Management of bone and metabolic effects of androgen deprivation therapy

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Urologic Oncology: Seminars and Original Investigations 000 (2018) 1−9

Seminars Article

Management of bone and metabolic effects of androgen deprivation therapy D1X XNicholas Russell, D2X XM.B.B.S.a,b,*, D3X XMathis Grossmann, D4X XM.D., Ph.D.a,b a

Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia b Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia Received 26 December 2017; received in revised form 20 July 2018; accepted 3 October 2018

Abstract Androgen deprivation therapy (ADT) is commonly given to men with prostate cancer. Both its benefits as well as its adverse effects are a direct consequence of sex steroid withdrawal. While ADT improves oncologic outcomes in appropriately selected men, it is associated with adverse effects, including accelerated bone loss leading to increased fracture risk, and with metabolically unfavorable body composition changes that predispose to diabetes and may increase cardiovascular risk. In this review, we will describe the pathophysiology behind these ADT-associated adverse effects, and discuss the clinical evidence guiding clinical assessment and management. A proactive approach is important to minimize ADT-associated adverse sequelae, so that the benefit-risk ratio of this treatment is optimized. Ó 2018 Elsevier Inc. All rights reserved.

Keywords: Androgen deprivation therapy; Prostate cancer; Osteoporosis; Diabetes

Abbreviations: 25(OH)D, 25-hydroxy vitamin D; ADT, androgen deprivation therapy; AR, androgen receptor; ARKO, androgen receptor knockout; BMD, bone mineral density; BP, blood pressure; CRPC, castrate-resistant prostate cancer; DBP, diastolic blood pressure; DXA, dual energy X-ray absorptiometry; GnRH, gonadotrophin-releasing hormone; HDL-C, high density lipoprotein cholesterol; HR-PQCT, high resolution-peripheral quantitative computed tomography; LBM, lean body mass; LDL-C, low density lipoprotein cholesterol; CaP, prostate cancer; RCT, randomized controlled trial; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides

1. Introduction Androgen Deprivation Therapy (ADT) has established roles in the neoadjuvant treatment of high risk localized prostate cancer (CaP) together with radiotherapy, and in biochemically recurrent nonmetastatic, and metastatic disease. Use of gonadotrophin-releasing hormone (GnRH) analogs as a means of blocking testosterone production is currently the most commonly used ADT modality. As long-term survival in men receiving ADT is the norm, it is appropriate to focus on identification and mitigation of adverse effects of this therapy. This short review will *Corresponding author. Tel.: + 613 9496 5000; fax: + 613 9496 3365. E-mail address: [email protected] (N. Russell). https://doi.org/10.1016/j.urolonc.2018.10.007 1078-1439/Ó 2018 Elsevier Inc. All rights reserved.

discuss the bone and metabolic effects of ADT and approaches to the management of these. We will not address constitutional, sexual, vasomotor, or cognitive effects of ADT, nor will we extensively review cardiovascular risk or exercise therapy, which are dealt with elsewhere in this issue. 2. Bone effects ADT is associated with an exposure-dependent decline in bone mineral density (BMD) and increase in fracture risk. The largest prospective controlled study of BMD over 12 months from ADT initiation observed declines in areal BMD of 2.5% at the hip and 4.0% at the lumbar spine, compared with no significant decline in age-matched healthy

