Physical activity and decreased risk of clinical gallstone disease among post-menopausal women

Preventive Medicine 41 (2005) 772 – 777 www.elsevier.com/locate/ypmed

Physical activity and decreased risk of clinical gallstone disease among post-menopausal women Kristi L. Storti, M.S., M.P.H.a,*, Jennifer S. Brach, Ph.D., P.T., G.C.S.b, Shannon J. FitzGerald, Ph.D.c, Joseph M. Zmuda, Ph.D.a, Jane A. Cauley, Dr.P.H.a, Andrea M. Kriska, Ph.D.a a

Department of Epidemiology, 505 Parran Hall, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261, USA b Department of Physical Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA c Division of Research, Cooper Institute, Dallas, TX 75230, USA Available online 20 July 2005

Abstract Background. Physical activity may play a role in preventing gallstone disease. Methods. The activity/gallstone relationship was examined in post-menopausal women from the Study of Osteoporotic Fractures (SOF; 1986 – 1988), a prospective study of fracture risk factors in 8010 women (mean age = 71.1 years, SD = 4.9). Results. Multivariate logistic regression indicated women in the lowest two quartiles of physical activity, according to questionnaire, had a 59% {OR = 1.59 (1.11 – 2.29), P = 0.02} and a 57% higher risk {OR = 1.57 (1.11 – 2.23), P = 0.01} of developing gallstone disease compared to women in the highest quartile of activity ( P Trend = <0.0001). Additionally, this relationship was examined in a cohort of 182 post-menopausal women (mean age 74.2 years, SD = 4.1) who participated in a randomized controlled trial of a walking intervention. Women in the randomized clinical trial in the lowest tertile of physical activity determined by a physical activity monitor had a higher risk of developing gallstone disease than women in the highest tertile of physical activity, 13% {OR-1.13 (1.01 – 1.28), P = 0.05, P Trend = <0.04}. Conclusion. Physical activity appears to be inversely related to the development of gallstone disease in post-menopausal women independent of body mass index. D 2005 Elsevier Inc. All rights reserved. Keywords: Exercise; Questionnaire; Female; Gallbladder

Introduction Gallstone disease is a striking public health problem affecting approximately 10–20% of the U.S. population (Bowen, 1992; Everhart et al., 1999). The economic burden of gallstone disease is tremendous due to lost working days from illness and therapy, and treatment cost. According to a report by The American Gastroenterological Association (2001), the total direct cost associated with treating gallstone disease in 1998 was 5.8 billion dollars in the United States alone. * Corresponding author. Fax: +1 412 624 7397. E-mail address: [email protected] (K.L. Storti). 0091-7435/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2005.04.002

Risk factors for gallstone disease include advancing age, obesity, parity, race and ethnicity, gender, as well as genetic predisposition (The American Gastroenterological Association, 2001; Kono et al., 1995; Barbara et al., 1987; Rissanen and Fogelholm, 1999; Hoffman, 1993; Maclure et al., 1989). The current risk factor profile identifies women who are older, overweight, and parous or on estrogen replacement therapy as having the greatest risk for gallstone disease (Everhart et al., 1999; Barbara et al., 1987; Rissanen and Fogelholm, 1999; Hoffman, 1993; Maclure et al., 1989). More recently, physical inactivity has been suggested as a risk factor for gallstone disease (Utter and Goss, 1997; Utter et al., 1996; Kato et al., 1992; Leitzmann et al., 1998, 1999). Findings from several early epidemiologic studies on the role of physical activity have been

