Is it possible to predict a risk of osteoporosis in patients with juvenile idiopathic arthritis? A study of serum levels of markers of bone turnover

  • Marta Janicka-Szczepaniak
  • Krzysztof Orczyk
  • Katarzyna Szymbor
  • Danuta Chlebna-Sokół
  • Elzbieta Smolewska Medical University of Lodz, Poland
Keywords: juvenile idiopathic arthritis, bone turnover, osteoporosis, glucocorticosteroids


Background: Low bone mineral density is a common finding in children with systemic connective tissue diseases, including juvenile idiopathic arthritis (JIA). The influence of the ongoing process of bone remodeling on the disease course merits further investigation. The aim of the study was to assess the clinical relevance of markers of bone turnover and their potential role as predictors of higher fracture risk and, by extension, risk of osteoporosis.

Materials and methods: Blood samples were collected from 59 patients diagnosed with JIA in order to determine serum levels of the following markers of bone turnover: Beta-Crosslaps, osteocalcin, bone alkaline phosphatase, osteoprotegerin and receptor activator for nuclear factor kappa-B ligand. The values were analyzed with laboratory parameters and results of dual X-ray absorptiometry (DXA).

Results: Osteoprotegerin and bone alkaline phosphatase levels were age-dependent. Beta‑Crosslaps values were significantly higher in patients with positive JADAS27 score (p=0.0410). Osteoprotegerin levels were higher in patients treated with biological agentsthan only withdisease-modifying anti-rheumatic drugs (p=0.0273). There was no relation between markers of bone turnover and sex, DXA results, dosage of glucocorticosteroids and disease duration.

Conclusions:Authors postulate performing DXA measurements every 6 months in patients with higher disease activity. The potential lower fracture risk in children with JIA within biological treatment needs future assessment. Age- and sex-adjusted reference rates of markers of bone turnover for Central Europe need to be developed in order to assess individual values properly.


Bazso A, Consolaro A, Ruperto N, Pistorio A, Viola S, Magni-Manzoni S, Malattia C, Buoncompagni A, Loy A, Martini A, Ravelli A, Pediatric Rheumatology International Trials Organization (2009) Development and testing of reduced joint counts in juvenile idiopathic arthritis. J Rheumatol 36: 183-90.

Billiau AD, Loop M, Le PQ, Berthet F, Philippet P, Kasran A, Wouters CH (2010) Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis. Rheumatology (Oxford) 49: 1550-8.

Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423: 337-42.

Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone (2002) Ann N Y Acad Sci 966: 73 81.

Caparbo VF, Prada F, Silva CA, Regio PL, Pereira RM (2009) Serum from children with polyarticular juvenile idiopathic arthritis (pJIA) inhibits differentiation, mineralization and may increase apoptosis of human osteoblasts "in vitro". Clin Rheumatol 28: 71-7.

Corrado A, Maruotti N, Cantatore FP (2017) Osteoblast Role in Rheumatic Diseases. Int J Mol Sci 18: 1272. doi: 10.3390/ijms18061272

Csakvary V, Puskas T, Oroszlan G, Lakatos P, Kalman B, Kovacs GL, Toldy E (2013) Hormonal and biochemical parameters correlated with bone densitometric markers in prepubertal Hungarian children. Bone 54: 106-12.

de Jager W, Hoppenreijs EP, Wulffraat NM, Wedderburn LR, Kuis W, Prakken BJ (2007) Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis 66: 589-98.

Delany AM, Durant D, Canalis E (2001) Glucocorticoid suppression of IGF I transcription in osteoblasts. MolEndocrinol 15: 1781-9.

Dhillon VB, Davies MC, Hall ML, Round JM, Ell PJ, Jacobs HS, Snaith ML, Isenberg DA (1990) 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 49: 624-6.

Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382: 448-52.

Eckard AR, OʼRiordan MA, Rosebush JC, Ruff JH, Chahroudi A, Labbato D, Daniels JE, Uribe-Leitz M, Tangpricha V, McComsey GA (2017) Effects of Vitamin D Supplementation on Bone Mineral Density and Bone Markers in HIV-Infected Youth. J Acquir Immune DeficSyndr 76: 539-546.

Engvall IL, Svensson B, Boonen A, van der Heijde D, Lerner UH, Hafström I, BARFOT study group (2013) Low-dose prednisolone in early rheumatoid arthritis inhibits collagen type I degradation by matrix metalloproteinases as assessed by serum 1CTP--a possible mechanism for specific inhibition of radiological destruction. Rheumatology (Oxford) 52: 733-42.

Gajewska J, Ambroszkiewicz J, Laskowska-Klita T (2006) Osteoprotegerin and C-telopeptide of type I collagen in Polish healthy children and adolescents. Adv Med Sci 51: 269-72.

Ginty F, Cavadini C, Michaud PA, Burckhardt P, Baumgartner M, Mishra GD, Barclay DV (2004) Effects of usual nutrient intake and vitamin D status on markers of bone turnover in Swiss adolescents. Eur J ClinNutr 58: 1257-65.

Gordon CM, Leonard MB, Zemel BS, International Society for Clinical Densitometry (2014) 2013 Pediatric Position Development Conference: executive summary and reflections. J ClinDensitom 17: 219-24.

Górska A, Urban M, Bartnicka M, Zelazowska-Rutkowska B, Wysocka J (2008) Bone mineral metabolism in children with juvenile idiopathic arthritis--preliminary report. OrtopTraumatolRehabil 10: 54-62.

Guo Q, Fan P, Luo J, Wu S, Sun H, He L, Zhou B (2017) Assessment of bone mineral density and bone metabolism in young male adults recently diagnosed with systemic lupus erythematosus in China. Lupus 26: 289-293.

