The role of genetic factors in the development of osteoporosis in postmenopausal female patients
Abstract. Article contains the results of a cross-sectional study assessing the contribution of single nucleotide polymorphisms to the development of osteoporosis (OP) in postmenopausal female individuals.Vikhareva A.A., Shambatov M.A., Ispavskaya K.S., Pashkina I.A., Izmozherova N.V., Kudryavtseva E.V., Zornikov D.L., Popov A.A., Kostash V.A.
The aim: to assess the detection rate of single nucleotide polymorphic variants of candidate genes for osteoporosis (OP) and their contribution to the development of this disease in postmenopausal females.
Material and methods. The study included 78 postmenopausal patients: Group 1 – 41 patient with OP; Group 2 – 37 females who did not meet the criteria for this diagnosis. All participants were assessed for single nucleotide polymorphisms of IL6, RANKL, COL1A1, VDR genes using real-time polymerase chain reaction.
Results. According to the main clinical characteristics, patients with OP had lower values of anthropometric parameters (body weight, waist and hip circumference), earlier age of menopause, and a significantly higher history of both osteoporotic and any other fractures. Females without OP were significantly more likely to be obese and more often used calcium channel blockers. The study did not reveal statistically significant intergroup differences in the frequency of detection of polymorphic variants of genotypes. A two-locus model was constructed, it included polymorphisms rs9594759 of RANKL gene and rs1107946 of COL1A1 gene; its sensitivity was 60%, specificity – 71%. The most significant contribution to the development of osteoporosis is made by the rs9594759 polymorphisms of RANKL gene and rs1800012 polymorphisms of COL1A1 gene, as well as the association of the rs1107946 polymorphisms of COL1A1 gene and rs9594759 polymorphisms of RANKL gene.
Conclusion. Multilocus analysis and prognostic model based on a combination of various polymorphic genes can assess the risk of developing osteoporosis in postmenopausal female patients.
Keywords
postmenopausal osteoporosis
osteoporotic fractures
single nucleotide polymorphism
genetic testing
bone mineral density
vitamin D deficiency
References
1. Salari N, Darvishi N, Bartina Y, Larti M, Kiaei A, Hemmati M et al. Global prevalence of osteoporosis among the world older adults: A comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):669.
PMID: 34774085. PMCID: PMC8590304. https://doi.org/10.1186/S13018-021-02821-8
2. Salari N, Ghasemi H, Mohammadi L, Behzadi MH, Rabieenia E, Shohaimi S, Mohammadi M. The global prevalence of osteoporosis in the world: A comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609.
PMID: 34657598. PMCID: PMC8522202. https://doi.org/10.1186/S13018-021-02772-0
3. Закроева А.Г., Бабалян В.Н., Габдулина Г.Х., Лобанченко О.В., Ершова О.Б., Исаева C.М. с соавт. Состояние проблемы остеопороза в странах Евразийского региона. Остеопороз и остеопатии. 2020;23(4):19–29. (Zakroyeva AG, Babalyan V, Gabdulina G, Lobanchenko О, Ershova ОB, Issaeva S et al. Burden of Osteoporosis in the Countries of the Eurasian Region. Osteoporoz i osteopatii = Osteoporosis and Bone Diseases. 2021;23(4):19–29 (In Russ.)).
EDN: LPVSJP. https://doi.org/10.14341/osteo12700
4. Chevalley T, Brandi ML, Cashman KD, Cavalier E, Harvey NC, Maggi S et al. Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group. Aging Clin Exp Res. 2022;34(11):2603–23.
PMID: 36287325. PMCID: PMC9607746. https://doi.org/10.1007/S40520-022-02279-6
5. Yong EL, Logan S. Menopausal osteoporosis: Screening, prevention and treatment. Singapore Med J. 2021;62(4):159–66.
PMID: 33948669. PMCID: PMC8801823. https://doi.org/10.11622/SMEDJ.2021036
6. Xiao PL, Cui AY, Hsu CJ, Peng R, Jiang N, Xu XH et al. Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: A systematic review and meta-analysis. Osteoporos Int. 2022;33(10):2137–53.
PMID: 35687123. https://doi.org/10.1007/S00198-022-06454-3
7. Li Q, Wang J, Zhao C. From genomics to metabolomics: Molecular insights into osteoporosis for enhanced diagnostic and therapeutic approaches. Biomedicines. 2024;12(10):2389.
