Association of Polymorphisms of the Estrogen Receptor α Gene With Bone Mineral Density and Fracture Risk in Women: A Meta-Analysis

Authors

  • John P. A. Ioannidis M.D.,

    Corresponding author
    1. Clinical and Molecular Epidemiology Unit and Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
    2. Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece
    • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece
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  • Ioanna Stavrou,

    1. Clinical and Molecular Epidemiology Unit and Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
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  • Thomas A. Trikalinos,

    1. Clinical and Molecular Epidemiology Unit and Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
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  • Christos Zois,

    1. Clinical and Molecular Epidemiology Unit and Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
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  • Maria Luisa Brandi,

    1. Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Florence, Florence, Italy
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  • Luigi Gennari,

    1. Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Florence, Florence, Italy
    2. Metabolic Diseases Unit, Department of Internal Medicine, University of Siena, Siena, Italy
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  • Omar Albagha,

    1. Bone Research Group, University of Aberdeen Medical School, Foresterhill, Aberdeen, Scotland, United Kingdom
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  • Stuart H. Ralston,

    1. Bone Research Group, University of Aberdeen Medical School, Foresterhill, Aberdeen, Scotland, United Kingdom
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  • Agathocles Tsatsoulis

    1. Division of Endocrinology, Department of Medicine, University of Ioannina School of Medicine, Ioannina, Greece
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  • The authors have no conflict of interest.

  • The following investigators contributed additional data and clarifications and reviewed the final draft: H. Mizumuna (Department of Obstetrics and Gynecology, Gumma University School of Medicine, Gumma, Japan), Z. Efstathiadou (Division of Endocrinology, Department of Internal Medicine, University of Ioannina School of Medicine, Greece), H.-W. Deng (Osteoporosis Research Center, Creighton University, Omaha, NE, USA), L. Becherini (Department of Internal Medicine, University of Florence, Florence, Italy), B. Langdahl (Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark), and K. Han (Department of Internal Medicine, Samsung Cheil Women's Healthcare Center and Hospital, Sungkyunkwan University College of Medicine, Seoul, Korea).

Abstract

The contribution of genetic polymorphisms to bone mineral density (BMD) and fracture risk in women is a controversial topic. We evaluated the effect of the XbaI and PvuII polymorphisms of the estrogen receptor α to BMD and fracture risk in a meta-analysis, including published data and additional information from investigators. Five thousand eight hundred thirty-four women from 30 study groups were analyzed with fixed and random effects models. The PvuII polymorphism was not associated with BMD at any skeletal site examined and 95% CIs exclude effects over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX homozygotes (women carrying two copies of the gene variant without an XbaI restriction site) consistently had higher BMD than other subjects. The magnitude of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95% CI, 0.003–0.025] and 0.015 g/cm2 [95% CI, 0.000–0.030], respectively; no between-study heterogeneity for either). Total body BMD was also significantly higher in XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx, respectively). Available data on fractures suggested a protective effect for XX (odds ratio [OR], 0.66 [95% CI, 0.47–0.93] among 1591 women), but not PP (OR, 0.93 [95% CI, 0.72–1.18] among 2229 women). In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk.

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