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Keywords:

  • prostate cancer;
  • androgen-deprivation therapy;
  • side effects;
  • fracture;
  • osteoporosis;
  • cardiovascular disease

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer. Although ADT is effective at suppressing prostate-specific antigen (PSA), stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival, it is not without serious side effects. However, to the authors' knowledge, there is lack of a systematic review of its major adverse effects to date. The authors of this report systematically reviewed and quantitatively assessed the literature on skeletal and cardiac side effects associated with ADT in men with prostate cancer. The PubMed database was searched for relevant published articles from 1966 to May 2008, and 683 articles were reviewed systematically from an original 20 different Medical Subject Heading search combinations. The focus of the review was on bone-related and cardiovascular-related outcomes. When appropriate, results were pooled from articles on specific adverse outcomes, summary risk estimates were calculated, and tests of heterogeneity were performed. Fourteen articles were identified that met inclusion criteria from the original 683 studies. Men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% (summary relative risk, 1.23; 95% confidence interval [95% CI], 1.10-1.38) compared with men who had prostate cancer but who did not undergo ADT. Furthermore, men who underwent ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo with ADT (summary hazards ratio, 1.17; 95% CI, 1.07-1.29). Significant elevations in the risk of diabetes also were observed from 2 large studies. ADT was associated with an increased risk of skeletal fracture, incident diabetes, and cardiovascular-related mortality, although the absolute risk of these events was low. Preventive measures against these adverse effects and careful assessment of patient's baseline health status should be considered. Cancer 2009. © 2009 American Cancer Society.

Prostate cancer is the most common solid organ cancer among men in the US. The American Cancer Society estimates that 186,320 incident cases will be diagnosed in 2008.1 Worldwide, over 679,000 cases of prostate cancer were diagnosed in 2002.2 Prostate cancer mortality has been declining steadily over the last 2 decades, which may be attributed to multiple reasons, including advances in treatment and early detection of the disease.3, 4 The most common form of treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), which can take the form of either surgical castration (orchiectomy) or chemical castration (with gonadotropin-releasing hormone [GnRH]). In addition, ADT is used increasingly as adjuvant therapy with radiotherapy for localized prostate cancers and as salvage therapy for increasing prostate-specific antigen (PSA) levels after localized treatment.5-7 The use of ADT as primary therapy has been increasing steadily over the last decade. A report by Shahinian et al indicated that use of ADT increased steadily throughout the 1990s among men of all ages with prostate cancer who had all stages and grades of tumor.8 Another study by Cooperberg et al indicated that, next to surgery, primary ADT was the most common treatment regimen for men with localized prostate carcinoma.9 ADT is effective at alleviating disease-specific symptoms,5, 10, 11 and some evidence suggests that it is effective at prolonging survival when used as an adjuvant with radiation therapy in patients with locally advanced prostate cancer.6, 12 Although it has been suggested that the use of primary ADT may directly prolong survival in patients with prostate cancer,13 2 recent studies indicated that primary ADT does not prolong survival.14, 15

Although ADT has been successful in improving overall quality of life in patients with advanced prostate cancer, it is not without side effects. Common side effects associated with ADT include skeletal complications, metabolic and cardiovascular complications, sexual dysfunction, hot flashes, periodontal disease, cognition, and mood disorders.5, 16-21 Whereas these complications are significant and may be associated with increased overall morbidity, skeletal, metabolic, and cardiovascular complications are particularly concerning because of their impact on morbidity as well as mortality. It has been demonstrated that the administration of ADT reduces bone mineral density (BMD),20, 22, 23 which leads to the increased risk of skeletal fracture. It also has been demonstrated that ADT decreases insulin sensitivity,24, 25 cholesterol levels26, 27 and the percentage of fat mass,24 all of which are risk factors for diabetes and/or cardiovascular-related morbidity and mortality. The association of ADT with these adverse outcomes, which may result in additional serious morbidity or mortality, has important clinical and public health implications for the treatment of prostate cancer.

