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Pharmacogenomics of Osteoporosis

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Abstract

Pharmacogenomics and pharmacogenetics are emerging interdisciplinary areas recently defined, respectively as “the investigation of variations of DNA and RNA characteristics as related to drug response”, and the study of “the influence of variations in DNA sequence on drug efficacy and toxicity”. A major challenge of future genetic studies in complex disorders such as osteoporosis is the development of specific genetic tests to identify responders from non-responders as well as to identify patients at higher risk to develop adverse reactions. Even though the knowledge of the genetic determinants of bone fragility and fracture risk has consistently increased over the past decade and despite the parallel development of multiple drugs with antiresorptive or anabolic activity in bone, there is still relatively little known about pharmacogenomics and pharmacogenetics of osteoporosis. This review provides an overview of available information and identifies potential targets for future studies in this field.

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References

  1. Albagha OM, Ralston SH. Genetics and osteoporosis. Rheum Dis Clin North Am. 2006;32:659–80.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Farber CR, Lusis AJ. Future of osteoporosis genetics: enhancing genome-wide association studies. J Bone Miner Res. 2009;24:1937–42.

    Article  PubMed  CAS  Google Scholar 

  4. Novelli G, Borgiani P, Ciccacci C, Di Daniele N, Sirugo G, Papaluca Amati M. Pharmacogenomics: role in medicines approval and clinical use. Public Health Genomics. 2009 (Epub ahead of print).

  5. Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet. 1999;56:247–58.

    Article  PubMed  CAS  Google Scholar 

  6. Spielberg SP. N-acetyltransferases: pharmacogenetics and clinical consequences of polymorphic drug metabolism. J Pharmacokinet Biopharm. 1996;24:509–19.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89–295.

    Article  PubMed  CAS  Google Scholar 

  8. Egan LJ, Derijks LJ, Hommes DW. Pharmacogenomics in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4:21–8.

    Article  PubMed  CAS  Google Scholar 

  9. Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001;98:231–4.

    Article  PubMed  CAS  Google Scholar 

  10. Shin J, Kayser SR, Langaee TY. Pharmacogenetics: from discovery to patient care. Am J Health Syst Pharm. 2009;6:625–37.

    Article  CAS  Google Scholar 

  11. Gennari L, Merlotti D, Martini G, Valleggi F, De Paola V, Nuti R. Vitamin D and its metabolites in the pathogenesis and treatment of osteoporosis. Clin Cases Bone Miner Metab. 2006;3:23–34.

    Google Scholar 

  12. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord. 2001;2:203–16.

    Article  PubMed  CAS  Google Scholar 

  13. Boyan BD, Schwartz Z. Rapid vitamin D-dependent PKC signaling shares features with estrogen-dependent PKC signaling in cartilage and bone. Steroids. 2004;69:591–7.

    Article  PubMed  CAS  Google Scholar 

  14. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting factors alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA. 1992;89:6665–9.

    Article  PubMed  CAS  Google Scholar 

  15. Morrison NA, Cheng JQI, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367:284–7.

    Article  PubMed  CAS  Google Scholar 

  16. Uitterlinden AG, Fang Y, van Meurs JBJ, Pols HAP, van Leeuwen JPTM. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–56.

    Article  PubMed  CAS  Google Scholar 

  17. Fang Y, van Meurs JB, d’Alesio A, Jhamai M, Zhao H, Rivadeneira F, 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;77:807–23.

    Article  PubMed  CAS  Google Scholar 

  18. Grundberg E, Lau EM, Pastinen T, Kindmark A, Nilsson O, Ljunggren O, et al. Vitamin D receptor 3′ haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the MrOS Study in Sweden and Hong Kong. J Bone Miner Res. 2007;22:832–40.

