Bone Biomarkers in Intrauterine Growth Restriction

  • Despina D. Briana
  • Ariadne Malamitsi-PuchnerEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


Bone tissue is subject to remodeling during the lifetime of an individual. Through a continuous remodeling cycle, old bone is resorbed by osteoclasts with the formation of cavities that are subsequently filled by osteoblasts, which induce bone formation. Fetal life is associated with a high rate of skeletal growth and intense bone modeling activity. Both fetal and neonatal calcium and bone metabolism are uniquely adapted to meet the specific needs of these developmental periods. The fetus must actively receive sufficient calcium across the placenta to meet the large demands of the rapidly mineralizing skeleton, whereas the neonate must quickly adjust to loss of placental calcium transport, while continuing to undergo rapid skeletal growth. Biochemical markers of bone turnover are reliable indices for measuring changes of bone formation and resorption, reflecting the dynamics of bone metabolism at the cellular level. Due to limitations in the application of bone densitometry during the perinatal period, bone biomarkers are effective alternatives to estimate bone turnover. There is considerable evidence that impaired fetal skeletal growth predisposes to late-onset disorders and an accelerated rate of bone loss during later life. As for other adult diseases, intrauterine growth restriction (IUGR) is considered a risk factor for altered bone growth and osteoporosis development. This notion appears to be confirmed by animal data. However, this is less clear in human IUGR neonates. Some studies show a relationship of fetal growth with bone mineral density (BMD), whereas others do not. Similarly, reports determining bone biomarkers provide evidence of unaltered bone metabolism in IUGR fetuses/neonates, although data are not consistent.


Intrauterine growth restriction Fetus Neonate Osteoporosis Bone turnover Biochemical markers 

