Hormonal Determinants and Disorders of Peak Bone Mass in Children1
Leslie A. Soyka,
Wesley P. Fairfield and
Anne Klibanski
Neuroendocrine Unit and the General Clinical Research Center
(W.P.F., A.K.), Massachusetts General Hospital and Harvard Medical
School, Boston, Massachusetts 02114; and Department of Pediatrics
(L.A.S.), University of Massachusetts Medical School, Worcester,
Massachusetts 01655
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Bulfinch 457, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail:
aklibanski{at}partners.org
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Introduction
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PEAK BONE MASS can be defined as the
maximal bone mineral density that is accrued during growth and
development plus subsequent consolidation that continues during early
adulthood (1). The precise age at which peak bone mineral
density is acquired is still unknown and may be site dependent. It is
generally accepted that maximal bone density is present during the
third to fourth decade, but this assumption is based upon data derived
from studies using densitometry techniques that are less precise than
newer methods. Normative data are derived primarily from
cross-sectional studies of adolescents and young adults, such as
cohorts of the National Health and Nutrition Examination Survey
(NHANES). Differences in absolute density depend on the various
techniques used for assessing bone density [i.e. single
photon absorptiometry, dual energy x-ray absorptiometry (DEXA),
quantitative computed tomography (QCT)] and differences using the same
method among different machines, emphasizing the importance of
methodology, including the type of machine used when referencing
normative databases. There are also ethnic differences in bone density,
with blacks reported as having higher bone density than whites. There
are gender differences in bone density during childhood and adolescence
due to differences in the timing of growth and puberty, resulting in
females reaching peak bone mass earlier than males, although bone
density values at peak bone mass are similar between the sexes. An
individuals height, bone size, and skeletal age may all impact bone
density values, particularly in growing children and adolescents. These
variables should be considered when assessing the normality of an
individuals bone density, but unfortunately current reference data do
not include information on these variables. More recent investigations
have suggested that peak bone mass may be attained as early as late
adolescence in the hip and spine (1). In healthy
adolescents, bone mass increases throughout childhood, with maximal
bone mass accrual occurring in early to midpuberty and slowing in late
puberty (2, 3, 4, 5). However, most published studies are
cross-sectional and do not include individuals in sufficient numbers
encompassing the entire age span of interest (i.e. teens to
fourth decade) followed prospectively to definitively determine the age
at which peak bone mass is attained. Longitudinal data from healthy
girls demonstrate that the gain in bone mass is most pronounced between
1114 yr of age and falls significantly after 16 yr of age and/or 2 yr
after menarche, as shown in Fig. 1
(4, 5). These data suggest that there is a critical window
in time to maximize bone density in early and midadolescence, and the
majority of bone mass will accumulate by late adolescence. It has been
shown in adult patients that each SD reduction in
bone density is associated with a doubling of fracture risk. In
children, as in adults, fracture rates have also been shown to be
higher in individuals with a lower bone mineral content
(6). Because an individuals bone density is determined
by peak bone density and the degree of later bone loss, an
understanding of the factors responsible for maximizing peak bone mass
is critical for preventing fractures in later life. In this review, the
factors that influence the attainment of peak bone mass, particularly
hormonal determinants and disorders, will be considered.

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Figure 1. Fig. 1. Gain in bone mass during adolescence.
Yearly increase in spine bone mineral content (L2-L4) during
adolescence in females ( ) and males (). (Reprinted with
permission from The Journal of Clinical Endocrinology &
Metabolism, 75:1062, 1992. Copyright © 1992 The
Endocrine Society. All rights reserved.)
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Genetic determinants of peak bone mass
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There are important genetic determinants of bone density, as
suggested by studies of twins and families (7, 8, 9), and the
specific inherited factors involved are under investigation.
Polymorphisms in the gene encoding the 1,25-dihydroxyvitamin D receptor
may in part underlie genetic variation in bone mass
(10, 11, 12). Studies examining the relationship between
vitamin D receptor (VDR) polymorphisms and bone density have provided
conflicting results, and a meta-analysis of studies in adults suggest
that the VDR genotype makes a small contribution to observed bone
density (11). In contrast, in a genetically homogeneous
population of children, Sainz et al. reported that VDR
polymorphisms accounted for a significant (>1
SD) difference in femoral and vertebral bone
density between the homozygous recessive (aa, bb) and the
dominant (AA, BB) genotypes (12). These data
suggest that genotype may be of greater importance in predicting bone
density early in life before age- and gonadal steroid-related factors
affect bone mass. Studies in adults have suggested that calcium intake
may be related to VDR genotype and bone density (13, 14).
Similarly, in a study of prepubertal girls, dietary calcium intake
correlated with change in bone density in those with homozygous
dominant and heterozygous (BB and Bb) genotypes,
but not in those subjects with the homozygous recessive (bb)
genotype (15). These data suggest that VDR genotyping may
be one factor determining the variation in bone density in children and
could potentially be helpful in predicting benefits from calcium
supplementation. Several other genetic loci that may play an important
role in peak bone mass accrual are under investigation. A polymorphism
in the Sp1 binding site of the collagen type 1
1 gene (COLIA1) is
one such candidate gene. This polymorphism is associated with decreased
spinal bone density in prepubertal children with heterozygous (s) and
homozygous recessive genotypes compared with the dominant (S) genotype,
similar to findings in adult patients (16). The
insulin-like growth factor I (IGF-I) gene is another important
candidate due to its significant effects as a bone trophic hormone,
although its role in peak bone mass has not been determined. The
important role of estrogen in both male and female bone maturation and
density suggests that estrogen receptor gene polymorphisms may also
influence bone density. The XbaI restriction site of the
estrogen receptor gene has been found to be related to bone density in
studies of both adolescent boys and premenopausal young women
(17, 18). Therefore, a growing number of candidate genes
have been identified that may be important determinants of peak bone
mass. Genetic studies in large populations with well characterized
phenotypes will be critical in assessing the impact of these factors on
peak bone mass.