    Article  PubMed  CAS  Google Scholar 

  19. Eisman JA. Pharmacogenetics of the vitamin D receptor and osteoporosis. Drug Metab Dispos. 2001;29:505–12.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Gennari L, De Paola V, Merlotti D, Martini G, Nuti R. Steroid hormone receptor gene polymorphisms and osteoporosis: a pharmacogenomic review. Expert Opin Pharmacother. 2007;8:537–53.

    Article  PubMed  CAS  Google Scholar 

  22. Gennari L, Merlotti D, De Paola V, Martini G, Nuti R. Update on the pharmacogenetics of the vitamin D receptor and osteoporosis. Pharmacogenomics. 2009;10:417–33.

    Article  PubMed  CAS  Google Scholar 

  23. Ferrari SL, Bonjour JP, Rizzoli R. The vitamin D receptor gene and calcium metabolism. Trends Endocrinol Metab. 1998;9:259–64.

    Article  PubMed  CAS  Google Scholar 

  24. Ferrari SL, Rizzoli R, Slosman DO, Bonjour JP. Do dietary calcium and age explain the controversy surrounding the relationship between bone mineral density and Vitamin D receptor gene polymorphisms? J Bone Miner Res. 1998;13:363–70.

    Article  PubMed  CAS  Google Scholar 

  25. Ferrari S, Rizzoli R, Chevallery T, Slosman D, Eisman JA, Bonjour JP. Vitamin D receptor gene polymorphisms and change in lumbar spine bone mineral density. Lancet. 1995;345:423–4.

    Article  PubMed  CAS  Google Scholar 

  26. Krall EA, Parry P, Lichter JB, Dawson-Hughes B. Vitamin D receptor alleles and rates of bone loss: influences of years since menopause and calcium intake. J Bone Miner Res. 1995;10:978–84.

    Article  PubMed  CAS  Google Scholar 

  27. Kiel DP, Myers RH, Cupples LA, Kong XF, Zhu XH, Ordovas J, et al. The Bsm I vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density. J Bone Miner Res. 1997;12:1049–57.

    Article  PubMed  CAS  Google Scholar 

  28. Salamone LM, Glynn NW, Black DM, Ferrell RE, Palermo L, Epstein RS, et al. Determinants of pre-menopausal bone mineral density: the interplay of genetic and lifestyle factors. J Bone Miner Res. 1996;11:1557–65.

    Article  PubMed  CAS  Google Scholar 

  29. Ferrari S, Manen D, Bonjour JP, Slosman D, Rizzoli R. Bone mineral mass and calcium and phosphate metabolism in young men: relationship with vitamin D receptor allelic polymorphisms. J Bone Miner Res. 1999;84:2043–8.

    CAS  Google Scholar 

  30. Morita A, Iki M, Dohi Y, Kagamimori S, Kagawa Y, Yoneshima H. Effects of the Cdx-2 polymorphism of the vitamin D receptor gene and lifestyle factors on bone mineral density in a representative sample of Japanese women: the Japanese Population-based Osteoporosis (JPOS) Study. Calcif Tissue Int. 2005;77:339–47.

    Article  PubMed  CAS  Google Scholar 

  31. Esterle L, Jehan F, Sabatier JP, Garabedian M. Higher milk requirements for bone mineral accrual in adolescent girls bearing specific Caucasian genotypes in the VDR promoter. J Bone Miner Res. 2009;24:1389–97.

    Article  PubMed  CAS  Google Scholar 

  32. Shiekh M, Ramirez A, Emmett M, Santa Ana C, Fordtran J. Role of vitamin D dependent and vitamin D independent mechanisms in absorption of food calcium. J Clin Invest. 1988;81:126–32.

    Article  Google Scholar 

  33. Dawson-Hughes B, Harrris SS, Finneran S. Calcium absorption on high and low calcium intake in relation to vitamin D receptor genotype. J Clin Endocrinol Metab. 1995;80:3657–61.

    Article  PubMed  CAS  Google Scholar 

  34. Wishart JM, Horowitz M, Need AG, Scopacasa F, Morris HA, Clifton PM, et al. Relations between calcium intake, calcitriol, polymorphisms of vitamin D receptor gene and calcium absorption in pre-menopausal women. Am J Clin Nutr. 1997;65:798–802.