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controls and men with CaP not undergoing ADT [1]. Longer-term studies have shown that BMD continues to decline after 12 months in men who continue ADT [2,3]. Dual energy X-ray absorptiometry (DXA) underestimates the extent of bone structural deterioration during ADT [4]. A study using high resolution-peripheral quantitative computed tomography (HR-pQCT) demonstrated that cortical porosity increases, and trabeculae are lost during 12 months of ADT, and that there are greater declines in volumetric BMD by HR-pQCT than areal BMD by DXA [4]. Bone loss is likely due to effects of sex hormone withdrawal on bone remodeling units, resulting in accelerated and unbalanced remodeling, as well as indirect effects due to mechanical and endocrine sequelae of muscle loss. Effects of aging, CaP itself, and nonhormonal therapies, cannot be excluded, given the nonrandomized nature of studies to date. Men who undergo ADT have substantially elevated risk of fracture. In more than 50,000 men diagnosed with CaP from 1992 to 1997, followed for 5 years, fractures occurring from 12 to 60 months following diagnosis were compared between men who received ADT and men who did not [5]. Fracture incidence was 19.4% in the ADT group and 12.6% in the non-ADT group (P < 0.001), independent of confounders. The number of men needed to treat to cause 1 fracture 12 to 60 months after CaP diagnosis was 28 (95% CI 26−31) for GnRH analogs and 16 (95% CI 13−19) for orchiectomy. There was a linear increase in risk with increasing number of GnRH analog doses administered in the first 12 months after diagnosis. 3. Management of bone effects 3.1. Assessment Published recommendations agree that men commencing ADT should undergo baseline assessment of BMD and fracture risk [6−12]. Assessments should include measurement of serum 25-hydroxyvitamin D (25(OH)D), calcium, and renal function, as well as evaluation of adequacy of dietary calcium intake, falls risk factors, participation in weight-bearing exercise, and exposures detrimental to BMD such as smoking, excessive alcohol, and glucocorticoids. Lateral thoracolumbar X-rays to identify occult vertebral fragility fractures are recommended in men with osteopenia [8]. A more extensive work up for other secondary causes of osteoporosis should be performed for men with low BMD Z-scores or prior fracture. Although still recommended, absolute fracture risk calculators such as fracture risk assessment tool (FRAX) (https://www. sheffield.ac.uk/FRAX/) are not specifically validated in this population and might underestimate fracture risk [13]. Reassessment of bone density and fracture risk should be undertaken periodically while castrate sex hormone levels persist. Recommendations differ, but annual to biannual clinical assessment and DXA scanning with additional clinical assessment following incident fracture is reasonable (Table 1).

Although more sensitive than DXA to ADT-induced change, HR-pQCT is not widely available in nonresearch settings. 3.2. Nutrition As there is no direct evidence to support particular recommendations regarding calcium and 25(OH)D in men receiving ADT, it is reasonable to extrapolate from those for the general population. These recommendations differ [14−16]. The US Institute of Medicine’s recommended dietary allowance for calcium is 1,000 mg per day for men aged 51 to 70 and 1,200 mg per day for men older than 70 [15]. The European Food Safety Authority derived a lower population reference intake of 950 mg per day for all men older than 24 years [16]. Calcium supplementation should be considered for ADT recipients with a daily calcium intake < 950 mg or indications for antiresorptive therapy and withheld from those with daily intake > 1,200 mg. Routine calcium supplementation, particularly without vitamin D, is not recommended as this has not been shown to reduce fracture risk. There is no evidence that an untargeted population-based approach to calcium and vitamin D supplementation is effective in reducing fractures [17]. We recommend men undergoing ADT achieve a 25(OH)D > 50 nmol/l at the end of winter and > 70 nmol/l at the end of summer [18,19] with supplementation for men below these targets. This recommendation is based on the seasonal variation in serum 25(OH)D and evidence that a level of 50 nmol/ l is sufficient for 97.5% of the population [15]. Low dose [20] but not high dose [21] supplementation might reduce risk of falls in the elderly, although the US Institute of Medicine assessed the overall evidence for falls prevention to be too inconsistent to include in the development of dietary reference intakes [15]. Men with 25(OH)D insufficiency should receive loading dose supplementation and monitoring of 25 (OH)D levels no more frequently than 3-monthly until target levels are achieved, followed by maintenance supplementation [18,22]. Ongoing monitoring is not required for men on stable or no supplementation, unless there is a change in risk factors for 25(OH)D deficiency [22] (Table 1). 3.3. Pharmacotherapy Bisphosphonates are effective in preventing BMD decline in men receiving ADT. In an open-label randomized trial in which men commencing ADT received either leuprolide or leuprolide with 12-weekly pamidronate, pamidronate was effective in preventing the leuprolideinduced decline in BMD over 48 weeks [23]. Subsequently, zoledronic acid [24], alendronate [25], and risedronate [26] also proved effective. There are no published studies designed or powered to determine whether bisphosphonates in doses approved for osteoporosis, reduce the risk of conventional osteoporosis-related fragility fractures in men receiving ADT.

