Skip to main content

Bone Disease of Prematurity: Calcium and Phosphorus as Urinary Biomarkers

  • Living reference work entry
  • First Online:
Biomarkers in Bone Disease

Abstracts

Urinary calcium and phosphorus have been used for the past decades as biomarkers for osteopenia of prematurity. As opposed to the actual diagnosis of decreased bone mineral content, studies have mainly focused on detecting the early phase of mineral deficiency, where bone demineralization might not yet be manifest in radiological images or, worse and as a late complication, by pathological bone fractures. Two methods of urinary mineral markers are used for this purpose: pure urine concentration of calcium and phosphorus or urine calcium/creatinine and phosphorus/creatinine ratios. Urinary calcium and phosphorus concentrations in spot urine samples have been used to guide individualized supplementation over and above the standardized fortified preterm nutrition to achieve bone mineral accretion rates similar to in utero conditions. The idea behind this concept, referred to as slight surplus supply, is that the simultaneous low-level excretion of calcium and phosphorus provides sufficient supply to guarantee adequate bone mineralization, independent of age, weight, and urine volume. Potential pitfalls include the immaturity of the kidneys in preterm infants as well as drugs and kidney diseases, both of which can alter the pattern of mineral excretion without accurately reflecting serum levels. With the other method of urinary mineral assessment, calcium/creatinine and phosphorus/creatinine ratios take into account volume-induced concentration changes. The measurement of excretion of any urine metabolite expressed as ratios over creatinine is standard practice in adult and pediatric nephrology. However, the creatinine excretion in preterm infants does not necessarily only express urine concentration but is possibly dependent on gestational and postnatal age, type of nutrition and renal function. The establishment of reference ranges for calcium/creatinine and phosphorus/creatinine ratios in preterm infants has been attempted but is subject to local nutritional practices and has not been tested against bone mineral content or in the context of individualized mineral supplementation. The existing literature does not answer the question of the superiority of either of the two methods in detecting osteopenia of prematurity. For guidance in individualized calcium and phosphorus supplementation, the concept of slight surplus supply has been shown to work in improving bone mineral accretion (despite methodological shortcomings), while the application of the mineral/creatinine ratios for this purpose is still lacking.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ALP:

Alkaline phosphatase

Ca:

Calcium

Crea:

Creatinine

DEXA:

Dual energy X-ray absorptiometry

DPA:

Double photon absorptiometry

LBW:

Low birth weight

P:

Phosphorus

SPA:

Single photon absorptiometry

VLBW:

Very low birth weight

References

  • Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, Domellof M, Embleton ND, Fusch C, Genzel-Boroviczeny O, Goulet O, Kalhan SC, Kolacek S, Koletzko B, Lapillonne A, Mihatsch W, Moreno L, Neu J, Poindexter B, Puntis J, Putet G, Rigo J, Riskin A, Salle B, Sauer P, Shamir R, Szajewska H, Thureen P, Turck D, Van Goudoever JB, Ziegler EE, Nutrition ECO. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50:85–91.

    Article  CAS  PubMed  Google Scholar 

  • Al-Dahhan J, Haycock GB, Chantler C, Stimmler L. Sodium homeostasis in term and preterm neonates. I. Renal aspects. Arch Dis Child. 1983;58:335–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aladangady N, Coen PG, White MP, Rae MD, Beattie TJ. Urinary excretion of calcium and phosphate in preterm infants. Pediatr Nephrol. 2004;19:1225–31.

    Article  PubMed  Google Scholar 

  • Applegarth DA, Ross PM. The unsuitability of creatinine excretion as a basis for assessing the excretion of other metabolites by infants and children. Clin Chim Acta. 1975;64:83–5.

    Article  CAS  PubMed  Google Scholar 

  • Baird J, Kurshid MA, Kim M, Harvey N, Dennison E, Cooper C. Does birthweight predict bone mass in adulthood? A systematic review and meta-analysis. Osteoporos Int. 2011;22:1323–34.

    Article  CAS  PubMed  Google Scholar 

  • Boehm G, Wiener M, Schmidt C, Ungethum A, Ungethum B, Moro G. Usefulness of short-term urine collection in the nutritional monitoring of low birthweight infants. Acta Paediatr. 1998;87:339–43.

    Article  CAS  PubMed  Google Scholar 

  • Bonjour JP. Calcium and phosphate: a duet of ions playing for bone health. J Am Coll Nutr. 2011;30:438S–48.

    Article  CAS  PubMed  Google Scholar 

  • Brown EM. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem. 2007;45:139–67.

