Skip to main content
SpringerLink
Log in

Genetics of Osteoporosis

  • Chapter
Women’s Health and Menopause

Part of the book series: Medical Science Symposia Series ((MSSS,volume 17))

  • 321 Accesses

Abstract

Osteoporosis (OP) is the most prevalent metabolic bone disease among developed countries and it is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to nontraumatic fracture [1]. OP recognizes a complex multifactorial pathogenesis. Although there are several environmental influences on bone mineral density (BMD), such as diet (calcium intake, alcohol consumption) and lifestyle factors (smoking and physical exercise), a genetic contribution to the pathogenesis of OP, accounting from 50% to 80% of the inter-individual variability in bone mass, has been recognized [2]. In rare instances, OP could be inherited in a simple Mendelian manner. Examples of this include familial osteoporotic syndromes due to mutations in the aromatase gene and estrogen receptor alpha (ERα) gene [3,4]. Families have also been described in which high bone mass is inherited as an autosomal dominant trait, consistent with the effect of a single gene located on chromosome 11 [5]. However, except for these rare conditions, OP has to be considered a multifactorial disease in which genetic determinants are modulated by hormonal, environmental, and nutritional factors. Most multifactorial diseases showing a clear genetic component, including OP, are often called “polygenic” diseases, to emphasise their determination by multiple genetic factors. Given the complex biology of the skeleton it is likely that bone mass is under the control of a large number of genes, many of which exert relatively small effects on BMD (minor genes) whereas a few contribute substantially to variation in this trait (major genes).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Consensus Development Conference. Diagnosis, prophylaxis and treatment of osteoporosis. Am J Med 1993;94:646–50.

    Article  Google Scholar 

  2. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC. Genetic factors in determining bone mass. J Clin Invest 1973;52:2800–8.

    Article  PubMed  CAS  Google Scholar 

  3. Smith EP, Boyod J, Frank GR, Talahashi H Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N Engl J Med 1994;331:1056–61.

    Article  PubMed  CAS  Google Scholar 

  4. Morishima A, Grumbach MM, Simpson ER, FisherC, Qin K. Aromatase deficiency in male and female sibilings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689–98.

    Article  PubMed  CAS  Google Scholar 

  5. Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11ql2–13). Am J Hum Genet 1997;60:1326–32.

    Article  PubMed  CAS  Google Scholar 

  6. Luckey MM, Meier DL, Mandeli IP, Da Costa MC, Hubbard ML, Goldsmith SI., Radial and vertebral bone density in white and black women: Evidence for racial differences i, premenopausal bone homeostasis. J Clin Endocrinol Metab 1989;69:762–70.

    Article  PubMed  CAS  Google Scholar 

  7. Daniels LD, Pettifor JM, Schnitzler CM, Russell S W, Patel DN. Ethnic differences in bone density in female South African nurses. J Bone Miner Res 1995;10:359–67.

    Article  PubMed  CAS  Google Scholar 

  8. Schnitzler CM, Pettifor JM, Mesquita JM, Bird MDT, Schnaid E, Smyth AE. Histomorphometry of iliac crest bone in 346 normal black and white South African adults. Bone Miner 1990;10:183–99.

    Article  PubMed  CAS  Google Scholar 

  9. Cundy T, Cornish J, Evans MC, Gamble G, Stapleton J, Reid IR. Sources of interracial variation in bone mineral density. J Bone Miner Res 1995;10:368–73.

    Article  PubMed  CAS  Google Scholar 

  10. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989;320:554–58.

    Article  PubMed  CAS  Google Scholar 

  11. Hansen MA, Hassager C, Jensen SB, Christiansen C. Is heritability a risk factor for postmenopausal osteoporosis? J Bone Miner Res 1992;7(9): 1037–43.

    Article  PubMed  CAS  Google Scholar 

  12. Lonzer MD, Imrie R, Rogers D, Worley D, Licata A, Secic M. Effects of heredity, age, weight, puberty, activity, and calcium intake on bone mineral density in children. Clin Pediatr 1996;35:185–89.

    Article  CAS  Google Scholar 

  13. Evans RA, Marel GM, Lancaster EK, Kos S, Evans M, Wong SY. Bone mass is low in relatives of osteoporotic patients. Ann Intern Med 1988;109:870–73.

    PubMed  CAS  Google Scholar 

  14. Soroko SB, Barrett-Connor E, Edelstein SL, Kritz-Silverstain D. Family history of osteoporosis and bone mineral density at the axial skeleton: The Rancho Bernardo Study. J Bone Miner Res 1994;9:761–69.