Table 1 Recommendations for bone and metabolic evaluation for men undergoing ADT Monitoring

Target

 Prior fragility fracture  T-score < ¡2.5  10-y major osteoporotic fracture risk of ≥ 20% or hip fracture risk of ≥ 3%  Dietary intake below target

Annual DXA

-

Calcium

Fracture history Falls history DXA scan FRAX calculation Dietary evaluation

Annually

25(OH)D

Baseline serum 25(OH)D

 25(OH)D concentration less than target

3-monthly until replete

BP

Repeated BP measurement

Annually

Lipids

Serum lipids

Diabetes

Fasting glucose HbA1c

Smoking Absolute ASCVD Risk

History Baseline absolute risk calculation plus evaluation of additional risk factors:  Renal function/urine ACR  Family history  Ethnicity BMI Waist circumference

 Secondary prevention of ASCVD or primary prevention when 10-y risk is ≥ 10%: SBP ≥ 130 and/or DBP ≥ 80  Primary prevention in lower risk individuals: SBP ≥ 140 and/or DBP ≥ 90 Statins are indicated for:  Secondary prevention of ASCVD  Primary prevention of ASCVD in high risk individuals who do not already have LDL-C < 1.8 mmol/l: ASCVD risk estimator 10-y risk > 5% Diabetes CKD 3−5 (nondialysis dependent) LDL-C ≥ 4.9 mmol/l  Confirmed diabetes (metformin, additional pharmacotherapy as required)  Prediabetes (intensive lifestyle intervention)  Current smoking  ASCVD risk estimator 10-y risk is > 5%

1,000−1,200 mg elemental calcium daily > 70 nmol/l end of summer > 50 nmol/l end of winter < 130/80

Annually Annually

 Individualised based on metabolic risk

Annually

Fracture risk

Weight

Fixed dose strategy vs. LDL-C targeted strategy is controversial

Annually in men without diabetes

Prevention of type 2 diabetes or individualised glycaemic control for men with diabetes Abstinence Lowest risk possible addressing modifiable risk factors

Prevention of ADT induced fat gain (individualised targets)

25(OH)D = 25-hydroxyvitamin D; ACR = albumin creatinine ratio; ADT = androgen deprivation therapy; ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; BP = blood pressure; CKD = chronic kidney disease; DBP = diastolic blood pressure; DXA = dual energy X-ray absorptiometry; FRAX = fracture risk assessment tool; HbA1c = haemoglobin A1c; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; SBP = systolic blood pressure.

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Pre-ADT

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Bisphosphonates, in higher or more frequent doses, are of benefit in men with bone metastatic castrate-resistant CaP but not in men with metastatic castrate sensitive or locally advanced disease. In a 24-month randomized controlled trial of 643 men with bone metastatic castrate resistant CaP, 3-weekly intravenous zoledronic acid reduced the proportion of patients sustaining a skeletal-related event (SRE; pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or change in antineoplastic therapy to treat bone pain) [27]. A similar benefit was not seen with zoledronic acid in men with bone metastatic castrate-sensitive CaP within 6 months of ADT commencement [28]. Previously, the PR05 trial had suggested an overall survival benefit for 3 years of oral clodronate in similar men (secondary endpoint) [29]. In the STAMPEDE trial, upfront use of zoledronic acid for 2 years for men with newly diagnosed metastatic, node positive, or high risk locally advanced or recurrent CaP within 3 months of ADT initiation, did not improve overall survival or the rate of SRE [30]. A meta-analysis of randomized controlled trials of bisphosphonates did not find a survival benefit in either the locally advanced or metastatic castrate sensitive categories [31]. A multicenter randomized trial in men receiving GnRH analogs and with at least 1 additional risk factor for fracture (age > 70, T-score < ¡1.0, or history of osteoporotic fracture) compared 6-monthly denosumab 60 mg with placebo [32]. Three-quarters of men had been receiving GnRH analogs for more than 6 months at study entry and 10% had received bisphosphonate in the past. Lumbar spine BMD increased by 5.6% in the denosumab group and declined by 1.0% in the placebo group at 24 months, P < 0.001 (primary endpoint). Significant differences in BMD were seen at other sites, and men receiving denosumab had a lower risk of incident vertebral fracture over 36 months (RR 0.38, 95% CI 0.17−0.78). High dose denosumab (120 mg monthly) also proved superior to zoledronic acid (4 mg monthly) in prevention of SRE in men with castrate resistant CaP [33]. Other than in the context of metastatic castrate resistant CaP, where the intent is to reduce SRE, the optimal timing and indications for commencement of antiresorptive therapy, especially with the view to prevent osteoporotic fractures in noncancerous bone, are not established and guidelines differ. Decisions need to be made based on absolute fracture risk, baseline BMD, planned duration of ADT, life expectancy, potential harms, and local cost effectiveness. Extrapolating from general recommendations for men, at minimum, treatment should be offered to men with osteoporosis as defined by prior fragility fracture or a T-score ≤ ¡2.5 [34] and, based on (US) cost-effectiveness data, men with FRAX 10-year absolute major osteoporotic fracture risk of ≥ 20% or hip fracture risk of ≥ 3% [35] (Table 1). While benefit is possible with initiation of antiresorptives in men below the current thresholds [8], particularly considering the expected deterioration in BMD with ADT,

