Best Practice & Research Clinical Endocrinology & Metabolism
Volume 22, Issue 5 , Pages 723-735 , October 2008

Human genetics of osteoporosis

  • Serge Ferrari, MD (Associate Professor of Medicine and Osteoporosis genetics)

      Affiliations

    • Corresponding Author InformationTel.: +4122 372 99 50; Fax: +4122 382 99 73.

References 

  1. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis International. Apr 2008;19(4):399–428
  2. Anonymous . NIH Consensus Development Panel on osteoporosis prevention, diagnosis, and therapy, March 7–29, 2000: highlights of the conference. The Southern Medical Journal. Jun 2001;94(6):569–573
  3. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. The New England Journal of Medicine. 1989;320(9):554–558
  4. Van Pottelbergh I, Goemaere S, Zmierczak H, et al. Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study. Journal of Bone and Mineral Research. Feb 2003;18(2):303–311
  5. Ferrari S, Rizzoli R, Slosman D, et al. Familial resemblance for bone mineral mass is expressed before puberty. The Journal of Clinical Endocrinology and Metabolism. 1998;83(2):358–361
  6. Liu YJ, Shen H, Xiao P, et al. Molecular genetic studies of gene identification for osteoporosis: a 2004 update. Journal of Bone and Mineral Research. Oct 2006;21(10):1511–1535
  7. Eisman JA. Genetics of osteoporosis. Endocrine Reviews. 1999;20(6):788–804
  8. Ferrari S. Genetics, nutrition and bone health. In:  Holick M,  Dawson-Hughes E editor. Nutrition and bone health. Totowa, NJ: The Humana press Inc.; 2004;p. 19–41
  9. Bonjour JP, Chevalley T, Rizzoli R, et al. Gene-environment interactions in the skeletal response to nutrition and exercise during growth. Medicine and Sport Science. 2007;51:64–80
  10. Karasik D, Ferrari S. Contribution of gender-specific genetic factors to osteoporosis risk. Annals of Human Genetics. 2008;72:1469–1809
  11. Deng HW, Livshits G, Yakovenko K, et al. Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density. Annals of Human Genetics. 2002;66(Pt 1):61–74
  12. Peacock M, Turner CH, Econs MJ, et al. Genetics of osteoporosis. Endocrine Reviews. Jun 2002;23(3):303–326
  13. Slemenda CW, Christian JC, Williams CJ, et al. Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates. Journal of Bone and Mineral Research. 1991;6(6):561–567
  14. Ferrari SL, Chevalley T, Bonjour JP, et al. Childhood fractures are associated with decreased bone mass gain during puberty: an early marker of persistent bone fragility?. Journal of Bone and Mineral Research. Apr 2006;21(4):501–507
  15. Kannus P, Palvanen M, Kaprio J, et al. Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly finnish twins. BMJ. Nov 20 1999;319(7221):1334–1337
  16. Deng HW, Chen WM, Recker S, et al. Genetic determination of Colles' fracture and differential bone mass in women with and without Colles' fracture. Journal of Bone and Mineral Research. Jul 2000;15(7):1243–1252
  17. Michaelsson K, Melhus H, Ferm H, et al. Genetic liability to fractures in the elderly. Archives of Internal Medicine. Sep 12 2005;165(16):1825–1830
  18. Deng HW, Mahaney MC, Williams JT, 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. Genetic Epidemiology. 2002;22(1):12–25
  19. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporosis International. Aug 2007;18(8):1033–1046
  20. Andrew T, Antioniades L, Scurrah KJ, et al. Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. Journal of Bone and Mineral Research. Jan 2005;20(1):67–74
  21. van Meurs JB, Schuit SC, Weel AE, et al. Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Human Molecular Genetics. Jul 15 2003;12(14):1745–1754
  22. Naganathan V, MacGregor A, Snieder H, et al. Gender differences in the genetic factors responsible for variation in bone density and ultrasound. Journal of Bone and Mineral Research. 2002;17(4):725–733
  23. Karasik D, Cupples LA, Hannan MT, et al. Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham study. Bone. Sep 2003;33(3):308–316
  24. Ralston SH, Galwey N, MacKay I, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Human Molecular Genetics. Apr 1 2005;14(7):943–951
  25. Brown LB, Streeten EA, Shuldiner AR, et al. Assessment of sex-specific genetic and environmental effects on bone mineral density. Genetic Epidemiology. Sep 2004;27(2):153–161