    Article  PubMed  CAS  Google Scholar 

  15. Diaz MN, O’Neill TW, Silman AJ. The influence of family history of hip fracture on the risk of vertebral deformity in men and women: The European Vertebral Osteoporosis Study. Bone 1997;20:145–49.

    Article  PubMed  CAS  Google Scholar 

  16. Arden NK, Baker J, Hogg C, Baan K, Spector TD. The heritability of bone mineral density, ultrasound of the calcaneous and hip axis length: A study of postmenopausal twins. J Bone Miner Res 1996; 11:530–34.

    Article  PubMed  CAS  Google Scholar 

  17. Flicker L, Faulkner KG, Hopper JL,et al. Determinants of hip axis length in women aged 10–89 years: A twin study. Bone 1996;8:41–45.

    Article  Google Scholar 

  18. Howard GM, Nguyen TV, Harris M, Kelly PJ, Eisman JA. Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: A twin study. J Bone Miner Res 1998;13:1318–27.

    Article  PubMed  CAS  Google Scholar 

  19. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994;265:2037–48.

    Article  PubMed  CAS  Google Scholar 

  20. Eisman JA. Genetics of osteoporosis. Endocr Rev 1999;20:788–804.

    Article  PubMed  CAS  Google Scholar 

  21. Stewart TL, Ralston SH. Role of genetic factors in the pathogenesis of osteoporosis. J Endocrinol 2000;166:235–45.

    Article  PubMed  CAS  Google Scholar 

  22. Brandi ML, Gennari L, Matucci Cerinic M, et al Genetic markers of osteoarticular disorders: facts and hopes. Arthritis Research 2001;45: in press.

    Google Scholar 

  23. Econs MJ, Speer MC. Genetic studies of complex diseases: Let the reader beware. J Bone Miner Res 1996;11:1835–40.

    PubMed  CAS  Google Scholar 

  24. Morrison NA, Cheng JQI, Akifumi T, et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284–87.

    Article  PubMed  CAS  Google Scholar 

  25. Cooper GS, Umbach DM. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res 1996;11:1841–49.

    Article  PubMed  CAS  Google Scholar 

  26. Gong G, Stern HS, Cheng SC, et al. The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 1999;9:55–64.

    Article  PubMed  CAS  Google Scholar 

  27. Ferrari SL, Rizzoli R, Slosman DO, Bonjour JP. Do dietary calcium and age explain the controversy surrounding the relationship between bone mineral density and vitamin D receptor gene polymorphisms? J Bone Miner Res 1998;13:363–70.

    Article  PubMed  CAS  Google Scholar 

  28. Kiel DP, Myers RH, Cupples LA, et al. The BsmI vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density. J Bone Miner Res 1997;12:1049–57.

    Article  PubMed  CAS  Google Scholar 

  29. Dawson-Hughes B, Harris SS, Finneran S. Calcium absorption on high and low calcium intake in relation to vitamin D receptor genotype. J Clin Endocrinol Metab 1995;80:3657–61.

    Article  PubMed  CAS  Google Scholar 

  30. Gennari L, Becherini L, Masi L, et al. Vitamin D and estrogen receptor allelic variants in postmenopausal women: Evidence of multiple gene contribution on bone mineral density. J Clin Endocrinol Metab 1998;83:939–44.

    Article  PubMed  CAS  Google Scholar 

  31. Haussler MR, Whitfield GK, Haussler CA, et al. The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed. J Bone Miner Res 1998; 13:325–49.

    Article  PubMed  CAS  Google Scholar 

  32. Ingles SA, Haile RW, Henderson BE, et al. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: Implications for association studies. Cancer Epidemiol Biomarkers Prev 1997;6:93–98.

    PubMed  CAS  Google Scholar 

  33. Mocharla H, Butch AW, Pappas AA, et al. Quantification of vitamin D receptor m RNA by competitive polymerase chain reaction in PBMC: Lack of correspondence with common allelic variants. J Bone Miner Res 1997;12:726–33.

    Article  PubMed  CAS  Google Scholar 

  34. Gross C, Musiol IM, Eccleshall TR, Mallory PJ, Feldman D. Vitamin D receptor gene polymorphism: Analysis of ligand binding and hormone responsiveness in cultured fibroblasts. Biochem Biophys Res Commun 1998;242:467–73.

    Article  PubMed  CAS  Google Scholar 

  35. Durrin LK, Haile RW, Ingles SA, Coetzee GA. Vitamin D receptor 3’-untranslated region polymorphisms: Lack of effect on mRNA stability. Biochim Biophys Acta 1999;1453:311–20.