fracture risk reduction, and cost effectiveness of this strategy has not been established.

4. Effects on body composition, glucose, and lipid metabolism 4.1. Body composition ADT promotes sarcopenic obesity in men. Activation of the androgen receptor (AR) provides anabolic and anticatabolic signals to muscle [36] and diverts mesenchymal stem cells along a myogenic rather than adipogenic differentiation pathway [37]. However, in mouse models, the sarcopenic phenotype demonstrated by global AR knockout (ARKO) is only partially recapitulated by muscle-specific ARKO, and adipose tissue-specific ARKO mice lack the obese phenotype of global ARKO mice. These observations raise the possibility that androgen actions on the AR in other tissues (such as brain or bone), may indirectly mediate effects on muscle and fat [36]. In men, androgen deficiency results in loss of muscle mass and function [38,39], although some muscles appear to be more sensitive than others. Detailed biomechanical analyses of muscle function have reported that ADT causes selective deficits in lower limb function, with prominent decreases in peak hip flexor and peak knee extensor torques, mediated by decreased force of the iliopsoas and quadriceps muscles respectively [38]. Muscle loss, through loss of myokines such as myostatin, may itself promote fat gain [40]. Changes in sex steroids may also influence body composition indirectly, through changes in mood, motivation, appetite, and activity. Body composition changes are detectable as early as 4 weeks after commencement of GnRH analogs in healthy volunteers [41] and occur rapidly after treatment initiation in men with CaP [42]. Haseen et al. conducted a meta-analysis of 16 longitudinal, nonrandomized, uncontrolled observational studies of ADT on body composition [43]. Study size ranged from 10 to 79 participants and duration from 12 to 96 weeks. The pooled mean increase in weight from 9 studies, was 2.1% (95% CI 1.4−2.9). From 7 studies, fat mass increased by 7.7% (95% CI 4.3−6.9) and from 6 studies, lean mass decreased by 2.8% (95% CI ¡3.6 to 2.0). Greenspan et al. reported a longitudinal, prospective study comparing BMD in 80 men on ADT with 72 non-ADT CaP controls and 43 age-matched healthy controls [1]. Body composition was reported as a secondary endpoint in this study and this data was not included in the meta-analysis of Haseen et al. Over 12 months, men who had been receiving ADT for < 6 months at study entry increased fat mass by 10.4 +/¡ 1.7% and decreased lean mass by 3.5 +/¡ 0.5%. Men with CaP on no ADT increased fat mass by 2.1 +/¡ 1.0% without change in lean mass. Body composition did not change in men on ADT for > 6 months at study entry, nor in age-matched healthy controls.

