The case-control study presented here was carried out to investigate whether the ..... The authors would like to thank Mrs Kilgle and her team,. INFRATEST, Munich ... Paganini-Hill A, Ross RK, Gerkins VR, Henderson BE,. Arthur M, Mack TM.
Thiazide diuretics and the risk of hip fracture among 70-79 year old women treated for hypertension STEPHAN K. WEILAND, ANJA RUCKMANN, ULRICH KEIL, MICHAEL LEWIS, HANS-JOACHIM DENNLER, DIETER WELZEL *
Key words: hip fracture, thiazide diuretics, case-control study
H
ip fractures among the elderly are afrequentand serious public health problem resulting in substantial loss of mobility and independence, excess mortality and major health care costs. Thiazide diuretics which are widely used to treat hypertension have been discussed as a potential means to prevent osteoporosis and related fractures.'"6 This group of agents has shown a long-term reduction of urinary calcium excretion7"9and has been associated with increased bone density and a slower rate of bone loss. '^•9~'' Several epidemiological studies have associated the use of thiazide diuretics with a reduction in the risk of hip fracture.3'4'''"'8 For example, Ray et al.3 observed an odds ratio of 0.5 for use of thiazides over 6 years and more in a case-control study using computerized pharmacy files of the Province of Sasketchewan, Canada. LaCroix et al.4 reported a 30% risk reduction among users of any thiazides • S.K. Weitand', A. ROdcmann', U. Keil', M. Lewis', H-J. Dennler4, D. Weizel4
1 Institute of Epidemiology and Social Medidne, University of Munster, Germany 2 Department of Social Medicine and Epidemiology. Ruhr-University Bochum, Germany 3 Potsdam Institute of PharmacoeptdemWogy and Technology Assessment, Potsdam, Germany 4 Sandoz AG, Numberg, Germany Correspondence: Ulrich Keil, MO, PhD, Instftut fur Epidemiologie und Sozlalmedizln, Universttit MOnster, Domagkstr 3, 0-48129 Munster, Germany, tel. +49 251 8355396, fax +49 251 8355300
at baseline in a prospective study of 9,518 men and women 65 years of age or older residing in 3 communities. In contrast, Heidrich et al.16 in a case-control study conducted among subjects enrolled in a health maintenance organization in Washington State observed a significantly increased risk of hip fracture among women who reported using thiazides. A nested case-control study of post-menopausal women in the Framingham cohort observed a risk reduction only among users of 'pure' thiazides.15 No protective effect was found for the use of drugs containing thiazides in combination with other agents, suggesting that the smaller amounts of thiazides contained in these drugs were not sufficient to preserve bone mass. A more recent prospective study of 9,704 ambulatory, non-black women observed a significantly higher bone mass among women who had used thiazide diuretics for more than 10 years." During the follow-up of this cohort the risk of hip fracture was lower among the users of thiazides, but the risk reduction was not statistically significant. Jones et al.6 estimated on the basis of a meta-analysis riiat current use of thiazides is protective against hip fracture with an odds ratio of 0.82 (95% Cl: 0.73-0.91) and suggested that thiazides may be particularly useful in hypertensive subjects. The case-control study presented here was carried out to investigate whether the prescription of thiazide diuretics
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A possible protective effect of thiazide diuretics against the risk of hip fracture was investigated in a case-control study among 70-79 year old women who had been continuously treated with anti-hypertensive drugs for at least 5 years. In 1992, 2 independent national random samples of general practitioners and internists from West Germany identified 311 cases, who had suffered from their first hip fracture in 1991 or 1992 and 414 controls without any fracture of the hip. Besides relevant information about personal characteristics and medical conditions, the physicians provided detailed documentation of all drug prescriptions between 1986 and 1992 using patient records. Odds ratios (adjusted ORs) with 95% confidence intervals (95% Cl) for the association between hip fracture and prescription of thiazides were adjusted for putative confounders such as age, body mass index, smoking habits, alcohol consumption and relevant medical conditions. For prescriptions of any thiazide diuretics for at least 2 consecutive quarters during the period 1986-1990 the adjusted odds ratio was 0.93 (95% Cl: 0.65-1.34). The OR was lower for drugs containing pure thiazides (adjusted OR = 0.74, 95% Cl: 0.33-1.67), but the risk reduction was not statistically significant. For drugs containing thiazides in combination with other agents the adjusted OR was 0.97 (95% Cl: 0.66-1.42). There was no significant association between the duration or cumulative doses of thiazide prescriptions and the risk of hip fracture. In conclusion, these data provide only little evidence, if any, of a protective effect of thiazide diuretics against the risk of hip fracture among 70-79 year old women treated for hypertension.
EUROPEAN JOURNAL OF PUBLIC HEALTH VOL. 7 1997 NO. 3 is associated with a reduction in the risk of hip fracture among 70-79 year old women treated for hypertension for at least 5 years. The design of the study paid special attention to the assessment of the effects of the duration and dose of the prescribed thiazides.
