Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density

The Pharmacogenomics Journal volume 15, pages 158–164 (2015)Cite this article

Subjects

Abstract

Alendronate is an antiosteoporotic drug that targets the mevalonate pathway. To investigate whether the genetic variations in this pathway affect the clinical efficacy of alendronate in postmenopausal Chinese women with osteopenia or osteoporosis, 23 single-nucleotide polymorphisms (SNPs) in 7 genes were genotyped in 500 patients treated with alendronate for 12 months. Bone mineral density (BMD) was measured at baseline and after 12 months. The rs10161126 SNP in the 3′ flanking region of MVK and the GTCCA haplotype in FDFT1 were significantly associated with therapeutic response. A 6.6% increase in BMD in the lumbar spine was observed in the GG homozygotes of rs10161126; AG heterozygotes and AA homozygotes experienced a 4.4 and 4.5% increase, respectively. The odds ratio (95% confidence interval) of G allele carriers to be responders in lumbar spine BMD was 2.06 (1.08–6.41). GTCCA haplotype in FDFT1 was more frequently detected in the group of responders than in the group of non-responders at the total hip (2.6 vs 0.5%, P=0.009). Therefore, MVK and FDFT1 polymorphisms are genetic determinants for BMD response to alendronate therapy in postmenopausal Chinese women.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Dawson-Hughes B, Looker AC, Tosteson AN, Johansson H, Kanis JA, Melton LJ 3rd . The potential impact of the National Osteoporosis Foundation guidance on treatment eligibility in the USA: an update in NHANES 2005-2008. Osteoporos Int 2012; 23: 811–820.

    Article  CAS  Google Scholar 

  2. 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 Miner Res 2012; 27: 125–129.

    Article  Google Scholar 

  3. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008; 19: 399–428.

    Article  CAS  Google Scholar 

  4. Watts NB, Adler RA, Bilezikian JP, Drake MT, Eastell R, Orwoll ES et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 1802–1822.

    Article  CAS  Google Scholar 

  5. Ogawa S, Ouchi Y . [Therapeutic purpose and treatment guideline of osteoporosis]. Clin Calcium 2012; 22: 885–889.

    PubMed  Google Scholar 

  6. Orimo H . Bone and calcium update; diagnosis and therapy of metabolic bone disease update. Guideline for prevention and treatment of osteoporosis update. Clin Calcium 2011; 21: 123–143.

    PubMed  Google Scholar 

  7. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation: Washington, DC, USA, 2008.

  8. Dawson-Hughes B . A revised clinician's guide to the prevention and treatment of osteoporosis. J Clin Endocrinol Metab 2008; 93: 2463–2465.

    Article  CAS  Google Scholar 

  9. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. Jama 1998; 280: 2077–2082.

    Article  CAS  Google Scholar 

  10. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM . Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc 2005; 80: 343–349.

    Article  CAS  Google Scholar 

  11. Gallagher JC, Rosen CJ, Chen P, Misurski DA, Marcus R . Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis. Bone 2006; 39: 1268–1275.

    Article  CAS  Google Scholar 

  12. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM et al. Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab 2006; 91: 2631–2637.

    Article  CAS  Google Scholar 

  13. Kim SW, Park DJ, Park KS, Kim SY, Cho BY, Lee HK et al. Early changes in biochemical markers of bone turnover predict bone mineral density response to antiresorptive therapy in Korean postmenopausal women with osteoporosis. Endocr J 2005; 52: 667–674.

    Article  CAS  Google Scholar 

  14. Crilly RG, Sebaldt RJ, Hodsman AB, Adachi JD, Brown JP, Goldsmith CH et al. Predicting subsequent bone density response to intermittent cyclical therapy with etidronate from initial density response in patients with osteoporosis. Osteoporos Int 2000; 11: 607–614.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. 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: 158–163.

    Article  CAS  Google Scholar 

  17. 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: 365–371.

    Article  CAS  Google Scholar 

  18. Palomba S, Orio F Jr., Russo T, Falbo A, Tolino A, Manguso F et al. BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial. Osteoporos Int 2005; 16: 943–952.

    Article  CAS  Google Scholar 

  19. Eisman JA . Pharmacogenetics of the vitamin D receptor and osteoporosis. Drug Metab Dispos 2001; 29 (4 Pt 2): 505–512.

    CAS  PubMed  Google Scholar 

  20. Coxon FP, Thompson K, Rogers MJ . Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006; 6: 307–312.

    Article  CAS  Google Scholar 

  21. Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann NY Acad Sci 2007; 1117: 209–257.

    Article  CAS  Google Scholar 

  22. Russell RG, Watts NB, Ebetino FH, Rogers MJ . Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19: 733–759.

    Article  CAS  Google Scholar 

  23. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G . Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 2000; 373: 231–241.