List of Abbreviations


Appropriate for gestational age


Alkaline phosphatase


Bone-specific alkaline phosphatase


Bone mineral content


Bone mineral density


Undercarboxylated osteocalcin


Cross-linked carboxyl terminal telopeptide of type I collagen


Intrauterine growth restriction


N-telopeptide of type 1 collagen






Carboxy-terminal propeptide of type I collagen


Amino-terminal propeptide of type I collagen




Receptor activator of nuclear factor-kB ligand


Small for gestational age


  1. Akcakus M, Kurtoglu S, Koklu E, et al. The relationship between birth weight leptin and bone mineral status in newborn infants. Neonatology. 2007;91:101–6.CrossRefPubMedGoogle Scholar
  2. Alexe DM, Syridou G, Petridou ET. Determinants of early life leptin levels and later life degenerative outcomes. Clin Med Res. 2006;4:326–35.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Beltrand J, Alison M, Nicolescu R, et al. Bone mineral content at birth is determined both by birth weight and fetal growth pattern. Pediatr Res. 2008;64:86–90.CrossRefPubMedGoogle Scholar
  4. Bhandari V, Fall P, Raisz L, et al. Potential biochemical growth markers in premature infants. Am J Perinatol. 1999;16:339–49.CrossRefPubMedGoogle Scholar
  5. Bollen AM, Eyre DR. Bone resorption rates in children monitored by the urinary assay of collagen type I cross-linked peptides. Bone. 1994;15:31–4.CrossRefPubMedGoogle Scholar
  6. Briana DD, Malamitsi-Puchner A. Intrauterine growth restriction and adult disease: the role of adipocytokines. Eur J Endocrinol. 2009;160:337–47.CrossRefPubMedGoogle Scholar
  7. Briana DD, Gourgiotis D, Boutsikou M, et al. Perinatal bone turnover in term pregnancies: the influence of intrauterine growth restriction. Bone. 2008;42:307–13.CrossRefPubMedGoogle Scholar
  8. Briana DD, Boutsikou M, Baka S, et al. Circulating osteoprotegerin and sRANKL concentrations in the perinatal period at term: the impact of intrauterine growth restriction. Neonatology. 2009;96:132–6.CrossRefPubMedGoogle Scholar
  9. Briana DD, Gourgiotis D, Georgiadis A, et al. Intrauterine growth restriction may not suppress bone formation at term, as indicated by circulating concentrations of undercarboxylated osteocalcin and Dickkopf-1. Metabolism. 2012;61:335–40.CrossRefPubMedGoogle Scholar
  10. Briana DD, Boutsikou M, Boutsikou T, et al. Associations of novel adipocytokines with bone biomarkers in intrauterine growth-restricted fetuses/neonates at term. J Matern Fetal Neonatal Med. 2014;27:984–8.CrossRefPubMedGoogle Scholar
  11. Brodsky D, Christou H. Current concepts in intrauterine growth restriction. J Intensive Care Med. 2004;19:307–19.CrossRefPubMedGoogle Scholar
  12. Cadogan J, Eastell R, Jones N, et al. Milk intake and bone mineral acquisition in adolescent girls: randomized, controlled intervention trial. BMJ. 1997;315:1255–60.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Camozzi V, Tossi A, Simoni E, et al. Role of biochemical markers of bone remodeling in clinical practice. J Endocrinol Invest. 2007;30(6 Suppl):13–7.PubMedGoogle Scholar
  14. Chen H, Miller S, Lane RH, et al. Intrauterine growth restriction decreases endochondral ossification and bone strength in female rats. Am J Perinatol. 2013;30:261–6.CrossRefPubMedGoogle Scholar
  15. Chunga Vega F, Gomez de Tejada MJ, Gonzalez Hachero J, et al. Low bone mineral density in small for gestational age infants: correlation with cord blood zinc concentrations. Arch Dis Child Fetal Neonatal Ed. 1996;75:F126–129.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cooper C, Cawley M, Bhalla A, et al. Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res. 1995;10:940–7.CrossRefPubMedGoogle Scholar
  17. Cooper C, Fall C, Egger P, et al. Growth in infancy and bone mass in later life. Ann Rheum Dis. 1997;56:17–21.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Cooper C, Javaid MK, Taylor P, et al. The fetal origins of osteoporotic fracture. Calcif Tissue Int. 2002;70:391–4.CrossRefPubMedGoogle Scholar
  19. Engelbregt MJ, van Weissenbruch MM, Lips P, et al. Body composition and bone measurements in intra-uterine growth retarded and early postnatally undernourished male and female rats at the age of 6 months: comparison with puberty. Bone. 2004;34:180–6.CrossRefPubMedGoogle Scholar