  26. Kammerer C, Schneider J, Cole S, et al. Quantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans. Journal of Bone and Mineral Research. 2003;18(12):2245–2252
  27. Amin S, Zhang Y, Sawin CT, et al. Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Annals of Internal Medicine. 2000;133(12):951–963
  28. Khosla S, Melton LJ, Robb RA, et al. Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men. Journal of Bone and Mineral Research. May 2005;20(5):730–740
  29. Mellstrom D, Johnell O, Ljunggren O, et al. Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. Journal of Bone and Mineral Research. Apr 2006;21(4):529–535
  30. Peacock M, Koller DL, Hui S, et al. Peak bone mineral density at the hip is linked to chromosomes 14q and 15q. Osteoporosis International. Jun 2004;15(6):489–496
  31. Peacock M, Koller DL, Lai D, et al. Sex-specific quantitative trait loci contribute to normal variation in bone structure at the proximal femur in men. Bone. Oct 2005;37(4):467–473
  32. Ioannidis JP, Ng MY, Sham PC, et al. Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. Journal of Bone and Mineral Research. Feb 2007;22(2):173–183
  33. Blangero J, Williams JT, Almasy L. Novel family-based approaches to genetic risk in thrombosis. Journal of Thrombosis and Haemostasis. Jul 2003;1(7):1391–1397
  34. Zhang H, Sol-Church K, Rydbeck H, et al. High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density. Osteoporosis International. Jul 3 2008;
  35. Ralston SH, de Crombrugghe B. Genetic regulation of bone mass and susceptibility to osteoporosis. Genes and Development. Sep 15 2006;20(18):2492–2506
  36. Thakkinstian A, D'Este C, Eisman J, et al. Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. Journal of Bone and Mineral Research. Mar 2004;19(3):419–428
  37. Fang Y, van Meurs JB, d'Alesio A, et al. Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study. American Journal of Human Genetics. Nov 2005;77(5):807–823
  38. Uitterlinden AG, Ralston SH, Brandi ML, et al. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Annals of Internal Medicine. Aug 15 2006;145(4):255–264
  39. Gennari L, Merlotti D, De Paola V, et al. Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. American Journal of Epidemiology. Feb 15 2005;161(4):307–320
  40. Ioannidis JP, Stavrou I, Trikalinos TA, et al. Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. Journal of Bone and Mineral Research. Nov 2002;17(11):2048–2060
  41. Ioannidis JP, Ralston SH, Bennett ST, et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA : The Journal of the American Medical Association. Nov 3 2004;292(17):2105–2114
  42. Shearman AM, Karasik D, Gruenthal KM, et al. Estrogen receptor Beta polymorphisms are associated with bone mass in women and men: the Framingham study. Journal of Bone and Mineral Research. May 2004;19(5):773–781
  43. Mann V, Hobson EE, Li B, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. The Journal of Clinical Investigation. 2001;107(7):899–907
  44. Uitterlinden AG, Burger H, Huang Q, et al. Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. The New England Journal of Medicine. Apr 9 1998;338(15):1016–1021
  45. Ralston SH, Uitterlinden AG, Brandi ML, et al. Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Medicine. Apr 2006;3(4):e90
  46. Langdahl BL, Uitterlinden AG, Ralston SH. Large-scale analysis of association between polymorphisms in the Transforming Growth Factor Beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone. 2008;Available from: 3 December 2007
  47. Ferrari SL, Deutsch S, Antonarakis SE. Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass. Current Opinion in Lipidology. Apr 2005;16(2):207–214
  48. Ferrari SL, Deutsch S, Choudhury U, 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. American Journal of Human Genetics. May 2004;74(5):866–875
  49. Grundberg E, Lau EM, Lorentzson M, et al. Large-scale association study between two coding LRP5 gene polymorphisms and bone phenotypes and fractures in men. Osteoporosis International. Nov 17 2007;
  50. van Meurs JB, Trikalinos T, Ralston SH, et al. Large-scale analysis of association between polymorphisms in the LRP-5 and -6 genes and osteoporosis: the GENOMOS study. JAMA : The Journal of the American Medical Association. Jan 2008;299(11):1277–1290
