Thiazide diuretic agents and the incidence of hip fracture. Thiazide diuretics and the risk of hip fracture. Results from the Framingham Study. A prospective study of thiazide use and fractures in women. Thiazide diuretics and the risk for hip fracture. Reduced fracture risk in users of thiazide diuretics. Diuretic drug use and the risk for hip fracture. Long-term use of thiazide diuretics and risk of hip fracture. Psychotropics, thiazide diuretics and hip fractures in the elderly. Current use of thiazide diuretics and prevention of femur fractures.
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 Mantel-Haenszel 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. Thiazide diuretics may preserve bone mass and prevent elderly women's osteopenic fractures, but studies have not distinguished between thiazide preparations or examined former users. We performed a case-control study looking at thiazide use and subsequent hip fracture in postmenopausal female members of the Framingham Study cohort. Cases who had experienced a first hip fracture (n = 176) were compared with age-matched controls (n = 672). Results showed a modest protective effect of any recent thiazide use (not significant). However, recent pure thiazide users experienced significant protection against fracture (adjusted odds ratio, 0.31; 95% confidence interval, 0.11 to 0.88), whereas recent users of combination drugs containing thiazides experienced no protection (adjusted odds ratio, 1.16; 95% confidence interval, 0.44 to 3.05). Combination drugs generally contained only 25 mg of hydrochlorothiazide, suggesting that the small amount of thiazide was insufficient to preserve bone mass. Former thiazide users were not protected against fracture. In sum, recent pure thiazide use in women protects against hip fracture. Thiazide diuretics reduce urinary calcium and may inhibit bone resorption, and hence may help to attenuate age-related bone loss and to lower the risk of osteoporotic fracture. We followed 83728 women, who were 36-61 years of age at baseline in 1982, for 10 years with biennial mailed questionnaires on which they reported incident fractures, use of thiazide diuretics, and other medical behavioral information. From descriptions of fracture sites and circumstances, 251 hip (proximal femur) and 1594 forearm (distal radius) fractures were identified as low or moderate trauma events. After controlling for age, body mass index, menopausal status, postmenopausal hormone use, cigarette smoking and dietary factors, we observed a statistically significant 22% reduction in the risk of forearm fractures among current thiazide users compared with women who reported no thiazide use. Risk appeared to decline with longer duration of use, reaching a 37% reduction in risk among women who had been using thiazides for 8 or more years. For hip fractures, thiazide use was protective among the postmenopausal women (relative risk = 0.69, 95% confidence interval 0.48-0.99). We conclude that the potential benefit of thiazide diuretics for osteoporosis should be considered when prescribing antihypertensive treatment. Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion.
                To examine the association between dose and duration of thiazide diuretic use and the risk for hip fracture and to study the consequences of discontinuing use.
                Prospective population-based cohort study.
                The Rotterdam Study.
                7891 individuals 55 years of age and older.
                Hip fractures were reported by the general practitioners and verified by trained research assistants. Details of all dispensed drugs were available on a day-to-day basis. Exposure to thiazides was divided into 7 mutually exclusive categories: 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.
                281 hip fractures occurred. Relative to nonuse, current use of thiazides for more than 365 days was statistically significantly associated with a lower risk for hip fracture (hazard ratio, 0.46 [95% CI, 0.21 to 0.96]). There was no clear dose dependency. This lower risk disappeared approximately 4 months after thiazide use was discontinued.
                Thiazide diuretics protect against hip fracture, but this protective effect disappears within 4 months after use is discontinued. Thiazide diuretics (TD) reduce renal calcium excretion and may increase bone mineral density. A reduced fracture risk has been reported in some but not all studies. The aim of this study was to assess fracture risk in users of TD. The study design was nationwide population-based pharmacoepidemiological case-control study with fracture in year 2000 as outcome and use of TD during the previous 5 years as the exposure variable. Individual use of TD was derived from the Danish National Pharmacological Database and related to fracture data from the National Hospital Discharge Register. These data were combined with information on use of other drugs, social status, working status, income, educational status, contacts with general practitioners and practicing specialists, and comorbidity. A total of 64,699 patients (age = 40 years) who sustained a fracture during the year 2000 were compared to 194,111 age- and gender-matched controls. After adjustment for potential confounders, current use of TD was associated with a 10% (95% confidence interval [CI], 7% to 12%) reduced risk of any fracture and a 17% (95% CI 11% to 23%) reduced risk of forearm fractures. In former TD users, the risk reduction was slightly less pronounced. Similar results were found in men and women, and in subjects younger or > or = 65 years of age. Dose-effect analysis revealed a decreased risk of any fracture and fractures at the forearm and hip with an increased number of redeemed defined daily dosages (DDDs) of TD. Therefore, use of more than 2000 DDD was associated with a 19% (95% CI 10% to 27%) decreased hip fracture risk. We conclude that use of TD is associated with a significantly reduced fracture risk. To test the hypothesis that use of thiazide diuretics prevents hip fracture and to study the risk for hip fracture associated with furosemide use.
