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LRP5 Polymorphisms and Response to Risedronate Treatment in Osteoporotic Men

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Abstract

Genetic factors are important in the pathogenesis of osteoporosis, but little is known about the genetic determinants of treatment response. Previous studies have shown that polymorphisms of the LRP5 gene are associated with bone mineral density (BMD), but the relationship between LRP5 polymorphisms and response to bisphosphonate treatment in osteoporosis has not been studied. In this study we investigated LRP5 polymorphisms in relation to treatment response in a group of 249 osteoporotic or osteopenic men who participated in a 24-month randomized double blind placebo-controlled trial of risedronate treatment. BMD and biochemical markers of bone turnover were measured at baseline and after 6, 12, and 24 months of follow-up. We analyzed two coding polymorphisms of LRP5, which have previously been associated with BMD, V667M (rs4988321) and A1330V (rs3736228), and found a significant association between the A1330V polymorphism and hip BMD at baseline. Subjects with the 1330 Val/Val genotype had 8.4% higher total-hip BMD compared with the other genotype groups (P = 0.009), and similar associations were observed at the femoral neck (P = 0.01) and trochanter (P = 0.002). There was no association between A1330V and spine BMD, however, or between the V667M polymorphism and BMD at any site. The difference in hip BMD between A1330V genotype groups remained significant throughout the study, but there was no evidence of a genotype–treatment interaction in either risedronate- or placebo-treated patients. In conclusion, the LRP5 A1330V polymorphism is associated with hip BMD in osteoporotic men, but allelic variations in LRP5 do not appear to be associated with response to bisphosphonate treatment.

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References

  1. Gullberg B, Johnell O, Kanis JA (1997) World-wide projections for hip fracture. Osteoporos Int 7:407–413

    Article  PubMed  CAS  Google Scholar 

  2. Wehren LE, Hawkes WG, Orwig DL, Hebel JR, Zimmerman SI, Magaziner J (2003) Gender differences in mortality after hip fracture: the role of infection. J Bone Miner Res 18:2231–2237

    Article  PubMed  Google Scholar 

  3. Seeman E, Bianchi G, Khosla S, Kanis JA, Orwoll E (2006) Bone fragility in men—where are we? Osteoporos Int 17:1577–1583

    Article  PubMed  CAS  Google Scholar 

  4. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults. A twin study. J Clin Invest 80:706–710

    Article  PubMed  CAS  Google Scholar 

  5. Nguyen TV, Blangero J, Eisman JA (2000) Genetic epidemiological approaches to the search for osteoporosis genes. J Bone Miner Res 15:392–401

    Article  PubMed  CAS  Google Scholar 

  6. Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML (1996) Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet 59:146–151

    PubMed  CAS  Google Scholar 

  7. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

    Article  PubMed  CAS  Google Scholar 

  8. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314

    Article  PubMed  CAS  Google Scholar 

  9. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70:11–19

    Article  PubMed  CAS  Google Scholar 

  10. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521

    Article  PubMed  CAS  Google Scholar 

  11. Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML (2005) Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25:4946–4955

    Article  PubMed  CAS  Google Scholar 

  12. Balemans W, Devogelaer JP, Cleiren E, Piters E, Caussin E, Van Hul W (2007) Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling. J Bone Miner Res 22:708–716

    Article  PubMed  CAS  Google Scholar 

  13. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE (2004) Polymorphisms in the low-density lipoprotein receptor–related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet 74:866–875

    Article  PubMed  CAS  Google Scholar 

  14. Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K (2004) LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 49:80–86

    Article  PubMed  CAS  Google Scholar 

  15. Ferrari SL, Deutsch S, Baudoin C, Cohen-Solal M, Ostertag A, Antonarakis SE, Rizzoli R, de Vernejoul MC (2005) LRP5 gene polymorphisms and idiopathic osteoporosis in men. Bone 37:770–775

    Article  PubMed  CAS  Google Scholar 

  16. Koller DL, Ichikawa S, Johnson ML, Lai D, Xuei X, Edenberg HJ, Conneally PM, Hui SL, Johnston CC, Peacock M, Foroud T, Econs MJ (2005) Contribution of the LRP5 gene to normal variation in peak BMD in women. J Bone Miner Res 20:75–80

    PubMed  CAS  Google Scholar 

  17. van Meurs JB, Rivadeneira F, Jhamai M, Hugens W, Hofman A, van Leeuwen JP, Pols HA, Uitterlinden AG (2006) Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res 21:141–150

    Article  PubMed  Google Scholar 

  18. Saarinen A, Valimaki VV, Valimaki MJ, Loyttyniemi E, Auro K, Uusen P, Kuris M, Lehesjoki AE, Makitie O (2007) The A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men. Bone 40:1006–1012

