European Journal of Clinical Nutrition (1998) 52, 431± 435
ß 1998 Stockton Press. All rights reserved 0954±3007/98 $12.00
http://www.stockton-press.co.uk/ejcn
Relationship between bone mineralization and aluminium in the
healthy infant
D BougleÂ1;2 , JP Sabatier3 , F Bureau4 , D Laroche3 , J Brouard2 , B Guillois5 and JF Duhamel2
1
Laboratoire de Physiologie Digestive et Nutritionnelle; 2 Service de PeÂdiatrie A; 3 Laboratoire des Radioisotopes; 4 Laboratoire de
Biochimie A; and 5 Service de NeÂonatologie, Centre Hospitalier Universitaire, Caen, France
Objective: This prospective study was designed to assess the relationship between variations of serum
Aluminium levels and bone mineralization, which is one of its target tissues, in healthy premature (PT) and
fullterm (FT) infants.
Study design: Lumbar spine bone mineral density (BMD) and content (BMC) studied by dual energy X-ray
absorptiometry were compared to serum aluminium (S-Al), Ca (S-Ca), P (S-P), osteocalcin, alkaline phosphatase
activity (S-AP), and 25 OH Vitamin D (25 OH D) by simple and multiple regressions in healthy PT (n ˆ 44)
following their hospital discharge and FT (n ˆ 82). PT (gestational age at birth (mean 1 s.d.) 32 2 weeks) and
FT were 43 39 and 36 32 weeks old respectively.
Results: In PT multiple stepwise regression analysis including gestational age at birth, postconceptional age and
postnatal age displayed only a signi®cant correlation between BMD or BMC and postnatal age and a negative
one with S-Al. In FT correlations were found between BMD or BMC and age and S-Ca.
Conclusions: In PT, variations in blood Al are associated with developmental delays. Care should be taken to
lessen Al levels, even in healthy PT babies.
Descriptors: bone mineral density; bone mineral content; aluminium; preterm infants; fullterm infants
Introduction
Aluminium (Al) has a well known toxicity for bone, liver,
brain, and hematopoietic system (Alfrey, 1986). Healthy
adults are protected from Al accumulation by a low ( < 1%)
digestive absorption of ingested intake and by the renal
excretion of most of the absorbed fraction (Alfrey, 1986);
therefore Al loading has been ®rst described in patients
with Al parenteral supply and=or renal failure; tissue Al
loading were described at necropsy of critically ill premature infants (PT), due to IV feeding and renal failure
(Freundlich et al, 1985; Sedman et al, 1985; Bishop et al,
1989; Bozynski et al, 1989). While in the young, growing
rat, small variations of Al intakes above the usual diet
concentrations were shown to impair bone mineralization
(Boudey et al, 1997), little is known, however, on the
potential Al toxicity in the healthy infant: increased Al
plasma levels were reported in full term infants fed Al rich
formulas or antacids containing Al (Goyens & Brasseur,
1990; Tsou et al, 1991; Hawkins et al, 1994) and in
healthy, renal disease free PT either IV (Stockhausen et
al, 1990) or enterally fed (Bougle et al, 1992); some others
observed nonsigni®cant trend toward correlations (Moreno
et al, 1994). Whether these variations in blood Al levels
represent a risk for the development of healthy infants
remains unknown (Bishop, 1992; Committee on Nutrition,
1996); serum Al, however, is higher in PT with than
without fractures or rickets (Koo et al, 1992).
Correspondence: Dr D BougleÂ, Service de PeÂdiatrie A, CHU CleÂmenceau,
F14033 CAEN Cedex, France.
Received 4 January 1998; revised 3 March 1998; accepted 9 March 1998
The aim of this study was to compare bone mineralization to Al plasma levels and usual parameters of calcium
metabolism in healthy infants formerly born prematurely or
at term (FT).