PMID: 39457701. PMCID: PMC11505085. https://doi.org/10.3390/biomedicines12102389
8. Wang X, Pei Z, Hao T, Ariben J, Li S, He W et al. Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis. Front Immunol. 2022;13:987937.
PMID: 36311708. PMCID: PMC9610549. https://doi.org/10.3389/FIMMU.2022.987937
9. Bai Q, Shi M, Sun X, Lou Q, Peng H, Qu Z et al. Comprehensive analysis of the m6A-related molecular patterns and diagnostic biomarkers in osteoporosis. Front Endocrinol (Lausanne). 2022;13:957742.
PMID: 36034449. PMCID: PMC9399504. https://doi.org/10.3389/fendo.2022.957742
10. Xu XH, Dong SS, Guo Y, Yang TL, Lei SF, Papasian CJ et al. Molecular genetic studies of gene identification for osteoporosis: The 2009 update. Endocr Rev. 2010;31(4):447–505.
PMID: 20357209. PMCID: PMC3365849. https://doi.org/10.1210/er.2009-0032
11. Wang S, Ai Z, Song M, Yan P, Li J, Wang S. The association between vitamin D receptor FokI gene polymorphism and osteoporosis in postmenopausal women: A meta-analysis. Climacteric. 2021;24(1):74–79.
PMID: 32551997. https://doi.org/10.1080/13697137.2020.1775806
12. Liao JL, Qin Q, Zhou YS, Ma RP, Zhou HC, Gu MR et al. Vitamin D receptor Bsm I polymorphism and osteoporosis risk in postmenopausal women: A meta-analysis from 42 studies. Genes Nutr. 2020;15(1):20.
PMID: 33238893. PMCID: PMC7687795. https://doi.org/10.1186/S12263-020-00679-9
13. Jiang LL, Zhang C, Zhang Y, Ma F, Guan Y. Associations between polymorphisms in VDR gene and the risk of osteoporosis: A meta-analysis. Arch Physiol Biochem. 2022;128(6):1637–44.
PMID: 32757960. https://doi.org/10.1080/13813455.2020.1787457
14. Chen B, Zhu WF, Mu YY, Liu B, Li HZ, He XF. Association between vitamin D receptor BsmI, FokI, and Cdx2 polymorphisms and osteoporosis risk: an updated meta-analysis. Biosci Rep. 2020;40(7):BSR20201200.
PMID: 32627819. PMCID: PMC7364509. https://doi.org/10.1042/BSR20201200
15. Zintzaras E, Rodopoulou P, Koukoulis GN. BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: A meta-analysis. Dis Markers. 2006;22(5–6):317–26.
PMID: 17264402. PMCID: PMC3851656. https://doi.org/10.1155/2006/921694
16. Fu L, Ma J, Yan S, Si Q. A meta-analysis of VDR polymorphisms and postmenopausal osteoporosis. Endocr Connect. 2020;9(9):834–41.
PMID: 32738125. PMCID: PMC7583137. https://doi.org/10.1530/EC-20-0296
17. Wang B, Li H, Yang C, Nie R, Zhang X, Pu C. VDR gene Apa I polymorphism and risk of postmenopausal osteoporosis: A meta-analysis from 22 studies. Climacteric. 2023;26(6):583–93.
PMID: 37477999. https://doi.org/10.1080/13697137.2023.2233421
18. Majchrzycki M, Bartkowiak-Wieczorek J, Wolski H, Drews K, Bogacz A, Czerny B et al. Polymorphisms of collagen 1A1 (COL1A1) gene and their relation to bone mineral density in postmenopausal women. Ginekol Pol. 2015;86(12):907–14.
PMID: 26995940. https://doi.org/10.17772/GP/60550
19. Wu J, Yu M, Zhou Y. Association of collagen type I alpha 1 +1245G/T polymorphism and osteoporosis risk in post-menopausal women: A meta-analysis. Int J Rheum Dis. 2017;20(7):903–10.
PMID: 28261929. https://doi.org/10.1111/1756-185X.13052
20. Xu P, Wang Y, Wu X, Wang W, Wang Q, Lin W et al. The COL1A1 rs1800012 polymorphism is associated with osteoporosis or fracture risk: A meta-analysis of 30 studies. Int J Burns Trauma. 2024;14(6):148–59.
