PERINATAL AND INFANT NUTRITION Nutrition Vol. 14, No. 10, 1998

Bone Mineralization in Preterm Infants

STEVEN RYAN, MD

From the Royal Liverpool Children’s NHS Trust, Alder Hey Hospital, Liverpool, UK

ABSTRACT

In preterm neonates a large skeletal mineral deficit builds up between birth and 40 wk postconception. During the phase ofcatch-up growth between 40 and 60 wk postconception there is a catch-up in peripheral skeletal mineralization, so that by theage of 1 y the skeletal mineral content is similar in preterm and term infants, despite the former being smaller, a finding that hasbeen replicated for lumbar spinal mineralization. Later follow-up studies suggest that this catch-up persists and mineralizationremains appropriate for body size. However, given the continuing abnormal growth experience of former preterm individuals,it would still be important to examine their bone mineralization in early adulthood. A number of interventions can improveperinatal bone mineralization, but few studies examine their long-term effectiveness. One such study has suggested that arelatively poor mineral diet in this period is, counterintuitively, associated with a later advantage in skeletal mineralization. Ifthis finding is repeatable, then it could result in a major change in nutrition strategy in the neonatal period.Nutrition 1998;14:745–747. ©Elsevier Science Inc. 1998

Key words: infant, premature, bone density, diet therapy, physiologic calcification

BONE MINERALIZATION IN UTERO

About 98% of body calcium is found in the skeleton where,combined with phosphorus, it forms hydroxyapatite, the chiefmineral of bone. Like many other nutrients, calcium and phos-phorus accretion occurs predominantly during the third trimester.At the end of the second trimester, the body content of calcium isaround 5 g, and this rises in an exponential fashion to 30 g by fullterm. The peak accretion rate of calcium is around 3–4 mmolzkg21 z day21. The calcium concentration in fetal plasma is main-tained at a higher level than that found in maternal plasma bymeans of an active ion pump located on the syncytiotrophoblast.

BONE MINERALIZATION EX UTERO IN FULL-TERM INFANTS

By early adulthood peak bone mass is reached and equates toaround 1000 g of calcium. The concept of peak bone mass isimportant since thereafter there is a natural fall in bone mass levelthroughout the rest of life. People with a lower peak mass may beexpected to manifest a significant deficit earlier and develop anincreased risk of osteoporotic fracture.

A number of factors are known to influence bone mineralaccretion, and these include exercise, sex, diet (particularly cal-cium and vitamin D), and hormonal influences, particularly pu-berty.1

BONE MINERALIZATION IN PRETERM INFANTS

Birth to Full Term

Bone mineral accretion in vivo is most commonly measured byabsorptiometric techniques. The pioneering technique was singlephoton absorptiometry in which the ability of bone mineral to

absorb and scatterg-rays was used to estimate bone mineralcontent.2 This technique had the disadvantage in that it could onlymeasure a peripheral skeletal site that was immersed in water—typically the forearm. From this were developed dual photontechniques that used two different energy beams that allowed thewhole body or its regions to be measured without the need forimmersion in water. This technique has been followed by thedevelopment of dual energy x-ray absorptiometry (DXA), whichworks in a similar manner, in which skeletal mineralization can bemeasured accurately in childhood and adulthood.3

Premature osteopenia is the term given to a range of clinical,radiologic, and biochemical disturbances of the skeleton seen inpreterm babies. Radiologic changes include bone demineraliza-tion, fractures of long bones and ribs, rachitic changes, and sub-periosteal new bone formation. Biochemical features includephosphorus deficiency, raised blood alkaline phosphatase, andhypercalcuria.

Initially this disorder was thought to be due to vitamin Ddeficiency, but a number of studies showed that if anything, thevitamin D response was elevated in preterm infants and was moreobvious in those babies who developed radiographic changes.4

Treatment with vitamin D has not been found to be helpful.Bone mineralization was studied in such infants using single

photon absorptiometry of the forearm. Intrauterine accretioncurves were constructed for such measurements using cross-sectional data obtained from newborn infants of varying gesta-tion.5 The curves obtained were exponential in nature, fitting inwith the exponential nature of in utero calcium accretion.

