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. Effects of thiazide diuretic therapy on bone mass, fractures, and falls. The Study of Osteoporotic Fractures Research Group. Role of drugs in fractures of the femoral neck. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. Prevention of hip fractures by external hip protectors: a randomized controlled trial. Educating nursing home staff on fracture prevention: a cluster randomised trial. An open-label trial comparing alendronate and alphacalcidol in reducing falls and hip fractures in disabled stroke patients. Randomised controlled trial of hip protectors for the prevention of second hip fractures. Prevention of thromboembolism in hip-fracture patients. Comparison of low-dose heparin and low-molecular-weight heparin combined with dihydroergotamine. Zolpidem use and hip fractures in older people.
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. 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 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. To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
                Pragmatic open randomised controlled trial.
                Practice nurse led clinics in primary care.
                3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
                Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
                Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
                69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
                We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry. Several randomized controlled trials have been performed to examine the effectiveness of external hip protectors in reducing the incidence of hip fractures, but the results are controversial.
                To examine the effectiveness of hip protectors in reducing the incidence of hip fractures in an elderly high-risk population.
                Randomized controlled trial of elderly persons aged 70 years or older, who have low bone density, and are at high risk for falls. Participants lived in apartment houses for the elderly, homes for the elderly, and nursing homes in Amsterdam and surrounding areas in the Netherlands. They were enrolled in the study between March 1999 and March 2001; the mean follow-up was 69.6 weeks. Of the 830 persons who were screened, 561 persons were enrolled.
                External hip protector. Both groups received written information on bone health and risk factors for falls.
                Time to first hip fracture. Survival analysis was used to include all participants for the time they participated.
                In the intervention group, 18 hip fractures occurred vs 20 in the control group. Four hip fractures in the intervention group occurred while an individual was wearing a hip protector. At least 4 hip fractures in the intervention group occurred late at night or early in the morning. Both in univariate analysis (log-rank P =.86) and in multivariate analysis (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.55-2.03), no statistically significant difference between the intervention group and control group was found with regard to time to first hip fracture. In addition, the per protocol analysis in compliant participants did not show a statistically significant difference between the groups (HR, 0.77; 95% CI, 0.25-2.38).
                The hip protector studied was not effective in preventing hip fractures. to assess whether specialist osteoporosis nurses delivering training to care home staff can reduce fractures and improve the prescription of treatments to reduce fractures versus usual care.
                pragmatic cluster randomised controlled trial (RCT) with randomisation at the Primary Care Organisation (PCO) level.
                care homes (residential, nursing and EMI) across England and Wales within PCOs.
                all 300 PCOs in England and Wales were invited to take part. Of these, 58 agreed to participate and gained ethical approval in time to start the study: 29 clusters were randomised to the intervention group and 29 to the control.
                specialist osteoporosis nurses undertaking short training sessions with care home staff emphase the importance of fracture and fall prevention and train staff on how to identify those residents at high risk of fracture. Residents' risk of fracture and falls was reported to general practitioners (GPs) of patients along with treatment recommendations.
                primary outcome measures were total fractures over the past 12 months and total hip fractures over past the 12 months. Secondary outcome measures were total home falls, number of residents sustaining a fall, number of residents prescribed bisphosphonates, number of residents prescribed calcium and vitamin D and number of residents wearing hip protectors. All outcomes were measured at the care home level.
                of the 230 care homes randomised data were collected from 209 of these containing 5,637 residents. There were no differences between the groups in the incidence rate ratios (IRRs) for total fractures (IRR = 0.94 [0.71, 1.26] P = 0.70) or total hip fractures (IRR = 0.86 [0.63, 1.18] P = 0.36). No differences were found between groups for home falls or hip protector use. A significant increase in bisphosphonate prescription was seen in the intervention group over the control group (IRR = 1.50 [1.00, 2.24] P = 0.05). Calcium and vitamin D prescription was significantly increased in the intervention group over the control group (IRR = 1.64 [1.23, 2.18] P<0.01).
                the intervention significantly increased the prescription of bisphosphonates and calcium/vitamin D, but was not associated with a significant effect on the rate of falls or fractures. Although vitamin D supplementation has been suggested to reduce the risk of falling in ambulatory or institutionalized elderly persons, no study has examined whether it reduces the frequency of falling in immobilized stroke patients who have immobilization-induced hypercalcemia reflecting increased bone resorption leading to inhibited renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D). Bisphosphonate is known to reduce immobilization-induced hypercalcemia by inhibiting bone resorption of calcium. This study compared the efficacy of 2 drugs in reducing the risk of falling in patients with long-standing stroke. Eighty-two elderly patients with poststroke hemiparesis were followed for 1 year. The patients were randomly assigned to one of 2 groups; 41 patients received alendronate 35 mg once weekly, and 41 patients received alphacalcidiol 1 μg daily. The number of falls per person and incidence of hip fracture in the 2 groups were compared. At baseline, all patients had a low serum 1, 25-[OH]2D level. Alphacalcidol therapy enhanced immobilization-induced hypercalcemia by increasing intestinal calcium absorption, leading to a reduction of serum 1, 25-[OH]2D level, while alendronate therapy enhanced 1, 25-[OH]2D production by decreasing hypercalcemia. Alendronate treatment accounted for a 55% reduction in falls (95% confidence interval [CI]=25-72%; P=.0021). During the 1-year study period, hip fracture occurred in 1 of 41 subjects in the alphacalcidol group and in no subjects in the alendronate group. Bone mineral density was increased by 3.2% in the alendronate group and decreased by 0.1% in the alphacalcidol group (P<.0001). Alendronate therapy increased serum 1, 25-[OH]2D levels by improving immobilization-induced hypercalcemia, which may lead to decreased falling and subsequent hip fractures.
                Copyright Â© 2011 National Stroke Association. Published by Elsevier Inc. All rights reserved. to assess whether the use of Safehip hip protectors would prevent second hip fractures among men and women living in the community.
                pragmatic randomised controlled trial.
                people living in the community.
                men and women aged 70 years and over who had sustained one hip fracture and who were living in the community.
                366 men and women who were either living outside residential care or were about to be discharged back home were randomised to receive three pairs of hip protectors or to act as controls. Approximately 34% of participants allocated to receive hip protectors wore them every day. After a median follow up of 14 months 8 participants had a second hip fracture with 6 in the intervention and 2 in the control group (Odds Ratio for second hip fracture=3.10, 95% confidence interval 0.62-15.58). Hip protectors had no effect on risk of other fractures or on falls.
                this trial does not suggest a benefit of the studied hip protector among people living outside residential accommodation. In a prospective, double-blind, controlled study, we compared the antithrombotic efficacy of low-dose heparin with dihydroergotamine (A), low-molecular-weight heparin with dihydroergotamine (B), and placebo (C). Two hundred and thirteen patients surgically treated for fractures of the hip were randomly divided into three groups. One hundred and sixty-one patients were analyzed. All thrombi were verified by ascending phlebography. Nine patients died within 1 month after operation. A and B proved to be equally safe but failed to provide any protection against deep-vein thrombosis, although B showed a tendency to reduce the incidence. Mortality within 1 month of operation was unaffected by the type of prophylaxis. 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.
Thiazides appear to reduce the risk of hip fracture based on observational studies. Randomized controlled trials are needed to confirm these findings.