Risk of the "androgen deprivation syndrome" in men receiving androgen deprivation for prostate cancer

BACKGROUND: Androgen deprivation therapy for prostate cancer has been associated with a spectrum of adverse effects, such as depression, memory difficulties, and fatigue, termed the androgen deprivation syndrome. Primary care physicians providing follow-up care for men with prostate cancer will be faced with managing these effects. We therefore sought to estimate the incidence of these effects and, by using a control group, ascertain whether these effects were related to androgen deprivation itself. METHODS: We assessed the risk of physician diagnoses of depression, cognitive impairment, or constitutional symptoms in Medicare data following androgen deprivation using a sample of 50 613 men with incident prostate cancer and 50 476 men without cancer, from 1992 through 1997, in the linked Surveillance, Epidemiology, and End Results-Medicare database. Cox proportional hazards regression was used to adjust for confounding variables. RESULTS: Of men surviving at least 5 years after diagnosis, 31.3% of those receiving androgen deprivation developed at least 1 depressive, cognitive, or constitutional diagnosis compared with 23.7% in those who did not (P<.001). After adjustment for variables such as comorbidity, tumor characteristics, and age, the risks associated with androgen deprivation were substantially reduced or abolished: relative risk (RR) for depression diagnosis, 1.08 (95% confidence interval [CI], 1.02-1.15); RR for cognitive impairment, 0.99 (95% CI, 0.94-1.04); and RR for constitutional symptoms, 1.17 (95% CI, 1.13-1.22). CONCLUSION: Depressive, cognitive, and constitutional disorders occur more commonly in patients receiving androgen deprivation, but this appears to be primarily because patients receiving androgen deprivation are older and have more comorbid conditions and more advanced cancers.     

性激素阻断治疗对前列腺癌患者骨代谢及骨量的影响

目的探讨药物去势方法治疗老年人前列腺癌对患者骨代谢和骨量的影响。方法以确诊的老年前列腺癌患者36例作为观察组（前列腺癌组），无前列腺癌及影响骨代谢疾病的老年男性13例作为对照组。前列腺癌组分别在诺雷德（Goserelin）去势前和去势后12个月测定2～4腰椎、左股骨颈、大转子、Ward’s三角和全髋的骨密度，并检测血中的骨特异性碱性磷酸酶（BALP）、骨钙素（BGP）、甲状旁腺素（PTH）、Ⅰ型前胶原末端肽（CICP）、抗酒石酸酸性磷酸酶（TRACP）及尿吡啶啉（PYD）、脱氧吡啶啉（DPD）、Ⅰ型胶原C端交联物（Cros）、尿钙／尿肌酐比值（Ca／Cr）等骨代谢指标，对照组同期检测上述项目。结果前列腺癌组在Goserelin去势前和对照组相比，骨密度和骨代谢各项指标差异无统计学意义（P〉0．05）；前列腺癌组经过Goserelin 12个月的治疗后，血雄激素和雌激素等性激素水平都显著性降低（P均〈0．01）；血BALP、尿DPD、Cros、Ca／Cr明显增高，全髋、左股骨颈、Ward’s三角3个部位的骨量丢失显著，变化率与对照组比较差异有统计学意义（均为P〈0．05）。结论前列腺癌患者接受Goserelin去势治疗后发生明显的骨转换增加和骨量丢失，与体内雄激素和雌激素水平极度降低有关，故对于这些患者监测骨密度和骨代谢指标有利于早期发现Goserelin去势治疗后发生的骨质疏松，并及时给予治疗。     

Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer

ObjectiveThis study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT.DesignBMD and samples of blood and urine were studied before and after 6 months of ADT in 70 patients with localized prostate cancer.ResultsBefore ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs = 0.344, p = 0.004; rs = 0.264, p = 0.027; rs = 0.329, p = 0.005; rs = 0.300, p = 0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p = 0.001). These relationships disappeared after ADT (p = 0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2 pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3 μmol/L and 5.6 to 2.9 nmol/L, respectively) (p < 0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3 nmol/L, p < 0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: + 2.2, ranged between ? 7.1 and + 15.3) were inversely correlated with the pretreatment (rs = ? 0.333 p = 0.005) and post-treatment (rs = ? 0.408, p = 0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs = 0.328, p = 0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs = 0.388, p = 0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs = ? 0.302, p = 0.024) among the bone formation/resorption markers including serum/urine N-telopeptide.ConclusionsSerum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.     

Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial

GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (+/-se) bone mineral density of the posteroanterior lumbar spine increased by 1.0 +/- 0.9% in men treated with raloxifene and decreased by 1.0 +/- 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 +/- 0.4% in men treated with raloxifene and decreased by 2.6 +/- 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine.     

