Mini Review
HOR MONE Horm Res Paediatr
RESEARCH I N DOI: 10.1159/000456662
PÆDIATRIC S
How Milk and Its Proteins Affect Growth,
Bone Health, and Weight
Michal Yackobovitch-Gavan a Moshe Phillip a–c Galia Gat-Yablonski a–c
a The
Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes,
Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; b Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel; c Felsenstein Medical Research Center, Petach Tikva, Israel
Keywords
Milk proteins · Linear growth · Catch-up growth · Bone
health · Weight gain · Body composition
Abstract
Milk has long been recognized to constitute a complete,
well-balanced source of the nutrients and energy required
to ensure the proper postnatal growth and development of
infants. A growing body of evidence suggests the positive
effects of dairy products and particularly of milk proteins on
linear growth also in older children, both healthy or during
recovery from malnutrition. This evidence led the way to the
performance of extensive research aimed to delineate the
components of milk and the mechanisms acting to make
milk so effective. The present review summarizes the current
knowledge regarding the influence of milk and its proteins
on linear growth in healthy and malnourished children, fo-
cusing also on other important aspects of healthy growth,
including bone health, weight status, and body composi-
tion. © 2017 S. Karger AG, Basel
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/hrp
Received: October 27, 2016
Accepted: January 18, 2017
Published online: March 2, 2017
Introduction
Mammalian milk has been engineered by evolution to
supply all nutrients and energy required to foster proper
postnatal growth and development of infants in the post-
natal period. Although in many societies, milk and milk
products of various domestic sources form an important
part of the local diet, in many others they do not, and be-
yond infancy, the growing child may not receive any form
of milk.
While the benefits of milk and its products have in
general long been recognized, the full picture of what
makes milk so effective remains to be elucidated.
A growing body of evidence has suggested the positive
effects of dairy products and milk proteins on linear
growth in children, and in recent years, many researchers
have focused upon the question of just what makes milk
so effective. The present review presents the current
knowledge on the identity of the most important compo-
nents of bovine milk and summarizes the results of recent
studies performed in children or animals, which have in-
vestigated the effect of milk on linear growth, focusing on
bone health, weight status, and body composition.
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Univ. of California San Diego
Michal Yackobovitch-Gavan, PhD
The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes
National Center for Childhood Diabetes
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SCMCI, 14 Kaplan Street, Petach Tikva 49202 (Israel)
E-Mail michalyg2000 @ gmail.com
 In general, milk and dairy foods are considered to be a
good, balanced source of nutrients supporting healthy
growth, providing proteins, vitamins (A, D, E, and B
complex vitamins such as thiamine and riboflavin), and
minerals (calcium, phosphorus, magnesium, zinc, and se-
lenium) [1]. Other components such as specific sugars
and bioactive peptides may have an active role, beyond
their role as building blocks.
In the human diet, milk is an important source of high-
quality proteins, supplying approximately 32 g protein/L
[1]. Milk proteins include 2 main fractions: whey and ca-
sein. Whey (20% of the milk protein) is the water-soluble
fraction comprising several globular proteins, including
beta-lactoglobulin, alpha-lactalbumin, albumin and oth-
ers, and is especially rich in branched-chain amino acids
(leucine, isoleucine, valine, and lysine) as well as sulfur-
containing amino acids. Casein (80% of the milk proteins)
consists of a family of water-insoluble phosphoproteins [2]
and is characterized by a higher proportion of histidine,
methionine, phenylalanine, and proline [1, 3, 4]. However,
both whey and casein are classified as high-quality proteins
and are frequently graded as the best protein source ac-
cording to their essential amino acid score and protein di-
gestibility-corrected amino acid score [1]. Casein also af-
fects growth by increasing calcium absorption from the
intestine, leading to greater bone mineralization [5].
The carbohydrate fraction of bovine milk is divided
into lactose (48 g/L), free oligosaccharides (0.05 g/L) [6],
and bound glycans or glycoconjugates present in milk
glycolipids and glycoproteins [7]. Casein and whey differ
in their glycoprotein content. For example, the glycosyl-
ated lactoferrin (LF; a member of the transferrin family),
an iron and Ca2+-binding protein present in the whey
protein fraction [8], was found to be an important physi-
ological regulator of bone growth [9–11]. Furthermore, a
recent publication has shown the specific effects of oligo-
saccharides released from milk glycoproteins on bacterial
growth [12], providing a possible explanation as to the
effect of milk on gut microbiome composition.
