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© Borgis - Postępy Nauk Medycznych 1/2017, s. 4-10
*Marek Tałałaj, Michał Wąsowski
Genetic factors, osteoporosis and bone fractures
Czynniki genetyczne, osteoporoza i złamania kości
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
Ryzyko złamań kości zależne jest od wielu czynników, takich jak gęstość mineralna (BMD) i jakość kości oraz od czynników pozaszkieletowych wpływających na ryzyko wystąpienia upadków. Każdy z tych czynników znajduje się, przynajmniej częściowo, pod kontrolą oddziaływań genetycznych. Wyniki przeprowadzonych badań sugerują, że 50-85% zmienności szczytowej masy kostnej jest uwarunkowane genetycznie. Przypuszcza się, że geny odgrywają również istotną rolę w regulacji utraty masy kostnej związanej z wiekiem oraz innych determinantów ryzyka złamań. Geny wiązane z rozwojem osteoporozy są klasyfikowane zgodnie z ich wpływem na metaboliczne lub hormonalne szlaki sygnałowe. Wykazano, że polimorfizm genów kodujących lub regulujących: szlaki sygnałowe Wnt/β-katenina, RANK-RANKL-OPG, receptor witaminy D (VDR) i białko wiążące witaminę D (DBP) oraz prokolagen typu 1 i receptor estrogenowy α wywiera istotny wpływ na BMD oraz ryzyko złamań kości.
Bone fracture risk is influenced by a number of factors, including bone mineral density (BMD), bone quality parameters and non-skeletal factors affecting the risk of falls. Each of these factors is itself under at least partial genetic control. Several studies suggested that between 50 and 85% of the variance in peak bone mass was genetically determined. It was also presumed that genes contributed significantly to variability in age-related bone loss and other determinants of fracture risk. Candidate genes for osteoporosis were classified according to metabolic or hormonal pathways. It was found that polymorphisms of genes encoding and/or regulating the Wnt/β-catenin signaling pathway, the RANK-RANKL-OPG pathway, vitamin D receptor (VDR) and vitamin D binding protein (DBP), procollagen 1 molecule, and the estrogen receptor α influenced BMD and bone fracture risk.

Current definition determines osteoporosis as a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue that result in reduced bone strength, bone fragility, and increased risk of fracture. The main clinical end points as well as complications of osteoporosis are skeletal fractures. The most common fracture sites are hip, spine and forearm although any bone can be affected (1).
Fracture risk is influenced by a number of factors, including bone mineral density (BMD), bone quality parameters and non-skeletal factors such as muscle strength, balance, cognition and cardiovascular function affecting the risk of falls (2). Each of these factors is itself under at least partial genetic control. BMD can be determined by dual energy X-ray absorptiometry (DXA) usually performed at the lumbar spine and hip. It was estimated that each standard deviation decrease in BMD from the age-adjusted mean was associated with a 2.3-fold increase in incidence of vertebral fractures and a 2.6-fold increase in hip fractures. Bone quality can be assessed by three-dimensional imaging modalities, such as peripheral computed tomography and high resolution magnetic resonance imaging, that allow to determine geometric parameters of the skeleton and to assess its microstructure (1).
Growing evidence indicates that fracture risk is influenced by a combination of genetic and environmental factors. Several twin and family studies suggest that between 50 and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (3, 4). It is also presumed that genes contribute significantly to variability in aging-related bone loss and other determinants of fracture risk, including femoral neck geometry, muscle strength, bone turnover, body mass index and age at menopause (1).
It is probably a multi-gene relation and no single gene was found to prevail over others in the determination of BMD and fracture risk. Studies of post-menopausal women and their first-degree relatives as well as twin studies (5) showed that the heritability of forearm fractures was about 25-50%, of hip fractures approximately 50% and of vertebral fractures 24% (6-8). In contrast, heritability study of elderly twins from Finland showed little evidence to suggest that fractures were heritable (9). These divergent results may be explained by the fact that the heritability of fracture decreases with age as environmental factors become more important. It was demonstrated in a large study of Swedish twins that the heritability of hip fractures was as high as 68% among persons under the age of 65 but dropped off rapidly with age to reach a value of almost zero by the eighth decade (6). It has been also shown that genetic component of low muscle mass, increasing the susceptibility to falls, was over 50% (4).
Early efforts to identify specific genes related to variation in BMD and fracture risk focused on identifying biologically motivated candidate genes and testing specific genotyped variants for association with BMD and/or fractures. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects were modest and together probably accounted for less than 5% of the heritable contribution to BMD. Candidate gene association studies are relatively easy to perform and a well validated method for the identification of genes responsible for monogenic diseases. However, they have low statistical power to detect genes having modest effects on BMD and fractures, and hence require family samples of several thousand people.