    Article  CAS  PubMed  Google Scholar 

  • Carroll WF, Fabres J, Nagy TR, Frazier M, Roane C, Pohlandt F, Carlo WA, Thome UH. Results of extremely-low-birth-weight infants randomized to receive extra enteral calcium supply. J Pediatr Gastroenterol Nutr. 2011;53:339–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan GM, Armstrong C, Moyer-Mileur L, Hoff C. Growth and bone mineralization in children born prematurely. J Perinatol. 2008;28:619–23.

    Article  CAS  PubMed  Google Scholar 

  • Cho WI, Yu HW, Chung HR, Shin CH, Yang SW, Choi CW, Kim BI. Clinical and laboratory characteristics of neonatal hypocalcemia. Ann Pediatr Endocrinol Metab. 2015;20:86–91.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cranefield DJ, Odd DE, Harding JE, Teele RL. High incidence of nephrocalcinosis in extremely preterm infants treated with dexamethasone. Pediatr Radiol. 2004;34:138–42.

    Article  PubMed  Google Scholar 

  • Engle WA, American Academy of Pediatrics Committee On, F. & Newborn. Age terminology during the perinatal period. Pediatrics. 2004;114:1362–4.

    Article  PubMed  Google Scholar 

  • Faerk J, Peitersen B, Petersen S, Michaelsen KF. Bone mineralisation in premature infants cannot be predicted from serum alkaline phosphatase or serum phosphate. Arch Dis Child Fetal Neonatal Ed. 2002;87:F133–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fewtrell MS, Loh KL, Chomtho S, Kennedy K, Hawdon J, Khakoo A. Quantitative ultrasound (QUS): a useful tool for monitoring bone health in preterm infants? Acta Paediatr. 2008;97:1625–30.

    Article  CAS  PubMed  Google Scholar 

  • Giapros VI, Papaloukas AL, Andronikou SK. Urinary mineral excretion in preterm neonates during the first month of life. Neonatology. 2007;91:180–5.

    Article  PubMed  Google Scholar 

  • Gillespie RS, Stapleton FB. Nephrolithiasis in children. Pediatr Rev. 2004;25:131–9.

    Article  PubMed  Google Scholar 

  • Gimpel C, Krause A, Franck P, Krueger M, Von Schnakenburg C. Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm infants. Pediatr Int. 2010;52:51–6.

    Article  CAS  PubMed  Google Scholar 

  • Grahnen H, Sjolin S, Stenstrom A. Mineralization defects of primary teeth in children born pre-term. Scand J Dent Res. 1974;82:396–400.

    CAS  PubMed  Google Scholar 

  • Greer FR. Calcium, phosphorus, and magnesium: how much is too much for infant formulas? J Nutr. 1989;119:1846–51.

    CAS  PubMed  Google Scholar 

  • Hallberg L. Does calcium interfere with iron absorption? Am J Clin Nutr. 1998;68:3–4.

    CAS  PubMed  Google Scholar 

  • Harrison CM, Gibson AT. Osteopenia in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2013;98:F272–5.

    Article  PubMed  Google Scholar 

  • Hung YL, Chen PC, Jeng SF, Hsieh CJ, Peng SS, Yen RF, Chou HC, Chen CY, Tsao PN, Hsieh WS. Serial measurements of serum alkaline phosphatase for early prediction of osteopaenia in preterm infants. J Paediatr Child Health. 2011;47:134–9.

    Article  PubMed  Google Scholar 

  • Imel EA, Carpenter TO. A practical clinical approach to paediatric phosphate disorders. Endocr Dev. 2015;28:134–61.

    PubMed  Google Scholar 

  • Kalkwarf HJ, Abrams SA, Dimeglio LA, Koo WW, Specker BL, Weiler H, International Society for Clinial, D. Bone densitometry in infants and young children: the 2013 ISCD Pediatric Official Positions. J Clin Densitom. 2014;17:243–57.

    Article  PubMed  Google Scholar 

  • Karlen J, Aperia A, Zetterstrom R. Renal excretion of calcium and phosphate in preterm and term infants. J Pediatr. 1985;106:814–9.

    Article  CAS  PubMed  Google Scholar 

  • Kaur S, Jain S, Saha A, Chawla D, Parmar VR, Basu S, Kaur J. Evaluation of glomerular and tubular renal function in neonates with birth asphyxia. Ann Trop Paediatr. 2011;31:129–34.

    Article  CAS  PubMed  Google Scholar 

  • Kilpelainen L, Ivaska KK, Kuiri-Hanninen T, Vaananen HK, Rehfeld JF, Goetze JP, Sankilampi U, Dunkel L. Urinary osteocalcin and serum pro-C-type natriuretic peptide predict linear catch-up growth in infants. J Bone Miner Res. 2012;27:1528–35.