    PubMed  CAS  Google Scholar 

  35. Gennari L, Becherini L, Masi L, Gonnelli S, Cepollaro C, Martini S, et al. Vitamin D receptor genotypes and intestinal calcium absorption in post-menopausal women. Calcif Tissue Int. 1997;61:460–3.

    Article  PubMed  CAS  Google Scholar 

  36. Ames SK, Ellis KJ, Gunn SK, Copeland KC, Abrams SA. Vitamin D receptor gene Fok I polymorphism predicts calcium absorption and bone mineral density in children. J Bone Miner Res. 1999;14:740–6.

    Article  PubMed  CAS  Google Scholar 

  37. Barger Lux MJ, Heaney RP, Hayes J, De Luca HF, Johnson ML, Gong G. Vitamin D receptor gene polymorphisms, bone mass, body size and mucosal VDR density. Calcif Tissue Int. 1995;57:161–2.

    Article  PubMed  CAS  Google Scholar 

  38. Kinyamu HK, Gallagher JC, Knezetic JA, De Luca HF, Prahl JM, Lanspa SJ. Effect of vitamin D receptor genotypes on calcium absorption, duodenal vitamin D receptor concentration and serum 1, 25-dihydroxy-vitamin D levels in normal women. Calcif Tissue Int. 1997;60:491–5.

    Article  PubMed  CAS  Google Scholar 

  39. Carling T, Kindmark A, Hellman P, Lundgren E, Ljunghall S, Rastad J, et al. Vitamin D receptor genotypes in primary hyperparathyroidism. Nature Med. 1995;1:1309–11.

    Article  PubMed  CAS  Google Scholar 

  40. Carling T, Ridefelt P, Hellman P, Rastad J, Akerstrom G. Vitamin D receptor polymorphisms correlate to parathyroid cell function in primary hyperparathyroidism. J Clin Endocrinol Metab. 1997;82:1772–5.

    Article  PubMed  CAS  Google Scholar 

  41. Yokoyama K, Shigematsu T, Tsukada T, Ogura Y, Takemoto F, Hara S, et al. Apa I polymorphism in the vitamin D receptor gene may affect the parathyroid response in Japanese with end-stage renal disease. Kidney Int. 1998;53:454–8.

    Article  PubMed  CAS  Google Scholar 

  42. McClure L, Eccleshall TR, Gross C, Villa ML, Lin N, Ramaswamy V, et al. Vitamin D receptor polymorphisms, bone mineral density, and bone metabolism in postmenopausal Mexican–American women. J Bone Miner Res. 1997;12:234–40.

    Article  PubMed  CAS  Google Scholar 

  43. Michaelsson K, Wolk A, Jacobsson A, Kindmark A, Grundberg E, Stiger F, et al. The positive effect of dietary vitamin D intake on bone mineral density in men is modulated by the polyadenosine repeat polymorphism of the vitamin D receptor. Bone. 2006;39:1343–51.

    Article  PubMed  CAS  Google Scholar 

  44. Ingles SA, Haile RW, Henderson BE, Kolonel LN, Nakaichi G, Shi CY, et al. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prev. 1997;6:93–8.

    PubMed  CAS  Google Scholar 

  45. Yamagata Z, Miyamura T, Iijima S, Asaka A, Sasaki M, Kato J, et al. Vitamin D receptor gene polymorphism and bone mineral density in healthy Japanese women. Lancet. 1994;344:1027.

    Article  PubMed  CAS  Google Scholar 

  46. Matsuyama T, Ishii S, Tokita A, Yabuta K, Yamamori S, Morrison NA, et al. Vitamin D receptor genotypes and bone mineral density. Lancet. 1995;345:1238–9.