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Hormonal determinants of peak bone mass
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The presence of osteopenia in patients with abnormal pubertal
development demonstrates the critical impact of pubertal hormone
changes on normal bone mineral acquisition. Adult patients with
hypogonadotropic hypogonadism commonly have osteopenia, resulting from
inadequate bone mineral accrual during puberty and/or abnormal bone
remodeling after puberty as shown in Fig. 2
(19). Adult men with a
history of constitutional delay of puberty have been reported to have
decreased bone mass (20), although data are conflicting
(21). Androgen receptors are located in growth plate
osteoblasts in males and females and are thought to mediate the
anabolic effects of testosterone in bone (22). However,
estrogen appears to be the more important sex steroid involved in
skeletal maturation and mineralization, although it is unknown whether
estradiol acts directly on bone or indirectly by stimulating other
mediators of bone growth (2, 3, 4, 5, 23, 24). There are reports
of rare patients with aromatase deficiency or estrogen receptor defects
resulting in complete resistance; these subjects have a phenotype that
includes tall stature and normal secondary sexual characteristics.
However, these patients have osteoporosis and skeletal immaturity in
adulthood despite normal androgen levels (25, 26, 27).
Treatment of a male patient with aromatase deficiency with estrogen
resulted in dramatic improvement in bone density and completion of
skeletal maturation, indicating the critical role of estrogen in
skeletal mineralization and maturation (see Fig. 3
) (28). In young women, a
high incidence of metatarsal stress fractures has been reported in
ballet dancers, particularly in those with late age of menarche and
long periods of secondary amenorrhea as shown in Fig. 4
(29). In female
adolescents, lower lumbar bone density is seen in amenorrheic teens
compared with those with normal menses, but the decrease in bone
density is generally not significant when bone density is controlled
for body weight (30, 31, 32). These data suggest that
nutritional status, including nutritionally dependent growth factors,
and gonadal status may be independent determinants of bone density.
Estrogen deficiency, particularly in the setting of undernutrition, can
lead to permanent osteopenia. Bachrach et al. found that one
third of females who recover from anorexia nervosa during adolescence
have persistent osteopenia (33). Women with anorexia
nervosa who have disease onset during adolescence have lower spinal
bone density than those with disease onset in adulthood
(34). These data are consistent with the hypothesis that
there may be a narrow window in time during adolescence in which
maximal bone mass accrues. Prolonged gonadal steroid deficiency during
this time will probably have a permanent impact on adult bone mass.

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Figure 2. Fig. 2. Reduced bone density in idiopathic
hypogonadotropic hypogonadism. Spinal trabecular bone density compared
with age in 23 men with idiopathic hypogonadotropic hypogonadism. ,
Patients with fused epiphyses; , patients with open epiphyses. The
solid line indicates the mean spinal bone density in normal
adult men, whereas the dotted line indicates ±1
SD from the mean. The stippled bar indicates the
fracture threshold. (Reprinted with permission from Annals of
Internal Medicine, 106:358, 1987. Copyright © 1987
American College of Physicians.)
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Figure 3. Increased bone density in a man with
aromatase deficiency during estrogen therapy. The percentage increase
from baseline values is shown for the lumbar spine. Specific
measurements were made at baseline, 12, 30, and 36 months. (Reprinted
with permission from New England Journal of Medicine,
339:602, 1998. Copyright © 1998 Massachusetts Medical
Society. All rights reserved.)
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Figure 4. Relationship between age at menarche and
the percentage of young dancers (n = 75) with fractures and stress
fractures. (Reprinted with permission from New England Journal of
Medicine, 314:1351, 1986. Copyright © 1986
Massachusetts Medical Society. All rights reserved.)
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Levels of GH and IGF-I increase dramatically during normal puberty,
augmented by increasing levels of sex steroids. Much of the GH action
on bone is mediated through IGF-I. IGF-I functions in an endocrine and
autocrine/paracrine manner as a bone trophic hormone that positively
affects bone growth and bone turnover by stimulating osteoblasts,
collagen synthesis, and longitudinal bone growth (35, 36, 37).
Therefore, in GH-deficient children, bone density and markers of bone
formation are significantly reduced and improve with recombinant human
GH treatment (38). Adult patients with untreated pubertal
GH deficiency have reduced bone mass compared with treated patients
(39). Therefore, GH deficiency during adolescence may lead
to persistent osteopenia in adulthood.
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Nutritional factors
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Body weight is a major determinant of bone density in
children and adolescents. Studies in healthy normal weight and obese
children and adolescents demonstrate that lean body mass correlates
with total and lumbar bone mineral content (40).
Adolescents with nutritional disorders are often also hypogonadal,
making it difficult to determine the impact of these individual factors
on bone density. In adolescents with nutritional disorders such as
anorexia nervosa, the relationship between body mass and bone density
is not present (41, 42), suggesting that multiple factors
probably interact. In adolescent anorexia nervosa patients there is an
imbalance in bone metabolism, with low bone formation uncoupled with
resorption, in association with low bone density (42).
IGF-I levels are reduced in these patients, probably due to combined
effects of GH resistance (43) in addition to reduced liver
IGF-I gene expression with undernutrition (37). Low bone
formation in adolescent girls with anorexia nervosa has been found to
correlate strongly with levels of IGF-I (42).
