Thiazide diuretics and the risk of hip fracture (Review) Aung K, Htay T This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2011, Issue 10 http://www.thecochranelibrary.com Thiazide diuretics and the risk of hip fracture (Review) Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 2 BACKGROUND .................................... 3 OBJECTIVES ..................................... 4 METHODS ...................................... 4 RESULTS....................................... 5 Figure1. ..................................... 6 Figure2. ..................................... 8 Figure3. ..................................... 8 Figure4. ..................................... 10 Figure5. ..................................... 11 ADDITIONALSUMMARYOFFINDINGS . 11 DISCUSSION ..................................... 12 AUTHORS’CONCLUSIONS . 13 ACKNOWLEDGEMENTS . 14 REFERENCES ..................................... 14 CHARACTERISTICSOFSTUDIES . 18 DATAANDANALYSES. 26 Analysis 1.1. Comparison 1 Current thiazide users vs nonusers (cohort studies), Outcome 1 Hip Fracture. 26 Analysis 2.1. Comparison 2 Current thiazide users vs nonusers (case-control studies), Outcome 1 Hip Fracture. 27 ADDITIONALTABLES. 27 APPENDICES ..................................... 31 HISTORY....................................... 35 CONTRIBUTIONSOFAUTHORS . 35 DECLARATIONSOFINTEREST . 36 SOURCESOFSUPPORT . 36 INDEXTERMS .................................... 36 Thiazide diuretics and the risk of hip fracture (Review) i Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Thiazide diuretics and the risk of hip fracture KoKo Aung1, Thwe Htay1 1Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Contact address: KoKo Aung, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, MC 7879, San Antonio, Texas, 78229, USA. [email protected]. Editorial group: Cochrane Hypertension Group. Publication status and date: New, published in Issue 10, 2011. Review content assessed as up-to-date: 30 September 2009. Citation: Aung K, Htay T. Thiazide diuretics and the risk of hip fracture. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD005185. DOI: 10.1002/14651858.CD005185.pub2. Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background Thiazide diuretics are one of the most commonly prescribed antihypertensive agents worldwide. Thiazides reduce urinary calcium excretion. Chronic ingestion of thiazides is associated with higher bone mineral density. It has been suggested that thiazides may prevent hip fracture. However, there are concerns that diuretics, by increasing the risk of fall in elderly, could potentially negate its beneficial effects on hip fracture. Objectives To assess any association between the use of thiazide diuretics and the risk of hip fracture in adults. Search methods We searched eligible studies up to December 2008 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), International Pharmaceutical Abstracts, the Database of Abstracts of Review of Effects (DARE) and reference lists of previous reviews and included studies. Selection criteria All randomized controlled trials and observational studies, which assessed the association between thiazide diuretic use and hip fracture. Data collection and analysis Two review authors independently applied the selection criteria, extracted data and assessed risk of bias of each study selected. The results were summarized descriptively and quantitatively. Cohort studies and case control studies were analysed separately. Main results No randomized control trials were found. Twenty-one observational studies with nearly four hundred thousand participants were included. Six of them were cohort studies and 15 were case-control studies. Two cohort studies appear to involve the same cohort so there were only 5 unique ones. The risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). Five cohort studies had low risk of bias and one had moderate risk of bias. Seven case control studies had low risk of bias and 8 had moderate risk of bias. Meta-analysis of cohort studies showed that thiazide use was associated with a reduction in risk of hip fracture by 24%, pooled RR 0.76 (95% CI 0.64-0.89; p = 0.0009). We chose not to provide a pooled summary statistics for case-control studies because of high heterogeneity (Tau2 = 0.03, I2 = 62%, p = 0.0008). Thiazide diuretics and the risk of hip fracture (Review) 1 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Authors’ conclusions Thiazides appear to reduce the risk of hip fracture based on observational studies. Randomized controlled trials are needed to confirm these findings. PLAIN LANGUAGE SUMMARY Thiazide diuretics and hip fracture Twenty-one studies of observational nature with nearly four hundred thousand participants were included in this systematic review. Studies looked for an association between thiazide diuretic use and hip fracture. The majority of included studies have low to moderate risk of bias. Thiazide diuretic use was associated with a reduction in risk of hip fracture. Randomized controlled trials are needed to confirm these findings. Thiazide diuretics and the risk of hip fracture (Review) 2 Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation] Thiazide users compared with nonusers for the risk of hip fracture Patient or population: adults 40 years or older Intervention: use of thiazide diuretics Comparison: nonusers Outcomes Relative effect Quality of the evidence Comments (95% CI) (GRADE) Hip Fracture RR 0.76 (0.64 to 0.89) ⊕⊕ low GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BACKGROUND mineral content of the forearms measured by single photon absorp- Thiazide diuretics have been a cornerstone of antihypertensive tiometry while a decrease of 2% per year took place in the placebo therapy for longer than half a century. They have been proven in group (Transbol 1982). The active treatment continued for a total large scale randomized controlled trials (MRC 1985, SHEP 1991, of 2 years, followed by placebo in both bendroflumethiazide group Hansson 1999, ALLHAT 2000, ALLHAT 2002) and systematic and placebo group for one more year. At the end of 3 years, no dif- reviews (Psaty 2003, Wright 2009) to reduce cardiovascular mor- ference in bone mineral content was found. A randomised, dou- bidity and mortality, particularly related to stroke, in individuals ble-masked, placebo-controlled trial of chlorthalidone and bone with persistently elevated blood pressure. One of the benefits of loss in hypertensive postmenopausal women showed that after a thiazides outside of the cardiovascular system is their hypocalciuric mean duration of 2.6 years, chlorthalidone use, at doses of 12.5- effect. In 1959, Lamberg and Kuhlbäck found that chlorothiazide 25 mg/day, was associated with bone gain at the calcaneus and and hydrochlorothiazide reduced the excretion of calcium in urine distal radius, and reduction of bone loss at proximal radius, result- (Lamberg 1959). This effect was used to prevent recurrence of cal- ing in an average increment for three appendicular sites of 0.9% cium containing urinary stones (Nassim 1965). In 1973, Middler per year (Wasnich 1995). This study was conducted as a prospec- et al demonstrated in an experimental study that thiazide diuretics tive ancillary study among women participating in SHEP (Systolic reduced urinary calcium excretion by about 40% in individuals Hypertension in Elderly Program), a double-masked placebo con- with intact parathyroid glands (Middler 1973). trolled study employing a thiazide-like diuretic chlorthalidone, at the SHEP Center in Hawaii. Epidemiological studies have associated chronic ingestion of thi- azides with higher bone mineral density in both women and men Whether the physiological effects of lowering urinary calcium ex- (Wasnich 1983, Bauer 1993, Morton 1994, Glynn 1995). A co- cretion and slowing the reduction of bone mineral density lead to hort study (LaCroix 2000) demonstrated that thiazide use pre- reduction in hip fractures, the most clinically important fracture served bone mineral density at the hip and spine in normoten- related to osteoporosis in older adults, is uncertain. While endocri- sive healthy men and women. In a randomized controlled trial of nologists are interested in potential beneficial effects of thiazides healthy