Vivek K. Wadhwa, Robin Weston and Nigel J. Parr Department of Urology, Wirral University Teaching Hospitals, Wirral, UK

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1 21 THE AUTHORS; 21 Urological Oncology BICALUTAMIDE MONOTHERAPY IN PROSTATE CANCER WADHWA ET AL. BJUI Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer Vivek K. Wadhwa, Robin Weston and Nigel J. Parr Department of Urology, Wirral University Teaching Hospitals, Wirral, UK Accepted for publication 17 June 21 Study Type Therapy (case series) Level of Evidence 4 OBJECTIVES To evaluate changes in bone mineral density (BMD), body composition, muscle strength and health-related quality of life (HRQL) during bicalutamide (15 mg) monotherapy in osteoporotic patients with non-metastatic locally advanced prostate cancer. Osteoporosis is prevalent in men presenting with prostate cancer and also a common side effect of treatment with luteinizing hormone-releasing hormone agonists, which are associated with decreased BMD and loss of lean body mass and suppress testosterone, unlike bicalutamide, which results in an increase in serum testosterone and oestrogen levels. PATIENTS AND METHODS Forty-two men with non-metastatic locally advanced prostate cancer and osteoporosis (T-score 2.5) were treated with bicalutamide (15 mg) monotherapy. BMD was measured at baseline and 1 year. HRQL was assessed 3-monthly using the RAND 36-Item Health Survey and University of California Los Angeles Prostate Cancer Index questionnaires. Bone turnover markers, liver function tests, prostate-specific antigen, testosterone, oestradiol and haemoglobin were measured What s known on the subject? and What does the study add? LH-RH agonists, by suppressing testosterone and oestrogen, cause rapid bone demineralization and reduce both muscle strength and health related quality of life (HRQOL) in prostate cancer. A significant proportion of patients about to commence ADT are already osteoporotic, placing them at fracture risk. Bicalutamide monotherapy elevates testosterone and oestrogen levels, is licensed in locally advanced disease, but significantly underutilised in this setting. Whereas previous studies have assessed BMD and HRQOL in men across a range of BMDs, this study specifically evaluated osteoporotic men who are often older, with reduced muscle strength and with potentially the most to gain from bicalutamide monotherapy. BMD, muscle strength and HRQOL were each maintained across a 12-month period, suggesting that this treatment option should be considered more often by physicians and patients counseled appropriately. at baseline, at 3 weeks and 3-monthly thereafter. Arm anthropometry and dynamometry assessed fat mass, skeletal muscle mass and quadriceps strength. RESULTS BMD was maintained (+2.1% lumbar spine, +1.2% total hip and +1.1% forearm). Prostate-specific antigen decreased by 88% at 3 months. Testosterone and oestradiol had increased at 1 year by 58% and 42%, respectively. No increase in bone turnover markers was seen over 1 year. Quadriceps muscle strength was maintained. General and prostate cancer-specific HRQL were maintained throughout the study, with no significant reductions in physical or sexual function. Adverse events included breast pain and gynaecomastia. CONCLUSIONS Bicalutamide preserves BMD, muscle strength and HRQL in osteoporotic men with non-metastatic locally advanced prostate cancer. It provides an alternative to medical castration for well informed men at high fracture risk and those wishing to retain physical and sexual activity, with luteinizing hormone-releasing hormone agonists being reserved for those failing to respond or relapsing. KEYWORDS androgen deprivation therapy, bicalutamide, bone density, healthrelated quality of life, osteoporosis, prostate cancer INTRODUCTION Prostate cancer is the most common male cancer and second leading cause of cancer death. Androgen deprivation therapy (ADT), the mainstay of treatment for advanced prostate cancer, is being used at earlier stages [1], leading to prolonged durations of treatment. The WHO definition of health refers to not only an absence of disease, but also to the patient s perception of physical, mental and social well-being and, for many, health-related quality of life (HRQL) is as important as survival [2]. HRQL is 21 THE AUTHORS 21 17, doi:1.1111/j x x 1923