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inconclusive (Friedman et al., 1966; Sarin et al., 1986; Basso et al., 1992; Jorgensen et al., 1990; GREPCO, 1984, 1988; Williams and Johnston, 1980); however, more recent studies suggest a protective effect (Kono et al., 1995; Kato et al., 1992; Leitzmann et al., 1998, 1999; Jorgensen, 1989; Sahi et al., 1998; Chuang et al., 2001). The exact mechanisms by which physical activity could influence the development of gallstone disease independent of its effect on body weight are unclear. A key factor in the pathogenesis of gallstone disease is hypomotility of the gallbladder, in which incomplete and infrequent emptying of the contents of the gallbladder allows for stasis of bile and crystal formation (Bowen, 1992). Physical activity is thought to reduce hypomotility (Veysey et al., 1999; Utter et al., 2000) and has been linked to lower levels of biliary cholesterol, which helps to prevent cholesterol from precipitating in the bile (Chuang et al., 2001). Furthermore, prolonged physical activity has been shown to elicit a significant increase in catecholamines, prostaglandins, endorphins, and many pancreatic and gastrointestinal hormones (Sullivan et al., 1984). These hormonal increases may, in turn, affect the gallbladder through three mechanisms: (1) a hormonally mediated increase in motility; (2) a neurogenically mediated increase in motility; and (3) a reduction in whole gut transit time which may aid in the proper physiological functioning of the gallbladder (Krotiewski, 1984; Moore, 1990; Oettle, 1991). The relationship between physical activity and gallstone disease was examined as a secondary analysis in a cohort of post-menopausal women who participated in the Study of Osteoporotic Fractures (SOF), a multicenter observational cohort study of 8010 women, aged 65 years and older, who were followed for a period of 7 years. Additionally, this relationship was examined in a small clinical trial of 182 post-menopausal women, the Walking Women Follow-up Study (WWF), in which objective physical activity monitors were utilized.

Methods The institutional review board at each institution approved the study. Informed consent was obtained from all participants prior to their participation in any part of these studies. Study subjects A total of 9704 non-black women 65 years of age and older participated in SOF, a prospective study of risk factors for fractures in older women (Cummings et al., 1990). Participants were recruited from population-based lists (e.g., health maintenance organizations, voter registration, and motor vehicle tapes) in Baltimore, MD; Minneapolis, MN; Portland, OR; and the Monongahela Valley, PA, from 1986 to 1988. Women were excluded if they had a bilateral hip replacement, were unable to walk without assistance of

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another person, or were institutionalized. Approximately 14% of the women enrolled in SOF at baseline were on hormone therapy. In order to be included in the analyses, women had to have complete gallstone disease information as well as complete physical activity data assessed at baseline. Complete gallstone disease information was comprised of information regarding gallstone disease status on questionnaires from both the visit 2 follow-up (1989 – 1990) and the visit 4 follow-up (1992 – 1994). If gallstone information was missing from either time point the women were excluded. Of the original 9704 women enrolled in SOF, 8104 had provided gallstone disease data at the visit 4 follow-up (1992 – 1994). Of the 8104, 44 had incomplete gallstone disease data at the visit 2 follow-up (1989 –1990) and an additional 50 women had incomplete physical activity data at baseline; therefore, a total of 8010 (83% of the original cohort) women were included in the analyses. Ascertainment of gallstone disease During the second visit (1989 –1990) and fourth visit (1992 – 1994) of the SOF study, participants completed questionnaires regarding health status, including questions regarding gallstone disease. The question ‘‘Have you ever had surgery to remove your gallbladder?’’ was asked at the second visit, and the question ‘‘Has a doctor ever told you that you have gallstones?’’ was asked at the fourth visit. Physical activity assessment and other measures Physical activity was assessed at baseline using a modified version of the Harvard Alumni Questionnaire (Paffenbarger et al., 1978; Pereira et al., 1998). Participants reported the frequency and duration of their participation in 33 different physical activities during the past year. Leisure time physical activities were scored using a modified Paffenbarger scale (Paffenbarger et al., 1978) and a summary estimate of total energy expenditure expressed in kilocalories per week was calculated for the week averaged over the past year. The summary estimate of total energy expenditure was the sum of kilocalories expended in sports and recreational activities, blocks walked, and stairs climbed. Body weight (in light clothes with shoes removed) and height were recorded at visit 4 using a calibrated balance beam scale and a wall-mounted stadiometer. Participants were also asked about their medical history including physician diagnosed medical conditions, alcohol intake, smoking history, and medication usage.