PMID: 39850783. PMCID: PMC11751553. https://doi.org/10.62347/KKAM3344
21. Garcia-Rojas MD, Palma-Cordero G, Martinez-Ramirez CO, Ponce de Leon-Suarez V, Valdes-Flores M, Castro-Hernandez C et al. Association of polymorphisms in estrogen receptor genes (ESR 1 and ESR 2) with osteoporosis and fracture-involvement of comorbidities and epistasis. DNA Cell Biol. 2022;41(4):437–46.
PMID: 35285722. https://doi.org/10.1089/DNA.2021.1165
22. Bai XH, Su J, Mu YY, Zhang XQ, Li HZ, He XF, He XF. Association between the ESR1 and ESR2 polymorphisms and osteoporosis risk: An updated meta-analysis. Medicine. 2023;102(41):E35461.
PMID: 37832086. PMCID: PMC10578747. https://doi.org/10.1097/MD.0000000000035461
23. Xia Y, Chen H. Association of osteoporosis risk and polymorphisms of osteoprotegerin gene T950C in postmenopausal Chinese women: A PRISMA-compliant meta-analysis. Medicine. 2023;102(14):E33511.
PMID: 37026909. PMCID: PMC10082231. https://doi.org/10.1097/MD.0000000000033511
24. Ding J, Zhang C, Guo Y. The association of OPG polymorphisms with risk of osteoporotic fractures: A systematic review and meta-analysis. Medicine (Baltimore). 2021;100(31):E26716.
PMID: 34397809. PMCID: PMC8341286. https://doi.org/10.1097/MD.0000000000026716
25. Przerwa F, Uzar I, Bogacz A, Kotrych K, Sulikowski T, Wolek M et al. Osteoprotegerin gene as a biomarker in the development of osteoporosis in postmenopausal women. Biomedicines. 2023;11(12):3218.
PMID: 38137439. PMCID: PMC10740651. https://doi.org/10.3390/BIOMEDICINES11123218
26. Zhu DL, Chen XF, Hu WX, Dong SS, Lu BJ, Rong Y et al. Multiple functional variants at 13q14 risk locus for osteoporosis regulate RANKL expression through long-range super-enhancer. J Bone Miner Res. 2018;33(7):1335–46.
PMID: 29528523. https://doi.org/10.1002/jbmr.3419
27. Kim JG, Kim JH, Kim JY, Ku SY, Jee BC, Suh CS et al. Association between osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL levels, and bone mineral density in Korean postmenopausal women. Menopause. 2007;14(5):913–18.
PMID: 17667143. https://doi.org/10.1097/gme.0b013e31802d976f
28. Abdi S, Bukhari I, Ansari MGA, BinBaz RA, Mohammed AK, Hussain SD et al. Association of polymorphisms in RANK and RANKL genes with osteopenia in Arab postmenopausal women. Dis Markers. 2020;2020:1285216.
PMID: 33376557. PMCID: PMC7746462. https://doi.org/10.1155/2020/1285216
29. Littman J, Yang W, Olansen J, Phornphutkul C, Aaron RK. LRP5, bone mass polymorphisms and skeletal disorders. Genes (Basel). 2023;14(10):1846.
PMID: 37895195. PMCID: PMC10606254. https://doi.org/10.3390/GENES14101846
30. Cui Y, Hu X, Zhang C, Wang K. The genetic polymorphisms of key genes in WNT pathway (LRP5 and AXIN1) was associated with osteoporosis susceptibility in Chinese Han population. Endocrine. 2022;75(2):560–74.
PMID: 34590211. https://doi.org/10.1007/S12020-021-02866-Z
31. Wang QF, Bi HS, Qin ZL, Wang P, Nie FF, Zhang GW. Associations of LRP5 gene with bone mineral density, bone turnover markers, and fractures in the elderly with osteoporosis. Front Endocrinol (Lausanne). 2020;11:571549.
PMID: 33101205. PMCID: PMC7545741. https://doi.org/10.3389/fendo.2020.571549
32. Wang Z, Yang Y, He M, Wang R, Ma J, Zhang Y et al. Association between interleukin-6 gene polymorphisms and bone mineral density: A meta-analysis. Genet Test Mol Biomarkers. 2013;17(12):898–909.
