Top

Published in:

Open Access 01-12-2023 | Juvenile Rheumatoid Arthritis | Research article

Bone mineral density in egyptian children with juvenile idiopathic arthritis: possible correlation to serum RANKL / osteoprotegerin (OPG) ratio and OPG gene polymorphisms

Authors: Riham Eid, Maha Abdelsalam, Aya Ahmed Fathy, Hadil M. Abolenein, Eman Bakr Elmarghany, Aya Ahmed El-Hanafy, Nashwa Hamdy, Dina Salama Abd-Elmagid, Nermeen A. Niazy, Dina M. Abd-El Ghaffar

Published in: Pediatric Rheumatology | Issue 1/2023

Abstract

Background

Children with juvenile idiopathic arthritis (JIA) are at higher risk of decreased bone mineral density (BMD) compared with healthy children due to genetic, disease and medication-related causes. This study aims to investigate the possible effects of osteoprotegerin (OPG) gene polymorphisms and serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor κB-ligand (RANKL) and RANKL/OPG ratio on BMD in children with JIA.

Methods

OPG gene rs2073617, rs3134069, serum RANKL, OPG and RANKL/OPG ratio were evaluated in 60 JIA children and 100 matched healthy controls. BMD was evaluated by lumbar dual energy X-ray absorptiometry (DEXA) according to which patients were classified in 2 groups (DEXA z-score above and below − 2). Composite disease activity was measured using the Juvenile Arthritis Disease Activity Score (JADAS) 27-joints. Articular damage was scored using the juvenile arthritis damage index (JADI).

Results

Patients aged 12.05 ± 3.2 years, included 38 females and 31% had BMD z-score below-2. Systemic-onset JIA was the most frequent phenotype (38%). Genotypes and alleles frequencies of the 2 studied polymorphisms did not differ between patients and controls (p > 0.05 for all) while serum RANKL and RANKL/OPG ratio were significantly higher in patients compared to controls (p = < 0.001 and 0.03 respectively). Patients with BMD < -2 had significantly greater frequencies of rs2073617 TT genotype and T allele (p < 0.001), higher serum RANKL, RANKL/OPG ratio (p = 0.01, 0.002), female predominance (p = 0.02), higher articular and extra-articular damage index (p = 0.008,0.009) and more frequent steroid usage (p = 0.02) compared to patients with BMD z-score >-2. Multivariate analysis showed rs2073617 TT genotype, RANKL/OPG ratio, long disease duration (above 36 months) and use of steroid to be associated with decreased BMD (p = 0.03,0.04,0.01,0.01 respectively) in JIA children.

Conclusions

Egyptian children with JIA have decreased BMD. rs2073617 TT genotype and T allele, RANKL/OPG ratio are possible determinants of reduced BMD in JIA. Our results underline the importance of frequent monitoring of BMD in JIA children and trying to control disease activity to preserve long term bone health.

Available only for authorised users

Lien G, Ueland T, Godang K, Selvaag AM, Førre OT, Flatø 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. https://doi.org/10.1186/1546-0096-8-30.CrossRefPubMedPubMedCentral

Bachrach LK. Measuring bone mass in children: can we really do it? Horm Res. 2006;65:11–6. https://doi.org/10.1159/000091749.CrossRefPubMed

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. https://doi.org/10.1007/s00467-010-1583-1.CrossRefPubMedPubMedCentral

Levälampi T, Honkanen V, Lahdenne P, Nieminen R, Hakala M, Moilanen E. Effects of infliximab on cytokines, myeloperoxidase, and soluble adhesion molecules in patients with juvenile idiopathic arthritis. Scand J Rheumatol. 2007;36(3):189–93. https://doi.org/10.1080/03009740601089234.CrossRefPubMed

Lerner UH. New molecules in the tumor necrosis factor ligand and receptor superfamilies with importance for physiological and pathologic bone resorption. Crit Rev Oral Biol Med. 2004;15(2):64–81. https://doi.org/10.1177/154411130401500202.CrossRefPubMed

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 Rheumatologist. 2011;33:217–23. https://doi.org/10.1016/j.ejr.2011.08.001.CrossRef

Panopalis P, Yazdany J. Bone health in systemic lupus erythematosus. Curr Rheumatol Rep. 2009;11:177–84. https://doi.org/10.1007/s11926-009-0024-2.CrossRefPubMed

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(10):1233–42. https://doi.org/10.1177/0961203319867129.CrossRefPubMed

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(3):977–83. https://doi.org/10.1002/art.22433.CrossRefPubMed

10.

Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. Genetic determinants of bone mass in adults: a twin study. J Clin Invest. 1987;80(3):706–10. https://doi.org/10.1172/JCI113125.CrossRefPubMedPubMedCentral

11.

Hofbauer LC, Heufelder AE. The role of osteoprotegerin and receptor activator of nuclear factor κB ligand in the pathogenesis and treatment of rheumatoid arthritis. Arthritis Rheum. 2001;44:253–9. https://doi.org/10.1002/1529-0131(200102)44:2<253::AID-ANR41>3.0.CO;2-S.CrossRefPubMed

12.

Itonaga I, Fujikawa Y, Sabokbar A, Murray DW, Athanasou NA. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol. 2000;192(1):97–104. https://doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH672>3.0.CO;2-W.CrossRefPubMed

13.

Eid R, Abdelsalam M, Fathy AA, Abd-El Ghaffar DM, Elmarghany EB, El-Hanafy AA, et al. Predictors of decreased bone mineral density in childhood systemic lupus erythematosus: possible role of osteoprotegerin gene polymorphisms. J Pediatr Endocrinol Metab. 2021;35(1):79–87. https://doi.org/10.1515/jpem-2021-0496. PMID: 34787382.CrossRefPubMed

14.

Zavala-Cerna MG, Moran-Moguel MC, Cornejo-Toledo JA, Gonzalez-Montoya NG, Sanchez-Corona J, Salazar-Paramo M et al. Osteoprotegerin Polymorphisms in a Mexican Population with Rheumatoid Arthritis and Generalized Osteoporosis: A Preliminary Report. J Immunol Res. 2015; 2015:376197. https://doi.org/10.1155/2015/376197.

15.

Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2. PMID: 14760812.PubMed

16.

Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31:2290–4. PMID: 15517647.PubMed

17.

Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011;63:929–36.CrossRefPubMed

18.

Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, et al. Paediatric Rheumatology International trials Organisation. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum. 2009;61(5):658–66. https://doi.org/10.1002/art.24516.CrossRefPubMed

19.

Viola S, Felici E, Magni-Manzoni S, Pistorio A, Buoncompagni A, Ruperto N et al. Development and validation of a clinical index for assessment of long-term damage in juvenile idiopathic arthritis. Arthritis Rheum.2005; 52:2092–102. https://doi.org/10.1002/art.21119. PMID: 15986372.

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. https://doi.org/10.1210/jc.2003-032054.CrossRefPubMed

21.

Pitocco D, Zelano G, Gioffre G, Di Stasio E, Zaccardi F, Martini F et al. Association between osteoprotegerin G1181C and T245G polymorphisms and diabetic charcot neuroarthropathy: Acase-control study. Diabetes Care 209; 32:1694–7. https://doi.org/10.2337/dc09-0243.

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. https://doi.org/10.1080/10245330500155598.CrossRefPubMed

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. https://doi.org/10.1080/08880010701640275.CrossRefPubMed

24.

Binkley N, Bilezikian JP, Kendler DL, Leib ES, Lewiecki EM, Petak SM, International Society for Clinical Densitometry. Official positions of the International Society for Clinical Densitometry and Executive Summary of the 2005 Position Development Conference. J Clin Densitom. 2006;9(1):4–14. https://doi.org/10.1016/j.jocd.2006.05.002.

25.

Consolaro A, Giancane G, Schiappapietra B, Davì S, Calandra S, Lanni S, Ravelli A. Clinical outcome measures in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2016;14(1):23. https://doi.org/10.1186/s12969-016-0085-5.CrossRefPubMedPubMedCentral

26.

