**10. Conclusions**

328 Prostate Cancer – Diagnostic and Therapeutic Advances

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

Both opioid and non-opioid analgesics are recommended for the symptomatic treatment of pain. Clinical trials show that bisphosphonate therapy improves pain control and allows most patients to use lower opioid doses; however, bisphosphonates should be viewed as

In patients with mild pain, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are acceptable agents to use. Acetaminophen is preferred in patients with thrombocytopenia, renal dysfunction, those receiving nephrotoxic agents, or at risk for gastrointestinal bleeds. In patients with liver dysfunction, NSAIDs are preferred for mild

Since most patients experience moderate to severe pain, opioid analgesics often are used. Patients naïve to opioid therapy should begin with low doses of immediate release agents (typically 5-15 mg orally morphine or 2-4 mg intravenous morphine) and reassessed every 1 to 2 hours for effect. After 24 hours of pain control on a short-acting regimen, patients should be converted to a long-acting agent such as sustained release morphine, oxycodone, fentanyl, or methadone for basal control. Patients who are opioid tolerant should begin with higher doses of short-acting agents; if they are on a long-acting product, this should be continued, increasing the dose as needed to account for short-acting opioid use. A similar approach should be taken in patients initiating opioid therapy as an outpatient, with a shortacting opioid available every 3 to 4 hours and close follow-up. A bowel regimen with a stimulant plus stool softener should be initiated to prevent constipation from opioid use. The National Comprehensive Cancer Network (NCCN) provides a useful guideline for pain

Adjunct agents such as anticonvulsants (gabapentin, lamotrigine, topiramate), tricyclic antidepressants (amitriptyline, imipramine, desipramine, nortriptyline), venlafaxine, duloxetine, or topical analgesics (lidocaine or capsaicin) may also help to reduce

The effects on BMD of toremifene citrate, a new SERM, were tested in a 6-month, placebocontrolled dose-finding study with 46 men with prostate cancer receiving ADT. An oral dose of 60 mg daily significantly improved BMD and decreased hot flushes (Steiner MS, et al., 2004). A 2-year, double blind, placebo- controlled phase-III multicentre study of oral toremifene 80 mg has been completed in 1389 ADT patients with advanced prostate cancer; this compound reduced new morphometric vertebral fractures (the primary endpoint) by 53% (p = 0.034). Bone mineral density at lumbar spine, hip, and femur was also increased significantly (p < 0.0001), and lipid profiles were improved compared with placebo (Smith

In advanced prostate cancer, metastasis is sadly inevitable. Although bone metastases from prostate cancer have a predominantly osteoblastic appearance, histological findings

adjunctive for pain control because nearly all patients will require analgesics.

these agents (Loblaw D, et al., 1998; Coleman RE, 2004).

management in cancer patients (Coleman RE, 2004).

MR, et al., 2004; Schwarz EM & Ritchlin CT, 2006).

neuropathic pain caused by nerve compression (Cole J, et al., 2008).

**9.7 Upcoming agents: Toremifene citrate and denosumab** 

**9.6 Analgesics** 

pain (Wadhwa VK, et al., 2008).

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 predict poor prognosis in men with prostate cancer.

### **11. References**


Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 331

Yaturu, S. DePrisco, C. & DjoDjo, S. (2002). Effect of bisphosphonates in osteoporosis

Greenspan, SL. (2008). Approach to the prostate cancer patient with bone disease. *Journal of* 

Gilbert, SM. & McKiernan, JM. (2005). Epidemiology of male osteoporosis and prostate

Amin, S. & Felson, DT. (2001). Osteoporosis in men. *Rheumathology Diseases Clinics of North* 

Smith, MR. McGovern, FJ. & Zietmna, AL. (2001). Pamidronate to prevent bone loss during

Morote, J. Planas, J. Orsola, A. Abascal, JM. Salvador, C. Trilla, E. Raventos, C. Cecchini,

Casey, R. Love, W. Mendoza, C. Reymond, D. & Zarenda, M. (2006). Zoledronic acid

Michaelson, MD. Kaufman, DS. Lee, H. McGovern, FJ. Kantoff, PW. & Fallon, MA. (2007).

Smith, MR. Eastham, J. Gleason, DM. Shasha, D. Tchekmedyian, S. & Zinner, N. (2003).

