Thiazide diuretic agents and the incidence of hip fracture. Diuretic drug use and the risk for hip fracture. Drugs affecting postural stability and other risk factors in the hip fracture epidemic--case-control study. Reduced fracture risk in users of thiazide diuretics. Zolpidem use and hip fractures in older people. A prospective study of thiazide use and fractures in women. Role of drugs in fractures of the femoral neck. Thiazide diuretics and the risk for hip fracture. Effects of thiazide diuretic therapy on bone mass, fractures, and falls. The Study of Osteoporotic Fractures Research Group. Psychotropics, thiazide diuretics and hip fractures in the elderly. Drugs and femoral neck fracture: a case-control study. Thiazide diuretics and the risk of hip fracture. Results from the Framingham Study. Long-term use of thiazide diuretics and risk of hip fracture. Do drugs affect the risk of hip fracture in elderly women? Risk factors for hip fracture in black women. The Northeast Hip Fracture Study Group. Current use of thiazide diuretics and prevention of femur fractures. Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
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. 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. A parallel rise in hip fracture incidence and the rate of prescription of drugs affecting postural stability have been investigated by a case-control study. Other risk factors were also considered. One hundred and seventy-three cases and 134 hospital emergency surgical controls were interviewed and briefly examined, and drug data were corroborated by letter to general practitioners. The analysis revealed no significant difference between consumption of benzodiazepines in cases and controls, major tranquillizers, diuretics or other anti-hypertensives. However, they differed significantly in their average body weight and incidence of stroke. It is suggested that hip fractures on the whole occur in a particularly frail group of elderly people and that the increased fracture incidence over the last 20 years results from the survival of a more frail or less active group than hitherto. 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. The widespread use of sedative-hypnotics in older populations makes it imperative to identify hazardous regimens that should be avoided and safer regimens that may be used preferentially by older people. Although benzodiazepines have been shown to increase fall and fracture risk, zolpidem, a nonbenzodiazepine hypnotic, has been advocated as a safer alternative.
                Case-control study of hip fracture cases and controls in 1994.
                All subjects were age 65 and older and enrolled in Medicare, and in Medicaid or the Pharmaceutical Assistance to the Aged and Disabled program of New Jersey.
                Cases (n=1,222) were patients who underwent surgical repair of a hip fracture. They were frequency-matched to four controls (n=4,888) based on age and gender.
                Use of sedative-hypnotics and other medications was assessed in the 180 days before the index event. We assessed other covariates, including demographic, clinical, and healthcare utilization variables in the prior 180 days.
                Zolpidem use was associated with a significant increased risk of hip fracture (adjusted odds ratio (AOR) 1.95; 95% confidence interval (CI)=1.09-3.51). Other psychotropic medication classes with significantly increased risks included benzodiazepines (AOR 1.46; 95% CI=1.21-1.76), antipsychotic medications (AOR 1.61; 95% CI=1.29-2.01), and antidepressants (AOR 1.46; 95% CI=1.22-1.75). In subanalyses, preferential use of zolpidem by subjects at greater risk of hip fracture did not appear to explain the apparent risk of hip fracture with zolpidem use.
                Use of zolpidem by older people was associated with nearly twice the risk of hip fracture, even after controlling for possible demographic and clinical confounders. Rather than being a safer alternative, zolpidem may be associated with risks that are as great as those seen with conventional benzodiazepines in older patients. 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. To investigate the role of drugs in the rising incidence of fractures of the femoral neck in the elderly a case-control study inquiring about the use of prescribed drugs was carried out. The drug histories of 102 patients with femoral neck fractures were obtained from general practice records and compared with those of 204 controls matched for age and sex from the same practices. At the time of fracture 41 patients with fractures and 126 controls were receiving at least one prescription (relative risk of fracture of the femoral neck in patients taking drugs = 0.42, p = 0.0006). For all types of prescribed drugs except antibiotics the risk of fracture of the femoral neck was less in patients taking drugs than in those not doing so, and this was true at all times in the year before fracture. Six patients with fractures were receiving thiazide diuretics compared with 37 controls (relative risk 0.28, p = 0.004). These results indicate that, contrary to popular belief, drugs that sedate or that impair postural control are not important factors in fractures of the femoral neck. The results are consistent with the hypothesis that the hypocalciuria induced by thiazides protects against fracture, but the degree of protection is not significantly greater than that associated with other drugs. 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. To determine the relation between the use of thiazide diuretics and bone mass, fractures, and falls in older women.
                Cross-sectional study of thiazide diuretics, bone mass, and prevalent vertebral deformities; cohort analysis of thiazide diuretics and nonspinal fractures and falls.
                Four clinical centers located in Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania.
                A total of 9704 ambulatory, nonblack women who were 65 years or older.
                Information on thiazide use, demographic data, medical history, and anthropometric measurements were obtained by questionnaire, interview, and examination. Appendicular bone mass was measured by single-photon absorptiometry. Incident falls and fractures were ascertained every 4 months.
                Women using thiazide diuretics for more than 10 years had significantly higher bone mass than women who had never used thiazide diuretics (for example, 0.381 g/cm2 compared with 0.355 g/cm2 for the distal radius [P < 0.001]). Current users of thiazide diuretics had an incidence of falls (relative risk, 1.06; 95% CI, 0.90 to 1.25) that was similar to that of those who had never used these drugs. After adjusting for age, body weight, functional status, total calcium intake, duration of estrogen replacement therapy, and self-reported health status, we found that current users of thiazide diuretics who had taken these drugs for more than 10 years had a risk for nonspinal (relative risk, 0.99; CI, 0.81 to 1.20) and osteoporotic (relative risk, 0.98; CI, 0.79 to 1.22) fractures that was similar to that of women who had never used thiazides; however, thiazide users did have a lower risk for fractures of the hip (relative risk, 0.63; CI, 0.34 to 1.16) and wrist (relative risk, 0.66; CI, 0.40 to 1.08), neither of which was significant.
