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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2546-2553 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.174 Bicalutamide Monotherapy Versus Leuprolide Monotherapy for Prostate Cancer: Effects on Bone Mineral Density and Body CompositionFrom the Massachusetts General Hospital, Boston, MA Address reprint requests to Matthew R. Smith, MD, PhD, Massachusetts General Hospital, Cox 640, 100 Blossom St, Boston, MA 02114; e-mail: smith.matthew{at}mgh.harvard.edu
PURPOSE: Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition. PATIENTS AND METHODS: In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography.
RESULTS: Mean (± standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% ± 0.5% in the leuprolide group and increased by 2.5 ± 0.5 in the bicalutamide group from baseline to 12 months (P < .001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P CONCLUSION: In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.
Androgen deprivation therapy by either bilateral orchiectomies or chronic administration of a gonadotropin-releasing hormone agonist is the cornerstone of treatment for advanced-stage prostate cancer. Gonadotropin-releasing hormone agonists decrease bone mineral density1–4 and increase fracture risk in men with prostate cancer.5–8 Gonadotropin-releasing hormone agonists also decrease lean body mass and increase fat mass.9–12 These adverse body composition changes may contribute to frailty, fatigue, emotional distress, and decreased quality of life during androgen deprivation therapy.13–15 Bicalutamide (Casodex, AstraZeneca PLC, London, UK) is a nonsteroidal antiandrogen that competitively inhibits the action of androgens by binding to androgen receptors in the target tissue.16 In randomized controlled trials of men with prostate cancer and no distant metastases, overall survival was similar for bicalutamide monotherapy (150 mg daily) and androgen deprivation therapy (by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone agonist).17–19 In men with bone metastases, however, bicalutamide monotherapy is less effective than androgen deprivation therapy.18 In randomized placebo-controlled trials in men with localized or locally advanced prostate cancer and negative bone scans, immediate or adjuvant bicalutamide (150 mg daily) in addition to standard therapy (radical prostatectomy, radiation therapy, or watchful waiting) significantly decreased the risk of clinical progression.20 Bicalutamide (150 mg daily) monotherapy is approved to treat prostate cancer in 55 countries. In the United States, bicalutamide is approved for use in combination with gonadotropin-releasing hormone agonist, but not as monotherapy. Bicalutamide monotherapy increases serum concentrations of testosterone and estradiol.21 Because estradiol plays an important role in skeletal homeostasis in normal men,22,23 bicalutamide monotherapy may lack the adverse skeletal effects of gonadotropin-releasing hormone agonists. In this study, we prospectively compared the effects of bicalutamide monotherapy and gonadotropin-releasing hormone agonist monotherapy on bone mineral density and body composition in men with recurrent or locally-advanced prostate cancer and no evidence of bone metastases.
Subjects Study participants were recruited at Massachusetts General Hospital and Dana-Farber Cancer Institute (Boston, MA) between May 2000 and May 2002. Subjects had locally advanced, lymph node-positive, or recurrent prostate cancer. Men with bone metastases by radionuclide bone scan were excluded. Men with Karnofsky performance status less than 90, history of hypogonadism, history of growth hormone or anabolic steroid use, Paget's disease, hyperthyroidism, Cushing's disease, hyperprolactinemia, chronic liver disease, corrected serum calcium < 8.4 mg/dL or > 10.6 mg/dL, or serum creatinine concentration > 2.0 mg/dL (177 µmol/L) were also excluded. Men with prior neoadjuvant or adjuvant hormone therapy were included if the interval between completion of treatment and study entry was greater than 1 year; 10 men had received neoadjuvant or adjuvant treatment with a gonadotropin-releasing hormone agonist. Men were excluded if they had received bisphosphonate, calcitonin, or glucocorticoid therapy, or suppressive doses of thyroxine within 1 year.
