Original Article
Thiazide Diuretic Agents and the Incidence of Hip Fracture
N Engl J Med 1990; 322:286-290February 1, 1990
- Abstract
- Abstract
Thiazide diuretic agents lower the urinary excretion of calcium. Their use has been associated with increased bone density, but their role in preventing hip fracture has not been established. We prospectively studied the effect of thiazide diuretic agents on the incidence of hip fracture among 9518 men and women 65 years of age or older residing in three communities.
At base line, 24 to 30 percent of the subjects were thiazide users. In the subsequent four years, 242 subjects had hip fractures. The incidence rates of hip fracture were lower among thiazide users than nonusers in each community; the MantelHaenszel relative risk of hip fracture, adjusted for community and age, was 0.63 (95 percent confidence interval, 0.46 to 0.86). The protective effect of the use of thiazides was independent of sex, age, impaired mobility, body-mass index, and current and former smoking status; the multivariate adjusted relative risk of hip fracture was 0.68 (95 percent confidence interval, 0.49 to 0.94). Furthermore, the protective effect was specific to thiazide diuretic agents, since there was no association between the use of antihypertensive medications other than thiazides and the risk of hip fracture.
These prospective data suggest that in older men and women the use of thiazide diuretic agents is associated with a reduction of approximately one third in the risk of hip fracture. (N Engl J Med 1990; 322:286–90.)
Media in This Article
Figure 1
Incidence Rates of Hip Fracture in Relation to the Use of Thiazide Diuretic Agents at the Time of Initial Interview.Table 1
Incidence Rates of Hip Fracture among 9518 Elderly Subjects Followed up for Four Years.*Article Activity
- Article
HIP fractures accounted for more than 3 million days of hospital care among Americans 65 years of age or older in 1987.1 The substantial effect of hip fractures on functional status, mobility, loss of independence, and survival in older people makes the search for safe, effective, low-cost strategies to prevent such fractures a national priority.2
Thiazide diuretic agents are known to lower the urinary excretion of calcium3 4 5 6 and improve calcium balance.5 , 7 Their use has also been associated with increased bone density.8 9 10 11 12 However, their role in the prevention of osteoporotic fractures has not been consistently supported by epidemiologic studies.8 9 10 , 13 14 15 16 17 18 Such studies have been limited by their use of cross-sectional or retrospective designs; to our knowledge, no study has yet compared the incidence rates of hip fracture in those who use thiazides and those who do not. Previous studies have also had limited ability to control directly for the effects of major risk factors for hip fracture that are likely to be associated with the use of thiazides, especially relative body weight13 , 15 16 17 18 and impaired mobility.8 9 10 , 13 14 15 16 17 18
A prospective study of people 65 or older in three communities provided the opportunity to investigate the relation between the use of thiazide diuretic agents and the risk of hip fracture during four years of follow-up. In this investigation, the differences between thiazide users and nonusers in body-mass index, impaired mobility, and several other potential risk factors for hip fracture were taken into consideration.
Methods
Study Populations
The data for this report came from the Established Populations for Epidemiologic Studies of the Elderly, a collaborative longitudinal study of older men and women living in the community, initiated and funded by the Epidemiology, Demography, and Biometry Program of the National Institute on Aging. Data collection began in 1981 in East Boston, Massachusetts; New Haven, Connecticut; and Iowa and Washington counties in rural Iowa. The study was approved by human-subjects review boards at the participating institutions (Brigham and Women's Hospital, Yale University, and the University of Iowa, respectively), and informed consent was obtained from the study subjects before enrollment and data collection.
Between 1981 and 1983, trained interviewers conducted household surveys to collect information on demographic characteristics, medical history, the use of prescription and nonprescription drugs, health behaviors, and functional status. For the few subjects who were unable to respond for themselves, surrogate or proxy informants were interviewed. The details of the methods used in the base-line surveys have been reported elsewhere.19 , 20 Full community surveys of those 65 or older were conducted in East Boston and rural Iowa; initial interviews were completed with 3812 subjects in East Boston (84 percent of the eligible respondents) and 3673 subjects in rural Iowa (80 percent of the eligible respondents). The New Haven population was drawn from a stratified random sample defined according to housing status (public or private), with an oversampling of men. Initial interviews were completed with 2812 New Haven subjects (82 percent of the eligible respondents). Four annual follow-up interviews ascertained vital status, the occurrence of hip fracture and other health events, and changes in functional status. Among those initially interviewed, the response rates for the follow-up interviews were above 90 percent in each community.