Data analysis Statistical analyses were performed for both population studies using Statistical Analysis Software, version 8.2 (SAS Institute Inc; Cary, North Carolina). Participants who had complete gallstone disease information and complete phys-

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ical activity measures were included in the analyses. T tests, chi-square, and Wilcoxon rank sum statistics were used to compare demographic characteristics between women with and without gallstone disease. Wilcoxon rank sum tests were calculated to determine whether differences existed in the median levels of physical activity between women with and without gallstone disease. The log of BMI was calculated in order to normalize BMI. A series of logistic regression models, unadjusted and multivariate, were utilized to evaluate the association of physical activity and gallstone disease. For regression analysis, participants who had reported having gallstone disease at or prior to the second visit (1989 – 1990) were excluded. In models 2 and 3, the following variables were controlled for: age, the log of body mass index (BMI), education, hormone use (ever vs. never), diabetes prevalence (yes vs. no), smoking status (ever vs. never), alcohol use (<1 drink/week vs. >1 drink/week), and parity (<2 live births vs. >2 live births). The first series of models included physical activity as a continuous variable from the Paffenbarger questionnaire (i.e., 500 kcal/week increments). The second series of models examined physical activity as a categorical variable (i.e., quartiles). We tested for statistical interactions between physical activity and BMI, as well as between physical activity and the other independent variables contained in the model by adding two-way interaction terms to the full models. The importance of these interactions was determined by examining the individual P values of the interaction coefficients and by assessing the impact of the addition of these terms to the overall fit of the model.

Results Follow-up characteristics at visit 4 (1992 – 1994) of women with and without gallstone disease are presented in Table 1. Body weight, BMI, prevalence of obesity, number of

live births, hormone use, and prevalence of diabetes were significantly higher among the women with gallstone disease compared to those without gallstone disease. Women with gallstone disease were younger at onset of menopause and reported less years of education than women who did not report gallstone disease. Prevalent gallstone disease The association between physical activity at study entry and prevalent gallstone disease at visit 4 follow-up was examined. Women who reported having prevalent gallstone disease were less physically active at study entry compared to those without gallstone disease according to the physical activity questionnaire (928.3 vs. 1249.8 kcal/week; P < 0.0001) (Table 1). Incident gallstone disease We also examined the association between physical activity and incidence of gallstone disease. Between visit 2 (1989 – 1990) and visit 4 (1992 – 1994) follow-up, 353 new cases of gallstone disease were reported. Women with incident gallstone disease reported significantly lower levels of physical activity at the study entry (1036 vs. 1260 kcal/week; P = 0.004) than women who reported not having gallstone disease at follow-up. In multivariate analysis, after controlling for age, log of BMI, education, hormone use, diabetes prevalence, smoking status, alcohol use, and parity, physical activity modeled as a continuous variable was a significant independent predictor of incident gallstone disease (Table 2). In addition, women who were in the lowest two quartiles of physical activity had a 59% (95% confidence interval: 1.11 – 2.29) (quartile 1) and a 57% (95% confidence interval: 1.11– 2.23) (quartile 2) higher risk of developing gallstone disease compared to women who were in the

Table 1 Characteristics of the Study of Osteoporotic Fractures participants by prevalent gallstone disease status (1992 – 1994)* Characteristics

Total sample, N = 8010

Gallstone disease, n = 1281

No gallstone disease, n = 6729

Pa

Age (years) Education (years) Weight (kg) Body mass indexb Obese (body mass index 30 kg/m2), n (%) Age at menopause (years) Parity (number of live births) Alcohol use (drinks per week) Hormone use ever, n (%) Smoking status current, n (%) Diabetes status, n (%) Physical activity by Paffenbarger Questionnaire (median kcal/week)

71.1 (4.9) 12.7 (2.8) 67.4 (12.4) 26.5 (4.7) 1379 (17.2) 47.1 (6.3) 2.7 (1.59) 1.08 (.85) 3380 (42.2) 472 (5.9) 523 (6.5) 1191.2

71.2 (5.0) 12.4 (2.7) 70.9 (13.3) 27.6 (5.0) 283 (22.1) 46.8 (6.5) 2.87 (1.64) 1.04 (.85) 608 (47.4) 64 (5.0) 141 (11.0) 928.3

71.1 (4.9) 12.7 (2.8) 66.8 (12.1) 26.3 (4.7) 1096 (15.9) 47.2 (6.2) 2.67 (1.57) 1.08 (.85) 2772 (33.7) 408 (6.1) 382 (5.7) 1249.8

0.53 0.0002 <0.0001 <0.0001 <0.0001 0.14 <0.0001 0.08 <0.0001 0.15 <0.0001 <0.0001

Values are mean (SD) unless otherwise noted. a Comparison of women with and without gallstone disease. b Weight (kg)/height (m2). * All measures are at visit 4 (1992 – 1994) follow-up except education, age at menopause, parity, alcohol use, and physical activity.