Calcium intake has been shown to correlate with bone density in healthy
children and adolescents. In a group of 151 healthy girls and boys,
715 yr old, Ruiz et al. reported that dietary calcium
intake was the most significant determinant of spinal bone density, and
that the majority of children with low spinal and femoral neck bone
density had low dietary calcium intake (44). Other studies
have found a small or negligible effect of dietary calcium on regional
bone density (3, 45). Dietary calcium requirements
increase substantially around the time of peak growth velocity and bone
mineral accrual (46). Dietary calcium supplementation has
been shown to improve bone density, but it is unclear whether the
effect is sustained once supplementation is stopped. A long-term
(3-yr), double blind, placebo-controlled trial of calcium
supplementation in identical twin pairs, 614 yr old, showed that
there was a significant effect of supplementation on radial and spinal
bone density in prepubertal subjects, but not in pubertal subjects
(47). A shorter term (18-month) trial did find a positive
effect of increasing calcium intake from below to above the recommended
daily allowance of calcium on bone density of the spine, but not of the
peripheral sites in adolescent girls (48). Whether calcium
or other micronutrient supplementation can lead to improvement in peak
bone mass remains unknown. Little is known regarding the definitive
role of these factors in younger patients. There is probably an
age-specific effect of many of these factors in the developing
skeleton; therefore, it is important to define the impact of these
variables on the development of bone density during childhood and
adolescence.
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Other determinants of peak bone mass
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Physical activity, particularly weight-bearing exercise, is
known to have a positive effect on bone density in children and
adolescents (3, 49). A study of 45 prepubertal gymnasts
showed increased bone density compared with controls, and the duration
of training correlated with bone density. Furthermore, the gymnasts had
a 3085% greater increase in areal bone density in the spine and legs
over 12 months than bone age-matched prepubertal controls. In addition,
a group of retired young adult female gymnasts had higher bone density
at all sites (z-score, 0.51.5) compared with age-, height-, and
weight-matched controls, suggesting a persistent beneficial effect of
prior physical activity (49). However, excessive exercise
during adolescence may lead to delayed puberty, amenorrhea, and low
bone density (50). Therefore, the timing, intensity, and
duration of the physical activity may determine whether it will have a
positive or negative effect on bone density.
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Disorders resulting in low peak bone mass
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Turner syndrome. Low bone density is seen in children,
adolescents, and adult patients with Turner syndrome, and an increased
incidence of wrist fractures has been reported. Although abnormalities
in gonadal steroids and GH secretion probably contribute to the
osteopenia in this disorder, abnormalities have also been reported in
prepubertal girls, suggesting an intrinsic bone defect. Bone metabolism
studies using surrogate markers and histomorphometric analysis in
children and adolescents with this disorder are consistent with a state
of low bone turnover. Deficits in bone density have been shown in both
cortical (radius) and trabecular (spine) bone. Data on bone density
reduction at the lumbar spine vary depending on whether values are in
reference to chronological or skeletal age, body mass index, or height
and whether patients have received GH or estrogen treatment
(51). In untreated young girls, 413 yr old, the largest
study, in 78 patients, demonstrated normal spinal bone density when
they were matched for bone age and height with prepubertal controls,
and normal radial bone density when they were matched for height
despite a significantly increased rate of wrist fractures
(52). The investigators suggest that the increase in
observed wrist fracture rate may be due to either an intrinsic
structural defect or an increased rate of falling in these girls. Other
studies have shown reduced bone density in these patients, but did not
account for the variables (height, bone age, and body size) that may
impact on bone density measurements. Of these factors, accounting for
height is particularly important in this patient group due to their
significant short stature and associated reduced bone size. Because the
most commonly used method of bone density measurement, DEXA, provides
an areal density measurement rather than a true volumetric density,
individuals with bigger bones will have a greater reported bone density
value. Methods to account for bone size when assessing bone density
include the use of QCT or calculated volumetric bone density
measurements (45) and are particularly useful in these
patients.
Bone density and fracture risk in Turner patients are dependent upon
treatment with GH and/or estrogen. In young Turner patients treated
with GH, lumbar bone density or bone mineral apparent density is normal
compared with that in healthy girls matched for bone age, height, and
pubertal stage (53). In small, short-term studies, bone
density increases with estrogen treatment (54), but there
are no long term studies to determine whether estrogen therapy improves
peak bone mass and, if so, what the timing and dosing requirements of
estrogen administration are. The importance of estrogen deficiency is
suggested by several studies in adult women with delayed exposure to
estrogen. Radial bone density has been negatively correlated with age
at initiation of estrogen replacement in adult Turner women (age,
2050 yr) who did not enter puberty spontaneously (55). A
significant reduction in spinal bone density has been shown in 40 women
with Turner syndrome compared with healthy women of similar height and
weight. The women with primary amenorrhea, indicating a longer duration
of estrogen deficiency, had a significantly higher rate of fractures
compared with women who had some spontaneous menses. Approximately 50%
of the women with Turner syndrome had sustained fractures at typical
postmenopausal osteoporotic sites, including the vertebrae, femoral
neck, and wrist (56). Adult women with Turner syndrome in
whom estrogen therapy was delayed or insufficient had significantly
lower lumbar bone density than women who had received estrogen
replacement beginning at 1618 yr of age. Both groups had
significantly reduced bone density compared with normal women, but
limitations of the study include lack of information on both height and
bone age in the untreated patients (57). Overall, these
data suggest that a prolonged duration of estrogen deficiency,
particularly during adolescence, probably contributes to low bone
density in women with Turner syndrome.
