Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter November 18, 2021

Predictors of decreased bone mineral density in childhood systemic lupus erythematosus: possible role of osteoprotegerin gene polymorphisms

  • Riham Eid ORCID logo EMAIL logo , Maha Abdelsalam , Aya A Fathy , Dena M Abd-El Ghaffar , Eman B Elmarghany , Aya A El-Hanafy , Nora Mostafa , Nashwa Hamdy ORCID logo , Nermeen A Niazy , Ayman Hammad ORCID logo and Hadil M Abolenein



This study aims to explore effects of osteoprotegerin (OPG) gene polymorphisms and other possible factors on bone mineral density (BMD) in children with systemic lupus erythematosus (SLE).


Osteoprotegerin gene rs2073617 and rs3134069 were evaluated in 74 SLE patients and 100 controls then genotypes, alleles and haplotypes’ frequencies were compared between cases and controls and between patients with BMD z-scores above and below −2 evaluated by dual energy X-ray absorptiometry (DEXA). Disease activity was evaluated by SLE disease activity index (SLEDAI).


The patients aged 14.01 ± 2.6 years and included 57 (77%) females and 27 (36%) patients with BMD z-score below −2. Genotypes, alleles, and haplotypes frequencies did not differ between patients and controls (p>0.05 for all). Rs3134069 GG genotype and G allele (p=0.001, 0.002) and rs2073617 TT genotype and T allele (p=0.01, 0.006) were significantly higher in patients with BMD below −2. Cumulative glucocorticoids dose, disease duration, and SLEDAI scores were higher in patients with BMD below −2 (p=0.01, 0.01, <0.001, respectively). Regression analysis showed T allele of rs2073617, duration of illness (above 36 months), and cumulative SLEDAI (above 10) as independent predictors of decreased BMD (p 0.02, 0.003, and 0.002, respectively).


This is the first study to demonstrate OPG gene influence on BMD in children with SLE. The studied SNPs are not risk for developing SLE but, rs2073617 T allele is a possible predictor for reduced BMD in SLE. Other predictors include long disease duration and high activity supporting that osteoporosis in SLE is multifactorial.

Corresponding author: Dr. Riham Eid, Lecturer of Pediatrics/Nephrology, Nephrology Unit, Mansoura University Children’s Hospital, Mansoura Faculty of Medicine, Mansoura, 35561, Egypt, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The study was reviewed and approved by Mansoura Faculty of Medicine Institutional Research Board (MFM-IRB) (R.20.08.989).


1. Regio, P, Bonfá, E, Takayama, L, Pereira, R. The influence of lean mass in trabecular and cortical bone in juvenile onset systemic lupus erythematosus. Lupus 2008;17:787–92. in Google Scholar

2. Bachrach, LK. Dual energy X-ray absorptiometry (DEXA) measurements of bone density and body composition: promise and pitfalls. J Pediatr Endocrinol Metab 2000;13:983–8. PMID: 11086651.Search in Google Scholar

3. Zhou, J, Zhao, Y. Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis susceptibility in a Chinese Han population. Med Sci Monit 2016;22:4271–6. in Google Scholar

4. Boroń, D, Kotrych, D, Bartkowiak-Wieczorek, J, Uzar, I, Bogacz, A, Kamiński, A. Polymorphisms of OPG and their relation to the mineral density of bones in pre- and postmenopausal women. Int Immunopharmacol 2015;28:477–86. in Google Scholar

5. Shaker, OG, Senousy, MA. Association of SNP-SNP interactions between RANKL, OPG, CHI3L1, and VDR genes with breast cancer risk in Egyptian women. Clin Breast Cancer 2019;19:220–38. in Google Scholar

6. Rouster-Stevens, KA, Langman, CB, Price, HE, Seshadri, R, Shore, RM, Abbott, K, et al.. RANKL: osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis. Arthritis Rheum 2007;56:977–83. in Google Scholar

7. Ali, R, Hammad, A, El-Nahrery, E, Hamdy, N, Elhawary, AK, Eid, R. Serum RANKL, osteoprotegerin (OPG) and RANKL/OPG ratio in children with systemic lupus erythematosus. Lupus 2019;28:1233–42. in Google Scholar

8. Xue, JB, Zhan, XL, Wang, WJ, Yan, YG, Liu, C. OPG rs2073617 polymorphism is associated with upregulated OPG protein expression and an increased risk of intervertebral disc degeneration. Exp Ther Med 2016;12:702–10. in Google Scholar

9. Nehring, P, Mrozikiewicz-Rakowska, B, Sobczyk-Kopcioł, A, Makowski, A, Krasnodębski, P, Płoski, R, et al.. Osteoprotegerin gene rs2073617 and rs3134069 polymorphisms in type 2 diabetes patients and sex-specific rs2073618 polymorphism as a risk factor for diabetic foot. Pol Arch Med Wewn 2013;123:176–82. in Google Scholar

10. 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. in Google Scholar

11. 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. in Google Scholar

12. Peng, Y, Sheng, X, Xue, F, Qian, Y. The genetic association between osteoprotegerin (OPG) gene polymorphisms and bone mineral density (BMD) in postmenopausal women: a meta-analysis. Medicine 2018;97:13507. in Google Scholar

