Osteoporosis in men with prostate cancer: now for the fracture data

Osteoporosis is an important but underappreciated problem in men worldwide. 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 gonadotropinreleasing 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. Longer treatment duration conferred greater fracture risk. Age and comorbidity were also associated with higher fracture incidence. GnRH agonists increase bone turnover and decrease bone mineral density, 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. Treatment-related sarcopenia appears to contribute to frailty and increased risk of falls in older men. 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. 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. Similar results have been reported with annual zoledronic acid. Oral bisphosphonates also increase bone mineral density during GnRH agonist therapy. In a randomized controlled trial of 112 men with prostate cancer, Greenspan et al 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. 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 welldesigned 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. 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. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 27 SEPTEMBER 2