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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4371-4372 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.9507
Osteoporosis in Men With Prostate Cancer: Now for the Fracture DataHematology Oncology Division, Massachusetts General Hospital Cancer Center, Boston, MA Osteoporosis is an important but underappreciated problem in men worldwide.1 In the United States, 2 million men have osteoporosis and another 12 million are at risk for the disease. After age 50 years, one in four men experiences a clinical fracture. Men suffer one third of all hip fractures and are more likely than women to die after a hip fracture. Hypogonadism, chronic glucocorticoid therapy, and alcohol abuse are the major causes of acquired osteoporosis in men. These causes account for approximately one half of all cases of osteoporosis in men. Smoking, low dietary calcium intake, vitamin D deficiency, and sedentary lifestyle also contribute to risk for osteoporosis. Androgen-deprivation therapy (ADT) for prostate cancer is a leading cause of hypogonadism in men. ADT with a gonadotropin-releasing hormone (GnRH) agonist is the cornerstone of treatment for metastatic prostate cancer. GnRH agonists are also commonly used to treat men with earlier-stage disease. Approximately one third of the estimated 2 million prostate cancer survivors in the United States currently receive treatment with a GnRH agonist. GnRH agonists are associated with risk for clinical fractures. In large population-based studies, for example, men receiving GnRH agonist had a 21% to 45% relative increase in fracture risk compared with men who did not receive a GnRH agonist.2-4 Longer treatment duration conferred greater fracture risk. Age and comorbidity were also associated with higher fracture incidence. GnRH agonists increase bone turnover5 and decrease bone mineral density,5-8 a surrogate for fracture risk. Bone mineral density of the hip and spine decrease by approximately 2% to 3% per year during initial therapy. Most studies have reported that bone mineral density continues to decline steadily during long-term therapy. Some, but not all, men develop osteoporosis during ADT for prostate cancer. Pretreatment bone mineral density varies between men because of individual differences in peak bone mass and rates of adult bone loss. Accordingly, men begin treatment with different relative risks for developing osteoporosis. Duration of treatment and rates of bone loss during treatment also vary between individuals. Other mechanisms may also contribute to fracture risk. GnRH agonists significantly decrease muscle mass.9 Treatment-related sarcopenia appears to contribute to frailty and increased risk of falls in older men.10 Accordingly, GnRH agonists may increase fracture risk by decreasing both bone mineral density and muscle mass. Several small randomized controlled trials have demonstrated that bisphosphonates increase bone mineral density during GnRH agonist treatment. Intravenous pamidronate significantly decreased biochemical markers of bone turnover and increased bone mineral density of the hip and spine in men receiving GnRH agonist therapy.5,11 In a 12-month multicenter, placebo-controlled study of 106 men with prostate cancer, intravenous zoledronic acid increased bone mineral density of the hip and spine by 3.9% and 7.3%, respectively.12 Similar results have been reported with annual zoledronic acid.13 Oral bisphosphonates also increase bone mineral density during GnRH agonist therapy. In a randomized controlled trial of 112 men with prostate cancer, Greenspan et al14 reported that alendronate increased bone mineral density of the hip and spine by 2.3% and 5.1%, respectively, after 12 months. In this issue of Journal of Clinical Oncology, Greenspan et al report the second-year results of this partial crossover study.17 All participants initially assigned to placebo were treated with alendronate during the second year. Participants initially assigned to alendronate were randomly reassigned to receive either alendronate or placebo during year 2. In year 2, bone mineral density increased in the men assigned to alendronate and remained stable at most skeletal sites in men assigned to placebo. Over the entire study, bone mineral density increased more in the men who received alendronate for 2 years than those who received alendronate for only 1 year. Among men who were assigned to alendronate for 1 year, the net change in bone mineral density over the 2 year study was similar for men assigned to alendronate for the first year compared with men assigned to alendronate for the second year. The results of this well-designed study confirm the expected increase in bone mineral density with continued bisphosphonate therapy and provide support for earlier intervention to prevent osteoporosis in this setting. Small randomized controlled trials have also demonstrated that selective estrogen-receptor modulators increase bone mineral density during GnRH agonist treatment for prostate cancer. In a 12-month open-label study, for example, raloxifene significantly increased bone mineral density of the hip and tended to increase bone mineral density of the spine.15 Raloxifene also significantly decreased biochemical markers of bone turnover. The results of this study are consistent with the key role of estrogens in bone metabolism in men. Taken together, these small randomized controlled trials have helped define the problem of osteoporosis in men with prostate cancer, understand the mechanisms of hypogonadal bone loss, and establish effective strategies to increase bone mineral density during GnRH agonist therapy. This groundbreaking work has also led to two large randomized placebo-controlled trials to prevent fractures during GnRH agonist therapy for prostate cancer. Final results of both studies will be reported this year.