In the following sections, we will address the influence
of milk and its proteins on linear growth in healthy and
malnourished children, focusing on bone health, weight,
and body composition.
The Effect of Milk and Its Proteins on Linear Growth
Milk and dairy products play an important role in ex-
plaining historical trends or regional differences in hu-
man height during the 19th and 20th centuries [13]. A
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DOI: 10.1159/000456662
recent extensive ecological study analyzed the main cor-
relates of male height in 105 countries in Europe, Asia,
North Africa, and Oceania [14]. Data on male height were
compared with the average consumption of protein from
28 different sources and with 7 socioeconomic indicators.
The most significant nutritional correlates of stature were
intake of milk proteins (r = 0.79; p < 0.001), followed by
total protein (r = 0.74; p < 0.001), and animal protein (r =
0.73; p < 0.001); while the most negative nutritional cor-
relate in the total sample was rice protein (r = –0.74; p <
0.001). The highest correlation with height (r = 0.85; p <
0.001) was achieved for the combination of proteins from
milk products, eggs, pork and beef meat, and potatoes.
The authors identified 3 primary types of diets based on
the major source of protein. The first, a rice protein-based
diet, characterized by a very low protein and energy con-
sumption, is typical of tropical Asia, and is associated
with a very short stature (162–168 cm). The second, a
wheat-based diet with a high plant-protein content, char-
acterized by a relatively high total protein and energy
consumption (comparable with that of European coun-
tries), is typical of the Muslim countries of North Africa
and the Near East, and is associated with a relatively short
stature (average male height <174 cm). The third, an ani-
mal protein-based diet consisting mostly of milk pro-
teins, is typical of Northern and Central Europe, and is
associated with the tallest mean stature in the world (>180
cm). Most importantly, these data showed a difference of
some 10 cm (174 vs. 184) between nations relying on
plant versus animal proteins, despite a comparable con-
sumption of total protein and energy. This indicates that
plant-based diets do not provide the optimal stimuli for
physical growth, even when protein and energy intakes
are adequate.
A recent meta-analysis of 12 studies conducted on
children aged 3–13 years in Europe, USA, China, North-
ern Vietnam, Kenya, Indonesia, and India, found a posi-
tive effect of milk products on linear growth, with an ef-
fect size of 0.4 cm/year per daily portion of 245 ml of milk
[13]. In addition, the meta-regression analysis indicated
that milk per se might have a greater effect on growth than
other dairy products; lower height-for-age and being a
teenager increased the effect. One of the main limitations
of this systematic review is that most of the studies had a
short-term follow-up, typical of most clinical trials. This
limits the knowledge of the cumulative effect of dairy
product consumption on adult stature. In this regard, co-
hort studies, although more vulnerable to bias than clini-
cal trials, can be helpful. A prospective cohort study of
pre-menarcheal girls aged ≥9 years in the USA (n = 5101;
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up to 8 years of follow-up) found that girls who drank
more than 750 mL of milk per day (3 glasses per day) from
the age of 10 years to adulthood had a net increase in adult
height of 2.3 cm greater than that of girls drinking <250
mL of milk per day (1 glass per day) [15].
Thus, both experimental and observational studies
have provided evidence that milk products positively af-
fect linear growth, supporting the assumption of the eco-
logical studies that consumption of dairy products con-
tributed to trends in increased height. However, the exact
mechanism or mechanisms by which milk and its com-
ponents stimulate growth is not clear. Potential candi-
dates are bioactive peptides, found in both casein and
whey, insulin-like growth factor, and various minerals,
including calcium and zinc [16].
Moreover, milk proteins, lipids and carbohydrates, in-
cluding lactose, free oligosaccharides [6], and bound gly-
cans or glycoconjugates [7] may affect the gut microbi-
ome, leading to a more efficient utilization of food. The
influence of diet on the gut microbiome has been receiv-
ing increasing attention, with studies showing the spe-
cific effect on bacterial growth of oligosaccharides re-
leased from milk glycoproteins [12] or in the whey and
casein fraction (our unpublished data). Current research
demonstrates that gut bacteria express numerous previ-
ously unknown enzymes possibly related to differential
efficiency of food utilization. Additional basic research is
required to more clearly identify the components in milk
that are most effective in promoting linear growth and to
further improve our understanding of the mechanisms
involved.
