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Pharmacogenetics of Osteoporosis: Future Perspectives

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Abstract

Drug response is known to be highly variable among treated patients and affected by many factors, such as age, sex, ethnicity, concomitant diseases, and pharmacological therapy. However, sequence variants in the human genome are now considered an important cause of differences in drug responses. Pharmacogenetics, which is the utilization of individual genetic data to predict the outcome of drug treatment with respect to both beneficial and adverse effects, represents an emerging field of genetics with the potential to become useful for the identification of the most effective drug and the most beneficial dose for a given individual. On the basis of these considerations and thanks to recent advances in genetics and molecular biology, pharmacogenetics is becoming a flowering field in both basic and clinical research. Nevertheless, to date the opportunity to apply pharmacogenetic approaches to drug response and the possibility to use genetic screenings to tailor decisions about pharmacological treatments have limited applications. And this is even truer in the field of osteoporosis, in which pharmacogenetic studies are in their infancy. In this paper we review the most recent data on pharmacogenetics of osteoporosis, highlighting the presentations at the Second International Meeting on Pharmacogenetics of Osteoarticular Disorders held in Florence in April 2008.

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References

  1. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA et al (2001) The sequence of the human genome. Science 291(5507):1304–1351

    Article  PubMed  CAS  Google Scholar 

  2. Zhang W, Ratain MJ, Dolan ME (2008) The HapMap resource is providing new insights into ourselves and its application to pharmacogenomics. Pharmacogenet Genomics 18(6):545–549

    Article  PubMed  CAS  Google Scholar 

  3. Huang RS, Duan S, Bleibel WK, Kistner EO, Zhang W, Clark TA, Chen TX, Schweitzer AC, Blume JE, Cox NJ, Dolan ME (2007) A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci USA 104(23):9758–9763

    Article  PubMed  CAS  Google Scholar 

  4. Huang RS, Duan S, Shukla SJ, Kistner EO, Clark TA, Chen TX, Schweitzer AC, Blume JE, Dolan ME (2007) Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am J Hum Genet 81(3):427–437

    Article  PubMed  CAS  Google Scholar 

  5. Schneeweiss S, Hasford J, Göttler M, Hoffmann A, Riethling AK, Avorn J (2002) Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study. Eur J Clin Pharmacol 58(4):285–291

    Article  PubMed  Google Scholar 

  6. Eichelbaum M, Ingelman-Sundberg M, Evans WE (2006) Pharmacogenomics and individualized drug therapy. Annu Rev Med 57:119–137

    Article  PubMed  CAS  Google Scholar 

  7. Marsh S, Van Booven DJ, McLeod HL (2006) Global pharmacogenetics: giving the genome to the masses. Pharmacogenomics 7(4):625–631

    Article  PubMed  CAS  Google Scholar 

  8. Goodsaid F, Frueh F (2006) Process map proposal for the validation of genomic biomarkers. Pharmacogenomics 7(5):773–782

    Article  PubMed  CAS  Google Scholar 

  9. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353(2):133–144

    Article  PubMed  CAS  Google Scholar 

  10. Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, Haber DA, Lynch TJ, Meyerson M, Johnson BE, Jänne PA (2006) Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 12(13):3908–3914

    Article  PubMed  CAS  Google Scholar 

  11. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287(13):1690–1698

    Article  PubMed  CAS  Google Scholar 

  12. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352(22):2285–2293

    Article  PubMed  CAS  Google Scholar 

  13. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353(9154):717–719

    Article  PubMed  CAS  Google Scholar 

  14. Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96(5):1816–1819

    PubMed  CAS  Google Scholar 

  15. Roche AmpliChip Package Insert. http://www.amplichip.us/documents/AmpliChip_CYP450_Test_Package_Insert.pdf

  16. www.emea.europa.eu/pdfs/human/pharmacogenetics/2022704en.pdf

  17. www.emea.europa.eu/pdfs/human/pharmacogenetics/12851706enfin.pdf

  18. Nguyen TV, Eisman JA (2006) Pharmacogenomics of osteoporosis: opportunities and challenges. J Musculoskelet Neuronal Interact 6:62–72

