Androgen Deprivation Therapy and Estrogen Deficiency Induced Adverse Effects in the Treatment of Prostate Cancer

Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer

SJ Freedland1, J Eastham2 and N Shore3 1Departments of Surgery (Urology) and Pathology, Durham VA Medical Center and Duke Prostate Center, Duke University School of Medicine, Durham, NC, USA; 2Memorial Sloan-Kettering Cancer Center—Urology, New York, NY, USA and 3Atlantic Urology Clinics/Carolina Urologic Research Center, Myrtle Beach, SC, USA

Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and is increasingly used to treat asymptomatic patients with prostate-specific antigen recurrence after failed primary therapy. Although effective, ADT is associated with multiple adverse effects, many of which are related to the estrogen deficiency that occurs as a result of treatment. These include increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss. By providing clinicians with a greater awareness of the estrogen deficiency induced adverse effects from ADT, they can proactively intervene on the physical and psychological impact these effects have on patients. Prostate Cancer and Prostatic Diseases (2009) 12, 333–338; doi:10.1038/pcan.2009.35; published online 1 September 2009

Keywords: adverse effects; androgen deprivation; estrogen; side effects; testosterone

Introduction number of patients receiving ADT is likely to see an increase. In 2008, prostate cancer was estimated to account for 25% Androgen deprivation therapy is typically performed of all new cancer cases and 10% of all cancer deaths through medical castration and, less frequently, surgical in men.1 Common treatment options for localized castration. Although there are several methods of prostate cancer include active surveillance, radical medical castration (Table 1), it is most commonly prostatectomy, radiation therapy and cryosurgery.2 achieved through the use of gonadotropin-releasing Some patients may experience an eventual increase in hormone (GnRH) agonists (for example, leuprolide, PSA or biochemical failure necessitating additional goserelin and triptorelin).7 GnRH is secreted by the treatment. hypothalamus and leads to the pulsatile release of Androgens and the functional status of androgen follicle-stimulating hormone and luteinizing hormone receptors are considered integral to both normal prostate by the pituitary gland. The release of follicle-stimulating development and prostate cancer progression;3 con- hormone and luteinizing hormone promotes testosterone sequently, androgen deprivation therapy (ADT) is a secretion by Leydig cells of the testes. High continuous common treatment for prostate cancer. Although ADT is exposure to GnRH, such as that which occurs through the standard of care for symptomatic and metastatic treatment with GnRH agonists, causes downregulation disease,4 its use has expanded to include patients who of receptors in the pituitary gland, leading to decreased show evidence of increased PSA recurrence or biochem- pituitary hormone production and ultimately a decrease ical failure.5 Although the mortality rates for prostate in the production of testosterone.8 cancer have been steadily decreasing since 1994 (whether Although ADT is effective in treating prostate cancer, it a result of improved screening, diagnosis or therapy), the is associated with adverse effects, some of which are due fact that the aging male population is increasing along- to a deficiency in testosterone levels (Figure 1). However, side a longer duration of survival is estimated to result in because estrogens are derived in men through the an increase in the number of men with prostate cancer by aromatization of testosterone, the reduction in testoster- more than 50% over the next 20 years.6 Consequently, the one due to ADT also decreases the levels of estrogen.9 This can lead to a number of estrogen deficiency induced side effects, including increased fracture risk, hot flashes, Correspondence: Dr SJ Freedland, Departments of Surgery (Urology) gynecomastia, serum lipid changes and memory loss and Pathology, Duke University School of Medicine, Box 2626 DUMC, (Figure 1). Although some of these estrogen related ADT 551 Research Drive, Room 475, Durham, NC 27710, USA. 10 E-mail: [email protected] side effects have been reviewed previously, it is Received 28 April 2009; revised 22 June 2009; accepted 25 June 2009; important to revisit and update the issue given the published online 1 September 2009 projected increase in the number of patients with Estrogen deficiency induced effects of ADT SJ Freedland et al 334 Table 1 Common methods of chemical androgen deprivation therapy Treatment type Example(s) Mechanism of action

Estrogen Diethylstilbestrol Inhibits hypothalamic–pituitary axis7 GnRH agonist Leuprolide Goserelin Triptorelin Suppresses GnRH secretion47 GnRH antagonist Degarelix Antagonizes GnRH receptor47 Antiandrogen Flutamide Nilutamide Bicalutamide Blocks the effects of testosterone at the androgen receptor7

Abbreviation: GnRH, gonadotropin-releasing hormone.

