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

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 TJ, 2008), and are at increased risk for skeletal-related events (SREs), which include pathological fractures, spinal cord compression (figure 4), and severe pain requiring radiotherapy or surgery for bone lesions. These SREs result in significant complications that reduce quality of life (Botteman MF, et al., 2010).

Fig. 4. Total disruption of the 9th dorsal vertebral body due to a metastatic prostate carcinoma, with spinal cord compression.

Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 323

metastases at initial presentation. Almost all patients who die of prostate cancer have bone

Men with prostate cancer that develops SRE have a poor prognosis. In a cohort study of 23,087 incident patients with prostate cancer, 569 (almost 3%) presented with bone metastasis at prostate cancer diagnosis, of whom 248 (43.6%) experienced a skeletal related event during follow-up. Of the 22,404 men (97% overall) without bone metastasis at diagnosis 2,578 (11.5%) were diagnosed with bone metastasis and 1,329 (5.9%) also experienced a skeletal related event during follow-up. One and 5-year survival was 87% and 56% in patients with prostate cancer without bone metastasis, 47% and 3% in those with bone metastasis, and 40% and less than 1% in those with bone metastasis and skeletal related events, respectively. Compared with men with prostate cancer without bone metastasis the adjusted 1-year mortality rate ratio was 4.7 (95% CI 4.3-5.2) in those with bone metastasis and no skeletal related events, and 6.6 (95% CI 5.9-7.5) in those with bone metastasis and a skeletal related event. The result of this study brings the conclusion, that bone metastasis and skeletal related events predict poor prognosis in men with prostate

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

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,

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

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

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

involvement (Egerdie B et al., 2010).

cancer (Norgaard M, et al., 2010).

experience an SRE increases.

**horizons** 

et al., 2008).

recommended.

Skeletal-related events (SRE) include any secondary complication from the presence of bone metastases and can occur in both osteolytic and osteoblastic lesions. Pain is the most common symptom of bone disease and is thought to be due to increased sensitization of nociceptors, tumor infiltration of nerve channels, and local tissue acidification during the bone resorption process. Often the pain is described as dull, aching, or constant, with increasing intensity with weight-bearing activities. In many patients, this is localized to the area of infiltration (most often the thoracic spine), but may be referred or radicular if there is compression of the nerve channels. In nearly one-third of patients with bone metastasis, pain is caused by pathologic fracture. Similar to osteoporosis, this is often caused by the lytic breakdown of bone, often in the ribs, spine, and long bones. Pain is the most common symptom of fracture, although some patients may develop kyphosis from compression of the spine. In approximately 6% of patients, fracture may lead to the development of neurologic symptoms (Boyle WJ, et al., 2003).

Another cause of neurologic symptoms in patients with metastatic bone disease is malignant spinal cord compression. This medical emergency often is caused by direct compression of the spinal canal by osteoblastic tumor formation and edema or necrosis of the spinal cord from alteration of arterial and venous blood flow. Patients often present with severe back pain, weakness, paralysis, paresthesias and decrease in bowel or bladder control (Sathiakumar N, et al., 2011). At presentation, up to 68% of patients are unable to walk. Prompt management of this complication is necessary to decrease the progression of irreversible neurologic damage. Prevention and early treatment is paramount because the ability to regain ambulation after treatment is a strong predictor of overall survival (Sathiakumar N, et al., 2011; Aljumaily R, & Mathew P, 2011).

Hypercalcemia, defined as serum calcium >10.5 mg/dl, is another common presentation of skeletal metastasis. While the release of calcium into the blood from bone breakdown is the most common mechanism in patients with bone metastasis, hypercalcemia may also occur due to parathryroid hormone imbalances in patients without skeletal lesions. Hypercalcemia is a multifactorial complication of malignancy. Radiation therapy, surgical stabilization, and/or decompression often are necessary in patients with bone metastasis, particularly when the spinal column is involved. Pharmacotherapy is the mainstay of hypercalcemia treatment and is almost always used adjunctively with surgery or radiation to manage fractures, malignant spinal cord compression, and the pain of skeletal-related events (Shahinia V, et al., 2005).

Bone pain is the most common type of cancer-related pain, and was deemed to be severe and debilitating in two-thirds of patients. Treating bone pain therefore remains a consideration when managing metastatic bone disease (Coleman RE, 2006).

SRE is a pathology of high cost. A study in 342 patients with prostate cancer and bone metastases revealed that the annual economic effect of medically treating SREs for these patients was \$12,469. Patients most frequently had radiation therapy (89%), followed by pathologic fracture (23%) and bone surgery (12%). Among patients diagnosed as having at least 1 SRE, 78% experienced 1 type of SRE, 17% had 2 types of SREs, and 5% had 3 or more distinct types of SREs. The mean costs associated with SREs in the year after the initial diagnosis of an SRE, adjusted for the censoring of the data, was \$12,469, with the highest costs associated with radiation therapy (\$5930), followed by pathologic fracture (\$3179) and bone surgery (\$2218) (Lage MJ, et al., 2008).)

