Relationship between bone mineral content and bone turnover markers, sex hormones and calciotropic hormones in pre- and early pubertal children

  • S. J. Zürcher
  • N. Borter
  • M. Kränzlin
  • P. Neyer
  • U. Meyer
  • R. Rizzoli
  • S. KriemlerEmail author
Original Article



We investigated associations between bone mineral content (BMC) and bone-related biomarkers (BM) in pre-and early pubertal children of both sexes. In this population, we found that bone turnover markers explain a small part of BMC variance.


It is still debated whether BM including bone turnover markers (BTM), sex hormones and calciotropic (including cortisol) hormones provide information on BMC changes during growth.


Three hundred fifty-seven girls and boys aged 6 to 13 years were included in this study. BM was measured at baseline and BMC twice at 9 months and 4 years using DXA. Relationship between BMs was assessed using principal component analysis (PCA). BM was tested in its ability to explain BMC variation by using structural equation modelling (SEM) on cross-sectional data. Longitudinal data were used to further assess the association between BM and BMC variables.


BMC and all BMs, except calciotropic hormones, increased with age. PCA in BM revealed a three-factor solution (BTM, sex hormones and calciotropic hormones). In the SEM, age accounted for 61% and BTM for 1.2% of variance in BMC (cross-sectional). Neither sex nor calciotropic hormones were BMC explanatory variables. In the longitudinal models (with single BM as explanatory variables), BMC, age and sex at baseline accounted for 79–81% and 70–75% in BMC variance at 9 months and 4 years later, respectively. P1NP was consistently associated with BMC.


BMC strongly tracks in pre- and early pubertal children. In this study, only a small part of BMC variance was explained by single BTM at the beginning of pubertal growth.


Bone mineral content Bone remodelling Bone turnover marker Calciotropic hormones Gonadal steroid hormones Puberty 



Biomarkers (including all markers measured in the blood)


Bone turnover marker




C-terminal telopeptide


Dehydroepiandrosterone sulphate


Dual-energy X-ray absorptiometry




Femoral neck


Lumbar spine




25-Hydroxy vitamin D/calcifediol


Principal component analysis


N-terminal propeptide




Intact parathyroid hormone


Structural equation modelling


Sex hormone-binding globulin




Whole body



We sincerely thank all children, teachers and parents for taking part in the study. We greatly appreciate the help of Giulio Conicella, Chantal Genet and Claude Kränzlin for their competent help in the bone measurements. We thank the foundation AETAS, Switzerland, for the use of their DXA-bus, the Swiss Heart Foundation for financial support of the current study and the funders of the initial study (KISS) including the Federal Council of Sports, Magglingen, Switzerland (grant number SWI05-013), and the Swiss National Foundation (grant number PMPDB-114401). And finally, also thanks to Erin Ashley West for proof-reading the manuscript.

Funding information

This study was funded by the Swiss Heart Foundation. Funding for the initial trial (Effect of a general school-based physical activity intervention on bone mineral content and density) was provided by Swiss Federal Office of Sports and the Swiss National Science Foundation.

Compliance with ethical standards

Conflicts of interest


Supplementary material

198_2019_5180_MOESM1_ESM.pptx (36 kb)
ESM 1 Fig. 1 appendix. Study flow diagram: relation between bone mineral content and bone turnover markers, sex hormones and calciotropic hormones in pre- and early pubertal children (PPTX 35 kb)