    Article  PubMed  Google Scholar 

  • Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev. 2014;94:1143–218.

    Article  CAS  PubMed  Google Scholar 

  • Kovar I, Mayne P, Barltrop D. Plasma alkaline phosphatase activity: a screening test for rickets in preterm neonates. Lancet. 1982;1:308–10.

    Article  CAS  PubMed  Google Scholar 

  • Kovar IZ, Mayne PD. Postnatal and gestational age and the interpretation of plasma alkaline phosphatase activity in preterm infants. Ann Clin Biochem. 1989;26(Pt 2):193–4.

    Article  PubMed  Google Scholar 

  • Kuschel CA, Harding JE. Multicomponent fortified humanmilk for promoting growth in preterminfants. CochraneDatabase of Systematic Reviews 2004, Issue 1. Art. No.: CD000343. DOI: 10.1002/14651858.CD000343.pub2.

    Google Scholar 

  • Masel JP, Tudehope D, Cartwright D, Cleghorn G. Osteopenia and rickets in the extremely low birth weight infant – a survey of the incidence and a radiological classification. Australas Radiol. 1982;26:83–96.

    Article  CAS  PubMed  Google Scholar 

  • Matkovic V, Ilich JZ, Andon MB, Hsieh LC, Tzagournis MA, Lagger BJ, Goel PK. Urinary calcium, sodium, and bone mass of young females. Am J Clin Nutr. 1995;62:417–25.

    CAS  PubMed  Google Scholar 

  • Matos V, Van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr. 1997;131:252–7.

    Article  CAS  PubMed  Google Scholar 

  • Mihatsch WA, Muche R, Pohlandt F. The renal phosphate threshold decreases with increasing postmenstrual age in very low birth weight infants. Pediatr Res. 1996;40:300–3.

    Article  CAS  PubMed  Google Scholar 

  • Miller ME. The bone disease of preterm birth: a biomechanical perspective. Pediatr Res. 2003;53:10–5.

    Article  PubMed  Google Scholar 

  • Mimouni FB, Mandel D, Lubetzky R, Senterre T. Calcium, phosphorus, magnesium and vitamin D requirements of the preterm infant. World Rev Nutr Diet. 2014;110:140–51.

    Article  PubMed  Google Scholar 

  • Murad R, Qadir M, Khalil R, Baig M. Association of urinary calcium and phosphate with bone mineral density among postmenopausal women. Biomedica. 2012;28:78–81.

    Google Scholar 

  • Namgung R, Tsang RC. Perinatal calcium and phosphorus metabolism. In: OH W, GUIGNARD JP, BAUMGART S, editors. Nephrology and fluid/electrolyte physiology. Neonatology questions and controversies. 2nd ed. Philadelphia: Elsevier Saunders; 2012.

    Google Scholar 

  • Nordin BE. Assessment of calcium excretion from the urinary calcium/creatinine ratio. Lancet. 1959;2:368–71.

    Article  CAS  PubMed  Google Scholar 

  • Peralta-Carcelen M, Jackson DS, Goran MI, Royal SA, Mayo MS, Nelson KG. Growth of adolescents who were born at extremely low birth weight without major disability. J Pediatr. 2000;136:633–40.

    Article  CAS  PubMed  Google Scholar 

  • Pittard 3rd WB, Geddes KM, Hulsey TC, Hollis BW. Osteocalcin, skeletal alkaline phosphatase, and bone mineral content in very low birth weight infants: a longitudinal assessment. Pediatr Res. 1992;31:181–5.

    Article  PubMed  Google Scholar 

  • Pohlandt F. Bone mineral deficiency as the main factor of dolichocephalic head flattening in very-low-birth-weight infants. Pediatr Res. 1994a;35:701–3.

    Article  CAS  PubMed  Google Scholar 

  • Pohlandt F. Hypothesis: myopia of prematurity is caused by postnatal bone mineral deficiency. Eur J Pediatr. 1994b;153:234–6.

    Article  CAS  PubMed  Google Scholar 

  • Pohlandt F. Prevention of postnatal bone demineralization in very low-birth-weight infants by individually monitored supplementation with calcium and phosphorus. Pediatr Res. 1994c;35:125–9.

    Article  CAS  Google Scholar 

  • Pohlandt F, Mihatsch WA. Reference values for urinary calcium and phosphorus to prevent osteopenia of prematurity. Pediatr Nephrol. 2004;19:1192–3.

    Article  CAS  PubMed  Google Scholar 

  • Quinlan PT, Lockton S, Irwin J, Lucas AL. The relationship between stool hardness and stool composition in breast- and formula-fed infants. J Pediatr Gastroenterol Nutr. 1995;20:81–90.

    Article  CAS  PubMed  Google Scholar 

  • Rassin DK, Gaull GE, Raiha NC, Heinonen K, Jarvenpaa AL. Protein quantity and quality in term and preterm infants: effects on urine creatinine and expression of amino acid excretion data. J Pediatr Gastroenterol Nutr. 1986;5:103–10.

    Article  CAS  PubMed  Google Scholar 

  • Rehman MU, Narchi H. Metabolic bone disease in the preterm infant: current state and future directions. World J Methodol. 2015;5:115–21.

    Article  PubMed  PubMed Central  Google Scholar 

  • Reitsma JB, Rutjes AW, Khan KS, Coomarasamy A, Bossuyt PM. A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard. J Clin Epidemiol. 2009;62:797–806.

    Article  PubMed  Google Scholar 

  • Rigo J, De Curtis M, Pieltain C, Picaud JC, Salle BL, Senterre J. Bone mineral metabolism in the micropremie. Clin Perinatol. 2000;27:147–70.

    Article  CAS  PubMed  Google Scholar 

  • Sargent JD, Stukel TA, Kresel J, Klein RZ. Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr. 1993;123:393–7.

    Article  CAS  PubMed  Google Scholar 

  • Schanler RJ, Garza C. Improved mineral balance in very low birth weight infants fed fortified human milk. J Pediatr. 1988;112:452–6.

    Article  CAS  PubMed  Google Scholar 

  • Schell-Feith EA, Kist-Van Holthe JE, Van Der Heijden AJ. Nephrocalcinosis in preterm neonates. Pediatr Nephrol. 2010;25:221–30.

    Article  PubMed  Google Scholar 

  • Schilling R, Haschke F, Kovarik J, Woloszczuk W. Phosphorus and calcium metabolism of premature infants fed human milk and formulated milk. Padiatr Padol. 1982;17:667–74.

    CAS  Google Scholar 

  • Sonntag J, Prankel B, Waltz S. Serum creatinine concentration, urinary creatinine excretion and creatinine clearance during the first 9 weeks in preterm infants with a birth weight below 1500 g. Eur J Pediatr. 1996;155:815–9.

    Article  CAS  PubMed  Google Scholar 

  • Staub E, Wiedmer N, Staub LP, Nelle M, Von Vigier RO. Monitoring of urinary calcium and phosphorus excretion in preterm infants: comparison of 2 methods. J Pediatr Gastroenterol Nutr. 2014;58:404–8.

    Article  CAS  PubMed  Google Scholar 

  • Tasian GE, Copelovitch L. Evaluation and medical management of kidney stones in children. J Urol. 2014;192:1329–36.

    Article  PubMed  Google Scholar 

  • Torres PU, Prie D, Molina-Bletry V, Beck L, Silve C, Friedlander G. Klotho: an antiaging protein involved in mineral and vitamin D metabolism. Kidney Int. 2007;71:730–7.

    Article  PubMed  Google Scholar 

  • Trotter A, Pohlandt F. Calcium and phosphorus retention in extremely preterm infants supplemented individually. Acta Paediatr. 2002;91:680–3.

    Article  CAS  PubMed  Google Scholar 

  • Trotter A, Stoll M, Leititis JU, Blatter A, Pohlandt F. Circadian variations of urinary electrolyte concentrations in preterm and term infants. J Pediatr. 1996;128:253–6.

    Article  CAS  PubMed  Google Scholar 

  • Tugay S, Bircan Z, Caglayan C, Arisoy AE, Gokalp AS. Acute effects of gentamicin on glomerular and tubular functions in preterm neonates. Pediatr Nephrol. 2006;21:1389–92.

    Article  PubMed  Google Scholar 

  • Weiler HA, Yuen CK, Seshia MM. Growth and bone mineralization of young adults weighing less than 1500 g at birth. Early Hum Dev. 2002;67:101–12.

    Article  CAS  PubMed  Google Scholar 

  • Zanardo V, Dani C, Trevisanuto D, Meneghetti S, Guglielmi A, Zacchello G, Cantarutti F. Methylxanthines increase renal calcium excretion in preterm infants. Biol Neonate. 1995;68:169–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eveline Staub .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Staub, E. (2016). Bone Disease of Prematurity: Calcium and Phosphorus as Urinary Biomarkers. In: Preedy, V. (eds) Biomarkers in Bone Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7745-3_43-1

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-7745-3_43-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-7745-3

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics