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  • Review Article
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Genetic epidemiology of age-related osteoporosis and its clinical applications

Nature Reviews Rheumatology volume 6, pages 507–517 (2010)Cite this article

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Abstract

Osteoporosis is an important and complex disorder that is highly prevalent worldwide. This disease poses a major challenge to modern medicine and its treatment is associated with high costs. Numerous studies have endeavored to decipher the pathogenesis of this disease. The clinical assessment of patients often incorporates information about a family history of osteoporotic fractures. Indeed, the observation of an increased risk of fracture in an individual with a positive parental history of hip fracture provides strong evidence for the heritability of osteoporosis. The onset and progression of osteoporosis are generally controlled by multiple genetic and environmental factors, as well as interactions between them, with rare cases determined by a single gene. In an attempt to identify the genetic markers of complex diseases such as osteoporosis, there has been a move away from traditional linkage mapping studies and candidate gene association studies to higher-density genome-wide association studies. The advent of high-throughput technology enables genotyping of millions of DNA markers in the human genome, and consequently the identification and characterization of causal variants and loci that underlie osteoporosis. This Review presents an overview of the major findings since 2007 and clinical applications of these genome-wide linkage and association studies.

Key Points

  • Osteoporosis is a complex disease and bone mineral density (BMD) and osteoporotic fractures are highly heritable traits

  • Genetic studies using linkage and association approaches have identified a number of osteoporosis susceptibility genes and loci that are associated with low BMD and fracture risk

  • The loci identified by candidate gene association and genome-wide association studies are involved in several well-defined biological pathways related to bone metabolism

  • This genetic information has potential clinical applications in terms of nosology, risk prediction, pharmacogenetics, and the development of biomarkers and therapeutic agents

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References

  1. [No authors listed]. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am. J. Med. 94, 646–650 (1993).

  2. Kaptoge, S. et al. Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures. J. Bone Miner. Res. 23, 1892–1904 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Greenspan, S. L., Beck, T. J., Resnick, N. M., Bhattacharya, R. & Parker, R. A. Effect of hormone replacement, alendronate, or combination therapy on hip structural geometry: a 3-year, double-blind, placebo-controlled clinical trial. J. Bone Miner. Res. 20, 1525–1532 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Uusi-Rasi, K. et al. Effects of teriparatide [rhPTH (1–34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 36, 948–958 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ng, M. Y., Sham, P. C., Paterson, A. D., Chan, V. & Kung, A. W. Effect of environmental factors and gender on the heritability of bone mineral density and bone size. Ann. Hum. Genet. 70, 428–438 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Deng, H. W. et al. Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases. Genet. Epidemiol. 22, 12–25 (2002).

    Article  PubMed  Google Scholar 

  7. Michaelsson, K., Melhus, H., Ferm, H., Ahlbom, A. & Pedersen, N. L. Genetic liability to fractures in the elderly. Arch. Intern. Med. 165, 1825–1830 (2005).

    Article  PubMed  Google Scholar 

  8. Kanis, J. A. et al. A family history of fracture and fracture risk: a meta-analysis. Bone 35, 1029–1037 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Fox, K. M., Cummings, S. R., Powell-Threets, K. & Stone, K. Family history and risk of osteoporotic fracture. Study of Osteoporotic Fractures Research Group. Osteoporos. Int. 8, 557–562 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Cheung, C. L., Huang, Q. Y., Chan, V. & Kung, A. W. Association of low-density lipoprotein receptor-related protein 5 (LRP5) promoter SNP with peak bone mineral density in Chinese women. Hum. Hered. 65, 232–239 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Ioannidis, J. P. et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292, 2105–2114 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Richards, J. B. et al. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann. Intern. Med. 151, 528–537 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Richards, J. B. et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371, 1505–1512 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu, Y. J. et al. Molecular genetic studies of gene identification for osteoporosis: a 2004 update. J. Bone Miner. Res. 21, 1511–1535 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cheung, W. M. et al. A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene. Bone 39, 470–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Little, R. D. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70, 11–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Ioannidis, J. P. et al. Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J. Bone Miner. Res. 22, 173–183 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, Q. Y. et al. Identification of two sex-specific quantitative trait loci in chromosome 11q for hip bone mineral density in Chinese. Hum. Hered. 61, 237–243 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Karasik, D., Cupples, L. A., Hannan, M. T. & Kiel, D. P. Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study. Bone 33, 308–316 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ralston, S. H. et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum. Mol. Genet. 14, 943–951 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Huang, Q. Y., Li, G. H. & Kung, A. W. Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese. Bone 44, 984–988 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, H. et al. High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density. Osteoporos. Int. 20, 341–346 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Cheung, C. L. et al. Confirmation of linkage to chromosome 1q for spine bone mineral density in southern Chinese. Hum. Genet. 120, 354–359 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Cheung, C. L. et al. Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation. Hum. Mol. Genet. 18, 679–687 (2009).