    PubMed  CAS  Google Scholar 

  19. Gennari L, Becherini L, Falchetti A, Masi L, Massart F, Brandi ML (2002) Genetics of osteoporosis: role of steroid hormone receptor gene polymorphisms. J Steroid Biochem Mol Biol 81(1):1–24

    Article  PubMed  CAS  Google Scholar 

  20. Liu YJ, Shen H, Xiao P, Xiong DH, Li LH, Recker RR, Deng HW (2006) Molecular genetic studies of gene identification for osteoporosis: a 2004 update. Bone Miner Res 21(10):1511–1535

    Article  CAS  Google Scholar 

  21. Rosen CJ, Kessenich CR (1997) The pathophysiology and treatment of postmenopausal osteoporosis. An evidence-based approach to estrogen replacement therapy. Endocrinol Metab Clin North Am 26:295–311

    CAS  Google Scholar 

  22. Ongphiphadhanakul B, Chanprasertyothin S, Payatikul P, Tung SS, Piaseu N, Chailurkit L, Chansirikarn S, Puavilai G, Rajatanavin R (2000) Oestrogen-receptor-alpha gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women. Clin Endocrinol (Oxf) 52:581–585

    Article  CAS  Google Scholar 

  23. Salmén T, Heikkinen AM, Mahonen A, Kröger H, Komulainen M, Saarikoski S, Honkanen R, Mäenpää PH (2000) The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpha genotype in early postmenopausal women. J Bone Miner Res 15:2479–2486

    Article  PubMed  Google Scholar 

  24. Yahata T, Quan J, Tamura N, Nagata H, Kurabayashi T, Tanaka K (2005) Association between single nucleotide polymorphisms of estrogen receptor alpha gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women. Hum Reprod 20:1860–1866

    Article  PubMed  CAS  Google Scholar 

  25. Rapuri PB, Gallagher JC, Knezetic JA, Haynatzka V (2006) Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen. Maturitas 53(4):371–379

    Article  PubMed  CAS  Google Scholar 

  26. Kurabayashi T, Tomita M, Matsushita H, Yahata T, Honda A, Takakuwa K, Tanaka K (1999) Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women. Am J Obstet Gynecol 180:1115–1120

    Article  PubMed  CAS  Google Scholar 

  27. Kurabayashi T, Matsushita H, Tomita M, Kato N, Kikuchi M, Nagata H, Honda A, Yahata T, Tanaka K (2004) Association of vitamin D and estrogen receptor gene polymorphism with the effects of longterm hormone replacement therapy on bone mineral density. J Bone Miner Metab 22:241–247

    Article  PubMed  CAS  Google Scholar 

  28. Giguère Y, Dodin S, Blanchet C, Morgan K, Rousseau F (2000) The association between heel ultrasound and hormone replacement therapy is modulated by a two-locus vitamin D and estrogen receptor genotype. J Bone Miner Res 15(6):1076–1084

    Article  PubMed  Google Scholar 

  29. Liel Y, Shany S, Smirnoff P, Schwartz B (1999) Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinology 140(1):280–285

    Article  PubMed  CAS  Google Scholar 

  30. Simsek M, Cetin Z, Bilgen T, Taskin O, Luleci G, Keser I (2008) Effects of hormone replacement therapy on bone mineral density in Turkish patients with or without COL1A1 Sp1 binding site polymorphism. J Obstet Gynaecol Res 34(1):73–77

    PubMed  CAS  Google Scholar 

  31. Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, Riggs BL (1998) Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 13:1747–1754

    Article  PubMed  CAS  Google Scholar 

  32. Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, Zullo F, Nappi C, Nunziata V (2003) Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes. Hum Reprod 18:192–198