Influence of Milk and Its Proteins on Catch-Up
Growth during Recovery from Malnutrition
In recently published figures on child malnutrition,
wasting has been estimated to affect some 52 million chil-
dren under the age of 5 years, and stunting some 165 mil-
lion children [17]. The need for new nutritional interven-
tions was highlighted in a recent paper on worldwide
progress in meeting the 2025 WHO targets for nutrition,
namely, reducing and maintaining the prevalence of
childhood wasting to <5% and the number of stunted
children by 40% [18].
In children recovering from severe acute malnutrition
(SAM), new tissues are created at a very rapid rate, lead-
ing to higher protein requirements than in healthy, well-
fed, and age- and gender-matched children [19]. In our
recent high-throughput quantitative proteomic analysis,
How Milk and Its Proteins Affect Growth,
Bone Health, and Weight
we studied young rats that were either fed ad libitum,
food restricted (RES) to 60%, or food restricted to 60%
followed by ad libitum feeding, leading to catch-up
growth (CU). When 10 days of the RES regimen were fol-
lowed by a single day of unlimited re-feeding (leading to
CU), there was a dramatic increase in liver weight. Anal-
ysis of liver proteins by mass spectrometry showed a fun-
damental difference between the RES and the CU groups:
re-feeding led to massive protein synthesis, necessitating
high levels of ribosomes and chaperones; many ribosom-
al and chaperone proteins became significantly more
abundant in the CU rats, implying that they were mas-
sively and preferably synthetized during the single day of
re-feeding [20].
The traditional assessment of protein adequacy by to-
tal protein consumption rather than protein quality has
led to a significant underestimation of the risk of protein
malnutrition, particularly in developing countries [21]. A
recent review by Ghosh [22] emphasizes the potential of
high-quality proteins to treat both moderate and SAM in
infancy and childhood and to prevent stunting. On the
basis of the current literature, Manary et al. [19] assessed
the relationships between protein quality and weight gain
in children with SAM and acute inflammation, as de­
termined by 2 different scoring methods (the Protein
Digestibility-Corrected Amino Acid Score [PDCAAS]
and the Digestible Indispensable Amino Acid Score
[DIAAS]). The results showed that during recovery from
SAM, protein quality scores correlated with the degree of
weight gain and that when SAM was associated with in-
fection, the effectivity of the immune response, i.e., the
concentrations of acute-phase proteins, was higher in
children receiving foods that contained the amino acids
required for these proteins. The authors concluded that a
balance of amino acids that matches the composition of
acute-phase proteins maximizes amino acid synthesis
[19].
Several recent randomized controlled trials (RCTs)
documented the effectiveness of milk protein in treating
malnourished children. In a double-blind RCT, the re-
covery rate in children aged 6–59 months (n = 1874) with
SAM who had received 25% milk ready-to-use supple-
mentary foods (RUSF) was greater than in those receiving
iso-caloric iso-protein RUSF containing 10% milk sup-
plemented with soy flour, and their rates of weight and
height gain were higher [23]. Similarly, a recent RCT of
533 preschool children provided with 1 of 2 RUSFs with
different concentrations of milk protein (15 vs. 33%) as a
second daily meal showed a small advantage [24] for the
RUSF containing the higher milk protein content, as ex-
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pressed by a lesser decrease in mid-upper arm circumfer-
ence and hemoglobin levels. These findings suggest that
increasing the dairy protein content of such supplements
may protect children from wasting and anemia [24].
A double-blind RCT found that malnourished tod-
dlers (aged 6–59 months, n = 2230) receiving a whey-
based RUSF showed better nutritional recovery than tod-
dlers receiving a soy-based RUSF, even though the whey
RUSF contained 33% less total protein and provided ap-
proximately 8% less energy [25]. This important study
presented the first specific evidence of the advantage of
whey proteins in treating moderate acute malnutrition
[25]. In previous studies reporting positive correlations
between the consumption of dairy protein and improved
outcomes in malnourished children, it was unclear
whether these results were attributable to the quality of
the proteins or to the total amounts of protein consumed
[22–24, 26, 27].
These data suggest that milk proteins may have an im-
portant role in rehabilitation from malnutrition and in
CU growth. However, further studies are needed to deter-
mine the best composition (quality and source) and
quantity of proteins required to match the physiological
demands of children during CU growth.
