Patients with advanced metastatic prostate cancer are candidates for hormonal or surgical castration to reduce the levels of circulating testosterone that allow prostate cancer cells to grow. Surgical castration, called bilateral orchiectomy, involves removal of the testicles, which are the main sources of testosterone. Although the majority of patients with advanced prostate cancer improve following castration, they may progress to a testicular androgen-independent state, in which androgens are produced by the adrenal glands rather than the testicles.

Hormonal castration is also available and involves the use of drugs. Some drugs, such as luteinizing hormone-releasing hormone (LHRH) agonists, affect the pituitary gland directly and include leuprolide, goserelin, and triptolen. Other drugs, the antiandrogens, block the effect of androgens that are produced in the adrenal glands, producing a total androgen blockade. Adverse events from androgen deprivation therapy (ADT) include bone loss, or treatment-related osteoporosis.

Researchers continue to look for new treatment options for advanced metastatic prostate cancer. In fact, current clinical trials are evaluating drugs that may interfere with mediators of bone metastases. This includes targeting the mediators RANKL, RANK, and osteoprotegerin (OPG) (see section on Healthy Bone), as well as endothelin-1 via a receptor antagonist.

As pain may be a component of advanced metastatic prostate cancer, particularly in hormone-resistant prostate cancer, palliative measures may be instituted. Options include chemotherapy, palliative radiation therapy, and pain medication.

Chemotherapeutic options, particularly in androgen-independent prostate cancer patients (ie, those refractory to hormone manipulation) include mitoxantrone and the taxanes, paclitaxel and docetaxel.

While local radiation therapy can provide symptomatic relief, there is a lack of specificity toward target tissue. Radioisotopes, however, can preferentially accumulate in tumor bone sites and thus provide more effective and targeted pain relief. The radioisotopes strontium-89 and samarium-153, which are approved by the US Food and Drug Administration, and other radioisotopes that are under investigation show promise in treating prostate cancer patients with metastases.

Pain medication is administered according to the level of pain and in response to increasing pain correlating with advanced disease. The pain medications used in the treatment of metastatic prostate cancer include nonopioid agents (eg, NSAIDs), with or without adjuvants (eg, antidepressants), weaker opioids (eg, codeine), and stronger opioids (eg, morphine).

The bisphosphonates are another treatment option. Using bisphosphonates to slow down bone damage caused by the cancer, to reduce hypercalcemia, and to lower the risk of bone fractures will also help to reduce bone pain associated with bone metastases.

Cancer treatments for hormone-responsive disease result in androgen deprivation and bone loss, and ADT significantly increases fracture risk. The longer treatment for cancer is continued, the greater the risk for fracture. Resulting fractures are associated with poorer survival and diminished quality of life.^1-4

However, treatment with bisphosphonates can delay the onset and reduce the incidence of skeletal complications of bone metastases.⁵ Bisphosphonates effectively target osteolytic bone destruction, the process responsible for the majority of skeletal morbidity from malignant bone disease (see Overview of Treatment Options).

The earlier bisphosphonates, such as clodronate and pamidronate, have demonstrated some palliative benefits in patients with prostate cancer; but in most studies, these benefits did not reach levels of significance (Table 1).

Only the more potent bisphosphonate, zoledronic acid, has demonstrated significant and durable clinical benefits in patients with advanced disease, as shown in Table 2.¹¹

ADT = Androgen deprivation therapy

Source: Saad F, Schulman CC. Eur Urol. 2004;45:26-34. Adapted with permission.

Specific clinical trials of the bisphosphonates for skeletal wellness will be discussed in the Clinical Trials section of this website. The Clinical Trials section will be updated periodically.

Several studies have reported marked decreases in bone mineral density (BMD) at the hip, spine, and other skeletal sites during initial ADT for nonmetastatic prostate cancer (Table 3).¹²

Source: Smith MR. Cancer Treatment Rev. 2003;29:211-218. Adapted with permission.

Intermittent administration of either intravenous pamidronate or zoledronic acid prevents treatment-related osteoporosis (bone loss) in men with prostate cancer. Results of two randomized trials are described in Table 4.¹²

Source: Smith MR. Cancer Treatment Rev. 2003;29:211-218. Adapted with permission.

By reducing the occurrence of fractures, prostate cancer patients may require less radiation therapy and fewer surgeries and hospitalizations. They also may experience less pain and, therefore, measurable improvements in quality of life and mobility.¹¹

1.	Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer. 2003;97(suppl 3):789-795.
2.	Melton LJ III, Alothman KI, Khosla S, et al. Fracture risk following bilateral orchiectomy. J Urol. 2003;169:1747-1750.
3.	Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005-1007.
4.	Mittan D, Lee S, Miller E, et al. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab. 2002;87:3656-3661.
5.	Coleman RE, Theriault RL, Smith MR, Rosen LS. The evolving role of bisphosphonates for cancer treatment-induced bone loss [monograph]. Release date June 2003. Available at: http://www.medscope.com/viewprogram/2511_pmt. Accessed November 29, 2004.
6.	Smith JA. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study. J Urol. 1989;141:85-87.
7.	Elomaa I, Kylmala T, Tammela T, et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer. Int Urol Nephrol. 1992;24:159-166.
8.	Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst. 2003;95:1300-1311.
9.	Small EJ, Smith MR, Seaman JJ, et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003;21:4277-4284.
10.	Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol. 2003;21:3335-3342.
11.	Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol. 2004;45:26-34.
12.	Smith MR. Management of treatment-related osteoporosis in men with prostate cancer. Cancer Treat Rev. 2003;29:211-218.