The receptor activator of NF- Toremifene in a selective estrogen-receptor modulator approved for the treatment of advanced breast cancer. Toremifene is also being developed for treatment of osteoporosis and other complications associated with ADT for prostate cancer. In a 6-month placebo-controlled study of 46 men with prostate cancer, toremifene significantly increased bone mineral density of the hip and spine during GnRH agonist therapy.18 In a recently completed multicenter study, 1,389 men in the United States and Mexico who are receiving a GnRH agonist for prostate cancer were randomly assigned to either toremifene or placebo. The primary study end point is new vertebral fractures; secondary end points include bone mineral density, serum lipids, vasomotor flushing, and breast symptoms. For most men, prostate cancer is a chronic disease. The American Cancer Society now estimates a 98% 5-year relative survival rate for all stages of prostate cancer combined.19 Men with prostate cancer are living longer, but with a greater burden of treatment. Medical oncologists will play an increasingly important role in treatment and prevention of chronic medical conditions, including osteoporosis, in men with prostate cancer. The pending results of the two recently completed large randomized controlled trials, the first fracture prevention studies in men, will provide critical new evidence to guide clinical management. These studies may also establish new standards of care for prostate cancer survivors. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Matthew R. Smith, Amgen (C), GTx Inc (C), Merck (C), Novartis (C) Stock Ownership: None Honoraria: Matthew R. Smith, Amgen, GTx Inc, Merck, Novartis Research Funding: Matthew R. Smith, Amgen, Merck, Novartis Expert Testimony: None Other Remuneration: None REFERENCES
1. Ebeling PR: Clinical practice. Osteoporosis in men. N Engl J Med 358:1474-1482, 2008 2. Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005 3. Smith MR, Lee WC, Brandman J, et al: Gonadotropin-releasing hormone agonists and fracture risk: A claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 23:7897-7903, 2005 4. Smith MR, Boyce SP, Moyneur E, et al: Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 175:136-139, 2006[CrossRef][Medline] 5. Smith MR, McGovern FJ, Zietman AL, et al: Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer. N Engl J Med 345:948-955, 2001 6. Diamond T, Campbell J, Bryant C, et al: The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: Longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 83:1561-1566, 1998[CrossRef][Medline] 7. Maillefert JF, Sibilia J, Michel F, et al: Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 161:1219-1222, 1999[CrossRef][Medline] 8. Daniell HW, Dunn SR, Ferguson DW, et al: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163:181-186, 2000[CrossRef][Medline] 9. Smith MR, Finkelstein JS, McGovern FJ, et al: Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87:599-603, 2002 10. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M156, 2001 11. Diamond TH, Winters J, Smith A, et al: The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: A double blind, randomized, placebo-controlled crossover study. Cancer 92:1444-1450, 2001[CrossRef][Medline] 12. Smith MR, Eastham J, Gleason D, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003[CrossRef][Medline] 13. Michaelson MD, Kaufman DS, Lee H, et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 25:1038-1042, 2007 14. Greenspan SL, Nelson JB, Trump DL, et al: Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 146:416-424, 2007 15. Smith MR, Fallon MA, Lee H, et al: Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized controlled trial. J Clin Endocrinol Metab 89:3841-3846, 2004 16. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 423:337-342, 2003[CrossRef][Medline] 17. Greenspan SL, Nelson JB, Trump DL, et al: Alendronate for prostate cancer skeletal health. J Clin Oncol 26:4426-4434, 2008 18. Steiner MS, Patterson A, Israeli R, et al: Toremifene citrate versus placebo for treatment of bone loss and other complications of androgen deprivation therapy in patients with prostate cancer. J Clin Oncol 22:406s, 2004 (suppl; abstr 4597) 19. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71-96, 2008 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B (RANK) signaling pathway regulates the activation, differentiation, proliferation, and apoptosis of osteoclasts.
