See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/309690126

The Determinants of Peak Bone Mass

Article in The Journal of pediatrics · November 2016

DOI: 10.1016/j.jpeds.2016.09.056

CITATION READS

1 54

9 authors, including:

Catherine M Gordon Mary B Leonard

Brown University Stanford Medicine
187 PUBLICATIONS 7,991 CITATIONS 234 PUBLICATIONS 7,037 CITATIONS

SEE PROFILE SEE PROFILE

Vicente Gilsanz Karen K Winer

University of Southern California National Institutes of Health
124 PUBLICATIONS 3,849 CITATIONS 67 PUBLICATIONS 1,775 CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

PTH Treatment of Hypoparathyroidism View project

Brown Adipose Tissue View project

All content following this page was uploaded by Karen K Winer on 30 December 2016.

The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document
and are linked to publications on ResearchGate, letting you access and read them immediately.
THE JOURNAL OF PEDIATRICS • www.jpeds.com
The Determinants of Peak Bone Mass
Catherine M. Gordon, MD, MSc1, Babette S. Zemel, PhD2, Tishya A. L. Wren, PhD3, Mary B. Leonard, MD, MSCE4,
Laura K. Bachrach, MD4, Frank Rauch, MD5, Vicente Gilsanz, MD, PhD3, Clifford J. Rosen, MD6, and Karen K. Winer, MD7
O
steoporosis poses a significant health burden for the
elderly. Although the medical community recog-
nizes the considerable impact of this disease in adult-
hood, many primary care providers do not realize that
osteoporosis has its origins in childhood and disorders of bone
accrual are often ignored. Various factors potentially inter-
fere with gains in bone density and structure during growth
and development and add to the risk of osteoporosis in adult-
hood. Therefore, it is critical to obtain a better understand-
ing of the determinants of bone acquisition, from infancy to
early adulthood, and strategies to optimize peak bone mass
(PBM).
Over one-half of the skeleton is laid down during the teenage
years, a period when lifestyle habits may impede optimal bone
accrual. The pubertal years are a critical period for bone mass
acquisition, but the process by which new tissue produced by
the growth plate is turned into metaphyseal bone (endochon-
dral ossification) and the relative roles of androgens, estro-
gens, and insulin-like growth factors in the adolescent growth
spurt requires further investigation. Furthermore, our under-
standing of the process of modeling, leading to increased bone
size and strength, is still lacking. Although there have been sig-
nificant advances including generation of sex- and race-
specific reference data for dual energy x-ray absorptiometry
(DXA) bone mineral content (BMC) and areal bone mineral
density (areal BMD [aBMD]), large gaps remain in our un-
derstanding of bone quality and strength, and in the preven-
tion and treatment of abnormal bone accretion rates in
childhood chronic disease. Scientific advances have led to a
population of children with chronic illness who live well
into their adulthood. Chronic illness poses threats to bone
health by interfering with bone accrual and often leads to
suboptimal PBM.
We recognized the need to account for major advances in
the field of pediatric bone health over recent years and, more
importantly, the need to identify critical research gaps in this
aBMD Areal BMD
BAT Brown adipose tissue
BMC Bone mineral content
BMD Bone mineral density
CSA Cross-sectional area
CT Computed tomography
DMPA Depot medroxyprogesterone acetate
DXA Dual energy x-ray absorptiometry
EE Ethinyl estradiol
GCs Glucocorticoids
OCs Oral contraceptives
PBM Peak bone mass
RCTs Randomized controlled trials
vBMD Volumetric BMD
WORKSHOP/SYMPOSIUM
SUMMARY
area. To address these important issues, a workshop entitled
“The Determinants of Peak Bone Mass” was held on Novem-
ber 17-18, 2015 at the National Institutes of Health in Bethesda,
Maryland. The workshop was open to the public. This meeting
brought together recognized leaders in the field of pediatric
and adolescent bone health to discuss the current state of
knowledge and identify research priorities. Herein, we sum-
marize highlights of this meeting and discuss advances in our
understanding of the development of PBM among children
and adolescents. We provide an overview of key research op-
portunities envisioned to move this field forward.
PBM: When Is It Achieved?
Rates of bone mineral accrual follow predictable patterns
through childhood and resemble percentile charts for height
velocity. Differences in the timing of bone mass accrual are
related to sex-specific patterns of pubertal maturation.1 PBM
is the amount of bone acquired when accrual ceases or pla-
teaus at some point after completion of growth and develop-
ment. The greatest gains in bone mass occur approximately
6 months after the adolescent growth spurt,2 but increases in
bone mass and density continue for years thereafter. Most es-
timates of the timing of PBM are based on cross-sectional
population surveys from US adolescents and young adults using
DXA such as the National Health and Examination Survey.3,4
Estimates of the timing of PBM based on longitudinal changes
in DXA-measured aBMD (or 2-dimensional BMD), as were
obtained in the Canadian Multicenter Osteoporosis Study, are
similar, except for total hip aBMD among females.5 One of the
primary aims of Canadian Multicenter Osteoporosis Study has
been to identify factors associated with osteoporosis and frac-
ture during adulthood. The study’s longitudinal design adds
significant value. Other recent studies identified lifestyle factors
that affect PBM during the transition to young adulthood. An
early study of college age women found substantial gains in
From the 1Cincinnati Children’s Hospital Medical Center, University of Cincinnati
College of Medicine, Cincinnati, OH; 2Children’s Hospital of Philadelphia, University
of Pennsylvania, Philadelphia, PA; 3Children’s Hospital Los Angeles, University of
Southern California, Los Angeles, CA; 4Stanford University School of Medicine,
Stanford, CA; 5Shriners Hospital for Children, McGill University, Montreal, Canada;
6
Maine Medical Center Research Institute, Scarborough, ME; and 7Eunice Kennedy
Shriver National Institute of Child Health and Human Development, Bethesda, MD
The workshop was funded by the Eunice Kennedy Shriver National Institute of Child
Health and Human Development, the National Institutes of Health Office of the
Director, Office of Research on Women’s Health, Office of Dietary Supplements, the
National Osteoporosis Foundation, and the American Society for Bone and Mineral
Research. C.G. served on the Editorial Board of The Journal of Pediatrics (2011-
2013). The other authors declare no conflicts of interest.
0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org10.1016/j.jpeds.2016.09.056
261
THE JOURNAL OF PEDIATRICS • www.jpeds.com
bone mass and density in the third decade of life (eg, 6.8% in-
crease in lumbar spine aBMD). Gains were associated with
dietary intake (calcium/protein ratio) and physical activity.6
A more recent 5-year prospective longitudinal study of young
Swedish men, ages 18-24 years, showed that gains in aBMD
were related to the timing of adolescent growth spurt and
changes in physical activity.7,8 Later timing of the adolescent
growth spurt was associated with lower cortical and trabecu-
lar volumetric BMD (vBMD) and cortical thickness of the
radius and tibia, and lower DXA aBMD of the total body, spine,
femoral neck, and radius. Moreover, in follow-up of this cohort,
