REVIEW

Effects of Anorexia Nervosa on Bone Metabolism

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Pouneh K. Fazeli1 and Anne Klibanski1

1
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
02114
ORCiD numbers: 0000-0003-1731-2927 (P. K. Fazeli); 0000-0003-4878-0205 (A. Klibanski).

ABSTRACT Anorexia nervosa is a psychiatric disease characterized by a low-weight state due to self-induced starvation. This disorder, which
predominantly affects women, is associated with hormonal adaptations that minimize energy expenditure in the setting of low nutrient
intake. These adaptations include GH resistance, functional hypothalamic amenorrhea, and nonthyroidal illness syndrome. Although these
adaptations may be beneficial to short-term survival, they contribute to the significant and often persistent morbidity associated with this
disorder, including bone loss, which affects .85% of women. We review the hormonal adaptions to undernutrition, review hormonal
treatments that have been studied for both the underlying disorder as well as for the associated decreased bone mass, and discuss the
important challenges that remain, including the lack of long-term treatments for bone loss in this chronic disorder and the fact that despite
recovery, many individuals who experience bone loss as adolescents have chronic deficits and an increased risk of fracture in
adulthood. (Endocrine Reviews 39: 895 – 910, 2018)

A norexia nervosa is a psychiatric disorder

characterized by low body weight due to self-
induced undernutrition. This disease predominantly
affects women, with a lifetime prevalence approaching
.% (). Typically presenting during adolescence (),
the long-term recovery rate for anorexia nervosa is
low. Only % to % of women with anorexia nervosa
have recovered even two decades after the initial di-
agnosis, and therefore the disease is also prevalent in
older individuals (, ).
Anorexia nervosa is associated with multiple
medical complications and comorbidities, the most
common of which is significant loss of bone mass ().
Almost % of women with anorexia nervosa have
bone mineral density (BMD) values . SD below the
mean of comparably aged women (, ). Studies of
bone microarchitecture and geometry in individuals
with anorexia nervosa demonstrate that this disease
affects both cortical and trabecular bone compart-
ments; adolescent girls with anorexia nervosa have
decreased cortical area and thickness and increased
cortical porosity and trabecular separation, as well as
reduced estimates of bone strength compared with
anorexia nervosa have worsened trabecular and cor-
tical parameters compared with normal-weight con-
trols, including decreased trabecular number and
thickness, increased trabecular separation, and de-
creased cortical thickness as well as lower estimates of
bone strength (–). Importantly, the low bone
mass and impaired microarchitecture are associated
with an increased risk of fracture in both adults and
adolescents with this disease (–).
In anorexia nervosa, loss of bone mass is the result
of hormonal adaptations to the state of starvation. Our
evolutionary past was marked by periods of famine,
and therefore several hormonal adaptations have
evolved that minimize the utilization of energy on
processes not necessary for survival, including re-
production and growth. Both starvation and anorexia
nervosa, a form of chronic undernutrition, are char-
acterized by hypogonadotropic hypogonadism, GH
resistance, and hypercortisolemia, all of which confer a ISSN Print: 0163-769X
survival advantage in the short term in the setting of ISSN Online: 1945-7189
extreme nutrient deficiency. However, these factors Printed: in USA
also contribute to low bone mass and an increased risk Copyright © 2018
of fracture in the long term. Nearly % of adolescent Endocrine Society

normal-weight controls (, ), and these differences in and adult women report a past history of fracture (, Received: 2 April 2018
Accepted: 21 August 2018
microarchitectural parameters have been shown to be ), and a prospective study of young women with First Published Online:
independent of BMD (). Similarly, adult women with anorexia nervosa demonstrated a sevenfold increased 27 August 2018

doi: 10.1210/er.2018-00063 https://academic.oup.com/edrv 895

REVIEW
ESSENTIAL POINTS
· Anorexia nervosa is a psychiatric disorder characterized by self-induced starvation and the inability to maintain a normal
body weight
· Nearly 90% of women with anorexia nervosa have low bone mineral density, and the disorder is associated with an
increased risk of fracture
·· The bone loss in anorexia nervosa is primarily the result of hormonal adaptations to chronic caloric deprivation
Both hormonal and nonhormonal therapeutic strategies may be effective in reducing the bone loss associated with this
disorder
risk of fracture when compared with similarly aged
normal-weight women (). Because anorexia nervosa
presents most commonly during adolescence, a critical
time for bone accrual, and because of the chronicity of
the disease, the risk of fracture persists many years
after diagnosis, as demonstrated by a population-based
cohort study that found a % cumulative incidence of
fracture in individuals with anorexia nervosa ().
Therefore, understanding the hormonal adaptations to
Deviations From Normal Bone Modeling and
Remodeling in Anorexia Nervosa
Anorexia nervosa has a lifetime prevalence in women
of ~.% (), with a peak age of onset of  to  years
of age (). Adolescence is a time of bone modeling
and accrual, with peak calcium accretion occurring at a
mean of . years of age (6. SD) in girls ();
therefore, alterations in the rate of bone formation
during adolescence may have lifelong impact with
respect to bone structure and fragility. Although
histomorphometric data in adolescents with anorexia
nervosa do not exist, markers of bone formation have
been used as a surrogate for bone formation in this
population, as bone formation markers have been
shown to be correlated with histomorphometrically
derived mineral apposition rates in adults (). As
compared with normal-weight adolescents, girls with
anorexia nervosa have lower levels of bone formation
markers and similar levels of surrogate markers of
bone resorption (–), suggestive of overall de-
creased bone accrual and a low remodeling state. A
study by Seeman et al. () exploited differences in
rates of bone growth and accrual in the axial vs ap-
pendicular skeleton () before as compared with after
puberty to demonstrate differential sites of deficits in
individuals with anorexia nervosa, depending on when
anorexia nervosa developed. Girls who developed
anorexia nervosa before  years of age were found to
have similar deficits in bone width in the vertebral
body and femoral neck, whereas those who developed
anorexia nervosa during puberty (. to  years of
age) had a greater reduction in vertebral body width as
compared with femoral neck width likely due to the
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undernutrition and how they contribute to the
prevalent bone loss and fracture risk will be critical to
determining strategies to prevent these complications.
In this review, we discuss the hormonal perturbations
that occur during periods of nutrient deficiency, their
effect on bone mass, and potential hormonal and
nonhormonal therapies for the treatment of the as-
sociated bone loss and/or failure to accrue peak bone
mass.
fact that there is an axial growth spurt during puberty
and appendicular growth occurs more rapidly before
puberty (, ). These reductions in bone size, coupled
with deficits in bone mineral accrual, which the authors
observed correlated with duration of disease, have
important implications for site of future fracture risk in
women with a history of anorexia nervosa () and may
explain persistently low BMD in adults who were di-
agnosed with anorexia nervosa during adolescence but
have recovered from the disease ().
In contrast to adolescents with anorexia nervosa
who have low levels of bone formation markers and
similar levels of bone resorption markers as compared
with healthy controls, adult women with anorexia
nervosa have suppressed markers of bone formation
and elevated levels of bone resorption markers when
compared with healthy controls (–). This differ-
ence may be due to the fact that prepubertal ado-
lescents all have low estrogen levels, whereas most
adult women with anorexia nervosa are hypo-
estrogenemic relative to healthy, normal-weight women
(see “Hypoestrogenemia” below), and estrogen de-
ficiency is associated with accelerated bone remodeling
and increased osteoclast longevity (–). Therefore, in
contrast to the likely low remodeling state in ado-
lescents with anorexia nervosa, in adult women
hypoestrogenemia may result in greater remodeling
activity but with resultant bone loss due to decreased
bone formation within each basic multicellular
unit—a unit of space within bone consisting of os-
teoblasts and osteoclasts where remodeling occurs
(). Because histomorphometric data in women
with anorexia nervosa are scant—there are a total of
six reports in the literature of tetracycline-labeled
Endocrine Reviews, December 2018, 39(6):895–910

biopsies in women with anorexia nervosa (–)—
bone formation and resorption markers are a surrogate
means of understanding bone remodeling in this dis-
ease. The first report of a tetracycline-labeled biopsy in
anorexia nervosa was of a single adult patient who
sustained a fracture of the proximal femur (); his-
tomorphometry demonstrated minimal osteoblastic
activity and increased resorptive surfaces and a slight
elevation in osteoclast number (), consistent with the
bone turnover marker data in adults.
Although markers of bone formation and resorption
are simply surrogate markers of osteoblast and osteoclast
activity, the differences observed in adults as compared
with adolescents may explain differences observed in
response to treatments for low BMD in adults with an-
orexia nervosa as compared with adolescents. For example,
although  months of treatment with bisphosphonates
significantly increased spine and hip BMD in adult women
with anorexia nervosa as compared with placebo-treated
patients () (see “Treatment of Low BMD in Anorexia
Nervosa” below), in adolescent girls, there was no sig-
nificant difference in change in spine or femoral neck
BMD in those treated with  months of bisphosphonates
as compared with placebo (). This difference may be due
to the fact that bisphosphonates are antiresorptive agents
and act by decreasing rates of bone remodeling ().
Therefore, bisphophonates may have more of an effect in
hypoestrogenemic adults with anorexia nervosa who likely
have a higher rate of remodeling as compared with ad-
olescents with anorexia nervosa and their overall low
remodeling state.
Hormonal Adaptations to
Nutrient Deprivation
For hormonal adaptations to starvation potentially
contributing to the low-bone-mass state of anorexia
nervosa, see Table  (–).
Table 1. Hormonal Adaptations to Starvation Potentially Contributing to the Low-Bone-Mass State of Anorexia Nervosa
Levels in Anorexia Nervosa
IGF-1 Low due to GH resistance
Estrogen Low due to hypogonadotropic hypogonadism
Testosterone Low
Cortisol Elevated
DHEA Low
FGF21 Low or similar to normal-weight controls
Leptin Low
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Functional hypothalamic amenorrhea
Hypoestrogenemia
Most postpubertal girls and women with anorexia
nervosa are amenorrheic, and this was previously part
of the diagnostic criteria for the disease prior to the
current version of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-) (, ).
Amenorrhea in anorexia nervosa is a result of dis-
ruption of the GnRH secretory pattern, which results
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in low-amplitude LH pulsatility (–). Although the
resulting hypogonadotropic hypogonadism diverts
energy away from the costly process of reproduction
during periods of nutrient deficiency, the hypo-
estrogenemic state is an important factor contributing
to the loss of bone mass in anorexia nervosa. Estrogen
deficiency is characterized by higher rates of bone
remodeling, an increase in surrogate markers of bone
resorption, and bone loss (, , , ), and in
anorexia nervosa, duration of amenorrhea is correlated
with decreased spine and femoral neck BMD (, ).
Importantly, although there is normalization of the
GnRH secretory pattern with weight recovery (),
because this disorder affects girls and women during
the time of critical bone mass accrual, the impact of
the amenorrhea can be long term (, ). A study
comparing women with anorexia nervosa who de-
veloped amenorrhea before as compared with after
the age of  years found that those who developed
amenorrhea during adolescence had significantly
lower spine BMD as compared with those who
developed amenorrhea after the age of  years,
despite both groups having similar durations of
amenorrhea (). Therefore, the time of onset of
amenorrhea, and specifically its relationship to
puberty, is also an important predictor of future
BMD ().
Although estrogen deficiency is an important
contributor to the loss of bone mass in anorexia
Association With Bone References
Low IGF-1 levels are associated with decreased BMD in anorexia nervosa (42, 43)
Duration of amenorrhea is associated with decreased BMD in anorexia nervosa (44)
Low testosterone levels are associated with low BMD and worsened parameters (11, 45, 46)
of bone microarchitecture in anorexia nervosa
High cortisol levels are associated with decreased BMD and decreased markers (47–50)
of bone formation in anorexia nervosa
Low DHEA levels are associated with low BMD in anorexia nervosa and increased (46, 51–53)
markers of bone resorption
FGF21 levels are associated with worsened parameters of bone microarchitecture (54–57)
Low leptin levels are associated with decreased BMD in anorexia nervosa and (11, 58–61)
worsened microarchitectural parameters
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nervosa, treatment with oral estrogen does not im-
prove BMD in women with this disease. Although
retrospective studies suggested beneficial effects of
oral estrogen in the form of oral contraceptive pills
(), randomized and/or prospective studies of oral
estrogen have shown no difference in BMD in those
receiving oral estrogen as compared with placebo
(–), except in the subset of very low–weight
patients (,% of ideal body weight) (). Impor-
tantly, compliance with estrogen use was monitored
and confirmed in at least one of the studies by vaginal
smears for evaluation of epithelial estrogenization
(). In contrast, in a study investigating the effects
of predominantly transdermal estrogen replace-
ment in adolescents with anorexia nervosa, we
demonstrated a .% increase in spine BMD after
 months compared with the untreated group
whose spine BMD increased ,.% (); impor-
tantly, however, the BMD in the treated group still
remained lower than in normal controls (). It is
not known why there is a difference in BMD re-
sponse to oral as compared with transdermal es-
trogen in anorexia nervosa, but the difference may
be due to the route of estrogen administration and/
or the doses of estrogen used. For example, in
postmenopausal women, oral estrogen has been
shown to suppress IGF-—a bone anabolic hor-
mone that is already decreased in states of un-
dernutrition () and levels of which have been
positively associated with BMD in women with
anorexia nervosa ()—whereas transdermal estro-
gen does not have the same IGF-–suppressing
effect (, ). Furthermore, higher doses of oral
estrogen, such as those found in oral contraceptive
pills, suppress IGF- more than do lower doses of
oral estrogen (). Studies are currently underway
investigating the role of physiologic, transdermal
estrogen replacement in the treatment of low bone
mass in adult women with anorexia nervosa. It is
important to note that the subset of women with
anorexia nervosa who are eumenorrheic and do not
develop hypogonadism also have low BMD (),
underscoring the fact that hypoestrogenemia is not
the only factor contributing to loss of bone mass in
this population.
Low testosterone
Levels of testosterone, an androgen produced in part
by the ovary, adrenal glands, and peripheral con-
version of androgen precursors, are also low in
women with anorexia nervosa (, ) and have been
associated with low BMD and worsened parameters
of bone microarchitecture (, ). However, a
randomized, double-blind, study in women with
anorexia nervosa found no effect of transder-
mal testosterone on BMD at a dose targeted to
keep testosterone levels in the normal range ().
Therefore, low levels of testosterone are not likely a
898 Fazeli and Klibanski Effects of Anorexia Nervosa on Bone Metabolism
significant contributor to loss of bone mass in this
population.
GH resistance
Acquired GH resistance is another important adap-
tation that decreases energy expenditure in states of
undernutrition (–), but it is also an important
contributor to the loss of bone mass in anorexia
nervosa. GH resistance is characterized by elevated
levels of GH coincident with low levels of IGF-, a
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hormone secreted by the liver in response to GH
stimulation. Elevated levels of GH are critical during
periods of starvation, as they help maintain a state of
euglycemia () in part through fat mobilization
(), but the growth-promoting effects of GH,
mediated predominantly by IGF-, would be mal-
adaptive during periods of nutrient deficiency.
Therefore, GH resistance is a hormonal adaptation
that allows for an uncoupling of the GH–IGF- axis
during starvation.
Ghrelin as a mediator of GH resistance
In the setting of undernutrition, GH levels rise in part
through a positive feedback response to the low IGF-
levels () and via stimulation by ghrelin, an orexigenic
hormone secreted by the fundal cells of the stomach.
Ghrelin levels drop in response to food intake, and
both girls and women with anorexia nervosa have
higher ghrelin levels as compared with normal-weight
controls (–). By attaching to its receptor, the GH
secretagogue receptor (GHSR) a, the active form of
ghrelin, acylated ghrelin, stimulates GH release and
thereby is an important mediator of increased GH
levels.
Despite having higher total ghrelin levels as
compared with normal-weight controls, women with
anorexia nervosa appear to be resistant to its effects.
Ghrelin is an appetite-stimulating hormone and a
potent stimulator of gastric motility, and even though
their levels of ghrelin are higher, women with anorexia
nervosa report experiencing less hunger compared
with controls, as measured by a visual analog scale (,
). Similarly, delayed gastric emptying is a common
finding in anorexia nervosa with rates reported to
approach % to % (–). It is not known whether
this observed resistance to ghrelin is due to differences
in the ratio of the active form of ghrelin (acylated
ghrelin) to total ghrelin or resistance at the level of, or
downstream of, GHSRa (, ). Recently, in a
double-blind, randomized placebo-controlled study,
we have shown that  weeks of treatment with a
GHSRa agonist in women with anorexia nervosa
significantly decreases gastric emptying time and leads
to a trend in weight gain as compared with women
randomized to placebo (). Importantly, although we
were not able to quantitatively detect changes in
hunger between subjects randomized to the GHSRa
agonist and those randomized to placebo, three
Endocrine Reviews, December 2018, 39(6):895–910

