Association between SOST gene polymorphisms and response to alendronate treatment in postmenopausal Chinese women with low bone mineral density

Abstract

The aim of this study was to explore the allelic association between SOST polymorphisms and the variance of clinical effects of alendronate in postmenopausal Chinese women with osteoporosis or osteopenia. In the study, 500 postmenopausal women in Shanghai area with osteoporosis or osteopenia were included. All participants were treated with weekly oral alendronate 70 mg, daily calcium 600 mg and vitamin D 125 IU for 12 months. Nine tagging single-nucleotide polymorphisms (SNPs) in SOST gene were genotyped. Bone mineral density of lumbar spine (L1–L4), left femoral neck and total hip were measured at baseline and after 1 year of treatment, respectively. In the study, 450 subjects completed the 1-year follow-up. The rs865429 was significantly associated with the % change of BMD at the femoral neck (P = 0.007). GG carriers seemed to be at an advantage after treatment of alendronate. Compared with AG and AA heterozygote, GG homozygote had the highest % change of BMD (3.100 ± 2.899%) at femoral neck. The odds ratio (95% confidence) of GG homozygote to be responders at femoral neck was 1.921 (1.211–3.048). Two haplotypes GG and AC constituted by rs865429 and rs851057 were associated with the % change of BMD at femoral neck and total hip, respectively. Therefore, the common variation of SOST gene contribute to the therapeutic response to alendronate treatment in Chinese women with osteoporosis or osteopenia.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1

References

  1. 1.

    Xia WB, He SL, Xu L, Liu AM, Jiang Y, Li M, et al. Rapidly increasing rates of hip fracture in Beijing, China. J Bone Mineral Res. 2012;27:125–9.

    Article  Google Scholar 

  2. 2.

    Evans WE, Relling MV. Moving towards individualized medicine with pharmacogenomics. Nature. 2004;429:464–8.

    CAS  Article  Google Scholar 

  3. 3.

    Conti V, Russomanno G, Corbi G, Toro G, Simeon V, Filippelli W, et al. A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy. Int J Mol Sci. 2015;16:5452–66.

    CAS  Article  Google Scholar 

  4. 4.

    Creatsa M, Pliatsika P, Kaparos G, Antoniou A, Armeni E, Tsakonas E, et al. The effect of vitamin D receptor BsmI genotype on the response to osteoporosis treatment in postmenopausal women: a pilot study. J Obstet Gynaecol Res. 2011;37:1415–22.

    Article  Google Scholar 

  5. 5.

    Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, et al. Effectiveness of alendronate treatment in postmenopausal women with osteoporosis: relationship with BsmI vitamin D receptor genotypes. Clin Endocrinol (Oxf). 2003;58:365–71.

    CAS  Article  Google Scholar 

  6. 6.

    Qureshi AM, Herd RJ, Blake GM, Fogelman I, Ralston SH. COLIA1 Sp1 polymorphism predicts response of femoral neck bone density to cyclical etidronate therapy. Calcif Tissue Int. 2002;70:158–63.

    CAS  Article  Google Scholar 

  7. 7.

    Wang C, Zheng H, He JW, Zhang H, Yue H, Hu WW, et al. Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. Pharm J. 2015;15:158–64.

    CAS  Google Scholar 

  8. 8.

    Zheng H, Wang C, He JW, Fu WZ, Zhang ZL. OPG, RANKL, and RANK gene polymorphisms and the bone mineral density response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia. Pharm Genom. 2016;26:12–19.

    CAS  Article  Google Scholar 

  9. 9.

    Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006;133:3231–44.

    CAS  Article  Google Scholar 

  10. 10.

    Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8:751–64.

    CAS  Article  Google Scholar 

  11. 11.

    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–76.

    CAS  Article  Google Scholar 

  12. 12.

    Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:6267–76.

    CAS  Article  Google Scholar 

  13. 13.

    Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280:26770–5.

    CAS  Article  Google Scholar 

  14. 14.

    Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Mineral Res. 2009;24:171–8.

    CAS  Article  Google Scholar 

  15. 15.

    Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19:1842–4.

    CAS  Article  Google Scholar 

  16. 16.

    van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CW. SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev. 2005;16:319–27.

    Article  Google Scholar 

  17. 17.

    Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet. 2002;110:144–52.

    Article  Google Scholar 

  18. 18.

    Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 2005;15:928–35.

    CAS  Article  Google Scholar 

  19. 19.

    Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43.

    CAS  Article  Google Scholar 

  20. 20.

    Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Mineral Res. 2008;23:860–9.

    Article  Google Scholar 

  21. 21.

    Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, et al. Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci USA. 2012;109:14092–7.

    CAS  Article  Google Scholar 

  22. 22.

    Tian X, Jee WS, Li X, Paszty C, Ke HZ. Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone. 2011;48:197–201.

    CAS  Article  Google Scholar 

  23. 23.

    Zhang H, He JW, Wang C, Zhang Z, Yue H, Hu WW, et al. Associations of polymorphisms in the SOST gene and bone mineral density in postmenopausal Chinese Women. Osteoporos Int. 2014;25:2797–803.

    CAS  Article  Google Scholar 

  24. 24.

    He J, Zhang H, Wang C, Zhang Z, Yue H, Hu W, et al. Associations of serum sclerostin and polymorphisms in the SOST gene with bone mineral density and markers of bone metabolism in postmenopausal Chinese women. J Clin Endocrinol Metab. 2014;99:E665–673.

    CAS  Article  Google Scholar 

  25. 25.

    Lee DO, Kim H, Ku SY, Kim SH, Kim JG. Association between polymorphisms in sclerostin, dickkopfs and secreted frizzled-related protein genes and bone mineral density in postmenopausal Korean women. Gynecol Obstet Invest. 2014;77:186–93.

    CAS  Article  Google Scholar 

  26. 26.

    Zhou PR, Xu XJ, Zhang ZL, Liao EY, Chen DC, Liu J, et al. SOST polymorphisms and response to alendronate treatment in postmenopausal Chinese women with osteoporosis. Pharmacogenomics. 2015;16:1077–88.

    CAS  Article  Google Scholar 

  27. 27.

    Gao G, Zhang ZL, Zhang H, Hu WW, Huang QR, Lu JH, et al. Hip axis length changes in 10,554 males and females and the association with femoral neck fracture. J Clin Densitom. 2008;11:360–6.

    Article  Google Scholar 

  28. 28.

    Zhang H, Huang QR, Gu JM, Hu WW, Liu YJ, Hu YQ, et al. Comparison of the effects of cholecalciferol and calcitriol on calcium metabolism and bone turnover in Chinese postmenopausal women with vitamin D insufficiency. Acta Pharmacol Sin. 2012;33:490–5.

    CAS  Article  Google Scholar 

  29. 29.

    Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA. 1999;96:133–8.

    CAS  Article  Google Scholar 

  30. 30.

    Zhou PR, Liu HJ, Liao EY, Zhang ZL, Chen de C, Liu J, et al. LRP5 polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis. Pharmacogenomics. 2014;15:821–31.

    CAS  Article  Google Scholar 

  31. 31.

    Wang JY, Zhou PR, Liu Y, Xu XJ, Ma DD, Xia WB, et al. The analysis of DKK1 polymorphisms in relation to skeletal phenotypes and bone response to alendronate treatment in Chinese postmenopausal women. Pharmacogenomics. 2016;17:209–17.

    CAS  Article  Google Scholar 

  32. 32.

    Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296:1644–6.

    CAS  Article  Google Scholar 

  33. 33.

    Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005;280:21162–8.

    CAS  Article  Google Scholar 

  34. 34.

    Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8:727–38.

    CAS  Article  Google Scholar 

  35. 35.

    Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, et al. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone. 2004;35:828–35.

    CAS  Article  Google Scholar 

  36. 36.

    Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37:148–58.

    CAS  Article  Google Scholar 

  37. 37.

    Kramer I, Loots GG, Studer A, Keller H, Kneissel M. Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Mineral Res. 2010;25:178–89.

    CAS  Article  Google Scholar 

  38. 38.

    Uitterlinden AG, Arp PP, Paeper BW, Charmley P, Proll S, Rivadeneira F, et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. Am J Hum Genet. 2004;75:1032–45.

    CAS  Article  Google Scholar 

  39. 39.

    Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, et al. Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Bone. 2002;31:515–9.

    CAS  Article  Google Scholar 

  40. 40.

    Lewiecki EM, Gordon CM, Baim S, Leonard MB, Bishop NJ, Bianchi ML, et al. International Society for Clinical Densitometry 2007 adult and pediatric official positions. Bone. 2008;43:1115–21.

    Article  Google Scholar 

  41. 41.

    Iwamoto J, Takeda T, Sato Y, Uzawa M. Early changes in urinary cross-linked N-terminal telopeptides of type I collagen level correlate with 1-year response of lumbar bone mineral density to alendronate in postmenopausal Japanese women with osteoporosis. J Bone Miner Metab. 2005;23:238–42.

    CAS  Article  Google Scholar 

  42. 42.

    Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al. Global variation in copy number in the human genome. Nature. 2006;444:444–54.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Z.-L. Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Fu, W., He, J. et al. Association between SOST gene polymorphisms and response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. Pharmacogenomics J 19, 490–498 (2019). https://doi.org/10.1038/s41397-018-0059-8

Download citation

Search