Shahinian, VB. Kuo, YF. Freeman, JL. & Goodwin, JS. (2005). Risk of fracture after androgen deprivation for prostate cancer. *New England Journal of Medicine* 352: 154-64. Smith, MR. Boyce, Sp. Moyneur, E. Duh, MS. Raut, MK. & Brandman, J. (2006). Risk of

Meng, MW. Grossfeld, GD. & Sadetsky, N. (2002). Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. *Urology* 60 (3): 7-11. Sharifi, N. Gulley, JL. & Dahut, WL. (2005). Androgen deprivation therapy for prostate

Mavrokokki, A. Cheng, A. Stein, B. & Goss, AN. (2007). Nature and frequency of

Body, JJ. (2003). Effectiveness and cost of bisphosphonate therapy in tumour bone disease.

Oefelein, MG. Ricchiuti, V & Conrad, W. (2002). Skeletal fractures negatively correlate with overall survival in men with prostate cancer. *Journal of Urology* 168: 1005-7. Coleman, RE. (2001). Metastatic bone disease: clinical features, pathophysiology and

cancer. *Journal of the American Medical Association* 294: 238-44.

treatment strategies. *Cancer Treatment Reviews* 27: 165-76.

therapy. *The 2006 Multidisciplinary Prostate Cancer Symposium,* 2006.

androgen-deprivation therapy for prostate cancer. *New England Journal of Medicine*

L. Encabo, G. Reventos J. (2007). Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. *Urology* 69 (3):

reduces bone loss in men with prostate cancer undergoing androgen deprivation

Randomized controlled trial of annual zoledronic acid to prevent gonadotrophinreleasing hormone agonist-induced bone loss in men with prostate cancer. *Journal* 

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for non-metastatic prostate cancer. Journal

clinical fractures after gonadotrophin-releasing hormone agonist therapy for

bisphosphonate-associated osteonecrosis of the jaws in Australia. *Journal of Oral* 

*Clinical Endocrinology and Metabolism* 93: 2-7.

cancer. *Current Opinion in Urology* 15: 23-27.

474-79.

*America* 27: 19-47.

*of Clinical Oncology* 25: 1038-42.

*Maxillofacial Surgery* 65: 415-23.

*Cancer* 97 (3): 859-65.

prostate cancer. *Journal of Urology* 175: 136-9.

of Urology 169: 2008-12.

341: 948-55.

500-4.

secondary to LHRH analogs for prostate cancer. *Journal of Bone Mineral Research* 17:

with prostate cancer without apparent bone metastases given androgen deprivation therapy. *Journal of Urology* 167: 2361-2367.


Diamond, TH. Higano, CS. Smith, MR. Guise, T. & Singer, F. (2004). Osteoporosis in men

Fowler, JE. Bigler, SA. White, PC. & Duncan, W. (2002). Hormone therapy for locally

Bolla, M. Gonzalez, D. & Warde, P. (1997). Improved survival in patients with locally

Elliot, ME. Wilcox, AJ. & Carnes, ML. (2002). Androgen deprivation in veterans with

Melton, LJ. Atkinson, EJ. O´Connor, MK. O´Fallon, WM. & Riggs, BL. (1998). Bone density and fracture risk in men. *Journal of Bone Mineral Research* 13: 1915-23. Binkley, NC. Schmeer, P. Wasnich, RD. & Lenchik, L. (2002). What are the criteria by which

Zmuda, JM. Cauley, JA. Glynn, NY. & Finkelstein, JS. (2000). Posterior-anterior and lateral

Weigert, JM. & Cann, CE. (1998). 3D QCT: a useful tool in following therapy. In:

*Meeting of the International Society of Densitometry.* West Hartford: ISCD, 1-4. Kaufman, JM. Johnell, O. & Abadie, E. (2000). Background for the studies on the treatment of male osteoporosis: state of the art. *Annals of Rheumathology Diseases* 59: 765-772. Lenchik, L. Kiebzak, GM. & Blunt, BA. (2002). What is the role of serial bone mineral density measurements in patient management?. *Journal of Clinical Densitometry* 5: 29-38. Delaet, C. van Hout, BA. Burger, H. Weel, AE. Hofman, A. & Pols, HA. Hip fracture

Jones, G. Nguyen, T. Sambrook, P. Kelly, P. & Eisman, JA. (2004). Progressive loss of bone in

Osteoporosis Epidemiology Study. *British Medicine Journal* 309: 691-95. Stepan, JJ. Lachman, MA. Svereina, J. Pacovsky, V. & Baylink, D. (1989). Castrated men

remodelling. *Journal of Clinical Endocrinology and Metabolism* 69: 523-27. Daniell, HW. (1997). Osteoporosis after orchiectomy for prostate cancer. *Journal of Urology*

deprivation. *Journal of Bone Mineral Research* 17: 411-21.