Although several reviews have been published on ADT and its side effects,5, 19, 20 most reviews have not been systematic and, to the best of our knowledge, have not provided summary risk estimates for specific outcomes from the studies that used similar methodology. Given the widespread use of ADT to treat prostate cancer of all stages and the previously reported associations between ADT and various adverse health outcomes, we conducted a review that included summary risk estimates for specific outcomes when appropriate to gain a better understanding of the magnitude of skeletal and cardiovascular side effects from ADT in the treatment of prostate cancer.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Selection of Studies

A National Library of Medicine PubMed search of MEDLINE citations was performed to identify English-language studies that were published from 1966 through May 16, 2008. Although we searched studies that investigated all potential adverse outcomes from ADT, our primary objective was to identify studies that addressed the incidence of bone- and cardiovascular-related outcomes because of the frequency and public health significance of these outcomes after treatment with ADT. We performed 20 separate searches combining any of the following Medical Subject Heading (MeSH) terms for adverse outcomes: osteoporosis, fracture, bone density, bone loss, cardiovascular, cardiovascular morbidity, cardiovascular events, diabetes, heart, and side-effect with the following terms for ADT: androgen-deprivation, ADT, GnRH agonist, lutenizing hormone-releasing hormone (LHRH), androgen suppression, and hormone therapy with prostate cancer. These separate searches yielded 683 publications in aggregate. After reviewing these 683 abstracts, we excluded any review articles, case reports, case series, studies that focused on therapies to alleviate the side effects (eg, bisphosphonates or vitamin D supplementation given to men undergoing ADT to prevent osteoporosis and fracture), and studies that did not exclusively investigate bone-related and cardiovascular-related adverse side effects of ADT. After these exclusions, 55 original articles remained (38 studies addressed bone-related side effects, and 17 studies addressed cardiovascular-related side effects). The reference lists from the remaining 55 studies also were reviewed for any potentially relevant studies that did not appear in the results of the above PubMed search. From the reference lists, we identified an additional 4 studies (1 study addressed bone-related side effects, and 3 studies addressed cardiovascular-related side effects), for a total of 59 studies. Then, we excluded studies that did not have an adequate comparison group (ADT vs no-ADT groups among patients with prostate cancer) and studies that had a total sample size <100. After applying these exclusions, 14 studies remained for the final report (8 studies addressed bone-related side effects, and 6 studies addressed cardiovascular-related side effects). For each of the 14 remaining studies, information on study design, study size, study setting, length of follow-up or duration of ADT, specific outcome(s), specific exposure(s), measures of association reported, and covariates/confounders considered in the final model carefully was abstracted and included in Tables 1 through 4. Studies were grouped primarily by major outcomes.

Table 1. Characteristics of Studies Investigating Fracture Risk From Androgen-deprivation Therapy
     No. Cases/Total No.  
ReferenceStudy DesignLength of Follow-upSettingFracture TypesExposedUnexposedMean Age, YearsResults
  • RC indicates retrospective cohort design; ADT, androgen-deprivation therapy; RR, relative risk; 95% CI, 95% confidence interval; SEER Program, Surveillance, Epidemiology, and End Results Program; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; CC, case-control design.

  • *

    This study reported odds ratios (ORs) from a case-control design (fracture vs no fracture), but the ORs were adjusted for prostate cancer, previous fracture, and age.