Klinefelter syndrome. It is not known whether the chromosomal
defect in Klinefelter syndrome (XXY) has an effect on bone density
independent of gonadal steroid deficiency. There are data to suggest,
however, that the characteristic long bone abnormality, with increased
lower body segment, is present before puberty and therefore is probably
attributable to the underlying genetic defect rather than androgen
deficiency (58). Young hypogonadal men with Klinefelter
syndrome are at risk for low bone density, although bone density
measurements in these patients have not been widely published. Horowitz
et al. (59) reported significantly decreased
forearm bone density in association with low bone formation and high
resorption assessed by bone turnover markers in 22 adult men (1968 yr
old) with Klinefelter syndrome. There was no significant difference in
forearm bone density between testosterone-treated or untreated
patients; however, there was a significant relationship between bone
density and serum testosterone levels. Sites composed of primarily
trabecular bone, which are generally more affected in hypogonadal
states, have not been examined in these studies. Therefore, although
early diagnosis and treatment of androgen deficiency is recommended,
site-specific data regarding testosterone administration on bone
density are lacking.
Gonadal steroid insufficiency. Apart from known genetic
syndromes, permanent or transient estrogen and testosterone deficiency
during adolescence due to a number of causes (Table 1
) can lead to reduced bone mass. Young
adults with hypogonadotropic hypogonadism have both reduced cortical
and trabecular bone density. Finkelstein et al. found that
in 23 such young adult men, 70% had a radial bone density less than 2
SD below the normal mean, and 35% had spinal
bone density below the fracture threshold (19). Patients
had a similar reduction in bone density regardless of whether they had
attained epiphyseal fusion, suggesting abnormal pubertal bone mineral
accretion rather than accelerated bone loss alone. Treatment of
patients with hypogonadotropic hypogonadism by maintenance of normal
adult levels of testosterone resulted in an improvement in bone
density. Patients with immature epiphyses had a greater response to
treatment than those with mature epiphyses, but neither group attained
normalization of bone density after an average of 2 yr
(60).
Estrogen deficiency in female adolescents is associated with reduced
bone density. There are multiple possible causes of estrogen deficiency
in female adolescents. Hypothalamic amenorrhea due to excessive
exercise or stress is the most common cause in otherwise healthy
adolescents, particularly athletes. Although weight-bearing activities
during adolescence can have positive effects on increasing bone
density, excess exercise can lead to low weight and amenorrhea. As
estrogen deficiency and low weight often occur together, their
independent effects on bone density are difficult to determine. Several
investigators have reported that teenage and adult amenorrheic patients
have reduced bone density compared with eumenorrheic controls. Warren
et al. found that among a large group of professional ballet
dancers, 1329 yr old, the age at menarche highly correlated with the
occurrence of stress fractures, and those with stress fractures had a
significantly later age of menarche than those without fractures
(31). However, when bone density measurements were
controlled for weight, much of the difference between amenorrheic and
eumenorrheic subjects became insignificant (30, 31, 32). In
the young ballet dancers reported by Warren et al., lumbar
spine bone density was not significantly different between age- and
weight-matched amenorrheic and eumenorrheic dancers when controlled for
weight; however, metatarsal bone density remained significantly lower
in the amenorrheic group. Therefore, nutritional status may mediate the
site-specific effects of estrogen deficiency on bone density.
Estrogen/progesterone treatment has been shown in a prospective study
of 24 young women runners (age, 1428 yr) to significantly improve
spinal and total bone density compared with that in
medroxyprogesterone- and placebo-treated subjects (61).
The effects of treatment with hormone replacement to improve bone
formation in adolescent girls with estrogen deficiency has not been
evaluated; therefore, it remains unknown what dose, timing, and
duration of therapy may be beneficial.
A delayed timing of puberty may be an independent predisposing factor
for reduced peak bone mass. Male patients with constitutional delay of
growth and pubertal maturation have been reported to have significantly
reduced bone mass during adulthood. Lumbar, femoral neck, and radial
bone density has been found to be 2 SD or greater below the
normal mean in one third of young adult men with a history of delayed
puberty who were not given androgen treatment during adolescence
(20). Significant differences in regional bone density
were present even when bone size was accounted for with calculated
volumetric bone density (62). Other investigators found a
similar reduction in areal bone density in young adult men with a
history of constitutional delay. However, there was no difference in
calculated volumetric bone density between patients and controls, and
there were no differences among those treated with testosterone, the
nonaromatizable androgen oxandrolone, or untreated patients
(21). Possible reasons for the discrepancy between these
data include the inability to adequately account for bone size with
calculated methods from DEXA measurements and the inclusion of patients
with various etiologies and duration of abnormal growth and
development. A further prospective study of this patient group
throughout adolescence until peak bone mass is attained is needed to
determine whether treatment with androgens in adolescent boys with
constitutionally delayed puberty is required to achieve normal bone
density. In female patients, data similarly suggest that a delay in the
normal timing of pubertal development results in reduced bone mass. An
increased fracture rate has been reported in young women with a history
of delayed menarche (29, 31). Women with anorexia who had
onset of the disorder during the teenage years have lower bone density
than those in whom the disorder developed in adulthood
(34) and, therefore, after the development of peak bone
mass. However, it is not known whether estrogen deficiency alone or
deficiency of other gonadal steroids (i.e. testosterone or
progesterone) or nutritional variables is most important during
development. Furthermore, the timing, dosage, and duration of estrogen
therapy needed to maximize peak bone mass are unknown.