    Article  PubMed  CAS  Google Scholar 

  36. Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R, Feldman D. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res 1996;11:1850–55.

    Article  PubMed  CAS  Google Scholar 

  37. Arai H, Myamoto K, Taketani Y, et al. A vitamin D receptor gene polymorphism in the translation initiation codon: Effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 1997;12:915–21.

    Article  PubMed  CAS  Google Scholar 

  38. Harris SS, Eccleshall TR, Gross C, Dawson-Hughes B, Feldman D. The vitamin D receptor start codon polymorphism (Fok I) and bone mineral density in premenopausal American black and white women. J Bone Miner Res 1997;12:1043–48.

    Article  PubMed  CAS  Google Scholar 

  39. Gennari L, Becherini L, Mansani R, et al. Fok I polymorphism at translation initiation site of the vitamin D receptor gene predicts bone mineral density and vertebral fractures in postmenopausal Italian women. J Bone Miner Res 1999;14:1379–86.

    Article  PubMed  CAS  Google Scholar 

  40. Eccleshall TR, Garnero P, Gross C, Delmas PD, Feldman D. Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: The OFELY study. J Bone Miner Res 1998;13:31–35.

    Article  PubMed  CAS  Google Scholar 

  41. Ferrari SL, Rizzoli R, Manen D, Slosman D, Bonjour JP. Vitamin D receptor gene start codon polymorphisms (Fok I) and bone mineral density: Interaction with age, dietary calcium, and 3’-end region polymorphisms. J Bone Miner Res 1998;13:925–30.

    Article  PubMed  CAS  Google Scholar 

  42. Jurutka PW, Remus LS, Whitfield GK, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 2000;14:401–20.

    CAS  Google Scholar 

  43. Eriksen EF, Colvard DS, Berg NJ, et al. Evidence of estrogen receptors in normal human osteoblast-like cells. Science 1988;241:84–86.

    Article  PubMed  CAS  Google Scholar 

  44. Korach KS. Insights from the study of animals lacking functional estrogen receptor. Science 1994;266:1524–27.

    Article  PubMed  CAS  Google Scholar 

  45. Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H. Association of bone mineral density with polymorphism of estrogen receptor gene. J Bone Miner Res 1996; 11: 306–11.

    Article  PubMed  CAS  Google Scholar 

  46. Han KO, Moon IG, Kang YS, Chung HY, Min HK, Han DC. Non association of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean postmenopausal women. J Clin Endocrinol Metab 1997;82: 991–95.

    Article  PubMed  CAS  Google Scholar 

  47. Becherini L, Gennari L, Masi L, et al. Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women. Hum Mol Genet 2000;12;9:2043–50.

    Article  Google Scholar 

  48. Sowers M, Willing M, Burns T, et al. Genetic markers, bone mineral density and serum osteocalcin levels. J Bone Miner Res 1999; 14:1411–19.

    Article  PubMed  CAS  Google Scholar 

  49. Langdahl BL, Lokke E, Carstens M, Stenkjaer LL, Eriksen EF. A TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not. J Bone Mineral Res 2000;15:2222–30.

    Article  CAS  Google Scholar 

  50. Albagha OM, McGuigan FE, Reid DM, Ralston SH. Estrogen receptor alpha gene polymorphisms and bone mineral density: Haplotype analysis in women from the United Kingdom. J Bone Mineral Res 2001;16:128–34.

    Article  CAS  Google Scholar 

  51. Sykes B. Bone disease cracks genetics. Nature 1990;348:18–20.

    Article  PubMed  CAS  Google Scholar 

  52. Grant SFA, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH Reduced bone density and osteoporosis associated with polymorphic SP1 site in the collagen type I alpha 1 gene. Nat Genet 1996;14:203–5.

    Article  PubMed  CAS  Google Scholar 

  53. Uitterlinden AG, Burger H, Huang Q, et al. Relation of alleles of the collagen type Ial gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 1998;338:1016–21.

    Article  PubMed  CAS  Google Scholar 

  54. Garnero P, Borel O, Grant SFA, Ralston SH, Delmas PD. Collagen Ial Sp 1 polymorphism, bone mass, and bone turnover in healthy French postmenopausal women: The OFELY study. J Bone Miner Res 1998;13:813–17.

    Article  PubMed  CAS  Google Scholar 

  55. Langdahl BL, Ralston SH, Grant SFA, Eriksen EF. An Spl binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in men and women. J Bone Miner Res 1998;13:1384–89.