Lopez 200528RCMean: ADT, 48 mo; no ADT, 69 moMedical records of prostate cancer patients from academic medical center in SpainPeripheral and vertebral fractures thought to be osteoporotic in nature25/28810/300ADT, 72; no ADT, 70RR, 3.6; 95% CI, 1.6-7.7
Shahinian 200529RCMean: 5.1 yDatabase of the SEER Program and MedicareAll sites2130/10,9944159/32,931All participants ≥661-4 Doses of GnRH: RR, 1.07; 95% CI, 0.98-1.16; 5-8 doses of GnRH: RR, 1.22; 95% CI, 1.11-1.35; ≥9 doses of GnRH: RR, 1.45; 95% CI, 1.36-1.56
Smith 200530RCMedian: ADT, 4.7 y; no ADT, 5.4 yClaims from public use file databases from a 5% national random sample of Medicare beneficiariesAll sites, hip/femur and vertebral fractures also analyzed separately1369/38872512/7774≥65Any fracture: HR, 1.14; 95% CI, 1.07-1.23; hip/femur fracture: crude RR, 1.30; 95% CI, 1.10-1.53; vertebral fracture: crude RR, 1.45; 95% CI, 1.19-1.75
Smith 200631RCEmployer database of billing claims from employees (and their beneficiaries) of 16 nationwide companiesAll sites, hip and vertebral fracture also analyzed separately572/3779975/8341ADT, 73.4; no ADT, 68.9Any fracture: OR, 1.13; 95% CI, 1.02-1.26; hip fracture: OR, 1.39; 95% CI, 1.03-1.88; vertebral fracture: OR, 1.22; 95% CI, 0.97-1.54
Abrahamsen 200732*CCMedian: 36 mo from first visit for prostate cancer to fractureStudy data from Danish national hospital discharge, statistic, and administrative databasesAll sites, hip fracture, spine fracture also analyzed separately79/17315,637/62,692Mean: Fracture group, 66.8; control group, 66.8All fractures: OR, 1.7; 95% CI, 1.2-2.5; hip fracture: OR, 1.9; 95% CI, 1.2-3.0; vertebral fracture: OR, 2.1; 95% CI, 1.2-4.9
Table 2. Characteristics of Studies Investigating the Association Between Androgen-deprivation Therapy and Osteoporosis or Bone Mineral Density
     No. Cases/Total No.  
ReferenceStudy DesignLength of Follow-upSettingOutcomesExposedUnexposedMean Age, YearsResults
  • CS indicates cross-sectional design; ADT, androgen-deprivation therapy; BMD, bone mineral density; OR, odds ratio; 95% CI, 95% confidence interval; RR, relative risk; PC, prospective cohort design.

  • *

    Crude ORs were calculated by authors given data presented in the current study.

Morote 200733CSDuration of ADT was 0 y, 2 y, 4 y, 6 y, 8 y, and 10 yStudy conducted using patients from academic medical center in SpainOsteoporosis, osteopenia, changes in BMDOsteoporosis: 2 y, 48/112; 4 y, 30/61; 6 y, 22/37; 8 y, 23/35; 10 y, 17/21; osteopenia: 2 y, 44/112; 4 y, 21/61; 6 y, 11/37; 8 y, 10/35; 10 y, 4/21Osteoporosis: No ADT, 44/124; osteopenia: no ADT, 56/12468.9Crude OR for osteoporosis: 0 y vs 2 y (OR, 1.36; 95% CI, 0.78-2.39); 0 y vs 4 y (OR, 1.76; 95% CI, 0.90-3.44); 0 y vs 6 y (OR, 2.67; 95% CI, 1.18-6.06); 0 y vs 8 y (OR, 3.48; 95% CI, 1.48-8.28)*
Morote 200334CSMedian: ADT group, 41 moStudy conducted using patients from academic medical center in SpainOsteoporosis and osteopenia (at femoral neck); estimated RR of hip fracture for duration of ADT22/5316/57ADT, 70.4; no ADT, 69.2Crude OR and RR for osteoporosis: OR, 1.82; 95% CI, 0.82-4.03 (RR, 1.48; 95% CI, 0.88-2.50); normal BMD significantly (P<.05) higher in unexposed group compared with ADT group; prevalence of osteoporosis increased as ADT duration increased
Greenspan 200535PCAll men followed for 12 mo from baseline; but, at baseline, the mean acute ADT duration was 2.9 mo (chronic ADT duration, 33.4 mo)Academic medical center (Pittsburgh, Pa); controls recruited through newspaperBMD of the total body, spine, wrist, and hip; biomarkers of bone turnover and body composition also measuredAcute ADT, 30; chronic ADT, 50No ADT, 72; healthy controls, 43All groups, 68; no ADT, 66.3; acute ADT, 68.8; chronic ADT, 71.3; controls, 66.6At 12-mo follow-up, men who received acute ADT had significantly (P<.05) lower BMD for total body, total hip, total radius, trochanter, and posterior spine; men who received chronic ADT had only significantly lower BMD at total radius; men who did not receive ADT or who were healthy controls did not have significantly different BMD levels after 12 mo of follow-up; men who received acute ADT had significantly elevated levels of bone turnover biomarkers at 6 mo and 12 mo compared with men who did not receive ADT and compared with controls
Table 3. Characteristics of Studies Investigating the Association Between Androgen-deprivation Therapy and Incident Diabetes Mellitus/Cardiovascular Morbidity
    No. Cases/Total No.   
ReferenceStudy DesignLength of Follow-upSettingExposedUnexposedOutcome InvestigatedMean Age, YearsResults
  1. RC indicates retrospective cohort design; SEER Program, Surveillance, Epidemiology, and End Results Program; HR, hazards ratio; 95% CI, 95% confidence interval; DM, diabetes mellitus; RR, relative risk; ICD-9, ninth edition of the International Classification of Diseases; ADT, androgen-deprivation therapy.