PMID: 24053561. PMCID: PMC3865625. https://doi.org/10.1089/gtmb.2013.0223.
33. Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Foger-Samwald U, Ellinger I. Immunology of osteoporosis: A mini-review. Gerontology. 2016;62(2):128–37.
PMID: 26088283. PMCID: PMC4821368. https://doi.org/10.1159/000431091
34. Umur E, Bulut SB, Yigit P, Bayrak E, Arkan Y, Arslan F et al. Exploring the role of hormones and cytokines in osteoporosis development. Biomedicines. 2024;12(8):1830.
PMID: 39200293. PMCID: PMC11351445. https://doi.org/10.3390/biomedicines12081830
35. Usategui-Martin R, De Luis-Roman DA, Fernandez-Gomez JM, Ruiz-Mambrilla M, Perez-Castrillon JL. Vitamin D receptor (VDR) gene polymorphisms modify the response to vitamin D supplementation: A systematic review and meta-analysis. Nutrients. 2022;14(2):360.
PMID: 35057541. PMCID: PMC8780067. https://doi.org/10.3390/nu14020360
36. Белая Ж.Е., Белова К.Ю., Бирюкова Е.В., Дедов И.И., Дзеранова Л.К., Драпкина О.М. с соавт. Федеральные клинические рекомендации по диагностике, лечению и профилактике остеопороза. Остеопороз и остеопатии. 2021;24(2):4–47. (Belaya ZhE, Belova KYu, Biryukova EV, Dedov II, Dzeranova LK, Drapkina OM et al. Federal clinical guidelines for diagnosis, treatment and prevention of osteoporosis. Osteoporoz i osteopatii = Osteoporosis and Bone Diseases. 2021;24(2):4–47 (In Russ.)).
EDN: TUONYE. https://doi.org/10.14341/osteo12930
37. Клинические рекомендации. Менопауза и климактерическое состояние у женщины. Общероссийская общественная организация «Российское общество акушеров-гинекологов». Рубрикатор клинических рекомендаций Минздрава России. 2021. ID: 117_2. Доступ: https://cr.minzdrav.gov.ru/view-cr/117_2 (дата обращения – 25.05.2025). (Clinical guidelines. Menopause and climacteric state in women. Russian Society of Obstetricians and Gynecologists. Rubricator of clinical guidelines of the Ministry of Healthcare of Russia. 2021. ID: 117_2. URL: https://cr.minzdrav.gov.ru/preview-cr/117_2 (date of access – 25.05.2025) (In Russ.)).
38. Дедов И.И., Шестакова М.В., Майоров А.Ю., Мокрышева Н.Г., Андреева Е.Н., Безлепкина О.Б. с соавт. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Под редакцией И.И. Дедова, М.В. Шестакова, А.Ю. Майорова. 11-й выпуск. Сахарный диабет. 2023; 26(S2):1–157. (Dedov II, Shestakova MV, Mayorov AYu, Mokrysheva N, Andreeva E, Bezlepkina O et al. Standards of specialized diabetes care. 11th edition. Edited by Dedov II, Shestakova MV, Mayorov AYu. Sakharnyy diabet = Diabetes Mellitus. 2023;26(S2):1–157 (In Russ.)).
EDN: DCKLCI. https://doi.org/10.14341/DM13042
39. Пигарова Е.А., Рожинская Л.Я., Белая Ж.Е., Дзеранова Л.К., Каронова Т.Л., Ильин А.В. с соавт. Клинические рекомендации Российской ассоциации эндокринологов по диагностике, лечению и профилактике дефицита витамина D у взрослых. Проблемы эндокринологии. 2016;62(4):60–84. (Pigarova EA, Rozhinskaya LYa, Belaya ZhE, Dzeranova LK, Karonova TL, Ilyin AV et al. Russian Association of Endocrinologists recommendations for diagnosis, treatment and prevention of vitamin D deficiency in adults. Problemy endokrinologii = Problems of Endocrinology. 2016;62(4):60–84 (In Russ.)).
