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      Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study

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          Abstract

          Summary

          Previous studies evaluated the association between proton pump inhibitor (PPI) use and subsequent fracture risk, but they showed ambiguous results. Therefore, the objective was to evaluate this association in a different study population. Our findings show that there is probably no causal relationship between PPI use and hip fracture risk.

          Introduction

          Previous studies evaluated the association between PPI use and subsequent fracture risk, but they showed ambiguous results. To further test these conflicting results, the objective of this study was to evaluate the association between the use of PPIs and the risk of hip/femur fracture in a different study population.

          Methods

          A case-control study was conducted using data from the Dutch PHARMO record linkage system. The study population included 6,763 cases aged 18 years and older with a first hip/femur fracture during enrolment and 26,341 age-, gender- and region-matched controls.

          Results

          Current users of PPIs had an increased risk of hip/femur fracture yielding an adjusted odds ratio (AOR) of 1.20 (95% CI 1.04–1.40). Fracture risk attenuated with increasing durations of use, resulting in AORs of 1.26 (95% CI 0.94–1.68) in the first 3 months, 1.31 (95% CI 0.97–1.75) between 3 and 12 months, 1.18 (95% CI 0.92–1.52) between 13 and 36 months and 1.09 (95% CI 0.81–1.47) for use longer than 36 months.

          Conclusion

          Our findings show that there is probably no causal relationship between PPI use and hip fracture risk. The observed association may be the result of unmeasured distortions: although current use of PPIs was associated with a 1.2-fold increased risk of hip/femur fracture, the positive association was attenuated with longer durations of continuous use. Our findings do not support that discontinuation of PPIs decreases risk of hip fracture in elderly patients.

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          Most cited references23

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          Dose-response and trend analysis in epidemiology: alternatives to categorical analysis.

          Standard categorical analysis is based on an unrealistic model for dose-response and trends and does not make efficient use of within-category information. This paper describes two classes of simple alternatives that can be implemented with any regression software: fractional polynomial regression and spline regression. These methods are illustrated in a problem of estimating historical trends in human immunodeficiency virus incidence. Fractional polynomial and spline regression are especially valuable when important nonlinearities are anticipated and software for more general nonparametric regression approaches is not available.
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            Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss.

            Recent studies have shown an association between proton-pump inhibitor use (PPI) and hip fracture. The mechanism by which PPI use promotes the development of hip fracture is uncharacterized. Therefore, we sought to determine whether PPI use is associated with osteoporosis or accelerated bone mineral density (BMD) loss. We used the Manitoba Bone Mineral Density Database to determine the relationship between chronic PPI use and osteoporosis on an initial assessment of BMD and on BMD loss between successive assessments of BMD. In the cross-sectional study, cases with osteoporosis at the hip or lumbar vertebrae (T-score or =-1.0). In the longitudinal analysis, the change in BMD among PPI users and nonusers between successive BMD assessments was assessed. Conditional logistic regression and multivariate linear regression were used to obtain estimates of the association between PPI use and osteoporosis and of the annualized change in BMD associated with PPI use. PPI use was not associated with having osteoporosis at either the hip (OR, 0.84; 95% CI, 0.55-1.34) or the lumbar spine (OR, 0.79; 95% CI, 0.59-1.06) for PPI use >1500 doses over the previous 5 years. In the longitudinal study no significant decrease was observed in BMD at either site attributable to PPI use. PPI use does not appear to be associated with either the presence of osteoporosis or accelerated BMD loss. The association between PPI use and hip fracture is probably related to factors independent of osteoporosis. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans.

              Omeprazole is an inhibitor of gastric H+,K(+)-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H(+)-ATPase which is different from the gastric H+,K(+)-ATPase, in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2-blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.
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                Author and article information

                Contributors
                +31-30-2537324 , +31-30-2539166 , f.devries@uu.nl
                Journal
                Osteoporos Int
                Osteoporosis International
                Springer-Verlag (London )
                0937-941X
                1433-2965
                29 June 2010
                29 June 2010
                March 2011
                : 22
                : 3
                : 903-910
                Affiliations
                [1 ]Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, P.O. Box 80082, 3508 TB Utrecht, The Netherlands
                [2 ]MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK
                [3 ]Institute of Musculoskeletal Sciences, University of Oxford, Oxford, UK
                [4 ]Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands
                [5 ]General Practice Research Database, Medicines and Healthcare Products Regulatory Agency, London, UK
                [6 ]Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands
                Article
                1337
                10.1007/s00198-010-1337-8
                3034906
                20585937
                165d8bcb-9e20-46f3-be28-c3bae30d11da
                © The Author(s) 2010
                History
                : 24 April 2010
                : 31 May 2010
                Categories
                Original Article
                Custom metadata
                © International Osteoporosis Foundation and National Osteoporosis Foundation 2011

                Orthopedics
                histamine h2-receptor antagonist,fracture risk,proton pump inhibitor
                Orthopedics
                histamine h2-receptor antagonist, fracture risk, proton pump inhibitor

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