Exposure assessment The physicians used patient records to provide by quarter (3 month periods), on a written form, a detailed documentation of all medications prescribed for at least 2 consecutive quarters between January 1986 and December 1992. For each of die quarters the trade name, die daily dose and die type of administration of each drug was reported. The information was analysed using die MEDAIS database. 19 This database (developed by die GSF Medis-Institute, Munich) contains, for most of die drugs commonly prescribed in West Germany, die name and dose of each agent and allows classification of die contents of die drugs according to pharmacological groups. For the 725 patients in die study, 6,823 drug prescriptions were reported. Of die prescribed drugs 241 could not be classified by die MEDAIS database. These presriptions were classified using die 'Rote Liste' 20 - an annual listing of all legal drugs in West Germany - to assess whether diese drugs contain diiazides. The length of the relevant period of exposure differs between cases and controls, since only the time before die fracture is relevant for die cases. The dates on which die hip fractures of die cases occurred are approximately evenly distributed throughout the period from die beginning of 1991 until die end of 1992, while all controls entered die study in the autumn of 1992. Thus, the documented period of potential exposure, which started for all study subjects in the first quarter of 1986, is on average longer for die controls dian for die cases. Consideration of die entire documentation period for die controls could bias die analysis towards an overestimation of a possible protective effect of diiazides. In turn, if one assumes a shift in die type of anti-hypertensive dierapy widi time - away from diiazides to ACE inhibitors and calcium channel blockers — die analysis could be biased towards an underestimation of a possible protective effect. In order to minimize diese possibilities of bias, it was decided to consider for die analyses bodi for cases and controls only die time period from the beginning of 1986 until die end of 1990. A patient was classified as a user of diiazide diuretics if drugs containing diiazides had been prescribed for at least 2 consecutive quarters during die period 1986-1990. The users of diiazide diuretics were categorized as users of'pure diiazides', if diey had received exclusively prescriptions of drugs containing only thiazides and users of'combination drugs', if diey were prescribed drugs containing
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MATERIALS AND METHODS Study population and data collection The study population was defined as women aged 70-79 years who had been treated with anti-hypertensive drugs continuously between 1986 and the autumn of 1992, when they were identified for the study. An additional criterion was that the patients' physicians could provide a detailed documentation of all prescriptions over this time period. Out of the study population, potential cases were defined as those for whom their doctor reported they had suffered from their first hip fracture, i.e. fracture of the proximal femur, in 1991 or 1992. Potential controls were those for whom their doctor reported they had not suffered from any hip fracture. Subjects with hip fractures due to major trauma, bone tumour or metastasis to the bone were excluded from the study. Potential cases and controls were ambulatory patients identified through national random samples of physicians which were drawn from a universe of 43,000 general practitioners and internists in western Germany. From this universe, 1 random sample of physician practices was drawn for the identification of cases and a second random sample was drawn for the finding of controls. Both samples are representative of the underlying universe of practices, but were chosen independently in order to avoid bias (e.g. towards matching of the drug treatment) which may occur if cases and controls were identified through the same physician. The samples were stratified by states (BundeslSnder), with sampling fractions proportional to the population size of die state. It was calculated that 308 cases and 308 controls would be needed to give the study a power of 90% to detect a risk reduction of 50% in a population with an exposure of 20%. On the basis of findings from a pilot study it was anticipated that it would be necessary to screen 2,063 physicians for the identification of the cases and 790 physicians for the controls. Telephone interviews were conducted with the sampled physicians in order to screen for suitable patients. The physicians were informed that die study was about longterm therapy and chronic illness in elderly women, so that they were unaware of the objectives of the study. During the screening process 205 physicians widi potential cases and 2 75 physicians with potential controls were identified and these were interviewed during die time period September - November 1992. If a physician could report more than 2 cases widi hip fracture in 1991 or 1992,diose 2 whose hip fractures had occurred most recently were included in die study. Out of die potential control subjects, those who had had the last consultations widi die doctor during die day of die interview were included in die study. A maximum of 2 controls was allowed per practice. All physicians were asked to provide relevant 3 information about the personal characteristics and med-
ical conditions of die patients, as well as a detailed documentation of drugs prescribed during die observation period. Eleven of die 333 potential cases had to be excluded from the data analysis because diey were younger dian 70 years or older dian 79 years. In addition, 9 cases who had suffered from hip fracture before 1991 and 2 cases widi incomplete documentation of drug prescriptions were excluded from die study. Seven patients widi ineligible age and 8 patients widi incomplete documentation of prescriptions were excluded from die control group.
Thiazide diuretics and hip fracture
as 'never', 'sometimes' or 'regular'. Lower-extremity mobility was defined by die capability of climbing stairs. Odier medical conditions of interest included coronary heart disease, cerebral insufficiency, cardiac insufficiency, renal insufficiency and rheumatism. The last blood pressure measurement before die fracture (cases) or die end of die documentation period (controls) was recorded. Patients were categorized as having 'uncontrolled hypertension' if die systolic blood pressure was above 160 mmHg and/or die diastolic blood pressure was above 95 mmHg. Statistical analyses
For bivariate comparisons, die y} test for categorical variables and die two-sample t-test for continuous variables were used. Crude odds ratios (OR) widi 95% confidence intervals (95% CI) were calculated to assess the association of categories of diiazide exposure and die risk of hip fracture using die Mantel-Haenszel mediod. Logistic regression analysis was used to adjust die odds ratios for die effect of putative confounders such as age, BMI, smoking habits, alcohol consumption, uncontrolled hypertension, impaired mobility, cardiac insufficiency and cerebral insufficiency. For each model die best set of parameters was determined by a backward stepping procedure. Since die point estimates of die odds ratio concerning the effect of diiazides did not change substantially after die removal of putative confounders, only variables contributing with a p-value of