gains in tibial cortical cross-sectional area (CSA) were posi-
tively associated with changes in physical activity and ad-
versely affected by initiation of smoking. 9 Quantitative
computed tomography (CT) measures of cortical and tra-
becular bone show very different trajectories of PBM. Tra-
becular losses in the peripheral skeleton are already occurring
among young adults in their early 20s, but cortical losses occur
later, well after age 40.10,11 In the axial skeleton, bone acquisi-
tion reaches peak values at the time of sexual and skeletal ma-
turity and reported increases in DXA measures of bone are likely
due to the influence of soft tissues, rather than to changes in
bone acquisition within the vertebral body.12 Thus, the timing
of PBM is dependent upon the skeletal site and bone com-
partment under consideration, sex, maturational timing, and
lifestyle factors.
Genetics of PBM
Osteoporosis has a strong heritable component,13 as sug-
gested by differences in aBMD for population ancestry
groups,1,14 and familial heritability estimates.13,15 Earlier can-
didate gene and family studies identified the vitamin D
receptor,16 collagen 1 alpha 1,17 and low-density lipoprotein
receptor-related protein 518,19 as determinants of BMD. In adults,
genome-wide association studies have identified 56 loci asso-
ciated with BMD and 14 loci associated with osteoporotic
fracture.20 Many loci are also associated with BMD in child-
hood, some with sex- and puberty-specific effects,21,22 and their
mechanism of action warrants further study. The rare variant,
EN1,23,24 and a common variant near SOX6,24 each associate
with high bone density in both children and adults,24 suggest-
ing that the risk of osteoporosis may be established during
childhood. Recent studies that used a “genetic risk score” based
on loci identified in adult bone studies have shown that genetic
risk for low BMD in adulthood was associated with de-
creased bone accretion from age 9 to 17 years.25 Further studies
are needed to determine the interaction of genetic predispo-
sition with modifiable factors such as diet and physical activ-
ity in determining the timing and magnitude of PBM.
Sex Differences in Bone Accrual and Structure
An area of progress in osteoporosis research is the identifica-
tion of the structural basis accounting for much of the varia-
tion in bone strength among humans. Progress in elucidating
the structural basis for sex differences in the prevalence of os-
262
Volume 180
teoporosis has been considerably greater for the axial than ap-
pendicular skeleton. Accumulating evidence suggests that
diminished bone accrual in girls is the basis for the lower PBM
in young women, which, in turn, is a major determinant of
their 2- to 4-fold higher incidence of vertebral fractures com-
pared with men.
Available data also indicate that sex differences in PBM in
the axial skeleton are the consequence of differences in ver-
tebral growth, rather than in bone density.26 The CSA of the
lumbar vertebrae is 25% smaller in young women than men,
even after accounting for body size. This disparity is also present
in children and has most recently been found to be present
as early as infancy; newborn girls across races/ethnicities have,
on average, 10.6% smaller vertebral cross-sectional dimen-
sions when compared with newborn boys.26
Because the CSA of the vertebral body is a major determi-
nant of its compressive strength, the smaller vertebral CSA of
females imparts a mechanical disadvantage that increases the
stress within vertebrae for all physical activities, and if such
stress persists, the susceptibility for fragility fractures later in
life. The smaller female vertebral CSA also results in greater
flexion/extension and lateral flexion. Because greater flexibil-
ity of the spine may facilitate the lordosis needed to main-
tain upright posture, it could be hypothesized that fetal load
during pregnancy is a selection factor in the evolution of the
discrepant spinal morphology between the sexes in humans.
Bone Strength Accrual, Tracking of Bone
Mass, and Fracture Risk
Among healthy children, approximately one-half of boys and
one-third of girls will sustain a fracture by age 18 years.27 The
skeleton is particularly vulnerable to fracture during early ado-
lescence when linear bone growth may outpace bone miner-
alization, causing a transient increase in bone fragility.28 Children
of European vs African ancestry have a greater fracture risk.
Although physical activity is critical to building bone, it is note-
worthy that more active children have greater exposure to
trauma that may cause fractures.29
Bone characteristics during childhood and adolescence are
associated with childhood fracture risk. Children with forearm
fractures tend to have lower bone mass, areal and vBMD, and
cortical thickness, area, and density. A 1 SD decrease in bone
mass or density has been associated with a substantial in-
crease in fracture risk.30 Forearm fractures reflect deficits in bone
mineral throughout the skeleton, not just at the forearm.
Fractures occur when loading exceeds skeletal strength.
Strength depends on both geometric properties (size, shape)
and material properties (density). The properties contribut-
ing most significantly to fracture risk differ depending on the
skeletal site. Optimizing bone strength accrual during growth
is important for fracture prevention. During growth, verte-
bral cancellous density is stable in both boys and girls prior
to puberty, increasing significantly between the ages of 12 and
17 years for boys and 10 and 15 years for girls.31 Density is
similar for black and white children through Tanner stage 3,
but diverges with higher density in blacks at Tanner stages 4
Gordon et al
January 2017
and 5.32 Vertebral CSA increases throughout growth and is larger
in males than females of similar stature at all ages, even at
birth.33 No differences in vertebral CSA are seen based on race.
In the appendicular skeleton, cortical bone area at the midshaft
of the femur increases during growth, correlated with body
weight independent of race and sex.34 Metaphyseal growth is
more difficult to characterize.35 In contrast to the axial skel-
eton, appendicular bone properties do not peak because the
periosteum and endosteum continue to expand throughout
life.36
Longitudinal growth during the adolescent years is rapid
compared with other periods. As the rate of longitudinal growth
increases during puberty, the age of the bone structural ele-
ments at a given distance to the growth plate decreases, leaving
less time for cortical thickening through trabecular coalescence.28
This leads to a discrepancy between older and more stable me-
taphyseal bone and recently formed bone. A greater volume
of newer bone compromises bone strength if challenged with
increased mechanical loading. In comparison with the me-
taphysis, diaphyseal bone develops more in line with the in-
creasing mechanical requirements, presumably because the bone
formation rates needed for diaphyseal growth in width are only
a fraction of the metaphyseal apposition rates. How local and
systemic signals are integrated to achieve site-specific changes
in bone structure is not understood. The timing of puberty
has a significant impact on bone development and a large
number of endocrine and other health-related outcomes.37,38
Delayed puberty is associated with lower bone density at ma-
