Nutritional Influences on Bone Growth in Children
Nutrition Influences Bone Development from Infancy through
Toddler Years1
Bonny Specker2
Ethel Austin Martin Program in Human Nutrition, South Dakota State University, Brookings, SD 57007
ABSTRACT During the last decade a greater appreciation has developed for determining factors that influence
bone accretion in healthy children. Nutritional factors that may contribute to bone accretion in infants and toddlers
include maternal nutritional status during pregnancy, type of infant feeding, calcium and phosphorus content of
infant formula, introduction of weaning foods, and diet during the toddler and preschool years. Maternal vitamin D
deficiency during pregnancy is associated with disturbances in neonatal calcium homeostasis, and maternal
calcium deficiency leads to reduced neonatal bone mineral content (BMC). Preterm infants are at increased risk of
osteopenia, and, although the use of high mineral formula has reduced the risk of osteopenia in these infants, it has
not eliminated it. The reason for the long-term bone deficiency among preterm infants is not clear, although lower
physical activity levels have been suggested as a potential cause. Studies find that human milk-fed infants have
lower bone accretion than do formula-fed infants; that the greater the mineral content of formula, the greater the
bone accretion; and that the inclusion of palm olein oil in infant formula may reduce bone mineral accretion. Bone
accretion is not influenced by the timing of the introduction of weaning foods, despite higher serum parathyroid
hormone (PTH) concentrations among infants who receive solids earlier. There is evidence of calcium intake-bygene and calcium intake-by-physical activity interactions among toddlers and young children. The long-term
effects of these early nutritional influences on later bone health are unknown. J. Nutr. 134: 691S– 695S, 2004.
KEY WORDS:
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bone
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children
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infants
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diet
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nutrition
During the last decade a greater appreciation has developed
for determining what factors influence bone mineral accretion
in healthy children. Part of this interest can be attributed to
the suggestion that osteoporosis has its origins in childhood.
This review focuses on nutritional factors that may contribute
to early bone mineral accretion: maternal nutritional status as
it relates to fetal and neonatal growth, type of infant feeding,
calcium and phosphorus content of infant formula, introduction of weaning foods, and diet during the toddler and preschool years. Nutrition-by-genetics and nutrition-by-physical
activity interactions are discussed, as well as the relationship
between early diet and bone health later in life.
plementation during pregnancy and neonatal outcomes. The
majority of studies find a relationship between maternal vitamin D status and neonatal calcium metabolism, with a greater
risk of hypocalcemia among infants born to vitamin D deficient mothers (1– 6). It is thought that maternal vitamin D
deficiency leads to secondary hyperparathyroidism, which results in a transitory hypoparathyroidism and hypocalcemia in
the neonate (7,8). Despite the numerous studies showing an
effect of maternal vitamin D deficiency on neonatal calcium
homeostasis, no studies have found a relationship between
neonatal bone mineral content (BMC)3 and maternal vitamin
D status.
Several studies have evaluated the effects of maternal calcium intake on neonatal bone mineral accretion. A study in
undernourished pregnant mothers who were supplemented
with 300 or 600 mg calcium/d during the last trimester showed
that these mothers had similar density (BMD) compared to
mothers not supplemented, but neonatal BMD was greater (9).
Koo and co-workers also reported similar results from a large
randomized trial of maternal calcium supplementation for the
prevention of preeclampsia (10). A total of 256 pregnant
women were enrolled in the randomized, double-blind, placebo-controlled trial. Among mothers in the lowest quintile of
Maternal nutritional status and early growth
Maternal diet during pregnancy. Numerous observational studies, as well as clinical trials, have been conducted to
determine the relationship between maternal vitamin D sup1
Presented at the Nutrition and Bone Health Working Group program at the
“American Society of Bone Mineral Research, 25th Annual Meeting,” held in
Minneapolis, MN, September 19 –23, 2003. The Nutrition and Bone Health Working Group program was organized by Susan J. Whiting and was sponsored by
The National Dairy Council. Supplement contents are solely the responsibility of
the authors and do not necessarily represent the official views of the National
Dairy Council. Guest editors for the supplement publication were Susan J. Whiting, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon,
Saskatchewan, and Frances A. Tylavsky, University of Tennessee, The Health
Science Center, Memphis, TN.
