Low bone mineral density in preterm infants: aspects of diagnosis, prevention and long-term outcome

Abstract

Tänä päivänä yhä pienemmät ennenaikaisena syntyneet jäävät terveenä henkiin ja siksi nykyään kiinnitetään huomiota heidän kokonaisvaltaiseen ja pitkäaikaiseen ennusteeseensa. Muun muassa erityisen mielenkiinnon kohteena on ollut ennenaikaisena syntyneiden luuston mineralisoituminen ja sen kestävyys. Tiedetään että heillä on vastasyntyneisyyskaudella hauraat luut ja jopa murtumat ovat tavallisia. Yli 10 vuotta sitten ennenaikaisena syntyneille ei osattu antaa mineraalilisää eli kalkkia ja fosforia, ja silloin murtumat olivat vielä tavallisempia. Nykyään tiedetään, että ennenaikaisena syntyneet tarvitsevat mineraalilisää, ja täten murtumariski vastasyntyneisyyskaudella on niin pieni kuin mahdollista. Kuitenkaan ei tiedetä varhaisruokinnan vaikutusta luuston kestävyyteen myöhemmin elämässä. Tutkimukseni tarkoitus oli selvittää varhaisruokinnan: rintamaidon, mineraalilisän ja D-vitamiiniannoksen, vaikutusta luuntiheyteen lyhyellä ja pitkällä aikavälillä. Tutkimukseni osoitti, että ennenaikaisena syntyneiden maitoon lisätty mineraalilisä merkittävästi paransi luuntiheyttä 3 kk:n iässä, mutta 9-11 vuoden iässä eroja ei enää ollut havaittavissa; kaikilla oli yhtä hyvä luuntiheys riippumatta saadusta mineraalilisästä. Ennenaikaisena syntyneiden lasten luuntiheys oli myös yhtä hyvä kuin täysiaikaisena syntyneiden lasten luuntiheys 9-11 vuoden iässä. Mitä pidempään rintaruokintaa oli alkuvaiheessa jatkettu mineraalilisää saavilla keskosilla, sitä parempi luuntiheys heillä oli. Nykyään Euroopassa suositellulla isolla D-vitamiiniannoksella ei sen sijaan ollut luuntiheyttä parantavaa vaikutusta. Päinvastoin ennenaikaisena syntyneillä, jotka olivat saaneet suuren D-vitamiiniannoksen, mutta eivät mineraalilisää, oli matalin luuntiheys 3 kk:n iässä. Pitkällä aikavälillä, 9-11 vuoden iässä, D-vitamiiniannoksen suuruudella ei ollut vaikutusta luuntiheyteen. Yhteenvetona tutkimus osoitti että ennenaikaisena syntyneet tarvitsevat varhaisvaiheessa mineraali- ja D-vitamiinilisää. D-vitamiiniannostus voi kuitenkin olla nykyisiä eurooppalaisia suosituksia pienempi. Ennenaikaisena syntyneiden lasten rintaruokinnan ylläpito mahdollisuuksien mukaan on luuston kehityksen kannalta suositeltavaa. Kuitenkin riippumatta varhaisvaiheen ruokinnasta ennenaikaisena syntyneiden lasten luuntiheysarvot vastasivat hyvin täysiaikaisena syntyneiden lasten arvoja ja todennäköistä on ettei ennenaikaisena syntyneillä ole lisääntynyttä riskiä saada osteoporoosia ja murtumia aikuisiässä.

One purpose of this study was to validate the DXA methodology for BMD measurements in preterm infants and to test the utility of serum total ALP, B-ALP and serum inorganic phospate as markers of low BMD. A further objective was to evaluate the early and late effects of early dietary vitamin D, mineral supplementation and human milk intake on bone mineral accretion.

For validation of the DXA method duplicate BMC measurements in mg and areal BMD in mg/cm2 were made at the left distal forearm and forearm shaft using DXA (Norland XR-26, Norland Corp., WI) at 3 (n=21) and 6 (+ / - 1) months´ (n=20) corrected age. DXA proved to be a precise and accurate tool for measuring BMD in preterm infants, provided a special software designed for small subjects and the optimal threshold of this software (i.e. 0.040 g/cm2 for Norland scanner) are used. Further, it is of vital importance that the chosen bone detection threshold is kept fixed and constant throughout the study, otherwise results are not comparable. Attention should also be paid to adequate immobilisation, since movement artefacts weaken precision. It seems relevant to measure both the distal forearm and forearm shaft sites in preterm infants at group level. At individual level, the reliability of the shaft measurement exceeds that of the distal site, and the shaft is thus to be recommended.