subjects dropped out of the study or stopped using the
treatment due to symptoms of increased hunger and
all three were randomized to the GHSRa agonist ().
Therefore, this study suggests that treatment with a
GHSRa agonist can potentially overcome the ob-
served resistance to the effects of endogenously se-
creted ghrelin and that the resistance does not occur
downstream from the receptor. Further studies will be
necessary to determine whether this will be a safe,
effective, long-term treatment for individuals with
anorexia nervosa.
Women with anorexia nervosa may also be re-
sistant to other effects of ghrelin, including potential
bone anabolic effects. In rodent models, GHSRa
has been identified on osteoblast-like cells and
ghrelin treatment has been shown to increase cell
proliferation (). In vivo administration of ghrelin
in rat models also leads to increases in BMD (). In
humans, ghrelin levels are positively associated with
BMD in normal-weight girls, but not in adolescent
girls with anorexia nervosa (, ). In fact, in
adolescent girls with anorexia nervosa there is an
inverse association between baseline ghrelin level
and longitudinal change in BMD (). Whether
treatment with a ghrelin agonist in women with
anorexia nervosa overcomes the resistance to the
potential bone anabolic effects of ghrelin is not
known.
Nutrient regulation of IGF-1
Therefore, in part through the effects of ghrelin, levels
of GH are elevated in anorexia nervosa but levels of
IGF-—the hormone secreted by the liver in response
to GH stimulation and that mediates most of the
growth-promoting effects of GH—are low. In addition
to being regulated by GH, IGF- is also exquisitely
sensitive to nutritional cues. Levels of IGF- decrease
by % after only  days of fasting in normal women
() and they are % lower in women with anorexia
nervosa as compared with normal-weight controls
(). Of note, the decrease in IGF- levels in healthy,
fasting women was accompanied by a significant
decrease in markers of bone formation (). Despite a
continued fast for an additional  days, administration
of recombinant human IGF- led to markedly in-
creased surrogate markers of bone formation (),
demonstrating the relationship between IGF- and
bone loss during starvation. IGF- levels also rise
dramatically (by %) after  days of refeeding therapy
in women with anorexia nervosa (), again dem-
onstrating the exquisite regulation of IGF- by nu-
trient availability. Given the fact that IGF- levels are
low in chronic starvation in the setting of normal or
elevated GH levels, the effects of nutritional status
supersede those of GH in the regulation of IGF-. This
is supported by the fact that  weeks of treatment
with supraphysiologic doses of recombinant human
GH do not increase IGF- levels in women with
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anorexia nervosa as compared with those treated with
placebo, despite the fact that fat mass significantly de-
creases in those treated with GH (). These data suggest
that the effects of GH that are critical for survival during
starvation are maintained, whereas the growth-promoting
effects of GH are minimized in anorexia nervosa.
Low levels of IGF-, a bone anabolic hormone, are
also an important contributor to the loss of bone mass
in individuals with anorexia nervosa. IGF- has been
shown to be a chemotactic factor, inducing osteoblast
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recruitment (), and in an in vitro rodent model,
IGF- increases bone collagen content (). In
women with anorexia nervosa, IGF- levels are pos-
itively associated with BMD () and treatment with
recombinant human IGF- increases surrogate
markers of bone formation in anorexia nervosa ().
Nine months of treatment with recombinant human
IGF- in combination with oral estrogen increases
lumbar spine BMD by .% in women with anorexia
nervosa (), further demonstrating the important
contribution of low IGF- levels to low bone mass in
this disease. The impact on BMD of coadministration
of IGF- with estrogen to adolescents with anorexia
nervosa is currently under investigation.
Fibroblast growth factor 21
Although the mechanism by which IGF- secretion is
“Weight recovery, coupled with
regulated by nutrient status in humans is not known, a resumption of menses,
fibroblast growth factor (FGF) may be an important remains the most effective
factor (Fig. ). FGF is a hormone secreted by the long-term treatment for bone
liver in states of starvation in both mice (–) and loss in anorexia nervosa.”
humans (). FGF transgenic mice are pheno-
typically similar to individuals with anorexia nervosa;
that is, their core body temperature and body weight
are lower than those of wild-type littermates (, )
and they manifest GH resistance (). The failure of
GH to induce IGF- secretion in FGF transgenic
mice is secondary to a reduction in STAT, a key
transcription factor in GH signaling (). In anorexia
nervosa, FGF may also be a key mediator of GH
resistance; FGF levels are inversely associated with
IGF- and positively associated with GH area under the
curve () in adolescent girls with anorexia nervosa. In
murine models and the human model of chronic star-
vation, that is, anorexia nervosa, FGF has also been
associated with decreased bone mass, worsened bone
microarchitecture parameters, and decreased bone
strength (, ). Whether these effects are independent
of or due to FGF’s effects on IGF- is not known.
Adrenal steroids
Hypercortisolemia
States of physiologic stress, including starvation, can
lead to activation of the hypothalamic–pituitary–
adrenal axis and an increase in levels of cortisol, an
important counterregulatory hormone (). In an-
orexia nervosa, cortisol levels are higher than those in
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Figure 1. Neuroendocrine adaptations to starvation contributing to loss of bone mass in anorexia nervosa. GH resistance—normal or elevated
GH levels in the setting of low IGF-1 levels—may be mediated by FGF21 in states of starvation (55, 109). Low estradiol levels, secondary to
hypothalamic amenorrhea, are likely a consequence of low leptin levels and elevated cortisol levels. Low IGF-1 levels, low estradiol
levels, and elevated cortisol levels all contribute to the loss of bone mass in anorexia nervosa. Dashed lines represent disruption of
the normal, physiologic pathway. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]

Energy Hypothalamus
intake
GnRH
Energy

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expenditure

Pituitary Leptin

+ LH
GH

Leptin
IGF-1 GH resistance GH LH Cortisol
Adipose

Ghrelin
IGF-1
? Cortisol
FGF-21 +
+
Adrenal
Liver Ghrelin
+

Estradiol
Stomach
© 2018 Illustration Presentation ENDOCRINE SOCIETY
Ovary

normal-weight controls and may be frankly elevated
in a subset of patients (–). The hypercortisolemia,
which is the result in part of a decrease in cortisol
clearance and an increase in the half-life of cortisol in the
setting of a normal circadian pattern of cortisol secretion
(), has been shown to normalize with weight recovery
(, ). Importantly, elevated cortisol levels are likely a
significant contributor to the loss of bone mass in states
of undernutrition. The mechanisms by which elevated
cortisol levels contribute to the loss of bone mass include
() a decrease in calcium absorption in the intestine and
likely an increase in urinary calcium excretion (–),
() a decrease in bone formation due to both a reduction
in osteoblast proliferation () as well as a decrease in
IGF- synthesis in bone-specific cells (), and () in-
creased bone resorption through inhibition of GnRH-
induced gonadotropin secretion () and potentially via
increased PTH receptor expression in osteoblasts ().
In clinical studies of individuals with anorexia nervosa,
adolescent girls have been shown to have a relative
decrease in calcium absorption and increase in urinary
calcium excretion concomitant with increased urinary
free cortisol levels (). Various measures of cortisol,
including urinary cortisol and pooled overnight cortisol
levels, have also been negatively associated with both
markers of bone formation and BMD in girls and
women with anorexia nervosa (, , ). Therefore,
increased cortisol levels are observed in states of un-
dernutrition, including anorexia nervosa, and are likely
an important mediator of the loss of bone mass.
Dehydroepiandrosterone
In contrast to cortisol, women with anorexia nervosa
have low levels of an adrenal androgen precursor,
dehydroepiandrosterone (DHEA), and its sulfated
form, DHEA-S (, ), which have been associated
with increased bone resorption () and decreased BMD
(). There have been several studies investigating the
effects of treatment with DHEA on BMD in anorexia
nervosa. Treatment with DHEA for  months or  year
did not improve BMD in girls and women randomized
to DHEA as compared with placebo (, ), whereas
 months of treatment in conjunction with oral con-
traceptives led to maintenance of both BMD and hip
structural geometry compared with the placebo-treated
group in whom a loss of these parameters was observed
(, ). Therefore, low levels of DHEA may be a factor
in the loss of bone mass in anorexia nervosa.
Nonthyroidal illness syndrome
Individuals with anorexia nervosa have low levels of
thyroid hormone levels (T and T) with normal levels