  1. 1.
    Rizzoli R, Bianchi ML, Garabedian M, McKay HA, Moreno LA (2010) Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 46:294–305PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R, O'Karma M, Wallace TC, Zemel BS (2016) The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int 27:1281–1386PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Seeman E, Tsalamandris C, Formica C (1993) Peak bone mass, a growing problem? Int J Fertil Menopausal Stud 38(Suppl 2):77–82PubMedPubMedCentralGoogle Scholar
  4. 4.
    Soyka LA, Fairfield WP, Klibanski A (2000) Hormonal determinants and disorders of peak bone mass in children1. J Clin Endocrinol Metab 85:3951–3963PubMedPubMedCentralGoogle Scholar
  5. 5.
    Holick MF (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80:1678s–1688sPubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Jurimae J (2010) Interpretation and application of bone turnover markers in children and adolescents. Curr Opin Pediatr 22:494–500PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Vasikaran S, Eastell R, Bruyère O et al (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Eapen E, Grey V, Don-Wauchope A, Atkinson SA (2008) Bone health in childhood: usefulness of biochemical biomarkers. EJIFCC 19:123–136PubMedPubMedCentralGoogle Scholar
  10. 10.
    Rauchenzauner M, Schmid A, Heinz-Erian P, Kapelari K, Falkensammer G, Griesmacher A, Finkenstedt G, Hogler W (2007) 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 92:443–449PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Mora S, Pitukcheewanont P, Kaufman FR, Nelson JC, Gilsanz V (1999) Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development. J Bone Miner Res 14:1664–1671PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Szulc P, Seeman E, Delmas PD (2000) Biochemical measurements of bone turnover in children and adolescents. Osteoporos Int 11:281–294PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    van Coeverden SC, Netelenbos JC, de Ridder CM, Roos JC, Popp-Snijders C, Delemarre-van de Waal HA (2002) Bone metabolism markers and bone mass in healthy pubertal boys and girls. Clin Endocrinol 57:107–116CrossRefGoogle Scholar
  14. 14.
    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 57:170–179PubMedPubMedCentralGoogle Scholar
  15. 15.
    Vandewalle S, Taes Y, Fiers T, Toye K, Van Caenegem E, Roggen I, De Schepper J, Kaufman JM (2014) Associations of sex steroids with bone maturation, bone mineral density, bone geometry, and body composition: a cross-sectional study in healthy male adolescents. J Clin Endocrinol Metab 99:E1272–E1282PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Csakvary V, Erhardt E, Vargha P, Oroszlan G, Bodecs T, Torok D, Toldy E, Kovacs GL (2012) Association of lean and fat body mass, bone biomarkers and gonadal steroids with bone mass during pre- and midpuberty. Horm Res Paediatr 78:203–211PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    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 54:106–112PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Yilmaz D, Ersoy B, Bilgin E, Gümüşer G, Onur E, Pinar ED (2005) Bone mineral density in girls and boys at different pubertal stages: relation with gonadal steroids, bone formation markers, and growth parameters. J Bone Miner Metab 23:476–482PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jolliffe IT (2002) Principal component analysis. Springer, New YorkGoogle Scholar
  20. 20.
    Kline RB (2005) Principles and practice of structural equation modeling, 2nd edn. Guilford Press, New YorkGoogle Scholar
  21. 21.
    Zahner L, Puder JJ, Roth R, Schmid M, Guldimann R, Puhse U, Knopfli M, Braun-Fahrlander C, Marti B, Kriemler S (2006) A school-based physical activity program to improve health and fitness in children aged 6-13 years ("Kinder-Sportstudie KISS"): study design of a randomized controlled trial [ISRCTN15360785]. BMC Public Health 6:147PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Meyer U, Romann M, Zahner L, Schindler C, Puder JJ, Kraenzlin M, Rizzoli R, Kriemler S (2011) Effect of a general school-based physical activity intervention on bone mineral content and density: a cluster-randomized controlled trial. Bone 48:792–797PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Rasmussen AR, Wohlfahrt-Veje C, Tefre de Renzy-Martin K, Hagen CP, Tinggaard J, Mouritsen A, Mieritz MG, Main KM (2015) Validity of self-assessment of pubertal maturation. Pediatrics 135:86–93PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J (2007) Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 85:660–667PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Meyer U, Ernst D, Zahner L, Schindler C, Puder JJ, Kraenzlin M, Rizzoli R, Kriemler S (2013) 3-Year follow-up results of bone mineral content and density after a school-based physical activity randomized intervention trial. Bone 55:16–22PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Zemel BS, Kalkwarf HJ, Gilsanz V et al (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160–3169PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Keel C, Kraenzlin ME, Kraenzlin CA, Muller B, Meier C (2010) Impact of bisphosphonate wash-out prior to teriparatide therapy in clinical practice. J Bone Miner Metab 28:68–76PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Schmidt-Gayk H, Spanuth E, Kotting J, Bartl R, Felsenberg D, Pfeilschifter J, Raue F, Roth HJ (2004) Performance evaluation of automated assays for beta-CrossLaps, N-MID-Osteocalcin and intact parathyroid hormone (BIOROSE Multicenter Study). Clin Chem Lab Med 42:90–95PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Janssen MJ, Wielders JP, Bekker CC, Boesten LS, Buijs MM, Heijboer AC, van der Horst FA, Loupatty FJ, van den Ouweland JM (2012) Multicenter comparison study of current methods to measure 25-hydroxyvitamin D in serum. Steroids 77:1366–1372PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Devine A, Dick IM, Dhaliwal SS, Naheed R, Beilby J, Prince RL (2005) Prediction of incident osteoporotic fractures in elderly women using the free estradiol index. Osteoporos Int 16:216–221PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Bui HN, Sluss PM, Hayes FJ, Blincko S, Knol DL, Blankenstein MA, Heijboer AC (2015) Testosterone, free testosterone, and free androgen index in women: reference intervals, biological variation, and diagnostic value in polycystic ovary syndrome. Clin Chim Acta 450:227–232PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Rosseel Y (2012) lavaan: an R package for structural equation modeling. J Stat Softw 1(2)Google Scholar
  33. 33.
    Schweizer K (2010) Some guidelines concerning the modeling of traits and abilities in test construction. Eur J Psychol Assess 26:1–2CrossRefGoogle Scholar
  34. 34.
    Berk R (1990) A primer on robust regression. In: Fox J, Long JS (eds) Modern Methods of Data Analysis. Sage, Newbury Park, pp 292–324Google Scholar
  35. 35.
    Saggese G, Baroncelli GI, Bertelloni S (2002) Puberty and bone development. Best Pract Res Clin Endocrinol Metab 16:53–64PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Hangartner TN, Huang X, Frederick MM, Winer KK, Zemel BS (2010) Tracking of bone mass and density during childhood and adolescence. J Clin Endocrinol Metab 95:1690–1698PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Chevalley T, Bonjour JP, van Rietbergen B, Ferrari S, Rizzoli R (2014) Tracking of environmental determinants of bone structure and strength development in healthy boys: an eight-year follow up study on the positive interaction between physical activity and protein intake from prepuberty to mid-late adolescence. J Bone Miner Res 29:2182–2192PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Yang Y, Wu F, Winzenberg T, Jones G (2017) Tracking of areal bone mineral density from age eight to young adulthood and factors associated with deviation from tracking: a 17-yr prospective cohort study. J Bone Miner ResGoogle Scholar
  39. 39.
    Jones RA, Hinkley T, Okely AD, Salmon J (2013) Tracking physical activity and sedentary behavior in childhood: a systematic review. Am J Prev Med 44:651–658PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gafni RI, Baron J (2007) Childhood bone mass acquisition and peak bone mass may not be important determinants of bone mass in late adulthood. Pediatrics 119(Suppl 2):S131–S136PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE (2017) Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology 83:25–41PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    La'ulu SL, Roberts WL (2010) Performance characteristics of six intact parathyroid hormone assays. Am J Clin Pathol 134:930–938PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Hutcheon JA, Chiolero A, Hanley JA (2010) Random measurement error and regression dilution bias. BMJ 340:c2289PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Frank GR (2003) Role of estrogen and androgen in pubertal skeletal physiology. Med Pediatr Oncol 41:217–221PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    van Rijn RR, van der Sluis IM, Link TM, Grampp S, Guglielmi G, Imhof H, Gluer C, Adams JE, van Kuijk C (2003) Bone densitometry in children: a critical appraisal. Eur Radiol 13:700–710PubMedPubMedCentralGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  1. 1.Epidemiology, Biostatistics and Prevention InstituteUniversity of ZurichZürichSwitzerland
  2. 2.Personality Psychology, Differential Psychology and Personality Assessment (PDD)University of BernBernSwitzerland
  3. 3.Division of Endocrinology, Diabetes, Metabolism and Bone ResearchUniversity Hospital Basel, and EndonetBaselSwitzerland
  4. 4.Department of Laboratory MedicineKantonsspital AarauAarauSwitzerland
  5. 5.Centre on Aging and MobilityUniversity Hospital Zurich, Waid City Hospital, and University of ZurichZurichSwitzerland
  6. 6.Division of Bone DiseasesGeneva University Hospitals and Faculty of MedicineGenevaSwitzerland

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