2 WADHWA ET AL. best evaluated using self-administered questionnaires. By suppressing testosterone, luteinizing hormone-releasing hormone agonists (LHRHA) are associated with increased bone turnover, decreased bone mineral density (BMD) and increased fracture risk [3]. Furthermore, they cause loss of sexual function, as well as adverse changes to body composition, increasing body fat and decreasing muscle strength [4]. The antiandrogen bicalutamide results in increased levels of testosterone and oestradiol, which may confer advantages compared to LHRHA, particularly in osteoporotics, at high risk of fracture. Previous studies assessing BMD, body composition and HRQL when on bicalutamide included men across a range of BMDs [4 6]. However, these parameters have not been specifically evaluated in osteoporotic men who are often older, with reduced muscle strength. The present study aimed to prospectively follow osteoporotic men with non-metastatic locally advanced, prostate cancer who were commencing bicalutamide to assess changes in BMD, muscle strength and HRQL. PATIENTS AND METHODS The study population consisted of hormone naive men with osteoporosis (T-score 2.5) and newly diagnosed locally advanced nonmetastatic prostate cancer initiating hormone manipulation. They were prospectively recruited from a single urology institution. Exclusion criteria included bone metastases, any history of illness or medication use that would affect bone metabolism, severe hepatic or renal insufficiency. Patients were commenced on bicalutamide (15 mg) once daily, as well as supplements of 5 mg of calcium and multivitamins containing 4 IU of vitamin D. A longitudinal observational study was performed over 12 months. Patients were reviewed in a dedicated clinic at baseline, at 3 weeks, and 3-monthly thereafter. Those failing to respond or escaping with bicalutamide were managed according to the clinical situation with second line therapy. Axial BMD of the lumbar spine (L2 4) and total hip were measured at baseline and one year by dual energy X-ray absorptiometry using Hologic QDR-45 DXA equipment (Hologic Inc., Waltham, MA, USA). Peripheral BMD of the non-dominant forearm was measured using an Osteometer DTX-2 scanner (Osteometer Meditech, Hawthorne, CA, USA). Calibration was carried out daily with a phantom. Patients were evaluated using the same densitometers to provide greater precision. Serum and urine samples (morning secondvoided) were taken at baseline, at 3 weeks and 3-monthly thereafter. Bone turnover marker (BTM) samples were analyzed at a central laboratory. Bone formation markers included serum bone-specific alkaline phosphatise (BSAP) (Access Ostase assay; Beckman Coulter, CA, USA), and serum N-terminal propeptide of type 1 collagen (P1NP) (Orion Diagnostica UniQ, Espoo, Finland). Bone resorption markers included serum C-telopeptide crosslinks of type I collagen (CTX) (Nordic Biosciences Diagnostics A/S, Herlev, Denmark), and urine N-telopeptide of type 1 collagen (NTX) (Johnson & Johnson Ortho-Clinical Diagnostics, Raritan, NJ, USA) corrected for creatinine. Renal and liver function tests were measured, as well as serum calcium, albumin, parathyroid hormone, -hydroxy-vitamin D, 17β-oestradiol, testosterone, serum hormone binding globulin (SHBG), PSA and haemoglobin. Patients had baseline radionucleotide bone scans. Thoracolumbar spine radiographs were obtained at baseline and at 1 year. Every 3 months, height, weight and body mass index (kg/m 2 ) was noted. Triceps skin-fold thickness was used to assess subcutaneous fat. Mid-upper-arm circumference was measured and mid-upperarm muscle area was calculated to estimate lean muscle mass. Dynamometry was used to assess quadriceps muscle strength (T.K.K Dynamometer; Takei Scientific Instruments Corp, Tokyo, Japan). General outcomes of HRQL were evaluated using the RAND 36-Item Health Survey (SF- 36), which includes eight multi-item scales assessing physical function, role limitations as a result of physical problems, role limitations