  20. Fall C, Hindmarsh P, Dennison E, et al. Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesis. J Clin Endocrinol Metab. 1998;83:135–9.PubMedGoogle Scholar
  21. Fujita K, Janz S. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL, and M-CSF. Mol Cancer. 2007;6:71.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gale CR, Martyn CN, Kellingray S, et al. Intrauterine programming of adult body composition. J Clin Endocrinol Metab. 2001;86:267–72.PubMedGoogle Scholar
  23. Gourgiotis D, Briana DD, Georgiadis A, et al. Perinatal collagen turnover markers in intrauterine growth restriction. J Matern Fetal Neonatal Med. 2012;25:1719–22.CrossRefPubMedGoogle Scholar
  24. Harrast SD, Kalkwarf HJ. Effects of gestational age, maternal diabetes, and intrauterine growth retardation on markers of fetal bone turnover in amniotic fluid. Calcif Tissue Int. 1998;62:205–8.CrossRefPubMedGoogle Scholar
  25. Holroyd CR, Harvey NC, Crozier SR, et al. Placental size at 19 weeks predicts offspring bone mass at birth: findings from the Southampton women’s survey. Placenta. 2012;33:623–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hytinantti T, Rutanen EM, Turpeinen M, et al. Markers of collagen metabolism and insulin-like growth factor binding protein-1 in term infants. Arch Dis Child Fetal Neonatal Ed. 2000;83(1):F17–20.Google Scholar
  27. Kajantie E, Hytinantti T, Koistinen R, et al. Markers of type I and type III collagen turnover, insulin-like growth factors, and their binding proteins in cord plasma of small premature infants: relationships with fetal growth, gestational age, preeclampsia, and antenatal glucocorticoid treatment. Pediatr Res. 2001;49:481–9.CrossRefPubMedGoogle Scholar
  28. Kaji T, Yasui T, Suto M, et al. Effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women. Bone. 2007;40:1088–94.CrossRefPubMedGoogle Scholar
  29. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050–5.CrossRefPubMedGoogle Scholar
  30. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116:1202–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–76.CrossRefPubMedGoogle Scholar
  32. Lanham SA, Roberts C, Perry MJ, et al. Intrauterine programming of bone. Part 2: alteration of skeletal structure. Osteoporos Int. 2008;19:157–67.CrossRefPubMedGoogle Scholar
  33. Lapillonne A, Travers R, DiMaio M, et al. Urinary excretion of cross-linked N-telopeptides of type 1 collagen to assess bone resorption in infants from birth to 1 year of age. Pediatrics. 2002;110:105–9.CrossRefPubMedGoogle Scholar
  34. Largo RH, Walli R, Duc G, et al. Evaluation of perinatal growth. Presentation of combined intra- and extrauterine growth standards for weight, length and head circumference. Helv Paediatr Acta. 1980;35:419–36.PubMedGoogle Scholar
  35. Lian JB, Stein GS. Concepts of osteoblast growth and differentiation: basis for modulation of bone cell development and tissue formation. Crit Rev Oral Biol Med. 1992;3:269–305.CrossRefPubMedGoogle Scholar
  36. Littner Y, Mandel D, Mimouni FB, et al. Bone ultrasound velocity of infants born small for gestational age. J Pediatr Endocrinol Metab. 2005;18:793–7.CrossRefPubMedGoogle Scholar
  37. Magni P, Dozio E, Galliera E, et al. Molecular aspects of adipokine-bone interactions. Curr Mol Med. 2010;10:522–32.PubMedGoogle Scholar
  38. McDevitt H, Ahmed SF. Quantitative ultrasound assessment of bone health in the neonate. Neonatology. 2007;91:2–11.CrossRefPubMedGoogle Scholar
  39. Miller JR. The Wnts. Genome Biol. 2002;3:3001.Google Scholar
  40. Mongelli M, Gardosi J. Longitudinal study of fetal growth in subgroups of a low-risk population. Ultrasound Obstet Gynecol. 1995;6:340–4.CrossRefPubMedGoogle Scholar
  41. Morvan F, Boulukos K, Clement-Lacroix P, et al. Deletion of a single allele of the Dkk 1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res. 2006;21:934–45.CrossRefPubMedGoogle Scholar
  42. Nakano K, Iwamatsu T, Wang CM, et al. High bone turnover of type I collagen depends on fetal growth. Bone. 2006;38:249–56.CrossRefPubMedGoogle Scholar
  43. Namgung R, Tsang R. Factors affecting newborn bone mineral content in utero: effects on newborn bone mineralization. Proc Nutr Soc. 2000;59:55–63.CrossRefPubMedGoogle Scholar