turity, which may track into adulthood. How hormonal changes
during puberty interact with mechanical factors to change bone
structure and strength merits further study.
Bone measures “track” longitudinally quite strongly from
childhood through young adulthood, with a transient decline
during early adolescence.39,40 This provides strong evidence that
bone status during childhood predicts PBM. However, life-
style factors such as changes in physical activity, nutrition, and
adiposity can alter bone status. Second hand smoke was shown
to be associated with osteoporosis in postmenopausal women,
which is a potential environmental pathogen that has not yet
been evaluated in children.41 Identification of factors that posi-
tively or negatively influence bone accrual may provide in-
sights into interventions that may optimize PBM. This may
be particularly important for vulnerable patient populations
such as those with decreased physical activity and loading of
the skeleton because of mobility impairments.42 Research is
needed to understand the magnitude and type of bone defi-
cits typical of different patient populations to mitigate frac-
ture risk during childhood and as these patients age.
The Regulation of Bone Acquisition
Skeletal growth is driven by myriad endocrine modulators,
cytokines, and growth factors, which act both systemically and
locally.43 More than one signal likely originates from osteo-
blasts and osteocytes that regulate insulin sensitivity and se-
cretion, as well as phosphate balance.44,45 The skeletal matrix
itself also contains growth factors and peptides that are re-
The Determinants of Peak Bone Mass
WORKSHOP/SYMPOSIUM SUMMARY
leased during bone remodeling.46 In turn, bone is a recipient
of multiple signals not only from the classic calcium regulat-
ing hormones (eg, parathyroid hormone, calcitonin, estro-
gens, and androgens), but also from other tissues, through both
endocrine and paracrine pathways. With respect to the latter,
neighboring muscle and adipose tissue exert significant control
over bone remodeling and in turn, there is an impact on af-
ferent signals from the skeleton back to other tissues. Hence,
a major challenge for investigators is to unravel this complex
and redundant system. Delineating such systems is made even
more challenging by the many processes involved in peak bone
acquisition.
Peak bone acquisition likely begins before birth, with genetic
programming and epigenetic modifications. Recent studies have
shown that dietary modifications (caloric- and nutrient-
specific) in both rodents and humans can impact that genetic
program, leading to subsequent changes in trajectories for skel-
etal modeling and consolidation.47 Interestingly, genome-
wide association studies have identified shared determinants
from genetic programming that affect the composition of
muscle fat and bone.48 In addition to those determinants, epi-
genetic marks that affect fetal and postnatal cell growth and
differentiation can ultimately define body composition in the
child.49 Decisions related to cell fate occur in niches that are
found in vessels, in muscle and adipose tissue stroma, and most
importantly in the bone marrow, which has been a focus of
recent investigations. For example, it has been well estab-
lished that bone marrow in the appendicular skeleton changes
from a purely hematopoietic composition to primarily
adipogenic during childhood growth.50 This process begins early
in life and reaches a peak at the time of maximum bone ac-
quisition, suggesting that there may be an important but poorly
defined relationship between adipocytes and osteoblasts during
adolescence. Moreover, these changes are very context- and
location-specific because increased bone marrow adiposity in
the aging individual is paradoxically associated with bone loss.51
Thus, a major challenge for investigators is defining how signals
between adipocytes and osteoblasts in situ can impact skel-
etal growth and acquisition in vivo. One novel approach has
been to create artificial bone marrow niches in which all the
cellular elements can coexist in a 3-dimensional matrix that
mimics skeletal composition.52
It has long been recognized that endocrine signals modu-
late the timing and magnitude of peak acquisition, although
only recently has the role of other tissues interfacing with bone
been shown to have additional, yet, important influences on
the magnitude of skeletal growth and maintenance. There is
no doubt that circulating estrogens, androgens, and growth
hormone, secreted in a critical and temporal manner, define
specific trajectories for peak bone acquisition during adoles-
cence. However, adipose and muscle mass and composition,
also modulated by sex steroids and growth hormone, contrib-
ute significantly to final adult bone density. Moreover, with
respect to adipose tissue, there may be regulatory determi-
nants that are tissue-specific. For example, recent data from
several groups have shown that greater brown adipose tissue
(BAT) volume is associated with greater cortical bone density
263
THE JOURNAL OF PEDIATRICS • www.jpeds.com
and thickness, as well as higher muscle mass.53,54 The link
between BAT and skeletal growth in children remains unknown.
Similarly, subcutaneous “white” adipose tissue that sur-
rounds muscle and bone may also be related to higher bone
density; on the other hand, higher visceral fat mass, as seen
in adolescent type 2 diabetes, is associated with lower trabecu-
lar bone volume fraction as measured by CT.55 Interestingly,
BAT vs white adipose tissues also differ with respect to their
insulin sensitivity and have varying effects on metabolic ho-
meostasis and skeletal acquisition.
Impact of Childhood Chronic Diseases and
Glucocorticoid Therapy on Bone Accrual
Chronic diseases and their therapies pose threats to muscu-
loskeletal development. The impact may be immediate, re-
sulting in fragility fractures during childhood,56-60 or delayed,
because of suboptimal PBM and consequent fractures in
adulthood.61,62 Glucocorticoids (GCs) are highly effective for
the treatment of many childhood diseases but are associated
with adverse effects on osteoblast, osteocyte, osteoclast, and
muscle cell metabolism. GCs result in significant reductions
in bone formation because of decreased differentiation of
osteoblast precursors, impaired osteoblast function, and
decreased osteoblast lifespan. 63,64 GC therapy results in
early increases in bone resorption as a result of enhanced
osteoclastogenesis and osteoclast survival; however, this effect
is transient and followed by reductions in osteoclast differen-
tiation and function.65 Finally, GCs adversely affect muscle mass
and function through decreased protein synthesis and in-
creased protein catabolism.66 Given the rapid bone accrual that
characterizes skeletal modeling during growth, and impor-
tance of the anabolic effects of biomechanical loading, the
growing skeleton is uniquely vulnerable to the effects of GCs
on bone formation and muscle metabolism.
Numerous DXA studies reported lower aBMD in children
with chronic inflammatory diseases treated with GCs. However,
imaging methods that provide insight into site-specific ab-
normalities in trabecular and cortical vBMD and cortical di-
mensions (periosteal and endosteal) are needed to understand
the impact on bone strength and identify therapeutic targets.
Prior DXA studies in children treated with GCs were con-
founded by GC effects to impair growth, resulting in under-