Al-Mayouf SM, Al Mutairi M, Bouayed K, Habjoka S, Hadef D, Lotfy HM et al. Epidemiology and demographics of juvenile idiopathic arthritis in Africa and Middle East. Pediatr Rheumatol Online J. 2021 Dec 2;19(1):166. https://doi.org/10.1186/s12969-021-00650-x.

27.

Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine. 2014;81(2):112–7. https://doi.org/10.1016/j.jbspin.2013.09.003.CrossRefPubMed

28.

Dagher R, Assi S. Juvenile idiopathic arthritis: a single center lebanese study. Pediatr Rheumatol. 2014;12:179. https://doi.org/10.1016/j.jbspin.2013.09.003.CrossRef

29.

Demirkaya E, Ozen S, Bilginer Y, Ayaz NA, Makay BB, Unsal E, et al. The distribution of juvenile idiopathic arthritis in the eastern Mediterranean: results from the registry of the turkish Paediatric Rheumatology Association. Clin Exp Rheumatol. 2011;29(1):111–6. PMID: 21269582.PubMed

30.

Hussein ZM, Wagdy R, Shawki M, Zohni S, Shehawy I. The pattern of juvenile idiopathic arthritis; a retrospective egyptian study. Egypt J Pediatr Allergy Immunol. 2018;16(1):7–14. https://doi.org/10.21608/ejpa.2018.10417.CrossRef

31.

Consolaro A, Giancane G, Alongi A, van Dijkhuizen EHP, Aggarwal A, Al-Mayouf SM, et al. Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. Lancet Child Adolesc Health. 2019;3(4):255–63. https://doi.org/10.1016/S2352-4642(19)30027-6.CrossRefPubMed

32.

Al-Mayouf SM, Hashad S, Khawaja K, Alrasheedi A, Abdwani R, Abushhaiwia A, et al. Cumulative damage in juvenile idiopathic arthritis: a Multicenter Study from the Pediatric Rheumatology Arab Group. Arthritis Care Res (Hoboken). 2021;73(4):586–92. https://doi.org/10.1002/acr.24436.CrossRefPubMed

33.

Abdwani R, Abdalla E, Al Abrawi S, Al-Zakwani I. Epidemiology of juvenile idiopathic arthritis in Oman. Pediatr Rheumatol Online J. 2015;13:33. https://doi.org/10.1186/s12969-015-0030-z.CrossRefPubMedPubMedCentral

34.

Al-Abrawi S, Al-Mayouf SM, Abdwani R, Abdalla E, Consolaro A, Bovis F, et al. The Omani Arabic version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). Rheumatol Int. 2018;38(1):299–306. https://doi.org/10.1007/s00296-018-3965-9.CrossRefPubMedPubMedCentral

35.

Saurenmann RK, Rose JB, Tyrrell P, Feldman BM, Laxer RM, Schneider R, et al. Epidemiology of juvenile idiopathic arthritis in a multi-ethnic cohort: ethnicity as a risk factor. Arthritis Rheum. 2007;56(6):1974–84. https://doi.org/10.1002/art.22709.CrossRefPubMed

36.

Sušić G, Pilipović N, Stojanović R. Bone Mineral density in patients with juvenile idiopathic arthritis. Srp Arh Celok Lek. 2009;137(7–8):396–401. https://doi.org/10.2298/sarh0908396s.CrossRefPubMed

37.

Galindo Zavala R, Núñez Cuadros E, Martín Pedraz L, Díaz-Cordovés Rego G, Sierra Salinas C, Urda Cardona A. Low bone mineral density in juvenile idiopathic arthritis: prevalence and related factors. An Pediatr (Barc). 2017;87(4):218–25. https://doi.org/10.1016/j.anpedi.2016.12.005.CrossRefPubMed

38.

Stagi S, Cavalli L, Signorini C, Bertini F, Cerinic MM, Brandi ML, et al. Bone mass and quality in patients with juvenile idiopathic arthritis: longitudinal evaluation of bone-mass determinants by using dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and quantitative ultrasonography. Arthritis Res Ther. 2014;16(2):R83. https://doi.org/10.1186/ar4525.CrossRefPubMedPubMedCentral

39.