2
To whom correspondence should be addressed.
E-mail: Bonny_Specker@sdstate.edu.
3
Abbreviations used: BMC, bone mineral content; BMD, bone mineral density; 25-OHD, 25-hydroxyvitamin D; DXA, dual energy X-ray absorptiometry; PTH,
parathyroid hormone; SPA, single photon absorptiometry; VDR, vitamin D receptor.
0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.
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calcium intake (⬍600 mg/d), the infants of those who were
randomized to calcium supplementation had higher total body
BMC compared to the infants of those mothers who were
randomized to placebo. There were no differences in neonatal
BMC between placebo and supplemented groups in the upper
four quintiles of maternal calcium intake (baseline intakes
⬎ 600 mg/d). These studies suggest that there is less fetal bone
accretion among mothers who have low calcium intakes
(⬍600 mg/d) compared to higher intakes during pregnancy.
Preterm birth and decreased intrauterine growth. The
majority of calcium accrued during pregnancy occurs during
the last trimester (11), and this increase in fetal demand is met
by an increase in maternal intestinal calcium absorption (12).
Because of the substantial bone accretion that occurs during
the last trimester, infants who are born preterm have lower
total body BMC than do term infants (13,14). Preterm infants
also are at increased risk of osteopenia (typically diagnosed
clinically by radiographs), rickets, and fracture due to postnatal nutrient deficiencies resulting from prolonged exclusive
human milk feeding, total parenteral nutrition with low calcium and phosphorus content, and medications or diseases
that may influence calcium or vitamin D metabolism (i.e.,
chronic diuretic use, anticonvulsant use, etc.). Although the
use of high-mineral– containing preterm formula has reduced
the occurrence of osteopenia in this high-risk group, it has not
eliminated it (15,16). Catch-up in radius BMC has been
reported in some studies of preterm infants, but not all (17,18).
Several studies have shown that former preterm infants tend to
be shorter and lighter than their term counterparts are (19,20),
and one study of 3- to 5-y-old children found that total body
BMC and cortical area of the 20% distal tibia were lower, even
after adjusting for current body weight, in former preterm
children vs. term children (21). The reason for this long-term
bone deficiency among preterm infants is not clear, although
lower physical activity levels, with the concomitant decrease
in bone loading, have been suggested as a potential cause
(21,22)
Type of infant feeding
Numerous studies have compared changes in BMD or BMC
at peripheral bone sites and total body BMC in both preterm
and term infants on different feeding regimens (23–31). Studies find that human milk-fed infants have lower bone accretion
compared to formula-fed infants. The type of formula also may
play an important role in determining bone mass accretion:
mineral content of formula, type of formula (soy vs. cow’s
milk), and inclusion of palm olein oil in infant formula may
influence bone mass accretion during infancy.
Human milk vs. formula. Infants exclusively fed human
milk have lower total body BMC than do formula-fed infants
(31). Both the low vitamin D content of human milk (32) and
the decreasing phosphorus concentrations with increasing
length of lactation (33,34) are thought to contribute to the
lower bone accretion observed among human milk-fed infants.
Theoretically, low vitamin D intake should be associated
with decreased BMD due to increased serum parathyroid hormone (PTH) concentrations, which should increase bone resorption. Very few pediatric studies have correlated BMD
measurements with serum 25-hydroxyvitamin D (25-OHD)
concentrations, and the results are not consistent among those
studies that have. In 1981 Greer and co-workers conducted a
vitamin D supplementation trial and found that 25-OHD
concentrations of 9 human milk-fed infants not receiving
supplemental vitamin D decreased during the winter months,
whereas the 25-OHD concentrations did not change among
the 9 infants randomized to receive 400 IU/d (35). By 12 wk
of age, BMC at the 1/3 distal radius [measured by single
photon absorptiometer (SPA)], was lower in infants randomized to placebo compared to infants randomized to 400 IU
vitamin D/d. By 26 wk of age, the BMC difference between
infants receiving vitamin D and those receiving placebo was
no longer significant (36). In 1989 these same investigators
reported the results of an additional randomized vitamin D
supplementation trial among 46 human milk-fed infants from
birth to 6 mo of age and found no difference in BMC at the 1/3
distal radius between supplemented and nonsupplemented infants, despite significant differences in serum 25-OHD concentrations (29). Park and co-workers measured BMC of the
lumbar spine using dual-energy X-ray absorptiometry (DXA)
in 2- to 5-mo-old Korean infants who were either breast-fed
without vitamin D supplementation or receiving infant formula containing 400 IU vitamin D/L (37). They found no
significant difference in lumbar BMC between the two groups
despite a greater serum 25-OHD concentration among the
formula-fed compared to the breast-fed infants. Lumbar BMC
was not correlated with serum 25-OHD concentrations.