    Article  PubMed  CAS  Google Scholar 

  56. Keen RW, Woodford-Richens KL, Grant SFA, Ralston SH, Lanchbury JS, Spector TD. Polymorphism at the type I collagen (COLIA1) locus is associated with reduced bone mineral density, increased collagen turnover. Arthritis Rheum 1996;42:285–90.

    Article  Google Scholar 

  57. Liden M, Wilen B, Ljunghall S, Melhus H. Polymorphism at the Spl binding site in the collagen type I alpha gene does not predict bone mineral density in postmenopausal women in Sweden. Calcif Tissue Int 1998;63:293–95.

    Article  PubMed  CAS  Google Scholar 

  58. Hustmyer FG, Lui G, Johnston CC, Christian J, Peacock M. Polymorphism at the Spl binding site of COLIA1 and bone mineral density in pre-menopausal female twins and elderly fracture patients. Osteoporosis Inter 1999;9:346–50.

    Article  CAS  Google Scholar 

  59. Mann V, Hobson EE, Li B, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 2001:107:899–907.

    Article  PubMed  CAS  Google Scholar 

  60. Murray RE, McGuian F, Grant SFA, Reid DM, Ralston SH. Polymorphisms of the interleukin-6 gene are associated with bone mineral density. Bone 1997;21:89–92

    Article  PubMed  CAS  Google Scholar 

  61. Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen EF. A sequence variation: 713-delC in the transforming growth factor-pl gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone 1997; 20:289–94.

    Article  PubMed  CAS  Google Scholar 

  62. Shiraki M, Shiraki Y, Aoki C, Inoue S, Kaneki M, Ouchi Y. Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 1997;12:1438–45.

    Article  PubMed  CAS  Google Scholar 

  63. Masi L, Becherini L, Colli E, et al. Polymorphisms of the calcitonin receptor gene are associated with bone mineral density in postmenopausal Italian women. Biochem Biophys Res Commun 1998;248:190–95.

    Article  PubMed  CAS  Google Scholar 

  64. Masi L, Becherini L, Gennari L, et al. Polymorphism of the aromatase gene in postmenopausal Italian women: Distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab 2001;86:2263–69.

    Article  PubMed  CAS  Google Scholar 

  65. Gong Y, Vikkula M, Boon L, et al. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12–13. Am J Hum Genet 1996;59:146–51.

    PubMed  CAS  Google Scholar 

  66. Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12–13). Am J Hum Genet 1997;60:1326–32.

    Article  PubMed  CAS  Google Scholar 

  67. Heaney C, Shalev H, Elbedour K, et al. Human autosomal recessive osteopetrosis maps to 1 lql3, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation. Hum Mol Genet 1998;7:1407–10.

    Article  PubMed  CAS  Google Scholar 

  68. Koller DL, Rodriguez LA, Christian JC, et al. Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12–13. J Bone Miner Res 1998;13:1903–8.

    Article  PubMed  CAS  Google Scholar 

  69. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516–17.

    Article  PubMed  CAS  Google Scholar 

  70. Spielman SR, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDMM). Am J Hum Genet 1993;52:506–16.

    PubMed  CAS  Google Scholar 

  71. Duncan EN, Brown MA, Sinsheimer J, et al. Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J Bone Miner Res 1999;14:1993–99.

    Article  PubMed  CAS  Google Scholar 

  72. VandeBerg JL, Williams-Blangero S. Advantages and limitations of non human primates as animal models in genetic research on complex disease. J Med Primatol 1997;26(3):113–19.

    Article  PubMed  CAS  Google Scholar 

  73. Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ER. Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res 1998;13:1648–56.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Luigi Gennari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucia Becherini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Falchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Masi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Luisa Brandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Columbia University, New York, New York, USA

    R. A. Lobo

  2. First Department of Obstetrics and Gynecology, University of Milan, Milan, Italy

    P. G. Crosignani  & F. Bruschi  & 

  3. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    R. Paoletti

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer Science+Business Media New York

About this chapter

Cite this chapter

Gennari, L., Becherini, L., Falchetti, A., Masi, L., Brandi, M.L. (2002). Genetics of Osteoporosis. In: Lobo, R.A., Crosignani, P.G., Paoletti, R., Bruschi, F. (eds) Women’s Health and Menopause. Medical Science Symposia Series, vol 17. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1061-1_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1061-1_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5375-1

  • Online ISBN: 978-1-4615-1061-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation