**9. Treatment for prostate cancer induced bone loss: Current options and new horizons**

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer deaths among men in the United States. The 5-year relative survival among men aged 65 years or older is 99.8% for all tumour stage groups combined but is considerably lower (5%) among men with distant metastatic disease at diagnosis (Aapro M, et al., 2008).

Advances in cancer therapies have extended patients' lives and improved patients' outcomes. Because cancer patients are living longer, they may be at an increased risk of metastatic bone pain and untreated bone metastases. As anticancer therapies have extended overall survival, the likelihood that a patient with advanced cancer will live long enough to experience an SRE increases.

Approximately 70% of patients with advanced prostate cancer develop skeletal metastases, which are often associated with significant morbidity and mortality (Coleman RE, 2001). In addition to the skeletal effects of cancer itself, bone loss resulting from treatment is an emerging problem. The causes of cancer treatment–induced bone loss (CTIBL) include the hypogonadal state induced by cancer therapies (testosterone deficiency secondary to androgen deprivation from gonadotrophin-releasing hormone [GnRH] agonists and surgical castration in prostate cancer). This hormone depletion promotes osteoporosis and increases the risk of fracture. This type of patients with malignant bone disease are at risk for skeletal-related events, including pathological fracture, metastases requiring surgery or radiation therapy to bone, and spinal cord compromise. They may experience fragility fractures either because of co-morbid conditions or because of toxicities of their cancer therapy, thus the prevalence of osteoporosis increases during ADT, preventive measures are recommended.

Fracture remains the most significant clinical end point related to CTIBL resulting from ADT. Moreover, fractures are an independent adverse predictor of survival in patients with prostate cancer (Oefelein MG, et al., 2002). No prospective data are yet available regarding the impact of ADT on fracture rates; nevertheless, several retrospective analyses provide

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 325

Bisphosphonates have some limitations. First, long-term efficacy data are sparse. Oral BPs are poorly absorbed, must be taken on an empty stomach and often produce gastrointestinal side effects. Thus, long-term adherence to oral BPs tends to be poor; studies of 1-year adherence to BPs in postmenopausal women have found adherence rates under 60% even with once monthly treatments (Boonen S, et al., 2008). Due to lack of compliance, intravenous BPs are preferred to oral BPs; influenza-like acute phase reactions on initial administration are common but mild, while acute tubular necrosis is rare but serious.

**9.2.1 Effect of bisphosphonates on preventing or treating bone complications** 

spine and hip by 7.1% and 2.6%, respectively (Berenson JR, 2005).

Bisphosphonates have been shown to decrease the risk of skeletal complications by approximately one third (Body JJ, 2003). In addition, bisphosphonates are clinically important for the treatment of hypercalcemia of malignancy and can reduce cancer induced bone pain. The two bisphosphonates approved by the FDA for use in patients with cancer involving bone are pamidronate and zoledronic acid. Clodronate and ibandronate have been licensed for use in malignant bone disease in other countries. Because of the high frequency of skeletal involvement in advanced cancers, bisphosphonates are routinely

A head-to-head non-inferiority trial of zoledronic acid vs pamidronate demonstrated no significant difference between the treatments. One thousand six hundred forty eight patients with osteolytic multiple myeloma or bone metastasis (osteoblastic or osteolytic) from breast cancer were randomized to receive monthly treatments with zoledronic acid (4 mg) or pamidronate (90 mg). The development of skeletal-related events was equivalent in the

prescribed in the practice of medical oncology (Ramaswamy B & Shapiro CL, 2003).