The Influence of Milk and Its Proteins on Bone Health
Low bone mass is the main risk factor for osteoporosis
and fractures. It is well established that the peak bone
mass achieved during childhood and adolescence will de-
termine bone mass in later life [1, 28, 29]. Bone mass is
acquired relatively slowly throughout childhood, but
with the onset of puberty and the growth spurt in height,
bone mineral accretion is rapid, reaching a peak shortly
after peak height gain at 12.5 ± 0.9 years in girls and 14.1
± 1.0 years in boys of European ancestry [30]. Within 4
years following this peak, 95% of the adult bone mass is
achieved [31]. This period of rapid accretion may be a
time of both opportunity and vulnerability for optimizing
peak bone mass [32]. The attainment of peak bone mass
is affected by multiple factors, including genetics and nu-
tritional and lifestyle factors [32–34]. Lifestyle choices,
including diet and physical activity, influence 20–40% of
the adult peak bone mass [32]; thus, optimization of life-
style factors is an important strategy for achievement of
the maximal bone mass to reduce the risk of osteoporosis
[32].
A meta-analysis of 21 RCTs aimed to determine the
impact of dietary intake of milk products and dietary cal-
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cium on bone mineral content (BMC), showed a statisti-
cally nonsignificant increase of 2 g in the BMC of children
who had received a diet supplemented by dairy products
or dietary calcium as compared to controls [35]. How-
ever, the data were very heterogeneous with respect to
baseline calcium intake. Among participants with normal
or near-normal baseline dietary calcium/dairy intakes,
supplemental dairy/calcium showed little impact on
BMC. The 3 studies found to contribute most (over 75%)
to the heterogeneity [36–38] included subjects with low
baseline calcium intakes, well below the recommended
levels. The combined analyses of these reports yielded a
significant increment in the mean BMC of 49 g (95% CI:
24.0–76.6; n = 1,183). While the authors of this meta-
analysis concluded that increasing dietary calcium/dairy
products significantly increased total BMC in children
with low baseline intakes [35], it was not possible to dis-
tinguish the effects of calcium from that of other compo-
nents of dairy products, such as high-quality proteins, vi-
tamins C, D, and K, or minerals such as copper, manga-
nese, and zinc, which are also thought to influence bone
matrix production and maintenance [1, 39]. Further-
more, calcium bioavailability and absorption of calcium
may be influenced and optimized by the presence of milk
proteins and lactose, as well as the ratio of calcium to
phosphorus [1, 40, 41].
A subgroup of children with low dairy and calcium in-
take comprises those children with IgE-mediated cow’s
milk allergy (IgE-CMA). A study by Nachshon et al. [42]
found a significant reduction in BMD and peak bone
mass after long-term dairy avoidance in young adults
with IgE-CMA. Of particular note was their finding that
IgE-CMA patients who had completed an oral immuno-
therapy program and had been on unlimited dairy intake,
routinely tolerating at least 4.5 g cow’s milk proteins dur-
ing 12–39 months before BMD analysis, had significantly
higher BMD T and Z scores at all measured sites (hip,
femoral neck, and lumbar spine) than the IgE-CMA pa-
tients avoiding cow’s milk proteins, with no significant
differences between the allergic patients who recently had
begun to consume milk and the healthy controls.
In 2016, the National Osteoporosis Foundation of the
US issued a scientific statement to provide evidence-
based guidelines for achieving maximal peak bone mass
early in life, based on a systematic review of the literature
[32]. Analysis of the effect of various lifestyle parameters,
e.g., nutrition and physical activity, on bone mass devel-
opment in youth indicated a positive effect of calcium
intake and of physical activity, especially during late
childhood and the peripubertal years (grade A evidence),
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as well as of vitamin D and dairy consumption (grade B
evidence). However, further research focusing on envi-
ronmental parameters is needed.
To study the effect of casein and whey on bone struc-
ture and quality we used a rat model of nutrition-induced
CU growth in which animals were allowed to eat 1 of 3
isocaloric, isoprotein diets differing in the origin of the
protein, whether vegetable, casein, or whey [43]. Animals
were analyzed after 24 or 40 days of re-feeding. After 24
days, the height of the epiphyseal growth plates in both
the casein and whey groups was greater than in the rats
fed vegetarian chow, suggesting a better growth potential
with milk-based diets. Of particular interest were the sig-
nificant differences between the casein and whey groups
in bone microstructure, as demonstrated by microcom-
puted tomography, which showed a greater cortical thick-
ness and a higher trabecular bone fraction in the casein-
refed animals. Mechanical testing confirmed the greater
bone strength in the latter. This clearly indicates that
bone quality during CU growth significantly depends on
the type of protein ingested. At 40 days, the differences
between the whey and casein groups were no longer sig-
nificant [43].