Bruder, JM. & Welch, MD. (2002). Prevalence of osteopenia and osteoporosis by central and

bone loss among older men. *Journal of Bone Mineral Research* 15: 1417-24. Faulkner, KG. (1998). Bone densitometry: choosing the proper skeletal site to measure.

deprivation therapy. *Journal of Urology* 167: 2361-2367.

advanced prostate cancer. *Journal of Urology* 168: 546-9.

Caucasians?. *Journal of Clinical Densitometry* 5: 19-27.

*Journal of Clinical Densitometry* 1: 279-85.

Miner Res 1998; 13: 1587-93.

157: 439-44.

*Journal of Medicine* 337: 295-300.

892-9.

366-71.

with prostate cancer without apparent bone metastases given androgen

with prostate carcinoma receiving androgen-deprivation therapy. *Cancer* 100 (5):

advanced prostate cancer treated with radiotherapy and gosarelin. *New England* 

prostate cancer: implications for skeletal health. *Journal of Bone Mineral Research* 17:

a densitometric diagnosis of osteoporosis ca be made in males and non-

dual-energy X-ray absorptometry for the assessment of vertebral osteoporosis and

International Society of Clinical Densitometry*. Proceedings of the 4th annual Scientific* 

prediction in elderly men and women: validation in the Rotterdam study. J Bone

the femoral neck in elderly people: longitudinal findings from the Dubbo

exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone

peripheral bone mineral density in men with prostate cancer during androgen


Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 333

Higano, CS. (2008). Androgen-deprivation therapy-induced fractures in men with non-

Perez, EA. Serene, M. & Durling, FC. (2006). Aromatase inhibitors and bone loss. *Oncology*

Clarke, BL. Ebeling, PR. & Jones, JD. (1996). Changes in qualitative bone histomorphometry in aging healthy men. *Journal of Clinical Endocrinology and Metabolism* 81: 2264-70.

Khosla, S. Melton, LJ. Atkinson, EJ. O´Fallon, WM. Klee, GG. & Riggs, BL. (1998).

Smith, MR. (2003). Diagnosis and management of treatment-related osteoporosis in men

Groot, MT. Kruger, CG. Pelger, RC. & Uyl-de Groot, CA. (2003). Financial cost of patients

Berruti, A. Dogliotti, R. Bitossi, R. Fasolis, G. Gorzegno, G. & Bellina, M. (2000). Incidence of

Saad, F. Adachi, JD. & Brown, JP. (2008). Cancer treatment-induced bone loss in breast and

Brufsky, AM. (2008). Cancer treatment-induced bone loss: pathophysiology and clinical

Polascik, TK. (2008). Bone health in prostate cancer patients receiving androgen-deprivation

Botteman, MF. Meijboom, M. Foley, I. Stephens, JM. Chen, YM. & Kaura, S. (2010). Cost-

Sathiakumar, N. Delzell, E. Morrisey, MA. Falkson, C. Yong, M. Chia, V. Blackburn, J.

Shahinian, V. Yong-Fang, K. Freeman, JL. & Goodwin, JS. (2005). Risk of fracture after

Lage, MJ. Barber, BL. Harrison, DJ. & Jun, S. (2008). The cost of treating skeletal-related

effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany and the United Kingdom. *European Journal of Health* 

Arora, T. & Kilgore, ML. (2011). Mortality following bone metastasis and skeletalrelated events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries. 1999-2006. *Prostate Cancer Prostatic Disease* 14 (2): 177-83. Aljumaily, R. & Mathew, P. (2011). Optimal management of bone metastases in prostate

androgen deprivation for prostate cancer. *New England Journal of Medicine* 352 (2):

events in patients with prostate cancer. *American Journal of Management Care* 14 (5):

markers evaluated at baseline. *Journal of Urology* 164: 1248-51.

therapy: the role of bisphosphonates. *Prostate Cancer* 11: 13-9.

prostate cancer. *Journal of Clinical Oncology* 26: 5465-76.

cancer. *Current Oncology Reports* 13 (3): 222-30.

perspectives. *Oncology* 13: 187-95.

*Economy* 31: 1117-23.

154-64.

317-22.

Singer, FE. Eyre, DR. (2008). *Cleveland Clinic Journal of Medicine*. 75: 739-50.