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In a 36-month, prospective, observational study the majority of 252 men receiving ADT lost lean body mass (LBM) [42]. Men entered the study with different durations of exposure to ADT, median 20.4 months. Mean decrements from study entry to 12, 24, and 36 months respectively, were 1.0% (95% CI 0.4−1.5, P < 0.01), 2.1% (95% CI 1.5−2.7, P < 0.01), and 2.4% (95% CI 1.6−3.2, P < 0.001). Men older than 70, and, consistent with the Greenspan trial, men with < 6 months ADT exposure at baseline lost more LBM than the average. Overall, from half to twothirds of men experienced a decline in LBM during the first 12 months of observation. In another observational study, men commencing combined androgen blockade for CaP lost 1.3 kg LBM and gained 2.3 kg fat mass over 9 months [44]. Both of these studies, like the studies in the meta-analysis of Haseen et al., lacked non-ADT groups and therefore were unable to control for age- or cancer-related declines in LBM [45]. Obesity at diagnosis is consistently associated with CaP progression and increased risk of CaP-specific mortality. It is unclear whether this reflects differences in the biology of CaPs arising in obese men, or an effect of obesity-induced adipokines, insulin resistance, IGF-1 pathway alterations, or other factors on transforming CaP once it develops [46−49]. The possibility of the latter provides impetus to try to prevent ADT-associated weight gain. 4.2. Glucose metabolism There is strong observational evidence to suggest that ADT increases insulin resistance and risk of diabetes. A meta-analysis of observational studies comparing men with CaP receiving ADT to men with CaP not receiving ADT, reported a pooled effects relative risk of 1.75 (95% CI 1.27 −1.41) for metabolic syndrome and 1.36 (95% CI 1.17 −1.58) for diabetes following ADT [50]. The adjusted hazard ratio for incident diabetes with ADT was 1.44 in a prospective analysis of over 70,000 men with nonmetastatic CaP, 40% of whom received ADT, observed for median 4.6 years [51]. The predominant pathophysiologic mechanism linking ADT with insulin resistance appears to be the adverse changes in body composition [52]. Muscle loss would be expected to promote insulin resistance because muscle is major site of postprandial insulin-dependent glucose uptake [53] and a source of insulin-sensitizing myokines such as interleukin-6 [54]. Some experimental manipulations of sex steroids in men have reported changes in insulin sensitivity preceding changes in body composition [55,56], raising the possibility of body composition-independent effects of sex steroids on insulin sensitivity. However, this hypothesis has been contradicted [41,57], and remains unproven. There may be differences between the metabolic syndrome as manifested in the general population, and ADTinduced metabolic changes. Data are conflicting on the depot specificity of lipid accumulation during ADT, with

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some studies indicating that this occurs predominantly in the subcutaneous depot [58−60] and other studies indicating both visceral and subcutaneous adipose tissue expansion [52]. There is imaging evidence of ectopic intramyocellular lipid accumulation during ADT [61], and this would be expected to promote skeletal muscle insulin resistance, atherogenic dyslipidemia, and inflammation [62,63]. However, ADT appears not to increase CRP or reduce adiponectin [60] and the induced lipid changes are different from those classically described in metabolic syndrome, and are likely to reflect integrated direct effects of hypogonadism and insulin resistance on lipoprotein metabolism. 4.3. Lipid metabolism Most of the literature describing changes in lipids during ADT for CaP is based on observational evidence. Findings have varied because of small sample size, variable duration and type of ADT, and variable adjustment for ADT-induced body composition and insulin resistance changes. Most studies agree that ADT using GnRH analogs, combined androgen blockade, or orchiectomy, increases total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) [64−68,59]. Some studies report increases in LDL-C [64,67] and some report no change [65,66,68]. In a 6-week trial of GnRH analog with or without T replacement in 15 healthy men, TC and HDL-C were increased by the GnRH analog with no change in LDL-C or TG [69]. These changes were prevented by T replacement. In a 24-week trial of GnRH analog treatment or placebo in 50 men with benign prostatic hypertrophy, TC, HDL-C, and TG were increased by GnRH analog treatment, with no change in LDL-C. These changes had returned to baseline 24 weeks after the end of the intervention [70]. In summary, ADT appears to increase TC. This is largely due to an increase in non-LDL-C, in particular HDL-C. ADT also appears to increase TG, and the magnitude of this effect may depend on the degree of increase in insulin resistance. Few studies have evaluated effects on LDL particle size or density. The net effect of these changes on atherosclerosis progression is unknown. 5. Management of effects on body composition, glucose, and lipid metabolism 5.1. Assessment Men commencing ADT should undergo holistic assessment of cardiovascular risk [8]. This includes history focusing on cardiovascular disease and risk factors, anthropometry, blood pressure (BP), fasting glucose and lipid levels, glycated hemoglobin, and renal function. Urinary albumin to creatinine ratio should be measured particularly when there is hypertension or diabetes to assess for chronic kidney disease and as a cardiovascular risk marker.