Keating 200636RC4.55 y (median)Database of the SEER Program and Medicare26,570 (29.0/1000 Person-y)41,575 (20.9/1000 Person-y)Incident DM74.2HR,1.44; 95% CI, 1.34-1.55
Lage 200737RC12 mo extended to 18 mo for additional analysesClaims-based analysis110/1231507/7250Incident DM64.7At 12 mo: RR, 1.36; 95% CI, 1.08-1.71; at 18 mo: RR, 1.49; 95% CI, 1.12-1.99
Saigal 200738RC5 yDatabase of the SEER Program and Medicare2646/48108463/18,006Cardiovascular morbidity as defined by ICD-9 codesRange, 70-74 (majority ADT and no ADT cohorts)Overall: HR, 1.20; 95% CI, 1.15-1.26; ADT ≤12 mo vs >12 mo: HR, 1.37; 95% CI, 1.29-1.46
Table 4. Characteristics of Studies Investigating the Association Between Androgen-deprivation Therapy and Cardiovascular-related Mortality
    No. Cases/Total No.  
ReferenceStudy DesignMedian Follow-up, YearsSettingExposedUnexposedAge Group, YearsResults
  • RC indicates retrospective cohort design; SEER Program, Surveillance, Epidemiology, and End Results Program; HR, hazards ratio; 95% CI, 95% confidence interval; CapSURE, Cancer of the Prostate Strategic Urologic Research Endeavor; RCT, randomized controlled trial; RTOG, Radiation Therapy Oncology Group; TROG, Trans Tasman Radiation Oncology Group.

  • *

    Cardiovascular-related mortality was defined as sudden death or life-threatening ventricular arrhythmia.

  • Cardiovascular mortality was defined as death from acute myocardial infarction (MI), sudden cardiac arrest or death, coronary artery disease, cardiac ischemia, malignant arrhythmia, or thromboembolic disease, such as pulmonary embolism or cerebrovascular accident.

  • Cardiovascular mortality was defined as coronary artery disease, cardiovascular disease, cardiac arrest, MI, congestive heart failure, cardiomyopathy, or cardiovascular arrhythmia.

  • §

    Cardiovascular mortality was defined as fatal MI.