The use of bisphosphonates is an emerging therapy for preventing and treating osteoporosis and fractures in the management of recurrent and advanced prostate cancer disease. Moreover, these substances can act as pain relief agents (Verreuther R, 1993; Rodrigues P, et al., 2004). Bisphosphonates, synthetic analogs of the endogenous pyrophosphate molecule, inhibit osteoclast-mediated bone destruction by a decrease bone resorption in patients receiving ADT and/or with metastatic disease (Smith MR, 2003; Ryan CW, et al., 2006; Lipton A, 2004). These drugs selectively adsorb to mineral surfaces on bone that are surrounded by osteoclasts. The bisphosphonates are then released from the bone surface, where they are internalized by and disrupt the bone-resorbing action of osteoclasts (Lipton A, 2004). At least two types of bisphosphonates exist: non-nitro-gen-containing bisphosphonates (clodronate, etidronate) and the more potent nitrogen-containing bisphosphonates (alendronate, ibandronate, pamidronate, risedronate, zoledronic acid) (Lipton A, 2004). Both types of bisphosphonates have been evaluated in prostate cancer patients at risk of bone complications. Pamidronate has been shown to maintain BMD during ADT, whereas alendronate and zoledronic acid have been shown to increase BMD during ADT (Casey R, et al., 2006; Greenspan SL, et al., 2007). Zoledronic acid has also been shown to prevent metastatic disease induced bone complications (for example, fractures, spinal cord compression) in patients with hormone-refractory disease (Saad F, et al., 2002; Saad F, et al., 2004). At this time, no bisphosphonate is indicated for the prevention or treatment of ADT-induced bone loss; however, alendronate is indicated for treatment of men with osteoporosis (Higano CS, 2004). A randomized controlled trial demonstrated that a single infusion of zoledronic acid suppressed bone turnover for at least 12 months and increased BMD of the hip and spine in men receiving a GnRH agonist for non-metastatic prostate cancer. Compared with placebo, zoledronic acid increased BMD of the lumbar

significant evidence for increased fracture risk. An analysis of 15,716 men with fractures and 47,149 matched controls in a nationwide, population-based, case-control study found that prostate cancer is associated with increased risk of fracture (odds ratio [OR] 1.8; 95% CI, 1.6 to 2.1), with an even higher increased risk of hip fracture (OR 3.7; 95% CI, 3.1 to 4.4). However, there was no increased risk of vertebral fractures, which are frequently underreported in the absence of sequential spine x-rays. When adjusted for prostate cancer, age, and previous fracture, an increased fracture risk was seen for both GnRH agonists, with or without non-steroidal anti-androgens (OR 1.7; 95% CI, 1.2 to 2.5; *P* .01), and orchiectomy (OR 1.7; 95% CI, 1.2 to 2.4; *P* .01).

Because survival in men with non-metastatic prostate cancer treated with hormone therapy is long (median survival time is 7 years), (Antonarakis ES, et al., 2007) long-term issues of bone health are of particular significance. Moreover, men with untreated disease tend to have lower BMD than their peers and, therefore, are at higher risk for fracture before beginning ADT (Smith MR, et al., 2001).

The identification of the incidence of CTIBL among patients with prostate cancer raises issues for clinicians, including the identification of those at increased fracture risk and appropriate preventative strategies. These questions are of concern not only for the specialist, but also for general practitioners who will frequently encounter these patients. Pharmacotherapy is key to the prevention and treatment of skeletal-related events. Successful treatment of the tumour is the best method of preventing skeletal-related events. Current measures in the treatment of CTIBL and others are cited below.

### **9.1 Lifestyle measures, calcium and vitamin D supplementation**

Lifestyle modifications to address osteoporosis include exercise, smoking cessation and moderating alcohol and caffeine intake. In addition, men over 50 should have a total of 1500 mg daily of calcium and 800 IU daily of vitamin D (D3 being preferable to D2) (Brown JP, et al., 2002). However, the Osteoporotic Society of Canada guidelines state that while adequate calcium and vitamin D (whether dietary or supplemented) are essential adjuncts to prevent and treat osteoporosis, they are insufficient by themselves as treatments.

#### **9.2 Bisphosphonates**

Bisphosphonates (BPs) are often used for patients with bone metastases to prevent pathologic fractures, reduce bone pain or control hypercalcemia, but they are not specifically indicated for the prevention and treatment of cancer treatment induced bone loss. Numerous randomized controlled trials have explored the effects of BPs on BMD in the setting of ADT for non-metastatic prostate cancer (Greenspan SL, et al., 2007; Greenspan SL, et al., 2008), but to date none have had sufficient power to demonstrate a reduction in fractures. These trials demonstrate clearly that BPs are effective in reducing BMD loss associated with ADT for at least 1 year (Saad F, et al., 2008).

Since the mid-1990s, bisphosphonates have become a mainstay of the management of metastatic bone disease from breast, lung, and prostate cancer. They are the primary treatment of hypercalcemia, widely recommended to reduce the pain associated with metastatic disease and are the only class of agents approved to prevent the development of skeletal-related events.