Sex hormone receptor types and localization Side effects of ADT of activity Estrogen Deficiency Estradiol Estrogen • Increased fracture risk receptors • Gynecomastia • Hot flashes • Adipose tissue • Lipid changes CYP19 • Bone • Memory loss Aromatase • Central nervous system Testosterone Deficiency Androgen • Erectile dysfunction Testosterone receptors • Diabetes • Muscle weakness • 2° Sex • Body composition characteristics • Skeletal muscle • Erythropoiesis Figure 1 Androgen deprivation therapy: estrogen versus testosterone deficiency adverse effects.48,49

prostate cancer who are receiving ADT. By potentially compared with those who did not receive ADT (12.6%; improving treatment through increased awareness of Po0.001). This risk began early in the course of these adverse effects and their mechanism of action, ADT administration and increased with the number of urologists can enhance overall patient care. doses of GnRH agonist administered within the first year. Patients who received 1–4 doses were at a 7% higher risk (95% CI, À2 to 16%) and those who received X9 doses were at a 45% higher risk (95% CI, Estrogen deficiency induced adverse 36–56%). A comparable pattern was seen with fractures effects of ADT that required hospitalization: 5.2% of patients receiving ADT required hospitalization compared with 2.4% of Increased fracture risk patients who did not receive ADT (Po0.001). Estrogens have a fundamental role in regulating Similar results were found in a population-based, bone integrity in men. In general, estrogen deficiency epidemiologic, case–control study in Denmark of 15 716 appears to accelerate bone remodeling by prolonging the men with fractures compared with 47 149 age-matched lifespan of osteoclasts,11 with converse effects on controls.17 Prostate cancer had been previously diag- osteoblasts and osteocytes.12,13 This disproportionate nosed in 2.5% of men in the fracture group (20% of lifespan between osteoclasts and osteoblasts/osteocytes whom received ADT) and 1.3% of men in the control leads to greater bone resorption than formation and group (15% of whom received ADT). Men with prostate contributes to the development of osteoporosis and an cancer were at an increased risk for any fracture (odds increased fracture risk.12 Although many men experience ratio ¼ 1.8), particularly hip fracture (odds ratio ¼ 3.7). both age-related hypogonadism14 and decreases in More importantly, ADT (once adjusted for prostate bone mineral density (BMD),15 the changes associated cancer, age and previous fracture) was also associated with ADT are far more severe. The result is reflected in a with an increased risk of any fracture with an odds ratio higher prevalence of fractures in men receiving ADT, of 1.7 and hip fracture with an odds ratio of 1.9. who show an average rate of fractures of 5–8% per year Finally, a Medicare claims-based cohort study of 11 661 of ADT therapy.10 eligible patients with nonmetastatic prostate cancer (3887 Several recent large studies have established a strong who received GnRH agonists and 7774 who did not) association between ADT and increased fracture examined the effect of ADT therapy on specific fractures, risk.16–18 One was a US study of the National Cancer including vertebral, hip and femur.18 On the basis of Institute’s Surveillance, Epidemiology, and End Results these results, there was a significant increase in the risk program and Medicare databases in a period from 1992 of fracture in men receiving ADT compared with control through 1997 that examined data from 50 613 men with patients: specifically, there was increased risk of any prostate cancer, 31% of whom received ADT.16 In the 12– fracture (21% higher risk; Po0.001), vertebral fracture 60 months after diagnosis, a significantly higher percen- (45% higher risk; Po0.001) and hip/femur fracture (30% tage of patients in the ADT group had a fracture (19.4%) higher risk; P ¼ 0.002).