Subjects and methods
PT were studied at=or following hospital discharge; they
were all growing, formula fed babies; none took any drug
known to contain Al such as antacids and none had renal
failure. FT were healthy infants attending a routine visit at
the outpatient clinic of the pediatric department. Parents
gave their informed consent to the study which was
approved by the Ethic Committee of the County of
Basse-Normandie; a blood sample was obtained for the
dosage of serum levels of Calcium (S-Ca), Phosphorus
(S-P), alkaline phosphatase activity (S-AP), 25 OH Vitamin
D (25 OHD), osteocalcin and Al (S-Al); S-Al was measured
by Atomic Absorption Spectrometry on a Perkin Elmer
3030, such as previously described (Bougle et al, 1992).
The detection limit of the method is 0.13 mg=dl
(0.005 mmol=dl); the precision on one day is
1.05 0.017 mmol=l, variation 1.62% (n ˆ 20); the precision on various days is 1.08 0.043 mmol=l, variation 4.0%
(n ˆ 20).
The day of drawing blood, a bone densitometry of the
lumber spine was performed by dual energy X-ray absorptiometry (DEXA) using an ODX 240 DEXA, (ORIS CEA,
Saclay, France). Precision of measure is 1%.
The relationships between bone mineral density (BMD),
bone mineral content (BMC) and clinical and biological data were assessed by simple and multiple stepwise
Bone mineralization and aluminium in the healthy infant
D Bougle et al
432
Table 1 Clinical characteristics of infants
n
Gestational age at birth (weeks)
Postnatal age (weeks)
Postconceptional age (weeks)
Serum Aluminium (m mol=l)
Serum Calcium (mmol=l)
Serum Phosphorus (mmol=l)
Serum 25 OH Vitamin D (ng=ml)
Serum Osteocalcin (m g=l)
Serum Alkaline Phosphatase activity (U=l)
Lumbar bone mineral density (g=cm2)
Lumbar bone mineral content (g)
a
Premature infants
Fullterm infants
44
32 2 (28 ± 36)a=
43 39 (3 ± 150)
74 40 (28 ± 186)
0.56 0.56 (0.07 ± 2.50)
2.53 0.12 (2.21 ± 2.90)
1.96 0.27 (1.45 ± 2.45)
44 34 (4 ± 200)
78 30 (36 ± 160)
487 165 (203 ± 851)
263 99 (101 ± 577)
2.94 2.04 (0.34 ± 10.80)
82
40 1 (37 ± 42)
36 32 (3 ± 153)
109 99 ± 6 (40 ± 532)
0.57 0.55 (0.07 ± 2.77)
2.55 0.12 (2.14 ± 2.80)
1.95 0.27 (1.21 ± 2.49)
30 21 (4 ± 117)
79 22 (30 ± 144)
414 171 (59 ± 920)
304 116 (95 ± 582)
3.89 3.14 (0.50 ± 15.25)
mean 1 s.d. (range).
regression analysis using StatView SE ‡ , Graphics TM
1988, (Abacus Concept Inc.).
Results
Clinical data concerning the infants are given in Table 1. In
FT infants a multiple regression analysis was performed
between clinical parameters (gestational age at birth, postnatal age, weight and height at study) and BMD or BMC: it
was highly signi®cant (F ˆ 121, F ˆ 179 respectively;
P ˆ 0.0001) for BMD and BMC; BMD was only correlated
with height (partial F ˆ 27); BMC was correlated with
postnatal age (partial F ˆ 16) and height (partial F ˆ 17).
The correlation between postnatal age and biological parameters and mineralization was ®rst assessed by simple
regression analysis: a signi®cant correlation was found
with S-Ca (P ˆ < 0.001), S-P (P ˆ < 0.001), BMD
(P < 0.001) and BMC (P < 0.001); no correlation was
found with osteocalcin, S-AP, 25 OH D, nor with S-Al.