Demonstration of an association between a candidate gene and BMD or fractures does not necessarily mean that the gene is causally responsible for the effect observed, as there may be linkage disequilibrium with a nearby causal gene. Linkage disequilibrium refers to the phenomenon whereby genes lying close together tend to be inherited together (10).
With advances in genomic technology genome-wide association studies (GWAS) have been published. GWAS is an approach that involves scanning of the entire genome to identify novel genes with modest effects on complex diseases or traits. Array GWAS technologies are capable of analyzing thousands of polymorphisms distributed throughout the genome. Through the use of dense genotyping, large study samples, and replication studies to confirm results, these studies have led to the discovery of many genetic variants that have robust statistical evidence for association with various diseases. It has become possible to perform association studies on a genome-wide basis by analyzing a large number of closely spaced single-nucleotide polymorphisms (SNPs) spread randomly across the genome (11). The GWAS studies published to date disclosed more than 82 loci significantly associated with BMD, of which at least 16 were found to be associated also with fractures. The effect sizes of these loci are small, each accounting for less than 1% of the total variation in BMD (1, 12). Finding genes for fracture risk is likely to be more difficult than for BMD due to the complexity of the fracture phenotype. The vast majority of SNPs that have been associated with fracture have odds ratios for fracture of 1.11 or lower (13).
Candidate genes for osteoporosis were classified according to metabolic or hormonal pathways, which regulate BMD and bone quality, however, to date no gene has been definitively identified as a major gene.
A large collaborative study of more than 19,000 men and women identified 241 SNPs from 9 genes, which were significantly associated with lumbar spine BMD (230 SNPs), femoral neck BMD (100 SNPs), or both (89 SNPs). Among them 60 SNPs from 4 genes were also significantly associated with risk for fracture. The effect of these SNPs on fracture rate ranged between an odds ratio (OR) of 1.13 and 1.43 for the allele that was associated with decreased BMD. These results confirmed the highly polygenic nature underlying BMD variation and the role of several biological pathways influencing osteoporosis and fracture susceptibility (12, 14).
The Wnt/β-catenin signaling pathway, also called the canonical Wnt pathway, is crucially important for a variety of processes, including bone cell differentiation, proliferation, and apoptosis. Interactions of Wnt proteins with their receptors cause an accumulation of β-catenin in the cytoplasm and then in the nucleus where it participates in gene transcription. In the canonical Wnt pathway Wnt proteins bind Frizzled proteins and either lipoprotein receptor-related proteins 5 or 6 (LRP5 or LRP6). This results in the inhibition of glycogen synthase kinase 3-dependent phosphorylation of β-catenin, followed by the stabilization of β-catenin (4, 10). Following the transfer of LRP and Frizzled proteins into the nucleus of the pre-osteoblast and binding to transcription factor TCFS, proliferation and differentiation of this cell is induced. The LRP5 pathway was discovered to be a key regulator of bone mass mainly by influence on osteoblast proliferation and bone matrix deposition (15, 16).
The Rotterdam Study, that included 2995 participants, revealed that SNP of the gene involved in osteoblast differentiation through activation of Wnt/β-catenin signals localized on chromosome 16q24, was significantly associated with an increased risk of vertebral fractures evident on the spinal radiographs. Compared to non-carriers, the heterozygous carriers of the minor allele (C) had the OR = 1.7 for vertebral fractures, and the homozygous carriers OR = 5.8. The vertebral fracture SNP was not associated with either lumbar spine or femoral neck BMD (17).
LRP5 and LRP6 genes have been implicated to play a role in bone metabolism, and LRP5 was thought to be important for the establishment of peak bone mass (15, 18). A study of 7983 inhabitants of Rotterdam, aged > 55 years, showed that in men, the Ala1330Val polymorphism in the LRP5 gene was associated with significantly decreased BMD at the lumbar spine and femoral neck, reduced vertebral body size and femoral neck width, and a 60% increased risk for fragility fractures. Carriers of two risk alleles LRP5 1330Val and LRP6 1062Val had a 2.4 and 1.9 times higher risk for fragility and vertebral fractures, respectively, compared with men not carrying a risk allele. It was suggested that both SNPs account for one-tenth of the fracture cases in men, while in women carrying those risk alleles only nonsignificant trend for 30% higher risk for both fragility fractures and vertebral fractures was found (19).
Large multicenter study including more than 37,000 participants from Europe and North America showed, that the Val667Met (in the exon 9) and Ala1330Val (in the exon 18) polymorphisms of LRP5 gene were associated with an increased incidence of vertebral fractures by 26 and 12% respectively and an increased incidence of all fractures by 14 and 6% respectively. These data suggest that SNPs in LRP5 and LRP6 may affect the pathogenesis of osteoporosis through decreasing activity of the WNT/β-catenin pathway (20).