  29. Ioannidis, J. P. et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int. J. Epidemiol. 37, 120–132 (2008).

    Article  PubMed  Google Scholar 

  30. Burgess, T. L. et al. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J. Cell Biol. 145, 527–538 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3602 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Dong, S. S. et al. Association analyses of RANKL/RANK/OPG gene polymorphisms with femoral neck compression strength index variation in Caucasians. Calcif. Tissue Int. 85, 104–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, Y. H., Woo, J. H., Choi, S. J., Ji, J. D. & Song, G. G. Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol. Biol. Rep. 37, 227–234 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Rivadeneira, F. et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41, 1199–1206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, Z. et al. Hormone therapy improves femur geometry among ethnically diverse postmenopausal participants in the Women's Health Initiative hormone intervention trials. J. Bone Miner. Res. 23, 1935–1945 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Johnson, K. A. Editorial: The SERM of my dreams. J. Clin. Endocrinol. Metab. 91, 3754–3756 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Cummings, S. R. et al. Lasofoxifene in postmenopausal women with osteoporosis. N. Engl. J. Med. 362, 686–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Smith, E. P. et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N. Engl. J. Med. 331, 1056–1061 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Smith, E. P. et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J. Clin. Endocrinol. Metab. 93, 3088–3096 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lau, H. H., Ng, M. Y., Ho, A. Y., Luk, K. D. & Kung, A. W. Genetic and environmental determinants of bone mineral density in Chinese women. Bone 36, 700–709 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Greendale, G. A. et al. The association of bone mineral density with estrogen receptor gene polymorphisms. Am. J. Med. 119, S79–S86 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Rivadeneira, F. et al. Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor α (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. J. Bone Miner. Res. 21, 1443–1456 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Ioannidis, J. P. et al. Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J. Bone Miner. Res. 17, 2048–2060 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, C. L. et al. Association of estrogen receptor alpha gene polymorphisms with bone mineral density in Chinese women: a meta-analysis. Osteoporos. Int. 18, 295–305 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, J. T. et al. Polymorphisms in the estrogen receptor genes are associated with hip fractures in Chinese. Bone 43, 910–914 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Lai, B. M., Cheung, C. L., Luk, K. D. & Kung, A. W. Estrogen receptor α CA dinucleotide repeat polymorphism is associated with rate of bone loss in perimenopausal women and bone mineral density and risk of osteoporotic fractures in postmenopausal women. Osteoporos. Int. 19, 571–579 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. van Meurs, J. B. et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299, 1277–1290 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Meurs, J. B. et al. Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J. Bone Miner. Res. 21, 141–150 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Ferrari, S. L. et al. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am. J. Hum. Genet. 74, 866–875 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kiel, D. P. et al. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Bone 40, 587–596 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Balemans, W. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68, 577–589 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kusu, N. et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J. Biol. Chem. 278, 24113–24117 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Winkler, D. G. et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 22, 6267–6276 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. van Bezooijen, R. L. et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J. Bone Miner. Res. 22, 19–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Huang, Q. Y., Li, G. H. & Kung, A. W. The −9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPα and FOXA1 binding is associated with osteoporosis. Bone 45, 289–294 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Sims, A. M. et al. Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J. Bone Miner. Res. 23, 499–506 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Banziger, C. et al. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125, 509–522 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Bost, B., Dillmann, C. & de Vienne, D. Fluxes and metabolic pools as model traits for quantitative genetics. I. The L-shaped distribution of gene effects. Genetics 153, 2001–2012 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Farrall, M. Quantitative genetic variation: a post-modern view. Hum. Mol. Genet. 13 (Spec. No. 1), R1–R7 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Livshits, G. et al. Genetics of bone mineral density: evidence for a major pleiotropic effect from an intercontinental study. J. Bone Miner. Res. 19, 914–923 (2004).

    Article  PubMed  Google Scholar 

  63. Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Siris, E. S. et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch. Intern. Med. 164, 1108–1112 (2004).

    Article  PubMed  Google Scholar 

  65. Lyssenko, V. et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41, 82–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Bouatia-Naji, N. et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 320, 1085–1088 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Yang, Q., Khoury, M. J., Botto, L., Friedman, J. M. & Flanders, W. D. Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes. Am. J. Hum. Genet. 72, 636–649 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang, Q., Khoury, M. J., Friedman, J., Little, J. & Flanders, W. D. How many genes underlie the occurrence of common complex diseases in the population? Int. J. Epidemiol. 34, 1129–1137 (2005).