Keating 200636*RC4.55Database of the SEER Program and Medicare26,570 (12.9/1000 Person-y)41,575 (9/1000 Person-y)Mean, 74.2HR, 1.16; 95% CI, 1.05-1.27
Tsai 200739RC3.8CapSURE database; men first underwent radical prostatectomy15/26646/2996Median, 64HR, 2.6; 95% CI, 1.4-4.7
Efstathiou 200840RCT8.1RTOG 92-02; all men treated first with radiation therapy then 4 mo of ADT; men then randomized to no further treatment or 24 mo adjuvant ADT201/75883/763Median, 70HR, 1.09; 95% CI, 0.81-1.47
D'Amico 200741§Pooled analysis of 3 RCTsTROG group, 5.9; US group, 6.7Men with prostate cancer enrolled on 1 of 3 trials from Australia/New Zealand and the US in addition to radiation therapyTROG group, 29/802US group, 16/206Median: TROG group, 68; US group, 72.5HR, 1.2; 95% CI, 0.5-2.8

Statistical Analyses

Given the heterogeneity of the reviewed studies with regard to timing and duration of ADT and inconsistent definitions of outcomes under study, we were unable to combine the results of all subcategories of studies to obtain a summary measure of association. However, the studies with similar methodology in investigating fracture risk, specific risk of vertebral fracture, and cardiovascular-related mortality subsequent to ADT treatment were synthesized for summary risk estimates. This was performed by calculating the natural logarithm of the measure of association (eg, odds ratio, relative risk [RR], etc) and the measure's standard error and then using the meta command in STATA statistical software (version 10.0; StataCorp, College Station, Tex). In 1 instance in which the original study did not calculate odds ratios of interest, we were able to calculate crude odds ratios given the number of exposed and unexposed participants in the study, as noted in Table 2. Fixed-effects and random-effects models were computed for each summary estimate. Q tests for heterogeneity were computed for each fixed-effect estimate. When a significant P value resulted (P < .05), indicating heterogeneity between studies (ie, variability between studies beyond sampling error), the random-effects model estimate was used under the assumption that any variation between studies beyond sampling error was random. When the P value from the Q test was not statistically significant (P > .05), the fixed-effects model estimate was used under the assumption that the studies were relatively homogeneous and that any variability was caused by sampling error. Finally, forest plots were constructed for the individual studies and are depicted in Figures 1 through 3.

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Figure 1. Forest plot of relative risks for studies investigating the association between androgen-deprivation therapy (ADT) and skeletal fracture. RR indicates relative risk; 95% CI, 95% confidence interval.

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Figure 2. Forest plot of relative risks for studies investigating the association between androgen-deprivation therapy (ADT) and vertebral fracture. RR indicates relative risk; 95% CI, 95% confidence interval.

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Figure 3. Forest plot of relative risks/hazards ratios for studies investigating the association between androgen-deprivation therapy (ADT) and cardiovascular-related mortality. RR indicates relative risk; 95% CI, 95% confidence interval.

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RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Fracture Risk

The 5 studies that investigated the risk of fracture as major side effect from ADT are listed in Table 1. Four of the 5 studies were retrospective cohort studies,28-31 and 1 study was a case-control study that presented data available to calculate a crude RR.32 All 5 studies reported significantly increased risks of overall fracture in patients with prostate cancer who underwent ADT compared with patients who did not undergo ADT. Although all 5 studies presented measures of association for overall fractures, Lopez et al28 only reported fractures for peripheral and vertebral fractures. All but 1 of the measures of association were adjusted for covariates such as age, previous history of fractures, and comorbidities.32 Three of the 5 studies also calculated separate measures of association for hip and/or vertebral fractures (or presented available data to calculate these estimates). All but 1 of the specific measures of association for hip and/or vertebral fracture were statistically significant.31 Four of the 5 studies had large sample sizes (>10,000 total), allowing greater precision of the estimates. The estimates from the studies that summarized overall fracture risk and vertebral fracture risk are shown in the forest plots in Figures 1 and 2, respectively.