Several placebo-controlled trials have demonstrated the (Coleman RE, 2004) benefit of using these agents to prevent skeletal-related events in patients with known bone metastasis.

significant evidence for increased fracture risk. An analysis of 15,716 men with fractures and 47,149 matched controls in a nationwide, population-based, case-control study found that prostate cancer is associated with increased risk of fracture (odds ratio [OR] 1.8; 95% CI, 1.6 to 2.1), with an even higher increased risk of hip fracture (OR 3.7; 95% CI, 3.1 to 4.4). However, there was no increased risk of vertebral fractures, which are frequently underreported in the absence of sequential spine x-rays. When adjusted for prostate cancer, age, and previous fracture, an increased fracture risk was seen for both GnRH agonists, with or without non-steroidal anti-androgens (OR 1.7; 95% CI, 1.2 to 2.5; *P* .01), and orchiectomy

Because survival in men with non-metastatic prostate cancer treated with hormone therapy is long (median survival time is 7 years), (Antonarakis ES, et al., 2007) long-term issues of bone health are of particular significance. Moreover, men with untreated disease tend to have lower BMD than their peers and, therefore, are at higher risk for fracture before

The identification of the incidence of CTIBL among patients with prostate cancer raises issues for clinicians, including the identification of those at increased fracture risk and appropriate preventative strategies. These questions are of concern not only for the specialist, but also for general practitioners who will frequently encounter these patients. Pharmacotherapy is key to the prevention and treatment of skeletal-related events. Successful treatment of the tumour is the best method of preventing skeletal-related events.

Lifestyle modifications to address osteoporosis include exercise, smoking cessation and moderating alcohol and caffeine intake. In addition, men over 50 should have a total of 1500 mg daily of calcium and 800 IU daily of vitamin D (D3 being preferable to D2) (Brown JP, et al., 2002). However, the Osteoporotic Society of Canada guidelines state that while adequate calcium and vitamin D (whether dietary or supplemented) are essential adjuncts to prevent

Bisphosphonates (BPs) are often used for patients with bone metastases to prevent pathologic fractures, reduce bone pain or control hypercalcemia, but they are not specifically indicated for the prevention and treatment of cancer treatment induced bone loss. Numerous randomized controlled trials have explored the effects of BPs on BMD in the setting of ADT for non-metastatic prostate cancer (Greenspan SL, et al., 2007; Greenspan SL, et al., 2008), but to date none have had sufficient power to demonstrate a reduction in fractures. These trials demonstrate clearly that BPs are effective in reducing BMD loss

Since the mid-1990s, bisphosphonates have become a mainstay of the management of metastatic bone disease from breast, lung, and prostate cancer. They are the primary treatment of hypercalcemia, widely recommended to reduce the pain associated with metastatic disease and are the only class of agents approved to prevent the development of

Several placebo-controlled trials have demonstrated the (Coleman RE, 2004) benefit of using these agents to prevent skeletal-related events in patients with known bone metastasis.

Current measures in the treatment of CTIBL and others are cited below.

and treat osteoporosis, they are insufficient by themselves as treatments.

associated with ADT for at least 1 year (Saad F, et al., 2008).

**9.1 Lifestyle measures, calcium and vitamin D supplementation** 

(OR 1.7; 95% CI, 1.2 to 2.4; *P* .01).

**9.2 Bisphosphonates** 

skeletal-related events.

beginning ADT (Smith MR, et al., 2001).

Bisphosphonates have some limitations. First, long-term efficacy data are sparse. Oral BPs are poorly absorbed, must be taken on an empty stomach and often produce gastrointestinal side effects. Thus, long-term adherence to oral BPs tends to be poor; studies of 1-year adherence to BPs in postmenopausal women have found adherence rates under 60% even with once monthly treatments (Boonen S, et al., 2008). Due to lack of compliance, intravenous BPs are preferred to oral BPs; influenza-like acute phase reactions on initial administration are common but mild, while acute tubular necrosis is rare but serious.

