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      Antiepileptic Drug Use, Falls, Fractures, and BMD in Postmenopausal Women: Findings From the Women's Health Initiative (WHI)

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          Abstract

          Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow-up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30–1.61], all site-specific fractures including the hip (HR = 1.51, 95% CI 1.05–2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20–2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11–1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29–1.65) and two or more falls (HR = 1.62, 95% CI 1.50–1.74) but not with baseline BMD or changes in BMD ( p ≥ .064 for all sites). Use of more than one and use of enzyme-inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15–2.09 and HR = 1.36, 95% CI 1.09–1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women. © 2010 American Society for Bone and Mineral Research.

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          Most cited references40

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          Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.

          The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.
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            Measurement characteristics of the Women's Health Initiative food frequency questionnaire.

            The Women's Health Initiative (WHI) is the largest research program ever initiated in the United States with a focus on diet and health. Therefore, it is important to understand and document the measurement characteristics of the key dietary assessment instrument: the WHI food frequency questionnaire (FFQ). Data are from 113 women screened for participation in the WHI in 1995. We assessed bias and precision of the FFQ by comparing the intake of 30 nutrients estimated from the FFQ with means from four 24-hour dietary recalls and a 4-day food record. For most nutrients, means estimated by the FFQ were within 10% of the records or recalls. Precision, defined as the correlation between the FFQ and the records and recalls, was similar to other FFQs. Energy adjusted correlation coefficients ranged from 0.2 (vitamin B12) to 0.7 (magnesium) with a mean of 0.5. The correlation for percentage energy from fat (a key measure in WHI) was 0.6. Vitamin supplement use was common. For example, almost half of total vitamin E intake was obtained from supplements. Including supplemental vitamins and minerals increased micronutrient correlation coefficients, which ranged from 0.2 (thiamin) to 0.8 (vitamin E) with a mean of 0.6. The WHI FFQ produced nutrient estimate, that were similar to those obtained from short-term dietary recall and recording methods. Comparison of WHI FFQ nutrient intake measures to independent and unbiased measures, such as doubly labeled water estimates of energy expenditure, are needed to help address the validity of the FFQ in this population.
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              Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone.

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                Author and article information

                Journal
                J Bone Miner Res
                jbmr
                Journal of Bone and Mineral Research
                Wiley Subscription Services, Inc., A Wiley Company
                0884-0431
                1523-4681
                April 2010
                17 October 2009
                : 25
                : 4
                : 873-881
                Affiliations
                [1 ]simpleDepartment of Veterans Affairs Medical Center Memphis, TN, USA
                [2 ]simpleDepartment of Medicine, University of Tennessee Health Science Center Memphis, TN, USA
                [3 ]simpleDepartment of Preventive Medicine, University of Tennessee Health Science Center Memphis, TN, USA
                [4 ]simpleDepartment of Medicine, University of California Davis, CA, USA
                [5 ]simpleFred Hutchinson Cancer Research Center Seattle, WA, USA
                [6 ]simpleDepartment of Geriatric Medicine, John A Burns School of Medicine, University of Hawaii Honolulu, HI, USA
                [7 ]simpleUniversity of Washington Seattle, WA, USA
                [8 ]simpleUniversity of Cincinnati Cincinnati, OH, USA
                Author notes
                Address correspondence to: Laura D Carbone, MD, MS, University of Tennessee Health Science Center, 956 Court Aveenue, Memphis, TN 38163, USA. E-mail: lcarbone@ 123456uthsc.edu
                Article
                10.1359/jbmr.091027
                3153335
                19839772
                b6ba0b05-3c61-4f2e-b371-bc27296c3859
                Copyright © 2010 American Society for Bone and Mineral Research

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 16 June 2009
                : 14 September 2009
                : 15 October 2009
                Categories
                Original Article

                Human biology
                aging,menopause,population studies
                Human biology
                aging, menopause, population studies

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