The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis

André G. Uitterlinden, Stuart H. Ralston, Maria Luisa Brandi, Alisoun H. Carey, Daniel Grinberg, Bente L. Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsxch, Jonathan Reeve, David M. Reid, Antonietta Amedei, Amelia Bassiti, Mariona Bustamante, Lise Bjerre Husted, Adolfo Diez-Perez, Harald Dobnig, Alison M. Dunning, Anna Enjuanes, Astrid Fahrleitner-PammerYue Fang, Elzbieta Karczmarewicz, Marcin Kruk, Johannes P.T.M. Van Leeuwen, Carmelo Mavilia, Joyce B.J. Van Meurs, Jon Mangion, Fiona E.A. McGuigan, Huibert A.P. Pols, Wilfried Renner, Fernando Rivadeneira, Natasja M. Van Schoor, Serena Scollen, Rachael E. Sherlock, John P.A. Ioannidis*, Claire Parsons, Stuart Bear, Rosie Farmer, J. Lukaszkiewicz, P. Bilinski, E. Czerwinski, A. Lewinski, E. Marcinowska-Suchowierska, A. Milewicz, M. Spaczynski, M. Jaworski, R. Nuti, S. Grazio, T. Miazgowski, R. Boonen, P. Masaryk, J. J. Stepan, A. Lopes Vaz, J. Cannata, K. Weber, L. I. Benevolenskaya, C. Todd, K. T. Khaw, J. Da Silva, A. Bhalla, G. Poor, J. Bruges Armas, G. Lyritis, T. W. O'Neill, M. Lunt, Juliet Compston, Cyrus Cooper, Emma Duncan, Richard Keen, Alastair McLellan, John Wass, Ebbo Dekema, Huub Van Essen, Saskia Pluijm, Natalie Bravenboer, Albert Hofman, Cornelia M. Van Duijn, Paulus J. De Jong, Monique M. Breteler, Bruno H. Stricker, Jacqueline C. Witteman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

230 Citations (Scopus)


Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design: Prospective multicenter large-scale association study. Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants: 26 242 participants (18 405 women). Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
JournalAnnals of internal medicine
Issue number4
Publication statusPublished - 15 Aug 2006


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