13. Bonfá, AC, Seguro, LP, Caparbo, V, Bonfá, E, Pereira, RM. RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus. Osteoporos Int 2015;26:1563–71. in Google Scholar

14. Yalaev, BI, Tyurin, AV, Mirgalieva, RI, Khusnutdinova, EK, Khusainova, RI. Investigating the role of osteoprotegerin gene polymorphic variants in osteoporosis. ROMJ 2021;10:e0101.10.15275/rusomj.2021.0101Search in Google Scholar

15. Hochberg, MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. in Google Scholar

16. Gladman, DD, Ibañez, D, Urowitz, MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288–91. PMID: 11838846.Search in Google Scholar

17. El-Ziny, MA, Al-Haggar, M, Chalaby, N, El-Sherify, E. Growth parameters and adiposity in Egyptian infants and children. Egypt J Community Med 2003;21:63–73.Search in Google Scholar

18. Wasilewska, A, Rybi-Szuminska, A, Zoch-Zwierz, W. Serum RANKL, osteoprotegerin (OPG), and RANKL/OPG ratio in nephrotic children. Pediatr Nephrol 2010;25:2067–75. in Google Scholar

19. Schwartz, GJ, Haycock, GB, Spitzer, A. Plasma creatinine and urea concentration in children: normal values for age and sex. J Pediatr 1976;88:828–30. in Google Scholar

20. Soufi, M, Schoppet, M, Sattler, AM, Herzum, M, Maisch, B, Hofbauer, LC, et al.. Osteoprotegerin gene polymorphisms in men with coronary artery disease. J Clin Endocrinol Metab 2004;89:3764–8. in Google Scholar PubMed

21. Pitocco, D, Zelano, G, Gioffrè, G, Di Stasio, E, Zaccardi, F, Martini, F, et al.. Association between osteoprotegerin G1181C and T245G polymorphisms and diabetic charcot neuroarthropathy: a case-control study. Diabetes Care 2009;32:1694–7. in Google Scholar PubMed PubMed Central

22. El-Ziny, MA, Al-Tonbary, YA, Salama, OS, Bakr, AA, Al-Marsafawy, H, Elsharkawy, AA. Low turnover bone disease in Egyptian children with acute leukemia. Hematology 2005;10:327–33. in Google Scholar PubMed

23. El-Ziny, MA, Al-Tonbary, YA, Salama, OS, Bakr, AA, Al-Marsafawy, H, Elsharkawy, AA. Low bone mass in children with malignant lymphoma. Pediatr Hematol Oncol 2007;24:577–85. in Google Scholar PubMed

24. Binkley, N, Bilezikian, JP, Kendler, DL, Leib, ES, Lewiecki, EM, Petak, SM, et al.. Official positions of the International Society for Clinical Densitometry and Executive Summary of the 2005 Position Development Conference. J Clin Densitom 2006;9:4–14. in Google Scholar PubMed

25. Sahin, S, Adrovic, A, Barut, K, Canpolat, N, Ozluk, Y, Kilicaslan, I, et al.. Juvenile systemic lupus erythematosus in Turkey: demographic, clinical and laboratory features with disease activity and outcome. Lupus 2018;27:514–9. in Google Scholar PubMed

26. Dhillon, VB, Davies, MC, Hall, ML, Round, JM, Ell, PJ, Jacobs, HS, et al.. Assessment of the effect of oral corticosteroids on bone mineral density in systemic lupus erythematosus: a preliminary study with dual energy x ray absorptiometry. Ann Rheum Dis 1990;49:624–6. in Google Scholar PubMed PubMed Central

27. Kalla, AA, Kataar, AB, Jessop, SJ, Bewerunge, L. Loss of trabecular bone mineral density in systemic lupus erythematosus. Arthritis Rheum 1993;36:1726–34. in Google Scholar PubMed

28. Almehed, K, Forsblad, DH, Kvist, G, Ohlsson, C, Carlsten, H. Prevalence and risk factors of osteoporosis in female SLE patients: extended report. Rheumatology (Oxford) 2007;1185:1190–246. in Google Scholar PubMed

29. Barbulescu, A, Vreju, FA, Criveanu, C, Rosu, A, Ciurea, P. Osteoporosis in systemic lupus erythematosus – correlations with disease activity and organ damage. Curr Health Sci J 2015;41:109–14. in Google Scholar PubMed PubMed Central

30. Lilleby, V, Lien, G, Frey Frøslie, K, Haugen, M, Flatø, B, Førre, Ø. Frequency of osteopenia in children and young adults with childhood-onset systemic lupus erythematosus. Arthritis Rheum 2005;52:2051–9. in Google Scholar PubMed

31. Alsufyani, KA, Ortiz-Alvarez, O, Cabral, DA, Tucker, LB, Petty, RE, Nadel, H, et al.. Bone mineral density in children and adolescents with systemic lupus erythematosus, juvenile dermatomyositis, and systemic vasculitis: relationship to disease duration, cumulative corticosteroid dose, calcium intake, and exercise. J Rheumatol 2005;32:729–33. PMID: 15801032.Search in Google Scholar