900 Fazeli and Klibanski Effects of Anorexia Nervosa on Bone Metabolism Endocrine Reviews, December 2018, 39(6):895–910

of TSH and elevated levels of reverse T, which are
hallmarks of the nonthyroidal illness syndrome
(–). Low T and T levels without an expected
increase in TSH suggests a central source of suppression
and is likely an adaptive response to decrease energy
expenditure in the setting of poor nutrient availability.
T levels increase with weight gain in anorexia nervosa
(, ) and are positively associated with changes in
resting energy expenditure (), demonstrating the
reversibility of this adaptive response.
Although loss of bone mass is characteristic of
states of hyperthyroidism (), low levels of thyroid
hormone and possibly TSH may also be associated
with abnormal skeletal development and homeostasis
(). Thyroid hormone receptors have been identified
on human osteoblasts (), and in murine models,
mice lacking thyroid hormone receptors have de-
creased trabecular BMD and increased marrow adi-
posity (), a characteristic finding in girls and
women with anorexia nervosa that has been inversely
associated with BMD (, ). IGF-, a bone anabolic
hormone, also increases with normalization of thyroid
hormone levels in individuals with hypothyroidism and
levels of IGF- are positively associated with free T and
T levels (), suggesting another mechanism by which
low levels of thyroid hormone may affect BMD. Despite
this possible contribution of low thyroid hormone levels
to the low-bone-mass state in anorexia nervosa, non-
thyroidal illness syndrome is an adaptive mechanism that
likely prevents unnecessary energy expenditure during
nutrient deprivation and therefore should not be treated
with thyroid hormone replacement.
Alterations in Adipokine Levels and Levels of
Appetite-Regulating Hormones
For hormonal adaptations to starvation potentially
contributing to the low-bone-mass state of anorexia
nervosa and other potential mediators of low bone
mass in anorexia nervosa, see Tables  and  (–),
respectively.
Low leptin levels
Levels of leptin, an anorexigenic hormone secreted
predominantly by subcutaneous adipose tissue, are
decreased in states of starvation, including anorexia
nervosa (, ). Leptin is likely an important
mediator between nutrient availability and hypo-
gonadotropic hypogonadism. In women with functional
hypothalamic amenorrhea, LH pulse frequency increases
after only  weeks of treatment with recombinant human
leptin (), and in a randomized placebo-controlled
study, more women with functional hypothalamic
amenorrhea recovered menstruation in the group treated
with recombinant human leptin as compared with
placebo-treated patients (). In women with functional
hypothalamic amenorrhea, treatment with recombinant
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human leptin increases osteocalcin and bone-specific
alkaline phosphatase levels, two markers of bone
formation (), and in anorexia nervosa, leptin
is positively associated with BMD (, ) and
microarchitectural parameters (). However, an
important potential side effect of treatment with
recombinant human leptin is weight loss, which may
be due to decreased appetite (). In a randomized,
placebo-controlled study of  women with hypo-
thalamic amenorrhea (), one participant had to be
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removed from the study due to significant weight loss
(.% of baseline body weight) and  additional
participants out of the  subjects in the recombinant
human leptin group required dose reductions due to
weight loss (). Although changes in appetite were not
directly measured, self-reported caloric intake was similar
in both groups during the course of the study (). The
treatment group also had a significant loss of fat mass
(mean loss of . kg) during the -week study com-
pared with participants in the placebo group, but whether
this was due to leptin-induced lipid mobilization could
not be determined (). Therefore, until the mechanisms
underlying the loss of weight and fat mass are better
delineated so that these side effects can be prevented,
recombinant human leptin is not a plausible treatment for
bone loss in individuals with anorexia nervosa.
Elevated peptide YY levels
Girls and women with anorexia nervosa have sig-
nificantly higher levels of peptide YY (PYY), an
intestinally secreted hormone with anorexigenic
properties (, ). Whether these inappropriately
elevated levels contribute to the decreased sensation
of hunger reported by individuals with anorexia
nervosa () and the decreased nutrient intake is not
known. Importantly, elevated levels of PYY may
contribute to the loss of bone mass in anorexia
nervosa. In animal models, the PYY receptor system
inhibits bone formation; the Y receptor is located
both in neuronal tissue as well as bone, and
osteoblast-specific Y receptor knockout mice have
increased trabecular thickness, number, and in-
creased femoral trabecular bone volume due to in-
creased osteoblast activity (). Similarly, mice who
lack the Y receptor have increased trabecular bone
volume, trabecular number, and trabecular thickness
(). Additionally, whereas PYY knockout mice
have increased BMD in the lumbar vertebrae and
greater trabecular bone volume in the femur as
compared with wild-type mice, PYY overexpressing
female mice have decreased femoral BMD and de-
creased trabecular bone volume in the both the femur
and lumbar vertebrae as compared with wild-type
littermates (). Elevated PYY has been associated
with decreased BMD in both girls and women with
anorexia nervosa (, ), suggesting that this
hormone may also be a mediator of the low-bone-
mass state characteristic of anorexia nervosa.
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Table 2. Other Potential Mediators of Low Bone Mass in Anorexia Nervosa

Levels in Anorexia Nervosa Association With Bone References

Ghrelin Elevated Ghrelin positively associated with BMD in normal-weight adolescents and inversely (85–87, 97, 98)
associated with change in BMD in adolescent girls with anorexia nervosa

PYY Elevated Elevated PYY levels are associated with decreased BMD in girls and women (98, 139, 140)
with anorexia nervosa

Adiponectin Elevated in most studies Adiponectin is inversely associated with BMD in anorexia nervosa (141–144)

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Amylin Low Amylin is positively associated with BMD in anorexia nervosa (145)

Oxytocin Low Low oxytocin levels are associated with decreased BMD (146, 147)

Sclerostin Elevated No known association between sclerostin and spine or hip BMD in anorexia nervosa (148)

DKK1 Low No known association between DKK1 and BMD in anorexia nervosa (148)

Pref-1 Elevated Pref-1 is inversely associated with BMD in anorexia nervosa (60)

Marrow adipose tissue Elevated Marrow adipose tissue is inversely associated with BMD (136, 137)

Elevated adiponectin levels pooling overnight frequent samples, was shown to be

Paradoxically, normal-weight individuals have higher
levels of adiponectin, an adipocyte-derived hormone,
compared with those who are obese (). In most
studies, individuals with anorexia nervosa have higher
total adiponectin levels as compared with normal-
weight controls (–). These higher levels of
adiponectin may be an important determinant of bone
mass in anorexia nervosa. In vitro studies demonstrate
that adiponectin negatively affects bone, predominantly
by increasing RANK ligand, an osteoclast activator
(). In murine models, mice that transgenically
overexpress adiponectin are observed to have decreased
femoral bone mineral content and strength as com-
pared with wild-type littermates of similar weight ().
Similarly, in anorexia nervosa, adiponectin is negatively
associated with BMD (), suggesting that high adi-
ponectin levels may be a determinant of low bone mass
in this disease.
Low oxytocin levels
Low oxytocin levels may also be a determinant of low
bone mass in anorexia nervosa. Levels of oxytocin, a
hormone secreted by the posterior pituitary, are lower
in anorexia nervosa than in normal-weight controls
(). Oxytocin, which serves important functions
during childbirth and lactation by promoting uterine
contractions and mediating milk ejection, may also
regulate appetite (–) and be a hormonal de-
terminant of bone mass (). In murine models, mice
deficient in oxytocin or its receptor have decreased
bone mass (), and subcutaneous oxytocin treat-
ment in osteoporotic mice improves parameters of
trabecular bone microarchitecture () and decreases
marrow adipocyte number, another possible mediator
of low bone mass. In anorexia nervosa, an integrated
measure of overnight oxytocin levels obtained by
positively associated with spine and hip BMD (,
).
Low amylin levels
Amylin, a hormone that is cosecreted with insulin by
the b cells of the pancreas, is a regulator of bone
resorption in mouse models (). In amylin-deficient
mice, cortical and trabecular thickness are decreased as
compared with wild-type mice, despite similar body
weight, fat pad weight, and food intake (). Similarly,
women with anorexia nervosa have lower amylin levels
compared with normal-weight controls, and amylin is
positively associated with BMD of the spine and hip
(). Therefore, low amylin levels may also be a
significant contributor to low bone mass in anorexia
nervosa.
Other Potential Mediators of Loss of Bone Mass
For other potential mediators of low bone mass in
anorexia nervosa, see Table .
Decreased nutrient intake and
electrolyte abnormalities
Calcium and vitamin D
Although women with anorexia nervosa are in a state
of negative energy balance due to insufficient caloric
intake, inadequate intake of calcium and vitamin D is
likely not an important contributor to the low bone
mass observed in this disease. Compared with normal-
weight girls, adolescent girls with anorexia nervosa
consume more calcium and vitamin D, predominantly
through supplements (). Adolescent girls with
anorexia nervosa are also less likely to be vitamin D

902 Fazeli and Klibanski Effects of Anorexia Nervosa on Bone Metabolism Endocrine Reviews, December 2018, 39(6):895–910

deficient compared with their normal-weight coun-
terparts (, ). Therefore, calcium and vitamin
D deficiency are not important mediators of loss
of bone mass in anorexia nervosa, unless inadequate
supplementation causes significant vitamin D deficiency.
Protein
Girls and women with anorexia nervosa are in an
overall state of negative energy balance. Importantly,
individuals who consume sufficient calories may still
be at risk for bone loss in the setting of isolated
nutrient deficiencies. For example, isolated protein
deficiency has been associated with low IGF- levels
() and decreased cortical bone thickness (). Low
protein intake in the setting of a vegetarian diet in
normal-weight individuals has also been associated
with low BMD (). Multiple studies examining
macronutritent intake in adolescent girls with anorexia
nervosa have shown no difference in protein intake in
the individuals with anorexia nervosa as compared
with normal-weight controls (, , ), sug-
gesting that low protein intake does not independently
contribute to low BMD in individuals with anorexia
nervosa.
Hyponatremia
Low solute intake is associated with a decreased ability
to excrete free water and resultant hyponatremia.
Therefore, girls and women with anorexia nervosa
are at risk for hyponatremia, and % to % of
women with anorexia nervosa have low plasma
sodium levels (, ). In rodent models, hypona-
tremia is associated with loss of BMD (), likely
due, in part, to increased osteoclast formation and
activity (). Hyponatremia has also been associ-
ated with a . increased odds of femoral neck
osteoporosis in a large population-based study
(), and in studies of both women () and men
(), hyponatremia is an independent predictor of
fracture. We have shown that in women with an-
orexia nervosa, those with hyponatremia (plasma
sodium , mmol/L) have lower BMD at the
spine and hip as compared with those without
hyponatremia, even after controlling for age, body
mass index, and disease duration (). Therefore,
low plasma sodium levels may contribute to the low
BMD in individuals with anorexia nervosa.
Exercise
Weight-bearing exercise is an important determinant
of BMD in normal populations (). In a group of
healthy, normal-weight and overweight adults ran-
domized to either weight loss through caloric re-
striction or weight loss through increased physical
activity, despite losing similar amounts of weight (a
mean of .% to .% weight loss during  months),
those randomized to caloric restriction lost a mean of
.% of BMD at their lumbar spine and hip, whereas
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those randomized to exercise did not exhibit signifi-
cant changes in BMD during the -month study
(). Therefore, in healthy populations, physical
activity in the setting of weight loss appears to have
bone-protective effects.
Multiple studies have also investigated the effects of
exercise and physical activity on bone in individuals
with anorexia nervosa, but in this population, the
results have been mixed. A number of studies in both
adolescents and adults have shown a positive associ-
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ation between physical activity level and BMD in the
hip, spine, and radius (, , –), whereas other
studies have shown no correlation between BMD and
degree of physical activity (, , ). Importantly,
one study demonstrated a dose-dependent effect,
such that individuals who were moderate exercisers,
defined as  to  h/wk of physical activity, had the
highest spine and femoral neck BMD compared
with individuals who exercised , h/wk or . h/wk
(). Data collection in these studies was pre-
dominantly based on individual recall and self-
report of activity, making interpretation of the
results even more challenging, but given the fact that
physical activity may be associated with delayed
menarche and amenorrhea () and will result in
increased caloric requirements, the totality of the
data do not support encouraging exercise as a means
of protecting BMD in this population, but moderate
physical activity likely need not be discouraged
either.
Depression and use of psychotropic medications
Depression is a common comorbidity in girls and
women with anorexia nervosa, and depressive symp-
toms have been associated with low BMD in this
population, potentially mediated in part by elevations in
cortisol levels (, ). Both selective serotonin
reuptake inhibitors (SSRIs) and antipsychotics are
commonly prescribed medications in this population
(). Mouse models have demonstrated impairments
in bone mineral accrual in predominantly weight-
bearing sites with SSRI treatment (). SSRIs have
also been associated with decreased BMD in adolescents
(), bone loss in postmenopausal women (), and
an increased risk of fracture (). Two studies in
adolescents with anorexia nervosa have demonstrated
that SSRI use is a predictor of low BMD in this pop-
ulation, although depressive symptoms were not
controlled for in either study (, ). Therefore,
whether SSRIs are an independent mediator of low
BMD in this population is not known. Atypical
antipsychotic medications, another psychotropic
medication frequently prescribed in this population
(), have been associated with hyperprolactinemia
(), low BMD (), and increased fracture risk
(). Thus, it is possible that use of antipsychotic
medications also contributes to low BMD in this
population.
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Marrow fat and preadipocyte factor-1
Marrow adipose tissue may be an important de-
terminant of BMD and fracture risk. We have reported
that levels of marrow adipose tissue are elevated in
anorexia nervosa, a disease state characterized by low
levels of subcutaneous and visceral adipose tissue
(). Although the function of marrow adipose tissue
is not currently known, the fact that this fat depot
increases in size when lipid is actively being used as
an energy source suggests that marrow fat serves an
important role. Marrow adipose tissue has been
associated with measures of decreased bone in-
tegrity (), and in anorexia nervosa, levels of
marrow adipose tissue are inversely associated with
BMD () and with estimated bone strength ().
However, it is unknown whether marrow adipose
tissue is a significant determinant of the increased
fracture risk observed in anorexia nervosa. Un-
derstanding the determinants of marrow adipose
tissue and its association with bone metabolism will
be critical to determining the role and function of
this fat depot.
One potential determinant of marrow adipose
tissue is preadipocyte factor (Pref)-, a member of
the epidermal growth factor family of proteins.
Circulating Pref- levels are higher in anorexia
nervosa as compared with healthy controls, and
although Pref- has been shown to inhibit both
adipocyte and osteoblast differentiation (), Pref-
 is positively associated with marrow adipose tissue
in anorexia nervosa (, ). In women with an-
orexia nervosa, BMD is also inversely associated
with Pref- (, ). Importantly, however, it is not
known whether Pref-’s association with BMD is
independent of its effects on marrow adipose tissue.
Further studies are necessary to better delineate the
relationship between Pref-, marrow adipose tissue,
and BMD.
Sclerostin and dickkopf-related protein 1
Secreted by osteocytes, sclerostin is an inhibitor of
bone formation through Wnt signaling inhibition. In
rodent models, treatment with a sclerostin monoclonal
antibody increases bone mass and strength (). In
postmenopausal women, treatment with a sclerostin
monoclonal antibody for  months also increases
spine and hip BMD (, ). It is not known
whether sclerostin is a mediator of bone loss in an-
orexia nervosa. Although sclerostin levels are higher in
individuals with anorexia nervosa as compared with
normal-weight controls (), sclerostin does not
mediate the increases in BMD observed with physi-
ologic estrogen replacement in girls with anorexia
nervosa () or the increases in spine BMD observed
in teriparatide-treated women with anorexia nervosa
().
Dickkopf-related protein (DKK) is also a Wnt
signaling pathway inhibitor. Unlike sclerostin, DKK
904 Fazeli and Klibanski Effects of Anorexia Nervosa on Bone Metabolism
levels are low in anorexia nervosa (). Although
DKK levels have been shown to be positively asso-
ciated with bone formation markers () in in-
dividuals with anorexia nervosa, no associations
between DKK and BMD have been observed in this
disorder. Therefore, further studies are needed to
better understand whether sclerostin and/or DKK
are mediators of anorexia nervosa–associated bone
loss.
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Treatment of Low BMD in Anorexia Nervosa
For therapies that have shown efficacy in the treatment
of low bone mass in anorexia nervosa, see Table 
().
Amenorrheic women with anorexia nervosa have a
rate of bone loss of .% per year in the spine and .%
per year in the hip (). Weight recovery, coupled
with a resumption of menses, remains the most ef-
fective long-term treatment for bone loss in women
with anorexia nervosa, as recovery results in a .% per
year increase in spine BMD and a .% per year in-
crease in hip BMD (). However, as only % to
% of women with anorexia nervosa recover even
two decades after their diagnosis (, ), therapeutic
treatment options must be considered in this pop-
ulation to reduce the chronic bone loss and the sig-
nificantly increased fracture risk observed in individuals
with anorexia nervosa.
Given the hypogonadotropic hypogonadism char-
acteristic of this disease, hormonal treatments
including estrogen, testosterone, and DHEA have
been extensively investigated. Whereas oral estrogen,
predominantly in the form of oral contraceptive pills,
does not improve BMD in adult women (, ) or
adolescents () with anorexia nervosa,  months of
treatment with physiologic, predominantly trans-
dermal estrogen replacement increases spine BMD by
.% in adolescent girls (). Oral estrogen has been
shown to be effective in maintaining BMD in a
population of adolescent and adult women with
anorexia nervosa when combined with the androgen
precursor DHEA (, ), and oral estrogen in-
creases spine BMD by .% in adult women with
anorexia nervosa when combined with recombinant
human IGF- for  months, although treatment with
recombinant human IGH- alone showed no effect
(). Therefore, although oral estrogen alone does
not increase bone mass, or prevent its decline in
anorexia nervosa, an estrogen-replete state appears
necessary for other hormonal therapies to affect bone
mass.
Other treatments that have been investigated in
girls and women with anorexia nervosa include short-
term treatments for hospitalized patients as well as
more long-term antiresorptive and anabolic treat-
ments. In hospitalized patients, standing on a platform
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Table 3. Therapies That Have Shown Efficacy in the Treatment of Low Bone Mass in Anorexia Nervosa
Duration of
Therapy Change in BMD (Population Studied) Treatment References