Given the relative homogeneity of outcome for the fracture-risk studies, we chose to calculate a summary measure of association and a Q test for heterogeneity in addition to estimates from individual studies. The results from the 5 fracture risk studies yielded a summary random-effects estimate of 1.23 (95% confidence interval [CI], 1.10-1.38) and a fixed-effects estimate of 1.17 (95% CI, 1.12-1.23). The Q statistic was 14.80 (P = .005), indicating significant heterogeneity between studies beyond sampling error; thus, the random-effects estimate was a more appropriate estimate. We conducted a sensitivity analysis by excluding the study by Lopez et al,28 and the random-effects and fixed-effects estimates changed very little. A summary estimate also was calculated for the 3 studies that reported specific estimates for vertebral fracture; that summary estimate indicated that ADT was associated significantly with an increased risk of vertebral fracture (fixed-effects estimate, 1.39; 95% CI, 1.20-1.60). The Q statistic indicated that these 3 studies were relatively homogeneous (Q statistic, 3.5; P = .17). However, it is important to note that the summary estimate for vertebral fractures was based on crude estimates for each individual measure of association.

Osteoporosis and Other Bone-related Studies

Studies that met our inclusion criteria and that examined other bone-related outcomes, such as osteoporosis, are presented in Table 2. All 3 studies reported an increased risk of osteoporosis or lower bone mineral density (BMD) among men who underwent ADT compared with men who did not. Both studies that specifically examined osteoporosis as an outcome33, 34 reported elevated associations between ADT and osteoporosis, but to our knowledge only the study by Morote et al33 indicated that this association was statistically significant. Because the significant associations between ADT and osteoporosis occurred only when comparing men who were treated for >6 years, both the strength and the significance of this association appear to be functions of the duration of ADT. The study by Morote et al34 had a mean follow-up of <4 years, which produced an elevated but not significant measure of association, supporting the idea that osteoporosis secondary to ADT in men with prostate cancer generally is not diagnosed until greater than 4 years after the initiation of ADT. Although osteoporosis secondary to ADT may not be associated with shorter term regimens of ADT, 1 study indicated that BMD was significantly lower after <1 year of treatment compared with baseline and compared with men who did not undergo ADT.35 On the basis of the results reported by Greenspan et al,35 we observed that men who underwent short-term treatment with ADT endured greater loss of BMD compared with men who underwent ADT for longer periods. This finding corroborates evidence that bone loss occurs more rapidly in the years immediately after the initiation of ADT treatment compared with later years of ADT treatment.

Diabetes and Cardiovascular Morbidity

Only 3 studies that met inclusion criteria investigated incident diabetes and other cardiovascular morbidity secondary to ADT treatment.36-38 All 3 studies reported a significantly increased risk of diabetes or cardiovascular morbidity subsequent to the initiation of ADT using retrospective cohort study designs. Participants in the study by Keating et al36 had a median follow-up of 4.5 years. By using Cox proportional hazards modeling with adjustment for numerous covariates, those authors observed a significant hazards ratio [HR] of 1.44 (95% CI, 1.34-1.55). Lage et al37 followed patients for up to 18 months after the initiation of ADT and also reported a significant increase in the risk of diabetes after adjustment for covariates (treatment for 12 months: RR, 1.36; 95% CI, 1.07-1.74; treatment for 18 months: RR, 1.49; 95% CI, 1.12-1.99). It also is noteworthy that there was a difference in mean age between the 2 studies at baseline; the population studied by Keating et al36 was nearly 10 years older on average than the population studied by Lage et al.37 The study by Saigal et al38 indicated that men who underwent ADT had a 20% increased risk of cardiovascular morbidity compared with men who did not undergo ADT. Moreover, those authors reported that the duration of ADT treatment was associated significantly with cardiovascular morbidity: Men who underwent ADT for ≤12 months had a 37% increased risk of cardiovascular morbidity compared with men who underwent ADT for >12 months (HR, 1.37, 95% CI, 1.29-1.46); however, that study did not assess the risk of specific cardiovascular-related outcomes secondary to ADT and defined cardiovascular morbidity broadly using the 9th edition of the International Classification of Diseases.