estimates of areal BMD for age.67 The differing impact of
inhaled vs enteral/parenteral administration on bone health
outcomes is also important to consider. A recent systematic
review and meta-analysis concluded that ≥12 months of inhaled
GCs in children and adults with asthma was not associated with
adverse effects on fractures or BMD.68 However, the detrimen-
tal effect of inhaled GCs on height, a variable that impacts the
interpretation of BMD in pediatric patients, is significant and
can persist into adulthood.69-71
Both glucocorticoids and inflammation are associated with
decreased trabecular vBMD, periosteal circumference, and con-
sistent bone formation; inflammation is associated with
endocortical bone loss consistent with increased bone resorp-
tion. The fact that studies in children and adolescents treated
264
Volume 180
with GC demonstrated impaired ability of periosteal expan-
sion to keep pace with linear growth confirms the vulnerabil-
ity of the growing skeleton. This will likely have lifelong and
irreversible implications for fracture risk.
Exercise
Periods of growth are characterized by high rates of bone mod-
eling and remodeling. Adolescence is considered the best time
to strengthen bone because periosteal surfaces are rapidly
growing. Physical activity during the rapid growing years of
adolescence adds bone mass to periosteal surfaces that enhance
bone strength. All physical activity is not necessarily benefi-
cial for bone. Targeted, impact- and muscle-loading physical
activities that are moderate-to-high magnitude, rapid and odd-
impact (have an effect on the entire circumference of bones,
achieved by incorporating motions in many directions) have
produced significant results in bone size. Two randomized, con-
trolled trials conducted by Gunter et al72,73 showed that 7-to
8-year-old children who participated in high-impact jumping
interventions for 7 months experienced some maintenance of
increased BMC years after the cessation of training. This cohort
was followed for another 7 years after the cessation of the box-
jumping intervention, with benefits to the hip persisting, and
jumpers maintained a benefit in hip BMC compared with
nonjumpers.74 Further study is necessary to determine if these
benefits continue throughout adulthood in the absence of con-
tinued exercise.75-77
Contraception
Data regarding the effect of combined oral contraceptives (OCs)
on bone density among adolescent girls are inconsistent. In one
study, OC use by healthy teenage girls did not affect PBM
acquisition.78 However, some data suggest that long-term receipt
of an oral monophasic contraceptive formulation (ethinyl es-
tradiol 20 mg + desogestrel 0.150 mg) may result in subopti-
mal PBM.79 The skeletal effects of combined OCs are of
particular concern in adolescents compared with adult
women.80,81 Initiation of combined OCs within the first 3 years
after menarche appears to be of highest concern.81 These prepa-
rations may suppress the hypothalamic-pituitary-ovarian axis,
thereby decreasing endogenous estradiol production. Ultra-
low-dose OCs containing 20 mg of ethinyl estradiol (EE) are
of most concern, although some studies in adolescents have
inherent limitations such as small sample size, inclusion of
smokers, and poor accounting for other confounders.82 A recent
clinical trial examining the skeletal effect of 20 vs 30 mg EE OCs
vs control subjects showed subnormal bone accrual only in the
20 mg EE recipients (compared with other groups).83 Whether
changes in BMD are reversible is unknown and merits
investigation.
Contraception via depot medroxyprogesterone acetate
(DMPA) injections is associated with skeletal deficits at the spine
and hip among adolescents. DMPA acts on the skeleton mainly
through estrogen deficiency.84 However, bone loss in adoles-
cent girls receiving DMPA for contraception is partly or fully
reversible following discontinuation of DMPA, with faster
recovery at the spine compared with hip.85 DMPA is still
Gordon et al
January 2017
recommended for use in adolescents, but with caution given
potential deleterious skeletal effects.
Both the American Academy of Pediatrics and American
Congress of Obstetricians and Gynecologists have published
guidelines to increase the use of long-acting reversible con-
traception in adolescents. Studies in women suggest neither
levonorgestrel-releasing intrauterine systems86 nor levonorgestrel
intrauterine devices87 to be associated with skeletal losses. The
impact on bone accrual in adolescents should be investi-
gated. However, the data that are available are encouraging and
suggest the skeletal effects of these implants and intrauterine
devices are less than that associated with DMPA.
Calcium and Vitamin D
Nutritional variables are important modifiable factors that
impact bone health. Over 99% of the body’s calcium is found
in skeletal stores, serving as a reserve in the face of deficiency
and playing an essential role in calcium homeostasis.88 Vitamin
D optimizes intestinal calcium absorption and therefore, affects
bone mineralization.89 Traditionally, supplementation with these
2 nutrients has been the mainstay of osteoporosis prevention.
A 6-year longitudinal assessment of calcium intake on bone
in a large diverse study cohort of 1743 children found that
dietary calcium had a positive effect, after adjustment for age,
height velocity, and physical activity, on bone accrual at the
lumbar spine in nonblack females90 with no effect on other
ethnic groups or in males. In a recent review,91 of 9 random-
ized controlled trials (RCTs), all but one found small (1%-
5%) gains, associated with oral calcium, on bone accrual by
DXA. Only 4 of the RCTs, however, used adjustment for body
size.92-94 This is noteworthy as longitudinal growth compli-
cates interpretation of changes in bone mass and density
variables.
Vitamin D is another important nutrient for bone health.
Since 2000, 8 RCTs have been conducted, with daily vitamin
D doses ranging from 200 to 2000 IU/day and have targeted
females ages, 10 and 17 years95-102 and males, ages 11-63
years.95,101 Of note, the mean baseline serum 25-hydroxyvitamin
D concentration for all RCTs was between 18 and 48 nmol/L
(45 and 120 ng/mL),91 which is lower than the 50 nmol/L
(20 ng/mL) accepted threshold for vitamin D sufficiency.103 Four
RCTs conducted in Lebanon, Finland, China, and the United
Kingdom provide evidence to support the effects of vitamin
D supplementation on childhood and adolescent bone mineral
accrual to improve hip BMC in females only. In subgroup analy-
ses, the vitamin D effect was more pronounced in prepuber-
tal or early pubertal vs postpubertal girls, as well as in those
with a lower compared with higher baseline 25-hydroxyvitamin
D. Therefore, there may be a “critical window” during which
the skeleton is most receptive to the effects of vitamin D.
Nutritional Deprivation
Chronic illness affecting absorption of nutrients such as in-
flammatory bowel disease or celiac disease may be associated
with malnutrition-induced growth failure and abnormal bone
The Determinants of Peak Bone Mass
WORKSHOP/SYMPOSIUM SUMMARY
accrual. Anorexia nervosa, another form of nutritional depri-
vation, is associated with decreased fat, muscle, and bone mass
and a cascade of hormonal alterations.104,105 Teenage girls with
anorexia nervosa have reduced aBMD,106 suppressed bone for-
mation and resorption markers,107 and reduced bone accrual,