Study Design Subjects were evaluated at the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital at baseline, 3, 6, 9, and 12 months. A serum sample was obtained at each visit and stored at –80°C. Bone mineral density and body composition were measured by dual energy x-ray absorptiometry at baseline, 6, and 12 months. Trabecular bone mineral density of the lumbar spine and cross-sectional thigh muscle area were measured by quantitative computed tomography at baseline and at 12 months. The institutional review board of Dana-Farber Partners Cancer Care approved the study. All subjects gave written informed consent. The study sponsors played no role in the study design, in collection, analysis and interpretation of data, or in writing of this report.
Outcomes Cross-sectional thigh muscle area was determined by quantitative computed tomography as described previously.24 The leg was scanned at the midpoint of the femur with the knee fully extended and the foot perpendicular to the table. Contours of the anterior and posterior thigh muscles were determined using image analysis software (General Electric Advantage Windows Workstation, Version 2.0). Cross-sectional thigh muscle area was defined as the sum of the cross-sectional areas for the anterior and posterior muscle groups. Lean mass and fat mass were determined by dual energy x-ray absorptiometry with a Hologic QDR 4500A densitometer. Effort-dependent lower extremity strength was assessed on the basis of maximum weight lifted for one repetition (1-RM) using a leg press (Air 300 Leg Press; Keiser Corp, Fresno, CA).25 To minimize the confounding influence of the learning effect, testing was repeated after a 2-day rest and the greater of the two values was recorded as the 1-RM strength. If the two values differed by more than 5%, testing was repeated a third time and the greatest of the three values was recorded as the 1-RM strength. Serum concentrations of testosterone, estradiol, 25-hydroxyvitamin D, parathyroid hormone, and osteocalcin were measured by radioimmunoassay or immunoradiometric assay. Serum concentrations of prostate specific antigen and N-telopeptide were measured by enzyme immunoassay. The lower limits of detection for serum testosterone and estradiol were 6 ng/dL (0.2 nmol/L) and 3 pg/mL (11 pmol/L), respectively. At each visit, a research nurse assessed adverse events by scripted interview. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria.
Disease progression was defined as either new metastatic disease, or a more than 25% increase in serum prostate specific antigen concentration from nadir value on two determinations and
Statistical Analyses Changes in serum concentrations of gonadal steroids and biochemical markers of bone turnover were compared between groups using repeated measures analysis of covariance controlling for baseline.27 Baseline characteristics were compared between groups using Fisher's exact test for categoric variables and t-tests for continuous variables.26 Statistical analyses were performed using SAS (version 8.1, SAS Institute, Cary, NC). Values are reported as mean ± SE unless specified otherwise. All P values are two sided and values less than .05 are considered significant.
Characteristics of the Subjects Fifty-two men were randomly assigned to either leuprolide monotherapy or bicalutamide monotherapy. Fifty-one men completed the baseline evaluation and initiated study treatment. Baseline characteristics of men assigned to leuprolide monotherapy and men assigned to bicalutamide monotherapy were similar (Table 1). Five men in each group had received prior treatment with a gonadotropin-releasing hormone agonist; the mean (± SD) duration of prior treatment was similar in both groups (5 ± 3 v 8 ± 2 months; P = .30).
Fifty-one subjects completed the study. All 51 subjects are included in the analyses, including three men who discontinued treatment early. Two subjects assigned to leuprolide discontinued treatment after 6 months because of adverse effects. One man treated with bicalutamide developed progressive disease at 9 months and did not respond to subsequent treatment with leuprolide. No other subject experienced disease progression during the study.
Gonadal Steroids
Bone Mineral Density Mean changes from baseline to 12 months in posterior-anterior lumbar spine, total hip, femoral neck, and total body bone mineral density differed significantly between groups (Fig 2). Mean (± SE) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% ± 0.5% in the leuprolide group and increased by 2.5 ± 0.5 in the bicalutamide group (P < .001). Bone mineral density of the total hip decreased by 1.4% ± 0.5% in the leuprolide group and increased by 1.1% ± 0.4% in the bicalutamide group (P = .003). Similar changes were observed for bone mineral density in the femoral neck (P = .002). Bone mineral density of the total body decreased by 0.3% ± 0.6% in the leuprolide group and increased by 2.1 ± 0.4 in the bicalutamide group (P = .002). The between-group differences in percent change at 12 months were 5.0% (95% CI, 3.6% to 6.3%) for the posterior-anterior lumbar spine, 2.5% (95% CI, 1.2% to 3.8%) for the total hip, 2.5% (95% CI, 0.9% to 4.1%) for the femoral neck, and 2.4% (95% CI, 0.8% to 3.9%) for the total body.