The reason for the lack of a correlation between BMC or
BMD and vitamin D status is unclear. In adults with primary
hyperparathyroidism, a selective reduction in cortical BMD
and preservation of trabecular BMD has been reported (38 –
41), and it has been suggested that assessment of BMD in
relation to PTH requires separation of cortical and trabecular
bone (41). Whether these disparate effects of elevated PTH
concentrations on trabecular and cortical bone occur in infants with secondary hyperparathyroidism resulting from vitamin D deficiency is not known. In addition, these differing
effects may be why bone findings using DXA or single photon
absorptiometry in infants with vitamin D deficiency are not
consistent. DXA methodology measures areal BMD in 2-dimensions and cannot separate trabecular and cortical bone;
this inability to accurately measure these different types of
bone may be the reason for discrepant findings on the relationship between BMC or BMD and vitamin D status.
The phosphorus content of human milk may explain the
lower bone accretion in breast-fed versus formula-fed infants.
Both milk and infant serum phosphorus concentrations decrease with increasing length of lactation and are correlated
with each other (34,42). Milk phosphorus concentrations at 1
mo of age are ⬃140 mg/L and decline to ⬍110 mg/L by 26 wk
of age (42). However, by 4 to 6 mo of age, most infants are
consuming additional phosphorus from solid foods. After the
introduction of these higher phosphorus-containing foods,
there is equalization in total body BMC between previously
human milk-fed and formula-fed infants (31).
Mineral content of formula. The mineral content of infant formula may affect calcium homeostasis and bone accretion. In the neonatal period, a low calcium to phosphorus ratio
(Ca:P) formula, which would exist in formulas with a higher
phosphorus content, leads to a decrease in serum calcium
resulting in an increase in serum PTH concentrations (43).
This increase in PTH concentrations should increase bone
turnover and may lead to a decrease in bone mineral accretion.
However, beyond the neonatal period, higher mineral content
formulas lead to a greater bone mass accretion.
A randomized trial in 101 infants was conducted during the
1st y of life (31). The trial was conducted in two phases: Phase
I was conducted during the first 6 mo of life when infants were
either breast-fed (⬃300 mg Ca/L and 150 mg P/L) or randomized to either a low mineral formula (430 mg Ca/L and 240 mg
P/L) or a moderate mineral-containing formula (510 mg Ca/L
and 390 mg P/L). Phase II involved the same infants who were
BONE IN INFANTS AND TODDLERS
re-randomized at 6 mo of age to one of three feeding groups:
moderate mineral-containing formula (510 mg Ca/L and 390
mg P/L), high mineral-containing formula (1350 mg Ca/L and
900 mg P/L) or cow’s milk (1230 mg Ca/L and 960 mg P/L).
Infants who received the moderate mineral containing formula
during the first 6 mo had a greater bone mass accretion than
did the other two feeding groups (human milk and low mineral-containing formula). During the second period, there was
no difference in total body BMC accrual based on the level of
mineral content of the formula fed during the second 6 mo.
However, the diets the infants received during the first 6 mo
were associated with BMC accrual during the second 6 mo
(Fig. 1). By 12 mo of age, there were no differences in BMC
among either the first or second 6-mo feeding groups. These
results indicate that early mineral intake is associated with
early bone mass accretion, but when mineral intakes are increased later in infancy, these differences disappear.