    Article  PubMed  CAS  Google Scholar 

  47. Graafmans WC, Lips P, Ooms ME, Van Leeuwen JP, Pols HA, Uitterlinden AG. 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. 1997;12:1241–5.

    Article  PubMed  CAS  Google Scholar 

  48. Hunter D, Major P, Arden N, et al. A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs. J Bone Miner Res. 2000;15:2276–83.

    Article  PubMed  CAS  Google Scholar 

  49. Morrison NA, George PM, Vaughan T, Tilyard MW, Frampton CM, Gilchrist NL. Vitamin D receptor genotypes influence the success of calcitriol therapy for recurrent vertebral fracture in osteoporosis. Pharmacogenet Genomics. 2005;15:127–35.

    Article  PubMed  CAS  Google Scholar 

  50. Jehan F, Gaucher C, Nguyen TM, Walrant-Debray O, Lahlou N, Sinding C, et al. Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment. J Clin Endocrinol Metab. 2008;93:4672–82.

    Article  PubMed  CAS  Google Scholar 

  51. Fang Y, van Meurs JB, Arp P, van Leeuwen JP, Hofman A, Pols HA, et al. Vitamin D binding protein genotype and osteoporosis. Calcif Tissue Int. 2009;85:85–93.

    Article  PubMed  CAS  Google Scholar 

  52. Zhang B, Xie W, Krasowski MD. PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics. 2008;9:1695–709.

    Article  PubMed  CAS  Google Scholar 

  53. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.

    Article  Google Scholar 

  54. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American menopause society. Menopause. 2008;15:584–602.

  55. Gennari L, Merlotti D, De Paola V, Calabrò A, Becherini L, Martini G, et al. Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. Am J Epidemiol. 2005;161:307–20.

    Article  PubMed  CAS  Google Scholar 

  56. Massart F, Reginster JY, Brandi ML. Genetics of menopause-associated diseases. Maturitas. 2001;40:103–16.

    Article  PubMed  CAS  Google Scholar 

  57. Tempfer CB, Schneeberger C, Huber JC. Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology. Pharmacogenomics. 2004;5:57–65.

    Article  PubMed  CAS  Google Scholar 

  58. Yamada Y, Ando F, Niino N, Ohta S, Shimokata H. Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density of the femoral neck in elderly Japanese women. J Mol Med. 2002;80:452–60.

    Article  PubMed  CAS  Google Scholar 

  59. Ioannidis JP, Stavrou I, Trikalinos TA, Zois C, Brandi ML, Gennari L, et al. Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res. 2002;17:2048–60.

    Article  PubMed  CAS  Google Scholar 

  60. Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, et al. GENOMOS study. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA. 2004;292:2105–14.

    Article  PubMed  CAS  Google Scholar 

  61. Nott SL, Huang Y, Fluharty BR, Sokolov AM, Huang M, Cox C, et al. Do estrogen receptor β polymorphisms play a role in the pharmacogenetics of estrogen signaling? Curr Pharmacogenomics Person Med. 2008;6:239–59.

    PubMed  CAS  Google Scholar 

  62. Hassager C, Jensen SD, Christiansen C. Non-responders to hormone replacement therapy for the prevention of postmenopausal bone loss: do they exist? Osteoporos Int. 1994;4:36–41.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  64. Ongphiphadhanakul B, Chanprasertyothin S, Payattikul P, Saetung S, Piaseu N, Chailurkit L, et al. Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women. J Endocrinol Invest. 2001;24:749–55.

    PubMed  CAS  Google Scholar 

  65. Han KO, Moon IG, Kang YS, Chung HY, Min HK, Han IK. Non-association of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean post-menopausal women. J Clin Endocrinol Metab. 1997;82:991–5.

    Article  PubMed  CAS  Google Scholar 

  66. Kobayashi N, Fujino T, Shirogane T, Furuta I, Kobamatsu Y, Yaegashi M, et al. Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen. Maturitas. 2002;41:193–201.