Mean changes in trabecular bone mineral density of lumbar spine as measured by quantitative computed tomography also differed significantly between groups (Fig 3). Trabecular bone mineral density decreased by 7.6% ± 1.2% in men treated with leuprolide and increased by 4.7% ± 1.5% in men treated with bicalutamide (P < .001). The between-group difference in percent change at 12 months was 12.7% (95% CI, 8.8% to 16.5%).
Biochemical Markers of Bone Turnover Changes from baseline to 12 months in serum osteocalcin and N-telopeptide concentrations differed significantly between groups (Fig 4). Mean (± SE) serum N-telopeptide concentrations increased by 55% ± 5% in the leuprolide group and decreased by 3% ± 4% in the bicalutamide group (P < .001). Serum osteocalcin concentrations increased by 82% ± 30% in the leuprolide group and decreased by 20% ± 5% in the bicalutamide group (P = .002).
Body Composition Mean changes in fat mass differed significantly between groups (Table 2). Fat mass increased by 11.1% ± 1.3% in men treated with leuprolide and by 6.4% ± 1.1% in men treated with bicalutamide from baseline to 12 months (P = .01). Changes in lean body mass and lower extremity strength tended to be less adverse in the bicalutamide group than in the leuprolide group. Lean mass decreased by 3.6% ± 0.5% in the leuprolide group and by 2.4% ± 0.4% in the bicalutamide group (P = .08). Lower extremity strength decreased by 1.2% ± 1.9% in the leuprolide group and increased by 3.7% ± 2.0% in the bicalutamide group (P = .08). Mean changes in body weight and thigh muscle area did not differ significantly between groups (P > .05 for each comparison; Table 2).
Adverse Events There were no grade 3 or 4 adverse events related to treatment in either group. Anemia was less common in men treated with bicalutamide than in men treated with leuprolide (Table 3). Mean hemoglobin concentration decreased by 0.9 ± 0.2 g/dL in men treated with leuprolide and by 0.4 ± 0.2 g/dL in men treated with bicalutamide (P = .04). Fatigue, loss of sexual interest, and vasomotor flushing were less common in men treated with bicalutamide than in men treated with leuprolide (Table 3). Breast enlargement and tenderness were more common in men treated with bicalutamide than in men treated with leuprolide. Two men in the leuprolide group discontinued treatment early because of vasomotor flushing and fatigue. Treatment was interrupted for 3 months in one man in the bicalutamide group because of elevated serum AST and ALT concentrations (1.5- and 2.5-fold above upper limits of normal, respectively).