We subsequently excluded from the study the subjects who had had a previous hip fracture at base line (3.8 percent in East Boston, 4.3 percent in Iowa, and 4.2 percent in New Haven). We also excluded subjects who were not interviewed during the four-year follow-up period (1.2 percent in East Boston, 3.9 percent in Iowa, and 6.0 percent in New Haven). The final sample therefore included 9518 participants (3620 in East Boston, 3372 in Iowa, and 2526 in New Haven).
Use of Thiazide Diuretic Agents and Risk Factors for Hip Fracture
The current use of thiazide diuretic agents was determined at the initial interview by an interviewer who asked about all prescription drugs taken during the preceding two weeks. Drug names were recorded directly from the container labels and coded uniformly. Information on dose was incomplete, and no information on the length of time the subjects had been taking thiazides was collected.
From the available data concerning drug use, the use of antihypertensive agents other than thiazides was also determined. Previous studies have suggested that the use of non-thiazide antihypertensive drugs may increase the risk of hip fracture by predisposing patients to falls associated with postural hypotension13 , 21 and hurried, sometimes nocturnal, ambulation to urinate.16 Subjects were classified as using non-thiazide antihypertensive agents if they were taking beta-adrenergic antagonists, reserpine, calcium-channel blockers, diuretic agents other than thiazides (including furosemide, spironolactone, triamterene, and ethacrynic acid), or other antihypertensive drugs.
The prevalence of estrogen use among women in these cohorts was low (≤2 percent in each community), and estrogen use was therefore not included in the analysis. Information on total intake of calcium (dietary calcium plus supplements) was not obtained.
During the initial interview, information on age, sex, race (in New Haven only), chronic conditions diagnosed by a physician (and those diagnosed by another health care provider, in East Boston), health habits, and functional status also was obtained. Impaired mobility was defined as the inability to walk up and down one flight of stairs without help or the inability to walk half a mile without help. Two habits found in previous studies to be risk factors for hip fracture were also considered: the consumption of alcohol and cigarette smoking.22 Alcohol consumption per day was calculated on the basis of a series of questions about how often and how much beer or ale, wine, or liquor had been consumed during the previous month. With respect to cigarette smoking, subjects were categorized as current smokers, former smokers, or never having smoked. Body-mass index was calculated on the basis of self-reported height and weight as the weight in kilograms divided by the square of the height in meters.
Information on the use of thiazides and other medications and on risk factors for hip fracture was obtained not at every annual follow-up interview, but only at the third. The analyses in this report are based solely on information on thiazide exposure collected at the initial interview.
Incidence of Hip Fracture
Cases of hip fracture were identified at the annual follow-up interviews, on the basis of a report by a respondent or proxy of hospitalization for a physician-diagnosed broken or fractured hip. For subjects who had died we sought proxy informants. Two hundred forty-two cases of hip fracture were identified during the four years of follow-up — 85 in East Boston, 82 in Iowa, and 75 in New Haven. In New Haven, hospital records were reviewed for the 65 subjects who reported a hip fracture and were hospitalized in one of two local hospitals under surveillance as part of this study. In these subjects, 94 percent of the cases of hip fracture were verified by our review of the hospital records. To evaluate how completely we were able to ascertain cases of hip fracture among the subjects who died, death certificates were reviewed in Iowa. No cases of hip fracture identified on death certificates were missed in the annual interviews.
Statistical Analysis
The incidence rates of hip fracture per 1000 person-years were examined according to community, sex, and age. Person-years were calculated by totaling the time between the initial interview and death, the occurrence of a hip fracture, the last interview, or the end of the fourth year of follow-up, whichever came first, for all participants. Thiazide users and nonusers were compared with respect to other potential risk factors for hip fracture, such as sex, age, impaired mobility, body-mass index, cigarette smoking, consumption of alcohol, and history of diabetes mellitus. Risk-factor levels were adjusted for sex and age with the three cohorts combined as a reference population.23
The relation of the use of thiazide to the incidence of hip fracture was assessed in each community separately. The incidence rates of hip fracture were calculated per 1000 person-years for those who used thiazides and those who did not at the time of the initial interview. The relative risk was defined as the rate of hip fracture among thiazide users divided by the rate among nonusers. The relative risks were adjusted for age in each community and for age and community in an overall stratified analysis, and corresponding 95 percent confidence intervals were calculated.24 A MantelHaenszel chi-square test for the uniformity (i.e., homogeneity) of the relative risk across the three communities was performed.25 For this chi-square test, a P value that is not significant (P>0.05) implies the uniformity of the relative risks. Cox proportional-hazards regression models were used to calculate the relative risk for the use of thiazides adjusted for sex, age, and other hip-fracture risk factors.26 The models for the New Haven subjects were also adjusted for race and type of housing. Overall estimates of relative risk were computed from Cox regression models stratified by community.27 All statistical tests were two-sided, and results were considered significant when P<0.05.