In PT a multiple regression analysis was performed
between clinical parameters (gestational age at birth, postnatal age, posconceptional age, weight and height at study)
and BMD or BMC: yet both tests gave signi®cant results
(F ˆ 39, F ˆ 68 respectively; P ˆ 0.0001) none of these
parameters was signi®cantly related to BMD or BMC.
The regression analysis with gestational age at birth,
posconceptional age and postnatal age as independent
variables is given in Table 2; S-P and osteocalcin displayed
a positive correlation, and S-Al a negative one with postnatal age; BMD and BMC were correlated with postnatal
and gestational age at birth. S-AP was correlated with
gestational age at birth; no correlations were found for
S-Ca or 25 OH D.
Simple regressions between BMD and BMC and other
parameters are given in Table 3; in FT signi®cant correlations were found between BMD or BMC and S-Ca, S-P, 25
OH D, S-AP and osteocalcin. PT displayed a negative
correlation between BMD or BMC and S-P, S-Al, and
osteocalcin.
Thereafter multiple stepwise regressions were performed between BMD or BMC as dependent variables
and parameters with which a signi®cant relation was displayed by previous regression analysis. Postnatal age and
gestational age at birth were added to biological independent variables as confounding variables in these multiple
regressions. The results are given in the Table 4, and in
Figures 1 and 2. In FT BMD and BMC were only correlated
with postnatal age and S-Ca. In PT they were correlated
with postnatal age and S-Al.
Discussion
High Al plasma levels were reported in hospitalized, sick,
premature newborns (Freundlich et al, 1985; Sedman et al,
1985; Bishop et al, 1989; Bozynski et al, 1989); these
values increase with age during the ®rst weeks of life
(Bougle et al, 1992); yet in sick infants they were associated with Al tissue accumulation, it is not known so far if
variations of Al levels are liable to have any signi®cance in
absence of life threatening events in healthy infants, either
Table 2 Stepwise regression (F levels) between gestational age at birth, posconceptional age and postnatal age as independent variables and lumbar Bone
Mineral Density (BMD), Bone Mineral Content (BMC) and biological data in healthy former premature infants
Gestational age at birth
Coef®cient
Post-conceptional age
F
Coef®cient
Postnatal age
F
Coef®cient
F
s.e.m.
Serum Calcium
Serum Phosphorus
2.5a
0.05
0.07
0.7
Serum Aluminium
0.001
0.2
25 OH Vitamin D
Osteocalcin
Alkaline Phosphatase
BMD
BMC
0.8
0.1
4.4
4.2
8.0
0.3
0.7
3.6
0.7
1.2
a
37.6 (17.9)
7 8.8 (4.3)
7 0.2 (0.07)
Signi®cance level for entry into the model: F > 4.
7 0.005
(0.001)
7 0.008
(0.003)
7 0.6 (0.1)
2.0 (0.2)
0.04 (0.003)
0.02
22.6
7.7
0.3
22.2
3.3
99.4
169.4
Bone mineralization and aluminium in the healthy infant
D Bougle et al
Table 3 Simple regressions between lumbar Bone Mineral Density (BMD), Bone Mineral Content (BMC) and biological data in healthy former
premature (PT) and fullterm (FT) infants
PT
Coef®cient
BMD
Serum Calcium
Serum Phosphorus
Serum Aluminium
25 OH Vitamin D
Alkaline Phosphatase
Osteocalcin
7 61.1
7 221.5
7 75.8
0.009
7 0.1
7 1.6
BMC
Serum Calcium
Serum Phosphorus
Serum Aluminium
25 OH Vitamin D
Alkaline Phosphatase
Osteocalcin
7 0.6
7 3.5
7 1.3
7 0.004
7 0.003
7 0.04
s.e.m.
137.2
51.1
21.6
0.5
0.1
0.5
2.2
0.7
0.4
0.008
0.002
0.006
FT
P
0.94
< 0.001
< 0.001
0.99
0.33
0.002
0.80
< 0.001
0.007
0.60
0.11
< 0.001
Coef®cient
s.e.m.
