Assessment of Biochemical Bone Turnover Markers in Polish Healthy Children and Adolescents

Gajewska, Joanna; Chełchowska, Magdalena; Rowicka, Grażyna; Klemarczyk, Witold; Głąb-Jabłońska, Ewa; Ambroszkiewicz, Jadwiga

doi:10.34763/jmotherandchild.20242801.d-23-00105

Abstract

Background

Assessing bone turnover in paediatric populations is crucial for understanding the physiological changes occurring during skeletal development and identifying potential abnormalities. The objective of this study was to assess osteocalcin (OC), bone alkaline phosphatase (BALP), and C-terminal telopeptide of type I collagen (CTX-I) levels reflecting bone formation and resorption for age and sex in Polish healthy children and adolescents.

Materials and Methods

A total of 355 healthy normal-weight children and adolescents (46.5% girls) aged 1–18 years old were recruited. Total body less head (TBLH) and spine L1-L4 were used in children to assess bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Bone marker concentrations were determined by immunoenzymatic methods.

Results

Bone marker levels in girls and boys started with higher values in the first year of life and subsequently decreased until reaching a nadir during the prepubertal period. The pubertal peak values of bone markers were reached at 11–13 years old in boys and at 9–11 years old in girls. After puberty, the adolescents showed a gradual decline in bone marker concentrations to the values observed in adults. We found positive correlations between OC level and TBLH-BMD (r = 0.329, p = 0.002), TBLH-BMD Z-score (r = 0.245, p = 0.023), and L1-L4 BMD (r = 0.280, p = 0.009) in the prepubertal group.

Conclusions

We showed serum levels of bone turnover markers—BALP, OC, and CTX-I—in relation to age and sex in healthy Polish children and adolescents. The age intervals of these markers for girls and boys aged 1–18 years old may be clinically useful in the assessment of bone metabolism in individuals with skeletal disorders.

