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Anorexia Nervosa and Osteoporosis: Pathophysiology and Treatment



Anorexia nervosa (AN) affects 2.9 million people, many of whom experience bone loss and increased fracture risk. In this article, we review data on the underlying pathophysiology of AN-related osteoporosis and possible approaches to disease management. Available research suggests that low body weight and decreased gonadal function are the strongest predictors of bone loss and fractures in patients with AN. Additionally, other metabolic disturbances have been linked to bone loss, including growth hormone resistance, low leptin concentrations, and hypercortisolemia, but those correlations are less consistent and lack evidence of causality. In terms of treatment of AN-related bone disease, weight gain has the most robust impact on bone mineral density (BMD). Restoration of gonadal function seems to augment this effect and may independently improve BMD. Bisphosphonates, insulin-like growth factor 1 supplementation, and teriparatide may also be reasonable considerations, however need long-term efficacy and safety data. 133
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Anorexia Nervosa and Osteoporosis:
Pathophysiology and Treatment
Jeremy Steinman, Amal Shibli-Rahhal
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Iowa Carver College of Medicine,
Iowa City, IA, USA
Anorexia nervosa (AN) affects 2.9 million people, many of whom experience bone loss
and increased fracture risk. In this article, we review data on the underlying pathophysi-
ology of AN-related osteoporosis and possible approaches to disease management.
Available research suggests that low body weight and decreased gonadal function are
the strongest predictors of bone loss and fractures in patients with AN. Additionally,
other metabolic disturbances have been linked to bone loss, including growth hormone
resistance, low leptin concentrations, and hypercortisolemia, but those correlations are
less consistent and lack evidence of causality. In terms of treatment of AN-related bone
disease, weight gain has the most robust impact on bone mineral density (BMD). Resto-
ration of gonadal function seems to augment this effect and may independently im-
prove BMD. Bisphosphonates, insulin-like growth factor 1 supplementation, and teripa-
ratide may also be reasonable considerations, however need long-term efficacy and
safety data.
Key Words: Anorexia · Bone density · Feeding and eating disorders · Osteoporosis
Anorexia nervosa (AN) is characterized by intense fear of weight gain resulting
in calorie restriction, weight loss, and pathologically low body weight. It has a
prevalence of 2.9 million people worldwide [1] with a yearly incidence of 8 per
AN is associated with a 3-fold increase in the lifetime risk of fractures [3] with up
to 57% of women with AN sustaining at least 1 fracture in their lifetime.[4] Much
of this risk is due to reduced bone mineral density (BMD); 38% of patients with AN
have T scores <-2.5 and 92% have T scores <-1.[5] This BMD reduction is believed
to be caused by varying degrees of increased bone resorption and decreased bone
formation. Observational studies have shown that bone formation markers such
as osteocalcin and bone-specific alkaline phosphatase (BSAP) are decreased in
adult patients with AN and low BMD, while bone resorption markers such as C-
terminal telopeptide of type I collagen (CTX) and N-terminal telopeptide of colla-
gen type I are elevated.[6-9]
Unfortunately, there is limited research that clearly elucidates the specific causes
and the most effective approaches to treatment of bone disease in patients with
Corresponding author
Amal Shibli-Rahhal
Division of Endocrinology, Diabetes and
Metabolism, Department of Internal
Medicine, University of Iowa Carver College
of Medicine, 200 Hawkins Drive, GH E400,
Iowa City, IA 52242, USA
Tel: +1-319-353-7812
Fax: +1-319-353-7850
Received: June 12, 2019
Revised: July 6, 2019
Accepted: July 21, 2019
Review Article
J Bone Metab 2019;26(3):133-143
pISSN 2287-6375 eISSN 2287-7029
Jeremy Steinman, et al.
AN. In this article, we provide an updated summary of ex-
isting data regarding the pathophysiology and treatment
of AN-related osteoporosis.
A manual search was conducted in PubMed, Medline,
Cochrane Library, and ClinicalTrials. Studies were encoun-
tered using search terms AN, osteoporosis, osteopenia,
BMD, bone density, weight gain, menstrual regulation/
amenorrhea/hypogonadism, fractures, hormones (leptin,
ghrelin, thyroxine, oxytocin, cortisol, estrogen, testoster-
one, insulin-like growth factor 1 [IGF-1]) and treatments
(risedronate, alendronate, menatetrenone, teriparatide,
denosumab). Wildcard qualifier (*) was affixed to each
search term. Only studies that specifically evaluated AN
and bone health were included.