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Other endocrine disorders
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GH deficiency. Untreated GH deficiency during childhood and
adolescence often leads to reduced peak bone mass. Adults with
untreated pubertal GH deficiency have reduced bone density at the
lumbar spine, femoral neck, and Wards triangle compared with treated
patients and normal controls (39). Kaufman et
al. studied 30 adult men with childhood-onset GH deficiency and
demonstrated a reduction of 2039% in cortical bone density (forearm)
and 919% in trabecular bone density (spine) (63). In a
larger study of 70 adult men with childhood-onset GH deficiency, one
third of patients had lumbar bone density 2 SD or
more below the normal mean (64). Low bone density
measurements may reflect reduced height and bone size in these
patients. Patients in whom volumetric bone density is measured by QCT
or estimated by calculated methods from DEXA measurements to correct
for bone size, however, also have been shown to have reduced spinal
bone density compared with age- and sex-matched reference data
(65, 66). Although a subset of patients studied had
received prior treatment with GH, the adequacy of treatment dosage and
timing has not been established. In children and adolescents with GH
deficiency, bone density and markers of bone formation are
significantly reduced and improve with recombinant GH treatment in
short-term studies (37, 67, 68). A 2-yr study of 38
treated GH-deficient children, 416.9 yr old, demonstrated increased
lumbar bone density by DEXA after 6 months of treatment but no
significant change in calculated volumetric bone density until after 2
yr of treatment. These data indicate that early changes in bone density
measurements may reflect changes in bone size, but prolonged treatment
results in improvement in net bone formation (68).
Longitudinal data in 32 GH-deficient children, 7.216.3 yr old,
treated with GH for an average of 4 yr demonstrated a significant
improvement in radial and lumbar bone density with therapy (Fig. 5
) (69). The greatest
improvement was observed with the longest treatment duration, and in
this group, z-scores approached mean reference values. A group of 11
patients, 1618.7 yr old, who had reached final height had
significantly reduced lumbar bone density compared with short normal
controls. Possible reasons for this include the interrupted and low
dose GH treatment the patients received during the era of
pituitary-derived GH. GH treatment appears to have a more pronounced
effect on bone density in patients with childhood-onset GH deficiency
than in those with adult-onset GH deficiency (70). Young
adult men with childhood-onset GH deficiency who resumed GH treatment
for 35 yr during adulthood demonstrated a significant (9.616.2%)
improvement in lumbar, femoral neck, and trochanter bone density, with
the most significant effects observed in those with lower baseline bone
density z-scores (71). These data suggest that GH
treatment leads to improved bone density, which is a function of the
dose and duration of treatment, and that patients may require prolonged
GH treatment beyond the time of growth to improve peak bone mass.

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Figure 5. Fig. 5. Increase in bone density in children with
GH deficiency receiving rhGH treatment. Mean radial BMD Z-score
(left) and mean lumbar BMDarea Z-score (right)
corrected for bone age in children with GH deficiency receiving rhGH
treatment. Parentheses enclose the number of examined
children. o, P < 0.001 vs. reference values; *,
P < 0.01; **, P < 0.001 vs. 0.
(Reprinted with permission from The Journal of Clinical
Endocrinology & Metabolism, 81:3080, 1996. Copyright ©
1996 The Endocrine Society. All rights reserved.)
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Cushings disease. Patients with Cushings disease may have
reduced bone mass due to the direct effect of hypercortisolemia on bone
and the secondary hypogonadal state. The presence of osteopenia and
vertebral collapse in a prepubertal child with Cushings disease
(72) suggests that cortisol excess is causative. Due to
the rarity of this disorder in children, limited data on bone density
are available. In the two largest published series of pediatric
patients with Cushings disease (n = 101 patients total, 420 yr
old), bone density measurements were performed at diagnosis in only
three patients, and only one patient had a fracture at diagnosis
(73, 74). The patients in whom densitometry was performed
had severe osteopenia (z-score = -3.9 to -7.0), which improved,
but remained reduced, after treatment (73). Leong and
colleagues described marked lumbar osteopenia (-3.2 SD) in
a 15-yr-old girl with long-standing Cushings disease during
adolescence. Serum osteocalcin was markedly reduced pretreatment,
suggesting low bone formation. After more than 2 yr of follow-up, bone
density increased considerably, but remained reduced compared with that
in her normal twin (75). These data suggest that reduced
peak bone mass is a complication of Cushings syndrome in childhood
and adolescence, and relates to the duration of increased cortisol
secretion. Specific hormonal or other therapeutic strategies to improve
bone mass in this patient group have not been investigated.
Hyperthyroidism. Reduced bone mineral density in adult
patients with untreated hyperthyroidism is common; however, data on the
effects of hyperthyroidism on peak bone mass are limited. A study of 13
girls with hyperthyroidism, 514.9 yr old, demonstrated significantly
reduced whole body and spinal bone density at diagnosis compared with
healthy girls matched for age and body size. The low bone density in
untreated hyperthyroid girls occurred in association with elevated bone
resorption as assessed by urinary N-telopeptide (76).
However, bone formation was not assessed. Thyroid hormone levels
correlated negatively with bone density and positively with
N-telopeptide in these patients. Both bone density and bone resorption
were no longer significantly different from control values at 12 and 24
months of follow-up in patients receiving successful medical treatment.
These data suggest that untreated hyperthyroidism negatively effects
bone metabolism and bone density in youths, but that the effects can be
corrected with treatment and are therefore unlikely to affect peak bone
mass in adequately treated patients.