#### **9.2.1 Effect of bisphosphonates on preventing or treating bone complications**

The use of bisphosphonates is an emerging therapy for preventing and treating osteoporosis and fractures in the management of recurrent and advanced prostate cancer disease. Moreover, these substances can act as pain relief agents (Verreuther R, 1993; Rodrigues P, et al., 2004). Bisphosphonates, synthetic analogs of the endogenous pyrophosphate molecule, inhibit osteoclast-mediated bone destruction by a decrease bone resorption in patients receiving ADT and/or with metastatic disease (Smith MR, 2003; Ryan CW, et al., 2006; Lipton A, 2004). These drugs selectively adsorb to mineral surfaces on bone that are surrounded by osteoclasts. The bisphosphonates are then released from the bone surface, where they are internalized by and disrupt the bone-resorbing action of osteoclasts (Lipton A, 2004). At least two types of bisphosphonates exist: non-nitro-gen-containing bisphosphonates (clodronate, etidronate) and the more potent nitrogen-containing bisphosphonates (alendronate, ibandronate, pamidronate, risedronate, zoledronic acid) (Lipton A, 2004). Both types of bisphosphonates have been evaluated in prostate cancer patients at risk of bone complications. Pamidronate has been shown to maintain BMD during ADT, whereas alendronate and zoledronic acid have been shown to increase BMD during ADT (Casey R, et al., 2006; Greenspan SL, et al., 2007). Zoledronic acid has also been shown to prevent metastatic disease induced bone complications (for example, fractures, spinal cord compression) in patients with hormone-refractory disease (Saad F, et al., 2002; Saad F, et al., 2004). At this time, no bisphosphonate is indicated for the prevention or treatment of ADT-induced bone loss; however, alendronate is indicated for treatment of men with osteoporosis (Higano CS, 2004). A randomized controlled trial demonstrated that a single infusion of zoledronic acid suppressed bone turnover for at least 12 months and increased BMD of the hip and spine in men receiving a GnRH agonist for non-metastatic prostate cancer. Compared with placebo, zoledronic acid increased BMD of the lumbar spine and hip by 7.1% and 2.6%, respectively (Berenson JR, 2005).

Bisphosphonates have been shown to decrease the risk of skeletal complications by approximately one third (Body JJ, 2003). In addition, bisphosphonates are clinically important for the treatment of hypercalcemia of malignancy and can reduce cancer induced bone pain. The two bisphosphonates approved by the FDA for use in patients with cancer involving bone are pamidronate and zoledronic acid. Clodronate and ibandronate have been licensed for use in malignant bone disease in other countries. Because of the high frequency of skeletal involvement in advanced cancers, bisphosphonates are routinely prescribed in the practice of medical oncology (Ramaswamy B & Shapiro CL, 2003).

A head-to-head non-inferiority trial of zoledronic acid vs pamidronate demonstrated no significant difference between the treatments. One thousand six hundred forty eight patients with osteolytic multiple myeloma or bone metastasis (osteoblastic or osteolytic) from breast cancer were randomized to receive monthly treatments with zoledronic acid (4 mg) or pamidronate (90 mg). The development of skeletal-related events was equivalent in the

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 327

 Patients taking bisphosphonates should be encouraged to maintain good oral hygiene and to have regular dental visits during which they can be instructed in proper dental hygiene and can receive proper dental care. They should be urged to report any oral

 Education of physicians and patients about bisphosphonate-associated ONJ is vitally important in all circumstances and particularly in circumstances or locations where the

Raloxifene is a selective estrogen receptor modulator (SERM) often used to treat osteoporosis in women. In a 12-month open-label study enrolling 48 men with nonmetastatic prostate cancer receiving Antiandrogen theraphy, the addition of raloxifene 60 mg daily significantly improved bone mass density at the total hip and spine (Smith MR,

Bicalutamide is a non-steroidal anti-androgen, which increases estradiol levels when given as monotherapy. A 12-month, openlabel comparison of leuprolide versus bicalutamide (150 mg daily) in 52 men with non-metastatic prostate cancer showed that bicalutamide increased bone mass density (BMD) at several sites (e.g., lumbar spine BMD +2.5% vs. −2.5%; p < 0.001), as well as decreasing fat mass, fatigue, loss of libido and hot flushes compared with leuprolide. Breast tenderness and enlargement were seen more frequently in the bicalutamide group (Smith MR, et al., 2004). Finally, a recent prospective study whose population included 253 prostate cancer patients with osteoporosis found that bicalutamide

Corticosteroids are used most commonly in patients that develop spinal cord compression, but may also be used in those with diffuse pain unresolved with bisphosphonate and analgesic use. As potent anti-inflammatory agents, they improve neurologic symptoms and pain through the reduction of vasogenic edema around the spinal cord. Dexamethasone is often the preferred agent due to its increased potency and central nervous system