*Clinical Endocrinology and Metabolism* 83: 2266-74.

with prostate carcinoma. *Cancer* 97 (3): 789-92.

*Urology* 5: 24-34.

20: 1029-48.

226-30.

metastatic prostate cancer: what do we really know?. *Nature Clinical of Practice* 

Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. *Journal of* 

with prostate cancer osseous metastasis in the Netherlands. *European Urology* 43:

skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease. Predictive role of bone resorption and formation


Rosen, LS. Gordon, D. & Tchekmedyian, NS. (2003). Zoledronic Acid Versus Placebo in

Coleman, RE. (2006). Clinical features of metastatic bone disease and risk of skeletal

Mundy GR. (2002). Metastasis: metastasis to bone: causes, consequences and therapeutic

Saad F. (2008). Targeting the receptor activator of nuclear factor-B (RANK) ligand in

Uehara, H. Kim, SJ. & Karashima, T. (2003). Effects of blocking platelet-derived growth

Yin, JJ. Selander, K. & Chirgwin, JM. (1999). TGF-B signaling blockade inhibits PTHrP

Gruber, R. Pietshcmann, P. & Peterlik, M. (2008). Introduction to bone development

Brown, JP. & Josse, RG. (2002). Scientific advisory council of the osteoporosis society of

osteoporosis in Canada. *Canadian Medical Association Journal* 167 (10): 1-34. Boyle, WJ. Simone, WS. Lacey, DL. (2003). Osteoclast differentiation and activation. *Nature*

Hofbauer, LC. & Schoppet, M. (2004). Clinical implications of the osteoprote-

Boonen, S. Vanderschueren, D. & Venkek, K. (2008). Recent developments in the

cancer and bone metastases. *American Society of Clinical Oncology* 22: 379-83. Major, PP. & Cook, R. (2002). Efficacy of bisphosphonates in the management of skeletal

Egerdie, B. & Saad, F. (2010). Bone health in the prostate cancer patient receiving androgen

efficacy by enhanced compliance. *Journal of Internal Medicine* 264: 315-32. Oefelein, MG. Ricchiuti, V. & Conrad, W. (2002). Skeletal fractures negatively correlate with overall survival in men with prostate cancer. Journal of Urology 168: 1005-7. Gleason, D. Saad, F. Goas, A. & Zheng, M. (2003). Continuing benefit of zoledronic acid in

metastases. *Journal of the National Cancer Institute* 95 (6): 458-70.

prostate cancer bone metastases. *British Journal of Urology Internationalis* 101(9):

factor-receptor signaling in a mouse model of experimental prostate cancer bone

secretion by breast cancer cells and bone metastases development. *Journal of Clinical* 

remodelling and repair. In: Grampp S, ed. *Radiology of Osteoporosis*. 2nd Ed.

Canada. 2002 Clinical practice guidelines for the diagnosis and management of

gerin/RANKL/RANK system for bone and vascular diseases. *Journal of the* 

management of postmenopausal osteoporosis with bisphosphonates: enhanced

preventing skeletal complications after the first occurrence in patients with prostate

complications of bone metastases and selection of clinical endpoints. *American* 

deprivation therapy: a review of present and future management options*. Can Urol* 

morbidity. *Clinical Cancer Research* 12 (20): 6243-49.

opportunities. *Nature Reviews of Cancer* 2 (8): 584.

*Oncology* 21: 3150-57.

*Investigation* 103 (2): 197-206.

*American Medical Association* 292: 490-95.

*Journal of Clinical Oncology* 25 (6): 10-18.

*Assoc J* 4 (2): 129–35.

Springer, 2008.

423: 337-42.

1071-5.

the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumours: A Phase III, Double-Blind, Randomized Trial-The Zoledronic Acid Lung Cancer and Other Solid Tumours Study Group. *Journal of Clinical* 


Skeletal Related Events in Prostate Cancer: Important Therapeutic Considerations 335

Khosla, S. Burr, D. Cauley, J. Dempster, D. Eheling, PR. Felsenberg, D. Gagci, RF. & Gilsanz

of the American Society for bone and mineral research *Oncology* 22: 1479-91. Bamias, A. Kastritis, E. Bamia, C. Moulopoulos, LA. Melakopoulos, I. Bozas, G. Koutsoukou,

Ruggiero, SL. Mehrotra, B. Rosenberg, TJ. & Engroff, SL. (2004). Osteonecrosis of the jaws