  51. Ferrari SL, Ahn-Luong L, Garnero P, et al. Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism. Jan 2003;88(1):255–259
  52. Ferrari SL, Karasik D, Liu J, et al. Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham osteoporosis study. Journal of Bone and Mineral Research. Apr 2004;19(4):552–559
  53. Moffett SP, Zmuda JM, Cauley JA, et al. Association of the G-174C variant in the interleukin-6 promoter region with bone loss and fracture risk in older women. Journal of Bone and Mineral Research. Oct 2004;19(10):1612–1618
  54. McLean RR, Karasik D, Selhub J, et al. Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. Journal of Bone and Mineral Research. Mar 2004;19(3):410–418
  55. 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. The Journal of Clinical Endocrinology and Metabolism. 2001;86(5):2263–2269
  56. Ferrari S, Rizzoli R, Chevalley T, et al. Vitamin-D-receptor-gene polymorphisms and change in lumbar-spine bone mineral density. [see comments] Lancet. 1995;345(8947):423–424
  57. Rizzoli R, Bonjour JP. Hormones and bones. Lancet. Mar 1997;349(Suppl. 1):sI20–sI23
  58. Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. [see comments] The New England Journal of Medicine. 1998;339(11):733–738
  59. Riggs BL, Khosla S, Melton LJ. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. Journal of Bone and Mineral Research. 1998;13:763–773
  60. Long JR, Zhang YY, Liu PY, et al. Association of estrogen receptor alpha and vitamin D receptor gene polymorphisms with bone mineral density in Chinese males. Calcified Tissue International. Mar 2004;74(3):270–276
  61. Koh JM, Kim DJ, Hong JS, et al. Estrogen receptor alpha gene polymorphisms Pvu II and Xba I influence association between leptin receptor gene polymorphism (Gln223Arg) and bone mineral density in young men. European Journal of Endocrinology. Dec 2002;147(6):777–783
  62. Langdahl BL, Lokke E, Carstens M, et al. A TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not. Journal of Bone and Mineral Research. Nov 2000;15(11):2222–2230
  63. Khosla S, Riggs BL, Atkinson EJ, et al. Relationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men. The Journal of Clinical Endocrinology and Metabolism. Apr 2004;89(4):1808–1816
  64. Boot AM, van der Sluis IM, de Muinck Keizer-Schrama SM, et al. Estrogen receptor alpha gene polymorphisms and bone mineral density in healthy children and young adults. Calcified Tissue International. Jun 2004;74(6):495–500
  65. Willing MC, Torner JC, Burns TL, et al. Gene polymorphisms, bone mineral density and bone mineral content in young children: the Iowa Bone Development Study. Osteoporosis International. Aug 2003;14(8):650–658
  66. Ogawa S, Hosoi T, Shiraki M, et al. Association of estrogen receptor beta gene polymorphism with bone mineral density. Biochemical and Biophysical Research Communications. 2000;269(2):537–541
  67. Lau HH, Ho AY, Luk KD, et al. Estrogen receptor beta gene polymorphisms are associated with higher bone mineral density in premenopausal, but not postmenopausal southern Chinese women. Bone. Aug 2002;31(2):276–281
  68. Scariano JK, Simplicio SG, Montoya GD, et al. Estrogen receptor beta dinucleotide (CA) repeat polymorphism is significantly associated with bone mineral density in postmenopausal women. Calcified Tissue International. Jun 2004;74(6):501–508
  69. Moron FJ, Mendoza N, Vazquez F, et al. Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis. Bone. Jul 2006;39(1):213–221
  70. Rivadeneira F, van Meurs JB, Kant J, et al. Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. Journal of Bone and Mineral Research. Sep 2006;21(9):1443–1456
  71. Scheidt-Nave C, Bismar H, Leidig-Bruckner G, et al. Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. The Journal of Clinical Endocrinology and Metabolism. 2001;86(5):2032–2042
  72. Murray RE, McGuigan F, Grant SF, et al. Polymorphisms of the interleukin-6 gene are associated with bone mineral density. Bone. 1997;21(1):89–92
  73. Tsukamoto K, Yoshida H, Watanabe S, et al. Association of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenopausal Japanese women. Journal of Human Genetics. 1999;44(3):148–151
