Search for genetic markers determining the efficiency of therapy with bisphosphonates in Russian women with postmenopausal osteoporosis: A pilot study

Many clinical observations show that patient’s genetic background is of great importance in determining the efficiency of treatment.

Subjects and methods. The instigation included 50 postmenopausal women with osteoporosis (OP), who were followed up at the Laboratory of osteoporosis, V.A. Nasonova Research Institute of Rheumatology. Body mineral density (BMD) in the lumbar spine (LI-IV), femoral neck (FN), and total hip was measured using dual-energy X-ray absorptiometry before and 12 months after treatment with bisphosphonates (BP). To estimate BMD changes, the investigators used ΔBMD in percent (Δ, %).

Results and discussion. The whole group showed a positive effect of BP therapy during a year, which was most pronounced in the lumbar spine (mean ΔBMD, about 4%), and a small increment in the proximal hip BMD (mean ΔBMD, about 2%). An analysis indicated a statistically significant correlation of MCP1 -2518A>G polymorphism with changes in LI-IV BMD after 12-month BP therapy. Thus, the female patients who were A allele carriers had a twice lower increase in LI-IV BMD due to BP therapy than those without this allele. The genetic variants of the CCR5 gene, which were related to Δ32 deletion, and IL1β -511C/T polymorphism were also associated with changes in FN BMD following 12-month BP therapy. The BMD increase due to BP therapy in the carriers of the CCR5 Δ32 mutation (wt/Δ32 genotype) was 3.5-fold than that in the carriers of the wild type gene (wt/wt genotype). Examination of IL1 -511C/T polymorphism demonstrated that the FN BMD increment in the carriers of the CC genotype was significantly higher than in those of the CT genotype (4.2±4.8 and 1.0±3.7%, respectively; р = 0.023). Our investigation revealed no significant relationship between VDR, LEPR, IL10, MHTFR, PPARG, SPP1, and CCR5(G/A) gene polymorphisms and 12-month BP therapy-induced BMD changes in the three study skeletal regions. The findings may suggest that genetic testing may be used to predict a response to BP. 

1. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009;122:S14-21. doi: 10.1016/j.amjmed.2008.12.003

2. Delmas PD. The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol. 2005;17:462-6. doi: 10.1097/01.bor.0000163448.51661.87

3. Nguyen TV, Eisman JA. Pharmacogenomics of osteoporosis: opportunities and challenges. J Musculoskelet Neuronal Interact. 2006;6:62-72.

4. Devogelaer JP. Treatment of bone diseases bisphosphonates, excluding osteoporosis. Curr Opin Rheumatol. 2000;12:331-5. doi: 10.1097/00002281-200007000-00017

5. Rogers MJ. From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates. Calcif Tissue Int. 2004;75:451-61. doi: 10.1007/s00223-004-0024-1

6. Benford HL, McGowan NW, Helfrich MH, et al. Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone. 2001;28:465-73. doi: 10.1016/S8756- 3282(01)00412-4

7. Marc J, Prezelj J, Komel R, Kocijancic A. VDR genotype and response to etidronate therapy in late postmenopausal women. Osteoporos Int. 1999;10:303-6. doi: 10.1007/s001980050231

8. Palomba S, Numis FG, Mossetti G, 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. doi: 10.1046/j.1365- 2265.2003.01724.x

9. Palomba S, Orio F Jr, Russo T, et al. BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, ran￾domized and controlled trial. Osteoporos Int. 2005;16:943-52. doi: 10.1007/s00198-004-1800-5

10. Mossetti G, Gennari L, Rendina D, 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. doi: 10.1007/s00223-008-9193-7

11. Corral-Gudino L, del Pino-Montes J, Garcia-Aparicio J, et al. 511 C/T IL1B gene polymorphism is associated to resistance to bisphosphonates treatment in Paget disease of bone. Bone. 2006;38:589-94. doi: 1016/j.bone.2005.09.010

12. Arko B, Prezelj J, Komel R, et al. 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. 2002;81:147-52. doi: 10.1016/S0960-0760(02)00061-4

13. Kruk M, Ralston SH, Albagha OM. LRP5 Polymorphisms and response to risedronate treatment in osteoporotic men. Calcif Tissue Int. 2009;84:171-9. doi: 10.1007/s00223-008-9207-5

14. Marini F, Falchetti A, Silvestri S, 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. doi: 10.1185 /03007990802352894

15. Eraltan H, Cacina C, Kahraman OT, et al. MCP-1 and CCR2 gene variations and the risk for osteoporosis and osteopenia. Genet Test Mol Biomarkers. 2012 Apr;16(4):229-33. doi: 10.1089/gtmb/2011.0216