Prostate Cancer and Prostatic Diseases Estrogen deficiency induced effects of ADT SJ Freedland et al

Several recent studies have also established that ADT receiving ADT, 43 (68%) reported experiencing hot 335 is associated with a significant decrease in BMD.19,20 In flashes at some point during treatment.24 Further- an analysis of prospective 12-month data from 65 men, more, nearly 50% of these patients reported that they ADT using GnRH agonists resulted in a significant were still experiencing hot flashes 5 years after treatment decrease in the mean BMD of the total hip by 1.9% at 12 and 40% continued to document them even 8 years after months (Po0.001).19 Similar results were seen in another ADT cessation.24 12-month prospective study that examined four groups The impact that hot flashes can have on patients is of men: those with prostate cancer receiving short-term variable, ranging from mild in some to debilitating in ADT (o6 months), those maintained on long-term ADT others. For example, in the previously mentioned (X6 months) or those not receiving ADT; and healthy study,24 at a median of 7.6 years after treatment initiation, men.20 Compared with the other groups, men receiving 28 patients were still experiencing hot flashes and were short-term ADT had significant reductions (Po0.05) in therefore queried regarding hot flash severity. Among BMD at the total hip (À2.5%), trochanter (À2.4%), total these patients, 5 reported not being distressed at all by radius (À2.6%), total body (À3.3%) and posteroanterior their hot flashes, 10 reported being seldom distressed, 8 spine (À4.0%). After long-term use, men on ADT had an reported being often distressed and 5 reported distress additional significant reduction in BMD only at the total all the time.24 radius (À2.0%, Po0.05).20 For those who are affected by hot flashes, they can be The increased risk of fracture associated with ADT is a both a physical and psychological distress. The impact of significant health concern, as evidenced by the correla- hot flashes on patient quality of life was evidenced in a tion of fractures with overall survival in men with study of 55 men (58% of whom suffered from hot flashes) prostate cancer.21 In 195 men with prostate cancer who currently receiving ADT for prostate cancer by using the were receiving long-term continuous ADT (24 of whom general and prostate cancer functional assessment reported at least 1 fracture), there was a 39-month of cancer therapy questionnaires (FACT-G and FACT-P, reduction in median overall survival after prostate respectively).26 The FACT questionnaires (available at cancer diagnosis for those with evidence of a fracture http://www.facit.org) consist of a series of questions compared with those without a fracture (121 vs 160 with answers ranging from ‘not at all’ to ‘very much’ that months, P ¼ 0.04). Despite the presence of skeletal address physical well-being (for example, I have a lack of fractures as an independent risk factor for mortality, a energy); social/family well-being (for example, I feel recent study determined that only one-third of patients close to my friends); emotional well-being (for example, with ADT-treated prostate cancer were receiving proper I am satisfied with how I am coping with my illness); screening, prevention or treatment for increased fracture functional well-being (for example, I am able to enjoy risk.22 This analysis included 174 men with prostate life); and, in the case of FACT-P, additional prostate cancer who had received ADT and determined whether cancer concerns (for example, I am able to feel like a they were receiving ‘recommended’ osteoporosis man- man).27,28 Patients who experienced hot flashes scored agement including diagnostic dual-energy X-ray absorp- significantly higher (denoting a greater impact of hot tiometry scans within the 2 years before the final ADT flashes) on total FACT-G score (P ¼ 0.029); total FACT-P treatment or concurrent use of bisphosphonates, calcito- score (P ¼ 0.030); and physical well-being (Po0.001), nin, calcium or vitamin D while on ADT. Only 60 of the social/family well-being (P ¼ 0.033), and prostate cancer- 174 patients (34%) had received the recommended dual- specific (P ¼ 0.041) subscales compared with patients energy X-ray absorptiometry scans or pharmacologic who did not have hot flashes.26 treatment. The researchers suggested that the reasons A more recent analysis examined the effect of hot were multifactorial but may include the lack of aware- flashes on cancer-related distress in 68 men with prostate ness in primary care providers of the increased fracture cancer during the first 3 months of ADT through the use risk associated with ADT and the lack of a Food and of the Impact of Event Scale (IES).29 The IES measures Drug Administration approved treatment for ADT- distress related to an event with particular regard to induced bone loss.22 intrusive (for example, unwanted thoughts and feelings) or avoidant (for example, behavior that allows people to avoid particular thoughts or feelings) responses.29,30 Hot flashes Results showed that men who did not have hot flashes Although not fully understood, estrogen withdrawal had a significant decrease in total cancer-related stress appears to have a prominent role in vasomotor symp- over the 3 months (P ¼ 0.01), whereas those with hot toms, or hot flashes. Hot flash pathogenesis is thought to flashes showed no change. Furthermore, on the basis of a begin with estrogen withdrawal leading to a decrease in hierarchical regression analysis, hot flash score (sever- endorphin and catecholamine levels and an increase in ity Â frequency) was determined to be a significant hypothalamic norepinephrine and serotonin release.23 predictor for greater increases in intrusion and total The increased norepinephrine and serotonin lower the cancer-related distress (Pp0.02). body’s thermoregulatory set point, and allow the heat loss mechanisms to result in hot flash symptoms with only subtle changes in body temperature.23 Gynecomastia Hot flashes are common in men receiving ADT, with Gynecomastia is characterized by excessive growth of nearly 70% reporting this adverse effect during treat- the male mammary glands and appears to be caused by a ment.24,25 Hot flashes are not limited to initial ADT, as change in the estrogen to testosterone ratio and the they have been shown to persist throughout ADT resulting effects on the hypothalamic–pituitary–gonadal and can continue for an extended period of time after axis.7 The specific reason for the change in ratio varies the cessation of treatment.24 In one study of 63 patients depending on the choice of treatment. Although GnRH

