Pediatric Nephrology

, Volume 29, Issue 5, pp 793–803 | Cite as

Bone metabolism in the fetus and neonate

Review

Abstract

During embryonic development most of the skeleton begins as a cartilaginous scaffold that is progressively resorbed and replaced by bone. Such endochondral bone development does not cease until the growth plates fuse during puberty. Growth and mineralization of the skeleton are dependent upon the adequate delivery of mineral. During fetal development, the placenta actively transports calcium, magnesium and phosphorus from the maternal circulation. After birth, the role of mineral transport is assumed by the intestines. The limited data currently available on fetal humans are largely based on cord blood samples from normal fetuses and pathological specimens from fetuses which died in utero or at birth. Consequently, much of our understanding of the regulation of fetal mineral and bone homeostasis comes from the study of animal fetuses that have been manipulated surgically, pharmacologically and genetically. Animal and human data indicate that fetal mineral homeostasis requires parathyroid hormone (PTH) and PTH-related protein—but not vitamin D/calcitriol, calcitonin or sex steroids. In the days to weeks after birth, intestinal calcium absorption becomes an active process, which necessitates that the infant depends upon vitamin D/calcitriol. However, even this postnatal function of calcitriol can be bypassed by increasing the calcium content of the diet or by administering calcium infusions.

Keywords

Fetus Calcium Phosphorus Skeletal development Placenta Gene knockout mice Human studies 