Results
The 9518 study subjects were observed for a total of 34,426 person-years during the four years of follow-up. The incidence rates of hip fracture increased with age in each community, and they were higher for women than men, with the exception of the 65-to-74-year-old group in East Boston (Table 1Table 1
Incidence Rates of Hip Fracture among 9518 Elderly Subjects Followed up for Four Years.*). The proportions of subjects who used thiazide diuretic agents at base line were similar in the three communities: 24.1 percent in New Haven, 26.2 percent in East Boston, and 29.9 percent in Iowa. The differences in potential risk factors for hip fracture between users and non-users were similar in the three communities, and the results are therefore presented for the three communities combined (Table 2Table 2
Relation of the Use of Thiazides to Potential Risk Factors for Hip Fracture.*). Among the users of thiazides, 71.6 percent were women, whereas 57.1 percent of the nonusers were women. The average age of the users and nonusers was similar (approximately 74 years). In each community, the users of thiazides were more likely than the nonusers to have impaired mobility; the difference was statistically significant overall and in Iowa (P<0.001). The users were significantly heavier than the nonusers. Current smoking and the consumption of at least 14.8 ml of alcohol per day were less common among users than nonusers, but the differences were small and statistically significant only in New Haven. The prevalence of a history of diabetes mellitus was higher among users than nonusers.The incidence rates of hip fracture for thiazide users and nonusers in each community are shown in Figure 1Figure 1
Incidence Rates of Hip Fracture in Relation to the Use of Thiazide Diuretic Agents at the Time of Initial Interview.. The rates among users ranged from 4.43 to 5.65 per 1000 person-years, whereas the rates among nonusers ranged from 7.14 to 9.36 per 1000 person-years. The relative risk for thiazide use was 0.79 in East Boston, 0.66 in Iowa, and 0.47 in New Haven; only in New Haven was the relative risk statistically significant (95 percent confidence interval, 0.25 to 0.91). The overall relative risk, adjusted for community, was 0.65 (95 percent confidence interval, 0.47 to 0.89). The MantelHaenszel chi-square value for the test of the uniformity of community-specific relative risks was 1.46 (0.70<P<0.80), indicating that the relative risks for thiazide diuretic agents were not statistically different across the three communities.The incidence rates of hip fracture were lower for users than nonusers among subjects 65 to 74 years old and among those 75 or older in each community (Table 3Table 3
Relative Risks Relating Thiazide Use to the Incidence of Hip Fracture.*). Adjusting the relative risks shown in Figure 1 for age did not alter the strength of the association (community- and age-adjusted relative risk, 0.63; 95 percent confidence interval, 0.46 to 0.86). The protective effect of thiazide diuretic agents also persisted after adjustment for sex and other hip-fracture risk factors; when each community was analyzed separately, the strength of the association was attenuated only slightly in multivariate analyses (Table 3). The association was not significant in any single community, since all confidence intervals included 1.0. When the risks were summarized across communities, however, the relative risk from a Cox regression model adjusting for sex, age, and hip-fracture risk factors was 0.68 (95 percent confidence interval, 0.49 to 0.94). The final multivariate models included age, impaired mobility, and body-mass index, each of which was strongly and significantly related to the risk of hip fracture. Sex and current smoking were also included because of their relation to hip fracture in preliminary models that adjusted for age alone. They did not independently increase the risk of hip fracture. Alcohol consumption and a history of diabetes mellitus were not included in the final model because they were unrelated to the risk of hip fracture in preliminary analyses. The protective effect of the use of thiazides was apparent in both sexes when the analyses were repeated for men and women separately (data not shown).The use of antihypertensive drugs other than those containing thiazide diuretic agents was not associated with the risk of hip fracture in any of the three populations (relative risks, 1.4 in East Boston, 1.1 in Iowa, and 0.8 in New Haven; all 95 percent confidence intervals included 1.0). The summary relative risk relating non-thiazide antihypertensive drugs to the risk of hip fracture, adjusted for sex, age, and the same risk factors as before, was 1.1 (95 percent confidence interval, 0.8 to 1.6). The reference group for these analyses comprised subjects not taking any antihypertensive medication.