  44. Namgung R, Tsang RC. Bone in the pregnant mother and newborn at birth. Clin Chim Acta. 2003;333:1–11.CrossRefPubMedGoogle Scholar
  45. Namgung R, Tsang RC, Specker BL, et al. Reduced serum osteocalcin and 1,25-dihydroxyvitamin D concentrations and low bone mineral content in small for gestational age infants: evidence of decreased bone formation rates. J Pediatr. 1993;122:269–75.CrossRefPubMedGoogle Scholar
  46. Namgung R, Tsang RC, Sierra RI, et al. Normal serum indices of bone collagen biosynthesis and degradation in small for gestational age infants. J Pediatr Gastroenterol Nutr. 1996;23:224–8.CrossRefPubMedGoogle Scholar
  47. Ogueh O, Khastgir G, Studd J, et al. The relationship of fetal serum markers of bone metabolism to gestational age. Early Hum Dev. 1998;51:109–12.CrossRefPubMedGoogle Scholar
  48. Okesina AB, Donaldson D, Lascelles PT, et al. Effect of gestational age on levels of serum alkaline phosphatase isoenzymes in healthy pregnant women. Int J Gynaecol Obstet. 1995;48:25–9.CrossRefPubMedGoogle Scholar
  49. Oliver H, Jameson KA, Sayer AA, et al. Growth in early life predicts bone strength in late adulthood: the Hertfordshire cohort study. Bone. 2007;41:400–5.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Prockop DJ, Kivirikko KI, Tuderman L, et al. The biosynthesis of collagen and its disorders (second of two parts). N Engl J Med. 1979;301:77–85.CrossRefPubMedGoogle Scholar
  51. Qiang YW, Barlogie B, Rudikoff S, et al. Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. Bone. 2008;42:669–80.CrossRefPubMedGoogle Scholar
  52. Rodin A, Duncan A, Quartero HW, et al. Serum concentrations of alkaline phosphatase isoenzymes and osteocalcin in normal pregnancy. J Clin Endocrinol Metab. 1989;68:1123–7.CrossRefPubMedGoogle Scholar
  53. Scariano JK, Vanderjagt DJ, Thacher T, et al. Calcium supplements increase the serum levels of crosslinked N-telopeptides of bone collagen and parathyroid hormone in rachitic Nigerian children. Clin Biochem. 1998;31:421–7.CrossRefPubMedGoogle Scholar
  54. Schreuder M, Delemarre-van de Waal H, van Wijk A. Consequences of intrauterine growth restriction for the kidney. Kidney Blood Press Res. 2006;29:108–25.CrossRefPubMedGoogle Scholar
  55. Shimizu N, Shima M, Hirai H, et al. Shift of serum osteocalcin components between cord blood and blood at day 5 of life. Pediatr Res. 2002;52:656–9.CrossRefPubMedGoogle Scholar
  56. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–19.CrossRefPubMedGoogle Scholar
  57. Strid H, Bucht E, Jansson T, et al. ATP dependent Ca2+ transport across basal membrane of human syncytiotrophoblast in pregnancies complicated by intrauterine growth restriction or diabetes. Placenta. 2003;24:445–52.CrossRefPubMedGoogle Scholar
  58. Tanner JM. Growth before birth. In: Tanner JM, editor. Foetus into man. Physical growth from conception to maturity. London: Castlemead; 1989. p. 36–50.Google Scholar
  59. Tenta R, Bourgiezi I, Aliferis E, et al. Bone metabolism compensates for the delayed growth in small for gestational age neonates. Organogenesis. 2013;9:55–9.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Tsang RC, Gigger M, Oh W, et al. Studies in calcium metabolism in infants with intrauterine growth retardation. J Pediatr. 1975;86:936–41.CrossRefPubMedGoogle Scholar
  61. Uemura H, Yasui T, Kiyokawa M, et al. Serum osteoprotegerin/osteoclastogenesis-inhibitory factor during pregnancy and lactation and the relationship with calcium-regulating hormones and bone turnover markers. J Endocrinol. 2002;174:353–9.CrossRefPubMedGoogle Scholar
  62. Verhaeghe J, Van Herck E, Bouillon R. Umbilical cord osteocalcin in normal pregnancies and pregnancies complicated by fetal growth retardation or diabetes mellitus. Biol Neonate. 1995;68:377–83.CrossRefPubMedGoogle Scholar
  63. Wada S, Fukawa T, Kamiya S. Biochemical markers of bone turnover. New aspect. Bone metabolic markers available in daily practice. Clin Calcium. 2009;19:1075–82.PubMedGoogle Scholar
  64. Wilkins BH. Renal function in sick very low birthweight infants: 1. Glomerular filtration rate. Arch Dis Child. 1992;67:1140–5.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of NeonatologyAthens University Medical SchoolAthensGreece

Personalised recommendations