Physiologic estrogen 2.6% increase in spine BMD (adolescents) 18 mo (74)

replacement

IGF-1 plus oral 1.8% increase in spine BMD (adults) 9 mo (73)

contraceptives

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DHEA plus oral Maintenance of BMD and parameters of hip structural geometry as compared with loss 18 mo (123, 124)
contraceptives of these parameters in placebo group (adolescents and adults)

Bisphosphonates 3% to 4% increase in spine BMD compared with placebo (adults; no significant increase 12 mo (39, 40)
in BMD in adolescents when compared with placebo)

2% increase in hip BMD compared with placebo (adults; no significant increase in BMD in
adolescents when compared with placebo)

Teriparatide 6% to 10% increase in spine BMD (adults) 6 mo (202)

Low-magnitude mechanical No data on BMD. Marker of bone formation (bone-specific alkaline phosphatase) maintained vs 10 min/d for 5 d (203)
stimulation a decrease in placebo group (adolescents)

that delivers low-magnitude mechanical stimulation Conclusions

for  minutes per day for  days prevented decreases
in bone-specific alkaline phosphatase, a marker of
bone formation (), and therefore further studies
will be necessary to determine whether this is an
effective means of reducing loss of bone mass in
anorexia nervosa. We have reported that oral
bisphosphonate therapy and the anabolic agent
teriparatide are very effective in increasing BMD in
adults with anorexia nervosa. Treatment with
 months of an oral bisphosphonate increased
spine and hip BMD by % to % compared with
placebo (), and  months of treatment with ter-
iparatide increased spine BMD by % to % ()
in adult women with anorexia nervosa. In contrast,
in a population of adolescents treated with a bisphosph-
onate for  months, there was no significant dif-
ference in change in BMD in the treatment group as
compared with the placebo group (), likely due to
differences in bone remodeling rates in the adolescent
vs adult populations (see “Deviations From Normal
Bone Modeling and Remodeling in Anorexia Nerv-
osa” above) and underscoring the importance of
evaluating treatments for bone loss in both adult and
adolescent populations. Importantly, we do not
know the effect of any of these treatments on
fractures in individuals with anorexia nervosa and
none of the described studies extended beyond
 months. Additionally, there are no studies in-
vestigating how to treat individuals with persistently
low BMD after recovery from anorexia nervosa.
Therefore, future studies are necessary to better
assess the long-term effects and safety of these
promising treatments on bone mass in girls and
women with anorexia nervosa and to determine the
best treatment strategies for individuals with per-
sistently low BMD after recovery.
Anorexia nervosa is a psychiatric illness in which
individuals are unable to maintain a normal weight
due to inappropriate caloric intake (, ). Only ~%
to % of women with this disorder recover . years
after their initial diagnosis and therefore the state of
negative energy balance is chronic for many patients
with anorexia nervosa (, ). The hormonal adapta-
tions that confer a survival advantage during short
periods of nutrient deficiency, including hypo-
gonadotropic hypogonadism and GH resistance, are
important mediators of the significant loss of bone
mass (, ) and increased risk of fracture observed in
individuals with anorexia nervosa (, ). Given the
chronicity of this disorder, therapeutic treatment
strategies are critical to prevent this long-term bone
loss and increased fracture risk. Although there are no
approved treatments for bone loss in this population, a
number of therapies have been investigated in short-
term studies and have demonstrated efficacy. How-
ever, a number of significant unmet challenges
remain for the treatment of bone loss in anorexia
nervosa. These include the lack of long-term treat-
ment options for loss of bone mass, particularly for
the % to % of patients that do not recover from
anorexia nervosa even  years after diagnosis (, ).
Although teriparatide and bisphosphonates have
shown promise in increasing BMD in adult women
with anorexia nervosa, neither of these treatments is a
long-term option owing to the fact that teriparatide is
only approved for  months of use and because of
the increased risk of atypical femoral fractures with
long-term bisphosphonate use (). Additionally,
more personalized treatment protocols that address
the differential patterns of bone loss that may develop
in individuals based on the timing of anorexia

doi: 10.1210/er.2018-00063 https://academic.oup.com/edrv 905

REVIEW
nervosa onset () may help address the difficult
challenge of treating long-term loss of bone mass
and increased fracture risk in individuals who de-
veloped the disease during adolescence but have since
References
1. Keski-Rahkonen A, Hoek HW, Susser ES, Linna MS,
Sihvola E, Raevuori A, Bulik CM, Kaprio J, Rissanen A.
Epidemiology and course of anorexia nervosa in
the community. Am J Psychiatry. 2007;164(8):
1259–1265.
2. Lucas AR, Crowson CS, O’Fallon WM, Melton LJ III.
The ups and downs of anorexia nervosa. Int J Eat
Disord. 1999;26(4):397–405.
3. Löwe B, Zipfel S, Buchholz C, Dupont Y, Reas DL,
Herzog W. Long-term outcome of anorexia nervosa
in a prospective 21-year follow-up study. Psychol
Med. 2001;31(5):881–890.
4. Eddy KT, Tabri N, Thomas JJ, Murray HB, Keshaviah
A, Hastings E, Edkins K, Krishna M, Herzog DB, Keel
PK, Franko DL. Recovery from anorexia nervosa and
bulimia nervosa at 22-year follow-up. J Clin Psy-
chiatry. 2017;78(2):184–189.
5. Miller KK, Grinspoon SK, Ciampa J, Hier J, Herzog D,
Klibanski A. Medical findings in outpatients with
anorexia nervosa. Arch Intern Med. 2005;165(5):
561–566.
6. Grinspoon S, Thomas E, Pitts S, Gross E, Mickley D,
Miller K, Herzog D, Klibanski A. Prevalence and
predictive factors for regional osteopenia in women
with anorexia nervosa. Ann Intern Med. 2000;
133(10):790–794.
7. Faje AT, Karim L, Taylor A, Lee H, Miller KK, Mendes
N, Meenaghan E, Goldstein MA, Bouxsein ML, Misra
M, Klibanski A. Adolescent girls with anorexia
nervosa have impaired cortical and trabecular
microarchitecture and lower estimated bone
strength at the distal radius. J Clin Endocrinol Metab.
2013;98(5):1923–1929.
8. Singhal V, Tulsiani S, Campoverde KJ, Mitchell DM,
Slattery M, Schorr M, Miller KK, Bredella MA, Misra
M, Klibanski A. Impaired bone strength estimates at
the distal tibia and its determinants in adolescents
with anorexia nervosa. Bone. 2018;106:61–68.
9. Bredella MA, Misra M, Miller KK, Madisch I, Sarwar
A, Cheung A, Klibanski A, Gupta R. Distal radius in
adolescent girls with anorexia nervosa: trabecular
structure analysis with high-resolution flat-panel
volume CT. Radiology. 2008;249(3):938–946.
10. Milos G, Spindler A, Rüegsegger P, Seifert B,
Mühlebach S, Uebelhart D, Häuselmann HJ. Cortical
and trabecular bone density and structure in an-
orexia nervosa. Osteoporos Int. 2005;16(7):783–790.
11. Lawson EA, Miller KK, Bredella MA, Phan C, Misra
M, Meenaghan E, Rosenblum L, Donoho D, Gupta R,
Klibanski A. Hormone predictors of abnormal bone
microarchitecture in women with anorexia nervosa.
Bone. 2010;46(2):458–463.
12. Walsh CJ, Phan CM, Misra M, Bredella MA, Miller
KK, Fazeli PK, Bayraktar HH, Klibanski A, Gupta R.
Women with anorexia nervosa: finite element and
trabecular structure analysis by using flat-panel
volume CT. Radiology. 2010;257(1):167–174.
13. Frølich J, Hansen S, Winkler LA, Andresen AK,
Hermann AP, Støving RK. The role of body weight
on bone in anorexia nervosa: a HR-pQCT study.
Calcif Tissue Int. 2017;101(1):24–33.
906 Fazeli and Klibanski
recovered (, ). Therefore, future studies are
necessary to optimize treatment strategies for the loss
of bone mass and increased fracture risk in anorexia
nervosa.
14. Rigotti NA, Neer RM, Skates SJ, Herzog DB,
Nussbaum SR. The clinical course of osteoporosis in
anorexia nervosa. A longitudinal study of cortical
bone mass. JAMA. 1991;265(9):1133–1138.
15. Vestergaard P, Emborg C, Støving RK, Hagen C,
Mosekilde L, Brixen K. Fractures in patients with
anorexia nervosa, bulimia nervosa, and other eating
disorders--a nationwide register study. Int J Eat
Disord. 2002;32(3):301–308.
16. Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi
S, Lee H, Mendes N, Snelgrove D, Meenaghan E,
Misra M, Klibanski A. Fracture risk and areal bone
mineral density in adolescent females with anorexia
nervosa. Int J Eat Disord. 2014;47(5):458–466.
17. Nagata JM, Golden NH, Leonard MB, Copelovitch L,
Denburg MR. Assessment of sex differences in
fracture risk among patients with anorexia nervosa:
a population-based cohort study using the health
improvement network. J Bone Miner Res. 2017;32(5):
1082–1089.
18. Lucas AR, Melton LJ III, Crowson CS, O’Fallon WM.
Long-term fracture risk among women with an-
orexia nervosa: a population-based cohort study.
Mayo Clin Proc. 1999;74(10):972–977.
19. Weaver L, Liebman R. Assessment of anorexia
nervosa in children and adolescents. Curr Psychiatry
Rep. 2011;13(2):93–98.
20. Bailey DA, Martin AD, McKay HA, Whiting S,
Mirwald R. Calcium accretion in girls and boys
during puberty: a longitudinal analysis. J Bone Miner
Res. 2000;15(11):2245–2250.
21. Eriksen EF, Charles P, Melsen F, Mosekilde L, Risteli L,
Risteli J. Serum markers of type I collagen formation
and degradation in metabolic bone disease: cor-
relation with bone histomorphometry. J Bone Miner
Res. 1993;8(2):127–132.
22. Saggese G, Bertelloni S, Baroncelli GI, Di Nero G.
Serum levels of carboxyterminal propeptide of type
I procollagen in healthy children from 1st year of life
to adulthood and in metabolic bone diseases. Eur J
Pediatr. 1992;151(10):764–768.
23. Heer M, Mika C, Grzella I, Heussen N, Herpertz-
Dahlmann B. Bone turnover during inpatient nu-
tritional therapy and outpatient follow-up in
patients with anorexia nervosa compared with that
in healthy control subjects. Am J Clin Nutr. 2004;
80(3):774–781.
24. 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(12):4489–4496.
25. Seeman E, Karlsson MK, Duan Y. On exposure to
anorexia nervosa, the temporal variation in axial and
appendicular skeletal development predisposes to
site-specific deficits in bone size and density: a cross-
sectional study. J Bone Miner Res. 2000;15(11):
2259–2265.
26. Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky
A, Seeman E. The differing tempo of growth in bone
size, mass, and density in girls is region-specific. J Clin
Invest. 1999;104(6):795–804.
Effects of Anorexia Nervosa on Bone Metabolism
Downloaded from https://academic.oup.com/edrv/article-abstract/39/6/895/5078825 by Research 4 Life user on 22 November 2018
27. Bachrach LK, Katzman DK, Litt IF, Guido D, Marcus
R. Recovery from osteopenia in adolescent girls with
anorexia nervosa. J Clin Endocrinol Metab. 1991;
72(3):602–606.
28. Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T,
Takano K. The relationship between bone turnover
and body weight, serum insulin-like growth factor
(IGF) I, and serum IGF-binding protein levels in
patients with anorexia nervosa. J Clin Endocrinol
Metab. 2000;85(1):200–206.
29. Weinbrenner T, Zittermann A, Gouni-Berthold I,
Stehle P, Berthold HK. Body mass index and disease
duration are predictors of disturbed bone turnover
in anorexia nervosa. A case-control study. Eur J Clin
Nutr. 2003;57(10):1262–1267.
30. Bolton JG, Patel S, Lacey JH, White S. A prospective
study of changes in bone turnover and bone density
associated with regaining weight in women with
anorexia nervosa. Osteoporos Int. 2005;16(12):
1955–1962.
31. Viapiana O, Gatti D, Dalle Grave R, Todesco T,
Rossini M, Braga V, Idolazzi L, Fracassi E, Adami S.
Marked increases in bone mineral density and
biochemical markers of bone turnover in patients
with anorexia nervosa gaining weight. Bone. 2007;
40(4):1073–1077.
32. Seeman E. Estrogen, androgen, and the pathogen-
esis of bone fragility in women and men. Curr
Osteoporos Rep. 2004;2(3):90–96.
33. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce
BF. Estrogen promotes apoptosis of murine oste-
oclasts mediated by TGF-b. Nat Med. 1996;2(10):
1132–1136.
34. Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM,
Eastell R, Khosla S. Relative contributions of tes-
tosterone and estrogen in regulating bone re-
sorption and formation in normal elderly men. J Clin
Invest. 2000;106(12):1553–1560.
35. Finkelstein JS, Lee H, Leder BZ, Burnett-Bowie SA,
Goldstein DW, Hahn CW, Hirsch SC, Linker A,
Perros N, Servais AB, Taylor AP, Webb ML,
Youngner JM, Yu EW. Gonadal steroid-dependent
effects on bone turnover and bone mineral density
in men. J Clin Invest. 2016;126(3):1114–1125.
36. Kaplan FS, Pertschuk M, Fallon M, Haddad J. Os-
teoporosis and hip fracture in a young woman with
anorexia nervosa. Clin Orthop Relat Res. 1986; (212):
250–254.
37. Kreipe RE, Hicks DG, Rosier RN, Puzas JE. Preliminary
findings on the effects of sex hormones on bone
metabolism in anorexia nervosa. J Adolesc Health.
1993;14(4):319–324.
38. Hiramatsu R, Ubara Y, Suwabe T, Hoshino J, Sumida
K, Hasegawa E, Yamanouchi M, Hayami N, Sawa N,
Takaichi K. Bone histomorphometric analysis in a
patient with anorexia nervosa. Bone. 2013;56(1):
77–82.
39. Miller KK, Meenaghan E, Lawson EA, Misra M,
Gleysteen S, Schoenfeld D, Herzog D, Klibanski A.
Effects of risedronate and low-dose transdermal tes-
tosterone on bone mineral density in women with
Endocrine Reviews, December 2018, 39(6):895–910