This randomized controlled trial demonstrates that bicalutamide monotherapy maintains bone mineral density in men with prostate cancer. Bone mineral density of the spine, hip, and total body increased in men treated with bicalutamide but decreased in men treated with leuprolide. Because low bone mineral density independently predicts fracture risk in men,28,29 these findings suggest that bicalutamide monotherapy may reduce fracture risk compared to treatment with a gonadotropin-releasing hormone agonist. Bicalutamide also lessened fat accumulation and caused less vasomotor flushing, fatigue, and loss of sexual interest than treatment with a gonadotropin-releasing hormone agonist. Both androgens and estrogens play important roles in skeletal homeostasis in men. Androgen and estrogen receptors are expressed in osteoblasts and osteoclasts.30–33 Androgens and estrogens contribute to the regulation of both bone formation and bone resorption in men.22,23 Increases in serum estrogen levels may explain the favorable effects of bicalutamide monotherapy on bone mineral density. In addition, increases in serum testosterone levels may have contributed to improvements in bone mineral density if bicalutamide blocks androgen action in bone incompletely. Bisphosphonates prevent bone loss in men undergoing androgen deprivation therapy for prostate cancer. In two randomized controlled trials, pamidronate prevented bone loss in men treated with a gonadotropin-releasing hormone agonist.2,34 In another randomized controlled trial, zoledronic acid increased bone mineral density in men treated with a gonadotropin-releasing hormone agonist or bilateral orchiectomies.35 Bicalutamide monotherapy may provide a more convenient strategy to maintain bone mineral density in men with prostate cancer, however, than treatment with both a gonadotropin-releasing hormone agonist and a bisphosphonate. Androgens are important determinants of body composition in men. Serum testosterone concentrations correlate positively with lean mass and negatively with fat mass.36 Testosterone replacement therapy increases lean mass and decreases fat mass in hypogonadal men.37,38 Testosterone supplementation increases lean mass, muscle size, and strength in eugonadal men.39 In our study, bicalutamide tended to mitigate the loss of lean mass muscle strength compared with gonadotropin-releasing hormone agonist therapy, although the between-group differences were not statistically significant. Larger studies are needed to compare the effects of antiandrogen monotherapy and medical castration on lean body mass and muscle strength. Estrogens play an important role in fat metabolism. Fat mass is increased in male mice with homozygous inactivation of either the estrogen receptor-alpha gene40 or aromatase gene.41 Estrogen administration prevented increases in fat mass as a result of castration in male mice.42 Estrogen replacement therapy lessened fat accumulation in postmenopausal women.43 In our study, fat mass increased significantly less in men treated with bicalutamide than in men treated with leuprolide. The important role of estrogens in fat metabolism suggests that bicalutamide may prevent fat accumulation by increasing estrogen levels. Men treated with bicalutamide were less likely to develop anemia or to report vasomotor flushing, fatigue, or loss of sexual interest than men treated with leuprolide. In contrast, breast enlargement and tenderness were more common in men treated with bicalutamide than in men treated with leuprolide. Antiestrogens and aromatase inhibitors may decrease breast symptoms in men treated with bicalutamide.44 By antagonizing estrogen action or decreasing serum estrogen concentrations, however, antiestrogens and aromatase inhibitors may diminish the benefits of bicalutamide on bone mineral density and body composition. This was a 1-year study, but additional studies are needed to assess the long-term effects of bicalutamide monotherapy on bone mineral density and body composition. Larger studies are required to assess differences in fracture incidence. Energy intake and activity were not controlled and differences in diet or exercise between the groups may have influenced body composition outcomes. Finally, the open-label design may have affected adverse event reporting. In summary, bicalutamide monotherapy increased bone mineral density and lessened fat accumulation compared to treatment with a gonadotropin-releasing hormone agonist. Bicalutamide monotherapy was also associated with less anemia, vasomotor flushing, fatigue, or loss of sexual interest than treatment with a gonadotropin-releasing hormone agonist. In considering bicalutamide monotherapy as an alternative to a gonadotropin-releasing hormone agonist, these advantages must be weighed against the increased risk of breast tenderness and enlargement.
The authors indicated no potential conflicts of interest.
We thank the dedicated staff of Mallinckrodt General Clinical Research Center and Massachusetts General Hospital Bone Density Center.
Supported by grants from the National Institutes of Health (R21 CA101353-01 [M.R.S.], K24 DK02759 [J.S.F.], and RR-1066), a Doris Duke Charitable Foundation Clinical Scientist Development Award (M.R.S.), and a research award from AstraZeneca PLC. Presented, in part, at the 4th International Conference on Cancer-Induced Bone Diseases, San Antonio, TX, December 8, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.003 for each comparison). Fat mass increased by 11.1% ± 1.3% in the leuprolide group and by 6.4% ± 1.1% in the bicalutamide group (P = .01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group. 
5 ng/mL absolute increase in prostate specific antigen. 
= .05). We assumed a 3.0% standard deviation (SD) of the change from baseline in bone mineral density of the posterior-anterior lumbar spine,