Cow’s milk vs. soy milk formula. Older infant feeding
studies found that infants fed soy-based formula had lower
radius BMD than did infants fed cow-milk based formula
(27,30). However, newer formulations of soy formulas have
improved calcium and phosphorus content and availability,
and no difference in bone accretion between these newer
formulas and cow-milk based formulas has been observed (44).
Palm olein oil. Some infant formula companies have
added palmitic acid to formula to mimic human milk fatty acid
profiles. Formulas with palm olein oil have 22–25% palmitic
acid compared to 8 –10% in formulas without palm olein oil.
The addition of palm olein oil to infant formula has been
found to decrease calcium and fat absorption (45– 47). A
randomized, double-blinded trial conducted in 128 infants
from 2 wk to 6 mo of age was conducted to test the hypothesis
that infants consuming formula with palm olein would have a
lower bone mineral accretion than would infants consuming
formula without palm olein (48). Significant differences in
total body bone mineral accretion were observed through 6 mo
of age, with infants consuming the palm-olein containing
formula to have less bone gain than did infants consuming the
formula without palm olein (Fig. 2).
Weaning foods. The introduction of usual weaning foods
into the formula-fed infant’s diet does not influence bone mass
accretion. Bainbridge and co-workers conducted a trial among
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FIGURE 2 Effect of palm olein oil supplemented formula on bone
mineral accretion. * ⫽ differences significant at P ⬍ 0.05. Data from
(48).
41 infants who were randomly assigned to receive formula
alone or formula plus infant cereal beginning at 16 wk of age
(49). Although serum PTH concentrations increased significantly by 26 wk of age in the cereal-fed group, there was no
difference between groups in BMC changes (1/3 distal radius
using SPA). Whether the effect of cereal feeding on serum
PTH concentrations was due to higher phosphorus content in
the cereal or the binding of calcium to phytates is not known.
These results are consistent with those of another randomized
trial on the timing of the introduction of solids to an infant’s
diet. Infants who had solids introduced at age 3 mo had similar
total body BMC at 6 and 12 mo of age compared to infants for
whom solids were withheld until age 6 mo (50).
Toddler and preschool years
Although various studies have explored the relationship
between BMC and calcium intake in older children, very few
studies have investigated the relationship between bone mass
accretion or BMC and nutritional intake in the toddler and
preschool years. Lee and co-workers reported in 1993 the
results of a longitudinal observational study of 128 children
from Hong Kong for whom they had collected extensive
dietary intake data during the first 5 y of life (51). They found
that BMC at the 1/3 distal radius was associated with the
cumulative calcium intake during the first 5 y of life. Calcium
intake during the 2nd y of life had the strongest correlation
with BMC at 5 y. A trial conducted in 239 children 3 to 5 y
of age did not find an effect of calcium supplements on total
body bone accretion over the 1-y study period, although the
high baseline calcium intake (⬃900 mg/d) may explain the
lack of significant findings (52). This study, however, did find
that those children who received calcium supplements had a
greater increase in leg BMC with gross motor activity than did
those children who did not receive supplemental calcium (see
below).
Nutrient interactions with genetics and physical activity
FIGURE 1 Effect of early diet during the first 6 mo of age on gain
in total body BMC from 6 to 12 mo of age. Data from (31).
Genetics. It is not clear whether genetic influences on
bone that have been reported are due to a bone-specific effect
or due to a general effect on growth. For example, if genes that
influence bone also influence early growth, this may lead to
early differences in bone size due to increased skeletal loading.
Vitamin D receptor (VDR) polymorphisms have been shown
to be associated with early growth (53,54), which may be
sex-dependent (55), and those differences in early growth may
ultimately lead to BMD differences. There are reports that
VDR polymorphisms are associated with femoral and vertebral
BMD prior to puberty (56), and that prepubertal girls with the
BB polymorphism have the lowest BMD but also are the most
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responsive to supplemental calcium (57). An association between the occurrence of calcium-deficiency rickets in Nigeria
and the Fok I VDR polymorphism, but not the Bsm I, Apa I,
or Taq I polymorphisms, has been reported, indicating that the
specific VDR polymorphisms may be important in determining
an infant’s risk of developing rickets when there is limited
calcium intake (58).
Physical activity. Nutrients may interact with other environmental factors in their effect on bone growth and mineralization. Increased bone loading through physical activity is
one of the major factors influencing regional and total body
bone mass accretion during growth (59,60). A 1-y randomized
trial on the effect of gross motor versus fine motor activities on
infant total body bone mass accretion found evidence that
calcium intake during infancy may modify the bone response
to activity (61). Gross motor activity had no effect on bone
mass accretion among infants receiving moderately high calcium intakes, whereas among infants with moderate to low
calcium intakes, gross motor activity actually resulted in less
gain in BMC than was shown in the fine motor activity group.
Calcium intake was not controlled in this infant study, and
these results led to an additional randomized trial in preschool
children that formally tested, using a factorial design, the
hypothesis that calcium intake modifies the bone response to
physical activity in young children.
A randomized trial, involving 239 children aged 3 to 5 y of
age, was conducted to determine whether there was a calcium
intake-by-physical activity interaction on total body bone gain
and tibia geometry (52). Children were randomized to participate in gross motor or fine motor activities for 30 min per day,
5 d per week for one year. Within each group, children were
blindly assigned to receive 5 d per week either a placebo or
1,000 mg/d of calcium carbonate. Overall, calcium intake did
not influence total body bone mass accretion. However, the
difference in leg BMC gain, obtained from the total body scan,
between gross motor and fine motor was more pronounced in
children receiving calcium vs. placebo. At study completion,
children in the gross motor group had greater periosteal and
endosteal circumferences at the tibia compared to children in
the fine motor group. There also was a significant calcium-byactivity interaction in both cortical thickness and cortical
area: among children receiving placebo, thickness and area
were smaller with gross motor vs. fine motor activity, but
among children receiving calcium, thickness and area were
larger with gross motor activity (Fig. 3). These results indicate
that the relationship of bone and calcium intake is not simple
and may depend upon other environmental factors that influence bone development, such as physical activity.
Early diet and later bone health
Although there are early nutritional influences on bone
mineral accretion, the long-term effect is not known. Bishop
and co-workers reported that preterm infants fed human milk
with high mineral fortifier in the neonatal period had lower
total body bone mass at 5 y of age compared to preterm infants
fed only human milk (62). These findings led to the speculation that there is “early programming,” such that infants who
have low mineral intakes early in life develop improved calcium retention later in life. However, a later report by these
same authors found no association between childhood total
body BMC and early infant feeding practices in a larger number of subjects (20).
Recent studies have reported associations between childhood BMD and both infant vitamin D supplementation and
length of breastfeeding. A retrospective study of 106 prepu-
FIGURE 3 Effect of gross motor vs. fine motor exercise programs
and calcium supplementation on bone changes in leg BMC determined
by DXA. There was a significant activity-by-calcium interaction for leg
BMC (P ⫽ 0.06). Figures above illustrate the bone geometry differences
observed by peripheral quantitative computed tomography (pQCT) after 12-mo intervention. Children in the gross motor group had greater
periosteal and endosteal circumferences at the tibia compared to children in the fine motor group (P ⬍ 0.05). There also was a significant
calcium-by-activity interaction for both cortical thickness and area (P
⬍ 0.01). Data from (52).
bertal girls (median age of 8 y) found that those who received
vitamin D supplements during the 1st y of life (n ⫽ 91) had
greater BMD at the radius, femoral neck, and greater trochanter than those who did not receive supplemental vitamin D (n
⫽ 15) (63). A study from Australia found that total body,
femoral neck and spine BMD were higher among prepubertal
8-y old children who were born at term and breastfed for ⬎3
mo compared to those children who were breastfed for ⬍3 mo
(64). Although these results are intriguing, it is important that
the results be replicated in larger studies using different study
designs.
In summary, nutritional influences of both the mother and
the infant and toddler affect bone mineral accretion. Despite
these early influences, the long-term implications on bone
health are unknown.
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