    Article  PubMed  Google Scholar 

  69. Cauchi, S. et al. Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value. PLoS ONE 3, e2031 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zheng, S. L. et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Humphries, S. E., Cooper, J. A., Talmud, P. J. & Miller, G. J. Candidate gene genotypes, along with conventional risk factor assessment, improve estimation of coronary heart disease risk in healthy UK men. Clin. Chem. 53, 8–16 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Talmud, P. J. et al. Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men. Clin. Chem. 54, 467–474 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Seddon, J. M., George, S., Rosner, B. & Klein, M. L. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum. Hered. 61, 157–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Kanis, J. A., Johnell, O., Oden, A., Johansson, H. & McCloskey, E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos. Int. 19, 385–397 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Klein, T. E. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360, 753–764 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Malloy, P. J. et al. Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 145, 5106–5114 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Liberman, U. A. Vitamin D-resistant diseases. J. Bone Miner. Res. 22 (Suppl. 2), V105–V107 (2007).

    Article  PubMed  Google Scholar 

  79. Koren, R. Vitamin D receptor defects: the story of hereditary resistance to vitamin D. Pediatr. Endocrinol. Rev. 3 (Suppl. 3), 470–475 (2006).

    PubMed  Google Scholar 

  80. Fang, Y. et al. Vitamin D binding protein genotype and osteoporosis. Calcif. Tissue Int. 85, 85–93 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Heilberg, I. P. et al. Estrogen receptor (ER) gene polymorphism may predict the bone mineral density response to raloxifene in postmenopausal women on chronic hemodialysis. Ren. Fail. 27, 155–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Trontelj, J., Marc, J., Zavratnik, A., Bogataj, M. & Mahar, A. Effect of UGT1A1*28 Polymorphism on raloxifene pharmacokinetics and pharmacodynamics. Br. J. Clin. Pharmacol. 67, 437–444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shu, Y. et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther. 83, 273–280 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Bone, H. G. et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J. Clin. Endocrinol. Metab. 93, 2149–2157 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Lewiecki, E. M. et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J. Bone Miner. Res. 22, 1832–1841 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Kostenuik, P. J. et al. OPG and PTH-(1–34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 142, 4295–4304 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Ominsky, M. S., Kostenuik, P. J., Cranmer, P., Smith, S. Y. & Atkinson, J. E. The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys. Osteoporos. Int. 18, 1073–1082 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Browner, W. S., Lui, L. Y. & Cummings, S. R. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J. Clin. Endocrinol. Metab. 86, 631–637 (2001).

    CAS  PubMed  Google Scholar 

  89. Rogers, A. & Eastell, R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J. Clin. Endocrinol. Metab. 90, 6323–6331 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Szulc, P., Hofbauer, L. C., Heufelder, A. E., Roth, S. & Delmas, P. D. Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J. Clin. Endocrinol. Metab. 86, 3162–3165 (2001).

    CAS  PubMed  Google Scholar 

  91. Mezquita-Raya, P. et al. The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos. Int. 16, 1368–1374 (2005).

    Article  PubMed  Google Scholar 

  92. Stern, A., Laughlin, G. A., Bergstrom, J. & Barrett-Connor, E. The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor kappaB legend with bone mineral density in older adults: the Rancho Bernardo study. Eur. J. Endocrinol. 156, 555–562 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kudlacek, S., Schneider, B., Woloszczuk, W., Pietschmann, P. & Willvonseder, R. Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 32, 681–686 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Samelson, E. J. et al. Increased plasma osteoprotegerin concentrations are associated with indices of bone strength of the hip. J. Clin. Endocrinol. Metab. 93, 1789–1795 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dobnig, H., Hofbauer, L. C., Viereck, V., Obermayer-Pietsch, B. & Fahrleitner-Pammer, A. Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients. Osteoporos. Int. 17, 693–703 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Kiel, D. P. et al. Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med. Genet. 8 (Suppl. 1), S14 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ralston, S. H. et al. Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med. 3, e90 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tran, B. N., Nguyen, N. D., Eisman, J. A. & Nguyen, T. V. Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis. BMC Med. Genet. 9, 55 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee, Y. H., Woo, J. H., Choi, S. J., Ji, J. D. & Song, G. G. Association between the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density: a meta-analysis. Rheumatol. Int. 29, 539–544 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Riancho, J. A., Valero, C. & Zarrabeitia, M. T. MTHFR polymorphism and bone mineral density: meta-analysis of published studies. Calcif. Tissue Int. 79, 289–293 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Yerges, L. M. et al. High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. J. Bone Miner. Res. 24, 2039–2049 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mullin, B. H. et al. Identification of a role for the ARHGEF3 gene in postmenopausal osteoporosis. Am. J. Hum. Genet. 82, 1262–1269 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yamada, Y., Ando, F. & Shimokata, H. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men. Int. J. Mol. Med. 19, 791–801 (2007).