The Influence of Milk and Its Proteins on Weight and
Body Composition
The influence of proteins, specifically dairy proteins,
on weight and body composition during childhood is
controversial. Studies performed during infancy suggest
that excess protein intakes during infancy and early child-
hood may enhance weight gain, and later risk of obesity
[44–47]. The mechanisms by which increased protein in-
take affects weight gain and body composition are not yet
understood. A suggested mechanism for the obesogenic
effect of dairy proteins is by induction of insulin and in-
sulin-like growth factor-1, which may result in a faster
weight gain [47].
A large double-blind RCT conducted by the European
Childhood Obesity Trial Study Group found that feeding
infants with infant formula and follow-on formulas with
a lower protein content (1.77 and 2.2 g protein/100 kcal,
respectively) during the first year of life reduced the obe-
sity risk at 2 and 6 years of age, as compared to that in-
curred by conventional infant formula and follow-on
high-protein formulas (2.9 and 4.4 g protein/100 kcal, re-
spectively) [44, 45]. A systematic review of the literature
assessing the effects of protein intake during childhood
led to the conclusion that a protein intake of between 15
How Milk and Its Proteins Affect Growth,
Bone Health, and Weight
and 20% of the energy intake in infancy is associated with
an increased risk of being overweight later in life, and that
the first 2 years of life are likely the most sensitive to high
protein intake. However, these authors indicated that the
exact level of protein intake above which there is an in-
creased risk for being overweight later in life has yet to be
established [46]. Another more recent systematic review
and meta-analysis of 12 RCTs investigated the effects of
infant formulas and follow-on formulas with different
protein concentrations on the future risk of overweight
and obesity [48]. The meta-analysis suggested similar
growth in the first months of life, with a lower mean
weight (and weight Z score) in infants fed lower-protein
formulas only from 6 to 12 months of age. Only 1 large
RCT found that consumption of a lower-protein infant
formula may reduce the body mass index beyond the first
year of life (2 and 6 years of age) [44, 45]. These authors
concluded that the current evidence is insufficient for as-
sessing the effects of protein concentration in infant for-
mulas on long-term outcomes, and that more studies on
long-term health outcomes are needed.
In contradiction to the studies indicating a possible
obesogenic influence of high protein intake during early
childhood, other studies on protein consumption and,
specifically milk protein consumption, in later childhood
suggest a beneficial effect in reducing the risk of child-
hood obesity.
A recent systematic review and meta-analysis exam-
ined the longitudinal association between milk consump-
tion and the risk of overweight and obesity in children
and adolescents [49]. This meta-analysis included 10 pro-
spective cohorts and approximately 46,000 children and
adolescents, with an average 3-year follow-up. Children
in the highest intake group were 38% less likely to have
childhood overweight or obesity than those with the low-
est milk consumption (OR = 0.62; 95% CI: 0.49, 0.80).
Moreover, per each 1 serving/day increment in dairy con-
sumption, the risk of overweight or obesity was reduced
by 13% (OR = 0.87; 95% CI: 0.74, 0.98), and the percent-
age of body fat was reduced by 0.65% (β = 0.65; 95% CI:
–1.35, 0.06; p = 0.07). Suggested mechanisms for this an-
tiobesogenic effect included increased satiety, increased
diet-induced thermogenesis, and preservation or increase
of the lean body mass [49]. However, it should be noted
that the conclusions of this meta-analysis are based on
milk as a whole-food and not on the isolated effect of
dairy proteins per se.
In our previously described study in RES rats refed
with casein- or whey-based diets [43], we found that re-
feeding with whey led in the long term to linear growth
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and bone health similar to that achieved by re-feeding
with casein, but with a lesser weight gain. These results
suggest that a whey-based diet may circumvent long-term
obesogenic complications of catch-up (CU) growth.
However, it is too early to translate these data into clinical
recommendations for humans.
bone and linear growth in healthy as well as malnourished
children? Do the effects on weight status and the risk of
obesity differ in infancy and later childhood? What are
the mechanisms by which milk components influence
body composition and height and weight gain? Further
clinical and laboratory studies are required to answer
these questions.

Conclusion
Acknowledgment
A growing body of evidence supports the positive ef-
The authors are grateful to Ruth Fradkin for the English edit-
fects of milk proteins on linear growth in healthy chil-
ing.
dren, as well as on CU growth during recovery from mal-
nutrition. However, many questions remain to be an-
swered. What is the ideal amount of milk proteins required
Disclosure Statement
to promote healthy bone and linear growth in healthy as
well as malnourished children? What is the ideal ratio be- All authors state that they have no conflicts of interest to dis-
tween milk proteins (whey and casein) to promote healthy close.