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Table 2 Association between physical activity at study entry (1986 – 1988) and gallstone disease at visit 4 (1992 – 1994) in the Study of Osteoporotic Fractures

Physical activity (500 kcal/week increments), n = 6495/353 cases Quartile 1 (<512 kcal/week), n = 1497/94 cases Quartile 2 (512 – 1189 kcal/week), n = 1638/99 cases Quartile 3 (1190 – 2244 kcal/week), n = 1640/89 cases Quartile 4 (>2244 kcal/week), n = 1720/71 cases

Model 1, unadjusted

Model 2, age and BMI adjusted

Model 3, multivariate adjusteda

Odds ratio (95% CI*)

Odds ratio (95% CI*)

Odds ratio (95% CI*)

0.96 (0.92 – 0.99)

0.95 (0.91 – 0.99)

0.94 (0.90 – 0.98)

1.56 (1.13 – 2.14) 1.49 (1.13 – 2.14) 1.33 (0.97 – 1.83) 1.00, referent

1.58 (1.10 – 2.23) 1.58 (1.12 – 1.78) 1.25 (0.87 – 1.79) 1.00, referent

1.59 (1.11 – 2.29) 1.57 (1.11 – 2.23) 1.25 (0.87 – 1.80) 1.00, referent

P Trend = <0.0001. a The multivariate model included age, body mass index (BMI), education, hormone use (ever vs. never), diabetes prevalence (yes vs. no), smoking status (ever vs. never), alcohol use (<1 drink/week vs. >1 drink/week), parity (<2 live births vs. >2 live births). * CI, confidence interval.

highest quartile of physical activity ( P Trend < 0.0001) (Table 2). The combined two-way interaction terms involving physical activity and the other independent variables did not significantly add to the model, so these interaction terms were not included in the full model. Additionally, part of the protective effect of physical activity on gallstone disease may be mediated through its effect on reducing body mass; therefore, additional models excluding BMI were created. No difference was noted between the models without BMI and those containing BMI. Walking Women Follow-up (WWF) substudy The opportunity to examine the physical activity –gallstone disease relationship was provided by a follow-up study to randomized clinical trial of a walking intervention. The original randomized controlled trial was conducted in a cohort of 229 post-menopausal women between the years of 1982 and 1985 (Sandler et al., 1987; Cauley et al., 1987; Kriska et al., 1986). In 1985, physical activity was assessed utilizing an objective physical activity monitor, the Large Scale Integrated activity monitor (LSI; GMM Electronics; Verona, Pennsylvania) (Black-Sandler et al., 1982; Cauley et al., 1982; LaPorte et al., 1982, 1983), and gallstone disease was assessed through self-report. In 1999, the women from the original clinical trial were invited to attend a comprehensive clinic evaluation. Included in this evaluation were measures of body composition, bone density, heart disease, physical activity levels, and health

status (gallstone disease status). Of the original 229 women, 171 women completed the clinic visit, 17 completed phone interviews, 8 were too sick to participate, 3 refused to participate, 20 were deceased, and 10 were lost to follow-up. For this analysis, 182 post-menopausal women (mean age = 74.2 years, SD = 4.1) with complete physical activity and gallstone disease information were included. Incident gallstone disease Women who reported prevalent gallstone disease prior to the end of the clinical trial (1985) were excluded from the incident analysis. During the 14 years of follow-up (1985 – 1999), 13 new cases of gallstone disease were reported. When examining the LSI monitor data in tertiles, women with incident gallstone disease participated in lower levels of physical activity in 1985 according to the LSI (19.2 vs. 38.6 counts/h, P = 0.008). After controlling for age, BMI, hormone use, diabetes prevalence, smoking status, and alcohol use, physical activity (1985) remained a significant predictor of incident gallstone disease (1999). Women who were in the lowest tertile of physical activity according to the LSI monitor were found to have a higher risk of developing gallstone disease than women who were in the highest tertile of physical activity, 13% (95% confidence interval: 1.01 – 1.28; P Trend = 0.04) (Table 3). The combined twoway interaction terms involving physical activity and the other independent variables did not significantly add to