as a result of emotional problems, vitality, mental health, social function, bodily pain and general health perceptions. Prostate cancerspecific outcomes of HRQL were evaluated using the University of California at Los Angeles (UCLA) Prostate Cancer Index, including six scales assessing urinary function and bother, bowel function and bother, sexual function and bother. Scales were scored separately from to 1, with higher scores representing better outcomes. Questions relating to sociodemographics, comorbitidy and adverse effects were asked. Questionnaires were completed at baseline and at 3-monthly intervals thereafter for 1 year to assess temporal progression. The Local Ethics Research Committee approved the study and patients provided their written informed consent. Significance of percentage change from baseline for BMD, BTMs, biochemical and anthropometric parameters was evaluated by t-tests for paired observations. Regarding the SF-36 and UCLA Prostate Cancer Index questionnaires, scores were calculated for each of the scales at each time point. The significance of change in scores from baseline to 12 months was examined for the entire group using paired t-tests. Analysis was performed using SPSS, version 15. (SPSS Inc., Chicago, IL, USA). P <.5 (two-sided) was considered statistically significant. RESULTS Baseline characteristics of the 42 patients (mean age 77.8 years, range years) are shown in Table 1. All were white, with most in a significant relationship and having retired from work. Mean comorbidity count was 1.3. One-fifth had a history of ischaemic heart disease and one-third had respiratory problems. One patient, who progressed on bicalutamide, required the addition of LHRHA, and responded well. Precision, assessed by coefficient of variation was 1.2% for lumbar spine, 1.4% for total hip and 1.6% for forearm. Relative to baseline, BMD at 12 months showed small nonsignificant increases (Fig. 1) at the lumbar spine (2.1 ±.4%), total hip (1.2 ±.3%) and forearm (1.1 ±.3%). Small nonsignificant increases in markers of bone resorption, serum CTX (6.2 ± 3.1%) and urinary NTX (1.7 ± 2.3%) were seen over 12 months (Fig. 2). Bone formation marker, serum BSAP, showed a small nonsignificant decrease of 2.5 ± 1.7%, whereas serum P1NP significantly decreased by 26.5 ± 11.2% (P =.3). Mean PSA at baseline was 71.1 ng/ml THE AUTHORS 21

3 BICALUTAMIDE MONOTHERAPY IN PROSTATE CANCER Variable n (%) Age (years) 77.8 ± 6.1 Vertebral fracture 11 (26) Race White/Caucasian 42 (1) Other () Relationship status Living with spouse/partner 3 (71) Not in a significant relationship 12 (29) Education Less than high school 24 (58) High school, trade school, some college 11 () College degree or higher 7 (17) Employment Full-time 2 (5) Part-time 2 (5) Retired 38 (9) Comorbidity Diabetes 5 (12) Heart attack/chest pain 9 (21) Stroke () Amputation 1 (2) Circulation problems in legs/feet 16 (38) Asthma, emphysema, breathing problems 12 (29) Stomach ulcer, irritable bowel 7 (17) Kidney disease 1 (2) Major depression 1 (2) Seizures () Alcoholism or alcohol problems 1 (2) Drug problems () Comorbidity count 1.3 Current or past cigarette smoker 3 (71) TABLE 1 Baseline demographics and comorbidity of subjects FIG. 1. Mean percentage changes in bone mineral density for (A) lumbar spine, (B) total hip and (C) forearm. A Mean C Baseline Time 12 months P = Baseline 12 months Time P values are for changes from baseline to 12 months. Mean P =.167 B Mean Baseline Time P = months (range ng/ml). Significant falls in mean PSA were seen at 3 weeks, and 3, 6, 9 and 12 months of 75%, 88%, 9%, 92% and 92%, respectively. Over the 12 months, serum testosterone, oestradiol and SHBG significantly increased by 58%, 42% and 42%, respectively (Table 2). There were no significant changes in serum calcium, albumin, parathyroid hormone, vitamin D, liver and renal function tests (Table 2). Haemoglobin significantly decreased by 4.4% over 12 months (P =.3). Thoracolumbar radiographs showed wedge fractures in 11 (26%), degenerative changes (osteophytosis/disc space narrowing), in 28 (67%) and normal vertebrae in three patients (7%). No new fractures were seen at 1 year. No significant