Cardiovascular-related Mortality

Four studies that assessed cardiovascular-related mortality secondary to ADT met our inclusion criteria. Two of those studies were retrospective cohorts in design,36, 39 and 2 studies were randomized clinical trials.40, 41 The 2 retrospective cohort studies both reported significantly increased risks of cardiovascular-related mortality from ADT (HR: 1.1636 and 2.639). Keating et al reported a more precise and perhaps more generalizable risk estimate given their large sample size and diverse study population. However, Tsai et al also included other antiandrogens in their exposed ADT group, which used a slightly different outcome definition and adjusted for fewer covariates that may have resulted in an augmented risk estimate. The 2 randomized clinical trials reported slightly elevated but nonsignificant increases in cardiovascular-related mortality secondary to ADT. All participants in the study by Efstathiou et al40 received 4 months of ADT treatment and then were randomized to receive either no further treatment or 24 months of adjuvant ADT. Thus, it is possible that the cardiovascular effects for only 4 months of ADT may be low or negligible. The study by D'Amico et al41 exclusively investigated fatal myocardial infarction as an outcome secondary to ADT. The nonsignificant elevated risk estimate reflects the risk of fatal myocardial infarction only. Both clinical trials had longer periods of follow-up than either of the cohort studies but also had smaller sample numbers, which can influence the precision of risk estimates. Risk estimates from those 4 studies are illustrated in a forest plot (Fig. 3). In addition to risk estimates from individual studies, summary statistics also are provided at the bottom of Figure 3. The fixed-effects estimate from the results of the 4 studies was 1.17 (95% CI, 1.07-1.29), and the random-effects estimate was 1.27 (95% CI, 0.98-1.65). The Q statistic from the test of heterogeneity was not significant (P = .084), supporting the use of the fixed-effects estimate from these relatively homogeneous studies.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

For the current report, we systematically reviewed and quantitatively assessed the literature that examined bone-related and cardiovascular-related adverse outcomes secondary to ADT. To the best of our knowledge, this is the only study to date that has systematically reviewed the literature on these common and serious side effects from ADT and that has provided summary risk estimates for specific outcomes where appropriate. From our analyses, it appears that individuals with prostate cancer who undergo ADT have an approximately 23% increase in overall skeletal fracture risk associated with ADT treatment. Because the studies varied with respect to magnitude of measures of association as well as lengths of follow-up and specific types of ADT, the magnitude of the summary estimate can only be an approximate average estimate. Although the RR of skeletal fracture increases among men who undergo ADT, it should be noted that the absolute risk of fracture remains relatively small.30, 31 Studies in 2 different populations by Smith et al30, 31 indicated that the incidence of overall skeletal fracture in men with prostate cancer who did not undergo ADT was approximately 6.5 per 100 person-years. Thus, under an overall RR of 1.23, the absolute risk of fracture among ADT-exposed men is only 7.2 per 100 person-years. The larger studies in the table that looked at GnRH agonists for ADT produced adjusted risk estimates between 13% and 22%.29-31 Although the overall risks of fracture varied, all were identified as significant. In addition, both articles by Smith et al30, 31 and the article by Abrahamsen et al32 reported significant elevations in risk for hip/femoral and/or vertebral fractures. The summary estimate for vertebral fracture secondary to ADT indicates a significant 40% increase in risk for vertebral fracture for men who undergo ADT compared with similar men who do not undergo ADT.

The studies listed in Table 2 reported both significant and nonsignificant increases in BMD loss and osteoporosis. The results obtained by Morote et al33 and the study by Smith et al30 indicated that duration of ADT is associated with osteoporosis and fracture risk, with longer duration of ADT associated with greater risk. Because it has been demonstrated consistently that the risk of fracture risk is associated with ADT, physicians may consider preventive therapies for these patients when appropriate, such as bisphosphonates, supplementary vitamin D, calcium, and a regular regimen of physical activity. Several studies have indicated that bisphosphonates, such as pamidronate and zoledronic acid, given to men with prostate cancer who are undergoing ADT significantly reduced the loss of BMD compared with a placebo group when measured after 12 months.42-45 Although intravenous administration of bisphosphonates may increase BMD in patients undergoing ADT, it also has been demonstrated that oral administration of alendronate significantly reduced the loss of BMD45, 46 and may be a less cumbersome method of administration. Limited evidence exists on bisphosphonate supplementation and the reduction of skeletal fracture incidence. However, 1 study reported that men with hormone-refractory prostate cancer who received zolendronic acid had a significant annual reduction in the median time to skeletal-related events, such as pathologic bone fracture and spinal cord compression, compared with placebo.47

Incident diabetes appears to be a side effect of ADT. The studies listed in Table 3 by Keating et al36 and Lage et al37 reported significantly increased risks of incident diabetes between 36% and 49%. This finding is not surprising given the results of previously published literature, which reported significant elevations of hyperglycemia and increased insulin resistance in men who underwent ADT as well as worsened glycemic control in diabetic men who underwent ADT.24, 25, 48-50 Furthermore, the association between ADT and diabetes is plausible biologically given the relation between hypogonadism and increased insulin resistance and hyperglycemia. Given the role of hyperinsulinemia on prostate cancer cells,25, 51, 52 Basaria et al proposed that ADT may contribute indirectly to prostate cancer growth and suggested that the prescription of “insulin-sensitizing agents” may help lower insulin levels in men who are undergoing ADT.25 However, further research beyond those 2 studies is needed to confirm the consistency and magnitude of the association.

Results from studies that investigated cardiovascular-related mortality secondary to ADT were relatively consistent. The summary risk estimate indicated a significantly increased risk in cardiovascular-related mortality of 17%. However, the absolute risk of cardiovascular-related mortality remained low. Assuming that the baseline risk for cardiovascular-related mortality among men with prostate cancer without ADT is between 9 deaths and 10 deaths per 1000 person-years,36 the observed 17% increase in RR would result in the increase of the absolute risk to 10.5 deaths and 11.7 deaths per 1000 person-years, respectively, for men who underwent ADT. Recent declines in deaths from prostate cancer may be related in part to competing causes of death among patients with prostate cancer, and cardiovascular-related mortality would be on the top of the list.11, 25 Therefore, it would be helpful for physicians to encourage patients with prostate cancer who are undergoing ADT to make lifestyle modifications (such as physical activity and diet, etc) and to be vigilant of abnormal lipoprofiles, increased BMI, and serum levels of insulin. Moreover, baseline morbidity should be considered when evaluating treatment options for prostate cancer. A study by D'Amico et al indicated that men who were randomized to receive radiation therapy had a significantly increased risk of all-cause mortality compared with men who received radiation therapy and ADT.53 It was reported that much of this increase was in men without any comorbidity or with only minor comorbidities; the increase in all-cause mortality in the radiation therapy group was not observed among men who had moderate to severe comorbidities.

Although a few studies included in this review had large sample sizes, the generalization of the findings still may be limited. Further research on serious side effects from ADT would benefit from larger prospective studies that include different ethnic and age groups (including men aged <65 years) with longer follow-up when possible. Additional research may be conducted on side effects outside the focus of this review.

As with evidence of any adverse side effects from common treatments, a benefit-risk analysis must be considered. Although there is no strong evidence of prolonged survival in men who undergo ADT, this treatment does provide relief from symptoms. Some patients may benefit from ADT more than others, and consideration of the patient's baseline health status and specific prostate cancer stage is warranted. Although the absolute risks of fracture and cardiovascular mortality are low among men treated with ADT, preventive treatments may reduce further the risk of these serious adverse outcomes related to ADT.

In conclusion although ADT may alleviate symptoms and potentially prolong survival for patients with prostate cancer, it is not without side effects that may lead to serious consequences for a patient's overall health and well being. In particular, ADT is associated with an increased risk of skeletal fracture, incident diabetes, and cardiovascular-related mortality, although the absolute risk of these events is low. Preventive measures against these adverse effects as well as careful assessment of patient's baseline health status should be considered.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Supported in part by a grant from the Agency for Healthcare Research and Quality (R01-HS016743).

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References