Background The use of androgen-deprivation therapy for prostatecancer has increased substantially over the past 15 years. Thistreatment is associated with a loss of bone-mineral density,but the risk of fracture after androgen-deprivation therapyhas not been well studied.
Methods We studied the records of 50,613 men who were listedin the linked database of the Surveillance, Epidemiology, andEnd Results program and Medicare as having received a diagnosisof prostate cancer in the period from 1992 through 1997. Theprimary outcomes were the occurrence of any fracture and theoccurrence of a fracture resulting in hospitalization. Cox proportional-hazardsanalyses were adjusted for characteristics of the patients andthe cancer, other cancer treatment received, and the occurrenceof a fracture or the diagnosis of osteoporosis during the 12months preceding the diagnosis of cancer.
Results Of men surviving at least five years after diagnosis,19.4 percent of those who received androgen-deprivation therapyhad a fracture, as compared with 12.6 percent of those not receivingandrogen-deprivation therapy (P<0.001). In the Cox proportional-hazardsanalyses, adjusted for characteristics of the patient and thetumor, there was a statistically significant relation betweenthe number of doses of gonadotropin-releasing hormone receivedduring the 12 months after diagnosis and the subsequent riskof fracture.
Conclusions Androgen-deprivation therapy for prostate cancerincreases the risk of fracture.
Androgen-deprivation therapy for prostate cancer can reducemorbidity, palliate metastases, and improve survival in locallyadvanced disease when combined with radiation.1,2,3 However,androgen-deprivation therapy alone, in the form of gonadotropin-releasinghormone agonists, is increasingly being used in men with localizedprostate cancer (cancer confined to the prostate) and in menin whom the level of prostate-specific antigen (PSA) rises afterprostatectomy4,5,6 — both situations in which most patientsare minimally symptomatic and no survival benefit has been demonstrated.1,7For these reasons, it is important to have accurate data onthe toxic effects of androgen deprivation.8,9 Bone fracturesare of particular concern, given their association with increasedmortality in prostate cancer.10
A rapid loss of bone-mineral density occurs within the first6 to 12 months of androgen-deprivation therapy.11,12 However,the assessment of the risk of fracture associated with thistreatment has been limited in previous studies by small numbersand the lack of a control group.13,14,15,16 We used the linkeddatabase of the National Cancer Institute's Surveillance, Epidemiology,and End Results (SEER) program and Medicare to assess the riskof fracture associated with androgen deprivation in the formof orchiectomy or treatment with gonadotropin-releasing hormoneagonists in a large population-based sample of men who receivedthe diagnosis of prostate cancer during the period from 1992through 1997.
Methods
The study protocol was approved by the local institutional reviewboard; because of the study design, the requirement of informedconsent was waived.
Data Sources
The SEER–Medicare database links two large population-basedsources of data that together provide information on older adultswith newly diagnosed cancer.17 During the 1990s, the SEER programconsisted of a group of 11 tumor registries that representedapproximately 14 percent of the population.
Study Subjects
Data on all men 66 years of age or older who received a firstdiagnosis of prostate cancer in the years from 1992 through1997 were selected, for a total of 92,474 subjects. To ensurecomplete information, we excluded patients who were not enrolledin both Part A and Part B Medicare for the 12 months beforethe diagnosis and the 12 months after the diagnosis (13,352cases), were members of a health maintenance organization (17,275cases), or whose disease had been diagnosed on autopsy or ona death certificate (1076 cases). We limited the comparisonsto men with prostate cancer who received at least one dose ofa gonadotropin-releasing hormone agonist or underwent orchiectomywithin six months after receiving the diagnosis with those withprostate cancer who received neither type of treatment at anytime after diagnosis. This limitation excluded 10,158 patientswho had started treatment with gonadotropin-releasing hormoneagonists or had undergone orchiectomy six months or more afterdiagnosis. We also performed an analysis that included all patientswho received androgen-deprivation therapy during the first 24months after diagnosis, and this analysis did not substantiallyalter our results. Overall, data were available for a totalof 50,613 patients for the primary sample, with follow-up through2001.