In advanced prostate cancer, 65–75% of patients may eventually develop bone metastases. It is also important to note that approximately 10% of men with prostate cancer have bone

Skeletal-related events (SRE) include any secondary complication from the presence of bone metastases and can occur in both osteolytic and osteoblastic lesions. Pain is the most common symptom of bone disease and is thought to be due to increased sensitization of nociceptors, tumor infiltration of nerve channels, and local tissue acidification during the bone resorption process. Often the pain is described as dull, aching, or constant, with increasing intensity with weight-bearing activities. In many patients, this is localized to the area of infiltration (most often the thoracic spine), but may be referred or radicular if there is compression of the nerve channels. In nearly one-third of patients with bone metastasis, pain is caused by pathologic fracture. Similar to osteoporosis, this is often caused by the lytic breakdown of bone, often in the ribs, spine, and long bones. Pain is the most common symptom of fracture, although some patients may develop kyphosis from compression of the spine. In approximately 6% of patients, fracture may lead to the development of

Another cause of neurologic symptoms in patients with metastatic bone disease is malignant spinal cord compression. This medical emergency often is caused by direct compression of the spinal canal by osteoblastic tumor formation and edema or necrosis of the spinal cord from alteration of arterial and venous blood flow. Patients often present with severe back pain, weakness, paralysis, paresthesias and decrease in bowel or bladder control (Sathiakumar N, et al., 2011). At presentation, up to 68% of patients are unable to walk. Prompt management of this complication is necessary to decrease the progression of irreversible neurologic damage. Prevention and early treatment is paramount because the ability to regain ambulation after treatment is a strong predictor of overall survival

Hypercalcemia, defined as serum calcium >10.5 mg/dl, is another common presentation of skeletal metastasis. While the release of calcium into the blood from bone breakdown is the most common mechanism in patients with bone metastasis, hypercalcemia may also occur due to parathryroid hormone imbalances in patients without skeletal lesions. Hypercalcemia is a multifactorial complication of malignancy. Radiation therapy, surgical stabilization, and/or decompression often are necessary in patients with bone metastasis, particularly when the spinal column is involved. Pharmacotherapy is the mainstay of hypercalcemia treatment and is almost always used adjunctively with surgery or radiation to manage fractures, malignant spinal cord compression, and the pain of skeletal-related

Bone pain is the most common type of cancer-related pain, and was deemed to be severe and debilitating in two-thirds of patients. Treating bone pain therefore remains a

SRE is a pathology of high cost. A study in 342 patients with prostate cancer and bone metastases revealed that the annual economic effect of medically treating SREs for these patients was \$12,469. Patients most frequently had radiation therapy (89%), followed by pathologic fracture (23%) and bone surgery (12%). Among patients diagnosed as having at least 1 SRE, 78% experienced 1 type of SRE, 17% had 2 types of SREs, and 5% had 3 or more distinct types of SREs. The mean costs associated with SREs in the year after the initial diagnosis of an SRE, adjusted for the censoring of the data, was \$12,469, with the highest costs associated with radiation therapy (\$5930), followed by pathologic fracture (\$3179) and

In advanced prostate cancer, 65–75% of patients may eventually develop bone metastases. It is also important to note that approximately 10% of men with prostate cancer have bone

consideration when managing metastatic bone disease (Coleman RE, 2006).

neurologic symptoms (Boyle WJ, et al., 2003).

events (Shahinia V, et al., 2005).

bone surgery (\$2218) (Lage MJ, et al., 2008).)

(Sathiakumar N, et al., 2011; Aljumaily R, & Mathew P, 2011).

metastases at initial presentation. Almost all patients who die of prostate cancer have bone involvement (Egerdie B et al., 2010).

Men with prostate cancer that develops SRE have a poor prognosis. In a cohort study of 23,087 incident patients with prostate cancer, 569 (almost 3%) presented with bone metastasis at prostate cancer diagnosis, of whom 248 (43.6%) experienced a skeletal related event during follow-up. Of the 22,404 men (97% overall) without bone metastasis at diagnosis 2,578 (11.5%) were diagnosed with bone metastasis and 1,329 (5.9%) also experienced a skeletal related event during follow-up. One and 5-year survival was 87% and 56% in patients with prostate cancer without bone metastasis, 47% and 3% in those with bone metastasis, and 40% and less than 1% in those with bone metastasis and skeletal related events, respectively. Compared with men with prostate cancer without bone metastasis the adjusted 1-year mortality rate ratio was 4.7 (95% CI 4.3-5.2) in those with bone metastasis and no skeletal related events, and 6.6 (95% CI 5.9-7.5) in those with bone metastasis and a skeletal related event. The result of this study brings the conclusion, that bone metastasis and skeletal related events predict poor prognosis in men with prostate cancer (Norgaard M, et al., 2010).