    Article  PubMed  CAS  Google Scholar 

  33. Graafmans WC, Lips P, Ooms ME, van Leeuwen JP, Pols HA, Uitterlinden AG (1997) The effect of vitamin D supplementation on the bone mineral density of the femoral neck is associated with vitamin D receptor genotype. J Bone Miner Res 12(8):1241–1245

    Article  PubMed  CAS  Google Scholar 

  34. Wishart JM, Horowitz M, Need AG, Scopacasa F, Morris HA, Clifton PM, Nordin BE (1997) Relations between calcium intake, calcitriol, polymorphisms of the vitamin D receptor gene, and calcium absorption in premenopausal women. Am J Clin Nutr 65(3):798–802

    PubMed  CAS  Google Scholar 

  35. Delmas PD (2005) The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol 17:462–466

    PubMed  CAS  Google Scholar 

  36. Farrugia MC, Summerlin DJ, Krowiak E, Huntley T, Freeman S, Borrowdale R, Tomich C (2006) Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 116:115–120

    Article  PubMed  Google Scholar 

  37. Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567–1575

    Article  PubMed  Google Scholar 

  38. Cummings SR, Schwartz AV, Black DM (2007) Alendronate and atrial fibrillation. N Engl J Med 356:1895–1896

    Article  PubMed  CAS  Google Scholar 

  39. Marc J, Prezelj J, Komel R, Kocijancic A (1999) VDR genotype and response to etidronate therapy in late postmenopausal women. Osteoporos Int 10:303–306

    Article  PubMed  CAS  Google Scholar 

  40. Palomba S, Orio F Jr, Russo T, Falbo A, Tolino A, Manguso F, Nunziata V, Mastrantonio P, Lombardi G, Zullo F (2005) 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 16:943–952

    Article  PubMed  CAS  Google Scholar 

  41. Arko B, Prezelj J, Komel R, Kocijancic A, Marc J (2002) No major effect of estrogen receptor beta gene RsaI polymorphism on bone mineral density and response to alendronate therapy in postmenopausal osteoporosis. J Steroid Biochem Mol Biol 81:147–152

    Article  PubMed  CAS  Google Scholar 

  42. Qureshi AM, Herd RJ, Blake GM, Fogelman I, Ralston SH (2002) Colia1 Sp1 polymorphism predicts response of femoral neck bone density to cyclical etidronate therapy. Calcif Tissue Int 70:158–163

    Article  PubMed  CAS  Google Scholar 

  43. Benford HL, Frith JC, Auriola S, Mönkkönen J, Rogers MJ (1999) Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 56:131–140

    PubMed  CAS  Google Scholar 

  44. van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S (1999) Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264:108–111

    Article  PubMed  Google Scholar 

  45. Marini F, Falchetti A, Silvestri S, Bagger Y, Luzi E, Tanini A, Christiansen C, Brandi ML (2008) 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 24(9):2609–2615

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This paper was supported by the Fondazione Ente Cassa di Risparmio di Firenze, Florence, Italy, through the project “Creazione di un laboratorio per lo studio della biologia dei tessuti calcificati,” and by FIRMO Fondazione Raffaella Becagli to M.L.B.

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Authors and Affiliations

  1. Mineral and Bone Metabolism Unit, Department of Internal Medicine, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Francesca Marini & Maria Luisa Brandi

  2. DeGene Spin-off, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Maria Luisa Brandi

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  1. Francesca Marini
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  2. Maria Luisa Brandi
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Correspondence to Maria Luisa Brandi.

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Marini, F., Brandi, M.L. Pharmacogenetics of Osteoporosis: Future Perspectives. Calcif Tissue Int 84, 337–347 (2009). https://doi.org/10.1007/s00223-009-9226-x

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  • DOI: https://doi.org/10.1007/s00223-009-9226-x

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