Wadhwa, VK. Weston, R. & Mistry, R. (2009). Long-term changes in bone mineral density

Kilmo, P. Kestle, JR. & Schmidt, MH. (2004). Clinical trials and evidence-based medicine for metastatic spine disease. *Neurosurgery Clinics of North America* 15 (4): 549-64. Cole, J. & Patchell, R. (2008). Metastatic epidural spinal cord compression. *Lancet Neurology* 7

Heimdal, K. Hirschberg, H. Slettebo, H, Watne, K. & Nome, O. (1992). High incidence of

Loblaw, D. & Laperriere, N. (1998). Emergency treatment of malignant extradural spinal

Steiner, MS. Patterson, A. & Israeli, R. (2004). Toremifene citrate versus placebo for

Schwarz, EM. & Ritchlin, CT. (2007). Clinical development of anti-RANKL therapy. *Arthritis* 

Roudier, MP. Morrissey, C. True, LD. Higano, CS. Vessella, RL. & Ott, SM. (2008).

Demers, LM. (2003). Bone markers in the management of patients with skeletal metastases.

Luo, JL. Tan, W. Ricono, JM, Korchynskyi, O. Zhang, M. Gonias, SL. Cheresh, DA. Karin, M.

McClung, MR. Lewiecki, EM. & Cohen, SB. (2006). Denosumab in postmenopausal women with low bone mineral density. *New England Journal of Medicine* 354: 821-31. Cummings, SR. San Martin, J. & McClung, MR. (2009). Denosumab for prevention of

spinal cord compression. *Journal of Neurooncology* 12 (2): 141-4.

women with breast cancer. *Journal of Clinical Oncology* 21: 4042-57.

and risk factors. *Journal of Clinical Oncology* 23: 8580-87.

*Maxillofacial Surgery* 62: 527-34.

*Clinical Oncology* 22: 4597-99.

*Research Therapy* 2007; 9: 57-63.

*Journal of Urology* 180: 1154-60.

*Medicine* 2009; 361: 756-65

repressing Maspin. *Nature* 446: 690-94.

*Cancer* 97: 874-9.

(5): 459-66.

1613-24.

*Journal of Urology Internationalis* 104: 800-5.

Clinical Oncology update on the role of bisphosphonates and bone health issues in

V. (2007). Bisphosphonate-associated osteonecrosis of the jaw: report of a task force

V. Gika, D. Anagnostopoulos, A. Papadimitriou, C. & Terpos, E. (2005). Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence

associated with the use of bisphosphonates: a review of 63 cases. *Journal of Oral* 

and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values. *British* 

serious side effects of high-dose desamethasone treatment in patients with epidural

cord compression: An evidence-based guideline. *Journal of Clinical Oncology* 16 (4):

treatment of bone loss and other complications of androgen deprivation therapy in patients with prostate cancer. ASCO Annual Meeting Proceedings. *Journal of* 

Histopathological assessment of prostate cancer bone osteoblastic metastases.

(2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by

fractures in postmenopausal women with osteoporosis. *New England Journal of* 


Norgaard, M. Jensen, A. Jacobsen, JB. Cetin, K. Fryzek, JP. & Sorensen, HT. (2010). Skeletal

Antonarakis, ES. Blackford, AL. & Garrett-Mayer, E. Survival in men with non-metastatic

Greenspan, SL. Nelson, JB. & Trump, DL. (2007). Effect of once-weekly oral alendronate on

Verreuther, R. (1993). Bisphosphonates as an adjunct to palliative therapy of bone

Rodrigues, P. Hering, F. & Campagnari, JC. (2004). Use of bisphosphonates can dramatically

Ryan, CW. Huo, D. Demers, LM. Beer, TM. & Lacerna, LV. (2006). Zoledronic acid initiated

Saad, F. Gleason, DM. Murray, R. Tchekmedyian, S. Venner, P. & Lacombe, L. (2002). A

Saad, F. Gleason, DM. Murray, R. Tchekmedyian, S. Venner, P. & Lacombe, L. (2004). Long-

Berenson, JR. (2005). Recommendations for zoledronic acid treatment of patients with bone

Ramaswamy, B. & Shapiro, CL. (2003). Bisphosphonates in the prevention and treatment of

Rosen, LS. Gordon, D. & Kaminski, M. (2003). Long-term efficacy and safety of zoledronic

Hillner, BE. Ingle, JN. Chlebowski, RT. Gralow, J. Yee, GC. Janjan, NA. Cauley, JA.

density in patients with prostate cancer. *Journal of Urology* 176: 972-78. Lipton, A. (2004). Pathophysiology of bone metastases: how this knowledge may lead to

therapeutic intervention. *Journal of Support Oncology* 2: 205-13.

cohort study in Denmark (1999 to 2007). *Journal of Urology* 184 (1): 162-7. Aapro, M. Abrahamsson, PA. Body, JJ. Coleman, RE. Colomer, R. Costa, L. Crino, L. Dirix,

panel. *Annals of Oncology* 19: 420-32.