In the period between birth and full term, preterm babiesappear to accrue very little mineral in the forearm site. Extremely

Correspondence to: Steven Ryan, MD, Royal Liverpool Children’s NHS Trust, Alder Hey Hospital, Eaton Road, Liverpool L12 2AP, UK.

Nutrition 14:745–747, 1998©Elsevier Science Inc. 1998 0899-9007/98/$19.00Printed in the USA. All rights reserved. PII S0899-9007(98)00074-4

low birth-weight babies achieved a measurement of 86 mg/cm byfull term compared with 196 mg/cm in term controls.5 Mineralaccretion from birth to full term was negligible. The deficit in-creases as birth gestation decreases. Many nutritional factors andfactors related to illness severity are related to the presence ofclinically recognized bone disease, but no studies have linked suchfactors (such as bronchopulmonary dysplasia and corticosteroidtreatment) with degree of demineralization measured by photonabsorptiometry, perhaps because studies have been too small.6

Hence, even though overt bone disorders are less frequentlyseen nowadays, unobserved skeletal demineralization will still bepresent.

The First Year After Full Term

Many well preterm babies develop great hunger around thetime of full term, and it is not unusual to see growth parameterscrossing centiles upwards. Intakes may increase from the modest150–180 mLz kg21 z d21 prescribed on the neonatal unit to 300mL z kg21 z d21 or more. At this time there is also a rapid increasein bone mineralization that mimics the gradient seen in the lasttrimester. The result is that despite being smaller and lighter thantheir term counterparts, there is complete catch-up in forearm bonemineralization in the preterm neonates.7 This process is completedby 25–50 wk after full term, but most of the catch-up occurs in thefirst 12 wk postterm.

Such findings with single photon absorptiometry have beenconfirmed by DXA for lumbar bone mineral density (BMD)within the first few years.3

Longer-term studies have been few and far between. The firstsuch study used single photon absorptiometry of the forearm andshowed initially an apparent deficit in bone mineral content inboys in later childhood, but after correction for height the deficitdisappeared.8

The Liverpool group has recently undertaken a study of 468-y-old preterm-born children and 40 term controls. Bone miner-alization was measured using DXA in the lumbar spine, forearm,and neck of femur. The preterm group were on average lighter by2.5 kg and shorter by 3.7 cm. Bone mineral content (the totalamount of mineral at the measurement site) was reduced at allmeasurements sites compared to controls. For example, at thefemoral neck bone mineral content (BMC) was 12.00 mg/cm inpreterms compared with 13.67 mg/cm in controls. This differenceis both meaningful and significant (P 5 0.004). When height andweight were taken into account, these differences disappeared.BMD is the quantity of bone mineral at the measurement sitedivided by the area of the measurement site and is a proxy for truemineral density. BMD is a meaningful biological entity because itcan be used to predict clinical outcomes such as fracture risk.BMD was reduced at the hip site in preterm babies compared tocontrols. BMD in the hips of preterm children averaged 0.644g/cm2 compared with 0.686 g/cm2 in controls. Again, the deficit issignificant (P 5 0.009) and meaningful.

The evidence tells us that the average preterm infant developsa skeletal mineral deficit in the in utero period, but that rapidcatch-up occurs. Bone mineral mass in later childhood is related to

body size and is reduced in light of the growth deficits in pretermchildren. There is a suggestion of decreased BMD in midchild-hood. There is evidence that when preterm-born children reachpuberty they are shorter than their term counterparts and have arelatively advanced bone age despite a relative lack of growthhormone. It is possible that ultimate body size may be furtherreduced and that the mineralization surge in the skeleton thataccompanies puberty will be ameliorated. It is thus important thatmineralization at peak bone mass be measured in preterm childrenbecause of the importance of this parameter for skeletal health.

NUTRITIONAL INTERVENTIONS IN PRETERM NEONATES

Low-mineral and particularly low-phosphorus diets, such ashuman milk and parenteral nutrition, are associated with overtmetabolic bone disease. Some studies have found a relative im-pairment in skeletal mineralization during breast feeding, and thismay persist through the first postnatal year, although it tends todisappear thereafter. The use of breast milk fortifiers and phos-phorus supplementation can reduce the incidence and severity ofmetabolic bone disease.9,10

In terms of formula milk feeding, early studies indicated that arate of skeletal mineralization equivalent to that seen in uterocould be achieved.2 This is probably unrealistic for the majority ofvery preterm babies who do not achieve the linear skeletal growthto accommodate the mineral. Nevertheless, modern preterm-infantformulas do contain additional calcium and phosphorus. A typicalcalcium content would be 2.5 mmol/100 mL compared with 1mmol/100 mL in term formulas. The effect of such supplementa-tion is an improvement in skeletal mineralization.

