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Thiazide Diuretics And The Risk For Hip Fracture

Mariette W C J Schoofs, M. van der Klift, A. Hofman, C. De laet, R. Herings, T. Stijnen, H. Pols, B. Stricker
Published 2003 · Medicine
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Context Thiazide diuretics reduce urinary calcium excretion and increase bone mineral density, but do they prevent bone fractures? Contribution In this population-based cohort study of 7891 older adults, patients taking thiazides for more than 1 year had a lower risk for hip fracture than those not taking thiazides (hazard ratio, 0.46 [95% CI, 0.21 to 0.96]). Within 4 months of stopping thiazides, the risk for hip fracture returned to its pretreatment value. Implications Thiazide diuretics may reduce hip fractures. Whether they have effects similar or additive to those of other bone protective agents merits study. The Editors Hip fractures are associated with substantial morbidity and mortality. The costs of surgery and rehabilitation are a burden on public health resources, especially because the incidence of hip fracture increases as the population ages (1, 2). Most hip fractures are related to osteoporosis, and treating accelerated bone loss may therefore be an important strategy to prevent hip fractures (3). Thiazide diuretics are widely used as antihypertensive agents. They are inexpensive and effective and have few important adverse effects (4). Thiazides are thought to protect against age-related bone loss by reducing urinary calcium excretion (5). This bone-sparing effect could lead to reduced fracture incidence in patients treated for hypertension. Several epidemiologic studies have examined the effect of thiazides on bone mineral density and fracture incidence. Although bone mineral density was found to be increased in thiazide users, the difference was often small (6-12). Thiazides were found to have a protective effect on hip fracture in most studies (9, 12-17), but occasionally an increased risk was found (18). Most of the studies, however, had limitations. Some studies included detailed drug-dispensing data but limited information on potential confounders and effect modifiers (15, 18, 19). Other studies had small patient samples or used only baseline interview data on thiazide use (9, 12, 16, 20) without accounting for timing of thiazide use (14, 20, 21). Detailed information on thiazide dose and duration of use was often absent or unreliable because no data on day-to-day use were available. Because of these limitations, it is still unclear how long thiazides have to be taken to affect fracture incidence and how long this effect persists after thiazide use is discontinued. We conducted a prospective, population-based cohort study using detailed drug-dispensing information, as well as extensive information on potential risk factors, to examine the association between current and past use of thiazides and the incidence of hip fractures in men and women 55 years of age and older. We also studied the effect of discontinuing thiazide use on fracture risk. Methods Study Sample This study was conducted as part of the Rotterdam Study, a prospective, population-based cohort study on the occurrence and determinants of disease and disability in elderly persons (22). In 1990, all inhabitants of Ommoord, a suburb of Rotterdam in the Netherlands, who were 55 years of age or older and had lived in the district for at least 1 year were invited to participate in the study. Of the 10 275 eligible persons, 7983 (78%) participated. Participants gave informed consent and permission to retrieve information from medical records. At baseline, between 1990 and 1993, trained interviewers administered an extensive questionnaire covering socioeconomic background and medical history, among other topics, during a home interview. During subsequent visits to the study center, additional interviewing, laboratory assessments, and clinical examinations were performed. Information on vital status is obtained at regular time intervals from the municipal authorities in Rotterdam. The Medical Ethics Committee of the Erasmus MC, Rotterdam, the Netherlands, approved the study. For the present study, all participants were followed from 1 June 1991 until they had an incident hip fracture, died, or reached the end of the study at 31 December 1999, whichever came first. Exposure Definition In the research area, there are 7 fully computerized pharmacies that are linked to 1 network. During the study, all participants filled their prescriptions in 1 of these 7 pharmacies. Data on all dispensed drugs since 1 January 1991 are available in computerized format on a day-to-day basis. The data include the date of prescribing, the total amount of drug units per prescription, the prescribed daily number of units, product name, and the Anatomical Therapeutic Chemical (ATC) code (23). The exposure of interest included plain thiazides and thiazides combined with potassium and potassium-sparing agents. Although formally not a thiazide, chlorthalidone was included because it has a similar effect on calcium excretion. In