especially at the lumbar spine.108,109 Some studies suggest that
bone structural variables are altered in this disease that may
explain the increased fracture risk.110 Adolescent boys with an-
orexia nervosa also have lower aBMD at multiple skeletal sites.111
Importantly, fracture rate is increased among these adoles-
cents, potentially as high as 7-fold.112 Given the high inci-
dence of eating disorders among contemporary youth, clinical
trials are underway to identify pharmacologic strategies to
counter bone loss in these young patients.113
Future Directions
This National Institutes of Health conference demonstrated the
considerable progress made over the last decade to under-
stand the complex factors controlling skeletal growth and ac-
quisition of PBM. Numerous studies have demonstrated that
the pace of bone accrual varies by sex, race, and maturation.
The discovery that bone accrual tracks over time, in a similar
manner to linear growth, has important implications for its
potential long-term impact on bone health into adulthood. Over
one-half the skeleton is laid down during the teenage years,
when onset of chronic disease or unhealthy lifestyle habits may
impede optimal bone accrual. Limited studies using periph-
eral quantitative CT have demonstrated that gains in appen-
dicular cortical bone density and thickness continue into the
third decade of life, even though trabecular density may decline
over the same interval.10,114-116 The impact of these opposing
changes on bone strength is not known.
In spite of major scientific advances, the burden of care as-
sociated with osteoporosis and fragility fractures continues to
grow at a rate exceeding that of inflation. There are multiple
bases for this disparity, including our escalating elderly popu-
lation and the relative ineffectiveness of treatments at the later
stages of disease. To overcome current treatment limitations
and effectively reduce the costs associated with osteoporosis,
research should be geared toward optimizing bone accrual in
childhood. PBM is one of the most important factors in pre-
venting osteoporosis; epidemiologic studies suggest that a 10%
increase in PBM at the population level would decrease the
risk of fracture later in life by 50%.117
Pediatricians who care for patients with chronic illness need
more information on how various disorders and their thera-
pies affect bone mass acquisition. Primary bone disorders in
children are relatively uncommon. In contrast, unhealthy life-
style habits or acquired disorders such as asthma, inflamma-
tory bowel disease, or malignancy, and the pharmacologic agents
used to treat them represent a more frequent threat to optimal
bone accrual and PBM. In the coming years, the research focus
should shift to the impact of risk factors and interventions on
peak bone strength (as opposed to bone mass or density).
Longitudinal studies in children with diabetes mellitus, an-
orexia nervosa, malignancy, and other chronic disorders are
265
THE JOURNAL OF PEDIATRICS • www.jpeds.com
needed to better understand the paracrine and endocrine effects
of fat and muscle on PBM. Observations from animal models
may also provide insight into human physiology.45 Longitu-
dinal studies using high-resolution modalities are needed to
determine how genetic, physiologic, and lifestyle factors in-
fluence trabecular and cortical compartments, bone geom-
etry and microarchitecture, and ultimately, bone strength. What
are the factors directing this development? When is peak bone
strength achieved and how long is it maintained? These studies
are necessary to develop strategies to maximize peak bone
strength, to intervene in disorders that impede skeletal devel-
opment, and to determine how long these interventions should
last. How long is the window of opportunity to reverse or ame-
liorate deficits in bone? Which pharmacologic agents might
counteract inflammation, immobilization, and other threats
to acquisition of bone strength? What is the optimal
anticatabolic agent(s), including dose and duration of use? Is
there an anabolic agent that is safe for growing patients? What
is the role for nonpharmacologic interventions such as me-
chanical stimulation? Are the effects of anabolic agents used
during growth maintained into adulthood? The above knowl-
edge gaps can best be addressed through multidisciplinary col-
laborations. Multicenter studies have an important role in
pediatric clinical trials by enabling investigators to share knowl-
edge and resources and to provide larger numbers of chil-
dren of various ages from diverse backgrounds to assure more
accurate clinical information.
Lastly, there is a need to increase awareness among health
care providers regarding risk factors for bone fragility from
infancy through adolescence. Osteoporosis prevention should
begin at birth and pediatricians should be educated about strat-
egies to optimize bone acquisition. The robust DXA refer-
ence data generated by the NICHD-funded Bone Mineral
Density in Childhood Study, and the evidence that DXA pre-
dicts fractures in healthy children and adolescents1,29,40 and those
with chronic disease 59,118 represent important advances.
However, the utility of DXA is limited in the absence of an
evidence-based arsenal of strategies to optimize bone mass and
strength. Research support for pediatric bone health has lagged
far behind the support for investigations of osteoporosis in
adults. The optimization of PBM has lifelong health benefits
and warrants significant investment in this research. ■
We acknowledge the important contributions of the workshop speak-
ers: Kathleen Janz, EdD, Ron Rosenfeld, MD (serves as a consultant for
OPKO Health Inc, Novo Nordisk, Pfizer, Ferring, Merck, Ascendis,
Versartis, and Genexine), Gerard Karsenty, MD, Heidi Kalkwarf, PhD,
Madhusmita Misra, MD, Connie Weaver, PhD (receives funding from
the Alliance of Potato Research and Education), Richard Lewis, PhD,
Joan Lappe, PhD, Jin-Ran Chen, PhD, and Struan Grant, PhD. We also
thank Taylor Wallace, PhD, for his support in all aspects of the meet-
ing’s planning and execution and for the generous support of the Na-
tional Osteoporosis Foundation.
Submitted for publication Jul 14, 2016; last revision received Aug 19, 2016;
accepted Sep 26, 2016
Reprint requests: Catherine M. Gordon, MD, MSc, Cincinnati Children’s
Hospital Medical Center, 3333 Burnet Ave, MLC 4000, Cincinnati, OH 45229.
E-mail: catherine.gordon@cchmc.org
266
Volume 180
References
1. Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA,
et al. Revised reference curves for bone mineral content and areal bone
mineral density according to age and sex for black and non-black chil-
dren: results of the bone mineral density in childhood study. J Clin
Endocrinol Metab 2011;96:3160-9.
2. 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 accrual study. J Bone Miner Res 1999;14:1672-9.
3. Looker AC, Borrud LG, Hughes JP, Fan B, Shepherd JA, Melton L Jr.
Lumbar spine and proximal femur bone mineral density, bone mineral
content, and bone area: United States, 2005-2008. Vital Health Stat
2012;11:1-132.
4. Kelly T, Wilson KE, Heymsfield SB. Dual energy x-ray absorptiometry
body composition reference values from NHANES. PLoS ONE
2009;4:e7038.
5. Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, Kreiger N, et al.
Peak bone mass from longitudinal data: implications for the preva-
lence, pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res
2010;25:1948-57.
6. Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR, Kimmel
DB. Bone gain in young adult women. JAMA 1992;268:2403-8.
7. Kindblom JM, Lorentzon M, Norjavaara E, Hellqvist A, Nilsson S,
Mellström D, et al. Pubertal timing predicts previous fractures and BMD
in young adult men: the GOOD study. J Bone Miner Res 2006;21:
790-5.
8. Nilsson M, Ohlsson C, Mellström D, Lorentzon M. Previous sport ac-
tivity during childhood and adolescence is associated with increased cor-
tical bone size in young adult men. J Bone Miner Res 2009;24:125-33.
9. Rudäng R, Darelid A, Nilsson M, Nilsson S, Mellström D, Ohlsson C,
et al. Smoking is associated with impaired bone mass development in
young adult men: a 5-year longitudinal study. J Bone Miner Res
2012;27:2189-97.
10. Riggs B, Melton LJ, Robb RA, Camp JJ, Atkinson EJ, McDaniel L, et al.
A population-based assessment of rates of bone loss at multiple skel-
etal sites: evidence for substantial trabecular bone loss in young adult
women and men. J Bone Miner Res 2008;23:205-14.
11. Khosla SS, Melton LJ 3rd, Achenbach SJ, Oberg AL, Riggs BL. Hor-
monal and biochemical determinants of trabecular microstructure at the
ultradistal radius in women and men. J Clin Endocrinol Metab
2006;91:885-91.
12. Wren TA, Kim P, Janicka A, Sanchez M, Gilsanz V. Timing of peak bone
mass: discrepancies between CT and DXA. J Clin Endocrinol Metab
2007;92:938-41.
13. Krall EA, Dawson-Hughes B. Heritable and life-style determinants of bone
mineral density. J Bone Miner Res 1993;8:1-9.
14. Bachrach LK, Hastie T, Wang MC, Narasimhan B, Marcus R. Bone
mineral acquisition in healthy Asian, Hispanic, black, and Caucasian
youth: a longitudinal study. J Clin Endocrinol Metab 1999;84:4702-12.
15. Seeman EE, Hopper JL, Bach LA, Cooper ME, Parkinson E, McKay J,
et al. Reduced bone mass in daughters of women with osteoporosis. N
Engl J Med 1989;320:554-8.
16. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Pre-
diction of bone density from vitamin D receptor alleles. Nature
1994;367:284-7.
17. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced
bone density and osteoporosis associated with a polymorphic Sp1 binding
site in the collagen type I alpha 1 gene. Nat Genet 1996;14:203-5.
18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High
bone density due to a mutation in LDL-receptor-related protein 5.
N Engl J Med 2002;346:1513-21.
19. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, et al.
A mutation in the LDL receptor-related protein 5 gene results in the
autosomal dominant high-bone-mass trait. Am J Hum Genet 2002;70:11-
9.
Gordon et al
January 2017
20. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani
EE, et al. Genome-wide meta-analysis identifies 56 bone mineral density
loci and reveals 14 loci associated with risk of fracture. Nat Genet
2012;44:491-501.
21. Mitchell JA, Chesi A, Elci O, McCormack SE, Kalkwarf HJ, Lappe JM,
et al. Genetics of bone mass in childhood and adolescence: effects of sex
and maturation interactions. J Bone Miner Res 2015;30:1676-83.
22. Chesi A, Mitchell JA, Kalkwarf HJ, Bradfield JP, Lappe JM, McCor-
mack SE, et al. A trans-ethnic genome-wide association study identi-
fies gender-specific loci influencing pediatric aBMD and BMC at the distal
radius. Hum Mol Genet 2015;24:5053-9.
23. Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, et al.
Whole-genome sequencing identifies EN1 as a determinant of bone
density and fracture. Nature 2015;526:112-7.
24. Mitchell JA, Chesi A, McCormack SE, Roy SM, Cousminer DL, Kalkwarf
HJ, et al. Rare EN1 variants and pediatric bone mass. J Bone Miner Res
2016;31:1513-7.
25. Warrington NM, Kemp JP, Tilling K, Tobias JH, Evans DM. Genetic vari-
ants in adult bone mineral density and fracture risk genes are associ-
ated with the rate of bone mineral density acquisition in adolescence.
Hum Mol Genet 2015;24:4158-66.
26. Gilsanz VV, Boechat MI, Gilsanz R, Loro ML, Roe TF, Goodman WG.
Gender differences in vertebral sizes in adults: biomechanical implica-
tions. Radiology 1994;190:678-82.
27. Jones IE, Williams SM, Dow N, Goulding A. How many children remain
fracture-free during growth? A longitudinal study of children and
adolescents participating in the Dunedin Multidisciplinary Health and
Development Study. Osteoporos Int 2002;13:990-5.
28. Rauch F. The dynamics of bone structure development during puber-
tal growth. J Musculoskelet Neuronal Interact 2012;12:1-6.
29. Wren TA, Shepherd JA, Kalkwarf HJ, Zemel BS, Lappe JM, Oberfield S,
et al. Racial disparity in fracture risk between white and nonwhite chil-
dren in the United States. J Pediatr 2012;161:1035-40.
30. Kalkwarf HJ, Laor T, Bean JA. Fracture risk in children with a forearm
injury is associated with volumetric bone density and cortical area (by
peripheral QCT) and areal bone density (by DXA). Osteoporos Int
2011;22:607-16.
31. Gilsanz V, Perez FJ, Campbell PP, Dorey FJ, Lee DC, Wren TA. Quan-
titative CT reference values for vertebral trabecular bone density in
children and young adults. Radiology 2009;250:222-7.
32. Gilsanz VV, Roe TF, Mora S, Costin G, Goodman WG. Changes in ver-
tebral bone density in black girls and white girls during childhood and
puberty. N Eng J Med 1991;325:1597-600.
33. Gilsanz VV, Kovanlikaya A, Costin G, Roe TF, Sayre J, Kaufman F. Dif-
ferential effect of gender on the sizes of the bones in the axial and
appendicular skeletons. J Clin Endocrinol Metab 1997;82:1603-7.
34. Moro MM, van der Meulen MC, Kiratli BJ, Marcus R, Bachrach LK,
Carter DR. Body mass is the primary determinant of midfemoral bone
acquisition during adolescent growth. Bone 1996;19:519-26.
35. Lee DC, Gilsanz V, Wren TA. Limitations of peripheral quantitative com-
puted tomography metaphyseal bone density measurements. J Clin
Endocrinol Metab 2007;92:4248-53.
36. van der Meulen MC, Beaupré GS, Carter D. Mechanobiologic influ-
ences in long bone cross-sectional growth. Bone 1993;14:635-42.
37. Bonjour JP, Chevalley T. Pubertal timing, bone acquisition, and risk of
fracture throughout life. Endocr Rev 2014;35:820-47.
38. Gilsanz V, Chalfant J, Kalkwarf H, Zemel B, Lappe J, Oberfield S, et al.
Age at onset of puberty predicts bone mass in young adulthood. J Pediatr
2011;158:100-5.
39. Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Hangartner
TN, et al. Tracking of bone mass and density during childhood and ado-
lescence. J Clin Endocrinol Metab 2010;95:1690-8.
40. Wren TA, Kalkwarf H, Zemel BS, Lappe JM, Oberfield S, Shepherd JA,
et al. Longitudinal tracking of dual-energy x-ray absorptiometry bone
measures over 6 years in children and adolescents: persistence of low bone
mass to maturity. J Pediatr 2014;164:1280-5.
41. Kim KH, Lee CM, Park SM, Cho B, Chang Y, Park SG, et al. Second-
hand smoke exposure and osteoporosis in never-smoking postmeno-
The Determinants of Peak Bone Mass
WORKSHOP/SYMPOSIUM SUMMARY
pausal women: the Fourth Korea National Health and Nutrition
Examination Survey. Osteoporos Int 2013;24:523-32.
42. Wren TA. Assessing bone accrual in cerebral palsy: new longitudinal data
and future needs. Dev Med Child Neurol 2015;57:990-1.
43. Nilsson O, Marino R, De Luca F, Phillip M, Baron J. Endocrine regu-
lation of the growth plate. Horm Res 2005;64:157-65.
44. Wojcik M, Dolezal-Oltarzewska K, Janus D, Drozdz D, Sztefko K, Starzyk
JB. FGF23 contributes to insulin sensitivity in obese adolescents – pre-
liminary results. Clin Endocrinol (Oxf) 2012;77:537-40.
45. Karsenty G, Ferron M. The contribution of bone to whole-organism