Discussion
In this prospective study, the use of thiazide diuretic agents at base line was associated with a reduction of approximately one third in the risk of hip fracture during a four-year follow-up period. The protective effect of the use of thiazides was independent of several other risk factors for hip fracture, including female sex, older age, low body-mass index, impaired mobility, and current smoking. Furthermore, the protective effect of thiazide diuretic agents was specific to thiazides, since there was no association between the use of other antihypertensive medications and the risk of hip fracture.
Previous epidemiologic studies of the use of thiazides and the risk of hip fracture yielded conflicting results. An inverse association between osteoporotic fracture and the use of thiazides was found in several cross-sectional or retrospective studies,8 , 9 , 14 , 15 , 18 but in the majority the differences were not statistically significant.8 , 9 , 14 Our findings agree with those of a recent, large population-based case–control study in which the use of thiazide diuretic agents for six years or more was associated with a lower risk of hip fracture (relative risk, 0.5).18 However, this and many other epidemiologic studies did not control for low relative body weight13 , 15 16 17 18 and impaired mobility,8 9 10 , 13 14 15 16 17 18 two major risk factors for hip fracture. We found that both these risk factors were significantly related to the use of thiazides, and both were strong and significant predictors of hip fracture. Neither, however, explained the relation between the use of thiazides and the incidence of hip fracture.
Several studies have examined the use of diuretic agents in general. Some found that diuretic agents increased the risk of hip fractures,16 , 17 whereas others found that they decreased the risk.13 , 15 In this study and that of Ray and coworkers,18 the use of antihypertensive medications, including diuretic agents, other than thiazides did not alter the risk of hip fracture. Thus, the totality of the evidence points to the importance of distinguishing between drugs containing thiazides and other types of diuretic agents.
A limitation of our study was that information on the duration of thiazide use before the initial interview was not obtained. We therefore cannot distinguish between long-term and short-term users. In the case–control study of Ray and coworkers,18 a short duration (less than two years) of thiazide use was not related to a decreased risk of hip fracture (relative risk, 1.2), and two to six years of use had a smaller protective effect (relative risk, 0.8) than six or more years of use (relative risk, 0.5). The long-term use of thiazides (average duration, >7 years) has been demonstrated to preserve bone mass in men.8 In a randomized clinical trial of 54 postmenopausal women, low-dose thiazide treatment preserved bone mineral content only for the first six months of a two-year trial.28 All the women in that trial, however, were short-term thiazide users according to the criteria used in the epidemiologic studies. In addition, the treatment dose was equivalent to approximately 25 percent of the usual dose of hydrochlorothiazide used for antihypertensive therapy.8 In sum, the available evidence is consistent with the interpretation that the protective effect of thiazides in maintaining bone mass and preventing fracture requires long-term exposure. In addition, the protective effects of the use of thiazides may not last long after the discontinuation of thiazide therapy.28
A major strength of our investigation was its prospective design, which allowed us to calculate incidence rates of hip fracture according to thiazide use. In addition, we were able to consider directly several potential confounding factors that have been considered only indirectly or not at all in previous studies. Furthermore, we were able to test in three cohorts of older people the hypothesis that thiazide diuretic agents decrease the risk of hip fracture. The similarity of the results in the three communities attests to the consistency of the association.