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Absolute cardiovascular risk should be calculated using a validated risk prediction model for the particular patient population. Many risk estimation models exist [71]. Recent US hypertension [75] and cholesterol treatment [72] guidelines both recommend the ACC/AHA Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator app (http:// tools.acc.org/ASCVD-RIsk-Estimator-Plus/). Management of modifiable risk factors is personalized based on absolute risk and individual comorbidities [72−75]. Attention to life-style factors follows recommendations for the general population [8] (Table 1). 5.2. Pharmacotherapy General population lipid, BP and glycemic management guidelines apply for men on ADT [8]. While ADT is associated with elevated cardiovascular risk, it is unclear whether ADT should modify estimates of absolute risk obtained from risk prediction models. Lipid guidelines recommend the use of absolute risk to guide decisions in the primary prevention context, and statin-based treatment in secondary prevention [71,72,76]. There is disagreement over whether treatment should be focused on specific LDL-C (and other) targets or not, and the exact thresholds for intervention [71,72]. Statins are of proven benefit in primary [77] and secondary prevention [78] of ASCVD. Statins should be strongly considered for men undergoing ADT who have clinical ASCVD or are at high 10-year risk (defined by persistent LDL-C ≥ 4.9 mmol/l, diabetes plus LDL-C ≥ 1.8 mmol/l, nondialysis requiring chronic kidney disease stage 3−5, or ASCVD Risk Estimator calculated 10-year risk > 5%) [71,72]. Statins increase incidence of diabetes to a very small extent but this is outweighed by their overall cardiovascular outcome benefit [79], and should not prevent their use in men undergoing ADT. In men with diabetes undergoing ADT, pharmacotherapy should focus on agents with evidence for preventing cardiovascular complications or mortality: metformin [80]; empagliflozin [81]; and liraglutide [82]. Glycemic control should be individualized [83]. Insulin sensitizing agents such as metformin and thiazolidinediones have unproven theoretical advantages because they may reduce the IGF-1 pathway alterations that are promoted by insulin resistance, and that have been implicated in CaP progression [46,84]. Ongoing clinical trials are examining metformin as an oncologic treatment in various stages of CaP (e.g., NCT03137186, NCT02945813, and NCT01864096). BP should be assessed and managed in line with existing guidelines, although these differ slightly [85−87,75]. Of note, the SPRINT trial [88] resulted in downward revision of BP targets to a general goal of < 130/80 for patients with an indication to treat [75]. Initiation of antihypertensive therapy is recommended for secondary prevention of ASCVD or for primary prevention when calculated 10-year risk is ≥ 10% at a threshold of systolic BP ≥ 130 and/or diastolic BP ≥

80. For primary prevention in lower risk individuals, thresholds of systolic BP ≥ 140 and diastolic BP ≥ 90 are used [75]. 6. Conclusion Although treatment approaches to CaP are constantly evolving, ADT is likely to remain a standard therapy in the foreseeable future. Men with CaP receiving ADT are a vulnerable population and at increased risk of developing ADT-associated adverse outcomes. ADT is associated with the development of osteosarcopenic obesity with subsequent increased risk of diabetes, fractures, frailty, and possibly cardiovascular events. Given the relatively good prognosis of CaP, ADT-associated adverse sequelae can contribute to competing mortality, and should be assessed and managed proactively. However, there is relatively limited high-level evidence specific to men treated ADT, and in part recommendations to mitigate risk are extrapolated from evidence available in the general population. Conflict of interest Mathis Grossmann has received research funding from Bayer Pharma, Novartis, Weight Watchers, Lilly and speaker’s honoraria from Besins Healthcare. Nicholas Russell declares that he has no conflict of interest. Acknowledgment Nicholas Russell is supported by an Australian Government Research Training Program Scholarship. References [1] Greenspan SL, Coates P, Sereika SM, Nelson JB, Trump DL, Resnick NM. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005;90:6410–7. https://doi.org/10.1210/jc.2005-0183. [2] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163:181–6. [3] Preston DM, Torr
ens JI, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis 2002;5:304–10. https://doi.org/10.1038/sj.pcan.4500599. [4] Hamilton EJ, Ghasem-Zadeh A, Gianatti E, Lim Joon D, Bolton D, Zebaze R, et al. Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 2010;95:E456–63. https://doi.org/10.1210/jc.20100902. [5] Shahinian VB, Kuo Y-F, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–64. https://doi.org/10.1056/NEJMoa041943. [6] Cianferotti L, Bertoldo F, Carini M, Kanis JA, Lapini A, Longo N, et al. The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation. Oncotarget 2017;8:75646–63. https://doi.org/ 10.18632/oncotarget.17980.

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