a previous study, these 2 diuretics did not differ (12). Therefore, we did not distinguish between them. When a hip fracture occurred, the date was defined as the index date and the cumulative duration of use of thiazides on that date was calculated for each participant. Current use was defined as use of thiazides at the index date and was expressed as the number of consecutive days of use. Past use was defined as use of thiazides after baseline and before but not on the index date itself. Past use was expressed as the number of days since discontinuing use. To study the effect of duration of thiazide use, exposure at the index date was divided into 7 mutually exclusive categories, defined a priori: never use, current use for 1 to 42 days, current use for 43 to 365 days, current use for more than 365 days, discontinuation of use since 1 to 60 days, discontinuation of use since 61 to 120 days, and discontinuation of use since more than 120 days. We selected the first duration of 42 days because in the first 6 weeks of thiazide use, the decrease in circulating volume can cause dizziness and relative cerebral ischemia. We anticipated that this might be associated with a transiently increased risk for falls that should be distinguished from a potentially protective effect after prolonged use. After 42 days, the circulating volume in most patients is within normal limits (24). The duration of more than 365 days was chosen because trials on incidence of nonvertebral fractures with use of antiosteoporotic agents, such as bisphosphonates, all had at least 1 year of follow-up as well. Finally, the duration of 60 days after discontinuing use was chosen because it was used in an earlier study (15). We expressed the prescribed daily dosage during current use at the index date as a proportion of the defined daily dosage (25). The defined daily dosage of thiazide diuretics is the standard recommended adult daily dosage for treating patients with hypertension in the Netherlands. To avoid potential misclassification of exposure at baseline, we ensured that all participants had potential pharmacy data for at least 5 months before baseline. Outcome Definition The study participants' general practitioners report all fatal and nonfatal events, such as fractures, through a computerized system. These data cover about 80% of the study sample. For participants who were not covered in this system, research physicians performed annual checks on the complete medical records of all general practitioners in the Rotterdam Study. Two research physicians independently coded all fractures that occurred during the study period using the International Classification of Diseases, 10th revision (ICD-10) (26). A medical expert in the field who was unaware of patients' history and medication use (including thiazides) reviewed all coded events for a final classification. Fractures with ICD-10 codes S72.0, S72.1, and S72.2 were included, but pathologic hip fractures (M84.4) and fractures in prosthetic hips (M96.6) were excluded. Cofactors The following baseline patient characteristics, all determined by interview, were individually assessed as potential confounders: age, sex, score on the Mini-Mental State Examination (<26 points) (27), use of a walking aid, any fracture in the past 5 years, history of hysterectomy, thyroid disease, frequency of falling (once per month), current smoking, intake of alcohol (>2 g/d), and dizziness. Participants were interviewed about a previous diagnosis of Parkinson disease or use of antiparkinsonian drugs and were screened for symptoms of Parkinson disease by study physicians at the research center. Diabetes mellitus was defined as the use of glucose-lowering medication or a random or postload serum glucose level of 11.1 mmol/L (200 mg/dL) or greater. Hypertension (systolic blood pressure > 160 mm Hg, diastolic blood pressure > 95 mm Hg, or use of any antihypertensive drug), visual impairment in 1 or both eyes, and body mass index (kg/m2) were measured at the research center. Presence of peripheral arterial disease was measured (as described elsewhere [28]) by using a single measurement of systolic blood pressure taken at both the left and the right posterior tibial artery. The ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the arm was calculated for each leg. Peripheral arterial disease was considered present when the blood pressure at the arm was lower than 0.9 mm Hg on at least 1 side. Lower-limb disability was assessed by using a modified version of the Stanford Health Assessment Questionnaire (29) and by calculating the mean score of answers to questions about rising, walking, bending, and getting in and out of a car (30). A score of 0 indicates no disability, a score between 0 and 1 indicates mild disability, and a score of more than 1 indicates severe disability. Intake of calcium was adjusted for the total caloric intake according to the method of Willett and associates (31). Bone mineral density of the femoral neck was measured by using dual-energy x-ray absorptiometry (DPX-L densitometer, Lunar Corp
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