatic prostate cancer who were being treated with ADT (see Table 1 ). Men were at high risk of fracture owing to low BMD or age older than 70 years. Subjects were randomized to receive oral toremifene daily or placebo, and they were followed for 2 years. The primary end point in the study was development of new vertebral fractures, and BMD was assessed as a secondary end point. This study revealed that toremifene was associated with a relative risk reduction of 50.0% in the incidence of new vertebral fractures, with a fracture incidence of 2.5% in the toremifene group versus 4.9% in the placebo group (95% CI –1.5 to 75.0, P = .05). Notably, toremifene was also associated with a higher rate of venous thromboembolic events than placebo, and has not been approved for fracture prevention in men receiving ADT (2.6% vs 1.1%, respectively).
Metastatic castration-resistant prostate cancer
There have been 3 contemporary randomized controlled trials of bisphosphonates to prevent skeletal complications in patients with CRPC and bone metastases ( Table 2 ). Zoledronic acid is the only bisphosphonate approved to prevent skeletal-related events in men with metastatic prostate cancer. In a recent global randomized-controlled trial, denosumab was superior to zoledronic acid for prevention of SREs in men with CRPC and bone metastases and is approved to prevent SREs in this setting.
| Study | N | Study Population | Arms | Outcome |
|---|---|---|---|---|
| Zometa 039 | 643 | Men with CRPC and symptomatic or minimally symptomatic bone metastases | Zoledronic acid 4 mg IV every 3 wk vs Placebo | Zoledronic acid was associated with significantly fewer SRE (33.2% vs 44.2%) and a trend toward improved overall survival. |
| CGP 032/INT 05 | 350 | Men with CRPC and symptomatic bone metastases | Pamidronate 90 mg IV every 3 wk or placebo | No difference in self-reported pain score, analgesic use, or SREs. |
| NCIC CTG PR.6 | 209 | Men with CRPC and symptomatic bone metastases | Clodronate 1500 mg IV every 3 wk or placebo | No difference in palliative response, overall quality of life, overall survival, duration of response, or symptomatic disease progression. |
| Denosumab protocol 20050103 | 1901 | Men with CRPC | Denosumab 120 mg subcutaneously or zoledronic acid 4 mg IV every 4 wk | Denosumab prolonged the median time to first on-study SRE by 3.6 mo (met both noninferior and superiority end points). No difference in overall survival or adverse events (including osteonecrosis of the jaw). |
| MRC PR05 | 311 | Men with castration-sensitive prostate cancer with bone metastases | Clodronate 2080 mg orally daily vs placebo | Trend toward improved progression-free and overall survival with clodronate on initial analysis, and significantly prolonged overall survival at 8-y analysis. |
| CALGB/CTSU | 680 a | Men with castration-sensitive prostate cancer with bone metastases | Zoledronic acid 4 mg IV every 4 weeks or placebo | Endpoints are SRE and prostate cancer death. Study is ongoing. |
Related posts:
Targeting the Androgen Receptor
Moving Toward Personalized Medicine in Castration-Resistant Prostate Cancer
Palliative Care in Castrate-Resistant Prostate Cancer
The Experience with Cytotoxic Chemotherapy in Metastatic Castration-Resistant Prostate Cancer
Management of Docetaxel Failures in Metastatic Castrate-Resistant Prostate Cancer
Targeting Angiogenesis as a Promising Modality for the Treatment of Prostate Cancer
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