change in height, weight or body mass index was seen (Table 2). Triceps skin-fold thickness significantly increased by 8.3% (P =.14). Mid-upper-arm circumference and mid-upper-arm muscle area did not significantly change. Quadriceps muscle strength was maintained (+4.5%). Temporal progression of general HRQL showed no significant deteriorations over 12 months (Fig. 3). Physical function was maintained with no increase in role limitations because of physical problems. There was a favourable small nonsignificant increase in the domain of mental health (Table 3). The UCLA Prostate Cancer Index showed no significant decreases in urinary, bowel or sexual function over 12 months. There was a favourable significant increase in urinary bother score, suggesting greater satisfaction in this domain following bicalutamide (Table 3). Bicalutamide was generally well tolerated with no patients discontinuing because of adverse events. By 1 year, the proportion with slight, moderate or large increase in breast size was 38%, 4% and 12%, respectively. The proportion complaining of slight, moderate or severe breast discomfort was 45%, 4% and 2%, respectively. Five patients (12%) required the use of oestrogen antagonists for mastalgia. Other events included constipation (14%), hot flushes (11%) and abdominal pain (7%). DISCUSSION LHRHA, by suppressing testosterone and oestrogen, cause bone demineralization, 21 THE AUTHORS 21 19

4 WADHWA ET AL. reduced muscle strength and HRQL [4 8]. Bicalutamide, a potent non-steroidal antiandrogen, competes with androgens for receptor binding sites on prostate cancer cells, maintaining testosterone levels. This may be particularly advantageous for patients found to be osteoporotic at presentation, and at high risk of fracture. We have previously shown, in 176 men, that even before receiving hormones, 4% presenting with prostate cancer are osteoporotic, which was significantly greater than in age-matched controls whose mean BMD was 6.6% higher [9]. These findings are similar to a study that found osteoporosis in 35% (37/16) of hormone-naive patients [1]. Despite this, most men do not undergo bone densitometry measurements before receiving hormone manipulation and relatively few are given the option of bicalutamide monotherapy. All the patients in the present study were instructed to take supplemental calcium and vitamin D. Nevertheless, we have previously shown that, in patients with prostate cancer commencing ADT, calcium and vitamin D alone are inadequate for protecting against bone loss [11]. Furthermore, this large cohort study, including patients with locally advanced and metastatic disease, showed that bicalutamide prevents further bone loss in osteoporotic men followed up for as long as 7 years [11]. Oral bisphosphonates generally prevent further bone loss but do not allow patients with established osteoporosis to regain BMD. This has only been seen more recently with more powerful, third-generation bisphosphonates, such as zoledronic acid. However, most of the studies evaluating zoledronic acid have excluded men with established osteoporosis. The advantage of bicalutamide monotherapy is that it treats prostate cancer and maintains BMD, as opposed to a combination of LHRHA and bisphosphonate, both of which can be associated with significant side effects. In the present study, patients had locally advanced non-metastatic prostate cancer, for which no significant difference has been shown for survival between bicalutamide and castration [7]. LHRHA was added for failure to respond or escape on bicalutamide. Two randomized studies compared bicalutamide (15 mg) with castration in 85 patients with metastatic prostate cancer [8]. There was a 6-week survival benefit in favour FIG. 2. Mean percentage change in bone turnover markers. BSAP, bone-specific alkaline phosphatise; P1NP, N-terminal propeptide of type 1 collagen; CTX, C-telopeptide crosslinks of type I collagen; untx/cr, urinary N- telopeptide of type 1 collagen corrected for creatinine. A C BSAP CTX TABLE 2 Changes in biochemical values and anthropometry over 12 months Variable Month Month 12 % Difference P Biochemistry PSA (ng/ml) 71.1 ± ± <.1 Testosterone (nmol/l) 15.1 ± ± <.1 Oestradiol (pg/ml) 13.3 ± ± SHBG (nmol/l) 53.4 ± ± <.1 Calcium (mmol/l) 2.35 ± ± Albumin (g/l) 41.9 ± ± Alkaline phosphatase (u/l) 76.6 ± ± γ-glutamyl transferase (iu/l) 34.4 ± ± Parathyroid hormone (pmol/l) 4.8 ± ± Vitamin D (nmol/l) 7.6 ± ± Urea (mmol/l) 7.7 ± ± Creatinine (μmol/l) ± ± Haemoglobin (g/dl) 13.9 ± ± Anthropometry Height (cm) ± ± Weight (kg) 76.2 ± 11, ± Body mass index (kg/m 2 ).7 ± ± Mid upper arm circumference (cm) 27.4 ± ± Triceps skin-fold (mm) 9.7 ± ± Mid upper arm muscle area (cm 2 ) 37.2 ± ± Quadriceps muscle strength 76. ± ± Mid upper arm muscle area = [(mid arm circumference 3.14 triceps skin fold) 2 /4π] 1. B D P = P = P =.165 P values are for changes from baseline to 12 months. 5 5 P1NP untx/cr P = THE AUTHORS 21

5 BICALUTAMIDE MONOTHERAPY IN PROSTATE CANCER TABLE 3 Changes in general and prostate-targeted health-related quality of life scale scores between baseline and 12 months Variable Month Month 12 Difference P RAND 36-Item Survey Physical function 67.7 ± ± Role limitation (Physical) 62.7 ± ± Role limitation (Emotional) 71.5 ± ± Vitality 55.1 ± ± Mental health 73.9 ± ± Social function 75. ± ± Bodily pain 78.8 ± ± General health 63.9 ± ± UCLA Prostate Cancer Index Urinary function 88.3 ± ± Urinary bother 73.9 ± ± Bowel function 82.4 ± ± Bowel bother 79.2 ± ± Sexual function 13.1 ± ± Sexual bother 34.4 ± ± UCLA, University of California at Los Angeles. of castration. However, the bicalutamide group did not routinely receive LHRHA on progression. Tyrell et al. reported that a significantly better HRQL with bicalutamide supports its use as an option for patients with metastatic prostate cancer for whom medical castration is not acceptable [8]. Indeed, those patients with metastases, on bicalutamide, experienced significantly less cancer-related pain and higher performance levels than those on LHRHA. The short overall survival benefit observed with castration has to be weighed against the significant morbidity and mortality associated with fractures for those patients already osteoporotic at presentation. The clinical efficiency of bicalutamide, a competitive antagonist, depends on the number of androgen receptors present and the extent that it is able to penetrate the tumour, both of which will vary according to tumour burden. Defining tumour burden in terms of baseline PSA, a further analysis of these data showed that survival did not significantly differ between bicalutamide and castration for those patients with a baseline PSA 4 ng/ml [12]. With large tumour bulk, such as those with presenting PSA >4 ng/ ml, the number of androgen receptors may exceed the binding capacity of bicalutamide. The ongoing Early Prostate Cancer Programme assessed the use of adjuvant bicalutamide (15 mg) vs placebo in addition to standard primary care (radical prostatectomy, radiotherapy, watchful waiting) in 8113 patients worldwide with localized and locally advanced prostate cancer. Although bicalutamide significantly improved progression free survival in locally advanced disease, after a median follow-up of 7.4 years, it decreased survival in patients otherwise undergoing watchful waiting in those with localized disease [13]. Current European guidelines support the use of bicalutamide monotherapy as an alternative to castration for patients with non-metastatic locally advanced prostate cancer and in highly selected, well informed cases of metastatic prostate cancer with a low PSA, but should be avoided in localized prostate cancer [14]. LHRHA are associated with a reduced HRQL, in particular, fatigue, loss of physical capacity, emotional distress and reduced sexual function [7,8]. Patients have been willing to trade quantity for quality [2]. In a study of 129 patients with prostate cancer, men were willing to give up a life expectancy (mean of 3 months) to avoid limitations in physical energy [15]. In the patients in the present study, temporal progression of general and prostate cancerspecific HRQL showed no significant decreases in physical and sexual function with bicalutamide. High psychosocial scores suggest that men maintained a positive emotional attitude. Maintenance of physical