References
  1 Pereira PC: Milk nutritional composition and
its role in human health. Nutrition 2014;30:
619–627.
  2 Kunz C, Lonnerdal B: Human-milk proteins:
analysis of casein and casein subunits by an-
ion-exchange chromatography, gel electro-
phoresis, and specific staining methods. The
Am J Clin Nutr 1990;51:37–46.
  3 Haug A, Hostmark AT, Harstad OM: Bovine
milk in human nutrition – a review. Lipids
Health Dis 2007;6:25.
  4 Severin S, Wenshui X: Milk biologically active
components as nutraceuticals: review. Crit
Rev Food Sci Nutr 2005;45:645–656.
  5 Scholz-Ahrens KE, Schrezenmeir J: Effects of
bioactive substances in milk on mineral and
trace element metabolism with special refer-
ence to casein phosphopeptides. Br nutrition
Nutr 2000;84(suppl 1):S147–S153.
  6 Bode L, Jantscher-Krenn E: Structure-func-
tion relationships of human milk oligosac-
charides. Adv Nutr 2012;3:383S–391S.
  7 O’Riordan N, Kane M, Joshi L, Hickey RM:
Structural and functional characteristics of
bovine milk protein glycosylation. Glycobiol-
ogy 2014;24:220–236.
  8 Kumari J, Swain T, Sahoo PK: Dietary bovine
lactoferrin induces changes in immunity level
and disease resistance in Asian catfish Clarias
batrachus. Vet Immunol Immunopathol
2003;94:1–9.
  9 Rossi P, Giansanti F, Boffi A, Ajello M, Va­
lenti P, Chiancone E, Antonini G: Ca2+ bind-
ing to bovine lactoferrin enhances protein
stability and influences the release of bacte-
rial lipopolysaccharide. Biochem Cell Biol
2002;80:41–48.
10 Cornish J: Lactoferrin promotes bone growth.
Biometals 2004;17:331–335.
11 Cornish J, Callon KE, Naot D, Palmano KP,
Banovic T, Bava U, Watson M, Lin JM, Tong
PC, Chen Q, Chan VA, Reid HE, Fazzalari N,
Baker HM, Baker EN, Haggarty NW, Grey
AB, Reid IR: Lactoferrin is a potent regulator
of bone cell activity and increases bone for-
mation in vivo. Endocrinology 2004;145:
4366–4374.
12 Karav S, Le Parc A, Leite Nobrega de Moura
Bell JM, Frese SA, Kirmiz N, Block DE, Barile
D, Mills DA: Oligosaccharides released from
milk glycoproteins are selective Growth sub-
strates for infant-associated bifidobacteria.
Appl Environ Microbiol 2016;82:3622–3630.
13 de Beer H: Dairy products and physical stat-
ure: a systematic review and meta-analysis of
controlled trials. Econ Hum Biol 2012;10:
299–309.
14 Grasgruber P, Sebera M, Hrazdira E, Cacek J,
Kalina T: Major correlates of male height: a
study of 105 countries. Econ Hum Biol
2016;21:172–195.
15 Berkey CS, Colditz GA, Rockett HR, Frazier
AL, Willett WC: Dairy consumption and fe-
male height growth: prospective cohort study.
Cancer Epidemiol Biomarkers Prev 2009;18:
1881–1887.
16 Hoppe C, Molgaard C, Michaelsen KF: Cow’s
milk and linear growth in industrialized
and developing countries. Annu Rev Nutr
2006;26:131–173.
17 UNICEF-WHO-The World Bank Group:
Joint child malnutrition estimates – levels and
trends (2015 edition). http://www.who.int/
nutgrowthdb/estimates2014/en/.
18 Haddad L, Achadi E, Bendech MA, Ahuja A,
Bhatia K, Bhutta Z, Blossner M, Borghi E,
Colecraft E, de Onis M, Eriksen K, Fanzo J,
Flores-Ayala R, Fracassi P, Kimani-Murage E,
Nago Koukoubou E, Krasevec J, Newby H,
Nugent R, Oenema S, Martin-Prevel Y, Ran-
del J, Requejo J, Shyam T, Udomkesmalee E,
Reddy KS: The Global Nutrition Report 2014:
actions and accountability to accelerate the
world’s progress on nutrition. J Nutr 2015;145:
663–671.
19 Manary M, Callaghan M, Singh L, Briend A:
Protein quality and growth in malnourished
children. Food Nutr Bull 2016;37(suppl
1):S29–S36.