anorexia nervosa: a randomized, placebo-controlled
study. J Clin Endocrinol Metab. 2011;96(7):2081–2088.
40. Golden NH, Iglesias EA, Jacobson MS, Carey D,
Meyer W, Schebendach J, Hertz S, Shenker IR.
Alendronate for the treatment of osteopenia in
anorexia nervosa: a randomized, double-blind,
placebo-controlled trial. J Clin Endocrinol Metab.
2005;90(6):3179–3185.
41. Seeman E. Reduced bone formation and increased
bone resorption: rational targets for the treatment
of osteoporosis. Osteoporos Int. 2003;14(Suppl 3):
S2–S8.
42. Counts DR, Gwirtsman H, Carlsson LM, Lesem M,
Cutler GB Jr. The effect of anorexia nervosa and
refeeding on growth hormone-binding protein, the
insulin-like growth factors (IGFs), and the IGF-
binding proteins. J Clin Endocrinol Metab. 1992;
75(3):762–767.
43. Grinspoon S, Miller K, Coyle C, Krempin J,
Armstrong C, Pitts S, Herzog D, Klibanski A. Severity
of osteopenia in estrogen-deficient women with
anorexia nervosa and hypothalamic amenorrhea.
J Clin Endocrinol Metab. 1999;84(6):2049–2055.
44. Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman
S, Klibanski A. Mechanisms of osteoporosis in adult
and adolescent women with anorexia nervosa. J Clin
Endocrinol Metab. 1989;68(3):548–554.
45. van Binsbergen CJ, Coelingh Bennink HJ, Odink J,
Haspels AA, Koppeschaar HP. A comparative and
longitudinal study on endocrine changes related to
ovarian function in patients with anorexia nervosa.
J Clin Endocrinol Metab. 1990;71(3):705–711.
46. Miller KK, Lawson EA, Mathur V, Wexler TL,
Meenaghan E, Misra M, Herzog DB, Klibanski A.
Androgens in women with anorexia nervosa and
normal-weight women with hypothalamic amen-
orrhea. J Clin Endocrinol Metab. 2007;92(4):
1334–1339.
47. Walsh BT, Katz JL, Levin J, Kream J, Fukushima DK,
Hellman LD, Weiner H, Zumoff B. Adrenal activity
in anorexia nervosa. Psychosom Med. 1978;40(6):
499–506.
48. Boyar RM, Hellman LD, Roffwarg H, Katz J, Zumoff
B, O’Connor J, Bradlow HL, Fukushima DK. Cortisol
secretion and metabolism in anorexia nervosa.
N Engl J Med. 1977;296(4):190–193.
49. Misra M, Miller KK, Almazan C, Ramaswamy K,
Lapcharoensap W, Worley M, Neubauer G, Herzog
DB, Klibanski A. Alterations in cortisol secretory
dynamics in adolescent girls with anorexia nervosa
and effects on bone metabolism. J Clin Endocrinol
Metab. 2004;89(10):4972–4980.
50. Lawson EA, Donoho D, Miller KK, Misra M,
Meenaghan E, Lydecker J, Wexler T, Herzog DB,
Klibanski A. Hypercortisolemia is associated with
severity of bone loss and depression in hypotha-
lamic amenorrhea and anorexia nervosa. J Clin
Endocrinol Metab. 2009;94(12):4710–4716.
51. Zumoff B, Walsh BT, Katz JL, Levin J, Rosenfeld RS,
Kream J, Weiner H. Subnormal plasma dehy-
droisoandrosterone to cortisol ratio in anorexia
nervosa: a second hormonal parameter of onto-
genic regression. J Clin Endocrinol Metab. 1983;56(4):
668–672.
52. Winterer J, Gwirtsman HE, George DT, Kaye WH,
Loriaux DL, Cutler GB Jr. Adrenocorticotropin-
stimulated adrenal androgen secretion in an-
orexia nervosa: impaired secretion at low weight
with normalization after long-term weight recovery.
J Clin Endocrinol Metab. 1985;61(4):693–697.
53. Gordon CM, Goodman E, Emans SJ, Grace E, Becker
KA, Rosen CJ, Gundberg CM, Leboff MS. Physiologic
regulators of bone turnover in young women with
anorexia nervosa. J Pediatr. 2002;141(1):64–70.
doi: 10.1210/er.2018-00063
54. Dostálová I, Kaválková P, Haluzı́ková D, Lacinová Z,
Mráz M, Papezová H, Haluzı́k M. Plasma concen-
trations of fibroblast growth factors 19 and 21 in
patients with anorexia nervosa. J Clin Endocrinol
Metab. 2008;93(9):3627–3632.
55. Fazeli PK, Misra M, Goldstein M, Miller KK, Klibanski
A. Fibroblast growth factor-21 may mediate growth
hormone resistance in anorexia nervosa. J Clin
Endocrinol Metab. 2010;95(1):369–374.
56. Fazeli PK, Faje AT, Cross EJ, Lee H, Rosen CJ,
Bouxsein ML, Klibanski A. Serum FGF-21 levels are
associated with worsened radial trabecular bone
microarchitecture and decreased radial bone
strength in women with anorexia nervosa. Bone.
2015;77:6–11.
57. Mikolajczak A, Oswiecimska JM, Swietochowska E,
Roczniak W, Ziora KT. Serum FGF21 in girls with
anorexia nervosa - comparison to normal weight
and obese female adolescents. Neuroendocrinol Lett.
2017;38(3):173–181.
58. Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon
C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang
F, Epelbaum J, Estour B. Balance in ghrelin and leptin
plasma levels in anorexia nervosa patients and
constitutionally thin women. J Clin Endocrinol
Metab. 2003;88(1):109–116.
59. Misra M, Miller KK, Kuo K, Griffin K, Stewart V,
Hunter E, Herzog DB, Klibanski A. Secretory dy-
namics of leptin in adolescent girls with anorexia
nervosa and healthy adolescents. Am J Physiol
Endocrinol Metab. 2005;289(3):E373–E381.
60. Fazeli PK, Bredella MA, Misra M, Meenaghan E,
Rosen CJ, Clemmons DR, Breggia A, Miller KK,
Klibanski A. Preadipocyte factor-1 is associated with
marrow adiposity and bone mineral density in
women with anorexia nervosa. J Clin Endocrinol
Metab. 2010;95(1):407–413.
61. Legroux-Gérot I, Vignau J, Biver E, Pigny P, Collier F,
Marchandise X, Duquesnoy B, Cortet B. Anorexia
nervosa, osteoporosis and circulating leptin: the
missing link. Osteoporos Int. 2010;21(10):1715–1722.
62. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV), 4th
ed. Washington, DC: American Psychiatric Associ-
ation; 1994.
63. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders (DSM-5), 5th
ed. Washington, DC: American Psychiatric Associ-
ation; 2013.
64. Wiegelmann W, Solbach HG. Effects of LH-RH on
plasma levels of LH and FSH in anorexia nervosa.
Horm Metab Res. 1972;4(5):404.
65. Mecklenburg RS, Loriaux DL, Thompson RH,
Andersen AE, Lipsett MB. Hypothalamic dysfunc-
tion in patients with anorexia nervosa. Medicine
(Baltimore). 1974;53(2):147–159.
66. Travaglini P, Beck-Peccoz P, Ferrari C, Ambrosi B,
Paracchi A, Severgnini A, Spada A, Faglia G. Some
aspects of hypothalamic-pituitary function in pa-
tients with anorexia nervosa. Acta Endocrinol
(Copenh). 1976;81(2):252–262.
67. Nillius SJ, Fries H, Wide L. Successful induction of
follicular maturation and ovulation by prolonged
treatment with LH-releasing hormone in women
with anorexia nervosa. Am J Obstet Gynecol. 1975;
122(8):921–928.
68. Boyar RM, Katz J, Finkelstein JW, Kapen S, Weiner H,
Weitzman ED, Hellman L. Anorexia nervosa. Im-
maturity of the 24-hour luteinizing hormone se-
cretory pattern. N Engl J Med. 1974;291(17):
861–865.
69. Riis BJ, Rødbro P, Christiansen C. The role of serum
concentrations of sex steroids and bone turn-
over in the development and occurrence of
https://academic.oup.com/edrv
REVIEW
postmenopausal osteoporosis. Calcif Tissue Int.
1986;38(6):318–322.
70. Seeman E, Szmukler GI, Formica C, Tsalamandris C,
Mestrovic R. Osteoporosis in anorexia nervosa: the
influence of peak bone density, bone loss, oral
contraceptive use, and exercise. J Bone Miner Res.
1992;7(12):1467–1474.
71. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB,
Saxe VC. The effects of estrogen administration on
trabecular bone loss in young women with anorexia
nervosa. J Clin Endocrinol Metab. 1995;80(3):
898–904.
Downloaded from https://academic.oup.com/edrv/article-abstract/39/6/895/5078825 by Research 4 Life user on 22 November 2018
72. Golden NH, Lanzkowsky L, Schebendach J, Palestro
CJ, Jacobson MS, Shenker IR. The effect of estrogen-
progestin treatment on bone mineral density in
anorexia nervosa. J Pediatr Adolesc Gynecol. 2002;
15(3):135–143.
73. Grinspoon S, Thomas L, Miller K, Herzog D,
Klibanski A. Effects of recombinant human IGF-I
and oral contraceptive administration on bone
density in anorexia nervosa. J Clin Endocrinol Metab.
2002;87(6):2883–2891.
74. Misra M, Katzman D, Miller KK, Mendes N,
Snelgrove D, Russell M, Goldstein MA, Ebrahimi S,
Clauss L, Weigel T, Mickley D, Schoenfeld DA,
Herzog DB, Klibanski A. Physiologic estrogen re-
placement increases bone density in adolescent
girls with anorexia nervosa. J Bone Miner Res. 2011;
26(10):2430–2438.
75. Weissberger AJ, Ho KK, Lazarus L. Contrasting ef-
fects of oral and transdermal routes of estrogen
replacement therapy on 24-hour growth hormone
(GH) secretion, insulin-like growth factor I, and GH-
binding protein in postmenopausal women. J Clin
Endocrinol Metab. 1991;72(2):374–381.
76. Kam GY, Leung KC, Baxter RC, Ho KK. Estrogens
exert route- and dose-dependent effects on insulin-
like growth factor (IGF)-binding protein-3 and the
acid-labile subunit of the IGF ternary complex. J Clin
Endocrinol Metab. 2000;85(5):1918–1922.
77. Miller KK, Grinspoon S, Gleysteen S, Grieco KA,
Ciampa J, Breu J, Herzog DB, Klibanski A. Preser-
vation of neuroendocrine control of reproductive
function despite severe undernutrition. J Clin
Endocrinol Metab. 2004;89(9):4434–4438.
78. Garfinkel PE, Brown GM, Stancer HC, Moldofsky H.
Hypothalamic-pituitary function in anorexia nerv-
osa. Arch Gen Psychiatry. 1975;32(6):739–744.
79. Scacchi M, Pincelli AI, Caumo A, Tomasi P, Delitala
G, Baldi G, Cavagnini F. Spontaneous nocturnal
growth hormone secretion in anorexia nervosa.
J Clin Endocrinol Metab. 1997;82(10):3225–3229.
80. Støving RK, Veldhuis JD, Flyvbjerg A, Vinten J,
Hangaard J, Koldkjaer OG, Kristiansen J, Hagen C.
Jointly amplified basal and pulsatile growth hor-
mone (GH) secretion and increased process ir-
regularity in women with anorexia nervosa: indirect
evidence for disruption of feedback regulation
within the GH-insulin-like growth factor I axis. J Clin
Endocrinol Metab. 1999;84(6):2056–2063.
81. Misra M, Miller KK, Bjornson J, Hackman A,
Aggarwal A, Chung J, Ott M, Herzog DB, Johnson
ML, Klibanski A. Alterations in growth hormone
secretory dynamics in adolescent girls with anorexia
nervosa and effects on bone metabolism. J Clin
Endocrinol Metab. 2003;88(12):5615–5623.
82. Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy
AJ, Valenzuela DM, Yancopoulos GD, Goldstein JL,
Brown MS. Ghrelin O-acyltransferase (GOAT) is
essential for growth hormone-mediated survival of
calorie-restricted mice. Proc Natl Acad Sci USA.
2010;107(16):7467–7472.
83. Gahete MD, Córdoba-Chacón J, Luque RM,
Kineman RD. The rise in growth hormone during
907
REVIEW
