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Osteoporosis. Excessive skeletal fragility leading to low trauma fractures. Intrinsic skeletal factors: low bone mass, unfavorable geometry at cortical bone sites, small bone size, poor bone structure at cancellous bone sites and sluggish or ineffective repair of microdamage.

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Presentation Transcript
  • Excessive skeletal fragility leading to low trauma fractures.
  • Intrinsic skeletal factors: low bone mass, unfavorable geometry at cortical bone sites, small bone size, poor bone structure at cancellous bone sites and sluggish or ineffective repair of microdamage.
  • Extrinsic factors: propensity to fall.


  • 1.7 million hip fractures 1990
  • 6.3 million hip fractures 2050
  • 40% of postmenopausal women, on average, will suffer at least one osteoporotic fracture
  • Osteoporosis incurs ~14 billion dollars in the US alone in 1997

WHO Criteria:bone mass values that is >2.5 SD below the young adult mean value.

BMD (bone mineral density):measured by techniques such as DXA (dual energy x-ray absorptiometry).

determination of bmd
Determination of BMD
  • By environmental factors(individual factors as well as E x E interaction) (Smoking, nutrition, exercises, diseases, medication, alcohol consumption etc.) ~15-45%.
  • By genetic factors
    • (individual genes as well as epistasis) ~55-85%.
  • By G x E Interaction~ ? %.
segregation analyses
Segregation analyses
  • No major genes: (Guegen et al., 1995);
  • Major genes: (Livshits et al., 1996; 1999; 2002; Cardon et al., 2000; Deng et al., 2002; Liu et al., 2003a, b).
genetic correlation
Genetic correlation
  • Significant between BMD at different sites (Pocock et al., 1987; Nguyen et al., 1998; Deng et al., 1999; Kobyliansky et al., 2000);
  • Not significant between BMD and osteoporotic fractures (OF) (Deng et al., 2002). At hip,
    • h2 BMD: 0.65, h2 OF: 0.53;
    • genetic correlation between BMD and OF: 0.05.
goals of molecular genetics of osteoporosis
Goals of Molecular Genetics of Osteoporosis
  • To identify genes for risk of osteoporotic fractures
    • develop molecular genetic markers for diagnosis, prevention, early intervention, and individualized treatment
    • study molecular and cell functions of mutations of genes identified for development of drug and effective treatment
  • Association studies
  • Linkage studies
  • Transmission Disequilibrium Test (TDT)
  • QTL mapping in mice
  • gene expression studies
  • Proteomics
vdr gene 12q12 14
VDR Gene (12q12-14)
  • VD modulates intestinal calcium absorption, osteoclastic and osteoblastic activities, PTH production.
  • VDR mediates the biological actions of 1,25(OH)2D3.
  • Mutations in VDR gene cause hereditary vitamin D-resistant rickets.
  • VDR gene knockout mice possess low bone mass, hypocalcemia, and hyperparathyroidism.
Morrison et al. (1994): a significant association between the Bsm I polymorphism and BMD.
  • Meta-analyses: BMD is associated with VDR gene (Cooper et al., 1996; Gong et al., 1999).



er gene 6q25
ER-Gene (6q25)
  • ER-mediates the physiologic effects of the estrogen.
  • ER- expression found in human osteoblasts and osteoclasts.
  • Estrogen resistance due to a nonsense mutation in ER- gene causes severe osteoporosis (Smith et al. 1994).
Sano et al. (1995): associations between the TA repeat polymorphism and BMD in Japanese women.
  • Meta-analysis: Xba I polymorphism is associated with BMD and OF(Ioannidis et al., 2002).
colia1 gene 17q21 q22
COLIA1 Gene(17q21-q22)
  • COLIA1 gene encodes the 1(I) protein chain of type I collagen, the most abundant extracellular bone matrix protein.
  • Mutations in the coding regions of the COLIA1 gene result in osteogenesis imperfecta.
  • COLIA1 knock-out mice exhibits low bone mass and high risk fractures.
Grant et al. (1996) described an association between a GT polymorphism in a binding motif for Sp1 with BMD and OF.
  • Meta-analysis: Sp1 polymorphism is associated with BMD and OF (Mann et al., 2001; Efstathiadou et al., 2001).
  • Sp1 polymorphism may be functional (Mann et al., 2001).
tdt of candidate genes
TDT of candidate genes
  • TGF-1 gene (hip BMD)(Keen et al., 2001);
  • VDR (hip BMD), BGP (spine BMD) and PTH genes (Deng et al., 2002)
  • BGP gene (spine BMD and ultrasound measurements of bone) (Andrew et al., 2002);
  • ER- gene(hip and spine BMD)(Qin et al., 2003).
interaction studies
Interaction studies
  • ER- and VDR genes for BMD (Willings et al., 1998);
  • VDR and COL1a1 genes for OF (Uitterlinden et al. 2001);
  • VDR gene and Ca2+ intake for BMD change (Ferrari et al., 1995; Krall et al., 1995; Kiel et al., 1997);
  • ER- and VDR genes for BMD change during HRT(Deng et al., 1998).
genetic basis of racial differentiation
Genetic basis of racial differentiation
  • VDR BsmI and hip OF (Young et al., 1996).
  • Sp1 and RsaI of Col1a1,–174G/C of IL-6, Asn363Ser of GR, and the T->C of TGF- 1(Lei et al., 2002).
  • BsaHI of CASR, SacI of AHSG, PvuII and XbaI ER-α, ApaI VDR, and BstBI PTH (Dvornyk et al., 2003).