capacity is advantageous because regular exercise reduces fracture risk by decreasing bone loss, increasing muscle strength and improving mobility [16]. LHRHA are associated with accelerated bone loss of % of spinal BMD and.6 6.5% of hip BMD annually [17]. For each standard deviation decrease in femoral neck BMD, the relative risk of hip fracture in men over 55 years is 3. [18]. Osteoporotic fractures are associated with significant mortality and morbidity in elderly men, with a 3% mortality rate from hip fracture at 1 year [19]. A study by Shahinian et al. [3] of men on the Surveillance, Epidemiology and End Results Medicare database showed a fracture rate of 19.4% in men undergoing ADT compared to 12.6% in those who did not [3]. Fracture rate increased with doses of LHRHA received. Vertebral crush fractures, causing pain, spinal deformity and limiting activities of daily living, were seen in one-fifth of our patients at baseline. In the present study, BMD was maintained at all sites (lumbar spine +2.1%, total hip +1.2%, forearm +1.1%). The results obtained are in accordance with a study of 13 men with localized or non-metastatic locally advanced prostate cancer randomized to bicalutamide (15 mg) or LHRHA [5]. At 2 years, BMD of the lumbar spine and hip decreased by 5.4% and 4.4% in the LHRHA group, whereas those on bicalutamide showed an increase of 2.4% and 1.1% respectively. In a further study of 52 men with non-metastatic locally advanced prostate cancer randomized to LHRHA or bicalutamide (15 mg), lumbar spine and total hip BMD decreased by 2.5% and 1.4% in the LHRHA group, whereas those on bicalutamide showed an increase of 2.5% and 1.1%, respectively, at 1 year [4]. Both of these studies were not exclusive to osteoporotics. BTMs correlate with rates of bone loss and predict fractures independent of BMD [2]. The patients in the present study showed no significant change in serum BSAP, CTX and urinary NTX over 1 year. Serum P1NP decreased significantly by 26%, suggesting reduced active bone turnover with bicalutamide. In the study by Smith et al. [4], serum osteocalcin and NTX increased in the LHRHA group by 82% and 55%, whereas those on bicalutamide showed decreases of 21 THE AUTHORS

6 WADHWA ET AL. 2% and 3%, respectively, at 1 year, confirming increased bone turnover in patients on LHRHA. In the patients on bicalutamide in the present study, testosterone and oestrogen significantly increased at 1 year by 58% and 42%, respectively. Smith et al. [21] showed that LHRHA decreases testosterone by >95% and oestrogen by >8%. LHRHA, by virtue of their testosterone suppressive effects, are associated with adverse changes in body composition. In 47 patients with nonmetastatic locally advanced prostate cancer initiating treatment with LHRHA, at 1 year, weight, fat body mass and abdominal subcutaneous fat significantly increased by 2.4%, 9.4% and 3.9% respectively, with lean body mass significantly decreasing by 2.7% [6]. The patients in the present study showed no significant loss of lean muscle mass or quadriceps muscle strength over 1 year. Fat mass significantly increased by 8.3%. The results obtained are in keeping with another study by Smith et al. [4]. in which fat mass increased by 11.1% with LHRHA and by only 6.4% with bicalutamide at 1 year. Lower extremity strength decreased by 1.2% with LHRHA but increased by 3.7% with bicalutamide. Haemoglobin significantly decreased in the patients in the present study. Androgens support erythropoiesis and hormonal suppression, with either LHRHA or antiandrogens, is associated with a decline in haemoglobin and symptomatic anaemia [22]. Hot flushes are the predominant adverse effect of LHRHA [4,5,7,8]. Common complaints made by patients in the present study were breast pain and gynaecomastia as a result of peripheral aromatization of testosterone leading to increased oestradiol levels. Management options include prophylactic radiotherapy, surgery and medical treatment (oestrogens antagonists/ aromatase inhibitors). In young men who elect to take bicalutamide predominantly for preservation of sexual function, there is a strong case to discuss the options of prophylactic low dose breast