starvation does not serve to maintain glucose levels
or lean mass but is required for appropriate adipose
tissue response in female mice. Endocrinology. 2013;
154(1):263–269.
84. Gianotti L, Pincelli AI, Scacchi M, Rolla M, Bellitti D,
Arvat E, Lanfranco F, Torsello A, Ghigo E, Cavagnini
F, Müller EE. Effects of recombinant human insulin-
like growth factor I administration on spontaneous
and growth hormone (GH)-releasing hormone-
stimulated GH secretion in anorexia nervosa.
J Clin Endocrinol Metab. 2000;85(8):2805–2809.
85. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny
C, Riepl RL, Heiman ML, Lehnert P, Fichter M,
Tschöp M. Weight gain decreases elevated plasma
ghrelin concentrations of patients with anorexia
nervosa. Eur J Endocrinol. 2001;145(5):669–673.
86. Misra M, Miller KK, Herzog DB, Ramaswamy K,
Aggarwal A, Almazan C, Neubauer G, Breu J,
Klibanski A. Growth hormone and ghrelin re-
sponses to an oral glucose load in adolescent girls
with anorexia nervosa and controls. J Clin Endocrinol
Metab. 2004;89(4):1605–1612.
87. Misra M, Miller KK, Kuo K, Griffin K, Stewart V,
Hunter E, Herzog DB, Klibanski A. Secretory dy-
namics of ghrelin in adolescent girls with anorexia
nervosa and healthy adolescents. Am J Physiol
Endocrinol Metab. 2005;289(2):E347–E356.
88. Flint A, Raben A, Blundell JE, Astrup A. Re-
producibility, power and validity of visual analogue
scales in assessment of appetite sensations in single
test meal studies. Int J Obes Relat Metab Disord.
2000;24(1):38–48.
89. Halmi KA, Sunday S, Puglisi A, Marchi P. Hunger and
satiety in anorexia and bulimia nervosa. Ann N Y
Acad Sci. 1989;575:431–444, discussion 444–445.
90. McCallum RW, Grill BB, Lange R, Planky M, Glass EE,
Greenfeld DG. Definition of a gastric emptying
abnormality in patients with anorexia nervosa. Dig
Dis Sci. 1985;30(8):713–722.
91. Domstad PA, Shih WJ, Humphries L, DeLand FH,
Digenis GA. Radionuclide gastric emptying studies
in patients with anorexia nervosa. J Nucl Med. 1987;
28(5):816–819.
92. Stacher G, Kiss A, Wiesnagrotzki S, Bergmann H,
Höbart J, Schneider C. Oesophageal and gastric
motility disorders in patients categorised as having
primary anorexia nervosa. Gut. 1986;27(10):1120–
1126.
93. Holsen LM, Lawson EA, Christensen K, Klibanski A,
Goldstein JM. Abnormal relationships between the
neural response to high- and low-calorie foods and
endogenous acylated ghrelin in women with active
and weight-recovered anorexia nervosa. Psychiatry
Res. 2014;223(2):94–103.
94. Hotta M, Ohwada R, Katakami H, Shibasaki T,
Hizuka N, Takano K. Plasma levels of intact and
degraded ghrelin and their responses to glucose
infusion in anorexia nervosa. J Clin Endocrinol Metab.
2004;89(11):5707–5712.
95. Fazeli PK, Lawson EA, Faje AT, Eddy KT, Lee H,
Fiedorek FT, Breggia A, Gaal IM, DeSanti R, Kli-
banski A. Treatment with a ghrelin agonist in
outpatient women with anorexia nervosa: a ran-
domized clinical trial. J Clin Psychiatry. 2018;79(1):
17m11585.
96. Fukushima N, Hanada R, Teranishi H, Fukue Y,
Tachibana T, Ishikawa H, Takeda S, Takeuchi Y,
Fukumoto S, Kangawa K, Nagata K, Kojima M.
Ghrelin directly regulates bone formation. J Bone
Miner Res. 2005;20(5):790–798.
97. Misra M, Miller KK, Stewart V, Hunter E, Kuo K,
Herzog DB, Klibanski A. Ghrelin and bone meta-
bolism in adolescent girls with anorexia nervosa and
908 Fazeli and Klibanski
healthy adolescents. J Clin Endocrinol Metab. 2005;
90(9):5082–5087.
98. Misra M, Prabhakaran R, Miller KK, Goldstein MA,
Mickley D, Clauss L, Lockhart P, Cord J, Herzog DB,
Katzman DK, Klibanski A. Prognostic indicators of
changes in bone density measures in adolescent
girls with anorexia nervosa-II. J Clin Endocrinol
Metab. 2008;93(4):1292–1297.
99. Grinspoon SK, Baum HB, Peterson S, Klibanski A.
Effects of rhIGF-I administration on bone turnover
during short-term fasting. J Clin Invest. 1995;96(2):
900–906.
100. Fazeli PK, Lawson EA, Prabhakaran R, Miller KK,
Donoho DA, Clemmons DR, Herzog DB, Misra M,
Klibanski A. Effects of recombinant human growth
hormone in anorexia nervosa: a randomized,
placebo-controlled study. J Clin Endocrinol Metab.
2010;95(11):4889–4897.
101. Nakasaki M, Yoshioka K, Miyamoto Y, Sasaki T,
Yoshikawa H, Itoh K. IGF-I secreted by osteoblasts
acts as a potent chemotactic factor for osteoblasts.
Bone. 2008;43(5):869–879.
102. Canalis E. Effect of insulinlike growth factor I on
DNA and protein synthesis in cultured rat calvaria.
J Clin Invest. 1980;66(4):709–719.
103. Misra M, McGrane J, Miller KK, Goldstein MA,
Ebrahimi S, Weigel T, Klibanski A. Effects of rhIGF-1
administration on surrogate markers of bone
turnover in adolescents with anorexia nervosa.
Bone. 2009;45(3):493–498.
104. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier
JS, Maratos-Flier E. Hepatic fibroblast growth factor
21 is regulated by PPARalpha and is a key mediator
of hepatic lipid metabolism in ketotic states. Cell
Metab. 2007;5(6):426–437.
105. Nishimura T, Nakatake Y, Konishi M, Itoh N.
Identification of a novel FGF, FGF-21, preferentially
expressed in the liver. Biochim Biophys Acta. 2000;
1492(1):203–206.
106. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L,
Parameswara V, Li Y, Goetz R, Mohammadi M, Esser
V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE,
Mangelsdorf DJ, Kliewer SA. Endocrine regulation of
the fasting response by PPARalpha-mediated in-
duction of fibroblast growth factor 21. Cell Metab.
2007;5(6):415–425.
107. Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S,
Zhang Y, Lee H, Catana C, Klibanski A, Patwari P,
Steinhauser ML. FGF21 and the late adaptive re-
sponse to starvation in humans. J Clin Invest. 2015;
125(12):4601–4611.
108. Kharitonenkov A, Shiyanova TL, Koester A, Ford
AM, Micanovic R, Galbreath EJ, Sandusky GE,
Hammond LJ, Moyers JS, Owens RA, Gromada J,
Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS,
Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a
novel metabolic regulator. J Clin Invest. 2005;115(6):
1627–1635.
109. Inagaki T, Lin VY, Goetz R, Mohammadi M,
Mangelsdorf DJ, Kliewer SA. Inhibition of growth
hormone signaling by the fasting-induced hormone
FGF21. Cell Metab. 2008;8(1):77–83.
110. Wei W, Dutchak PA, Wang X, Ding X, Wang X,
Bookout AL, Goetz R, Mohammadi M, Gerard RD,
Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y.
Fibroblast growth factor 21 promotes bone loss by
potentiating the effects of peroxisome proliferator-
activated receptor g. Proc Natl Acad Sci USA. 2012;
109(8):3143–3148.
111. Fichter MM, Pirke KM. Effect of experimental and
pathological weight loss upon the hypothalamo-
pituitary-adrenal axis. Psychoneuroendocrinology.
1986;11(3):295–305.
Effects of Anorexia Nervosa on Bone Metabolism
112. Kling MA, Demitrack MA, Whitfield HJ Jr, Kalogeras
KT, Listwak SJ, DeBellis MD, Chrousos GP, Gold PW,
Brandt HA. Effects of the glucocorticoid antagonist
RU 486 on pituitary-adrenal function in patients
with anorexia nervosa and healthy volunteers:
enhancement of plasma ACTH and cortisol se-
cretion in underweight patients. Neuroendocrinol-
ogy. 1993;57(6):1082–1091.
113. Morris HA, Need AG, O’Loughlin PD, Horowitz M,
Bridges A, Nordin BE. Malabsorption of calcium in
corticosteroid-induced osteoporosis. Calcif Tissue
Int. 1990;46(5):305–308.
Downloaded from https://academic.oup.com/edrv/article-abstract/39/6/895/5078825 by Research 4 Life user on 22 November 2018
114. Hansen JW, Gordan GS, Prussin SG. Direct mea-
surement of osteolysis in man. J Clin Invest. 1973;
52(2):304–315.
115. Canalis E. Clinical review 83: Mechanisms of glu-
cocorticoid action in bone: implications to
glucocorticoid-induced osteoporosis. J Clin Endo-
crinol Metab. 1996;81(10):3441–3447.
116. Rauch A, Seitz S, Baschant U, Schilling AF, Illing A,
Stride B, Kirilov M, Mandic V, Takacz A, Schmidt-
Ullrich R, Ostermay S, Schinke T, Spanbroek R, Zaiss
MM, Angel PE, Lerner UH, David JP, Reichardt HM,
Amling M, Schütz G, Tuckermann JP. Glucocorti-
coids suppress bone formation by attenuating
osteoblast differentiation via the monomeric glu-
cocorticoid receptor. Cell Metab. 2010;11(6):
517–531.
117. McCarthy TL, Centrella M, Canalis E. Cortisol in-
hibits the synthesis of insulin-like growth factor-I in
skeletal cells. Endocrinology. 1990;126(3):1569–1575.
118. Padmanabhan V, Keech C, Convey EM. Cortisol
inhibits and adrenocorticotropin has no effect on
luteinizing hormone-releasing hormone-induced
release of luteinizing hormone from bovine pitui-
tary cells in vitro. Endocrinology. 1983;112(5):
1782–1787.
119. Ureña P, Iida-Klein A, Kong XF, Jüppner H,
Kronenberg HM, Abou-Samra AB, Segre GV. Reg-
ulation of parathyroid hormone (PTH)/PTH-related
peptide receptor messenger ribonucleic acid by
glucocorticoids and PTH in ROS 17/2.8 and OK
cells. Endocrinology. 1994;134(1):451–456.
120. Abrams SA, Silber TJ, Esteban NV, Vieira NE, Stuff JE,
Meyers R, Majd M, Yergey AL. Mineral balance and
bone turnover in adolescents with anorexia nerv-
osa. J Pediatr. 1993;123(2):326–331.
121. Gordon CM, Grace E, Emans SJ, Feldman HA,
Goodman E, Becker KA, Rosen CJ, Gundberg CM,
LeBoff MS. Effects of oral dehydroepiandrosterone
on bone density in young women with anorexia
nervosa: a randomized trial. J Clin Endocrinol Metab.
2002;87(11):4935–4941.
122. Bloch M, Ish-Shalom S, Greenman Y, Klein E, Latzer
Y. Dehydroepiandrosterone treatment effects on
weight, bone density, bone metabolism and mood
in women suffering from anorexia nervosa-a pilot
study. Psychiatry Res. 2012;200(2-3):544–549.
123. Divasta AD, Feldman HA, Giancaterino C, Rosen CJ,
Leboff MS, Gordon CM. The effect of gonadal and
adrenal steroid therapy on skeletal health in ado-
lescents and young women with anorexia nervosa.
Metabolism. 2012;61(7):1010–1020.
124. DiVasta AD, Feldman HA, Beck TJ, LeBoff MS,
Gordon CM. Does hormone replacement nor-
malize bone geometry in adolescents with anorexia
nervosa? J Bone Miner Res. 2014;29(1):151–157.
125. Moshang T Jr, Parks JS, Baker L, Vaidya V, Utiger RD,
Bongiovanni AM, Snyder PJ. Low serum tri-
iodothyronine in patients with anorexia nervosa.
J Clin Endocrinol Metab. 1975;40(3):470–473.
126. Miyai K, Yamamoto T, Azukizawa M, Ishibashi K,
Kumahara Y. Serum thyroid hormones and thyrotropin
Endocrine Reviews, December 2018, 39(6):895–910