physiology. Nature 2012;481:314-20.
46. Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, et al. Matrix IGF-1 main-
tains bone mass by activation of mTOR in mesenchymal stem cells. Nat
Med 2012;18:1095-101.
47. Ge K. Epigenetic regulation of adipogenesis by histone methylation.
Biochim Biophys Acta 2012;1819:727-32.
48. Zhang X, Bailey SD, Lupien M. Laying a solid foundation for Manhat-
tan – ‘setting the functional basis for the post-GWAS era’. Trends Genet
2014;30:140-9.
49. Chen JR, Zhang J, Lazarenko OP, Kang P, Blackburn ML, Ronis MJ, et al.
Inhibition of fetal bone development through epigenetic down-
regulation of HoxA10 in obese rats fed high-fat diet. FASEB J
2012;26:1131-41.
50. Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and
the bone microenvironment: developmental, functional, and pathologi-
cal implications. Crit Rev Eukaryot Gene Expr 2009;19:109-24.
51. Griffith JF, Yeung DK, Antonio GE, Lee FK, Hong AW, Wong SY, et al.
Vertebral bone mineral density, marrow perfusion, and fat content in
healthy men and men with osteoporosis: dynamic contrast-enhanced MR
imaging and MR spectroscopy. Radiology 2005;236:945-51.
52. Reagan MR, Mishima Y, Glavey SV, Zhang Y, Manier S, Lu ZN. Inves-
tigating osteogenic differentiation in multiple myeloma using a novel
3D bone marrow niche model. Blood 2014;124:3250-9.
53. Ponrartana SS, Aggabao PC, Hu HH, Aldrovandi GM, Wren TA, Gilsanz
V. Brown adipose tissue and its relationship to bone structure in pedi-
atric patients. J Clin Endocrinol Metab 2012;97:2693-8.
54. Bredella MA, Gill CM, Rosen CJ, Klibanski A, Torriani M. Positive effects
of brown adipose tissue on femoral bone structure. Bone 2014;58:55-
8.
55. Leonard MB, Shults J, Wilson BA, Tershakovec AM, Zemel BS. Obesity
during childhood and adolescence augments bone mass and bone
dimensions. Am J Clin Nutr 2004;80:514-23.
56. Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression frac-
tures in pediatric patients with Crohn’s disease. Gastroenterology
1997;112:1710-3.
57. Helenius I, Remes V, Salminen S, Valta H, Mäkitie O, Holmberg C, et al.
Incidence and predictors of fractures in children after solid organ trans-
plantation: a 5-year prospective, population-based study. J Bone Miner
Res 2006;21:380-7.
58. Lentle B, Ma J, Jaremko JL, Siminoski K, Matzinger MA, Shenouda N,
et al. The radiology of vertebral fractures in childhood osteoporosis related
to glucocorticoid administration. J Clin Densitom 2016;19:81-8.
59. LeBlanc CM, Ma J, Talijaard M, Roth J, Scuccimarri R, Miettunen P, et al.
Incident vertebral fractures and risk factors in the first three years
following glucocorticoid initiation among pediatric patients with
rheumatic disorders. J Bone Miner Res 2015;30:1667-75.
60. Cummings EA, Ma J, Fernandez C, Halton J, Alos N, Miettunen PM,
et al. Incident vertebral fractures in children with leukemia during the
four years following diagnosis. J Clin Endocrinol Metab 2015;100:3408-
17.
61. Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 dia-
betes is associated with an increased risk of fracture across the life span:
a population-based cohort study using The Health Improvement Network
(THIN). Diabetes Care 2015;38:1913-20.
62. Burnham JM, Shults J, Weinstein R, Lewis JD, Leonard MB. Child-
hood onset arthritis is associated with an increased risk of fracture: a
population based study using the General Practice Research Database.
Ann Rheum Dis 2006;65:1074-9.
267
THE JOURNAL OF PEDIATRICS • www.jpeds.com
63. Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone.
Ann N Y Acad Sci 2002;966:73-81.
64. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of
osteoblastogenesis and promotion of apoptosis of osteoblasts and os-
teocytes by glucocorticoids. Potential mechanisms of their deleterious
effects on bone. J Clin Invest 1998;102:274-82.
65. Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, et al.
Glucocorticoids and the Osteoclast. Ann N Y Acad Sci 2007;1116:335-
9.
66. Schakman O, Kalista S, Barbé C, Loumaye A, Thissen JP. Glucocorticoid-
induced skeletal muscle atrophy. Int J Biochem Cell Biol 2013;45:2163-
72.
67. Tsampalieros A, Berkenstock MK, Zemel BS, Griffin L, Shults J, Burnham
JM, et al. Changes in trabecular bone density in incident pediatric Crohn’s
disease: a comparison of imaging methods. Osteoporos Int 2014;25:1875-
83.
68. Loke Y, Gilbert D, Thavarajah M, Blanco P, Wilson AM. Bone mineral
density and fracture risk with long-term use of inhaled corticosteroids
in patients with asthma: systematic review and meta-analysis. BMJ Open
2015;5:e008554.
69. Szefler S, Weiss S, Tonascia J. Long-term effects of budesonide
or nedocromil in children with asthma. The Childhood Asthma
Management Program Research Group. N Engl J Med 2000;343:1054-
63.
70. Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger
RS, et al. Effect of inhaled glucocorticoids in childhood on adult height.
N Engl J Med 2012;367:904-12.
71. Pruteanu AI, Pruteanu A, Chauhan BF, Zhang L, Prietsch SO, Ducharme
FM. Inhaled corticosteroids in children with persistent asthma: dose-
response effects on growth. Evid Based Child Health 2014;9:931-1046.
72. Gunter K, Baxter-Jones A, Mirwald RL, Almstedt H, Fuller A, Durski
S, et al. Jump starting skeletal health: a 4-year longitudinal study as-
sessing the effects of jumping on skeletal development in pre and circum
pubertal children. Bone 2008;42:710-8.
73. Gunter KK, Baxter-Jones AD, Mirwald RL, Almstedt H, Fuchs RK, Durski
S, et al. Impact exercise increases BMC during growth: an 8-year lon-
gitudinal study. J Bone Miner Res 2008;23:986-93.
74. Gunter KB, Almstedt HC, Janz KF. Physical activity in childhood may
be the key to optimizing lifespan skeletal health. Exerc Sport Sci Rev
2012;40:13-21.
75. Warden SJ, Mantila Roosa SM. Physical activity completed when young
has residual bone benefits at 94 years of age: a within-subject con-
trolled case study. J Musculoskelet Neuronal Interact 2014;14:239-43.
76. Warden SJ, Mantila Roosa SM, Kersh ME, Hurd AL, Fleisig GS, Pandy
MG, et al. Physical activity when young provides lifelong benefits to
cortical bone size and strength in men. Proc Natl Acad Sci USA
2014;111:5337-42.
77. Bogenschutz ED, Smith HD, Warden SJ. Midhumerus adaptation in fast-
pitch softballers and the effect of throwing mechanics. Med Sci Sports
Exerc 2011;43:1698-706.
78. Lloyd TT, Chinchilli VM, Johnson-Rollings N, Kieselhorst K, Eggli DF,
Marcus R. Adult female hip bone density reflects teenage sports-
exercise patterns but not teenage calcium intake. Pediatrics 2000;106:40-
4.
79. Polatti FF, Perotti F, Filippa N, Gallina D, Nappi RE. Bone mass and
long-term monophasic oral contraceptive treatment in young women.
Contraception 1995;51:221-4.
80. Warholm LL, Petersen KR, Ravn P. Combined oral contraceptives’ in-
fluence on weight, body composition, height, and bone mineral density
in girls younger than 18 years: a systematic review. Eur J Contracept
Reprod Health Care 2012;17:245-53.
81. Trémollieres F. Impact of oral contraceptive on bone metabolism. Best
Pract Res Clin Endocrinol Metab 2013;27:47-53.
82. Ziglar S, Hunter TS. The effect of hormonal oral contraception on ac-
quisition of peak bone mineral density of adolescents and young women.
J Pharm Pract 2012;25:331-40.
83. Gersten J, Hsieh J, Weiss H, Ricciotti NA. Impact of extended 30 mcg
EE with continuous low-dose EE and cyclic 20 mcg EE oral contracep-
268
Volume 180
tion on adolescent bone density: a randomized trial. J Pediatr Adolesc