Often a loading dose of 10 to 100 mg is administered, followed by a 16- to 96-mg/day maintenance dose, although controversy exists over which dose is more efficacious. High doses have been recommended (100 mg loading dose followed by 24 mg every 6 hours × 3 days) to quickly restore ambulation, although may increase the incidence of serious adverse effects (Kilmo P, et al., 2004; Cole J, et al., 2008; Heimdal K, et al., 1992). Systematic reviews of the literature found a shortage of quality data, but came to the following conclusions: "There is good evidence to support the use of high-dose dexamethasone (96 mg/d)" in nonambulatory patients, "but inconclusive evidence for the use of moderate-dose steroids (16 mg/d) in conjunction with radiotherapy for the treatment of MSCC (Loblaw D, et al., 1998). They also state that there is fair evidence for not using steroids in non-paretic patients,

although this is not common practice (Loblaw D, et al., 1998; Coleman RE, 2004).

resources to provide dental examinations and treatment are limited.

risk factors for developing ONJ (Ruggerio SL, et al., 2004).

treatment maintained BMD over 6 years (Wadhwa VK, et al., 2009).

problems to their dentist and physician.

**9.3 Raloxifene** 

et al., 2004).

**9.4 Bicalutamide** 

**9.5 Corticosteroids** 

penetration (Kilmo P, et al., 2004).

bisphosphonates, including the risk of ONJ, the signs and symptoms of ONJ, and the

zoledronic acid and pamidronate groups (47% vs 51%, respectively), although fewer patients on zoledronic acid required radiotherapy (19% vs 24%; p = 0.037). Likewise, the time to skeletal-related events was similar at 376 days in the zoledronic acid group vs 356 days in patients treated with pamidronate (p = 0.151), although in a subgroup analysis of breast cancer patients on hormonal therapy, zoledronic acid appeared slightly more efficacious (p = 0.047). From this trial it was determined that there was equal benefit for patients using pamidronate or zoledronic acid (Rosen LS, 2003). When treating patients with skeletal lesions from cancer, current oncology practice in the United States typically uses either pamidronate, 90 mg, infused over at least 2 h every 3–4 wk, or zoledronic acid, 4 mg, infused over at least 15 min every 3–4 wk (Hillner BE, et al., 2003; Coleman RE, 2004). With the FDA approval of zoledronic acid in 2001, this agent has gained popularity in clinical practice because of its efficacy in reducing skeletal-related events and the shorter infusion time. Because of the lifelong risk of skeletal-related events in patients with metastatic bone disease, the clinical practice in the palliative setting has been to continue bisphosphonate therapy indefinitely.

#### **9.2.2 Adverses effects of biphosphonates**

Bisphosphonate-associated osteonecrosis of de jaw (ONJ) in patients with malignancy has come to the attention of the medical and dental communities primarily through case reporting, and the number of reported cases has been increasing over the past 3 yr. All bisphosphonates have been associated with cases of ONJ; however, this must be tempered with the acknowledgment of the lack of a consensus definition for ONJ and the unknown incidence of ONJ in the general population. The published literature reviewed by the task force identified <1000 cases (Khosla S, et al., 2007)). There are established guidelines for oral health care before initiating chemotherapy (Bamia A, et al., 2005).

A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region (Khosla S, et al., 2007).

A suspected case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that had been identified by a health care provider and had been present for <8 wk in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region (Khosla S, et al., 2007).

The risk factors for bisphosphonate-associated ONJ are:

Oral bone manipulating surgery, poor fitting dental appliances, intraoral trauma, duration of exposure to bisphosphonate treatment, co-administration of glucocorticoids, comorbid conditions (such as alcohol, tabacco, and malignancies), and pre-existing dental or periodontal disease.

Suggest recommendations for clinical management before initiating bisphosphonate therapy and when the diagnosis of ONJ has been made are as follows.

General recommendations:


bisphosphonates, including the risk of ONJ, the signs and symptoms of ONJ, and the risk factors for developing ONJ (Ruggerio SL, et al., 2004).