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.     

Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment

OBJECTIVES: To determine the effects of once-weekly oral alendronate on indices of bone size, density and resorption in children with chronic illness being treated with glucocorticoids. METHODS: Twenty-two children with chronic illness treated with prednisone were randomized to receive 1 year's treatment with either once-weekly oral placebo or alendronate (1-2 mg/kg body weight) in a double-blind study. The main outcome measures were changes in lumbar spine and femoral shaft size and volumetric density (measured by dual energy X-ray absorptiometry) and N-telopeptide excretion (a marker of bone resorption). RESULTS: Once-weekly alendronate was well tolerated, and there were no major adverse events. In both groups bone size and bone mineral content increased through growth. Volumetric bone density of the lumbar spine increased significantly in the alendronate group (P = 0.013), but not in the placebo group. There were no differences between the groups in growth in the cortical width of the femoral shaft, but the cross-sectional moment of inertia per unit length-a derived estimate of mechanical strength-increased significantly in the alendronate group (P = 0.014) but not in the placebo group. Urine N-telopeptide excretion was suppressed significantly in the alendronate group (P = 0.007) but not in the placebo group. Height velocity was positively correlated with changes in both lumbar spine area and the total width of the femoral shaft (P = 0.015, P = 0.026, respectively). CONCLUSION: Once-weekly oral alendronate is well tolerated, suppresses bone resorption and may improve volumetric bone density at the lumbar spine and mechanical strength of the femoral shaft in children with chronic illness taking glucocorticoids. It does not affect bone growth. Larger controlled studies are needed to determine if these changes translate into reduced fracture incidence or greater peak bone mass. This study highlights the importance of differentiating between changes in bone size and changes in volumetric bone density in assessing bone in children, and also having control subjects in intervention studies.     

Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer

Purpose  

Primary androgen deprivation therapy (PADT) is an important treatment modality for men with localized or locally advanced prostate cancer and without bone metastasis. There is, however, a lack of data on the biochemical relapse (BR) outcomes in these patients. Here, we studied the outcome of a contemporary series of men treated by PADT and investigated predictive risk factors for BR.     

Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review

Increasing numbers of men with non-metastatic disease are receiving androgen deprivation therapy (ADT) for a variety of indications, some of which are supported by evidence from randomized trials. Balanced against possible survival benefits and better disease control are data that ADT adversely affects quality of life, particularly in the areas of sexual function, physical function, and energy. There is some evidence of worsening upper extremity physical strength but no clear evidence of decline in daily function with ADT. The impact of ADT on cognitive function is not clear at this time. ADT is associated with declines in bone mineral density within 6–12 months of commencing treatment, with increased fracture rates within 5 years of treatment. ADT use is also associated with a 10–15 g/L decline in hemoglobin, although the clinical significance of this drop appears to be limited for most patients. It is reasonable for physicians who are about to start men on ADT to obtain a baseline bone mineral density, to counsel them about the impact on sexual function and possible treatments for sexual dysfunction, and to encourage regular exercise. Further insight into adverse effects of ADT and strategies to minimize these adverse effects await data from ongoing studies.     

Changes in body composition during androgen deprivation therapy for prostate cancer

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.     

Medication utilization evaluation of androgen deprivation therapy for prostate cancer in Taiwan

Prostate cancer is one of the most common cancer in males. Both the incidence and the mortality rates of prostate cancer show an increasing trend. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. The aim of our study was to show the epidemiology of prostate cancer and the proportion of patients utilizing ADT.This study used Taiwan''s National Health Insurance Research Database (NHIRD) and identified the patients who had been diagnosed with prostate cancer (International Classification of Disease (ICD)-10: C61) and followed up between Jan 1, 2008 and Dec 31, 2015. The ADT drugs used by prostate cancer patients were recorded: Gonadotropin-releasing hormone (GnRH) agonists; GnRH antagonist; estrogen analogs and androgen receptor antagonist.A total of 25,233 patients with newly diagnosed prostate cancer in 2008–2014 were enrolled. The utilization of ADT increased from more than 7,000 person-time in 2008 to more than 50,000 person-time in 2014. Cyproterone acetate was the most commonly used drug in 2008–2015, but its proportion of utilization, which was the highest in stage 2 cancer, dropped from 43% in 2008 to 15% in 2015. Bicalutamide was the second most used drug from 2008 to 2015, but its utilization was not different for different stages.The incidence rate of prostate cancer increased in the study period and medical expenditure also increased in ADT treatment. Health insurance benefits for various ADT drugs should be further evaluated.     