When analysing the BMD of subjects with different body size, e.g. growing preterm infants, care must also be taken to eliminate the effect of body size. Since the present study showed that BMAD is completely independent of BW, length and ulnar length and that the projectional area can be accurately measured, this variable serves as a reasonable alternative to BMC or BMD when studying associations for which body or bone size is a confounding factor. There are no normative data for forearm shaft and distal forearm BMD in preterm infants. Here the diagnostic cut-off value at 3 months´ corrected age, corresponding to 1 SD below the mean BMAD measured at the forearm site in a subpopulation of preterm infants with uncomplicated course of prematurity was used, i.e. 95 mg/cm3 . Consequently, 10 out of 42 infants at 3 months´ corrected age were diagnosed as having unacceptable low BMAD.

To evaluate the utility of serum total ALP, B-ALP and serum inorganic phosphate as markers of low BMAD, these biochemical markers and BMAD by DXA were measured in preterm infants at a corrected age of 3 (n=42) and 6 months (n=43). With the aid of ROC analysis it was found that at 3 months´ corrected age serum total ALP activity above 900 IU/L detects low BMAD with a sensitivity of 88 % and a specificity of 71 %, but B-ALP provided no additional benefit at a corrected age of 3 months. Serum inorganic phosphate concentrations below 1.8 mmol/l detected preterm infants with low BMAD at 3 months´ corrected age highly specifically (96%), but sensitivity was only 50 %. By combining serum total ALP activity above 900 IU/L and serum inorganic phosphate concentrations below 1.8 mmol/l, all of the infants with low BMAD at 3 months´ corrected age were found. The specificity of this combination was 70 % and more specific biochemical markers are needed to detect preterm infants with low BM! AD of other origin than phosphorus deficiency. Moreover, the utility of these biochemical markers in detecting low BMAD at other ages than 3 months´ corrected age must be assessed.

To test the hypothesis that a small weight-related dose of vitamin D, i.e. 200 IU/kg BW/day up to 400 IU/day, maintains normal serum concentrations of 25OHD and 1,25(OH)2D and results in as good a bone mineral accretion rate as the ESPGAN-recommended dose of 960 IU/day, 43 infants were randomised to receive either vitamin D 200 IU/kg BW/day up to 400 IU/day or 960 IU/day. Although the serum concentration of 25OHD was low at birth, probably indicating low vitamin D status in the mothers, it was well corrected within 6 weeks after birth with the small weight-related vitamin D dose. Even after correction for body size and risk factors there was no difference in BMD in the forearm shaft nor the distal forearm as measured by DXA at 3 and 6 months´ corrected age between infants receiving the small vitamin D dose as compared to those given the high dose, which ESPGAN recommends. In these infants long duration of lactation was associated with low BMAD at 6 months´ corrected age. This is probably attributable to inadequate mineral supply in the neonatal period.

The short- and long-term effects of early dietary vitamin D, mineral and human milk intake were evaluated in 70 preterm infants randomly assigned to 4 groups to receive either vitamin D supplementation 500 or 1000 IU/day from the time of tolerance of total enteral nutrition until 6 months´ chronological age and either unsupplemented human milk or human milk supplemented with calcium 108 mg/kg/day and phosphorus 53 mg/kg/day until they reached a BW of 2000 g. At 12 weeks´ chronological age samples for plasma 25OHD and 1,25(OH)2D concentrations were drawn from all study subjects and BMC at the forearm shaft was measured by SPA in 37 of the infants of the original group. Both vitamin D and mineral supplementation had a clear short-term impact on BMC at the forearm shaft at 12 weeks´ chronological age, although there was no difference in plasma 25OHD and 1,25(OH)2D concertrations between the groups. The lowest BMC was found in the preterm infants receiving exclusively human milk and vitamin D 1000 IU/day.

At the age of 9-11 years BMD measurement was performed at lumbar spine, forearm shaft and distal forearm by DXA in 35 eligible subjects from the original group. In the long term vitamin D and mineral supplementation had no impact on bone mineral status. The lumbar spine BMAD at 9 to 11 years of age did not differ from that of age-matched healthy Finnish children born at term, but a fairly long lactation period (> 6 months) improved long-term bone mineral acquisition in children born preterm.