in anorexia nervosa. J Clin Endocrinol Metab. 1975;40(2):
334–338.
127. Croxson MS, Ibbertson HK. Low serum tri-
iodothyronine (T3) and hypothyroidism in anorexia
nervosa. J Clin Endocrinol Metab. 1977;44(1):
167–174.
128. Leslie RD, Isaacs AJ, Gomez J, Raggatt PR, Bayliss R.
Hypothalamo-pituitary-thyroid function in an-
orexia nervosa: influence of weight gain. BMJ. 1978;
2(6136):526–528.
129. Casper RC, Frohman LA. Delayed TSH release in
anorexia nervosa following injection of thyrotropin-
releasing hormone (TRH). Psychoneuroendocrinol-
ogy. 1982;7(1):59–68.
130. Moore R, Mills IH. Serum T3 and T4 levels in pa-
tients with anorexia nervosa showing transient
hyperthyroidism during weight gain. Clin Endocrinol
(Oxf). 1979;10(5):443–449.
131. Onur S, Haas V, Bosy-Westphal A, Hauer M, Paul T,
Nutzinger D, Klein H, Müller MJ. L-tri-iodothyronine
is a major determinant of resting energy expendi-
ture in underweight patients with anorexia nervosa
and during weight gain. Eur J Endocrinol. 2005;
152(2):179–184.
132. Fraser SA, Anderson JB, Smith DA, Wilson GM.
Osteoporosis and fractures following thyrotoxicosis.
Lancet. 1971;1(7707):981–983.
133. Bassett JH, Williams GR. Critical role of the
hypothalamic-pituitary-thyroid axis in bone. Bone.
2008;43(3):418–426.
134. Abu EO, Bord S, Horner A, Chatterjee VK,
Compston JE. The expression of thyroid hormone
receptors in human bone. Bone. 1997;21(2):
137–142.
135. Kindblom JM, Gevers EF, Skrtic SM, Lindberg MK,
Göthe S, Törnell J, Vennström B, Ohlsson C. In-
creased adipogenesis in bone marrow but de-
creased bone mineral density in mice devoid of
thyroid hormone receptors. Bone. 2005;36(4):
607–616.
136. Bredella MA, Fazeli PK, Miller KK, Misra M, Torriani
M, Thomas BJ, Ghomi RH, Rosen CJ, Klibanski A.
Increased bone marrow fat in anorexia nervosa.
J Clin Endocrinol Metab. 2009;94(6):2129–2136.
137. Ecklund K, Vajapeyam S, Feldman HA, Buzney CD,
Mulkern RV, Kleinman PK, Rosen CJ, Gordon CM.
Bone marrow changes in adolescent girls with
anorexia nervosa. J Bone Miner Res. 2010;25(2):
298–304.
138. Miell JP, Taylor AM, Zini M, Maheshwari HG, Ross
RJ, Valcavi R. Effects of hypothyroidism and hy-
perthyroidism on insulin-like growth factors (IGFs)
and growth hormone- and IGF-binding proteins.
J Clin Endocrinol Metab. 1993;76(4):950–955.
139. Misra M, Miller KK, Tsai P, Gallagher K, Lin A, Lee N,
Herzog DB, Klibanski A. Elevated peptide YY levels
in adolescent girls with anorexia nervosa. J Clin
Endocrinol Metab. 2006;91(3):1027–1033.
140. Utz AL, Lawson EA, Misra M, Mickley D, Gleysteen S,
Herzog DB, Klibanski A, Miller KK. Peptide YY (PYY)
levels and bone mineral density (BMD) in women
with anorexia nervosa. Bone. 2008;43(1):135–139.
141. Misra M, Miller KK, Cord J, Prabhakaran R, Herzog
DB, Goldstein M, Katzman DK, Klibanski A. Re-
lationships between serum adipokines, insulin
levels, and bone density in girls with anorexia
nervosa. J Clin Endocrinol Metab. 2007;92(6):
2046–2052.
142. Tagami T, Satoh N, Usui T, Yamada K, Shimatsu A,
Kuzuya H. Adiponectin in anorexia nervosa and
bulimia nervosa. J Clin Endocrinol Metab. 2004;89(4):
1833–1837.
143. Housova J, Anderlova K, Krizová J, Haluzikova D,
Kremen J, Kumstyrová T, Papezová H, Haluzik M.
doi: 10.1210/er.2018-00063
Serum adiponectin and resistin concentrations in
patients with restrictive and binge/purge form of
anorexia nervosa and bulimia nervosa. J Clin
Endocrinol Metab. 2005;90(3):1366–1370.
144. Cawthorn WP, Scheller EL, Learman BS, Parlee SD,
Simon BR, Mori H, Ning X, Bree AJ, Schell B, Broome
DT, Soliman SS, DelProposto JL, Lumeng CN, Mitra
A, Pandit SV, Gallagher KA, Miller JD, Krishnan V,
Hui SK, Bredella MA, Fazeli PK, Klibanski A,
Horowitz MC, Rosen CJ, MacDougald OA. Bone
marrow adipose tissue is an endocrine organ that
contributes to increased circulating adiponectin
during caloric restriction. Cell Metab. 2014;20(2):
368–375.
145. Wojcik MH, Meenaghan E, Lawson EA, Misra M,
Klibanski A, Miller KK. Reduced amylin levels are
associated with low bone mineral density in women
with anorexia nervosa. Bone. 2010;46(3):796–800.
146. Lawson EA, Donoho DA, Blum JI, Meenaghan EM,
Misra M, Herzog DB, Sluss PM, Miller KK, Klibanski
A. Decreased nocturnal oxytocin levels in anorexia
nervosa are associated with low bone mineral
density and fat mass. J Clin Psychiatry. 2011;72(11):
1546–1551.
147. Schorr M, Marengi DA, Pulumo RL, Yu E, Eddy KT,
Klibanski A, Miller KK, Lawson EA. Oxytocin and its
relationship to body composition, bone mineral
density, and hip geometry across the weight
spectrum. J Clin Endocrinol Metab. 2017;102(8):
2814–2824.
148. Maı̈moun L, Guillaume S, Lefebvre P, Philibert P,
Bertet H, Picot MC, Gaspari L, Paris F, Courtet P,
Thomas E, Mariano-Goulart D, Bringer J, Renard E,
Sultan C. Role of sclerostin and dickkopf-1 in the
dramatic alteration in bone mass acquisition in
adolescents and young women with recent an-
orexia nervosa. J Clin Endocrinol Metab. 2014;99(4):
E582–E590.
149. Grinspoon S, Gulick T, Askari H, Landt M, Lee K,
Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D,
Klibanski A. Serum leptin levels in women with
anorexia nervosa. J Clin Endocrinol Metab. 1996;
81(11):3861–3863.
150. Welt CK, Chan JL, Bullen J, Murphy R, Smith P,
DePaoli AM, Karalis A, Mantzoros CS. Recombinant
human leptin in women with hypothalamic
amenorrhea. N Engl J Med. 2004;351(10):987–997.
151. Chou SH, Chamberland JP, Liu X, Matarese G, Gao
C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi
K, Mantzoros CS. Leptin is an effective treatment
for hypothalamic amenorrhea. Proc Natl Acad Sci
USA. 2011;108(16):6585–6590.
152. Lee NJ, Nguyen AD, Enriquez RF, Doyle KL, Sainsbury
A, Baldock PA, Herzog H. Osteoblast specific Y1
receptor deletion enhances bone mass. Bone. 2011;
48(3):461–467.
153. Baldock PA, Sainsbury A, Couzens M, Enriquez RF,
Thomas GP, Gardiner EM, Herzog H. Hypothalamic
Y2 receptors regulate bone formation. J Clin Invest.
2002;109(7):915–921.
154. Wong IP, Driessler F, Khor EC, Shi YC, Hörmer B,
Nguyen AD, Enriquez RF, Eisman JA, Sainsbury A,
Herzog H, Baldock PA. Peptide YY regulates bone
remodeling in mice: a link between gut and skeletal
biology. PLoS One. 2012;7(7):e40038.
155. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K,
Miyagawa J, Hotta K, Shimomura I, Nakamura T,
Miyaoka K, Kuriyama H, Nishida M, Yamashita S,
Okubo K, Matsubara K, Muraguchi M, Ohmoto Y,
Funahashi T, Matsuzawa Y. Paradoxical decrease of
an adipose-specific protein, adiponectin, in obesity.
Biochem Biophys Res Commun. 1999;257(1):79–83.
156. Luo XH, Guo LJ, Xie H, Yuan LQ, Wu XP, Zhou HD,
Liao EY. Adiponectin stimulates RANKL and
https://academic.oup.com/edrv
REVIEW
inhibits OPG expression in human osteoblasts
through the MAPK signaling pathway. J Bone Miner
Res. 2006;21(10):1648–1656.
157. Ealey KN, Kaludjerovic J, Archer MC, Ward WE.
Adiponectin is a negative regulator of bone mineral
and bone strength in growing mice. Exp Biol Med
(Maywood). 2008;233(12):1546–1553.
158. Arletti R, Benelli A, Bertolini A. Influence of oxytocin
on feeding behavior in the rat. Peptides. 1989;10(1):
89–93.
159. Björkstrand E, Uvnäs-Moberg K. Central oxytocin
increases food intake and daily weight gain in rats.
Downloaded from https://academic.oup.com/edrv/article-abstract/39/6/895/5078825 by Research 4 Life user on 22 November 2018
Physiol Behav. 1996;59(4-5):947–952.
160. Lawson EA, Marengi DA, DeSanti RL, Holmes TM,
Schoenfeld DA, Tolley CJ. Oxytocin reduces caloric
intake in men. Obesity (Silver Spring). 2015;23(5):
950–956.
161. Colaianni G, Tamma R, Di Benedetto A, Yuen T, Sun
L, Zaidi M, Zallone A. The oxytocin-bone axis.
J Neuroendocrinol. 2014;26(2):53–57.
162. Tamma R, Colaianni G, Zhu LL, DiBenedetto A,
Greco G, Montemurro G, Patano N, Strippoli M,
Vergari R, Mancini L, Colucci S, Grano M, Faccio R,
Liu X, Li J, Usmani S, Bachar M, Bab I, Nishimori K,
Young LJ, Buettner C, Iqbal J, Sun L, Zaidi M, Zallone
A. Oxytocin is an anabolic bone hormone. Proc Natl
Acad Sci USA. 2009;106(17):7149–7154.
163. Elabd C, Basillais A, Beaupied H, Breuil V, Wagner N,
Scheideler M, Zaragosi LE, Massiéra F, Lemichez E,
Trajanoski Z, Carle G, Euller-Ziegler L, Ailhaud G,
Benhamou CL, Dani C, Amri EZ. Oxytocin controls
differentiation of human mesenchymal stem cells
and reverses osteoporosis. Stem Cells. 2008;26(9):
2399–2407.
164. Dacquin R, Davey RA, Laplace C, Levasseur R, Morris
HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac
JD, Karsenty G. Amylin inhibits bone resorption
while the calcitonin receptor controls bone for-
mation in vivo. J Cell Biol. 2004;164(4):509–514.
165. Misra M, Tsai P, Anderson EJ, Hubbard JL, Gallagher
K, Soyka LA, Miller KK, Herzog DB, Klibanski A.
Nutrient intake in community-dwelling adolescent
girls with anorexia nervosa and in healthy adoles-
cents. Am J Clin Nutr. 2006;84(4):698–706.
166. Haagensen AL, Feldman HA, Ringelheim J, Gordon
CM. Low prevalence of vitamin D deficiency among
adolescents with anorexia nervosa. Osteoporos Int.
2008;19(3):289–294.
167. Isley WL, Underwood LE, Clemmons DR. Dietary
components that regulate serum somatomedin-C
concentrations in humans. J Clin Invest. 1983;71(2):
175–182.
168. Garn SM, Rohmann CG, Behar M, Viteri F, Guzman
MA. Compact bone deficiency in protein-calorie
malnutrition. Science. 1964;145(3639):1444–1445.
169. Fontana L, Shew JL, Holloszy JO, Villareal DT. Low
bone mass in subjects on a long-term raw veg-
etarian diet. Arch Intern Med. 2005;165(6):