Prostate Cancer and Prostatic Diseases Estrogen deficiency induced effects of ADT SJ Freedland et al

336 agonists eliminate gonadal androgens, adrenal andro- significant increases from baseline were noted in total gens are still produced and their aromatization cholesterol by 9.0% (Po0.001), HDL cholesterol by 11.3% to estrogen can cause an increased estrogen-to-testoster- (Po0.001), low-density lipoprotein cholesterol by 7.3% one ratio.31 Antiandrogens, however, block the effect of (P ¼ 0.05) and triglycerides by 26.5% (P ¼ 0.01).38 androgens in the body, which leads to a reduction in Although observational data suggest that ADT is feedback to the hypothalamus and pituitary gland, thus associated with increased risk of heart disease,34 a recent resulting in increased testosterone release and aromati- randomized clinical study contradicts the assertion, zation to estrogen.7 Regardless of the specific etiology, finding a lack of increased risk of cardiovascular the outcome of the change in the estrogen-to-testosterone mortality.39 Data from this study of 945 men found that ratio is the same—breast enlargement frequently accom- after 9 years the cardiovascular mortality rate for men panied by pain or tenderness. receiving adjuvant treatment with the GnRH agonist The incidence of gynecomastia varies widely based on goserelin after primary radiotherapy was 8.4% compared the selected method of ADT. As shown in a recent with 11.4% for those who did not receive adjuvant review, antiandrogen monotherapy was associated with goserelin (P ¼ 0.17). The difference between the epide- an incidence range of 30–79%, estrogens 40–77%, miologic and clinical data suggests that further studies orchiectomy 1–14% and GnRH agonists 1–16%.32 are needed to clearly ascertain the effect of ADT on Unfortunately, little is known regarding the physio- cardiovascular mortality. logical impact that gynecomastia has on men treated What is clear, however, is that estrogen deficiency with ADT. However, as reported in a recent review of the associated with ADT has a significant impact on serum social context for gynecomastia, for many men it can be lipid levels, as evidenced above. While increased psychologically distressing, even to the point of requir- triglycerides and cholesterol are independent risk factors ing psychological support or intervention.33 for cardiovascular disease, they also contribute to metabolic syndrome, as defined by the National Choles- terol Education Program’s Adult Treatment Panel III Lipid changes criteria of X3 of the following criteria for men: waist Recent observational data from a Medicare enrollees circumference 4102 cm, triglycerides X150 mg per database suggest that treatment with GnRH agonists is 100 ml, HDL cholesterol o40 mg per 100 ml, blood associated with an increased risk of coronary heart pressure X130/X85 mm Hg and fasting glucose disease, acute myocardial infarction and sudden cardiac X110 mg per 100 ml.40 In fact, a recent study of 58 men death.34 Specifically, this study examined 73 196 men (20 with prostate cancer who received ADT for X12 with prostate cancer aged 66 years or older, 43% of months, 18 with prostate cancer who did not receive whom received ADT (36.3% with GnRH agonists and ADT and had increasing PSA levels and 20 age-matched 6.9% through