    Article  PubMed  CAS  Google Scholar 

  67. Kurabayashi T, Matsushita H, Kato N, Kato N, Kikuchi M, Nagata H, et al. Effect of vitamin D receptor and estrogen receptor gene polymorphism on the relationship between dietary calcium and bone mineral density in Japanese women. J Bone Miner Metab. 2004;22:139–47.

    Article  PubMed  CAS  Google Scholar 

  68. Salmén T, Heikkinen AM, Mahonen A, Kröger H, Komulainen M, Saarikoski S, et al. Early post-menopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy. J Bone Miner Res. 2000;15:315–21.

    Article  PubMed  Google Scholar 

  69. Bagger YZ, Hassager C, Heegaard AM, Christiansen C. Vitamin D receptor and estrogen receptor gene polymorphisms in postmenopausal Danish women: no relation to bone markers or serum lipoproteins. Climacteric. 2000;3:84–91.

    Article  PubMed  CAS  Google Scholar 

  70. Deng HW, Li J, Li JL, Johnson M, Gong G, Davis KM, et al. Change of bone mass in post-menopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes. Hum Genet. 1998;103:576–85.

    Article  PubMed  CAS  Google Scholar 

  71. Giguere Y, Dodin S, Blanchet C, Morgan K, Rousseau F. 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. 2000;15:1076–84.

    Article  PubMed  CAS  Google Scholar 

  72. Kurabayashi T, Tomita M, Matsushita H, Yahata T, Honda A, Takakuwa K, et al. 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. 1999;180:1115–20.

    Article  PubMed  CAS  Google Scholar 

  73. Ongphiphadhanakul B, Chanprasertyothin S, Payatikul P, Tung SS, Piaseu N, Chailurkit L, et al. Oestrogen-receptor-alpha gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women. Clin Endocrinol. 2000;52:581–5.

    Article  CAS  Google Scholar 

  74. Salmén T, Heikkinen AM, Mahonen A, Kröger H, Komulainen M, Saarikoski S, et al. The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor-α genotype in early post-menopausal women. J Bone Miner Res. 2000;15:2479–86.

    Article  PubMed  Google Scholar 

  75. Yahata T, Quan J, Tamura N, Nagata H, Kurabayashi T, Tanaka K. 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. 2005;20:1860–6.

    Article  PubMed  CAS  Google Scholar 

  76. Silvestri S, Thomsen AB, Gozzini A, Bagger Y, Christiansen C, Brandi ML. Estrogen receptor alpha and beta polymorphisms: is there an association with bone mineral density, plasma lipids, and response to postmenopausal hormone therapy? Menopause. 2006;13:451–61.

    Article  PubMed  Google Scholar 

  77. Rapuri PB, Gallagher JC, Knezetic JA, Haynatzka V. Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen. Maturitas. 2006;53:371–9.

    Article  PubMed  CAS  Google Scholar 

  78. Massart F. Human races and pharmacogenomics of effective bone treatments. Gynecol Endocrinol. 2005;20:36–44.

    Article  PubMed  CAS  Google Scholar 

  79. Ohlendorff SD, Tofteng CL, Jensen JE, Petersen S, Civitelli R, Fenger M, et al. Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics. 2007;17:555–67.

    Article  PubMed  CAS  Google Scholar 

  80. Langhdal BL. The genetics of response to estrogen treatment. Clin Cases Miner Bone Metab. 2009;6(1):44–9.

    Google Scholar 

  81. Quan J, Yahata T, Tamura N, Nagata H, Tanaka K. Relationship between single nucleotide polymorphisms in CYP1A1 and CYP1B1 genes and the bone mineral density and serum lipid profiles in postmenopausal Japanese women taking hormone therapy. Menopause. 2009;16:171–6.

    Article  PubMed  Google Scholar 

  82. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002;105:1879–82.

    Article  PubMed  CAS  Google Scholar 

  83. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med. 2002;346:967–74.