The variables used in this study are defined in the Supplementary Appendix,which is available with the full text of this articleat www.nejm.org.18,19,20,21,22,23,24,25,26,27,28 The primaryoutcomes were any fracture and fracture resulting in hospitalization.Secondary outcomes were a new diagnosis of osteoporosis andfractures at specific sites.
Statistical Analysis
The chi-square test was used to compare the proportions of patientswho were treated with androgen deprivation according to differentcategories of baseline characteristics and to compare the proportionsof patients with bone-related toxic effects according to thepresence or absence of androgen-deprivation therapy. The Kaplan–Meiermethod was used to generate estimates of unadjusted, fracture-freesurvival. Survival analyses were performed with the use of Coxproportional-hazards regression. The dependent variable waseither the time to a first fracture or the time to a first fracturethat resulted in hospitalization, depending on the outcome beinganalyzed. Patients were censored at death, the loss of coverageunder Medicare Part A or Part B, or a change to coverage undera health maintenance organization. An examination for interactionbetween prespecified variables of interest (age, cancer stage,race, and score on a modified form of the Charlson comorbidityindex18,19) and the presence or absence of androgen-deprivationtherapy on the relative risk of fracture was performed withthe use of a Cox model. Race was determined on the basis ofthe codes for racial and ethnic groups used in the SEER database.
The numbers needed to harm were calculated by taking the inverseof the difference between the rates of fracture adjusted inthe Cox model at five years after diagnosis for the group thatdid not receive androgen-deprivation therapy and the group thatdid receive it. Although numbers needed to harm are usuallyreserved for the analysis of clinical trials, we use them hereto provide a measure of the absolute effect of androgen-deprivationtherapy on the risk of fracture. All analyses were performedwith the use of SAS software (version 8.2) (SAS Institute).
Results
Proportion of Patients Receiving Study Treatment
Table 1 presents the percentages of 50,613 men 66 years of ageor older with prostate cancer who received androgen-deprivationtherapy (in the form of either gonadotropin-releasing hormoneagonists or orchiectomy) within six months after diagnosis asa function of the characteristics of the patients and the cancer.The rate of use of androgen-deprivation treatment increasedwith increasing age, the stage of the cancer at diagnosis, thegrade of prostate cancer, and the presence of coexisting conditions.In addition, there was an increase in the use of androgen-deprivationtherapy over the period from 1992 to 1997, and the lowest tothe highest rates of use among the SEER geographic regions differedby a factor of two.
Proportion of Patients with Bone-Related Toxic Effects
The rates of occurrence of various bone-related toxic effectsduring the 12 months before the diagnosis of prostate cancerand during the period of 12 to 60 months after diagnosis werecompared between the group that received androgen-deprivationtherapy and the group that did not (Table 2). To ensure completefollow-up, data on patients who died or lost coverage underMedicare Part A or Part B during the 60 months after diagnosiswere excluded. In addition, data on patients with bone-relatedtoxic effects that occurred during the first 12 months afterdiagnosis were excluded, because these outcomes were consideredunlikely to be related to the therapy (and reanalysis includingthese patients did not substantially alter the results).
Table 2. Proportions of Patients with Bone-Related Toxic Effects before and after the Diagnosis of Prostate Cancer, According to the Presence or Absence of Androgen-Deprivation Therapy.
There was a small but statistically significant increase inthe proportion of patients with any fracture during the 12 monthsbefore diagnosis in the group that received androgen-deprivationtherapy as compared with the group that did not receive androgen-deprivationtherapy. All bone-related toxic effects developed significantlymore frequently during the 12 to 60 months after diagnosis inthe androgen-deprivation group. During this period, 19.4 percentof those in the androgen-deprivation group had a fracture, ascompared with 12.6 percent of those not receiving the studytreatment (P<0.001). In the same four-year period, 5.2 percentof those treated with androgen-deprivation therapy were hospitalizedwith a fracture, as compared with 2.4 percent of those not treated(P<0.001).