GnRH类似物治疗对男性前列腺癌患者骨丢失的影响

目的探讨GnRH类似物治疗对老年男性前列腺癌患者骨量丢失、骨转换及身体成分的影响。方法确诊前列腺癌患者33人,同年龄健康男性35人,分别在治疗前、治疗12个月后测定受试者腰椎24（L2-4）、左股骨颈（FN）、全髋（Total Hip）的骨密度及全身总骨量、体脂（Total fat mass）和肌肉（Total lean mass）含量,并检测血清骨特异性碱性磷酸酶（BALP）、骨钙素（BGP）、250HD、尿Ⅰ型胶原C端交联物（CTX）等骨转换指标。结果前列腺癌GnRH类似物治疗组和对照组相比基线水平的骨密度和骨代谢各项指标间都没有显著性差异,GnRH类似物治疗12个月后,血FSH、T、E2分别下降了66．0％、87．5％和75．0％（P〈0．01）,血PSA水平下降100％（P〈0．001）;腰椎、股骨颈、全髋及全身骨量丢失率分别为-2．05％、-3．55％、-3．47％和-3．64％,与对照组相比各部位骨量的下降均有显著性差异（P〈0．05）;Total fat mass和Total lean mass变化率分别为＋12．6％和-10．8％,与对照组相比lean mass下降具有显著性差异（P〈0．05）;尿CTX／Cr和血250HD变化率分别为＋54．71％和-43．75％,与对照组相比变化率有显著性差异（P〈0．05）。6个月时骨转换标记物尿CTX／Cr的变化率与12个月时骨丢失率呈负相关。结论前列腺癌患者接受GnRH类似物治疗后出现明显的骨转换加速、骨量丢失增加及身体脂肪肌肉成分的改变,对这些病人及时监测骨密度和骨转换指标有利于早期诊断早期防治。     

Intermittent androgen deprivation in advanced prostate cancer: a review

At present androgen ablation therapy is the therapy of choice for the treatment of metastatic prostate cancer. However, in more than 50 % of the patients the disease will ultimately progress within 2?years.On the basis of the postulation from Bruchovsky et al. that intermittent androgen deprivation maintains the apoptotic potential, this may lead to a delay in tumour progression. By periodically changing phases from on to off the treatment quality of life for the patient may be improved. Most recent clinical data of phase?II and III studies imply that IAB is equal effective as CAB. Although data about quality of life and overall survival are still limited, results seem to be comparable. In order to decide which patient groups are most likely to benefit from IAB, final phase?III results need to be available.     

Quality of life in prostate cancer patients taking androgen deprivation therapy

OBJECTIVES: To examine the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL), self-reported HRQOL was compared in prostate cancer patients receiving short- (< 6 months) or long-term (> or = 6 months) ADT and healthy controls. DESIGN: Cross-sectional study. SETTING: Academic medical center in Pittsburgh, Pennsylvania. PARTICIPANTS: Ninety-six men, including those with prostate cancer receiving short-term, long-term, and no ADT and healthy controls. Men taking medications or having diseases known to affect bone mineral metabolism were excluded. MEASUREMENTS: The 36-item Short Form Medical Outcomes Study Health Survey (an HRQOL assessment) and a comorbidity index were administered to each participant. Characteristics, including body composition (assessed using dual-energy x-ray absorptiometry) and gonadal status (serum total and free testosterone) were measured approximately 3 months or less before the HRQOL assessment. RESULTS: As expected, men receiving ADT had significantly lower levels of testosterone, free testosterone, and lean body mass, as well as greater body fat and comorbidity index (all P<.01) than men not receiving ADT (i.e., men with prostate cancer and healthy controls). Participants receiving ADT reported significantly poorer QOL in the areas of physical function (P<.001), general health (P<.001), and physical health component summary (P<.001) than men not receiving ADT. There were no significant differences in HRQOL outcomes between participants receiving short- or long-term ADT. Comorbidity and testosterone levels were associated with several QOL scales. After controlling for the significant joint predictors of comorbidity and total testosterone using hierarchical regression analysis, ADT was no longer a significant predictor, and only comorbidity and total testosterone contributed to the explanation of the variance of the physical health component summary. Comorbidity alone contributed to the explanation of the variance in physical function, bodily pain, general health, and vitality. CONCLUSION: Patients with prostate cancer who were receiving ADT experience worse HRQOL than those not receiving ADT, but duration of ADT was not a contributing factor. After controlling for comorbidity, total testosterone level rather than ADT accounted for a small yet statistically significant percentage of the total variance of the physical health component summary. These findings have important clinical implications regarding the decision to treat prostate cancer patients with ADT.