    CAS  PubMed  Google Scholar 

  104. Stolk, L. et al. The catechol-O-methyltransferase Met158 low-activity allele and association with nonvertebral fracture risk in elderly men. J. Clin. Endocrinol. Metab. 92, 3206–3212 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Lorentzon, M., Eriksson, A. L., Nilsson, S., Mellstrom, D. & Ohlsson, C. Association between physical activity and BMD in young men is modulated by catechol-O-methyltransferase (COMT) genotype: the GOOD study. J. Bone Miner. Res. 22, 1165–1172 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Hong, X. et al. CYP19A1 polymorphisms are associated with bone mineral density in Chinese men. Hum. Genet. 121, 491–500 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Limer, K. L. et al. Genetic variation in sex hormone genes influences heel ultrasound parameters in middle-aged and elderly men: results from the European Male Aging Study (EMAS). J. Bone Miner. Res. 24, 314–323 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Riancho, J. A. et al. Association of the aromatase gene alleles with BMD: epidemiological and functional evidence. J. Bone Miner. Res. 24, 1709–1718 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Ermakov, S. et al. Association of ALPL and ENPP1 gene polymorphisms with bone strength related skeletal traits in a Chuvashian population. Bone 46, 1244–1250 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Cheung, C. L. et al. Hip geometry variation is associated with bone mineralization pathway gene variants: The Framingham Study. J. Bone Miner. Res. 25, 1564–1571 (2010).

    CAS  PubMed  Google Scholar 

  111. Wilson, S. G. et al. Common sequence variation in FLNB regulates bone structure in women in the general population and FLNB mRNA expression in osteoblasts in vitro. J. Bone Miner. Res. 24, 1989–1997 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Li, G. H., Kung, A. W. & Huang, Q. Y. Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women. Osteoporos. Int. 21, 1009–1020 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Kuipers, A. et al. Association of a high mobility group gene (HMGA2) variant with bone mineral density. Bone 45, 295–300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mullin, B. H. et al. Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis. Bone 45, 387–391 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Grundberg, E. et al. Vitamin D receptor 3′ haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong. J. Bone Miner. Res. 22, 832–840 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Moffett, S. P. et al. Association of the VDR translation start site polymorphism and fracture risk in older women. J. Bone Miner. Res. 22, 730–736 (2007).

    Article  PubMed  Google Scholar 

  117. Yang, T. L. et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am. J. Hum. Genet. 83, 663–674 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Styrkarsdottir, U. et al. New sequence variants associated with bone mineral density. Nat. Genet. 41, 15–17 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Cho, Y. S. et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Xiong, D. H. et al. Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups. Am. J. Hum. Genet. 84, 388–398 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Guo, Y. et al. PTH and IL21R may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study. J. Bone Miner. Res. 25, 1042–1048 (2010).

    CAS  PubMed  Google Scholar 

  122. Zhao, L. J. et al. Genome-wide association study for femoral neck bone geometry. J. Bone Miner. Res. 25, 320–329 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  123. Kung, A. W. et al. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am. J. Hum. Genet. 86, 229–239 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  125. Stephens, M. & Donnelly, P. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Choi, J. Y. et al. Genetic polymorphisms of OPG, RANK, and ESR1, and bone mineral density in Korean postmenopausal women. Calcif. Tissue Int. 77, 152–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Zmuda, J. M. et al. Association analysis of WNT10B with bone mass and structure among individuals of African ancestry. J. Bone Miner. Res. 24, 437–447 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Research Grant Council of the Hong Kong Government, The Osteoporosis Research Fund and Matching Grant of the University of Hong Kong.

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Authors and Affiliations

  1. Department of Medicine, The University of Hong Kong, Room 420, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China

    Ching-Lung Cheung, Su-Mei Xiao & Annie W. C. Kung

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  1. Ching-Lung Cheung
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  2. Su-Mei Xiao
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Contributions

C.-L. Cheung, S.-M. Xiao and A. W. C. Kung researched the data for the article. C.-L. Cheung and A. W. C. Kung provided a substantial contribution to discussion of the content and to writing the article. A. W. C. Kung reviewed and/or edited the manuscript before submission.

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Correspondence to Annie W. C. Kung.

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Supplementary information

Supplementary Table 1

Single nucleotide polymorphisms associated with osteoporosis and osteoporosis-related phenotypes identified in genome-wide association studies. (DOC 194 kb)

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Cheung, CL., Xiao, SM. & Kung, A. Genetic epidemiology of age-related osteoporosis and its clinical applications. Nat Rev Rheumatol 6, 507–517 (2010). https://doi.org/10.1038/nrrheum.2010.106

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