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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of California, Davis; Department of Epidemiology and Biostatistics, University of California, San Francisco; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco; and San Francisco Coordinating Center, Research Institute at California Pacific Medical Center, San Francisco, California.
Address reprint requests to: L. Elaine Waetjen, MD, Assistant Professor, Department of Obstetrics and Gynecology, 4860 Y Street, Suite 2500, Sacramento, CA 95817; e-mail: lewaetjen{at}ucdavis.edu.
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ABSTRACT |
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METHODS: We used measures of urinary incontinence severity, frequency, and type in the Multiple Outcomes of Raloxifene trial, a multicenter randomized, controlled trial of women who were at least 2 years postmenopausal with osteoporosis. At 10 U.S. sites of this trial, 963 women randomly assigned to raloxifene or placebo completed questionnaires about incontinence at baseline and 3 years later. We analyzed the odds of worsening severity and frequency of incontinence and type of incontinence after 3 years of treatment with raloxifene.
RESULTS: The mean age of our subjects was 68.3 ± 7 years. After 3 years of treatment, there was no significant difference between raloxifene and placebo groups in urinary incontinence severity (multivariable odds ratio [OR] 1.02; 95% [CI] 0.78, 1.34). The majority of the women (60%) had no change in urinary incontinence episodes from baseline to year 3. The odds of worsening urinary incontinence severity after 3 years of raloxifene treatment were 1.05 (95% CI 0.75, 1.48). Similarly, the odds of developing new onset incontinence were 0.95 (95% CI 0.59, 1.52). Finally, raloxifene did not effect the odds of having stress (OR 1.01; 95% CI 0.71, 1.43) or urge (OR 1.20; 95% CI 0.86, 1.68) incontinence after 3 years of use.
CONCLUSION: In postmenopausal women with osteoporosis, 3 years of treatment with raloxifene had no effect on urinary incontinence.
LEVEL OF EVIDENCE: I
Common treatments for osteoporosis include selective estrogen receptor modulators. These bind preferentially to 
and ß estrogen receptors in various tissues such as bone. Each selective estrogen receptor modulator has receptor-ligand conformations that are functionally unique, translating into a spectrum of estrogenic and antiestrogenic activity depending on receptor type and coregulators present.7 Both and ß estrogen receptors have been identified throughout the urogenital tract,8,9 but how SERMS interact with these receptors and translate into urogenital function is not clear.
Raloxifene hydrochloride is a second-generation selective estrogen receptor modulator that is approved for the prevention and treatment of osteoporosis in post-menopausal women. It has estrogenic effects on bone and lipid metabolism,10,11 antiestrogenic effects on breast tissue,12 and neutral effects on the endometrium and vaginal mucosa.13–15 The understanding of the effect of raloxifene on urinary incontinence is limited.
Given the widespread use of raloxifene in a population of women with a high prevalence of incontinence, knowing whether this selective estrogen receptor modulator may worsen or improve incontinence is important. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a multicenter, randomized, controlled trial among postmenopausal women with osteoporosis that evaluated the effect of daily raloxifene on the prevention and treatment of osteoporosis. We measured the effect of raloxifene on incontinence after 3 years of treatment in 963 women from this trial.
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MATERIALS AND METHODS |
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Our ancillary study of urinary incontinence included English-speaking participants from 10 sites in the United States. At baseline, participants completed a questionnaire on age; ethnicity; level of education; parity; alcohol, smoking and medication use; and medical conditions, such as heart disease, diabetes, and stroke. Physical examination at baseline included body mass index measurements.
At baseline and year 3, participants completed the same questionnaire assessing incontinence within the last year by type, frequency, and amount of urine loss. Our questionnaire also collected information about previous treatments for incontinence, usage of incontinence pads, and how the participants felt incontinence affected their daily lives. Frequency of incontinence was recorded as daily, weekly, monthly, or less than once a month. The usual amount of urine leakage was reported as drops, about a tablespoon, or a large amount. We calculated severity of incontinence using the validated Sandvik 4-level index by multiplying the reported frequency and amount of leakage.16 Severity was categorized as mild, moderate, severe, and very severe. Changes in severity of incontinence were classified as "worsened" if the severity score was higher 3 years after baseline, "no change" when there was no change from baseline, and "improved" if the severity score decreased. Type of incontinence was categorized as stress incontinence if participants reported leakage "when I cough, sneeze, lift, stand-up, exercise" or as urge incontinence if participants reported leakage "when I have the urge to urinate and cannot get to the toilet fast enough." Affirmative responses to both circumstances of leakage were categorized as mixed incontinence. Incontinence that did not fit these 3 types was categorized as "other." The effect of incontinence on daily activities was asked on a 0-to-10–point scale. We categorized 0 as none, 1 to 5 as sometimes, and 6 to 10 as most of the time. The effect of incontinence on the way the participant felt was also recorded on a 0-to-10–point scale with 0 as not at all, 1 to 5 as somewhat disturbing, and 6 to 10 as extremely disturbing. Incontinence surgeries that occurred between baseline and year 3 were identified through adverse events.
Because the 60-mg/d and 120-mg/d doses of raloxifene had similar results with regard to incontinence in both our preliminary and final models, we pooled these 2 groups into 1 treatment group. All results are presented for the pooled treatment group.