Hampson G, Bhargava N, Cheung J, Vaja S, Seed PT, Fogelman I (2002) Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis. Metabolism 51: 1458-62.

Herrmann M, Pape G, Herrmann W (2002) Measurement of serum beta-crosslaps is influenced by proteolytic conditions. Clin Chem Lab Med 40:790-4.

Hofbauer LC (1999) Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism. Eur J Endocrinol 141: 195-210.

Jelusic M, Lukic IK, Batinic D (2007) Biological agents targeting interleukin-18. Drug News Perspect 20: 485-94.

Kim EY, Moudgil KD (2008) Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunol Lett 120: 1-5.

Lambrinoudaki I, Tsouvalas E, Vakaki M, Kaparos G, Stamatelopoulos K, Augoulea A, Pliatsika P, Alexandrou A, Creatsa M, Karavanaki K (2013) Osteoprotegerin, Soluble Receptor Activator of Nuclear Factor- κ B Ligand, and Subclinical Atherosclerosis in Children and Adolescents with Type 1 Diabetes Mellitus. Int J Endocrinol 2013: 102120.

Lien G, Ueland T, Godang K, Selvaag AM, Førre OT, Flatø B (2010) Serum levels of osteoprotegerin and receptor activator of nuclear factor -κB ligand in children with early juvenile idiopathic arthritis: a 2-year prospective controlled study. PediatrRheumatol Online J 8: 30.

Lukert BP, Raisz LG (1994) Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 20: 629 50.

Macaubas C, Nguyen K, Milojevic D, Park JL, Mellins ED (2009) Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol 5: 616-26.

Malysheva K, de Rooij K, Lowik CW, Baeten DL, Rose-John S, Stoika R, Korchynskyi O (2016) Interleukin 6/Wnt interactions in rheumatoid arthritis: interleukin 6 inhibits Wnt signaling in synovial fibroblasts and osteoblasts. Croat Med J 57: 89-98.

Masi L, Simonini G, Piscitelli E, Del Monte F, Giani T, Cimaz R, Vierucci S, Brandi ML, Falcini F (2004) Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? J Rheumatol 31: 986-91.

Molines L, Darmon P, Raccah D (2010) Charcot's foot: newest findings on its pathophysiology, diagnosis and treatment. Diabetes Metab 36: 251-5.

Napoli N, Strollo R, Pitocco D, Bizzarri C, Maddaloni E, Maggi D, Manfrini S, Schwartz A, Pozzilli P, IMDIAB Group (2013) Effect of calcitriol on bone turnover and osteocalcin in recent-onset type 1 diabetes. PLoS One 8: e56488.

Okazaki R, Riggs BL, Conover CA (1994) Glucocorticoid regulation of insulin-like growth factor-binding protein expression in normal human osteoblast-like cells. Endocrinology 134: 126-32.

Pereira RM, Falco V, Corrente JE, Chahade WH, Yoshinari NH (1999) Abnormalities in the biochemical markers of bone turnover in children with juvenile chronic arthritis. Clin Exp Rheumatol 17: 251-5.

Petty RE (2001) Growing pains: the ILAR classification of juvenile idiopathic arthritis. J Rheumatol 28: 927-8.

Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, Dunstan CR, Martin TJ, Gillespie MT (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 161: 1419-27.

Sarma PK, Misra R, Aggarwal A (2008) Elevated serum receptor activator of NFkappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and ProMMP1 in patients with juvenile idiopathic arthritis. Clin Rheumatol 27: 289-94.

Schou AJ, Heuck C, Wolthers OD (2003) Vitamin D supplementation to healthy children does not affect serum osteocalcin or markers of type I collagen turnover. Acta Paediatr 92: 797-801.

Shimizu S, Asou Y, Itoh S, Chung UI, Kawaguchi H, Shinomiya K, Muneta T (2007) Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum 56: 3358-65.

Skowrońska-Jóźwiak E, Lorenc RS (2006) Metabolic bone disease in children: etiology and treatment options. Treat Endocrinol 5: 297-318.

Spelling P, Bonfá E, Caparbo VF, Pereira RM (2008) Osteoprotegerin/RANKL system imbalance in active polyarticular-onset juvenile idiopathic arthritis: a bone damage biomarker? Scand J Rheumatol 37: 439-44.

Thiering E, Brüske I, Kratzsch J, Hofbauer LC, Berdel D, von Berg A, Lehmann I, Hoffmann B, Bauer CP, Koletzko S, Heinrich J (2015) Associations between serum 25-hydroxyvitamin D and bone turnover markers in a population based sample of German children. Sci Rep 5: 18138.

van der Sluis IM, Hop WC, van Leeuwen JP, Pols HA, de Muinck Keizer-Schrama SM (2002) A cross-sectional study on biochemical parameters of bone turnover and vitamin D metabolites in healthy Dutch children and young adults. Horm Res 57: 170-9.

Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA, IOF-IFCC Bone Marker Standards Working Group (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22: 391-420.

von Scheven E, Corbin KJ, Stagi S, Cimaz R (2014) Glucocorticoid-associated osteoporosis in chronic inflammatory diseases: epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep 12: 289-99.

Ward L, Petryk A, Gordon CM (2009) Use of bisphosphonates in the treatment of pediatric osteoporosis. Int J Clin Rheumtol 4: 657-672.

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

Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102: 274-82.

Weinstein RS, Nicholas RW, Manolagas SC (2000) Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85: 2907-12.

Zdzisińska B, Kandefer-Szerszeń M (2006) [The role of RANK/RANKL and OPG in multiple myeloma]. Postepy Hig Med Dosw (Online)60: 471-82.