    Article  CAS  Google Scholar 

  24. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP et al. Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci USA 2007; 104: 10022–10027.

    Article  CAS  Google Scholar 

  25. Choi HJ, Choi JY, Cho SW, Kang D, Han KO, Kim SW et al. Genetic polymorphism of geranylgeranyl diphosphate synthase (GGSP1) predicts bone density response to bisphosphonate therapy in Korean women. Yonsei Med J 2010; 51: 231–238.

    Article  CAS  Google Scholar 

  26. Olmos JM, Zarrabeitia MT, Hernandez JL, Sanudo C, Gonzalez-Macias J, Riancho JA . Common allelic variants of the farnesyl diphosphate synthase gene influence the response of osteoporotic women to bisphosphonates. Pharmacogenomics J 2012; 12: 227–232.

    Article  CAS  Google Scholar 

  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: 360–366.

    Article  Google Scholar 

  28. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008; 371: 1505–1512.

    Article  CAS  Google Scholar 

  29. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  30. Colon-Emeric CS . Ten vs five years of bisphosphonate treatment for postmenopausal osteoporosis: enough of a good thing. JAMA 2006; 296: 2968–2969.

    Article  CAS  Google Scholar 

  31. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995; 333: 1437–1443.

    Article  CAS  Google Scholar 

  32. 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: 1115–1121.

    Article  Google Scholar 

  33. Marini F, Falchetti A, Silvestri S, Bagger Y, Luzi E, Tanini A et al. Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis. Curr Med Res Opin 2008; 24: 2609–2615.

    Article  CAS  Google Scholar 

  34. Turner CH . Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 2002; 13: 97–104.

    Article  CAS  Google Scholar 

  35. Schechter I, Conrad DG, Hart I, Berger RC, McKenzie TL, Bleskan J et al. Localization of the squalene synthase gene (FDFT1) to human chromosome 8p22-p23.1. Genomics 1994; 20: 116–118.

    Article  Google Scholar 

  36. Do R, Kiss RS, Gaudet D, Engert JC . Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway. Clin Genet 2009; 75: 19–29.

    Article  CAS  Google Scholar 

  37. Breitling R, Laubner D, Clizbe D, Adamski J, Krisans SK . Isopentenyl-diphosphate isomerases in human and mouse: evolutionary analysis of a mammalian gene duplication. J Mol Evol 2003; 57: 282–291.

    Article  CAS  Google Scholar 

  38. Clizbe DB, Owens ML, Masuda KR, Shackelford JE, Krisans SK . IDI2, a second isopentenyl diphosphate isomerase in mammals. J Biol Chem 2007; 282: 6668–6676.

    Article  CAS  Google Scholar 

  39. Kato T, Emi M, Sato H, Arawaka S, Wada M, Kawanami T et al. Segmental copy-number gain within the region of isopentenyl diphosphate isomerase genes in sporadic amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2010; 402: 438–442.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC) (81070692, 81170803 and 81370978 to ZL Zhang, 81270964 to C Wang and 81200646 to JM Gu), the National Basic Research Program of China (Grant No. 2014CB942903 to ZL Zhang), Academic Leaders in Health Sciences in Shanghai (XBR2011014) and Shanghai Leading Talents Award (051 to ZL Zhang), the Science and Technology Commission of Shanghai municipality (11ZR1427300 to C Wang), the Frontier Technology Joint Research Program of the Shanghai municipal hospitals (SHDC12013115 to ZL Zhang) and the Science and Technology Commission of Chongqing municipality (CSTC2013jcyjC00009 to ZL Zhang). We thank all participants for their cooperation as well as the Drug Innovation Program of the National Science and Technology Project (2011zx09307-001-02).

Author information

Authors and Affiliations

  1. Department of Osteoporosis and Bone Diseases, Metabolic Bone Disease and Genetics Research Unit, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

    C Wang, H Zheng, J-W He, H Zhang, H Yue, W-W Hu, J-M Gu, C Shao, W-Z Fu, Y-Q Hu, M Li, Y-J Liu & Z-L Zhang

  2. Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China

    C Wang, H Zheng, J-W He, H Zhang, H Yue, W-W Hu, J-M Gu, C Shao, W-Z Fu, Y-Q Hu, M Li, Y-J Liu & Z-L Zhang

Authors
  1. C Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-W He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W-W Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-M Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W-Z Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y-Q Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y-J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Z-L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z-L Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, C., Zheng, H., He, JW. et al. Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. Pharmacogenomics J 15, 158–164 (2015). https://doi.org/10.1038/tpj.2014.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2014.52

This article is cited by

Search

Advanced search

Quick links