Type 1 diabetes mellitus. There are conflicting data regarding
whether reduced bone density is a complication of type 1 diabetes
mellitus. The majority of studies in adults demonstrate osteopenia of
cortical and trabecular sites, which is generally correlated with the
level of blood glucose control and duration of diabetes, and the
incidence is increased in patients with other chronic complications of
diabetes (77, 78, 79). Although an increased fracture risk has
not been found in this patient group, increased calcaneal fractures
have been reported in patients with long-term vascular complications
and in those receiving steroid treatment (80, 81).
Osteopenia appears to be minimally progressive in adulthood (77, 82), suggesting that the low bone density seen in adult patients
may result from a reduction in peak bone mass. Studies in children and
adolescents with a short duration of diabetes, however, have shown no
differences in spinal and peripheral bone density assessed by DEXA
between patients and age- and sex-matched controls
(83, 84, 85). Using QCT, which allows selective measurement of
trabecular and cortical bone, the largest study (86) of 48
diabetic children and adolescents, 5.219.6 yr old, found a small
significant decrease (3.5%) in cortical bone density and no difference
in trabecular bone density in patients compared with controls matched
for age, sex, skeletal and pubertal maturation, and anthropometric
measurements. The reduction in cortical bone density did not correlate
with the duration of diabetes or the level of control, as assessed by
glycosylated hemoglobin. In contrast, Lettgen et al.
(87) studied a smaller group (n = 21) of diabetic
children and adolescents, 6.219.9 yr old, of variable disease
duration (0.818. yr) using forearm QCT and demonstrated significantly
decreased trabecular bone density (-18.9%) and a smaller (-5.1%),
nonsignificant decrease in cortical bone density compared with age-,
pubertal stage-, and sex-matched controls. The duration of diabetes and
glycosylated hemoglobin was significantly inversely correlated with
trabecular bone density in these patients. Therefore, the majority of
data demonstrate a small or negligible reduction in bone density in
children and adolescents with diabetes mellitus; however, data are
limited to cross-sectional studies. Longitudinal data on bone mineral
accretion during childhood and adolescence are needed to identify those
patients who may be at risk for low peak bone mass. Osteopenia may
develop over the long term, with patients in poor control and with
other diabetic complications at highest risk.
Glucocorticoid therapy. Osteopenia and growth retardation are
common complications of glucocorticoid therapy in pediatric patients.
The rate of bone loss is related to glucocorticoid dose, but osteopenia
occurs in children receiving less than 0.16 mg prednisone/kg·day
(88). Loss of bone occurs most rapidly in the first 6
months of glucocorticoid therapy (89) predominantly in
trabecular bone (90, 91, 92). Glucocorticoid-induced
osteopenia and failure to achieve peak bone mass are thought to result
from multiple factors, including direct effects of glucocorticoids on
bone, impaired calcium absorption, abnormal renal calcium handling,
reduced gonadal steroid secretion, and changes in the GH/IGF-I axis
(89).
Bone undergoes constant remodeling, and any factor causing bone
resorption to exceed bone formation will result in bone loss. Several
lines of evidence suggest that glucocorticoids impair bone formation
(93, 94, 95). Glucocorticoid administration may also increase
bone resorption, although the evidence of a direct effect of
glucocorticoids on bone resorption is less extensive (95, 96).
Glucocorticoid effects on mineral metabolism represent a partial
explanation for glucocorticoid-induced alterations in bone formation
and resorption. Glucocorticoids impair calcium absorption in the
duodenum (97) and result in secondary hyperparathyroidism,
stimulating osteoclastic activity and bone resorption
(98). Glucocorticoid-induced alterations in vitamin D
metabolism are also postulated, but are controversial (99, 100).
Glucocorticoids may impair the attainment of peak bone mass through
alterations in gonadal function at the level of the pituitary and
through direct effects on the gonads (101, 102, 103). Although
hypogonadism may be a contributing factor to glucocorticoid-induced
osteoporosis in adolescents, bone loss still occurs in the presence of
clinically normal gonadal function (89).
Glucocorticoids may also impair the attainment of peak bone mass via
effects on the GH/IGF-I axis. High dose, long-term glucocorticoid
therapy markedly attenuates GH secretion (104). The impact
of short-term glucocorticoid exposure on skeletal development in
children varies from study to study depending upon the dose and timing
of glucocorticoid therapy and the method used to assess GH secretion.
However, regardless of the effects on circulating IGF-I, IGF-I activity
appears to fall within hours of glucocorticoid administration in
children whose peripheral IGF-I levels remain unchanged
(105).
Bone loss in children receiving glucocorticoids is dose related, and
therefore it is prudent to prescribe the lowest effective dose.
Although preserving the normal function of the
hypothalamic-pituitary-adrenal axis, alternate-day glucocorticoid
regimens do not prevent bone loss (106). Therefore,
children and adolescents receiving glucocorticoid therapy may be at
risk for effects on attainment of peak bone mass and bone loss.
Specific interventions to protect bone mass in glucocorticoid-treated
children have not been assessed, although maintaining normal calcium
and vitamin D intake is recommended. In addition, postpubertal
adolescents receiving chronic glucocorticoid therapy should be
monitored for development of hypogonadism.
Nutritional disorders. Multiple disorders resulting in
deficient caloric and micronutrient (calcium and vitamin D) intake
during childhood may affect peak bone mass. Specific nutritional
disorders associated with reduced bone density include inflammatory
bowel disease (IBD), celiac disease, and anorexia nervosa.