Islam MF, Islam MI, Talukdar MK, Rahman SA. Bone mineral density in children with juvenile idiopathic arthritis: a hospital-based study. Bangladesh J Child Health. 2013;37:18–21. https://doi.org/10.3329/bjch.v37i1.15347.CrossRef

40.

Thornton J, Pye SR, O’Neill TW, Rawlings D, Francis RM, Symmons DP, et al. Bone health in adult men and women with a history of juvenile idiopathic arthritis. J Rheumatol. 2011;38(8):1689–93. https://doi.org/10.3899/jrheum.101232.CrossRefPubMed

41.

Charuvanij S, Malakorn H, Densupsoontorn N, Nakavachara P. Bone Mineral density and serum 25OHD in children and adolescents with juvenile idiopathic arthritis. Clin Pediatr (Phila). 2022 Nov 10:99228221136982. https://doi.org/10.1177/00099228221136982. Epub ahead of print.

42.

El Badri D, Rostom S, Bouaddi I, Hassani A, Chkirate B, Amine B, et al. Bone Mineral density in moroccan patients with juvenile idiopathic arthritis. J Arthritis. 2014;3:131. https://doi.org/10.11604/pamj.2014.17.115.1838.CrossRef

43.

Tsentidis C, Gourgiotis D, Kossiva L, Doulgeraki A, Marmarinos A, Galli-Tsinopoulou A, et al. Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signalling and predisposition to lower bone mass: a multivariate cross-sectional analysis. Osteoporos Int. 2016;27(4):1631–43. https://doi.org/10.1007/s00198-015-3422-5.CrossRefPubMed

44.

Ozkaya O, Buyan N, Bideci A, Gonen S, Ortac E, Fidan K, et al. Osteoprotegerin and RANKL serum levels and their relationship with serum ghrelin in children with chronic renal failure and on dialysis. Nephron Clin Pract. 2007;105(4):c153–8. https://doi.org/10.1159/000099005.CrossRefPubMed

45.

Spelling P, Bonfa ́ E, Caparbo VF, Pereira RM. Osteoprotegerin/ RANKL system imbalance in active polyarticular-onset juvenile idiopathic arthritis: a bone damage biomarker? Scand J Rheumatol. 2008;37:439–44. https://doi.org/10.1080/03009740802116224.CrossRefPubMed

46.

Buzi F, Maccarinelli G, Guaragni B, Ruggeri F, Radetti G, Meini A, et al. Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner’s syndrome and rheumatoid arthritis. Clin Endocrinol (Oxf). 2004;60(1):87–91. https://doi.org/10.1111/j.1365-2265.2004.01951.x.CrossRefPubMed

47.

Masi L, Simonini G, Piscitelli E, Del Monte F, Giani T, Cimaz R, et al. Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? J Rheumatol. 2004;31(5):986–91. PMID: 15124262.PubMed

48.

Sarma PK, Misra R, Aggarwal A. Elevated serum receptor activator of NFkappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and ProMMP1 in patients with juvenile idiopathic arthritis. Clin Rheumatol. 2008;27(3):289–94. https://doi.org/10.1007/s10067-007-0701-3.CrossRefPubMed

49.

Varsani H, Patel A, van Kooyk Y, Woo P, Wedderburn LR. Synovial dendritic cells in juvenile idiopathic arthritis (JIA) express receptor activator of NF-kappaB (RANK). Rheumatol Oxf. 2003;42:583–90. PMID: 12649407.

50.

Agarwal S, Misra R, Aggarwal A. Synovial fluid RANKL and matrix metalloproteinase levels in enthesitis related arthritis subtype of juvenile idiopathic arthritis. Rheumatol Int. 2009;29:907–11. https://doi.org/10.1007/s00296-008-0805-3.CrossRefPubMed

51.

Shalaby RH, Kassem EM, El-Gazzar NM, Hammoudah SAF, El-Barbary AM. P013 serum osteoprotegerin and RANKL in patients with juvenile idiopathic arthritis and their correlation with bone mineral density. Rheumatology. 2021;60(5). https://doi.org/10.1093/rheumatology/keab722.005.