                A case-control study.
                Hospitals owned by a health maintenance organization in Washington.
                Elderly patients (n = 462) hospitalized because of a hip fracture between 1977 and 1983 and an equal number of age- and sex-matched population-based control patients.
                Use of thiazide diuretics and furosemide was ascertained from medical records and computerized pharmacy records. The relative risk for hip fracture associated with diuretic use was calculated and adjusted for the potentially confounding effects of nursing home residence; previous hospitalizations; a history of stroke, alcoholism, or the organic brain syndrome; body weight; leg paralysis; and use of phenobarbital, corticosteroids, or other diuretics. Current and former users of diuretics were analyzed separately.
                The adjusted risk for hip fracture was 1.6 (95% CI, 1.0 to 2.5) for current thiazide users. The adjusted risk for hip fracture for current furosemide use was 3.9 (CI, 1.5 to 10.4).
                According to this study, use of thiazide diuretics did not protect against hip fracture and cannot be recommended for fracture prevention. Current furosemide use was also associated with hip fracture. To assess whether long-term thiazide use is associated with a decreased risk of hip fracture, a nested case-control study was done in the Canadian province of Saskatchewan between 1984 and 1985 among residents who were 65 years of age or older and who were not receiving other drugs thought to affect bone mass. There were 905 hip fractures identified from hospital discharge records and 5137 population controls matched for age, sex, and calendar year. Drug use was ascertained from computerised pharmacy records. Risk of hip fracture decreased significantly with increasing duration of current thiazide use: relative risk (95% confidence interval) of 1.2 (0.9-1.5) for less than 2 years use, 0.8 (0.7-1.0) for use of 2-5 years, and 0.5 (0.3-0.7) for 6 or more years. In contrast, there was no such trend for use of other antihypertensive-diuretic drugs (relative risk 0.9 [0.6-1.3] for use of 6 or more years). This protective effect was not altered by age, sex, nursing home residence, previous hospital admission, or use of other antihypertensive-diuretic drugs or psychotropic drugs. Medical record review for a sample of 235 cases suggested this finding was not due to confounding by body mass, ambulatory status, functional status, or dementia. These results support the hypothesis that thiazides protect against osteoporosis in elderly people. To determine whether psychotropic medications increase, and thiazide diuretics decrease, the risk of hip fractures in elderly Australians.
                Population-based case-control study.
                The population aged 65 years and over living in a defined area in western Sydney, Australia, during 1990-1991. Cases (n = 209) were recruited from hospitals and controls (n = 207) were selected by an area probability sampling method, with additional sampling from nursing homes. Response rates were 96% for cases and 84% for controls.
                Data were collected directly from subjects by questionnaire; a proxy respondent was required for 27% of subjects. In addition to medication use, information was also collected on potential confounders: alcohol consumption, body mass index, cognitive status, dairy product consumption, health status, physical activity, smoking history and type of residence.
                The use of temazepam, a short-acting benzodiazepine, was associated with an increase in the risk of hip fracture--odds ratio, adjusted for age, gender and residence is 3.78; 95% confidence interval (CI), 1.60-8.92. After adjusting for multiple potential confounders by logistic regression, the odds ratio for temazepam use was 3.52. There was a non-significant (P > 0.05) increase in hip fracture risk associated with the use of antidepressants and antipsychotics. Thiazide diuretics were not associated with a risk of hip fracture--the multivariate-adjusted odds ratio was 0.98 (95% CI, 0.49-1.99).
                Temazepam may increase the risk of hip fracture in elderly people. The effect of thiazide diuretics on fracture risk should be assessed in a large randomised trial. A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.
Thiazides appear to reduce the risk of hip fracture based on observational studies. Randomized controlled trials are needed to confirm these findings.