Inflammatory bowel disease. Both types of IBD are associated
with an increased prevalence of osteopenia (107), although
among patients with IBD, those with Crohns disease have been noted to
have a higher risk of osteopenia than those with ulcerative colitis
(108). Semeao et al. (109) found
that of 119 children and young adults with Crohns disease, 70% of
patients had bone mineral density z-scores at least 1
SD below the normal mean, and 32% had scores at
least 2 SD below the normal mean. Nutritional
factors such as the use of hyperalimentation, vitamin D deficiency, and
calcium malabsorption may contribute to bone loss in adolescents with
IBD (110). In the above-mentioned cross-sectional study of
119 children and young adults with Crohns disease, low bone density
was associated with the use of nasogastric tube feeds and total
parenteral nutrition independent of glucocorticoid use
(109). Although alterations in vitamin D metabolism as
well as calcium/mineral metabolism are thought to contribute to bone
loss in IBD, this has not been demonstrated in some clinical studies
(111).
The reduction in bone density in children with IBD is probably
multifactorial. In addition to nutritional factors, other complicating
factors include poor linear growth, delayed puberty, and therapies used
to treat IBD. Although several studies have found glucocorticoid
treatment to have the strongest correlation with bone density in these
patients (112, 113), IBD is a risk factor for accelerated
bone loss independent of the use of glucocorticoids (114, 115). In addition to glucocorticoid therapy, accelerated bone
loss may occur due to the use of cyclosporin and 6-mercaptopurine
(109, 110). Bone loss associated with IBD may also result
from the production of inflammatory cytokines (110).
Cytokines such as interleukin-1, interleukin-6, and tumor necrosis
factor, released during the inflammatory state, are thought to recruit
and activate osteoclasts, perhaps contributing to bone loss and failure
to attain peak bone mass (116).
Therapy for the prevention of bone loss in children with IBD is
limited. There are no studies directly comparing calcitonin with
vitamin D and calcium supplementation in this population.
Bisphosphonates have been shown to prevent glucocorticoid-induced
osteoporosis in a multicenter study of 477 corticosteroid treated
adults (24 with IBD) (117) and in a small series of
corticosteroid-treated children (118). However, the
long-term impact of bisphosphonate therapy upon skeletal development in
children is unknown, and the use of bisphosphonates in children remains
experimental at the present time (119).
Celiac disease. Children with the common pediatric enteropathy
celiac disease, in which nutrient absorption is impaired, are also at
risk for reduced bone density. Mora et al. demonstrated
significantly reduced lumbar and total bone density at diagnosis of
celiac disease in 44 patients, 2.620.4 yr old, after controlling for
anthropometric measurements (120). Follow-up studies of
these patients on a gluten-free diet demonstrated normalization of bone
density.
Anorexia nervosa. Anorexia nervosa is another important
nutritional cause of osteopenia commonly seen in adolescent girls, with
spinal (trabecular) bone density most commonly affected. Lumbar bone
density is reduced more than 1 SD below the normal mean in
nearly half of height- and bone age-matched adolescent girls
(42) and correlates with the duration of anorexia
(41, 42). Adult women with anorexia nervosa who had onset
of the disorder during adolescence have more severe osteopenia than
those who developed the disorder during adulthood (34),
indicating that abnormal bone mineral accrual occurs in adolescent
patients. Surrogate markers of bone turnover demonstrate reduced bone
formation uncoupled to bone resorption in adolescent girls with
anorexia nervosa (Fig. 6
), with the
majority of the variation in bone formation due to the nutritionally
dependent bone trophic hormone IGF-I (42). Therefore,
nutritional status, in addition to gonadal steroid deficiency, is an
important factor in the development of osteopenia in adolescents with
anorexia nervosa. Improvement in bone density is seen with weight
recovery before resumption of menses, suggesting the importance of
nutritional status; however, significant osteopenia may persist
(33). Potential negative effects on bone density from
excessive exercise, increased cortisol secretion, and reduced calcium
and vitamin D intake in these patients have not been proven. These data
emphasize the importance of early diagnosis and treatment of underlying
nutritional disorders in childhood to acquire normal peak bone
mass.

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|
Figure 6. Reduced bone formation uncoupled from bone
resorption in adolescent girls with anorexia nervosa. Comparison of
bone turnover markers in subjects with anorexia nervosa (AN; n = 11)
and controls (n = 15). OC, Osteocalcin; BSAP, bone-specific alkaline
phosphatase; DPD, deoxypyridinoline. *, P = 0.02 for AN
subjects vs. bone age-matched controls. (Reprinted with
permission from The Journal of Clinical Endocrinology &
Metabolism, 84:4494, 1999. Copyright © 1999 The
Endocrine Society. All rights reserved.)
|
|
 |
Chronic diseases of childhood and adolescence
|
---|
Cancer. Children and adolescents who undergo treatment for
malignancy are at risk for poor bone mineral accrual due to the
combined effects of the disease and treatment with glucocorticoids,
chemotherapeutic agents, and cranial irradiation. The endocrine effects
of treatment that contribute to osteopenia include GH deficiency and
hypogonadism. In addition, these patients may have poor nutritional
intake, reduced vitamin D levels, and low levels of physical activity,
which may impact bone development. In a study of 28 children with
leukemia or solid tumors, 2.916 yr old, calculated volumetric femoral
and lumbar bone density was normal at diagnosis, but femoral bone
density decreased by 11.3% over 1 yr. A small decrease (2.4%) in
lumbar bone density in patients older than 7 yr was seen, but was not
significant (121). Bone markers demonstrated reduced bone
formation at diagnosis, with bone formation normalizing and resorption
increasing with treatment, suggesting that the disease and its
treatment may have differing effects on bone turnover. Patients with
acute lymphoblastic leukemia (ALL) appear to be at a higher risk for
osteopenia than those with other malignancies. Warner et al.
found that in 35 child and adolescent survivors of ALL (719 yr of
age, minimum of 18 months after completion of therapy), the percentage
of predicted bone mineral content was reduced at the hip compared with
20 age-matched survivors of other malignancies and 31 sibling controls.
