**4. Mechanism of metastatic development**

In healthy adults, bone physiology is a dynamic, coordinated process controlled by 2 types of cells: osteoclasts and osteoblasts. Through a balanced remodeling process, osteoclasts resorb bone, and osteoblasts build bone at the same site (Coleman RE, 2001; Rosen LS, et al., 2003). This bone remodeling sequence consists of 4 distinct phases: activation, resorption, reversal, and formation.

Bone metastases are often characterized by their radiographic appearance as either osteolytic, osteoblastic, or mixed or mixed. Most patients with breast cancer have predominantly mixed or osteolytic lesions (Coleman RE, 2001; Rosen LS, et al., 2003). In contrast, patients with prostate cancer are often found to have predominantly osteoblastic lesions. However, regardless of appearance, there is significant osteolytic activity. In fact, osteolytic activity in these lesions often is comparable with, if not higher than, that typically seen in breast cancer and multiple myeloma. Such activity has been demonstrated by markedly elevated biochemical markers of bone resorption in the serum and urine of such patients. Only in multiple myeloma do purely lytic bone lesions develop (Coleman RE, 2001; Rosen LS, et al., 2003).

Several mechanisms have been proposed for metastatic spread to the bone. Early animal and human evaluations demonstrated that breast and pelvis tissue drain directly into the veins of the spine, increasing the deposition of metastatic cells into the bone marrow (Coleman

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 319

individuals with osteoporosis, bone fractures represent life-threatening events, and today there are in excess of 70 million people worldwide at risk (Brown JP & Jasse RG, 2002). Recent breakthroughs in our understanding of osteoclast differentiation and activation have come from the analysis of a family of biologically related tumour necrosis factor (TNF) receptor (TNFR)/TNF-like proteins: osteoprotegerin (OPG), receptor activator of nuclear factor (NF)-kB (RANK) and RANK ligand (RANKL), which together regulate osteoclast function. Binding of RANKL to RANK on the surfaces of osteoclast precursors will trigger maturation, activation, and prolonged survival of these cells. Thus, RANKL promotes bone resorption. In contrast, OPG is a "decoy receptor" that binds and neutralizes RANKL, thus inhibiting bone resorption (Bayle WJ, et al., 2003). There is

The ratio of RANKL to OPG is a critical factor determining the balance between bone resorption and bone formation. Vitamin D3, parathyroid hormone, tumour necrosis factor-α (TNF-α), activated T-cells, and glucocorticoid therapy all increase this ratio, promoting bone resorption. Estrogen deficiency states (including menopause) also produce osteoporosis because normal levels of 17β-estradiol inhibit RANKL production and stimulate OPG. (Bayle WJ, et al., 2003; Hofbauer LC & Schoppet M, 2004). Testosterone stimulates osteoblasts, inhibits the apoptosis of both osteoblasts and osteoclasts, and is a precursor of estrogen via aromatization; its net effect is to stimulate bone formation. Estrogens are essential in bone formation and resorption in men, and low levels are associated with loss of

 In osteoporosis, resorption usually exceeds formation with the net effect of bone loss, decreased strength, and an increased risk of fracture. The hypogonadal state resulting from cancer therapy enhances osteoclastic bone resorption, promoting bone loss, which along with other important clinical factors such as age, prior fragility fracture, and family history lead to increasing fracture risk (Gleason D, et al., 2003; Major PP & Cook R, 2002). In males with hypogonadism (whether induced by orchiectomy, ADT, hyperparathyroidism, or other causes), both testosterone and estrogen levels fall, shifting the balance of bone turnover toward resorption (Higano CS, 2008; Perez et al., 2006). It has been hypothesized that several malignancies including prostate and breast cancer and multiple myeloma also promote bone

The use of androgen deprivation therapy (ADT) in prostate cancer patients induces hypogonadism causing significant bone loss often leading to osteoporosis and an increased risk of fracture that may be compounded by the presence of bone metastases. Bone metastases disrupt the normal bone remodeling process by increasing bone resorption, which weakens the bone matrix and increases the risk of other bone complications, such as spinal cord compression, impaired mobility and bone pain (Berruti A, et al., 2001). Bone mineral density (BMD) is reduced by 0.6–5.3% annually in patients with locally advanced disease and 2.3–6.6% in patients with metastatic disease receiving ADT, exceeding by 5 to 10 fold the normal bone loss rates of similarly aged otherwise healthy men and prostate cancer patients not receiving ADT (Casey R, et al., 2006; Michaelson MD, et al., 2007; Smith MR, et al., 2008). Consequently, patients receiving ADT are 7–45% more likely to experience a fracture than patients not receiving ADT (Shahinian VB, et al., 2005; Smith MR, et al., 2006). Bisphosphonates have been shown to prevent bone loss and related complications in patients with locally advanced and metastatic prostate cancer and should be considered as part of cancer treatment when ADT is initiated in these patients. Androgen deprivation therapy is increasingly being prescribed both for men with locally advanced or high-risk non-

interplay between RANKL and OPG.