684–689.
170. Fernstrom MH, Weltzin TE, Neuberger S, Srinivasagam
N, Kaye WH. Twenty-four-hour food intake in
patients with anorexia nervosa and in healthy
control subjects. Biol Psychiatry. 1994;36(10):
696–702.
171. Mehler PS, Blalock DV, Walden K, Kaur S, McBride
J, Walsh K, Watts J. Medical findings in 1,026
consecutive adult inpatient-residential eating
disordered patients. Int J Eat Disord. 2018;51(4):
305–313.
172. Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams
DJ, Carter EA, Resnick HE. Hyponatremia-induced
osteoporosis. J Bone Miner Res. 2010;25(3):
554–563.
909
REVIEW
173. Barsony J, Sugimura Y, Verbalis JG. Osteoclast re-
sponse to low extracellular sodium and the
mechanism of hyponatremia-induced bone loss.
J Biol Chem. 2011;286(12):10864–10875.
174. Kinsella S, Moran S, Sullivan MO, Molloy MG,
Eustace JA. Hyponatremia independent of osteo-
porosis is associated with fracture occurrence. Clin J
Am Soc Nephrol. 2010;5(2):275–280.
175. Jamal SA, Arampatzis S, Harrison SL, Bucur RC,
Ensrud K, Orwoll ES, Bauer DC. Hyponatremia and
fractures: findings from the MrOS study. J Bone
Miner Res. 2015;30(6):970–975.
176. Lawson EA, Fazeli PK, Calder G, Putnam H, Misra M,
Meenaghan E, Miller KK, Klibanski A. Plasma so-
dium level is associated with bone loss severity in
women with anorexia nervosa: a cross-sectional
study. J Clin Psychiatry. 2012;73(11):e1379–e1383.
177. Etherington J, Harris PA, Nandra D, Hart DJ,
Wolman RL, Doyle DV, Spector TD. The effect of
weight-bearing exercise on bone mineral density:
a study of female ex-elite athletes and the general
population. J Bone Miner Res. 1996;11(9):1333–1338.
178. Villareal DT, Fontana L, Weiss EP, Racette SB, Steger-
May K, Schechtman KB, Klein S, Holloszy JO. Bone
mineral density response to caloric restriction-
induced weight loss or exercise-induced weight
loss: a randomized controlled trial. Arch Intern Med.
2006;166(22):2502–2510.
179. Rigotti NA, Nussbaum SR, Herzog DB, Neer RM.
Osteoporosis in women with anorexia nervosa.
N Engl J Med. 1984;311(25):1601–1606.
180. DiVasta AD, Feldman HA, O’Donnell JM, Long J,
Leonard MB, Gordon CM. Effect of exercise and
antidepressants on skeletal outcomes in adolescent
girls with anorexia nervosa. J Adolesc Health. 2017;
60(2):229–232.
181. Nagata JM, Carlson JL, Golden NH, Murray SB, Long
J, Leonard MB, Peebles R. Associations between
exercise, bone mineral density, and body compo-
sition in adolescents with anorexia nervosa [pub-
lished online ahead of print 8 June 2018]. Eat Weight
Disord. Accessed 17 September 2018.
182. Bachrach LK, Guido D, Katzman D, Litt IF, Marcus R.
Decreased bone density in adolescent girls with
anorexia nervosa. Pediatrics. 1990;86(3):440–447.
183. Joyce JM, Warren DL, Humphries LL, Smith AJ, Coon
JS. Osteoporosis in women with eating disorders:
comparison of physical parameters, exercise, and
menstrual status with SPA and DPA evaluation.
J Nucl Med. 1990;31(3):325–331.
184. Frisch RE, Gotz-Welbergen AV, McArthur JW,
Albright T, Witschi J, Bullen B, Birnholz J, Reed RB,
Hermann H. Delayed menarche and amenorrhea of
college athletes in relation to age of onset of
training. JAMA. 1981;246(14):1559–1563.
185. Konstantynowicz J, Kadziela-Olech H, Kaczmarski
M, Zebaze RM, Iuliano-Burns S, Piotrowska-
Jastrzebska J, Seeman E. Depression in anorexia
nervosa: a risk factor for osteoporosis. J Clin Endo-
crinol Metab. 2005;90(9):5382–5385.
186. Fazeli PK, Calder GL, Miller KK, Misra M, Lawson EA,
Meenaghan E, Lee H, Herzog D, Klibanski A. Psy-
chotropic medication use in anorexia nervosa
910 Fazeli and Klibanski
between 1997 and 2009. Int J Eat Disord. 2012;45(8):
970–976.
187. Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner
CH. Inhibition of the serotonin (5-hydroxytryptamine)
transporter reduces bone accrual during growth. Endo-
crinology. 2005;146(2):685–693.
188. Feuer AJ, Demmer RT, Thai A, Vogiatzi MG. Use of
selective serotonin reuptake inhibitors and bone
mass in adolescents: An NHANES study. Bone. 2015;
78:28–33.
189. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM,
Bliziotes MM, Ensrud KE. Use of antidepressants
and rates of hip bone loss in older women: the
study of osteoporotic fractures. Arch Intern Med.
2007;167(12):1240–1245.
190. Wu Q, Bencaz AF, Hentz JG, Crowell MD. Selective
serotonin reuptake inhibitor treatment and risk of
fractures: a meta-analysis of cohort and case-control
studies. Osteoporos Int. 2012;23(1):365–375.
191. Misra M, Le Clair M, Mendes N, Miller KK, Lawson E,
Meenaghan E, Weigel T, Ebrahimi S, Herzog DB,
Klibanski A. Use of SSRIs may impact bone density
in adolescent and young women with anorexia
nervosa. CNS Spectr. 2010;15(9):579–586.
192. Wudarsky M, Nicolson R, Hamburger SD, Spechler L,
Gochman P, Bedwell J, Lenane MC, Rapoport JL.
Elevated prolactin in pediatric patients on typical
and atypical antipsychotics. J Child Adolesc Psy-
chopharmacol. 1999;9(4):239–245.
193. Bolton JM, Targownik LE, Leung S, Sareen J, Leslie
WD. Risk of low bone mineral density associated
with psychotropic medications and mental disor-
ders in postmenopausal women. J Clin Psycho-
pharmacol. 2011;31(1):56–60.
194. Lee SH, Hsu WT, Lai CC, Esmaily-Fard A, Tsai YW,
Chiu CC, Wang J, Chang SS, Lee CC. Use of anti-
psychotics increases the risk of fracture: a systematic
review and meta-analysis. Osteoporos Int. 2017;
28(4):1167–1178.
195. Schellinger D, Lin CS, Hatipoglu HG, Fertikh D.
Potential value of vertebral proton MR spectros-
copy in determining bone weakness. AJNR Am J
Neuroradiol. 2001;22(8):1620–1627.
196. Abdallah BM, Jensen CH, Gutierrez G, Leslie RG,
Jensen TG, Kassem M. Regulation of human skeletal
stem cells differentiation by Dlk1/Pref-1. J Bone
Miner Res. 2004;19(5):841–852.
197. Fazeli PK, Bredella MA, Freedman L, Thomas BJ,
Breggia A, Meenaghan E, Rosen CJ, Klibanski A.
Marrow fat and preadipocyte factor-1 levels de-
crease with recovery in women with anorexia
nervosa. J Bone Miner Res. 2012;27(9):1864–1871.
198. Li X, Warmington KS, Niu QT, Asuncion FJ, Barrero
M, Grisanti M, Dwyer D, Stouch B, Thway TM,
Stolina M, Ominsky MS, Kostenuik PJ, Simonet WS,
Paszty C, Ke HZ. Inhibition of sclerostin by
monoclonal antibody increases bone formation,
bone mass, and bone strength in aged male rats.
J Bone Miner Res. 2010;25(12):2647–2656.
199. McClung MR, Grauer A, Boonen S, Bolognese MA,
Brown JP, Diez-Perez A, Langdahl BL, Reginster JY,
Zanchetta JR, Wasserman SM, Katz L, Maddox J,
Yang YC, Libanati C, Bone HG. Romosozumab in
Effects of Anorexia Nervosa on Bone Metabolism
postmenopausal women with low bone mineral
density. N Engl J Med. 2014;370(5):412–420.
200. Langdahl BL, Libanati C, Crittenden DB, Bolognese
MA, Brown JP, Daizadeh NS, Dokoupilova E, Engelke
K, Finkelstein JS, Genant HK, Goemaere S, Hyldstrup
L, Jodar-Gimeno E, Keaveny TM, Kendler D, Lakatos
P, Maddox J, Malouf J, Massari FE, Molina JF, Ulla
MR, Grauer A. Romosozumab (sclerostin mono-
clonal antibody) versus teriparatide in postmeno-
pausal women with osteoporosis transitioning
from oral bisphosphonate therapy: a randomised,
open-label, phase 3 trial. Lancet. 2017;390(10102):
Downloaded from https://academic.oup.com/edrv/article-abstract/39/6/895/5078825 by Research 4 Life user on 22 November 2018
1585–1594.
201. Faje AT, Fazeli PK, Katzman DK, Miller KK, Breggia A,
Rosen CJ, Mendes N, Klibanski A, Misra M. Scle-
rostin levels and bone turnover markers in ado-
lescents with anorexia nervosa and healthy
adolescent girls. Bone. 2012;51(3):474–479.
202. Fazeli PK, Wang IS, Miller KK, Herzog DB, Misra M,
Lee H, Finkelstein JS, Bouxsein ML, Klibanski A.
Teriparatide increases bone formation and bone
mineral density in adult women with anorexia
nervosa. J Clin Endocrinol Metab. 2014;99(4):
1322–1329.
203. DiVasta AD, Feldman HA, Rubin CT, Gallagher JS,
Stokes N, Kiel DP, Snyder BD, Gordon CM. The
ability of low-magnitude mechanical signals to
normalize bone turnover in adolescents hospital-
ized for anorexia nervosa. Osteoporos Int. 2017;28(4):
1255–1263.
204. Miller KK, Lee EE, Lawson EA, Misra M, Minihan J,
Grinspoon SK, Gleysteen S, Mickley D, Herzog D,
Klibanski A. Determinants of skeletal loss and re-
covery in anorexia nervosa. J Clin Endocrinol Metab.
2006;91(8):2931–2937.
205. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K.
Risk of atypical femoral fracture during and after
bisphosphonate use. N Engl J Med. 2014;371(10):
974–976.
Acknowledgments
Financial Support: This work was supported by National
Institutes of Health Grants R01 DK052625 (to A.K.), R01
DK062249 (to A.K.), K23 DK094820 (to P.K.F.), and R03
DK106410 (to P.K.F.). The content is solely the responsibility
of the authors and does not necessarily represent the official
views of the National Institutes of Health.
Correspondence and Reprint Requests: Pouneh K.
Fazeli, MD, Neuroendocrine Unit, Massachusetts General
Hospital, 55 Fruit Street, Bulfinch 457, Boston, Massachusetts
02114. E-mail: pkfazeli@partners.org.
Disclosure Summary: A.K. received grant support from
Motus Therapeutics (formerly Rhythm Pharmaceuticals,
Boston, MA) for an investigator-initiated study. P.K.F. has
nothing to disclose.
Abbreviations
BMD, bone mineral density; DHEA, dehydroepiandrosterone;
DKK, dickkopf-related protein; FGF, fibroblast growth factor;
GHSR, GH secretagogue receptor; Pref, preadipocyte factor;
PYY, peptide YY; SSRI, selective serotonin reuptake inhibitor.
Endocrine Reviews, December 2018, 39(6):895–910