16. Крылов МЮ, Беневоленская ЛИ, Мякоткин ВА. Полиморфизм A19G гена лептина и полиморфизмы Gln223Arg и Lys109Arg гена рецептора лептина при постменопаузальном остеопорозе. Научно-прктическая ревматология. 2010;48(5):27-31 [Krylov MY, Benevolenskaya LI, Myakotkin VA. Leptin A19G polymorphism and leptin receptor Gln223Arg and Lys109Arg polymorphismsin postmenopausal osteoporosis. Nauchno-Prkticheskaya Revmatologiya = Rheumatology Science and Practice. 2010;48(5):27-31 (In Russ.)]. doi: 10.14412/1995-4484-2010-727

17. Crabbe P, Goemaere S, Zmierczak H, et al. Are serum leptin and the Gln223Arg polymorphism of the leptin receptor determinants of bone homeostasis in elserly men? Eur J Endocrinol. 2006 May;154(5):707-14. doi: 10.1530/eje.1.02130

18. Tural S, Alayli G, Kara N, et al. Association between osteoporosis and polymorphisms of the IL-10 and TGF-beta genes in Turkish postmenopausal women. Hum Immunol. 2013 Sep;75(9):1179-83. doi: 10.1016/j.humimm.2013.03.005

19. Zhu H, Beiby J, Dick IM, et al. The effects of homocysteine and MHTFR genotype on hip bone loss and fracture rick in elderly women. Osteoporos Int. 2009 Jul: 20(7):1183-91. doi: 10.1007/s00198-008-0804-y

20. Chao TH, Yu HN, Huang CC, et al. Association of interleukin-1 beta (-511C/T) polymorphism in postmenopausal women. Ann Daudi Med. 2010 Nov-Dec;30(6):437-41. doi: 10.4103/0256- 4947.71062

21. Крылов МЮ, Никитинская ОА, Самаркина ЕЮ, Торопцова НВ. Ассоциация полиморфизма интерлейкина 1β с постменопаузальным остеопорозом у женщин в российской популяции. Научно-практическая ревматология. 2015;53(5):502-5 [Krylov MY, Nikitinskaya OA, Samarkina EY, Toroptsova NV. Association of interleukin-1β gene polymorphism with postmenopausal osteoporosis in women in the Russian population. Nauchno-Prkticheskaya Revmatologiya = Rheumatology Science and Practice. 2015;53(5):502-5 (In Russ.)]. doi: 10.14412/1995-4484-2015- 502-505

22. Wei QS, Huang L, Tan X, et al. Serum osteopontin levels in relation to bone mineral density and bone turnover markers in postmenopausal women. Scand J Clin Lab Invest. 2016;76(1):33-9. doi: 10.3109/00365513.2015.1087045. Epub 2015 Sep 28.

23. Harslof T, Tofteng CL, Husted LB, et al. Polymorphisms of the peroxisome proliferator-activator receptor gamma (PPARγ) gene are associated with osteoporosis. Osteoporos Int. 2011 Oct;22(10):2655-66. doi: 10.1007/s00198-010-1491-z

24. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491- 501. doi: 10.1038/ng.2249

25. Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev. 2010;31(5):629-62. doi: 10.1210/er.2009-0044

26. Horst-Sicorska W, Dytfeld J, Wawrzyniak A, et al. Vitamin D receptor gene polymorphisms, bone mineral density and fractures in postmenopaysal women with osteoporosis. Mol Biol Rep. 2013 Jan;40(1):383-90. doi: 10.1007/s11033-012-2072-3

27. Moran JM, Pedrera-Canal M, Rodriguez-Velasco FJ, et al. Lack association of vitamin D receptor BsmI gene polymorphism with bone mineral density in Spanish postmenopausal women. Peer J. 2015 Jul 2;3:e953. doi: 10.7717/peerj.953. e Collection 2015.

28. Bai J, Sonq H, Cai C, et al. The association of monocyte chemotactic protein-1 and CC chemokine receptor 2 gene variants with chronic obstructive pulmonary disease. DNA Cell Biol 2012;Jun;31(6):1058-63. doi: 10.1089/dna.2011.1520

29. Kucukgergin C, Isman FK, Cakmakoglu B, et al. Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer. DNA Cell Biol. 2012 Aug; 31(8):1418-24. doi: 10.1089/dna.2012.1716

30. Nakamura I, Jimi E. Regulation of osteoclast differentiation and function by interleukin-1. Vitamins Hormones. 2006;74:357-70. doi: 10.1016/s0083-6729(06)74015-8

31. Dundar U, Kavuncu V, Ciftci IH, et al. The effect of risedronate treatment on serum cytokines in postmenopausal osteoporosis: a 6-month randomized and controlled study. J Bone Mineral Metab. 2009;27(4):464-70. doi: 10.1007/s00774-009-0055-9.