52.

Geusens PP, Landewé RB, Garnero P, Chen D, Dunstan CR, Lems WF, et al. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction. Arthritis Rheum. 2006;54(6):1772–7. https://doi.org/10.1002/art.21896.CrossRefPubMed

53.

Shunle C. The significance of the RANKL and OPG gene expression in the initial systemic lupus erythematosus patients. Chin J Osteoporos. 2009;1:36–9.

54.

Zhizho Y, Bo L, Jianso L, Fenlia G, Junhan Z. Bone mineral density in patients with juvenile rheumatoid arthritis. Pediatr Rheumatol Online J. 2008;6(1):P80. https://doi.org/10.1186/1546-0096-6-S1-P80.CrossRefPubMedCentral

55.

Davies JH, Evans BA, Jenney ME, Gregory JW. Skeletal morbidity in childhood acute lymphoblastic leukaemia. Clin Endocrinol (Oxf). 2005;63(1):1–9. https://doi.org/10.1111/j.1365-2265.2005.02263.x.CrossRefPubMed

56.

Lahdenne P, Vähäsalo P, Honkanen V. Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis. 2003;62(3):245–7. https://doi.org/10.1136/ard.62.3.245.CrossRefPubMedPubMedCentral

57.

Simonini G, Giani T, Stagi S, de Martino M, Falcini F. Bone status over 1 year of etanercept treatment in juvenile idiopathic arthritis. Rheumatology (Oxford). 2005;44:777–80. https://doi.org/10.1093/rheumatology/keh592.CrossRefPubMed

58.

Vojvodich PF, Hansen JB, Andersson U, Sävendahl L, Hagelberg S. Etanercept treatment improves longitudinal growth in prepubertal children with juvenile idiopathic arthritis. J Rheumatol. 2007;34(12):2481-5. PMID: 18050366.

59.

Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med. 2000;6(5):521-8. https://doi.org/10.1038/74999. Erratum in: Nat Med 2000;6(7):838.

60.

Bateman TA, Dunstan CR, Ferguson VL, Lacey DL, Ayers RA, Simske SJ. Osteoprotegerin mitigates tail suspension-induced osteopenia. Bone. 2000;26:443–9. https://doi.org/10.1016/S8756-3282(00)00256-8.CrossRefPubMed

61.

Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res. 2001;16(2):348–60. https://doi.org/10.1359/jbmr.2001.16.2.348.CrossRefPubMed

Title: Bone mineral density in egyptian children with juvenile idiopathic arthritis: possible correlation to serum RANKL / osteoprotegerin (OPG) ratio and OPG gene polymorphisms
Authors: Riham Eid
Maha Abdelsalam
Aya Ahmed Fathy
Hadil M. Abolenein
Eman Bakr Elmarghany
Aya Ahmed El-Hanafy
Nashwa Hamdy
Dina Salama Abd-Elmagid
Nermeen A. Niazy
Dina M. Abd-El Ghaffar
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Juvenile Rheumatoid Arthritis
Juvenile Rheumatoid Arthritis
Juvenile Arthritis
Published in: Pediatric Rheumatology / Issue 1/2023
Electronic ISSN: 1546-0096
DOI: https://doi.org/10.1186/s12969-023-00843-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Bone mineral density in egyptian children with juvenile idiopathic arthritis: possible correlation to serum RANKL / osteoprotegerin (OPG) ratio and OPG gene polymorphisms

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2023

Pain-coping scale for children and their parents: a cross-sectional study in children with musculoskeletal pain

Systemic lupus erythematosus combined with Castleman disease and secondary paraneoplastic pemphigus: a case report

Impact of SARS-CoV-2 on the clinical presentation of juvenile idiopathic inflammatory myopathies

MicroRNA-27a-3p enhances the inflammatory phenotype of Juvenile Idiopathic Arthritis fibroblast-like synoviocytes

Clinical characteristics and risk factors of coronary artery lesions in chinese pediatric Takayasu arteritis patients: a retrospective study

Is it possible to extend the dose interval of canakinumab treatment in children with familial Mediterranean fever? PeRA group experience