References

Nandiraju D, Ahmed I. Human skeletal physiology and factors affecting its modelling and remodelling. Fertil Steril. 2019;112(5):775–781. doi: 10.1016/j.fertnstert.2019.10.005.
Open DOI Search in Google Scholar Back to article
Gómez-Alonso C. Paediatric metabolic bone disease: A lifetime ahead. Adv Ther. 2020;37(Suppl 2):38–46. doi: 10.1007/s12325-019-01174-3.
Open DOI Search in Google Scholar Back to article
Guss CE, McAllister A, Gordon CM. DXA in children and adolescents. J Clin Densitom. 2021;24(1):28–35. doi: 10.1016/j.jocd.2020.01.006.
Open DOI Search in Google Scholar Back to article
Ladang A, Rauch F, Delvin E, Cavalier E. Bone turnover markers in children: from laboratory challenges to clinical interpretation. Calcif Tissue Int. 2023;112(2):218–232. doi: 10.1007/s00223-022-00964-2.
Open DOI Search in Google Scholar Back to article
Hart NH, Newton RU, Tan J, Rantalainen T, Chivers P, Siafarikas A, et al. Biological basis of bone strength: anatomy, physiology and measurement. J Musculoskelet Neuronal Interact. 2020;20(3):347–371.
Search in Google Scholar Back to article
Neve A, Corrado A, Cantatore FP. Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol. 2013;228:1149–1153. doi: 10.1002/jcp.24278.
Open DOI Search in Google Scholar Back to article
Golub EE, Boesze-Battaglia K. The role of alkaline phosphatase in mineralization. Curr Opin Orthop. 2007;18:444–448. doi: 10.1097/BCO.0b013e3282630851.
Open DOI Search in Google Scholar Back to article
Szulc P. Bone turnover: biology and assessment tools. Best Pract Res Clin Endocrinol Metab. 2018;32(5):725–738. doi: 10.1016/j.beem.2018.05.003.
Open DOI Search in Google Scholar Back to article
Hwang JS, Lee S, Gong HS. The impact of acute fracture on interpretation of bone turnover marker measurements for patients starting anti-resorptive therapies. Bone. 2022;154:116199. doi: 10.1016/j.bone.2021.116199.
Open DOI Search in Google Scholar Back to article
van Coeverden SC, Netelenbos JC, de Ridder CM, Roos JC, Popp-Snijders C, Delemarre-van de Waal HA. Bone metabolism markers and bone mass in healthy pubertal boys and girls. Clin Endocrinol (Oxf). 2002;57(1):107–16. doi: 10.1046/j.1365-2265.2002.01573.x.
Open DOI Search in Google Scholar Back to article
Ambroszkiewicz J, Gajewska J, Laskowska-Klita T. Serum osteocalcin and bone alkaline phosphatase in healthy children in relation to age and gender. Med Wieku Rozwoj. 2002;6(3):257–65.
Search in Google Scholar Back to article
Gajewska J, Ambroszkiewicz J, Laskowska-Klita T. Osteoprotegerin and C-telopeptide of type I collagen in Polish healthy children and adolescents. Adv Med Sci. 2006;51:269–72.
Search in Google Scholar Back to article
Geserick M, Vogel M, Eckelt F, Schlingmann M, Hiemisch A, Baber R, et al. Children and adolescents with obesity have reduced serum bone turnover markers and 25-hydroxyvitamin D but increased parathyroid hormone concentrations - results derived from new pediatric reference ranges. Bone. 2020;132:115124. doi: 10.1016/j.bone.2019.115124.
Open DOI Search in Google Scholar Back to article
Diemar SS, Lylloff L, Rønne MS, Møllehave LT, Heidemann M, Thuesen BH, et al. Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP). Bone. 2021;146:115879. doi: 10.1016/j.bone.2021.115879.
Open DOI Search in Google Scholar Back to article
Kułaga Z, Różdżyńska-Świątkowska A, Grajda A, Gurzkowska B, Wojtyło M, Góźdź M, et al. Percentile charts for growth and nutritional status assessment in Polish children and adolescents from birth to 18 year of age. Stand. Med. 2015;12:119–135.
Search in Google Scholar Back to article
Maggioli C, Stagi S. Bone modeling, remodeling, and skeletal health in children and adolescents: mineral accrual, assessment and treatment. Ann Pediatr Endocrinol Metab. 2017;22(1):1–5. doi: 10.6065/apem.2017.22.1.1.
Open DOI Search in Google Scholar Back to article
Cook SJ, Wall C. Paget’s disease of bone: A clinical update. Aust J Gen Pract. 2021;50(1–2):23–29. doi: 10.31128/AJGP-10-20-5690.
Open DOI Search in Google Scholar Back to article
Okten A, Cakir M, Makuloglu M. Bone mineral status, bone turnover markers and vitamin D status in children with congenital adrenal hyperplasia. Minerva Endocrinol. 2012;37(3):275–82.