    Article  PubMed  CAS  Google Scholar 

  84. Herrington DM, Howard TD. ER-alpha variants and the cardiovascular effects of hormone replacement therapy. Pharmacogenomics. 2003;4:269–77.

    Article  PubMed  CAS  Google Scholar 

  85. Herrington DM. Role of estrogen receptor-alpha in pharmacogenetics of estrogen action. Curr Opin Lipidol. 2003;14:145–50.

    Article  PubMed  CAS  Google Scholar 

  86. Lamon-Fava S, Asztalos BF, Howard TD, Reboussin DM, Horvath KV, Schaefer EJ, Herrington DM. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women. Clin Endocrinol (Oxf). 2009 (Epub ahead of print).

  87. Van Duijnhoven FJ, Peeters PH, Warren RM, et al. Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density. Cancer Epidemiol Biomarkers Prev. 2006;15:462–7.

    Article  PubMed  Google Scholar 

  88. Herrington DM, Klein KP. Invited review: pharmacogenetics of estrogen replacement therapy. J Appl Physiol. 2001;91:2776–84.

    PubMed  CAS  Google Scholar 

  89. Bray PF, Howard TD, Vittinghoff E, Sane DC, Herrington DM. Effect of genetic variations in platelet glycoproteins Ibalpha and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy. Blood. 2007;109:1862–9.

    Article  PubMed  CAS  Google Scholar 

  90. Riggs L, Hartmann LC. Selective estrogen-receptor modulators-mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618–29.

    Article  PubMed  CAS  Google Scholar 

  91. Gennari L, Merlotti D, Valleggi F, Martini G, Nuti R. Selective estrogen receptor modulators for postmenopausal osteoporosis: current state of development. Drugs Aging. 2007;24:361–79.

    Article  PubMed  CAS  Google Scholar 

  92. Heilberg IP, Hernandez E, Alonzo E, Valera R, Ferreira LG, Gomes SA, et al. Estrogen receptor (ER) gene polymorphism may predict the bone mineral density response to raloxifene in postmenopausal women on chronic hemodialysis. Ren Fail. 2005;27:155–61.

    PubMed  CAS  Google Scholar 

  93. Zhang ZL, He JW, Qin YJ, Huang QR, Liu YJ, Hu YQ, et al. Association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride on bone mineral density and bone turnover markers in postmenopausal women with osteoporosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006;23:129–33.

    PubMed  CAS  Google Scholar 

  94. Yoneda K, Tanji Y, Ikeda N, Miyoshi Y, Taguchi T, Tamaki Y, et al. Influence of adjuvant treatment on bone mineral density and bone turnover markers in postmenopausal breast cancer patients in Japan. Cancer Lett. 2002;186:223–30.

    Article  PubMed  CAS  Google Scholar 

  95. Garber K. Tamoxifen pharmacogenetics moves closer to reality. J Natl Cancer Inst. 2005;97:412–3.

    Article  PubMed  Google Scholar 

  96. Brauch H, Mürdter TE, Eichelbaum M, Schwab M. Pharmacogenomics of tamoxifen therapy. Clin Chem. 2009;55:1770–82.

    Article  PubMed  CAS  Google Scholar 

  97. Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, et al. Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes. Hum Reprod. 2003;18:192–8.

    Article  PubMed  CAS  Google Scholar 

  98. 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;16:943–52.

    Article  PubMed  CAS  Google Scholar 

  99. Gennari L, Merlotti D, Nuti R. Perspectives in the treatment and prevention of osteoporosis. Drugs Today (Barc). 2009;45:629–47.

    Article  CAS  Google Scholar 

  100. Delmas PD. The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol. 2005;17:462–6.

    PubMed  CAS  Google Scholar 

  101. Nguyen TV. Pharmacogenetics of anti-resorptive therapy efficacy: a Bayesian interpretation. Osteoporos Int. 2005;16:857–60.

    Article  PubMed  Google Scholar 

  102. 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.