irradiation or later subcutaneous mastectomy for those in whom gynaecomastia becomes cosmetically bothersome. However, in elderly men with osteoporosis (mean age in the present study of 77.8 years), most decline irradiation and rarely become symptomatic enough to consider subcutaneous mastectomy at a later date. FIG. 3. Mean change in (A) general health-related quality of life (HRQL), using eight scales of SF-36 and (B) prostate-targeted HRQL, using six scales of UCLA Prostate Cancer Index. A B : Physical Function P = : Role Limitation (Emotional) P = : Mental Health P = : Bodily Pain P = : Urinary Function P = : Bowel Function P = : Sexual Function P = P values are for changes from baseline to 12 months : Role Limitation (Physical) P = : Vitality (Energy/ Fatigue) P = : Social Function P = : General Health P = : Urinary Bother P = : Bowel Bother P = : Sexual Bother P = THE AUTHORS 21

7 BICALUTAMIDE MONOTHERAPY IN PROSTATE CANCER The present study has limitations. There was no control group, which ideally would have consisted of osteoporotics on LHRHA. However, in view of previous trials confirming significant bone loss [4,5] and increased fracture rate [3] with LHRHA, we felt, in accordance with our Local Ethics Research Committee, that it would be unethical to subject men already identified with osteoporosis, and at high risk of fractures, to LHRHA. In conclusion, bicalutamide preserves BMD, muscle strength and HRQL in osteoporotic men with non-metastatic locally advanced prostate cancer. It provides an alternative to medical castration for well informed men at high fracture risk and those wishing to retain physical and sexual activity, with LHRHA being reserved for those either failing to respond or relapsing. ACKNOWLEDGEMENTS Statistical advice was given by Dr Helen Wong (Statistician, Clatterbridge Centre for Oncology, UK). BTMs were analyzed at the Academic Unit of Bone Metabolism (University of Sheffield, UK). We would like to thank the patients who kindly gave their time and cooperation, which was much appreciated. This trial is registered with ClinicalTrials.gov (NCT55144). CONFLICT OF INTEREST None declared. Source of Funding: AstraZeneca. REFERENCES 1 Cooperberg MR, Grossfeld GD, Lubeck DP, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst 23; 95: Singer PA, Tasch ES, Stocking C, Rubin S, Siegler M, Weichselbaum R. Sex or survival: tradeoffs between quality and quantity of life. J Clin Oncol 1991; 9: Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med ; 352: Smith MR, Goode M, Zietman L, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 24; 22: Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S. Bicalutamide 15 mg maintains bone mineral density during monotherapy for localised or locally advanced prostate cancer. J Urol 24; 171: Smith MR, Finkelstein JS, McGovern FJ et al. Changes in body composition during androgen deprivation for prostate cancer. J Clin Endocrinol Metab 22; 87: Iversen P, Tyrrell CJ, Kaisary AV et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2; 164: Tyrrell CJ, Kaisary AV, Iversen P et al. A randomised comparison of Casodex 15 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33: Hussain SA, Weston R, Stephenson RN, George E, Parr NJ. Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation. 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BMJ 1996; 312: Smith MR, Fallon MA, Goode MJ. Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer. Urology 23; 6: Smith MR. Complimentary and alternative therapies for advanced prostate cancer. Hematol Oncol Clin North Am 21; 15: Correspondence: Nigel J. Parr, Department of Urology, Ward 14, Wirral University Teaching Hospitals, Arrowe Park, Upton, Wirral, Merseyside CH49 5PE, UK. nigelparr@dsl.pipex.com Abbreviations: ADT, androgen deprivation therapy; BMD, bone mineral density; BSAP, bone-specific alkaline phosphatise; BTMs, bone turnover markers; CTX, C-telopeptide crosslinks of type I collagen; LHRHA, luteinizing hormone-releasing hormone agonist; HRQL, health-related quality of life; NTX, N-telopeptide of type 1 collagen; P1NP, N-terminal propeptide of type 1 collagen; UCLA, University of California Los Angeles. 21 THE AUTHORS