20 Gat-Yablonski G, Finka A, Pinto G, Quadroni
M, Shtaif B, Goloubinoff P: Quantitative pro-
teomics of rat livers shows that unrestricted
feeding is stressful for proteostasis with impli-
cations on life span. Aging (Albany NY)
2016;8:1735–1758.
21 Ghosh S, Suri D, Uauy R: Assessment of pro-
tein adequacy in developing countries: quality
matters. BrJ Nutr 2012;108(suppl 2):S77–S87.
22 Ghosh S: Protein quality in the first thousand
days of life. Food Nutr Bull 2016;37(suppl
1):S14–S21.
23 Oakley E, Reinking J, Sandige H, Trehan I,
Kennedy G, Maleta K, Manary M: A ready-to-
use therapeutic food containing 10% milk is
less effective than one with 25% milk in the
treatment of severely malnourished children.
J Nutr 2010;140:2248–2252.
132.239.1.231 - 4/4/2017 2:37:27 AM
Univ. of California San Diego

6 Horm Res Paediatr Yackobovitch-Gavan/Phillip/

DOI: 10.1159/000456662 Gat-Yablonski
Downloaded by:
24 Batra P, Schlossman N, Balan I, Pruzensky W,
Balan A, Brown C, Gamache MG, Schleicher
MM, de Sa AB, Saltzman E, Wood L, Roberts
SB: A randomized controlled trial offering
higher- compared with lower-dairy second
meals daily in preschools in Guinea-Bissau
demonstrates an attendance-dependent in-
crease in weight gain for both meal types and
an increase in mid-upper arm circumference
for the higher-dairy meal. J Nutr 2016;146:
124–132.
25 Stobaugh HC, Ryan KN, Kennedy JA, Grise
JB, Crocker AH, Thakwalakwa C, Litkowski
PE, Maleta KM, Manary MJ, Trehan I: Includ-
ing whey protein and whey permeate in
ready-to-use supplementary food improves
recovery rates in children with moderate
acute malnutrition: a randomized, double-
blind clinical trial. Am J Clin Nutr 2016;103:
926–933.
26 Grillenberger M, Neumann CG, Murphy SP,
Bwibo NO, van’t Veer P, Hautvast JG, West
CE: Food supplements have a positive impact
on weight gain and the addition of animal
source foods increases lean body mass of Ke-
nyan schoolchildren. J Nutr 2003;133:3957S–
3964S.
27 Murphy SP, Allen LH: Nutritional impor-
tance of animal source foods. J Nutr 2003;133:
3932S–3935S.
28 Boot AM, de Ridder MA, van der Sluis IM,
van Slobbe I, Krenning EP, Keizer-Schrama
SM: Peak bone mineral density, lean body
mass and fractures. Bone 2010;46:336–341.
29 Rizzoli R, Bianchi ML, Garabedian M, McKay
HA, Moreno LA: Maximizing bone mineral
mass gain during growth for the prevention of
fractures in the adolescents and the elderly.
Bone 2010;46:294–305.
30 Bailey DA, McKay HA, Mirwald RL, Crocker
PR, Faulkner RA: A six-year longitudinal
study of the relationship of physical activity to
bone mineral accrual in growing children: the
university of Saskatchewan bone mineral ac-
crual study. J Bone Miner Res 1999;14: 1672–
1679.
31 Baxter-Jones AD, Faulkner RA, Forwood
MR, Mirwald RL, Bailey DA: Bone mineral
accrual from 8 to 30 years of age: an estima-
tion of peak bone mass. J Bone Miner Res
2011;26:1729–1739.
How Milk and Its Proteins Affect Growth,
Bone Health, and Weight
32 Weaver CM, Gordon CM, Janz KF, Kalkwarf
HJ, Lappe JM, Lewis R, O’Karma M, Wallace
TC, Zemel BS: The National Osteoporosis
Foundation’s position statement on peak
bone mass development and lifestyle factors:
a systematic review and implementation
recommendations. Osteoporos Int 2016;27:
1281–1386.
33 Matkovic V, Fontana D, Tominac C, Goel P,
Chesnut CH, 3rd: Factors that influence peak
bone mass formation: a study of calcium bal-
ance and the inheritance of bone mass in ado-
lescent females. Am J Clin Nutr 1990;52:878–
888.
34 Heaney RP: BMD: the problem. Osteoporos
Int 2005;16:1013–1015.
35 Huncharek M, Muscat J, Kupelnick B: Impact
of dairy products and dietary calcium on
bone-mineral content in children: results of a
meta-analysis. Bone 2008;43:312–321.