Search in Google Scholar Back to article
Karava V, Dotis J, Christoforidis A, Kondou A, Printza N. Muscle-bone axis in children with chronic kidney disease: current knowledge and future perspectives. Pediatr Nephrol. 2021;36(12):3813–3827. doi: 10.1007/s00467-021-04936-w.
Open DOI Search in Google Scholar Back to article
Guandalini S, Assiri A. Celiac disease: a review. JAMA Pediatr. 2014;168(3):272–278. doi: 10.1001/jamapediatrics.2013.3858.
Open DOI Search in Google Scholar Back to article
Wei H, Zhao Y, Xiang L. Bone health in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2023;17(9):921–935. doi: 10.1080/17474124.2023.2248874.
Open DOI Search in Google Scholar Back to article
Gajewska J, Ambroszkiewicz J, Laskowska-Klita T. Some bone turnover markers in serum of healthy children and adolescents in relation to age and gender. Wiad Lek. 2005;58(9–10):476–80.
Search in Google Scholar Back to article
Wang X, Liu L, Li P, Ma J, Jiang R, Wang R, et al. Reference and influential factors of serum bone markers in Chinese adolescents. Sci Rep. 2017;7(1):17340. doi: 10.1038/s41598-017-17670-x.
Open DOI Search in Google Scholar Back to article
Paldánius PM, Ivaska KK, Mäkitie O, Viljakainen H. Serum and urinary osteocalcin in healthy 7- to 19-year-old Finnish children and adolescents. Front Pediatr. 2021;9:610227. doi: 10.3389/fped.2021.610227.
Open DOI Search in Google Scholar Back to article
Rand MS, Diemar SS, Møllehave LT, Heidemann M, Thuesen BH, Petersen JH, et al. Z-scores of bone turnover markers calculated from new established sex- and age-specific reference curves are associated to future change in BMD in children and adolescents. Bone. 2023;167:116641. doi: 10.1016/j.bone.2022.116641.
Open DOI Search in Google Scholar Back to article
Chubb SAP, Vasikaran SD, Gillett MJ. Reference intervals for plasma β-CTX and P1NP in children: A systematic review and pooled estimates. Clin Biochem. 2023;118:110582. doi: 10.1016/j.clinbiochem.2023.05.001.
Open DOI Search in Google Scholar Back to article
Federico G, Baroncelli GI, Vanacore T, Fiore L, Saggese G. Pubertal changes in biochemical markers of growth. Horm Res. 2003;60(Suppl1):46–51. doi: 10.1159/000071225.
Open DOI Search in Google Scholar Back to article
Diemar SS, Møllehave LT, Quardon N, Lylloff L, Thuesen BH, Linneberg A, et al. Effects of age and sex on osteocalcin and bone-specific alkaline phosphatase-reference intervals and confounders for two bone formation markers. Arch Osteoporos. 2020;15(1):26. doi: 10.1007/s11657-020-00715-6.
Open DOI Search in Google Scholar Back to article
Huang Y, Eapen E, Steele S, Grey V. Establishment of reference intervals for bone markers in children and adolescents. Clin Biochem. 2011;44(10–11):771–778. doi: 10.1016/j.clinbiochem.2011.04.008.
Open DOI Search in Google Scholar Back to article
Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, Venner AA, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58(5):854–868. doi: 10.1373/clinchem.2011.177741.
Open DOI Search in Google Scholar Back to article
Fischer DC, Mischek A, Wolf S, Rahn A, Salweski B, Kundt G, et al. Paediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase. Ann Clin Biochem. 2012;49(Pt 6):546–553. doi: 10.1258/acb.2012.011274.
Open DOI Search in Google Scholar Back to article
Rauchenzauner M, Schmid A, Heinz-Erian P, Kapelari K, Falkensammer G, Griesmacher A, et al. Sex- and age-specific reference curves for serum markers of bone turnover in healthy children from 2 months to 18 years. J Clin Endocrinol Metab. 2007;92(2):443–449. doi: 10.1210/jc.2006-1706.
Open DOI Search in Google Scholar Back to article
Bayer M. Reference values of osteocalcin and procollagen type I N-propeptide plasma levels in a healthy Central European population aged 0–18 years. Osteoporos Int. 2014;25(2):729–736. doi: 10.1007/s00198-013-2485-4.
Open DOI Search in Google Scholar Back to article
Herrmann D, Intemann T, Lauria F, Mårild S, Molnár D, Moreno LA, et al. Reference values of bone stiffness index and C-terminal telopeptide in healthy European children. Int J Obes (Lond). 2014;38(Suppl 2):S76–85. doi: 10.1038/ijo.2014.138.