7 561.7
7 304.4
7.6
7 1.7
7 0.2
7 1.8
89.7
37.6
25.1
0.7
0.1
0.6
7 16.5
7 8.4
0.2
7 0.04
7 0.006
0.03
2.4
1.0
0.6
0.02
0.002
0.02
P
< 0.001
< 0.001
0.76
0.02
0.007
0.004
< 0.001
< 0.001
0.73
0.02
0.01
0.04
Table 4 Multiple stepwise regression of biological parameters and age, possibly contributing to Bone Mineral Density and Content in healthy premature
(PT) and fullterm (FT) infants
PT
Coef®cient
BMD
Postnatal age
Postconceptional age
Serum Aluminium
Serum Calcium
Serum Phosphorus
25 OH Vitamin D
Alkaline Phosphatase
Osteocalcin
BMC
Postnatal age
Postconceptional age
Serum Aluminium
Serum Calcium
Serum Phosphorus
25 OH Vitamin D
Alkaline Phosphatase
Osteocalcin
a
FT
s.e.m.
F
Coef®cient
s.e.m.
F
1.4
0.3
2.1
0.2
92.4
7 51.6
19.1
26.4a
0.33
7.3
0.2
0.1
0.1
0.2
0.6
509.0
141.9
0.03
7 0.7
0.004
0.3
48.3*
1.6
5.0
1.2
2.4
0.3
0.3
0.2
0.05
0.004
8.9
2.6
0.02
12.9
1.6
0.5
1.2
0.03
176.8
2.4
12.0
3.2
0.7
3.3
0.3
Signi®cance level for entry into the model: F > 4.
PT or FT (Goyens & Brasseur, 1990; Bishop, 1992;
Committee on Nutrition, 1996). Almost all premature
infants showed some degree of hypomineralization or
frank osteopenia during their evolution (Beyers et al,
1994; Greer, 1994). The etiology of this metabolic bone
disease is multifactorial: the main suggested factors are low
Ca and low P supply and bioavailability, and Vitamin D
de®ciency (Beyers et al, 1994; Greer, 1994). Since bone is
one of the target tissue of Al toxicity (Alfrey, 1986), this
study looked at the relationship which could occur between
this osteopenia and variations of blood Al.
The rather high serum Al levels displayed by some
infants, both preterm and fullterm, could not be explained
by drug intake or renal failure at the time of the study.
These instant values, however, were only related with bone
mineralization in preterms. BMD and BMC were similar to
previously reported normal values (Pettifor et al, 1989;
Salle et al, 1992; Schanler et al, 1992; Tsukahara et al,
1993).
As expected, this study showed that postnatal age is the
main determining factor of bone mineralization in PT and
FT infants (Hillman et al, 1988; Glastre et al, 1990; Pittard
et al, 1990; Rubinacci et al, 1993). The in¯uence of
gestational age at birth on bone mineralization of PT
(Salle et al, 1992), which was suggested by simple regression, did not remain signi®cant when regression included
postnatal age (Bishop et al, 1993).
Similarly, simple regression displayed signi®cant correlations between bone mineralization and several biological
parameters namely, S-P, S-Al and osteocalcin in PT, and
S-Ca, S-P, S-AP, 25 OH D and osteocalcin in FT; multiple
regression, however, showed that among the different
biological parameters which were tested, bone mineralization was only associated with S-Al, in the PT, and with
S-Ca and S-P in FT infant, during several months after
birth.
It is not known whether an increase in blood Al is liable
to impair bone mineralization or if it is an indicator of
organ storage: the increase of Al serum levels which occurs
in PT during the ®rst weeks of life (Bougle et al, 1992) and
the decrease which was observed in the present study after
their discharge from hospital suggest that Al could accumulate early and be slowly released from loaded tissues
during growth turnover. PT are at higher risk of Al loading
433
Bone mineralization and aluminium in the healthy infant
D Bougle et al
434
Figure 1 Relationship between serum Al levels (mmol=l) and BMD
(g=cm2) and BMC (g) in healthy premature infants, assessed by multiple
stepwise regression. Preterm infants.