36 Du X, Zhu K, Trube A, Zhang Q, Ma G, Hu
X, Fraser DR, Greenfield H: School-milk in-
tervention trial enhances growth and bone
mineral accretion in Chinese girls aged 10–12
years in Beijing. Br J Nutr 2004;92:159–168.
37 Lau EM, Lynn H, Chan YH, Lau W, Woo J:
Benefits of milk powder supplementation on
bone accretion in Chinese children. Osteopo-
ros Int 2004;15:654–658.
38 Cadogan J, Eastell R, Jones N, Barker ME:
Milk intake and bone mineral acquisition in
adolescent girls: randomised, controlled in-
tervention trial. BMJ 1997;315:1255–1260.
39 Huth PJ, DiRienzo DB, Miller GD: Major sci-
entific advances with dairy foods in nutrition
and health. J Dairy Sci 2006;89:1207–1221.
40 Hunt JR, Johnson LK, Fariba Roughead ZK:
Dietary protein and calcium interact to influ-
ence calcium retention: a controlled feeding
study. Am J Clin Nutr 2009;89:1357–1365.
41 Liu J, Bollinger DW, Ledoux DR, Venum TL:
Effects of dietary calcium:phosphorus ratios
on apparent absorption of calcium and phos-
phorus in the small intestine, cecum, and co-
lon of pigs. J Anim Sci 2000;78:106–109.
42 Nachshon L, Goldberg MR, Schwartz N, Sinai
T, Amitzur-Levy R, Elizur A, Eisenberg E,
Katz Y. Decreased bone mineral density in
young adult IgE-mediated cow’s milk-allergic
patients. J Allergy Clin Immunol. 2014;134:
1108–1113.
Horm Res Paediatr
DOI: 10.1159/000456662
43 Masarwi M, Gabet Y, Dolkart O, Brosh T,
Shamir R, Phillip M, Gat-Yablonski G: Skel-
etal effect of casein and whey protein intake
during catch-up growth in young male
Sprague-Dawley rats. Br J Nutr 2016;116:59–
69.
44 Koletzko B, von Kries R, Closa R, Escribano J,
Scaglioni S, Giovannini M, Beyer J, Demmel-
mair H, Gruszfeld D, Dobrzanska A, Sengier
A, Langhendries JP, Rolland Cachera MF,
Grote V, European Childhood Obesity Trial
Study G: Lower protein in infant formula is
associated with lower weight up to age 2 y: a
randomized clinical trial. Am J Clin Nutr
2009;89:1836–1845.
45 Weber M, Grote V, Closa-Monasterolo R, Es-
cribano J, Langhendries JP, Dain E, Giovan-
nini M, Verduci E, Gruszfeld D, Socha P, Ko-
letzko B; European Childhood Obesity Trial
Study G: Lower protein content in infant for-
mula reduces BMI and obesity risk at school
age: follow-up of a randomized trial. Am J
Clin Nutr 2014;99:1041–1051.
46 Hornell A, Lagstrom H, Lande B, Thorsdottir
I: Protein intake from 0 to 18 years of age and
its relation to health: a systematic literature
review for the 5th Nordic Nutrition Recom-
mendations. Food Nutr Res 2013;57.
47 Suthutvoravut U, Abiodun PO, Chomtho S,
Chongviriyaphan N, Cruchet S, Davies PS,
Fuchs GJ, Gopalan S, van Goudoever JB, Nel
Ede L, Scheimann A, Spolidoro JV, Tontisirin
K, Wang W, Winichagoon P, Koletzko B:
Composition of follow-up formula for young
children aged 12–36 months: recommenda-
tions of an international expert group coordi-
nated by the Nutrition Association of Thai-
land and the Early Nutrition Academy. Ann
Nutr Metab 2015;67:119–132.
48 Patro-Golab B, Zalewski BM, Kouwenhoven
SM, Karas J, Koletzko B, Bernard van Goud­
oever J, Szajewska H: Protein concentration
in milk formula, growth, and later risk of obe-
sity: a systematic review. J Nutr 2016;146:
551–564.
49 Lu L, Xun P, Wan Y, He K, Cai W: Long-term
association between dairy consumption and
risk of childhood obesity: a systematic review
and meta-analysis of prospective cohort stud-
ies. Eur J Clin Nutr 2016;70:414–423.
132.239.1.231 - 4/4/2017 2:37:27 AM
Univ. of California San Diego
7
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