  74. Duncan EL, Brown MA, Sinsheimer J, et al. Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. [see comments] Journal of Bone and Mineral Research. 1999;14(12):1993–1999
  75. Hamanaka Y, Yamamoto I, Takada M, et al. Comparison of bone mineral density at various skeletal sites with quantitative ultrasound parameters of the calcaneus for assessment of vertebral fractures. The Journal of Clinical Endocrinology and Metabolism. 1999;17(3):195–200
  76. Takacs I, Koller DL, Peacock M, et al. Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus. Bone. 2000;27(1):169–173
  77. Ferrari SL, Garnero P, Emond S, et al. A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women. Arthritis and Rheumatism. 2001;44(1):196–201
  78. Yamada Y, Ando F, Niino N, et al. Association of polymorphisms of interleukin-6, osteocalcin, and vitamin D receptor genes, alone or in combination, with bone mineral density in community-dwelling Japanese women and men. The Journal of Clinical Endocrinology and Metabolism. Jul 2003;88(7):3372–3378
  79. Nordstrom A, Gerdhem P, Brandstrom H, et al. Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women. Osteoporosis International. Oct 2004;15(10):820–826
  80. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. Nov 16 2001;107(4):513–523
  81. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. The New England Journal of Medicine. 2002;346(20):1513–1521
  82. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. American Journal of Human Genetics. 2002;70(1):11–19
  83. Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. American Journal of Human Genetics. Mar 2003;72(3):763–771
  84. Ferrari SL, Deutsch S, Baudoin C, et al. LRP5 gene polymorphisms and idiopathic osteoporosis in men. Bone. Dec 2005;37(6):770–775
  85. van Meurs JB, Rivadeneira F, Jhamai M, et al. Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. Journal of Bone and Mineral Research. Jan 2006;21(1):141–150
  86. Kiel DP, Ferrari SL, Cupples LA, 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. Mar 2007;40(3):587–596
  87. Styrkarsdottir U, Cazier JB, Kong A, et al. Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biology. Dec 2003;1(3):E69
  88. Langdahl BL, Stenkjaer L, Carstens M, et al. A CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fractures. Calcified Tissue International. Oct 6 2003;
  89. Sowers M, Willing M, Burns T, et al. Genetic markers, bone mineral density, and serum osteocalcin levels. Journal of Bone and Mineral Research. 1999;14(8):1411–1419
  90. Richert L, Chevalley T, Manen D, et al. Bone mass in prepubertal boys is associated with a Gln223Arg amino acid substitution in the leptin receptor. The Journal of Clinical Endocrinology and Metabolism. Nov 2007;92(11):4380–4386
  91. Uitterlinden AG, Arp PP, Paeper BW, et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. American Journal of Human Genetics. Dec 2004;75(6):1032–1045
  92. Arko B, Prezelj J, Komel R, et al. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. The Journal of Clinical Endocrinology and Metabolism. Sep 2002;87(9):4080–4084
  93. Langdahl BL, Carstens M, Stenkjaer L, et al. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. Journal of Bone and Mineral Research. Jul 2002;17(7):1245–1255
  94. Kiel DP, Demissie S, Dupuis J, et al. Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Medical Genetics. 2007;8(Suppl. 1):S14
  95. Richards JB, Rivadeneira F, Inouye M, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet. May 3 2008;371(9623):1505–1512
  96. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, et al. Multiple genetic loci for bone mineral density and fractures. The New England Journal of Medicine. May 29 2008;358(22):2355–2365
  97. Ferrari S. Osteoporosis: a complex disorder of aging with multiple genetic and environmental determinants. In:  Simopoulos A editors. Nutrition and fitness: mental health, aging, and the implementation of a healthy diet and physical activity lifestyle. vol. 95:Basel: Karger; 2005;p. 35–51

PII: S1521-690X(08)00093-6

doi: 10.1016/j.beem.2008.08.007

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 22, Issue 5 , Pages 723-735 , October 2008

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