We repeated the analysis shown in Table 2, restricting it todata on patients with stage I, II, or III disease accordingto the criteria of the American Joint Committee on Cancer (AJCC)and low-grade or moderate-grade prostate cancer. The resultsof the two analyses were similar. For example, the rate of hospitalizationwith fracture in the latter analysis was 4.9 percent among patientswho received androgen-deprivation therapy as compared with 2.2percent among those who did not (P<0.001).
Unadjusted Fracture-Free Survival
The Kaplan–Meier method was used to generate unadjustedestimates of survival free of any fracture among the groupsthat did or did not receive androgen-deprivation therapy (Figure 1).All subjects who survived at least 12 months after the diagnosisof prostate cancer were included in the analysis. Androgen-deprivationtherapy was divided between those who underwent orchiectomyand those who received gonadotropin-releasing hormone agonists,stratified according to the number of doses received (one tofour, five to eight, or nine or more doses) in the year afterdiagnosis. Patients who had fractures in the first year afterdiagnosis were excluded. Those who underwent orchiectomy andthose who received nine or more doses of gonadotropin-releasinghormone agonists in the year after diagnosis had the lowestrates of fracture-free survival. The curves for the groups thatunderwent orchiectomy or received five to eight doses or nineor more doses of gonadotropin-releasing hormone agonists divergedfrom that for the group that did not receive androgen-deprivationtherapy over the entire period of follow-up.
Figure 1. Unadjusted Fracture-free Survival among Patients with Prostate Cancer, According to Androgen-Deprivation Therapy.
The survival curves start at 12 months after diagnosis, and androgen deprivation was initiated within 6 months after diagnosis. GnRH denotes gonadotropin-releasing hormone. The number of doses is the number administered within 12 months after diagnosis.
Fracture Risk and Androgen-Deprivation Therapy
The risk of any fracture associated with androgen-deprivationtherapy was assessed with the use of a Cox regression modeladjusted for variables related to the patient and the cancer,other cancer treatment received, and a diagnosis of fracture,osteoporosis, or osteopenia during the year before the diagnosisof cancer (Table 3). Patients who died during the year afterdiagnosis or who had fractures during those 12 months were excluded.Subjects were followed for a mean of 5.1 years after diagnosis.
Table 3. Risk of Fracture Associated with Androgen-Deprivation Therapy.
The relative risk of the occurrence of any fracture or a fracturethat resulted in hospitalization increased steadily with theincreasing number of doses of a gonadotropin-releasing hormoneagonist received during the first year after diagnosis (P<0.001for linear trend). This trend was also significant (P<0.001)when the number of doses of a gonadotropin-releasing hormoneagonist received during the 24 months after diagnosis was examined(data not shown). The relative risk of any fracture was 1.45(95 percent confidence interval, 1.36 to 1.56) among those receivingnine or more doses of gonadotropin-releasing hormone agonistin the first 12 months after diagnosis and 1.54 (95 percentconfidence interval, 1.42 to 1.68) among those who underwentorchiectomy. For the relative risk of fracture resulting inhospitalization, the risk was 1.66 (95 percent confidence interval,1.47 to 1.87) for nine or more doses of gonadotropin-releasinghormone agonist and 1.70 (95 percent confidence interval, 1.48to 1.96) for orchiectomy.
With reference to the sites of fracture typically associatedwith osteoporosis (e.g., hip, spine, and forearm), the relativerisk was 1.62 (95 percent confidence interval, 1.47 to 1.78)for nine or more doses of gonadotropin-releasing hormone agonistin the year after diagnosis and 1.63 (95 percent confidenceinterval, 1.45 to 1.82) for orchiectomy. Among patients withnonmetastatic disease (AJCC stage I, II, or III and a low-to-moderategrade of prostate cancer), the relative risk of any fracturewas 1.37 (95 percent confidence interval, 1.20 to 1.57) fornine or more doses of gonadotropin-releasing hormone agonist.In the analyses limited to patients who received androgen deprivationas primary therapy (with patients who underwent radical prostatectomyor radiation excluded) or to patients who received androgendeprivation as adjuvant therapy (concomitantly with radicalprostatectomy or radiation), the relative risks of any fracturewere 1.44 (95 percent confidence interval, 1.33 to 1.56) and1.53 (95 percent confidence interval, 1.32 to 1.78), respectively,among those receiving nine or more doses of gonadotropin-releasinghormone agonist.
Examination for Interaction
Interactions were tested on the basis of the Cox model presentedin Table 3. There were no statistically significant interactionsbetween cancer stage or race or ethnic group and androgen deprivation.There were significant interactions between scores on the comorbidityindex and androgen deprivation (P=0.005), and between age andandrogen deprivation (P=0.01) on the risk of fracture. The relativerisk of any fracture at different doses of gonadotropin-releasinghormone agonist or with orchiectomy tended to decline with advancingage, although subjects 80 years of age or older who receivednine or more doses of gonadotropin-releasing hormone agonistwere still at an increased risk of subsequent fracture (relativerisk, 1.32; 95 percent confidence interval, 1.18 to 1.48). Therelative risk of fracture related to androgen-deprivation therapydecreased with an increasing score on the modified Charlsoncomorbidity index.18,19 For instance, the relative risk of fracturewith nine or more doses of gonadotropin-releasing hormone agonistwas 1.62 (95 percent confidence interval, 1.48 to 1.76) fora score of 0 on the comorbidity index, but it was 1.03 (95 percentconfidence interval, 0.82 to 1.31) for a score of 3 or moreon the comorbidity index. The full model for these interactionsis presented in the Supplementary Appendix.
Numbers Needed to Harm
The number needed to harm for the occurrence of any fractureduring the period 12 to 60 months after the diagnosis of prostatecancer was 28 (95 percent confidence interval, 26 to 31) forany use of a gonadotropin-releasing hormone agonist and 16 (95percent confidence interval, 13 to 19) for orchiectomy. Becausethe relative risk of fracture varied according to the age ofthe subject and the total number of doses of gonadotropin-releasinghormone agonist received in the year after diagnosis, this relationshipwas expressed by calculating the number needed to harm accordingto age and number of doses (Table 4). There was a pattern oflower numbers needed to harm with an increasing total numberof doses of gonadotropin-releasing hormone agonist administeredand with increasing age. For example, the number needed to harmwas 74 (95 percent confidence interval, 50 to 146) among those66 to 69 years of age who received one to four doses of a gonadotropin-releasinghormone agonist during the year after receiving the diagnosisof prostate cancer, whereas it was 12 (95 percent confidenceinterval, 11 to 13) among those 80 years of age or older whoreceived nine or more doses during the same period.
Table 4. Estimated Number Needed to Harm for the Occurrence of Any Fracture within 12 to 60 Months after Diagnosis, According to Age and Extent of Androgen Deprivation.
Discussion
We found that androgen-deprivation therapy is associated withan increase in the risk of fracture among older men with prostatecancer. The risk increases with the number of doses of a gonadotropin-releasinghormone agonist administered during the first year after diagnosis.This study provides an estimate of the risk of fracture thatis attributable to androgen-deprivation therapy by includingpatients who were not treated with androgen deprivation andadjusting for confounding variables.
The hazard ratios we found were moderate but could neverthelessbe clinically important, given the substantial underlying rateof fracture in our study population, which consisted of elderlymen. Given an annual incidence of prostate cancer of more than220,000, given that more than 40 percent of patients receivegonadotropin-releasing hormone agonists as an initial treatment,5,6and given a number needed to harm of 28, approximately 3000excess fractures per year would be attributable to the use oftreatment with gonadotropin-releasing hormone agonists.
Several confounding factors may account for the apparent riskof fracture related to androgen deprivation. Older age and moreadvanced stages of cancer are associated with both androgen-deprivationtreatment4 and fracture.29 In addition, patients who are aboutto undergo androgen-deprivation therapy tend already to havelower bone-mineral density.12,30 However, the association betweenandrogen deprivation and fracture remained after extensive adjustmentfor known confounders and preexisting bone disease, and ourresults have biologic plausibility. Both orchiectomy and gonadotropin-releasinghormone agonists accelerate bone loss,29,31 and low bone-mineraldensity is strongly associated with an increased risk of fracture.32Moreover, there was a significant dose–response relationbetween the number of doses of gonadotropin-releasing hormoneagonists administered and the risk of fracture.
A limitation of the study was that we did not exclude from theanalysis fractures that were related to bone metastases. However,only 7 to 16 percent of the fractures in prostate cancer aresecondary to bone metastases.14,15 In addition, the risk offracture associated with androgen-deprivation therapy was notreduced when the analysis was restricted to patients with early-stagecancer, who would be less likely to have bone metastases. Anotherlimitation was that we restricted our analysis to the risk offracture associated with the number of doses of a gonadotropin-releasinghormone agonist given in the first year after diagnosis. Longerperiods of exposure to gonadotropin-releasing hormone agonistsmay be associated with a higher risk of fracture.33
One important implication of this study concerns the assessmentof the risks and benefits of androgen-deprivation therapy. Therewas a dramatic increase in the use of such therapy during the1990s4,5,6 (Table 1). The reasons for this increase may includedemonstrated efficacy in patients with locally advanced cancer,the financial incentives to providers, and the urge, on thepart of physicians and patients, to do something in the faceof a rising PSA level. Our findings, along with those of smallerclinical series,13,14,15 underscore that such treatment is notbenign. The risk of fracture and other toxic effects shouldtherefore figure prominently in discussions between physicianand patient with regard to the decision to initiate androgen-deprivationtherapy, particularly in settings where its efficacy is uncertain.Most of the patients in whom androgen deprivation is used asthe primary therapy have localized prostate cancer,4 and gonadotropin-releasinghormone agonists are commonly prescribed for patients with arising PSA level after radical prostatectomy. Yet there is noevidence from clinical trials of a survival benefit for androgen-deprivationtherapy in either of these settings.1
A second implication is that trials of interventions to lowerthe risk of fracture among patients with prostate cancer areneeded. Parenterally administered bisphosphonates have beenshown to prevent the loss of bone-mineral density after androgen-deprivationtherapy for prostate cancer.34,35 Current recommendations arethat men with prostate cancer who are being treated with androgendeprivation should have their bone-mineral density monitoredand should commence bisphosphonate therapy if osteoporosis developsor a fracture occurs.16 Large prospective trials are requiredto assess the efficacy and the cost-effectiveness of bisphosphonatetreatment to reduce the risk of fracture among men receivingandrogen-deprivation therapy.
In conclusion, our study shows that androgen deprivation inthe form of orchiectomy or treatment with gonadotropin-releasinghormone agonists is associated with an increased risk of fracturein patients with prostate cancer. This finding underscores theneed for caution in the use of these therapies in settings withoutclear evidence of a benefit. Trials of therapies such as bisphosphonatesto lower the risk of fracture are needed in patients for whomgonadotropin-releasing hormone agonists are clearly indicated.
Supported in part by grants (P50CA12385 and R24HS51161) fromthe Public Health Service.
We are indebted to the Applied Research Program, National CancerInstitute; to the Office of Research, Development, and Information,Centers for Medicare and Medicaid Services; to Information ManagementServices; and to the SEER Program for the creation of the SEER–Medicaredatabase. The interpretation and reporting of the data are thesole responsibility of the authors.
Source Information
From the Departments of Internal Medicine (V.B.S., Y.-F.K., J.L.F., J.S.G.) and Preventive Medicine and Community Health (Y.-F.K., J.L.F., J.S.G.), and the Sealy Center on Aging (V.B.S., Y.-F.K., J.L.F., J.S.G.) — all at the University of Texas Medical Branch, Galveston.
Address reprint requests to Dr. Shahinian at the Department of Internal Medicine, University of Texas Medical Branch, John Sealy Annex, Rm. 4.200, 301 University Blvd., Galveston, TX 77555-0562, or at vbshahin{at}utmb.edu.
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