orchiectomy). Treatment with GnRH healthy men with normal PSA) found that significantly agonists was associated with an adjusted hazard ratio more men who received ADT (55%; overall P ¼ 0.03) met of 1.16 (95% CI, 1.10–1.21; Po0.001) for coronary heart the Adult Treatment Panel III’s criteria for metabolic disease, 1.11 (95% CI, 1.01–1.21; P ¼ 0.03) for myocardial syndrome compared with those who did not receive infarction and 1.16 (95% CI, 1.05–1.27; P ¼ 0.004) for ADT (22%) and healthy men (20%).41 However, several sudden cardiac death. These associations may be due to of the effects associated with ADT differ from this metabolic changes related to ADT (primarily GnRH definition of metabolic syndrome (for example, ADT is agonists), including increases in body weight and fat associated with an increase in ‘good’ HDL cholesterol), mass, decreases in lean body mass, decreased insulin suggesting that although there are similarities and sensitivity and changes in serum lipid levels.35 However, lipid changes should be monitored as a cardiovascular only changes in serum lipid levels appear to be disease risk factor, the ADT-associated changes are associated with estrogen deficiency (through estrogen– different from the classic metabolic syndrome.35 receptor-mediated changes in hepatic apoprotein gene expression36) and will, therefore, be the focus of this section. Memory loss In general, ADT is associated with notable effects on Although evidence suggests that ADT is associated with total cholesterol, low-density lipoprotein cholesterol, memory loss,42,43 it remains unclear whether this is due high-density lipoprotein (HDL) cholesterol and trigly- to an estrogen or testosterone deficiency as both estrogen cerides.37,38 Specifically, a cross-sectional study evaluated and testosterone receptors are found in the portions serum lipid levels in 44 men: 16 men with prostate cancer of the brain that control two of the major forms of who received ADT for at least 12 months, 14 age- memory (working memory and verbal long-term mem- matched men with nonmetastatic prostate cancer who ory).42 However, a study examining the contribution of did not receive ADT and had rising PSA levels, and 14 conversion of testosterone to estradiol on cognitive age-matched healthy men with normal PSA.37 After processing in healthy older men showed that improve- adjustment for body mass index, men receiving ADT had ment in verbal memory depended on aromatization of higher levels of total cholesterol compared with both the testosterone to estradiol.44 healthy controls (P ¼ 0.02) and men who did not receive Similar analyses have been carried out on men with ADT (P ¼ 0.06), and significantly higher low-density lipo- prostate cancer receiving ADT. In one study, the impact protein (P ¼ 0.04) and non-HDL cholesterol (P ¼ 0.03) of the ADT-induced decline in estrogen on cognition was compared with the control group.37 Similar changes in examined over a period of 1 year in 23 men with prostate lipid levels within individual patients were seen in 32 cancer, all of whom were receiving ADT.43 Cognition was asymptomatic men with nonmetastatic prostate cancer assessed using a standardized, cognitive test battery that who were receiving GnRH agonists.38 After 48 weeks, measured verbal, visuomotor and memory performance,