References

  1. 1.
    Kovacs CS (2011) Fetal mineral homeostasis. In: Glorieux FH, Pettifor JM, Jüppner H (eds) Pediatric bone: Biology and diseases, 2nd edn. Elsevier/Academic Press, San Diego, pp 247–275Google Scholar
  2. 2.
    Kovacs CS (2011) Fetus, Neonate and Infant. In: Feldman D, Pike WJ, Adams JS (eds) Vitamin D, 3rd edn. Academic, New York, pp 625–646CrossRefGoogle Scholar
  3. 3.
    Kovacs CS (2012) The role of vitamin d in pregnancy and lactation: insights from animal models and clinical studies. Annu Rev Nutr 32:97–123PubMedCrossRefGoogle Scholar
  4. 4.
    Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM (1998) Regulation of murine fetal–placental calcium metabolism by the calcium-sensing receptor. J Clin Invest 101:2812–2820PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Kovacs CS, Woodland ML, Fudge NJ, Friel JK (2005) The vitamin D receptor is not required for fetal mineral homeostasis or for the regulation of placental calcium transfer. Am J Physiol Endocrinol Metab 289:E133–E144PubMedCrossRefGoogle Scholar
  6. 6.
    Kovacs CS, Chafe LL, Woodland ML, McDonald KR, Fudge NJ, Wookey PJ (2002) Calcitropic gene expression suggests a role for intraplacental yolk sac in maternal-fetal calcium exchange. Am J Physiol Endocrinol Metab 282:E721–E732PubMedGoogle Scholar
  7. 7.
    Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Hediger MA (2008) Calcium TRPV6 is involved in murine maternal–fetal calcium transport. J Bone Miner Res 23:1249–1256PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Yang Y (2009) Skeletal morphogenesis during embryonic development. Crit Rev Eukaryot Gene Expr 19:197–218PubMedCrossRefGoogle Scholar
  9. 9.
    Simmonds CS, Karsenty G, Karaplis AC, Kovacs CS (2010) Parathyroid hormone regulates fetal–placental mineral homeostasis. J Bone Miner Res 25:594–605PubMedCrossRefGoogle Scholar
  10. 10.
    Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM (2001) Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 107:1007–1015PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM (1996) Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 93:15233–15238PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Kovacs CS, Chafe LL, Fudge NJ, Friel JK, Manley NR (2001) PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. Endocrinology 142:4983–4993PubMedCrossRefGoogle Scholar
  13. 13.
    Manley NR, Capecchi MR (1995) The role of Hoxa-3 in mouse thymus and thyroid development. Development 121:1989–2003PubMedGoogle Scholar
  14. 14.
    Bond H, Dilworth MR, Baker B, Cowley E, Requena Jimenez A, Boyd RD, Husain SM, Ward BS, Sibley CP, Glazier JD (2008) Increased maternofetal calcium flux in parathyroid hormone-related protein-null mice. J Physiol 586:2015–2025PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, Vasavada RC, Weir EC, Broadus AE, Stewart AF (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127–173PubMedGoogle Scholar
  16. 16.
    Riddle RC, Macica CM, Clemens TL (2008) Vascular, cardiovascular, and neurologic actions of parathyroid-related protein. In: Bilezikian JP, Raisz LG, Martin TJ (eds) Principles of bone biology, 3rd edn. Academic, New York, pp 733–748CrossRefGoogle Scholar
  17. 17.
    Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Indian hedgehog and parathyroid hormone-related protein regulate the rate of cartilage differentiation. Science 273:613–622PubMedCrossRefGoogle Scholar
  18. 18.
    Karsenty G, Kronenberg HM, Settembre C (2009) Genetic control of bone formation. Annu Rev Cell Dev Biol 25:629–648PubMedCrossRefGoogle Scholar
  19. 19.
    Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8:277–289PubMedCrossRefGoogle Scholar
  20. 20.
    Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize L, Ho C, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666PubMedCrossRefGoogle Scholar
  21. 21.
    Weir EC, Philbrick WM, Amling M, Neff LA, Baron R, Broadus AE (1996) Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc Natl Acad Sci USA 93:10240–10245PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Schipani E, Lanske B, Hunzelman J, Luz A, Kovacs CS, Lee K, Pirro A, Kronenberg HM, Jüppner H (1997) Targeted expression of constitutively active PTH/PTHrP receptors delays endochondral bone formation and rescues PTHrP-less mice. Proc Natl Acad Sci USA 94:13689–13694PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Lanske B, Divieti P, Kovacs CS, Pirro A, Landis WJ, Krane SM, Bringhurst FR, Kronenberg HM (1998) The parathyroid hormone/parathyroid hormone-related peptide receptor mediates actions of both ligands in murine bone. Endocrinology 139:5192–5204Google Scholar
  24. 24.
    Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, Karaplis AC (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1–34. J Clin Invest 115:2402–2411PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rubin LP, Kovacs CS, De Paepe ME, Tsai SW, Torday JS, Kronenberg HM (2004) Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein. Dev Dyn 230:278–289PubMedCrossRefGoogle Scholar
  26. 26.
    Klopocki E, Hennig BP, Dathe K, Koll R, de Ravel T, Baten E, Blom E, Gillerot Y, Weigel JF, Kruger G, Hiort O, Seemann P, Mundlos S (2010) Deletion and point mutations of PTHLH cause brachydactyly type E. Am J Hum Genet 86:434–439PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Miao D, He B, Karaplis AC, Goltzman D (2002) Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest 109:1173–1182PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Farrugia W, de Gooyer T, Rice GE, Moseley JM, Wlodek ME (2000) Parathyroid hormone(1–34) and parathyroid hormone-related protein(1–34) stimulate calcium release from human syncytiotrophoblast basal membranes via a common receptor. J Endocrinol 166:689–695PubMedCrossRefGoogle Scholar
  29. 29.
    Karaplis AC, He B, Nguyen MT, Young ID, Semeraro D, Ozawa H, Amizuka N (1998) Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia. Endocrinology 139:5255–5258PubMedCrossRefGoogle Scholar
  30. 30.
    Oostra RJ, van der Harten JJ, Rijnders WP, Scott RJ, Young MP, Trump D (2000) Blomstrand osteochondrodysplasia: three novel cases and histological evidence for heterogeneity. Virchows Arch 436:28–35PubMedCrossRefGoogle Scholar
  31. 31.
    McDonald KR, Fudge NJ, Woodrow JP, Friel JK, Hoff AO, Gagel RF, Kovacs CS (2004) Ablation of calcitonin/calcitonin gene related peptide-a impairs fetal magnesium but not calcium homeostasis. Am J Physiol Endocrinol Metab 287:E218–E226PubMedCrossRefGoogle Scholar
  32. 32.
    Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac JD, Karsenty G (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164:509–514PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Halloran BP, De Luca HF (1981) Effect of vitamin D deficiency on skeletal development during early growth in the rat. Arch Biochem Biophys 209:7–14PubMedCrossRefGoogle Scholar
  34. 34.
    Miller SC, Halloran BP, DeLuca HF, Jee WS (1983) Studies on the role of vitamin D in early skeletal development, mineralization, and growth in rats. Calcif Tissue Int 35:455–460PubMedCrossRefGoogle Scholar
  35. 35.
    Brommage R, DeLuca HF (1984) Placental transport of calcium and phosphorus is not regulated by vitamin D. Am J Physiol 246:F526–F529PubMedGoogle Scholar
  36. 36.
    Lachenmaier-Currle U, Harmeyer J (1989) Placental transport of calcium and phosphorus in pigs. J Perinat Med 17:127–136PubMedCrossRefGoogle Scholar
  37. 37.
    Glazier JD, Mawer EB, Sibley CP (1995) Calbindin-D9K gene expression in rat chorioallantoic placenta is not regulated by 1,25-dihydroxyvitamin D3. Pediatr Res 37:720–725PubMedCrossRefGoogle Scholar
  38. 38.
    Marche P, Delorme A, Cuisinier-Gleizes P (1978) Intestinal and placental calcium-binding proteins in vitamin D-deprived or -supplemented rats. Life Sci 23:2555–2561PubMedCrossRefGoogle Scholar
  39. 39.
    Verhaeghe J, Thomasset M, Brehier A, Van Assche FA, Bouillon R (1988) 1,25(OH)2D3 and Ca-binding protein in fetal rats: relationship to the maternal vitamin D status. Am J Physiol 254:E505–E512PubMedGoogle Scholar
  40. 40.
    Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, Goltzman D (2001) Targeted ablation of the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci USA 98:7498–7503PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Dardenne O, Prud’homme J, Arabian A, Glorieux FH, St-Arnaud R (2001) Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology 142:3135–3141PubMedGoogle Scholar
  42. 42.
    Li YC, Amling M, Pirro AE, Priemel M, Meuse J, Baron R, Delling G, Demay MB (1998) Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 139:4391–4396PubMedGoogle Scholar
  43. 43.
    Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB (1997) Targeted ablation of the vitamin D receptor: an animal model of vitamin D dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94:9831–9835PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, Demay MB (1999) Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140:4982–4987PubMedGoogle Scholar
  45. 45.
    Dardenne O, Prudhomme J, Hacking SA, Glorieux FH, St-Arnaud R (2003) Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses. J Bone Miner Res 18:637–643PubMedCrossRefGoogle Scholar
  46. 46.
    Maxwell JP, Miles LM (1925) Osteomalacia in China. J Obstet Gynaecol Br Empire 32:433–473CrossRefGoogle Scholar
  47. 47.
    Pereira GR, Zucker AH (1986) Nutritional deficiencies in the neonate. Clin Perinatol 13:175–189PubMedGoogle Scholar
  48. 48.
    Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 160:491–497PubMedCrossRefGoogle Scholar
  49. 49.
    Mohapatra A, Sankaranarayanan K, Kadam SS, Binoy S, Kanbur WA, Mondkar JA (2003) Congenital rickets. J Trop Pediatr 49:126–127PubMedCrossRefGoogle Scholar
  50. 50.
    Innes AM, Seshia MM, Prasad C, Al Saif S, Friesen FR, Chudley AE, Reed M, Dilling LA, Haworth JC, Greenberg CR (2002) Congenital rickets caused by maternal vitamin D deficiency. Paediatr Child Health 7:455–458PubMedCentralPubMedGoogle Scholar
  51. 51.
    Begum R, Coutinho ML, Dormandy TL, Yudkin S (1968) Maternal malabsorption presenting as congenital rickets. Lancet 1:1048–1052PubMedCrossRefGoogle Scholar
  52. 52.
    Congdon P, Horsman A, Kirby PA, Dibble J, Bashir T (1983) Mineral content of the forearms of babies born to Asian and white mothers. Br Med J (Clin Res Ed) 286:1233–1235CrossRefGoogle Scholar
  53. 53.
    Sann L, David L, Thomas A, Frederich A, Chapuy MC, Francois R (1976) Congenital hyperparathyroidism and vitamin D deficiency secondary to maternal hypoparathyroidism. Acta Paediatr Scand 65:381–385PubMedCrossRefGoogle Scholar
  54. 54.
    Weiler HA, Fitzpatrick-Wong SC, Schellenberg JM (2008) Bone mass in First Nations, Asian and white newborn infants. Growth Dev Aging 71:35–43PubMedGoogle Scholar
  55. 55.
    Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, Robinson VP, Winder SM (1980) Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 280:751–754PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL (2011) Vitamin D supplementation during pregnancy: double blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 26:2341–2357PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Morley R, Carlin JB, Pasco JA, Wark JD (2006) Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab 91:906–912PubMedCrossRefGoogle Scholar
  58. 58.
    Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, Swaminathan R, Cooper C, Godfrey K (2010) Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res 25:14–19PubMedCrossRefGoogle Scholar
  59. 59.
    Viljakainen HT, Saarnio E, Hytinantti T, Miettinen M, Surcel H, Makitie O, Andersson S, Laitinen K, Lamberg-Allardt C (2010) Maternal vitamin D status determines bone variables in the newborn. J Clin Endocrinol Metab 95:1749–1757PubMedCrossRefGoogle Scholar
  60. 60.
    Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C (2006) Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 367:36–43PubMedCrossRefGoogle Scholar
  61. 61.
    Kovacs CS (2012) Fetal control of calcium and phosphate homeostasis—lessons from mouse models. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T (eds) Genetics of bone biology and skeletal disease. Academic Press/Elsevier, San Diego, pp 205–220Google Scholar

Copyright information

© IPNA 2013

Authors and Affiliations

  1. 1.Faculty of Medicine, Memorial University of NewfoundlandHealth Sciences CentreSt. John’sCanada

Personalised recommendations