#### **9.3 Raloxifene**

326 Prostate Cancer – Diagnostic and Therapeutic Advances

zoledronic acid and pamidronate groups (47% vs 51%, respectively), although fewer patients on zoledronic acid required radiotherapy (19% vs 24%; p = 0.037). Likewise, the time to skeletal-related events was similar at 376 days in the zoledronic acid group vs 356 days in patients treated with pamidronate (p = 0.151), although in a subgroup analysis of breast cancer patients on hormonal therapy, zoledronic acid appeared slightly more efficacious (p = 0.047). From this trial it was determined that there was equal benefit for patients using pamidronate or zoledronic acid (Rosen LS, 2003). When treating patients with skeletal lesions from cancer, current oncology practice in the United States typically uses either pamidronate, 90 mg, infused over at least 2 h every 3–4 wk, or zoledronic acid, 4 mg, infused over at least 15 min every 3–4 wk (Hillner BE, et al., 2003; Coleman RE, 2004). With the FDA approval of zoledronic acid in 2001, this agent has gained popularity in clinical practice because of its efficacy in reducing skeletal-related events and the shorter infusion time. Because of the lifelong risk of skeletal-related events in patients with metastatic bone disease, the clinical practice in the palliative setting has been to continue

Bisphosphonate-associated osteonecrosis of de jaw (ONJ) in patients with malignancy has come to the attention of the medical and dental communities primarily through case reporting, and the number of reported cases has been increasing over the past 3 yr. All bisphosphonates have been associated with cases of ONJ; however, this must be tempered with the acknowledgment of the lack of a consensus definition for ONJ and the unknown incidence of ONJ in the general population. The published literature reviewed by the task force identified <1000 cases (Khosla S, et al., 2007)). There are established guidelines for oral

A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had

A suspected case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that had been identified by a health care provider and had been present for <8 wk in a patient who was receiving or had been exposed to a bisphosphonate

Oral bone manipulating surgery, poor fitting dental appliances, intraoral trauma, duration of exposure to bisphosphonate treatment, co-administration of glucocorticoids, comorbid conditions (such as alcohol, tabacco, and malignancies), and pre-existing dental or

Suggest recommendations for clinical management before initiating bisphosphonate therapy

 There should be free and complete communication between health care professionals (physicians and dentists) involved in treatment and between health care professionals and patients (Ruggerio SL, et al., 2004). Physicians should encourage patients to inform

 All patients starting or taking bisphosphonates should be informed of the benefits of bisphosphonate treatment. They should also be informed of the risks of

and had not had radiation therapy to the craniofacial region (Khosla S, et al., 2007).

bisphosphonate therapy indefinitely.

**9.2.2 Adverses effects of biphosphonates** 

health care before initiating chemotherapy (Bamia A, et al., 2005).

The risk factors for bisphosphonate-associated ONJ are:

and when the diagnosis of ONJ has been made are as follows.

their dentist that they are taking a bisphosphonate.

periodontal disease.

General recommendations:

not had radiation therapy to the craniofacial region (Khosla S, et al., 2007).

Raloxifene is a selective estrogen receptor modulator (SERM) often used to treat osteoporosis in women. In a 12-month open-label study enrolling 48 men with nonmetastatic prostate cancer receiving Antiandrogen theraphy, the addition of raloxifene 60 mg daily significantly improved bone mass density at the total hip and spine (Smith MR, et al., 2004).

#### **9.4 Bicalutamide**

Bicalutamide is a non-steroidal anti-androgen, which increases estradiol levels when given as monotherapy. A 12-month, openlabel comparison of leuprolide versus bicalutamide (150 mg daily) in 52 men with non-metastatic prostate cancer showed that bicalutamide increased bone mass density (BMD) at several sites (e.g., lumbar spine BMD +2.5% vs. −2.5%; p < 0.001), as well as decreasing fat mass, fatigue, loss of libido and hot flushes compared with leuprolide. Breast tenderness and enlargement were seen more frequently in the bicalutamide group (Smith MR, et al., 2004). Finally, a recent prospective study whose population included 253 prostate cancer patients with osteoporosis found that bicalutamide treatment maintained BMD over 6 years (Wadhwa VK, et al., 2009).

#### **9.5 Corticosteroids**

Corticosteroids are used most commonly in patients that develop spinal cord compression, but may also be used in those with diffuse pain unresolved with bisphosphonate and analgesic use. As potent anti-inflammatory agents, they improve neurologic symptoms and pain through the reduction of vasogenic edema around the spinal cord. Dexamethasone is often the preferred agent due to its increased potency and central nervous system penetration (Kilmo P, et al., 2004).