Prostate Cancer and Prostatic Diseases Estrogen deficiency induced effects of ADT SJ Freedland et al along with cognitive processing from various domains of sanofi-aventis, Dendreon, Novartis, Ferring, Endo Phar- 337 attention.43 Significant cognitive declines (compared maceuticals, GP Pharm. with baseline) in association with reduced estradiol levels were identified at 6 months (albeit insignificant at 12 months) in visual memory of figures (P ¼ 0.022), recognition speed of numbers (P ¼ 0.030) and verbal Acknowledgements fluency (P ¼ 0.019). Furthermore, the magnitude of the impact was associated with the degree in estrogen Editorial assistance was provided by Michael Malia, decline, for example, the highest impairment occurred PhD. This assistance was funded by GTx Inc. in patients with the greatest decline in estrogen.43 Another study examined the impact of not only ADT on cognition, but also of subsequent estrogen replace- ment in men with prostate cancer.42 Eighteen men with References prostate cancer who completed ADT were given replace- 1 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer ment estrogen and compared with 18 age-matched statistics, 2008. CA Cancer J Clin 2008; 58: 71–96. men currently receiving ADT and 17 healthy controls. 2 Pirtskhalaishvili G, Hrebinko RL, Nelson JB. The treatment of Intelligence levels were measured using the Wechsler prostate cancer: an overview of current options. Cancer Pract Adult Intelligence Scale-Revised Vocabulary subtest. At 2001; 9: 295–306. baseline, all patients receiving ADT scored significantly 3 Heinlein CA, Chang C. Androgen receptor in prostate cancer. worse than healthy patients in immediate and delayed Endocr Rev 2004; 25: 276–308. verbal memory (Pp0.01). However, in subsequent 4 Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy testing, patients who received estrogen showed a for prostate cancer. JAMA 2005; 294: 238–244. 5 Higano CS. Side effects of androgen deprivation significant improvement in both immediate and delayed therapy: monitoring and minimizing toxicity. Urology 2003; 61 verbal memory compared with their baseline scores (2 Suppl 1): 32–38. (Pp0.01); there was no change in the other two groups. 6 Chan JM, Jou RM, Carroll PR. The relative impact and future Although these studies suggest that estrogen defi- burden of prostate cancer in the United States. JUrol2004; 172 ciency related to ADT may affect areas of cognition such (5 Part 2): S13–S16; discussion S17. as visual memory of figures and recognition speed of 7 Flaig TW, Glode LM. Management of the side effects of numbers, similar studies have suggested a role for androgen deprivation therapy in men with prostate cancer. testosterone deficiency as well, including influence on Expert Opin Pharmacother 2008; 9: 2829–2841. visuomotor slowing, working memory and recognition 8 Hellerstedt BA, Pienta KJ. The current state of hormonal therapy 52 of letters.45 As such, it appears that both estrogen and for prostate cancer. CA Cancer J Clin 2002; : 154–179. 9 Smith MR, Malkowicz SB, Chu F, Forrest J, Price D, Sieber P et al. testosterone deficiency may have a role in ADT-related Toremifene increases bone mineral density in men receiving memory loss; however, further study is needed. androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. JUrol2008; 179: 152–155. 10 Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Summary and conclusions Smith MR. Estrogenic side effects of androgen deprivation therapy. Rev Urol 2007; 9: 163–180. Because of the increase in PSA testing, prostate cancer is 11 Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF. A being diagnosed earlier in the course of the disease and new model for the regulation of bone resorption, with particular patients are receiving ADT both earlier in treatment reference to the effects of bisphosphonates. J Bone Miner Res 1996; and for longer duration.46 Many clinicians, however, may 11: 150–159. not be aware of the adverse effects associated with 12 Manolagas SC. Birth and death of bone cells: basic regulatory estrogen deficiency that results from ADT, including mechanisms and implications for the pathogenesis and treat- increased fracture risk, hot flashes, gynecomastia, ad- ment of osteoporosis. Endocr Rev 2000; 21: 115–137. 13 Manolagas SC, Weinstein RS, Bellido T, Bodenner DL. Opposite verse lipid changes and memory loss. Not only do these effects of estrogen on the life span of osteoblasts/osteocytes vs. adverse effects create physical and psychological dis- osteoclasts in vivo and in vitro: an explanation of the imbalance tress, but as is the case with increased fracture and lipid between formation and resportion in estrogen deficiency. J Bone changes, they can also greatly impact patients’ overall Miner Res 1999; 14: S169. (Abstract). health and have a significant impact on survival. 14 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Although treatment options exist for many of the Longitudinal effects of aging on serum total and free testoster- individual adverse effects, none are Food and Drug one levels in healthy men. Baltimore Longitudinal Study of Administration approved for ADT-induced adverse Aging. J Clin Endocrinol Metab 2001; 86: 724–731. effects, and there is currently no single treatment option 15 Hannan MT, Felson DT, Anderson JJ. Bone mineral density in that can manage multiple adverse effects. elderly men and women: results from the Framingham osteoporosis study. J Bone Miner Res 1992; 7: 547–553. 16 Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154–164. Conflict of interest 17 Abrahamsen B, Nielsen MF, Eskildsen P, Andersen JT, Walter S, Brixen K. Fracture risk in Danish men with prostate cancer: a Stephen J Freedland worked as a consultant and/or was nationwide register study. BJU Int 2007; 100: 749–754. present on the advisory board and speakers’ bureau for 18 Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos AstraZeneca, Amgen and GTx Inc. James Eastham has CL. Gonadotropin-releasing hormone agonists and fracture risk: no conflict of interest to declare. Neal Shore worked as a claims-based cohort study of men with nonmetastatic prostate the consultant/investigator for Amgen, GTx Inc., Pfizer, cancer. 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