                Thiazide diuretics have no effect on a women's risk for falling or for experiencing nonspinal fractures. The trend toward a lower risk for hip and wrist fractures is consistent with findings in previous cohort studies but may reflect selection factors for the use of thiazide diuretics. A randomized trial is needed to determine the effect ot thiazide diuretics on the incidence of fractures. 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. Two hundred consecutive patients with femoral neck fractures (FNF) and 200 controls matched by age, sex, nursing home residency and number of admissions within the last 2 years, were interviewed about recent drug use. The matching criteria were chosen to achieve case and control groups that were comparable with regard to overall physical disability. Thus a preliminary study had shown FNF to be strongly associated with nursing home residency and to be correlated with the number of recent hospital admissions. FNF was found to be negatively associated with use of coronary drugs (OR = 0.27; 95% CI = 0.11-0.70) and positively associated with drug use in general (OR = 2.00; 95% CI = 1.04-3.05). The OR for the various classes of psychotropic drugs was consistently greater than 1., although this was not statistically significant. An inherent problem in interpreting such findings is that underlying disease may predispose the subject to both FNF and drug use, thus creating a non-causal relationship. 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. 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. The drugs prescribed for 280 women with hip fractures (mean age 83 years) were compared with those prescribed for 145 women controls (mean age 81 years) as recorded in a family practice age-sex register. Thirty-three percent of the fracture patients were taking diuretics compared with 24% of the controls (.10 greater than P greater than .05). Forty-six percent of these diuretics taken by the fracture group (compared with 40% taken by the controls) were either loop or potassium sparing diuretics in combination with another diuretic. Twenty-five percent of the controls (compared with 9% of the fracture patients) were taking nonsteroidal anti-inflammatory drugs (NSAIDs) (P less than .001). The greater use of NSAIDs by control subjects may be due to the small overlap between osteoporosis and osteoarthritis. No significant differences were found for digoxin, anti-hypertensive drugs, and those taking no drugs. Thirty percent of fracture patients were taking sedatives and hypnotics compared with 28% of controls. Within this category, 54% of the fracture patients and 80% controls were receiving drugs (mainly benzodiazepines) with half-lives longer than 24 hours. Thus, this population did not confirm a previously identified association between long-acting sedatives and the risk of fracture. As only 3.5% of fracture patients and 2.1% controls were receiving phenothiazines, a role for these drugs in hip fracture cannot be ruled out. In summary, hip fracture patients were slightly more likely to be taking diuretics and somewhat less likely to be taking NSAIDs than controls but there were no differences with respect to other drugs. Although more than 1 percent of black women 80 years of age or older have hip fractures each year, little is known about risk factors for hip fracture in these women.
                We carried out a case-control study involving 144 black women admitted with a first hip fracture to 1 of 30 hospitals in New York and Philadelphia. The control were 218 black women living in the community who were matched to the case patients according to age and ZIP Code or telephone exchange and 181 hospitalized black women matched according to age and hospital. Information was obtained through personal interviews and was studied by multivariable logistic-regression analysis.
                When the case patients were compared with the control subjects from the community, the women in the lowest quintile for body-mass index had a markedly increased risk of hip fracture as compared with the women in the highest quintile (odds ratio, 13.5; 95 percent confidence interval, 4.2 to 43.3). Postmenopausal estrogen therapy for one year or more was protective for women under 75 years of age (odds ratio, 0.1; 95 percent confidence interval, < 0.1 to 0.5). Factors associated with an increased risk of hip fracture included a history of stroke (odds ratio, 3.1; 95 percent confidence interval, 1.2 to 8.1), use of aids in walking (odds ratio, 5.6; 95 percent confidence interval, 2.7 to 11.5), and consumption of seven or more alcoholic drinks per week (odds ratio, 4.6; 95 percent confidence interval, 1.5 to 14.1). The results were similar when the case patients were compared with the hospitalized control subjects.
                Among black women thinness, previous stroke, use of aids in walking, and alcohol consumption are associated with an increased risk of hip fracture. Postmenopausal estrogen therapy protects against hip fracture in women under 75 years of age. 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. The authors examined the effects of cognitive function, as assessed by the Mini-Mental State Examination, and drug use on the incidence of hip fracture in a community-based Swedish population of 1,608 subjects who were aged > or = 75 years on October 1, 1987, and who had not had a hip fracture. During the 7,123.8 person-year follow-up, 134 first hip fractures were identified. The Cox proportional hazards model was used to estimate the relative risk of developing hip fracture, taking into account several potential confounders. Compared with those without cognitive impairment, subjects with mild impairment (Mini-Mental State Examination scores 18-23) had a relative risk of 2.04 (95% confidence interval (CI) 1.29-3.24), and subjects with moderate-severe impairment (Mini-Mental State Examination score < 18) had a relative risk of 2.09 (95% CI 1.17-3.72). Subjects using opioid analgesics (97% took propoxyphene) had a relative risk of 2.01 (95% CI 1.19-3.40). Taking potassium supplements (99% took potassium chloride) was related to a reduced risk of hip fracture (relative risk = 0.55, 95% CI 0.31-0.98), while diuretics did not have an independent impact. In summary, the results show that cognitive impairment and use of propoxyphene are associated with increased risk of hip fracture. The observed protection of potassium chloride merits further attention. The limitation of the study was that the assessment of drug use was made only at baseline. Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study.
                We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films.
                During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using one's arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age.
                Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.
Thiazides appear to reduce the risk of hip fracture based on observational studies. Randomized controlled trials are needed to confirm these findings.