Gynecol 2016;doi:10.1016/j.jpag.2016.05.012.
84. Walsh JS, Eastell R, Peel NF. Effects of depot medroxyprogesterone acetate
on bone density and bone metabolism before and after peak bone mass:
a case-control study. J Clin Endocrinol Metab 2008;93:1317-23.
85. Harel Z, Johnson CC, Gold MA, Cromer B, Peterson E, Burkman R, et al.
Recovery of bone mineral density in adolescents following the use of
depot medroxyprogesterone acetate contraceptive injections. Contra-
ception 2010;81:281-91.
86. Yang KY, Kim YS, Ji YI, Jung MH. Changes in bone mineral density of
users of the levonorgestrel-releasing intrauterine system. J Nippon Med
Sch 2012;79:190-4.
87. Bahamondes MV, Monteiro I, Castro S, Espejo-Arce X, Bahamondes L.
Prospective study of the forearm bone mineral density of long-term users
of the levonorgestrel-releasing intrauterine system. Human Reprod
2010;25:1158-64.
88. Abrams SA, Stuff JE. Calcium metabolism in girls: current dietary intakes
lead to low rates of calcium absorption and retention during puberty.
Am J Clin Nutr 1994;60:739-43.
89. Kitchin B, Morgan SL. Not just calcium and vitamin D: other nutri-
tional considerations in osteoporosis. Curr Rheumatol Rep 2007;9:85-
92.
90. Lappe JM, Watson P, Gilsanz V, Hangartner T, Kalkwarf H, Oberfield
S, et al. The longitudinal effects of physical activity and dietary calcium
on bone mass accrual across stages of pubertal development. J Bone Miner
Res 2015;30:156-64.
91. Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R. The
National Osteoporosis Foundation’s position statement on peak bone
mass development and lifestyle factors: a systematic review and imple-
mentation recommendations. Osteoporos Int 2016;27:1281-386.
92. Dibba BB, Prentice A, Ceesay M, Stirling DM, Cole TJ, Poskitt EM. Effect
of calcium supplementation on bone mineral accretion in gambian chil-
dren accustomed to a low-calcium diet. Am J Clin Nutr 2000;71:544-9.
93. Cameron MA, Paton LM, Nowson C, Margerison C, Frame M, Wark JD.
The effect of calcium supplementation on bone density in premenarcheal
females: a co-twin approach. J Clin Endocrinol Metab 2004;89:4916-
22.
94. Prentice A, Ginty F, Stear SJ, Jones SC, Laskey MA, Cole TJ. Calcium
supplementation increases stature and bone mineral mass of 16- to 18-
year-old boys. J Clin Endocrinol Metab 2005;90:3153-61.
95. Cheng SS, Lyytikäinen A, Kröger H, Lamberg-Allardt C, Alén M, Koistinen
A, et al. Effects of calcium, dairy product, and vitamin D supplemen-
tation on bone mass accrual and body composition in 10-12-y-old girls:
a 2-y randomized trial. Am J Clin Nutr 2005;82:1115-26.
96. Du XX, Zhu K, Trube A, Zhang Q, Ma G, Hu X, et al. School-milk in-
tervention trial enhances growth and bone mineral accretion in Chinese
girls aged 10-12 years in Beijing. Br J Nutr 2004;92:159-68.
97. Mølgaard CC, Larnkjaer A, Cashman KD, Lamberg-Allardt C, Jakobsen
J, Michaelsen KF. Does vitamin D supplementation of healthy Danish
Caucasian girls affect bone turnover and bone mineralization? Bone
2010;46:432-9.
98. Al-Shaar LL, Nabulsi M, Maalouf J, El-Rassi R, Vieth R, Beck TJ, et al.
Effect of vitamin D replacement on hip structural geometry in adoles-
cents: a randomized controlled trial. Bone 2013;56:296-303.
99. Viljakainen HT, Natri AM, Kärkkäinen M, Huttunen MM, Palssa A,
Jakobsen J, et al. A positive dose-response effect of vitamin D supple-
mentation on site-specific bone mineral augmentation in adolescent girls:
a double-blinded randomized placebo-controlled 1-year intervention.
J Bone Miner Res 2006;21:836-44.
100. Khadilkar AV, Sayyad MG, Sanwalka NJ, Bhandari DR, Naik S, Khadilkar
VV, et al. Vitamin D supplementation and bone mass accrual in un-
derprivileged adolescent Indian girls. Asia Pac J Clin Nutr 2010;19:465-
72.
101. Andersen RR, Mølgaard C, Skovgaard LT, Brot C, Cashman KD, Jakobsen
J, et al. Effect of vitamin D supplementation on bone and vitamin D
status among Pakistani immigrants in Denmark: a randomised double-
blinded placebo-controlled intervention study. Br J Nutr 2008;100:197-
207.
Gordon et al
January 2017
102. El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife
H, et al. Effect of vitamin D replacement on musculoskeletal param-
eters in school children: a randomized controlled trial. J Clin Endocrinol
Metab 2006;91:405-12.
103. Del Valle HB, Yaktine AL, Taylor CL, Ross A, eds. Dietary reference intakes
for calcium and vitamin D health. Washington (DC): National Acad-
emies Press (US); 2011.
104. Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA,
et al. Effects of oral dehydroepiandrosterone on bone density in young
women with anorexia nervosa: a randomized trial. J Clin Endocrinol
Metab 2002;87:4935-41.
105. Faje AA, Klibanski A. Body composition and skeletal health: too heavy?
Too thin? Curr Osteoporos Rep 2012;10:208-16.
106. Bachrach LK, Guido D, Katzman D, Litt IF, Marcus R. Decreased bone
density in adolescent girls with anorexia nervosa. Pediatrics 1990;86:440-
7.
107. Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A. The effects
of anorexia nervosa on bone metabolism in female adolescents. J Clin
Endocrinol Metab 1999;84:4489-96.
108. Soyka LA, Misra M, Frenchman A, Miller KK, Grinspoon S, Schoenfeld
DA, et al. Abnormal bone mineral accrual in adolescent girls with an-
orexia nervosa. J Clin Endocrinol Metab 2002;87:4177-85.
109. Divasta AD, Feldman H, Giancaterino C, Rosen CJ, Leboff MS, Gordon
CM. The effect of gonadal and adrenal steroid therapy on skeletal health
in adolescents and young women with anorexia nervosa. Metabolism
2012;61:1010-20.
110. DiVasta AD, Feldman HA, Beck TJ, LeBoff MS, Gordon CM. Does
hormone replacement normalize bone geometry in adolescents with an-
orexia nervosa? J Bone Miner Res 2014;29:151-7.
The Determinants of Peak Bone Mass
View publication stats
WORKSHOP/SYMPOSIUM SUMMARY
111. Misra M, Katzman DK, Cord J, Manning SJ, Mendes N, Herzog DB, et al.
Bone metabolism in adolescent boys with anorexia nervosa. J Clin
Endocrinol Metab 2008;93:3029-36.
112. Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Kilbanski A.
Mechanisms of osteoporosis in adult and adolescent women
with anorexia nervosa. J Clin Endocrinol Metab 1989;68:548-
54.
113. Donaldson A, Gordon CM. Musculoskeletal consequences of eating dis-
orders. Metabolism 2015;64:943-51.
114. Leonard MB, Elmi A, Mostoufi-Moab S, Shults J, Burnham J, Thayu M,
et al. Effects of sex, race, and puberty on cortical bone and the func-
tional muscle bone unit in children, adolescents, and young adults. J Clin
Endocrinol Metab 2010;95:1681-9.
115. Ohlsson C, Darelid A, Nilsson M, Melin J, Mellström D, Lorentzon M.
Cortical consolidation due to increased mineralization and endosteal con-
traction in young adult men: a five-year longitudinal study. J Clin
Endocrinol Metab 2011;96:2262-9.
116. Khosla SS, Riggs B, Atkinson E, Oberg A, McDaniel L, Holets M, et al.
Effects of sex and age on bone microstructure at the ultradistal radius:
a population-based noninvasive in vivo assessment. J Bone Miner Res
2006;21:124-31.
117. Bonjour JP, Chevalley T, Ferrari S, Rizzoli R. Peak bone mass and its
regulation. In: Glorieux F, Pettifor J, Jüppner H, eds. Pediatric bone:
biology and disease. 2nd ed. San Diego (CA): Academic Press; 2012.
p. 120.
118. Cummings EA, Ma J, Fernandez CV, Halton J, Alos N, Miettunen PM,
et al. Incident vertebral fractures in children with leukemia during the
four years following diagnosis. J Clin Endocrinol Metab 2015;100:3408-
17.
269