Often a loading dose of 10 to 100 mg is administered, followed by a 16- to 96-mg/day maintenance dose, although controversy exists over which dose is more efficacious. High doses have been recommended (100 mg loading dose followed by 24 mg every 6 hours × 3 days) to quickly restore ambulation, although may increase the incidence of serious adverse effects (Kilmo P, et al., 2004; Cole J, et al., 2008; Heimdal K, et al., 1992). Systematic reviews of the literature found a shortage of quality data, but came to the following conclusions: "There is good evidence to support the use of high-dose dexamethasone (96 mg/d)" in nonambulatory patients, "but inconclusive evidence for the use of moderate-dose steroids (16 mg/d) in conjunction with radiotherapy for the treatment of MSCC (Loblaw D, et al., 1998). They also state that there is fair evidence for not using steroids in non-paretic patients, although this is not common practice (Loblaw D, et al., 1998; Coleman RE, 2004).

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 329

(Roudier MP, et al., 2008) and analysis of bone turnover markers (Brown JE, et al., 2005; Demers LM, 2003), support the view that excess osteoclastic activity induces bone destruction in these metastases. The Receptor Activator of NF-B Ligand (RANKL) is the main driver of osteoclast formation, function, and survival (Boyle WJ, et al., 2003). Lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-Kappa B (RANK) ligand (RANKL) and lymphotoxin (Luo et al., 2007). Denosumab is a fully human monoclonal antibody that specifically targets RANKL and is delivered by subcutaneous injection twice a year (Schwarz EM & Ritchlin CT, 2006). This therapy was found to be very effective in reducing fractures and was well-tolerated in the clinical settings of osteoporotic postmenopausal women (McClung MR, et al., 2006; Cummings SR, et al., 2009) and protecting BMD in osteopenic postmenopausal women receiving adjuvant aromatase inhibitors for breast cancer (Ellis GK, et al., 2008). More recently, denosumab (60 mg subcutaneously, every 6 months) was evaluated in a 36-month, phase-III, placebocontrolled randomized clinical trial involving 1468 men with non-metastatic prostate cancer who were receiving ADT.48 Compared with placebo, denosumab significantly improved BMD at all sites measured, including lumbar spine (the primary endpoint) by 6.7% (p < 0.001), total hip by 4.8% (p < 0.001), femoral neck by 3.9% (p < 0.001), and distal radius by 5.5% (p < 0.001) at 24 months; by the end of the trial (36 months), denosumab dramatically reduced the risk of new vertebral fractures (a secondary endpoint) by 62% (p = 0.006), but

A recent phase-III study comparing denosumab versus zoledronic acid (Fizazi K, et al., 2011) showed that denosumab was better than the established therapy, zoledronic acid, for the delay or prevention of skeletal-related events in patients with advanced prostate cancer,

Disease-related skeletal complications are common in men with metastatic prostate cancer. Such events, including fracture, hypercalcemia, spinal cord compression, and severe pain are serious complications of several malignancies. Agents such as bisphosphonates should be used to prevent skeletal-related events; they and other agents such as corticosteroids and analgesics are effective in symptom management of skeletal-related events. Through the use of these agents, along with radiation and surgical therapy, outcomes and quality of life can be improved in patients with metastatic disease. Bone metastasis and skeletal related events

Jemal, A. Siegel, R. Xu, J. & Ward, E. Cancer statistics, 2010. (2010). CA *Cancer Journal Clinics*

Ferlay, J. Parkin, DM. & Steliarova-Foucher, E. (2010). Estimates of cancer incidence and

Schulman, KL. & Kohles, J. (2007). Economic burden of metastatic bone disease in the US.

Berruti, A. Dogliotti, L. & Terrone, C. (2002). Changes in bone mineral density, lean body

mass and fat content as measured by dual energy X-ray absorptiometry in patients

mortality in Europe in 2008. *European Journal of Cancer* 46: 765-81.

not overall survival in prostate cancer (Fizzazi et al., 2011).

predict poor prognosis in men with prostate cancer.

**10. Conclusions** 

**11. References** 

60: 277-300.

*Cancer* 109: 2334-42.

while there was no difference in overall survival or disease progression.

Adverse effects of steroids include insomnia, increased appetite, edema, hyperglycemia, leukocytosis, increased risk of infection, and gastrointestinal bleeding. Patients receiving high doses are at increased risk of these effects and should receive close monitoring; ulcer prophylaxis should be considered. Since adrenal suppression is likely when doses are continued beyond 5 to 7 days, doses should be tapered when discontinuing therapy with these agents (Loblaw D, et al., 1998; Coleman RE, 2004).
