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Complications of Androgen Deprivation Therapy: Prevention and Treatment

Complications of Androgen Deprivation Therapy: Prevention and Treatment

Androgen deprivation therapy (ADT) with a gonadotropinreleasing hormone agonist is the cornerstone of treatment for metastatic prostate cancer. Patterns of care have changed dramatically over the past decade, and gonadotropin-releasing hormone agonists are now routinely administered to men without radiographic evidence of metastases. These agents account for about onethird of Medicare expenditures for the treatment of prostate cancer[1]; in 1999, that portion exceeded $800 million. The routine use of gonadotropin- releasing hormone agonists in men with nonmetastatic prostate cancer increases the importance of understanding and preventing treatment-related adverse effects. In this issue of ONCOLOGY, Dr. Holzbeierlein and colleagues provide a timely summary of the adverse effects of ADT. Osteoporosis
Androgen deprivation therapy decreases bone mineral density and increases risk of fracture in men with prostate cancer. Although commonly compared to menopausal bone loss, treatment-related bone loss in prostate cancer patients is distinct from postmenopausal bone loss in two important ways. First, the rate of bone loss during initial ADT for prostate cancer is substantially higher than the rate of bone loss during early menopause. Second, high rates of bone loss appear to persist indefinitely during ADT, whereas bone loss slows in late menopausal women. Despite these important clinical distinctions, the mechanisms of bone loss are similar in men receiving ADT and postmenopausal women. Available evidence indicates that estrogen is more important than testosterone for maintaining bone mass in both men and women. In addition, bone loss in hypogonadal men and postmenopausal women is characterized by osteoclast activation and increased bone turnover. Screening for osteoporosis by measurement of bone mineral density is necessary in this setting, because prostate cancer patients on ADT are at high risk for osteoporosis and will remain asymptomatic until they experience a fracture. Given interpatient differences in peak bone mass and rates of bone loss during ADT, some but not all men will develop osteoporosis during treatment. Vitamin D deficiency and inadequate dietary calcium intake are common, and I recommend calcium (500-1,000 mg/d) and vitamin D (400 IU/d) supplementation for all men receiving ADT. I also recommend bisphosphonates for men with either a clinical fracture, osteopenia prior to ADT (bone mineral density T score between -1.0 and -2.5), or osteoporosis (T score less than -2.5). Bisphosphonates may also be appropriate for men who have normal bone mineral density but are at high risk for falls. Body Composition
Prospective studies have shown that gonadotropin-releasing hormone agonists increase fat mass and decrease lean body mass. The magnitude of the changes is remarkable, with most studies reporting approximately a 10% increase in fat mass. Treatment-related changes in body composition appear within the first few months, but in contrast to the ongoing high rates of bone loss, changes in body composition appear to slow during long-term treatment. These changes may lead to frailty and a risk of falls in older men, as well as fatigue, insulin resistance, and increased cardiovascular disease risk. Exercise is a reasonable but unproven strategy to mitigate the adverse body composition effects of ADT. Resistance exercise training increases muscle size and strength in men with other chronic diseases and normal or moderately low serum testosterone concentrations. It also reduces fatigue in men receiving ADT for prostate cancer,[2] but its effects on body composition have not been adequately evaluated in this setting. Insulin Resistance and Cardiovascular Disease Risk
Insulin resistance is a common metabolic abnormality that characterizes individuals with type 2 diabetes and is prevalent in about 20% to 25% of nondiabetic individuals. The condition is an independent risk factor for cardiovascular disease and is associated with a variety of abnormalities related to increased cardiovascular disease risk, including central obesity, hypertension, elevated triglyceride levels, decreased high-density-lipoprotein cholesterol levels, and elevated markers of fibrinolysis. This constellation of abnormalities is collectively known as the insulin resistance syndrome or the metabolic syndrome.[3,4] The phenotype of men receiving ADT shares many but not all of the features associated with the insulin resistance syndrome. Androgen deprivation therapy increases weight and fat mass as well as fasting plasma insulin levels,[5] a marker of insulin resistance. No other study has evaluated treatment-related changes in fasting plasma insulin levels or more reliable measures of insulin sensitivity. Additional research is needed to better characterize this metabolic syndrome and the potential impact of ADT on cardiovascular disease risk.

Disclosures

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article

References

1. Agency for Health Care Policy and Research: Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, evidence report/technology assessment: No. 4. Available at http://ahcpr.gov/ clinic/tp/prostp. Accessed Feb 4, 2004.
2. Segal RJ, Reid RD, Courneya KS, et al: Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 21:1653-1659, 2003.
3. Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988.
4. DeFronzo RA, Ferrannini E: Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194, 1991.
5. Smith JC, Bennett S, Evans LM, et al: The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 86:4261-4267, 2001.
 
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