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1. Mitchell BD, Streeten EA: Clinical impact of recent genetic discoveries in osteoporosis. Appl Clin Gen 2013; 6: 75-85.
2. Ohlsson C: Bone metabolism in 2012: novel osteoporosis targets. Nat Rev Endocrinol 2013; 9: 72-74.
3. Ralston SH, de Crombrugghe B: Genetic regulation of bone mass and susceptibility to osteoporosis. Genes & Dev 2006; 20: 2492-2506.
4. Urano T, Inoue S: Recent genetic discoveries in osteoporosis, sarcopenia and obesity. Endocrine J 2015; 62: 475-484.
5. Deng HW, Chen WM, Recker S et al.: Genetic determination of Colles’ fracture and differential bone mass in women with and without Colles’ fracture. J Bone Miner Res 2000; 15: 1243-1252.
6. Michaelsson K, Melhus H, Ferm H et al.: Genetic liability to fractures in the elderly. Arch Intern Med 2005; 165: 1825-1830.
7. 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. J Bone Miner Res 2005; 20: 67-74.
8. Wagner H, Melhus H, Pedersen NL et al.: Heritable and environmental factors in the causation of clinical vertebral fractures. Calcif Tissue Int 2012; 90: 458-464.
9. 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 1999; 319: 1334-1337.
10. Williams FMK, Spector TD: Recent advances in the genetics of osteoporosis. J Musculoskelet Neuronal Interact 2006; 6: 27-35.
11. Cardon LR, Abecasis GR: Using haplotype blocks to map human complex trait loci. Trends Genet 2003; 19: 135-140.
12. Estrada K, Styrkarsdottir U, Evangelou E et al.: Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012; 44: 491-501.
13. Guo Y, Tan LJ, Lei SF et al.: Genome-wide association study identifies ALDH7a1 as a novel susceptibility gene for osteoporosis. PLoS Genet 2010; 6: e1000806.
14. Richards JB, Kavvoura FK, Rivadeneira F et al.: Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 2009; 151: 528-537.
15. Zofkova I, Nemcikova P, Kuklik M: Polymorphisms associated with low bone mass and high risk of atraumatic fracture. Physiol Res 2015; 64: 621-631.
16. Kato M, Patel MS, Levasseur R et al.: Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 2002; 157: 303-314.
17. Oei L, Estrada K, Duncan EL et al.: Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone 2014; 59: 20-27.
18. Gong Y, Slee RB, Fukai N et al.: LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001; 107: 513-523.
19. van Meurs JBJ, 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. J Bone Miner Res 2006; 21: 141-150.
20. van Meurs JBJ, Trikalinos TA, Ral SH et al.: Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 2008; 299: 1277-1290.
21. Wang C, He JW, Qin YJ et al.: Osteoprotegerin gene polymorphism and therapeutic response to alendronate in postmenopausal women with osteoporosis. Zhonghua Yi Xue Za Zhi 2009; 89: 2958-2962.
22. Mencej-Bedrač S, Preželj J, Marc J: TNFRSF11B gene polymorphisms 1181G > C and 245T > G as well as haplotype CT influence bone mineral density in postmenopausal women. Maturitas 2011; 69: 263-267.
23. Boroń D, Kamiński A, Kotrych D et al.: Polymorphism of vitamin D3 receptor and its relation to mineral bone density in perimenopausal women. Osteoporos Int 2015; 26: 1045-1052.
24. Langdahl BL, Gravhold CH, Brixen K et al.: Polymorphism in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest 2000; 30: 608-617.
25. Sainz J, Van Tornout JM, Lord ML et al.: Vitamin D receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 1997; 337: 77-82.
26. Riggs BL, Nguyen TV, Melton LJ et al.: The contribution of vitamin D receptor gene alleles to the determination of bone mineral density in normal and osteoporotic women. J Bone Miner Res 1995; 10: 991-996.
27. Horst-Sikorska W, Wawrzyniak A, Celczyńska-Bajew L et al.: Polymorphism of VDR gene – the most effective molecular marker of osteoporotic bone fractures risk within postmenopausal women from Wielkopolska region of Poland. Pol J Endocrinol 2005; 3: 233-239.
28. Springer JE, Cole DE, Rubin LA et al.: Vitamin-D receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis. Gastroenterology 2000; 118: 145-151.
29. 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. J Bone Miner Res 2004; 19: 419-428.
30. Chatzipapas C, Boikos S, Drosos GI et al.: Polymorphisms of the vitamin D receptor gene and stress fractures. Horm Metab Res 2009; 41: 635-640.
31. Arai H, Miyamoto KI, Yoshida M et al.: The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 2001; 16: 1256-1264.
32. Fang Y, van Meurs JB, Bergink AP et al.: Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res 2003;18: 1632-1641.
33. 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. Am J Hum Genet 2005; 77: 807-823.