Others have indicated an approach based on individual pre-scription of calcium and phosphorus based on biochemical mea-surements made on blood and urine.11 One group has suggestedthat a physical activity program in preterm babies, mimicking theeffects of exercise in older individuals, can also improve neonatalbone mineralization.12

Until recently nutritional intervention in preterm babies endedwhen they were discharged from the neonatal unit. Now postdis-charge formulations are available that bridge the gap betweenpreterm and term formulations. The use of such formulas isassociated with enhanced bone mineralization at 1 y, as measuredby single photon absorptiometry of the forearm.13

A FLY IN THE OINTMENT

One study has looked at the effect of the nutritional source inthe neonatal period on long-term bone mineralization.14 It foundthat bone mineralization, measured by single photon absorption ofthe forearm, was better in those infants who had received the mosthuman milk compared with those children who had received apreterm formula. The difference was large; BMC was 250 mg/cmafter preterm formula and 350 mg/cm after feeding with mother’sown milk. If this study is replicated it might suggest that a periodof mineral deprivation in the newborn period is good for long-termbone mineralization! This would represent another example ofprogramming. It could also represent the action of other factorswithin breast milk, such as growth factors.

REFERENCES

1. Boot AM, de Ridder MA, Pols HA, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density in children and adolescents:relation to puberty, calcium intake, and physical activity. J ClinEndocrinol Metab 1997;82:57

2. Steichen JJ, Gratton TL, Tsang RC. Ostepenia of prematurity: thecause and possible treatment. J Pediatr 1980;96:528

3. Hori C, Tsukahara H, Fujii Y, et al. Bone mineral status in preterm-born children: assessment by dual energy X-ray absorptiometry. BiolNeonate 1995;68:254

4. Steichen JJ, Tsang RC, Greer FR, Ho M, Hug G. Elevated serum 1,25dihydroxyvitamin D concentrations in rickets of very low-birth weightinfants. J Pediatr 1981;99:293

5. Horsman A, Ryan SW, Congdon PJ, Truscott JG, James JR. Ostepeniain extremely low birth weight infants. Arch Dis Child 1989;64:485

6. Weiler HA, Paes B, Shah JK, Atkinson SA. Longitudinal assessmentof growth and bone mineral accretion in prematurely born infantstreated for chronic lung disease with dexamethasone. Early HumDevel 1997;47:271

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7. Congdon PJ, Horsman A, Ryan SW, Truscott JG, Durward H. Spon-taneous resolution of bone mineral depletion in preterm infants. ArchDis Child 1990;65:1038

8. Helin I, Landin LA, Nilsson BE. Bone mineral content in preterminfants at age 4–16. Acta Paediatr Scand 1985;74:264

9. Abrams SA, Schanler RJ, Tsang RC, Garza C. Bone mineralization informer very low-birth weight infants fed either human milk or com-mercial formula: one-year follow-up observation. J Pediatr 1989;114:1041

10. Greer FR, McCormick A. Improved bone mineralization and growthin premature infants fed fortified own mother’s milk. J Pediatr 1988;112:961

11. Polhandt F. Prevention of postnatal bone demineralization in verylow-birth weight infants by individually monitored supplementationwith calcium and phosphorus. Pediatr Res 1994;35:125

12. Moyer-Mileur L, Luetkemeier M, Boomer L, Chan GM. Effect ofphysical activity on bone mineralization in premature infants. J Pediatr1995;127:620

13. Bishop NJ, King FJ, Lucas A. Increased bone mineral content ofpreterm infants with a nutrient enriched formula after discharge fromhospital. Arch Dis Child 1993;68:F573

14. Bishop NJ, Dahlenburg SL, Fewtrell MS, Morley R, Lucas A. Earlydiet of preterm infants and bone mineralization at age five years. ActaPaediatr 1996;85:230

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