BMD and fracture risk. (Boonen S, et al., 2008).

resorption by expressing or stimulating RANKL (Boyle WJ, 2003).

RE, 2006). More recent studies have demonstrated how metastatic lesions develop once cancer cells reside in the marrow. Cellular modulators such as Receptor Activator for Nuclear Factor κ B Ligand (RANKL), parathyroid hormone–related protein (PTHrP), and serine protease urokinase (uPA) disrupt the balance of osteoblast and osteoclast activity that are involved in the formation of metastatic lesions (Mundy GR, 2002). Most bone lesions are classified as osteolytic or osteoblastic, depending on the direction of the bone breakdown/rebuilding imbalance. In osteoblastic lesions (prostate cancer metastases), the production of endothelin-1, transforming growth factor β (TGF-β) and uPA directly increase osteoblast activity and the formation of space-occupying bone lesions. In osteolytic lesions (primarily breast and lung cancer metastases), osteoclast activity is increased through the production of PTHrP, which stimulates nuclear factor κB (NF-κB) from stromal cells of bone, leading to increased osteoclast differentiation and activity (Mundy GR, 2002; Saad F, 2008). Newer studies have also shown that RANKL activity in both osteolytic and osteoblastic

lesions also may lead to increased tumour proliferation (Uehara H, et al., 2003; Yin JJ, et al., 1999). As osteoclasts break down bone, growth factors are released to stimulate the production of osteoblasts, allowing for bone repair and remodeling. These factors, including TGF-β and platelet derived growth factor have been shown to perpetuate bone metastases in both breast and prostate cancer models (Uehara H, et al., 2003; Yin JJ, et al., 1999).

 In metastatic bone disease, RANK Ligand has been implicated in a "vicious cycle" of bone destruction and tumour growth. Some tumours that have metastasized to the bone produce growth factors that can increase expression of RANK Ligand by osteoblasts. This stimulates osteoclast activity and leads to excess bone loss (Coleman RE, 2001; Rosen LS, et al., 2003). Osteoclast-mediated bone resorption leads to the release of growth factors and calcium from the bone matrix, that can in turn stimulate the tumour cell, further contributing to this cycle of bone destruction (Rosen LS, et al., 2003).

#### **5. Bone tissue and effects of hormonal therapy**

In life, bone is a rigid yet dynamic organ that is continuously moulded, shaped and repaired. Bone microstructure is patterned to provide maximal strength with minimal mass, as determined by the physiological needs of the organism. How are bone structure and function maintained, and how are changes in bone metabolism induced? Once formed, bone undergoes a process termed remodelling that involves break down (resorption) and buildup (synthesis) of bone; this occurs in micro scale throughout the skeleton. This remodeling cycle is a coupled process; in a normal young adult after completion of normal linear growth, bone resorption and formation are roughly equivalent, resulting in a net bone balance. Bones are composed of 2 main types of tissues: cortical bone and trabecular bone. Cortical bone is 80% to 90% calcified and has mainly mechanical and protective functions. Trabecular bone is only 15% to 25% calcified and constitutes only 20% of the total bone mass, but carries out most of the bone's metabolic function. Bone strength is a function of bone mass and of other parameters including geometry (the diameter of the cortical bone), material properties (the quality of the bone matrix and inorganic crystals) and microstructure (the diameter and interconnectivity of the trabeculae) (Gruber R, et al., 2008). The bone mass of a normal adult is the outcome of a dynamic equilibrium between bone formation (mediated by osteoblasts) and bone resorption (mediated by osteoclasts).

Most adult skeletal diseases are due to excess osteoclastic activity, leading to an imbalance in bone remodelling which favours resorption. Such diseases would include osteoporosis, periodontal disease, rheumatoid arthritis, multiple myeloma and metastatic cancers. For

RE, 2006). More recent studies have demonstrated how metastatic lesions develop once cancer cells reside in the marrow. Cellular modulators such as Receptor Activator for Nuclear Factor κ B Ligand (RANKL), parathyroid hormone–related protein (PTHrP), and serine protease urokinase (uPA) disrupt the balance of osteoblast and osteoclast activity that are involved in the formation of metastatic lesions (Mundy GR, 2002). Most bone lesions are classified as osteolytic or osteoblastic, depending on the direction of the bone breakdown/rebuilding imbalance. In osteoblastic lesions (prostate cancer metastases), the production of endothelin-1, transforming growth factor β (TGF-β) and uPA directly increase osteoblast activity and the formation of space-occupying bone lesions. In osteolytic lesions (primarily breast and lung cancer metastases), osteoclast activity is increased through the production of PTHrP, which stimulates nuclear factor κB (NF-κB) from stromal cells of bone, leading to increased osteoclast differentiation and activity (Mundy GR, 2002; Saad F, 2008). Newer studies have also shown that RANKL activity in both osteolytic and osteoblastic lesions also may lead to increased tumour proliferation (Uehara H, et al., 2003; Yin JJ, et al., 1999). As osteoclasts break down bone, growth factors are released to stimulate the production of osteoblasts, allowing for bone repair and remodeling. These factors, including TGF-β and platelet derived growth factor have been shown to perpetuate bone metastases in

both breast and prostate cancer models (Uehara H, et al., 2003; Yin JJ, et al., 1999).

of bone destruction (Rosen LS, et al., 2003).

**5. Bone tissue and effects of hormonal therapy** 

 In metastatic bone disease, RANK Ligand has been implicated in a "vicious cycle" of bone destruction and tumour growth. Some tumours that have metastasized to the bone produce growth factors that can increase expression of RANK Ligand by osteoblasts. This stimulates osteoclast activity and leads to excess bone loss (Coleman RE, 2001; Rosen LS, et al., 2003). Osteoclast-mediated bone resorption leads to the release of growth factors and calcium from the bone matrix, that can in turn stimulate the tumour cell, further contributing to this cycle

In life, bone is a rigid yet dynamic organ that is continuously moulded, shaped and repaired. Bone microstructure is patterned to provide maximal strength with minimal mass, as determined by the physiological needs of the organism. How are bone structure and function maintained, and how are changes in bone metabolism induced? Once formed, bone undergoes a process termed remodelling that involves break down (resorption) and buildup (synthesis) of bone; this occurs in micro scale throughout the skeleton. This remodeling cycle is a coupled process; in a normal young adult after completion of normal linear growth, bone resorption and formation are roughly equivalent, resulting in a net bone balance. Bones are composed of 2 main types of tissues: cortical bone and trabecular bone. Cortical bone is 80% to 90% calcified and has mainly mechanical and protective functions. Trabecular bone is only 15% to 25% calcified and constitutes only 20% of the total bone mass, but carries out most of the bone's metabolic function. Bone strength is a function of bone mass and of other parameters including geometry (the diameter of the cortical bone), material properties (the quality of the bone matrix and inorganic crystals) and microstructure (the diameter and interconnectivity of the trabeculae) (Gruber R, et al., 2008). The bone mass of a normal adult is the outcome of a dynamic equilibrium between bone

formation (mediated by osteoblasts) and bone resorption (mediated by osteoclasts).

Most adult skeletal diseases are due to excess osteoclastic activity, leading to an imbalance in bone remodelling which favours resorption. Such diseases would include osteoporosis, periodontal disease, rheumatoid arthritis, multiple myeloma and metastatic cancers. For individuals with osteoporosis, bone fractures represent life-threatening events, and today there are in excess of 70 million people worldwide at risk (Brown JP & Jasse RG, 2002).

Recent breakthroughs in our understanding of osteoclast differentiation and activation have come from the analysis of a family of biologically related tumour necrosis factor (TNF) receptor (TNFR)/TNF-like proteins: osteoprotegerin (OPG), receptor activator of nuclear factor (NF)-kB (RANK) and RANK ligand (RANKL), which together regulate osteoclast function. Binding of RANKL to RANK on the surfaces of osteoclast precursors will trigger maturation, activation, and prolonged survival of these cells. Thus, RANKL promotes bone resorption. In contrast, OPG is a "decoy receptor" that binds and neutralizes RANKL, thus inhibiting bone resorption (Bayle WJ, et al., 2003). There is interplay between RANKL and OPG.

The ratio of RANKL to OPG is a critical factor determining the balance between bone resorption and bone formation. Vitamin D3, parathyroid hormone, tumour necrosis factor-α (TNF-α), activated T-cells, and glucocorticoid therapy all increase this ratio, promoting bone resorption. Estrogen deficiency states (including menopause) also produce osteoporosis because normal levels of 17β-estradiol inhibit RANKL production and stimulate OPG. (Bayle WJ, et al., 2003; Hofbauer LC & Schoppet M, 2004). Testosterone stimulates osteoblasts, inhibits the apoptosis of both osteoblasts and osteoclasts, and is a precursor of estrogen via aromatization; its net effect is to stimulate bone formation. Estrogens are essential in bone formation and resorption in men, and low levels are associated with loss of BMD and fracture risk. (Boonen S, et al., 2008).

 In osteoporosis, resorption usually exceeds formation with the net effect of bone loss, decreased strength, and an increased risk of fracture. The hypogonadal state resulting from cancer therapy enhances osteoclastic bone resorption, promoting bone loss, which along with other important clinical factors such as age, prior fragility fracture, and family history lead to increasing fracture risk (Gleason D, et al., 2003; Major PP & Cook R, 2002). In males with hypogonadism (whether induced by orchiectomy, ADT, hyperparathyroidism, or other causes), both testosterone and estrogen levels fall, shifting the balance of bone turnover toward resorption (Higano CS, 2008; Perez et al., 2006). It has been hypothesized that several malignancies including prostate and breast cancer and multiple myeloma also promote bone resorption by expressing or stimulating RANKL (Boyle WJ, 2003).

The use of androgen deprivation therapy (ADT) in prostate cancer patients induces hypogonadism causing significant bone loss often leading to osteoporosis and an increased risk of fracture that may be compounded by the presence of bone metastases. Bone metastases disrupt the normal bone remodeling process by increasing bone resorption, which weakens the bone matrix and increases the risk of other bone complications, such as spinal cord compression, impaired mobility and bone pain (Berruti A, et al., 2001). Bone mineral density (BMD) is reduced by 0.6–5.3% annually in patients with locally advanced disease and 2.3–6.6% in patients with metastatic disease receiving ADT, exceeding by 5 to 10 fold the normal bone loss rates of similarly aged otherwise healthy men and prostate cancer patients not receiving ADT (Casey R, et al., 2006; Michaelson MD, et al., 2007; Smith MR, et al., 2008). Consequently, patients receiving ADT are 7–45% more likely to experience a fracture than patients not receiving ADT (Shahinian VB, et al., 2005; Smith MR, et al., 2006). Bisphosphonates have been shown to prevent bone loss and related complications in patients with locally advanced and metastatic prostate cancer and should be considered as part of cancer treatment when ADT is initiated in these patients. Androgen deprivation therapy is increasingly being prescribed both for men with locally advanced or high-risk non-

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 321

Prostate cancer itself is associated with osteoporosis, even among ADT-naïve patients without metastatic disease. In a cross-sectional study, 45.2% of such patients had osteopenia and 35.4% had osteoporosis even before starting ADT. Systematic retrospective reviews have also shown the association between ADT and increased fracture risk (Saad F, et al.,

Because age and hypogonadism are both considered major risk factors for osteoporosis, all prostate cancer patients beginning ADT should be screened with DXA scans at baseline; anyone aged ≥ 65 and anyone with kyphosis, back pain, substantial height loss, or other symptoms suggesting vertebral fractures should also be screened with thoracic and lumbar

The progression of metastatic bone disease in patients with prostate cancer can lead to debilitating skeletal-related events (SREs) (Oofelein MG, et al., 2002). About 70–80% of patients with metastatic prostate cancer present with or develop bone metastasis (Polascik

pathological fractures, spinal cord compression (figure 4), and severe pain requiring radiotherapy or surgery for bone lesions. These SREs result in significant complications that

Fig. 4. Total disruption of the 9th dorsal vertebral body due to a metastatic prostate

and are at increased risk for skeletal-related events (SREs), which include

**8. Incidence and presentation of skeletal-related events** 

reduce quality of life (Botteman MF, et al., 2010).

carcinoma, with spinal cord compression.

2008; Brufsky AM, 2008).

spine x-rays.

TJ, 2008),

metastatic prostate cancer and for those with recurrent disease (Meng MW, et al., 2002; Sharifi N, et al., 2005). With this increased exposure to ADT, clinicians have seen the emergence of longer-term treatment complications, including osteoporosis and osteopenia. Although osteoporosis is generally less frequent in men, it is increasingly recognized as a source of substantial morbidity and even mortality in the aging male. Men suffer one third of all hip fractures. Osteoporotic vertebral fractures have a radiological prevalence of up to 50% in both sexes; they often cause chronic pain, and even clinically silent fractures are associated with increased risks of future fracture (both vertebral and hip), kyphosis, restricted lung function, impaired activities of daily living and even increased mortality (Mavrokokki A, et al., 2007). A study of Canadian prostate cancer patients who were orchiectomized found that their 5-year risks of vertebral and hip fractures were 2.2 fold higher than those of patients who had not been orchiectomized (p < 0.001 for both) (Body JJ, 2003).

Fractures also independently predict diminished survival in prostate cancer patients on ADT. In one retrospective study, a history of fracture since the diagnosis of prostate cancer decreased median overall survival from 160 months to 121 months (p = 0.04) (Oefelein MG, 2002).