34. Fang Y, van Meurs JBJ, Arp P et al.: Vitamin D binding protein genotype and osteoporosis. Calcif Tissue Int 2009; 85: 85-93.
35. Tran BN, Nguyen ND, Center JR et al.: Enhancement of absolute fracture risk prognosis with genetic marker: the collagen 1 alpha 1 gene. Calcif Tissue Int 2009; 85: 379-388.
36. 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.
37. 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 Med 2006; 3: e90.
38. Efstathiadou Z, Tsatsoulis A, Ioannidis JP: Association of collagen Iα 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis. J Bone Miner Res 2001; 16: 1586-1592.
39. Mann V, Ralston SH: Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone 2003; 32: 711-717.
40. Uitterlinden AG, Burger H, Huang Q et al.: Relation of alleles of collagen type I alpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 1998; 338: 1016-1021.
41. Tang L, Cheng G-L, Xu Z-H: Association between estrogen receptor α gene (ESR1) PvuII (C/T) and XbaI (A/G) polymorphisms and hip fracture risk: evidence from a meta-analysis. PloS ONE 2013; 8: e82806
42. Riancho JA, Hernández JL: Pharmacogenomics of osteoporosis: a pathway approach. Pharmacogenomics 2012; 13: 815-829.
43. Ioannidis JP, Stavrou I, Trikalinos TA et al.: Association of polymorphisms of the estrogen receptor α gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 2002; 17: 2048-2060.
44. Ioannidis JP, Ralston SH, Bennett ST et al.: Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 2004; 292: 2105-2114.
45. Zhang SQ, Zhang WY, Ye WQ et al.: Apolipoprotein E gene E2/E2 genotype is a genetic risk factor for vertebral fractures in humans: a large-scale study. Int Orthop (SICOT) 2014; 38: 1665-1669.
46. Dieckmann M, Beil FT, Mueller B et al.: Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo. J Bone Miner Res 2013; 28: 236-245.
47. Ralston SH: Apolipoprotein E isoforms and bone of mice and men. J Bone Miner Res 2013; 28: 234-235.
48. Shiraki M, Shiraki Y, Aoki C et al.: Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 1997; 12: 1438-1445.
49. Johnston JM, Cauley JA, Ganguli M: APOE 4 and hip fracture risk in a community-based study of older adults. J Am Geriatr Soc 1999; 47: 1342-1345.
50. Massaguè J, Chen YG: Controlling TGF-β signaling. Genes & Dev 2000; 14: 627-644.
51. Langdahl BL, Carstens M, Stenkjaer L et al.: Polymorphisms in the transforming growth factor β 1 gene and osteoporosis. Bone 2003; 32: 297-310.
52. Yamada Y, Miyauchi A, Takagi Y et al.: Association of the C-509 → T polymorphism, alone or in combination with the T869 → C polymorphism, of the transforming growth factor-1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J Mol Med 2001; 79: 149-156.
53. Styrkarsdottir U, Cazier J-B, Kong A et al.: Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 2003; 1: E69.
54. Ramesh BL, Wilson SG, Dick IM et al.: Bone mass effects of a BMP4 gene polymorphism in postmenopausal women. Bone 2005; 36: 555-561.
55. Devoto M, Specchia C, Li HH et al.: Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum Mol Genet 2001; 10: 2447-2452.
56. Spotila LD, Rodriguez H, Koch M et al.: Association analysis of bone mineral density and single nucleotide polymorphisms in two candidate genes on chromosome 1p36. Calcif Tissue Int 2003; 73: 140-146.
57. Shiraki M, Urano T, Kuroda T et al.: The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. J Bone Miner Metab 2008; 26: 595-602.
58. Bathum L, von Bornemann Hjelmborg J, Christiansen L et al.: Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int 2004; 15: 659-664.
59. Villadsen MM, Bünger MH, Carstens M et al.: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a week predictor of BMD. Osteoporos Int 2005; 16: 411-416.
60. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM et al.: Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004; 350: 2033-2041.
61. Costa LG, Cole TB, Jarvik GP et al.: Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism. Annu Rev Med 2003; 54: 371-392.
62. Kim B-J, Kim S-Y, Cho YS et al.: Association of Paraoxonase 1 (PON1) polymorphisms with osteoporotic fracture risk in postmenopausal Korean women. Exp Mol Med 2011; 43: 71-81.
otrzymano: 2016-12-07
zaakceptowano do druku: 2016-12-28

Adres do korespondencji:
*Marek Tałałaj
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases Centre of Postgraduate Medical Education
Czerniakowska 231, 00-416 Warszawa
tel. +48 (22) 584-11-47

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