    Article  CAS  Google Scholar 

  103. Mossetti G, Gennari L, Rendina D, De Filippo G, Merlotti D, De Paola V, et al. Vitamin D receptor gene polymorphisms predict acquired resistance to clodronate treatment in patients with Paget’s disease of bone. Calcif Tissue Int. 2008;83:414–24.

    Article  PubMed  CAS  Google Scholar 

  104. Stewart TL, Roschger P, Misof BM, Mann V, Fratzl P, Klaushofer K, et al. Association of COLIA1 Sp1 alleles with defective bone nodule formation in vitro and abnormal bone mineralisation in vivo. Calcif Tissue Int. 2005;77:113–8.

    Article  PubMed  CAS  Google Scholar 

  105. Jin H, van’t Hof RJ, Albagha OM, Ralston SH. Promoter and intron 1 polymorphisms of COL1A1 interact to regulate transcription and susceptibility to osteoporosis. Hum Mol Genet. 2009;18:2729–38.

    Article  PubMed  CAS  Google Scholar 

  106. 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.

    Article  PubMed  CAS  Google Scholar 

  107. Meyer S, Haist M, Schaefer S, Ivan D, Ittner JR, Nawroth PP, et al. Association of COLIA1 Sp1 polymorphism with the effect of subcutaneously injected recombinant hGH in GH-deficient adults. Pharmacogenomics. 2008;9:1017–26.

    Article  PubMed  CAS  Google Scholar 

  108. Levy ME, Parker RA, Ferrell RE, Zmuda JM, Greenspan SL. Farnesyl diphosphate synthase: a novel genotype association with bone mineral density in elderly women. Maturitas. 2007;57:247–52.

    Article  PubMed  CAS  Google Scholar 

  109. 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;24:2609–15.

    Article  PubMed  CAS  Google Scholar 

  110. Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood. 2008;112:2709–12.

    Article  PubMed  CAS  Google Scholar 

  111. Ioannidis JP, Ng MY, Sham PC, Zintzaras E, Lewis CM, Deng HW, et al. Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res. 2007;22:173–83.

    Article  PubMed  CAS  Google Scholar 

  112. Vilariño-Güell C, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, et al. PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton. Calcif Tissue Int. 2007;81:270–8.

    Article  PubMed  CAS  Google Scholar 

  113. Minagawa M, Yasuda T, Watanabe T, Minamitani K, Takahashi Y, Goltzman D, et al. Association between AAAG repeat polymorphism in the P3 promoter of the human parathyroid hormone (PTH)/PTH related peptide receptor gene and adult height, urinary pyridinoline excretion and promoter activity. J Clin Endocrinol Metab. 2002;87:1791–6.

    Article  PubMed  CAS  Google Scholar 

  114. Fonseca JE. Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength. Rheumatology (Oxford). 2008;47(Suppl 4):iv17–9.

    Article  CAS  Google Scholar 

  115. Yun FH, Wong BY, Chase M, Shuen AY, Canaff L, Thongthai K, et al. Genetic variation at the calcium-sensing receptor (CASR) locus: implications for clinical molecular diagnostics. Clin Biochem. 2007;40:551–61.

    Article  PubMed  CAS  Google Scholar 

  116. Rothe HM, Shapiro WB, Sun WY, Chou SY. Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl. Pharmacogenet Genomics. 2005;15:29–34.

    Article  PubMed  CAS  Google Scholar 

  117. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155–92.

    Article  PubMed  CAS  Google Scholar 

  118. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008;358:2355–65.

    Article  PubMed  CAS  Google Scholar 

  119. 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;371:1505–12.

    Article  PubMed  CAS  Google Scholar 

  120. O’Rielly DD, Roslin NM, Beyene J, Pope A, Rahman P. TNF-alpha-308 G/A polymorphism and responsiveness to TNF-alpha blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis. Pharmacogenomics J. 2009;9:161–7.

    Article  PubMed  CAS  Google Scholar 

  121. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007;18:1319–28.