Differences in baseline characteristics between the placebo and raloxifene groups were assessed by using t, rank sum, 
2, and Fisher exact tests as appropriate. Incontinence outcomes at year 3, including the impact of incontinence on quality of life among affected women, were compared by using 2 and Fisher exact tests for trend for ordinal variables17 or homogeneity for categorical variables. To better characterize the precision of negative findings and to account for the ordinal nature of our outcome, we also used proportional odds models18 for the effects of treatment on incontinence severity at year 3, adjusting for baseline severity, site, and age. This analysis was repeated among the subgroup of women who reported urinary incontinence at baseline. Similarly, a logistic model was used to examine treatment effects on onset of at-least-weekly incontinence in the complimentary subgroup of women who did not report incontinence at baseline, adjusting for site and age. We also used logistic regression to analyze the effect of treatment assignment on report of at-least-weekly stress and urge incontinence at year 3, adjusting for reported incontinence at baseline, clinical site, and age. For the proportional odds analysis of our ordinal variables, we estimated that we would have 80% power to detect an odds ratio for treatment of 0.6. For our binary analysis we had 80% power to detect an odds ratio of 0.5 in either of the subgroups and 0.6 for the combined groups.
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RESULTS |
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The baseline characteristics of the 963 women in our analysis are presented by treatment assignment in Table 1
. There were no significant differences between treatment groups in any other demographic, reproductive, and medical characteristics. The participants ranged in age from 35 to 80 years, with a mean age of 68.3 ± 7 years. Almost 90% of the women in both groups were parous, about 27% had undergone hysterectomy, and 42% had used hormones in the past.
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). Overall, incontinence was reported by 564 (59%) women at baseline. Among the women with incontinence in both groups, severity was classified as slight in 57%, moderate in about 38%, and severe to very severe in 6%. The frequency of incontinence was similar between groups, with approximately one quarter reporting weekly and 12% reporting daily leakage. Stress, urge, and mixed incontinence were reported with about equal frequency. Finally, the reported impact of incontinence, including treatments tried, pad usage, restrictions on daily activities, and effect on feelings, were similar among treatment groups.
Severity, frequency, and type of incontinence as well as reported impact remained similar in the 2 groups after 3 years of treatment (Table 2). Most women with incontinence reported little impact on their daily activities or on their feelings about themselves. Less than 1% reported curtailing their daily activities most of the time and only about 5% reported that their incontinence had an extreme effect on the way they felt about themselves.
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). Overall, about 60% had no change in incontinence severity, 13% worsened, and 27% improved.
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). The proportions reporting weekly stress (odds ratio 1.01; 95% confidence interval 0.71, 1.43) or urge incontinence (odds ratio 1.20; 95% confidence interval 0.86, 1.68) were also comparable in the 2 treatment groups.
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DISCUSSION |
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and ß estrogen receptors. Additionally, the proportions of these receptors vary throughout the tissues of the urogenital tract.21 These different levels of estrogen agonist or antagonist activity may be responsible for the different effects noted by selective estrogen receptor modulators on urogenital symptoms. For example, clinical development of levormeloxifene was abandoned because of a negative impact on the pelvic floor. It was associated with a 4-fold increased incidence of urinary incontinence (17% versus 4%),22 and new-onset incontinence appeared to be dose related, with more incontinence developing in women on the higher doses of levormeloxifene.23 Similarly, incident or worsening of a related condition, pelvic organ prolapse, was twice as common (9% compared with 4% on placebo). In contrast, women taking raloxifene were half as likely to have prolapse surgery compared with women taking placebo.24 Although the increase in genitourinary symptoms in levormeloxifene is hypothesized to be related to a high estrogenic activity, increasing uterine size and weight, raloxifene has been noted to have a neutral effect on the uterus and vaginal mucosa.13–15 Our data span 3 years of treatment with raloxifene, providing information about use of this medication during this time frame. In addition, our response rate was high (about 80%). Although our study was based on the responses of healthy, mostly white, postmenopausal women with osteoporosis, women with these characteristics represent the population most likely to use raloxifene. These women are also most likely to incur the morbidity that might be associated with increased incontinence.
Although our point estimates suggest that raloxifene does not improve or exacerbate incontinence, we could have missed a small (less than 50%) effect. Our incontinent women at baseline who did not complete visit 3 were statistically different from our study population. However it is unlikely that 1 year of additional education, slightly more diuretic use, and a slightly higher likelihood of alcohol use would impact our reported results.
In summary, the results of this study suggest that women who use raloxifene for 3 years do not increase their risk for the development or worsening of urinary incontinence. As new selective estrogen receptor modulators are developed, their impact on urinary incontinence should be assessed in large randomized trials.
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Footnotes |
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doi: 10.1097/01.AOG.0000109429.67671.d1
Received June 25, 2003. Received in revised form October 2, 2003. Accepted October 9, 2003.
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REFERENCES |
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2. Brown JS, Grady D, Ouslander JG, Herzog AR, Varner RE, Posner SF. Prevalence of urinary incontinence and associated risk factors in postmenopausal women: Heart & Estrogen/Progestin Replacement Study (HERS) Research Group. Obstet Gynecol 1999;94:66–70.
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