    Article  PubMed  CAS  Google Scholar 

  19. Brixen K, Beckers S, Peeters A, Piters E, Balemans W, Nielsen TL, Wraae K, Bathum L, Brasen C, Hagen C, Andersen M, Van Hul W, Abrahamsen B (2007) Polymorphisms in the low-density lipoprotein receptor–related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense Androgen Study. Calcif Tissue Int 81:421–429

    Article  PubMed  CAS  Google Scholar 

  20. Kiel DP, Ferrari SL, Cupples LA, Karasik D, Manen D, Imamovic A, Herbert AG, Dupuis J (2007) Genetic variation at the low-density lipoprotein receptor–related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Bone 40:587–596

    Article  PubMed  CAS  Google Scholar 

  21. Ezura Y, Nakajima T, Urano T, Sudo Y, Kajita M, Yoshida H, Suzuki T, Hosoi T, Inoue S, Shiraki M, Emi M (2007) Association of a single-nucleotide variation (A1330V) in the low-density lipoprotein receptor–related protein 5 gene (LRP5) with bone mineral density in adult Japanese women. Bone 40:997–1005

    Article  PubMed  CAS  Google Scholar 

  22. Bollerslev J, Wilson SG, Dick IM, Islam FM, Ueland T, Palmer L, Devine A, Prince RL (2005) LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women. Bone 36:599–606

    Article  PubMed  CAS  Google Scholar 

  23. van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290

    Article  PubMed  Google Scholar 

  24. Giroux S, Elfassihi L, Cardinal G, Laflamme N, Rousseau F (2007) LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women. Bone 40:1299–1307

    Article  PubMed  CAS  Google Scholar 

  25. Balemans W, Van Hul W (2007) The genetics of low-density lipoprotein receptor–related protein 5 in bone: a story of extremes. Endocrinology 148:2622–2629

    Article  PubMed  CAS  Google Scholar 

  26. 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 

  27. 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 

  28. Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, Zullo F, Nappi C, Nunziata V (2003) Effectiveness of alendronate treatment in postmenopausal women with osteoporosis: relationship with BsmI vitamin D receptor genotypes. Clin Endocrinol (Oxf) 58:365–371

    Article  CAS  Google Scholar 

  29. 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 

  30. Yao W, Cheng ZQ, Busse C, Pham A, Nakamura MC, Lane NE (2008) Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis—a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 58:1674–1686

    Article  PubMed  CAS  Google Scholar 

  31. Yao W, Pham A, Cheng Z, Busse C, Lane NE (2006) Glucocorticoid suppression of the canonical Wnt signaling is partially reversed by PTH and risedronate in mice. J Bone Miner Res 21:S122

    Google Scholar 

  32. Becker T, Knapp M (2004) Maximum-likelihood estimation of haplotype frequencies in nuclear families. Genet Epidemiol 27:21–32

    Article  PubMed  Google Scholar 

  33. Koay MA, Tobias JH, Leary SD, Steer CD, Vilarino-Guell C, Brown MA (2007) The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood. Calcif Tissue Int 81:1–9

    Article  PubMed  CAS  Google Scholar 

  34. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512

    Article  PubMed  CAS  Google Scholar 

  35. 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 

  36. Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974

    Article  PubMed  CAS  Google Scholar 

  37. Akhter MP, Wells DJ, Short SJ, Cullen DM, Johnson ML, Haynatzki GR, Babij P, Allen KM, Yaworsky PJ, Bex F, Recker RR (2004) Bone biomechanical properties in LRP5 mutant mice. Bone 35:162–169

    Article  PubMed  CAS  Google Scholar 

  38. McGuigan FE, Murray L, Gallagher A, Davey-Smith G, Neville CE, Van’t Hof R, Boreham C, Ralston SH (2002) Genetic and environmental determinants of peak bone mass in young men and women. J Bone Miner Res 17:1273–1279

    Article  PubMed  CAS  Google Scholar 

  39. Dhamrait SS, James L, Brull DJ, Myerson S, Hawe E, Pennell DJ, World M, Humphries SE, Haddad F, Montgomery HE (2003) Cortical bone resorption during exercise is interleukin-6 genotype-dependent. Eur J Appl Physiol 89:21–25

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The study was supported by a research grant from Procter & Gamble Pharmaceuticals. O. M. E. A. is funded by the Arthritis Research Campaign UK (15389 and 16303). S. H. R. acted as a consultant for Novartis, Procter & Gamble, and Sanofi Aventis pharmaceuticals.

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  1. Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK

    Marcin Kruk, Stuart H. Ralston & Omar M. E. Albagha

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  1. Marcin Kruk
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  2. Stuart H. Ralston
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  3. Omar M. E. Albagha
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Correspondence to Omar M. E. Albagha.

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Kruk, M., Ralston, S.H. & Albagha, O.M.E. LRP5 Polymorphisms and Response to Risedronate Treatment in Osteoporotic Men. Calcif Tissue Int 84, 171–179 (2009). https://doi.org/10.1007/s00223-008-9207-5

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