The biologic plausibility of a role for thiazide diuretic agents in the prevention of hip fracture is supported by several studies in which the use of thiazides has been related to higher levels of bone density and bone mineral content in both men and women.8 9 10 11 12 Thiazide diuretic agents lower the urinary excretion of calcium3 4 5 6 and improve calcium balance.5 , 7 However, the mechanisms by which they do so are not well understood: for example, the administration of thiazides reduces the intestinal absorption of calcium.6 , 29 Nevertheless, our findings support the need for randomized clinical trials and other careful clinical investigations of the use of thiazides in preserving bone density and preventing osteoporotic fractures.8 , 18 , 22 A primary goal of future clinical trials should be to determine the minimal dose and duration of thiazide therapy necessary to produce sustained effects on bone mineral content and the risk of fracture. Equally important is the need to evaluate potential deleterious effects of the administration of thiazides that may offset its benefits in slowing osteoporosis. Well-documented sequelae of thiazide therapy include potassium deficiency30 , 31; increased serum cholesterol,32 , 33 triglycerides,33 34 35 glucose,36 37 38 and uric acid concentrations34 , 39; and decreased serum high-density lipoprotein concentrations.35 Thiazides may also increase the risk of cardiac arrhythmias, acute myocardial infarction, and death from coronary heart disease, although these effects remain controversial.30 , 40 , 41
Our findings support a protective association between the use of thiazide diuretic agents and the risk of hip fracture in older men and women, independent of other risk factors. If this is indeed a causal association, the use of thiazides may have prevented approximately 9.1 percent (the "prevented fraction")24 of the potential new cases of hip fracture in the three communities overall. Applying this percentage to the 217,000 hospitalizations for hip fracture among persons 65 or older in the United States in 1987,1 the use of thiazides could have prevented an additional 21,600 cases of hip fracture (i.e., 9.1 percent of the hypothetical total number if no exposure to thiazides had occurred). This finding may be useful to clinicians in choosing among the agents available to treat hypertension in their older patients. If the efficacy of thiazide diuretic agents in preventing fractures is verified in future clinical trials and if the benefits are found to outweigh the attendant risks, then the use of thiazides may have a valuable role in the primary prevention of this substantial cause of morbidity and mortality in older people.
Supported by contracts (N01-AG-0–2105, N01-AG-0–2106, N01-AG-0–2107, and N01-AG-4–2110) with the National Institute on Aging.
Presented in part at the 22nd annual meeting of the Society for Epidemiologic Research, Birmingham, Ala., June 14 to 16, 1989.
We are indebted to the co-investigators and staff members of the National Institutes of Health program center and three field centers of the Established Populations for Epidemiologic Studies of the Elderly: Epidemiology, Demography, and Biometry Program, National Institute on Aging, Bethesda, Md. — Samuel P. Korper (Acting Associate Director), Dwight Brock, Paulette Campbell, Joan Cornoni-Huntley, Josephine Cruz, J. David Curb, Don Everett, Mary Farmer, Daniel Foley, Jack Guralnik, Andrea LaCroix, Mary Lafferty, Caroline Phillips, and Lon White; Brigham and Women's Hospital, Boston — James O. Taylor (Principal Investigator), Marilyn Albert, Laurence Branch, Nancy Cook, Denis Evans, Harris Funkenstein, Liesi Hebert, Charles Hennekens, Paul Scherr, Laurel Smith, and Terrie Wetle; University of Iowa, Iowa City —Robert B. Wallace (Principal Investigator), Gregg Drube, Daniel Heckert, Ellen Heywood, James Hulbert, Frank Kohout, Jon Lemke, Michael Mueller, and Margaret Voelker; and Yale University, New Haven, Conn. — Adrian M. Ostfeld (Principal Investigator), Lisa Berkman, Wanda Carr, Peter Charpentier, Stanislav Kasl, Linda Leo-Summers, Joanne McGloin, and Janet Nabors. We are also indebted to Elizabeth Chrischilles at the University of Iowa for special assistance with drug coding, and to the residents of East Boston, Iowa County, Washington County, and New Haven for their sustained participation in the study.
Source Information
From the Epidemiology, Demography, and Biometry Program, National Institute on Aging, Bethesda, Md. (A.Z.L., J.W., L.R.W., J.C.-H.); the Center for Health Studies, Group Health Cooperative of Puget Sound, and the Department of Epidemiology, University of Washington, Seattle (A.Z.L.); the Department of Preventive Medicine and Environmental Health, University of Iowa, Iowa City (R.B.W.); the Department of Medicine. Channing Laboratory, Harvard Medical School, and Brigham and Women's Hospital. Boston (P.A.S.); the Center for the Study of Aging and Human Development. Department of Psychiatry, Duke University Medical Center, Durham, N.C. (L.K.G.); and the Department of Epidemiology and Public Health. Yale University School of Medicine, New Haven, Conn. (A.M.O.). Address reprint requests to Dr. LaCroix at the Center for Health Studies, Group Health Cooperative of Puget Sound, 521 Wall St., Seattle, WA 98121.
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