Table 3 Association between physical activity in 1985 and gallstone disease in 1999 in the Walking Women Follow-up Study

LSI monitor, n = 124/9 cases Tertile 1 (<25.8 counts/h), n = 41/6 cases Tertile 2 (25.8 – 48.6 counts/h), n = 41/3 cases Tertile 3 (>48.6 counts/h), n = 42/0 cases

Model 1, unadjusted

Model 2, age and BMI adjusted

Model 3, multivariate adjusteda

Odds ratio (95% CI*)

Odds ratio (95% CI*)

Odds ratio (95% CI*)

0.57 (0.37 – 0.89) 1.16 (1.04 – 1.29) 1.08 (0.97 – 1.20) 1.00, referent

0.57 (0.36 – 0.91) 1.15 (1.03 – 1.29) 1.08 (0.96 – 1.20) 1.00, referent

0.54 (0.31 – 0.99) 1.13 (1.01 – 1.28) 1.08 (0.96 – 1.22) 1.00, referent

P Trend = 0.04. a The multivariate model included age, body mass index (BMI), hormone use (ever vs. never), diabetes prevalence (yes vs. no), smoking status (ever vs. never), alcohol use (<0.9 oz/day vs. >0.9 oz/day). * CI, confidence interval.

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the model, so these interaction terms were not included in the full model. No difference was noted between the models without BMI and those containing BMI.

R01-AM35584, 1-R01-AG05395, 1-R01-QG05407; (WWF): R01AG//HL14753.

References Discussion Our findings support the hypothesis that physical activity plays a role in the prevention of gallstone disease in older women. Physical activity was inversely related to the development of gallstone disease in post-menopausal women independent of body mass index and other covariates. The results of this study are similar to those previously reported by Kato et al. (1992), Leitzmann et al. (1998, 1999), and Chuang et al. (2001) showing an inverse relationship between physical activity and the risk of developing gallstone disease in cohort of men and women. In men, Kato et al. (1992) reported a relative risk of 0.60 (95% CI, 0.5 –0.8) and Leitzmann et al. (1998) a relative risk of 0.63 (95% CI, 0.51 –0.79) when men in the highest quintile of physical activity were compared to those in the lowest. In women, a relative risk of 0.69 (95% CI, 0.61 –0.78) was found in comparing the highest quintile of physical activity with the lowest quintile (Leitzmann et al., 1999). Interestingly, of the four aforementioned studies two focused solely on men, a group that appears to have a much lower risk of developing gallstone disease according to the proposed risk factor profile. Despite the consistency of our findings in analyses, there are several limitations to our study. Diagnosis of gallstone disease was not confirmed by diagnostic procedure, such as ultrasound; therefore, we may have underestimated the prevalence and incidence of gallstone disease in both populations since many cases of gallstone disease are asymptomatic (GREPCO, 1984). In addition, the study participants were primarily Caucasian volunteers living independently in the community; therefore, our results may not be generalizable to women from other racial/ethnic groups. Yet, the similarity of the participants could also be viewed as a strength since there is less of a need to control for confounding factors such as gender and race, which could ultimately influence the results. Additional investigations of the relationship between physical activity and gallstone disease are needed in more diverse populations. In conclusion, the data from the present analysis suggest an inverse relationship between physical activity and gallstone disease in post-menopausal women. Public health recommendations to increase physical activity may likely reduce the risk of gallstone disease in post-menopausal women.

Acknowledgments This study was funded in part by Public Health Service Grants (SOF): 1-R01-AAAR35582, 1-R01-AR35582, 1-

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