EDN: WMZICF. https://doi.org/10.14341/probl201662460-84
40. Кудрявцева Е.В., Березина Д.А., Корнилов Д.О., Симарзина В.М., Тряпицын М.А., Бехтер А.А. с соавт. Некоторые молекулярно-генетические детерминанты преждевременного старения женщины. Consilium Medicum. 2024;26(12):809–814. (Kudryavtseva EV, Berezina DA, Kornilov DO, Simarzina VM, Tryapitsyn MA et al. Some molecular-genetic determinants of premature aging in women. Consilium Medicum. 2024;26(12):809–814 (In Russ.)).
EDN: OCALLY. https://doi.org/10.26442/20751753.2024.12.202970
41. Takeuchi T, Yoshida H, Tanaka S. Role of interleukin-6 in bone destruction and bone repair in rheumatoid arthritis. Autoimmunity reviews. 2021;20(9):102884.
PMID: 34229044. https://doi.org/10.1016/j.autrev.2021.102884
42. Horwood NJ, Elliott J, Martin TJ, Gillespie MT. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology. 1998;139(11):4743–46.
PMID: 9794488. https://doi.org/10.1210/endo.139.11.6433
43. Posa F, Di Benedetto A, Colaianni G, Cavalcanti-Adam EA, Brunetti G, Porro C et al. Vitamin D effects on osteoblastic differentiation of mesenchymal stem cells from dental tissues. Stem Cells Int. 2016;2016:9150819.
PMID: 27956902; PMCID: PMC5124467. https://doi.org/10.1155/2016/9150819.
About the Authors
Anna A. Vikhareva, MD, PhD (Medicine), associate professor of the Department of pharmacology and clinical pharmacology, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.E-mail: anna1993vi@yandex.ru
ORCID: https://orcid.org/0000-0002-5951-2110. Scopus ID: 57355952100. eLibrary SPIN: 3475-5279
Muraz A. Ogly Shambatov, MD, PhD (Medicine), associate professor of the of the Department of pharmacology and clinical pharmacology, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: shambatovma@gmail.com
ORCID: https://orcid.org/0000-0001-7312-415X. Scopus ID: 57216921642. eLibrary SPIN: 6693-5347
Ksenia S. Ispavskaya, assistant at the Department of pharmacology and clinical pharmacology, Ural State Medical University of the Ministry of Healthcare of Russia Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: chuhareva.ksy@yandex.ru
ORCID: https://orcid.org/0000-0003-2268-2164. eLibrary SPIN: 6673-8969
Inna A. Pashkina, assistant at the Department of hospital therapy, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: close.in215@gmail.com
ORCID: https://orcid.org/0009-0007-0859-6389. eLibrary SPIN: 2831-6160
Nadezhda V. Izmozherova, MD, Dr. Sci. (Medicine), professor, director of the institute of Clinical Pharmacology and Pharmacy, head of the Department of pharmacology and clinical pharmacology, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: nadezhda_izm@mail.ru
ORCID: https://orcid.org/0000-0001-7826-9657. Scopus ID: 19337559100. eLibrary SPIN: 4738-3269
Elena V. Kudryavtseva, MD, Dr. Sci. (Medicine), associate professor, leading researcher at the Department of reproductive function preservation, Ural Scientific Research Institute for Maternal and Child Care. Address: 620000, Yekaterinburg, 1 Repina St.
E-mail: elenavladpopova@yandex.ru
ORCID: https://orcid.org/0000-0003-2797-1926. Scopus ID: 57211989398. eLibrary SPIN: 7232-3743
Danila L. Zornikov, MD, PhD (Medicine), associate professor of the Department of medical microbiology and clinical laboratory diagnostics, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: zornikovdl@yandex.ru
ORCID: https://orcid.org/0000-0001-9132-215X. Scopus ID: 57195637975. eLibrary SPIN: 8119-6035
Artem A. Popov, MD, Dr. Sci. (Medicine), professor, director of the Institute of clinical medicine, head of the Department of hospital therapy, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: art_popov@mail.ru
ORCID: https://orcid.org/0000-0001-6216-2468. Scopus ID: 24390984000. eLibrary SPIN: 5083-9389
Victoria A. Kostash, MD, postgraduate student of the Department of pharmacology and clinical pharmacology, Ural State Medical University of the Ministry of Healthcare of Russia. Address: 620028, Yekaterinburg, 3 Repina St.
E-mail: ruh32@rambler.ru
eLibrary SPIN: 8622-8960
Similar Articles