32. Compeyrot-Lacassagne, S, Tyrrell, PN, Atenafu, E, Doria, AS, Stephens, D, Gilday, D, et al.. Prevalence and etiology of low bone mineral density in juvenile systemic lupus erythematosus. Arthritis Rheum 2007;56:1966–73. in Google Scholar PubMed

33. Alkady, EA, Rashad, SM, Khedr, TM, Mossad, E, Abdel-Wahab, N. Early predictors of increased bone resorption in juvenile idiopathic arthritis: OPG/RANKL ratio, as a key regulator of bone metabolism. Egypt Rheumatol 2011;33:217–23. in Google Scholar

34. Lien, G, Ueland, T, Godang, K, Selvaag, AM, rre OT, F, Flat, B. Serum levels of osteoprotegerin and receptor activator of nuclear factor -kB ligand in children with early juvenile idiopathic arthritis: a 2-year prospective controlled study. Pediatr Rheumatol Online J 2010;8:30. in Google Scholar PubMed PubMed Central

35. Choi, JY, Shin, A, Park, SK, Chung, HW, Cho, SI, Shin, CS, et al.. Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 2005;77:152–9. in Google Scholar

36. Liu, YP, Zhao, DW, Wang, WM, Wang, BJ, Zhang, Y, Li, ZG. Association of the g.27563G>A osteoprotegerin genetic polymorphism with bone mineral density in Chinese women. Genet Mol Res 2014;13:3560–6. in Google Scholar

37. Liu, S, Yi, Z, Ling, M, Shi, J. Association between g.19163A>G and g.23298T>C genetic variants of the osteoprotegerin gene and bone mineral density in Chinese women. Hormones (Athens) 2013;12:578–83. in Google Scholar

38. Gupta, R, Aggarwal, A, Sinha, S, Rajasekhar, L, Yadav, A, Gaur, P, et al.. Urinary osteoprotegerin: a potential biomarker of lupus nephritis disease activity. Lupus 2016;25:1230–6. in Google Scholar

39. Yijun, Z, Hu, D, Shunle, C. The significance of the RANKL and OPG gene expression in the initial systemic lupus erythematosus patients. Chinese J Osteo 2009;1:36–9.Search in Google Scholar

40. Hofbauer, LC, Gori, F, Riggs, BL, Lacey, DL, Dunstan, CR, Spelsberg, TC, et al.. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999;140:4382–9. in Google Scholar

41. Coimbra, IB, Costallat, LT. Bone mineral density in systemic lupus erythematosus and its relation to age at disease onset, plasmatic estradiol and immunosuppressive therapy. Joint Bone Spine 2003;70:40–5. in Google Scholar

42. Castro, TC, Terreri, MT, Szejnfeld, VL, Castro, CH, Fisberg, M, Gabay, M, et al.. Bone mineral density in juvenile systemic lupus erythematosus. Braz J Med Biol Res 2002;35:1159–63. in Google Scholar PubMed

43. El-Hady, HA, Abd-El Aziz Kora, M, Soliman, SG, Ragheb, A, Zahran, ES. Study of bone mineral density in patients with systemic lupus erythematosus. Menoufia Med J [serial online] 2014 [cited 2021 Sep 27]:27;556–61. Available from in Google Scholar

44. Ponnapakkam, T, Katilkaneni, R, NicholsT, Tobin, G, Sakon, J, Matsushita, O, et al.. Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone. J Endocrinol Invest 2011;34:392–7. in Google Scholar PubMed

45. Lee, C, Almagor, O, Dunlop, DD, Manzi, S, Spies, S, Chadha, AB, et al.. Disease damage and low bone mineral density: an analysis of women with systemic lupus erythematosus ever and never receiving corticosteroids. Rheumatology (Oxford) 2006;45:53–60. in Google Scholar PubMed

46. Zhang, F, Su, M, Li, P. Bone mineral density and disease activity in untreated systemic lupus erythematosus patients. Zhonuga Yi Xue Zhi 2012;2331:2334. 92. PMID: 23158562.Search in Google Scholar

47. Johnston, CCJr, Miller, JZ, Slemenda, CW, Reister, TK, Hui, S, Christian, JC, et al.. Calcium supplementation and increases in bone mineral density in children. N Engl J Med 1992;327:82–7. in Google Scholar PubMed

48. Bhattoa, HP, Kiss, E, Bettembuk, P, Balogh, A. Bone mineral density, biochemical markers of bone turnover, and hormonal status in men with systemic lupus erythematosus. Rheumatol Int 2001;21:97–102. in Google Scholar PubMed

49. Formiga, F, Nolla, JM, Mitjavila, F, Bonnin, R, Navarro, MA, Moga, I. Bone mineral density and hormonal status in men with systemic lupus erythematosus. Lupus 1996;15:623–6. in Google Scholar PubMed

Received: 2021-07-23
Accepted: 2021-11-02
Published Online: 2021-11-18
Published in Print: 2022-01-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 7.6.2023 from
Scroll to top button