In addition, although there was an improvement in the percentage of
predicted bone mineral content at the spine with increasing duration of
time off therapy, there was significantly less improvement in the ALL
group compared with the group with other malignancies
(122). In some studies, regional bone density has been
correlated with previous exposure to specific chemotherapeutic agents
as well as cumulative dosing (121, 122).
Among the long-term consequences of treatment of childhood malignancy,
GH deficiency due to hypothalamic-pituitary damage from intracranial
radiation therapy is common. In a study of 21 young adults who were
treated for intracranial malignancy during childhood, all developed GH
deficiency by the end of puberty. Those who did not receive GH
treatment were osteopenic at the femoral neck, lumbar spine, and
Wards triangle compared with the GH-treated patients
(123). However, other published data indicate that
osteopenia may be present despite GH replacement in childhood brain
tumor survivors (124). Therefore, the etiology of
osteopenia in this patient group is probably multifactorial. What
specific interventions may improve bone density in this patient
population remain unknown; however, maximizing nutritional status,
including calcium and vitamin D intake; minimizing immobilization; and
replacing hormonal deficiencies when present should be part of the
standard treatment.
Cystic fibrosis. Osteopenia is a common complication of cystic
fibrosis in children and adults, which will probably significantly
impact the quality of life in these patients as they continue to live
longer. In adults, fracture rates have been reported to be 2 times
greater in young women and men with cystic fibrosis than in the general
population, with a particularly high risk for rib and vertebral
compression fractures (10- to 100-fold risk) (125).
Analysis of surrogate markers of bone turnover demonstrates an
imbalance, with low bone formation and increased resorption in pubertal
and young adult patients (126). Both poor bone mineral
accrual and accelerated bone loss are implicated in the pathogenesis of
osteopenia in these patients (126, 127, 128); however, few
longitudinal data are available. One longitudinal study of 41 youths
and adults with cystic fibrosis (950 yr of age) evaluated interval
change in bone density over an average follow-up period of 17 months.
Although spinal hip and whole body bone density were reduced at
baseline in all subjects, continued decreases were seen only in
subjects less than 18 yr old. These data are consistent with poor bone
mineral accretion in young patients with cystic fibrosis
(128). The cause of the low bone density in this
population appears to be multifactorial, being variably correlated with
low body mass, vitamin D insufficiency, glucocorticoid therapy,
severity of illness, decreased physical activity, and hypogonadism
(127, 129, 130, 131, 132). There are no published therapeutic trials
of treatment of low bone density in cystic fibrosis; however, one
randomized controlled study in adults reported severe bone pain after
iv pamidronate therapy, possibly related to increased production of
inflammatory cytokines (133, 134).
Rheumatological disorders. Rheumatological disorders such as
juvenile rheumatoid arthritis (JRA) have been associated with growth
retardation (135) and low bone mineral density even in the
absence of therapy with glucocorticoids (136, 137, 138).
Osteoporosis associated with pathological long bone fractures as well
as vertebral compression fractures have been reported in 20% of
children with JRA (139). In one cross-sectional study,
30% of children with mild to moderate JRA had low total body bone
mineral density (137). JRA appears to be associated with a
low bone turnover state, as determined by reductions in both markers of
bone formation as well as markers of bone resorption
(138). The etiology of bone loss in JRA is probably
multifactorial, with possible contributions from inflammatory cytokine
production, diminished physical activity, alterations in nutritional
factors, and the use of immunomodulatory agents (137, 138).
Other systemic rheumatological diseases, such as systemic lupus
erythematosus and juvenile dermatomyositis, have been associated with
reductions in bone mineral density. However, given the widespread
therapeutic use of corticosteroids, it is difficult to demonstrate
independent effects of these diseases on bone density. One prospective
study of 113 children with chronic rheumatological diseases (including
systemic lupus erythematosus, juvenile dermatomyositis, and JRA)
demonstrated a reduction in osteocalcin, which was greatest in children
with active disease before any treatment with corticosteroids
(140). The precise mechanisms by which these chronic
inflammatory diseases result in osteopenia remain unclear and are
likely to be multifactorial.
 |
Conclusions
|
---|
Normal bone mineral accretion during childhood and adolescence is
a complex process involving genetic determinants, gonadal steroids,
GH/IGF-I effects, and nutritional and other environmental factors.
Assessing the normality of bone density measurements in childhood by
the current methods is complicated by the lack of normative data in
large populations of children who are well characterized in terms of
anthropometric measurements and pubertal and skeletal maturation.
Nevertheless, data identify numerous hormonal disorders that predispose
young patients to reduced peak bone mass and thereby increased risk of
life-long osteoporosis. These data support the importance of the
awareness of risk factors for osteopenia in adolescents at risk and of
correcting hormonal and nutritional disorders when present. The cause
of many osteopenic disorders in childhood is multifactorial; therefore,
there is a need for further elucidating the pathogenesis of poor bone
mineral development. Future research is clearly needed in this area to
develop treatment strategies to preserve maximal bone mass in patients
at the highest risk for reduced peak bone mass.
 |
Footnotes
|
---|
1 This work was supported in part by NIH Grants R01-DK-52625,
M01-RR-01066, and T32-DK-0702825. 
Received May 10, 2000.
Revised August 2, 2000.
Accepted August 9, 2000.
 |
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