Open DOI Search in Google Scholar Back to article
Crabtree NJ, Arabi A, Bachrach LK, Fewtrell M, El-Hajj Fuleihan G, et al. Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions. J Clin Densitom. 2014;17(2):225–242. doi: 10.1016/j.jocd.2014.01.003.
Open DOI Search in Google Scholar Back to article
Dimitri P, Wales JK, Bishop N. Fat and bone in children: differential effects of obesity on bone size and mass according to fracture history. J Bone Miner Res. 2010;25(3):527–536. doi: 10.1359/jbmr.090823.
Open DOI Search in Google Scholar Back to article
Vandewalle S, Taes Y, Van Helvoirt M, Debode P, Herregods N, Ernst C, et al. Bone size and bone strength are increased in obese male adolescents. J Clin Endocrinol Metab. 2013;98(7):3019–28. doi: 10.1210/jc.2012-3914.
Open DOI Search in Google Scholar Back to article
Nagasaki K, Kikuchi T, Hiura M, Uchiyama M. Obese Japanese children have low bone mineral density after puberty. J Bone Miner Metab. 2004;22(4):376–81. doi: 10.1007/s00774-004-0498-y.
Open DOI Search in Google Scholar Back to article
Gajewska J, Ambroszkiewicz J, Klemarczyk W, Chełchowska M, Weker H, Szamotulska K. The effect of weight loss on body composition, serum bone markers, and adipokines in prepubertal obese children after 1-year intervention. Endocr Res. 2018;43(2):80–89. doi: 10.1080/07435800.2017.1403444.
Open DOI Search in Google Scholar Back to article
Zürcher SJ, Borter N, Kränzlin M, Neyer P, Meyer U, Rizzoli R, et al. Relationship between bone mineral content and bone turnover markers, sex hormones and calciotropic hormones in pre- and early pubertal children. Osteoporos Int. 2020;31(2): 335–349. doi: 10.1007/s00198-019-05180-7.
Open DOI Search in Google Scholar Back to article
Monjardino T, Silva P, Amaro J, Carvalho O, Guimarães JT, Santos AC, et al. Bone formation and resorption markers at 7 years of age: Relations with growth and bone mineralization. PLoS One. 2019;14(8):e0219423. doi: 10.1371/journal.pone.0219423.
Open DOI Search in Google Scholar Back to article
Jürimäe J. Interpretation and application of bone turnover markers in children and adolescents. Curr Opin Pediatr. 2010;22(4):494–500. doi: 10.1097/MOP.0b013e32833b0b9e.
Open DOI Search in Google Scholar Back to article
Rosenquist C, Qvist P, Bjarnason N, Christiansen C. Measurement of a more stable region of osteocalcin in serum by ELISA with two monoclonal antibodies. Clin Chem. 1995;41(10):1439–45.
Search in Google Scholar Back to article
Cavalier E, Delanaye P, Collette J, Krzesinski JM, Chapelle JP. Evaluation of different bone markers in hemodialyzed patients. Clin Chim Acta. 2006;371(1–2):107–11. doi: 10.1016/j.cca.2006.02.029.
Open DOI Search in Google Scholar Back to article
Diemar SS, Dahl SS, West AS, Simonsen SA, Iversen HK, Jørgensen NR. A systematic review of the circadian rhythm of bone markers in blood. Calcif Tissue Int. 2023; 112(2):126–147. doi: 10.1007/s00223-022-00965-1.
Open DOI Search in Google Scholar Back to article
Oladipo OO, DeCrescenzo AJ, Marquez CP, Okorodudu AO. Increased alkaline phosphatase in a child. Clin Chem. 2017;63(6):1174–1175. doi: 10.1373/clinchem.2016.268904.
Open DOI Search in Google Scholar Back to article
Bianchi ML, Leonard MB, Bechtold S, Högler W, Mughal MZ, Schönau E, et al. Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions. J Clin Densitom. 2014;17(2):281–94. doi: 10.1016/j.jocd.2014.01.005.
Open DOI Search in Google Scholar Back to article
Höppner J, Steff K, Misof BM, Schündeln MM, Hövel M, Lücke T, et al. Clinical course in two children with Juvenile Paget’s disease during long-term treatment with intravenous bisphosphonates. Bone Rep. 2021;14:100762. doi: 10.1016/j.bonr.2021.100762.
Open DOI Search in Google Scholar Back to article
Arundel P, Borg SA. Early life management of osteogenesis mperfecta. Curr Osteoporos Rep. 2023;21(6):779–786. doi: 10.1007/s11914-023-00823-5.
Open DOI Search in Google Scholar Back to article
Weber DR. Bone health in childhood chronic disease. Endocrinol Metab Clin North Am. 2020;49(4):637–650. doi: 10.1016/j.ecl.2020.07.002.
Open DOI Search in Google Scholar Back to article