Figure 2 Relationship between serum Al levels (mmol=l) and BMD
(g=cm2) and BMC (g) in healthy fullterm infants, assessed by multiple
stepwise regression.
than FT infants, according to higher Al supply, and renal
immaturity: due to neonatal illness they are often IV fed
with Al rich solutes (Koo et al, 1986; Chappuis et al, 1991);
later they are fed low-birth-weight formulas which are
more Al contaminated than standard formulas (Koo et al,
1988; Bougle et al, 1989). Renal immaturity of PT could
impair Al excretion which is delayed even by a moderate
decrease of renal functions (Mertz, 1986), and explain the
slow decrease of Al=creatinine ratio in urine (Moreno et al,
1994). Therefore in PT the risk of tissue loading is
increased by high intakes and=or absorption and low
excretion rate.
Interactions between Al and Ca occur at every step of
their metabolism: they share the same saturable Vitamin D
dependent absorption pathway (Adler et al, 1991; Moon et
al, 1992; Dunn et al, 1993); Al and P interact in the digestive
tract to form insoluble complexes (Moon et al, 1992).
Al effects on bone are both direct by inhibiting its
mineralization, and indirect through interactions with Ca
and P metabolism: Al is deposited at the calci®cation front,
preventing further mineralization of osteoids (Boudey et al,
1997); it may reduce the total quantity of mineralizable
osteoids and induces Ca release from bone (Bushinsky et
al, 1995).
Several studies compared bone mineralization to its
related biological parameters in PT (Greer et al, 1991,
1994; Pittard et al, 1990; Lucas et al, 1992; Namgung et al,
1993, 1994; Chan, 1993; Ryan et al, 1993; Hayashi et al,
1994; Pohlandt, 1994), and in FT (Roberts et al, 1981;
Schanler et al, 1992; Namgung et al, 1994); only part of PT
show signi®cant correlations between BMD or BMC and
S-Ca (Pettifor et al, 1989; Tsukahara et al, 1993) or
25 OH D (Chan, 1993). P de®ciency is a limiting factor of
bone mineralization (Brooke & Lucas, 1985; Greer et al,
1991, 1994), as shown by its statistical correlation with
BMD and BMC (Pettifor et al, 1989; Chan, 1993; Ryan et
al, 1993), and by the positive effect of its dietary supplementation on bone mineralization (Hayashi et al, 1994;
Pohlandt, 1994). The relationships displayed between bone
mineralization and S-AP (Abrams et al, 1988; Chan, 1993;
Ryan et al, 1993) is in agreement with the high turnover
osteopenia (Greer, 1994). However even when such correlations were found, they could only explain part of the
variation of bone mineralization in the PT (Abrams, 1988;
Ryan et al, 1993).
In FT infants, BMC is not correlated with S-Ca, S-P,
osteocalcin or 25 OH D (Roberts et al, 1981; Namgung et
al, 1994). Therefore in healthy FT development of bone
mineralization seems to be partly independent of nutritional
variations; on the contrary even healthy PT seem to be able
to accumulate Al, that could have long term detrimental
effects, on bone such as on neurologic development
(Bishop et al, 1997).
Conclusions
In preterm infants Al serum levels and age appear to be
mainly associated with the development of bone
Bone mineralization and aluminium in the healthy infant
D Bougle et al
mineralization, as compared to the usual parameters of Ca
metabolism; although the causal relationship between
increased Al levels and impaired bone mineralization is
not precisely determined, this observation points at the
great dependence of preterm infants on environmental
and nutritional factors, which are liable to have long term
developmental effects; on the other hand, the development
of bone mineralization seems to be more ef®ciently regulated in fullterm infants. Exposure of PT to Al should be
reduced.
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