    Article  PubMed  CAS  Google Scholar 

  122. Van Rossum EF, Lambert SW. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Prog Horm Res. 2004;59:333–57.

    Article  PubMed  Google Scholar 

  123. Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF. Clinical features associated with glucocorticoid receptor polymorphisms. Ann N Y Acad Sci. 2009;1179:179–98.

    Article  PubMed  CAS  Google Scholar 

  124. Draper N, Walker EA, Bujalska IJ, Tomlinson JW, Chalder SM, Arlt W, et al. Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet. 2003;34:434–9.

    Article  PubMed  CAS  Google Scholar 

  125. Løvås K, Gjesdal CG, Christensen M, Wolff AB, Almås B, Svartberg J, et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur J Endocrinol. 2009;160:993–1002.

    Article  PubMed  CAS  Google Scholar 

  126. Pariante CM. The role of multi-drug resistance p-glycoprotein in glucocorticoid function: studies in animals and relevance in humans. Eur J Pharmacol. 2008; 583263–71.

  127. Choong CS, Wilson EM. Trinucleotide repeats in the human androgen receptor: a molecular basis for disease. J Mol Endocrinol. 1998;21:235–57.

    Article  PubMed  CAS  Google Scholar 

  128. Langley E, Zhou ZX, Wilson EM. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem. 1995;270:29983–90.

    Article  PubMed  CAS  Google Scholar 

  129. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expression with first exon CAG repeat expansions. Mol Endocrinol. 1996;10:1527–35.

    Article  PubMed  CAS  Google Scholar 

  130. Zitzmann M. Mechanisms of disease: pharmacogenetics of testosterone therapy in hypogonadal men. Nat Clin Pract Urol. 2007;4:161–6.

    Article  PubMed  CAS  Google Scholar 

  131. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. Prostate volume and growth in testosterone- substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study. J Clin Endocrinol Metab. 2003;88:2049–54.

    Article  PubMed  CAS  Google Scholar 

  132. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab. 2004;89:6208–17.

    Article  PubMed  CAS  Google Scholar 

  133. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab. 2007;92:3844–53.

    Article  PubMed  CAS  Google Scholar 

  134. Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.

    Article  PubMed  CAS  Google Scholar 

  135. Jorgensen AL, Williamson PR. Methodological quality of pharmacogenetic studies: issues of concern. Stat Med. 2008;27:6547–69.

    Article  PubMed  Google Scholar 

  136. Roses AD. Pharmacogenetics in drug discovery and development: a translational perspective. Nat Rev Drug Discov. 2008;7:807–17.

    Article  PubMed  CAS  Google Scholar 

  137. McLean LA, Gathmann I, Capdeville R, Polymeropoulos MH, Dressman M. Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib. Clin Cancer Res. 2004;10(1 Pt 1):155–65.

    Article  PubMed  CAS  Google Scholar 

  138. Gagna CE, Lambert WC. Novel multistranded, alternative, plasmid and helical transitional DNA and RNA microarrays: implications for therapeutics. Pharmacogenomics. 2009;10:895–914.

    Article  PubMed  CAS  Google Scholar 

  139. Gomez A, Ingelman-Sundberg M. Epigenetic and microRNA-dependent control of cytochrome P450 expression: a gap between DNA and protein. Pharmacogenomics. 2009;10:1067–76.

    Article  PubMed  CAS  Google Scholar 

  140. Mishra PJ, Bertino JR. MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics. 2009;10:399–416.

    Article  PubMed  CAS  Google Scholar 

  141. Howard G, Nguyen T, Morrison N, Watanabe T, Sambrook P, Eisman J, et al. Genetic influences on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women. J Clin Endocrinol Metab. 1995;80:2800–5.

    Google Scholar 

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Correspondence to Luigi Gennari.

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Gennari, L. Pharmacogenomics of Osteoporosis. Clinic Rev Bone Miner Metab 8, 77–94 (2010). https://doi.org/10.1007/s12018-010-9071-5

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