*Cancer Prostatic Diseases* 7: 350-54.

*Urology* 72: 792-5.

1458-68.

*Institute* 96: 879-82.

*Cancer* 98 (8): 1735-44.

metastases. *Oncologist* 10: 52-62.

bone metastases. *Oncology* 17: 1261-70.

*Journal of Clinical Oncology* 25: 4998-5008.

randomised trial. *Annals of Internal Medicine* 146: 416-24. Coleman, RE. (2004). Bisphosphonates: clinical experience. *Oncologist* 9 (4): 14-27.

related events, bone metastasis and survival of prostate cancer: a population based

L. Gnant, M. Gralow, J. Hadji, P. Hortobagyi, GN. Jonat, W. Lipton, A. Monnier, A. Paterson, AH. Rizzoli, R. Saad, F. & Thürlimn, B. (2008). Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert

prostate cancer treated with hormone therapy: A quantitative systematic review.

bone loss in men receiving androgen deprivation therapy for prostate cancer: a

metastases from prostatic carcinoma. A pilot study on Clodronate. *British Journal of* 

improve pain in advanced hormone refractary prostate cancer patients. *Prostate* 

during the first year of androgen deprivation therapy increases bone mineral

randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma. *Journal of the National Cancer Institute* 94:

term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. *Journal National Cancer* 

acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma.

Blumenstein, BA. Albain, KS. Lipton, A. & Brown, S. (2003). American Society of

Clinical Oncology update on the role of bisphosphonates and bone health issues in women with breast cancer. *Journal of Clinical Oncology* 21: 4042-57.


**16** 

**Androgen Deprivation Therapy** 

*University Hospital in Bratislava, Urology Clinic, Comennius University* 

Since 1941, when Huggins and Hodges proved the favourable effect of surgical castration and oestrogen administration on the progression of metastatic prostate cancer (PCa) (1,2), androgen deprivation therapy (ADT) became the mainstay of management of advanced PCa till now. They demonstrated for the first time the responsiveness of PCa to androgen

ADT effectively palliates the symptoms of advanced disease, significantly reduces tumor growth, but there is no conclusive evidence at present that it prolongs survival. Moreover, significant amount of data report that ADT is associated with several adverse effects. The most prominent include: loss of bone mineral density (BMD), which leads into increased fracture risk (3), induction of insulin resistance (4), unfavorable changes in serum lipid profile (5), changes in body composition (6) which can lead into increased cardiovascular

The aim of ADT is to cause severe hypogonadism, and adverse effects of ADT clearly demonstrate the essential and pluripotent role of male´s most important androgen –

**2. Testosterone: A basal overview of biosynthesis, metabolism and its action**  In the human male, the main circulating androgen is testosterone (TST). More than 95% of circulating TST is secreted by the testis (Leydig cells) which produce aproximately 6-7 mg of TST daily (9). The rest is secreted by the adrenal cortex, and very small quantities (especially

Physiologic TST level in a male is 3-8 ng / ml. The source for the synthesis of steroids is cholesterol. This substrate may be synthetized *de novo* from acetate but it may be also taken up from plasma lipoproteins. Cleavage of the side chain of cholesterol in the mitochondria and the formation of pregnenolone (biologically inactive) is the start of steroidogenic cascade. Pregnenolone is further converted into various steroids by enzymes (cytochromes

TST secretion is regulated by the hypothalamic-pituitary-gonadal axis. The hypothalamic luteinising hormone-releasing hormone (LHRH) stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). The main regulator of Leydig cell function is LH, acting through the LH receptor (LHr) in Leydig cells.

morbidity (7) and changes in cognitive functions (8).

pregnan derivatives) are formed by the cells of the brain (10).

P450) in the endoplasmatic reticulum.

**1. Introduction** 

deprivation.

testosterone (TST).

**for Prostate Cancer** 

Stanislav Ziaran

*Slovakia* 