In AN, the body is in a state of starvation and low energy
leading to numerous metabolic and physiologic alterations
that are described individually in this section.
1. Amenorrhea and gonadal hormones
Alterations of menstrual cycles are common, seen in up
to 70% of females with AN.[4] This typically manifests with
amenorrhea, decreased estrogen concentrations, and low
or low-normal gonadotropins suggesting central suppres-
sion of the hypothalamic-pituitary-gonadal axis.[10] Low
BMD is often seen in amenorrheic women, while eumen-
orrhea seems to be protective against bone loss.[11] Estro-
gen deficiency is believed to be the main factor mediating
AN-related bone loss [12] and several studies have shown
a direct correlation between estradiol concentrations and
BMD in patients with AN.[11,13,14] This is likely due to the
loss of the inhibitory effect of estrogen on osteoclasts lead-
ing to increased bone resorption.[15,16] Notably, women
with AN who remain eumenorrheic have estradiol concen-
trations about 3 times higher compared to amenorrhoeic
patients with similar body mass index (BMI) [17] and bet-
ter BMD in this subgroup of patients has been attributed
to their higher estradiol concentrations.
Longer duration and earlier age of onset of amenorrhea
both correlate with lower BMD.[8,12,18,19] Biller et al.[12]
demonstrated that women with AN and peripubertal on-
set of amenorrhea have a 20% larger BMD deficit com-
pared to those who experience amenorrhea after comple-
tion of the pubertal transition. Since puberty is a time of
increased bone formation, it stands to reason that altera-
tions in hormones that affect bone accrual during this pe-
riod of time (e.g. decreased estrogen) are likely to result in
more deleterious effects on BMD,[20] as achievement of
peak bone mass during adolescence and early adulthood
may attenuate the risk of osteoporosis later in life.
Women with AN and low BMD also have lower concen-
trations of testosterone [6] and dehydroepiandrosterone
(DHEA).[21] However, since testosterone naturally under-
goes aromatization to estrogen,[16] it is difficult to eluci-
date whether the low BMD is due to the low testosterone
itself or to decreased estrogen activity.
Males with AN have been noted to have lower testoster-
one concentrations which correlate with lower BMD,[22]
but no studies have assessed the effect of androgen re-
placement on BMD in these patients. In hypogonadal men
without AN, testosterone therapy improves BMD,[23] but
administration of synthetic androgens which cannot be
converted to estrogens has no effect on BMD.[23] This again
suggests that testosterone exerts much of its effect on bone
through its aromatization to estrogen.
2. Body mass index and leptin
By definition, patients with AN have low BMI.[24] Lower
BMI correlates with lower BMD [25,26] and the lowest life-
time BMI in these patients predicts a higher risk of osteo-
porosis.[27-30] In addition, the duration of time of low BMI
inversely correlates with their BMD.[5,8]
Leptin is a hormone directly affected by weight. It is se-
creted by adipocytes when energy stores are increased,
but its production is decreased in low energy states such
as AN [31] due to low fat mass. In patients with AN, a direct
correlation exists between leptin concentrations and BMD,
independent of BMI.[13,27]
3. Other hormonal alterations
Research by Misra et al.[32] showed that patients with
AN manifest elevated growth hormone (GH) and low IGF-1
concentrations, suggesting some degree of resistance to
GH. Since IGF-1 exerts stimulatory effects on osteoblasts,[33]
Anorexia Nervosa and Osteoporosis 135
it has been postulated that the low IGF-1 in patients with
AN may contribute to their low bone density.[28,34] Later
studies have confirmed an association between IGF-1 and
BMD in patients with AN independent of their BMI.[13,35]
Cortisol, a catabolic hormone, is increased in AN likely as
a reflection of chronic physiologic stress.[36] In general,
hypercortisolemia is deleterious to bone by inhibiting os-
teoblast proliferation and bone formation [36] and studies
in patients with AN suggest an inverse relation between
cortisol concentrations and bone density.[27,37] It is how-
ever unclear whether this observed correlation reflects a
direct effect of cortisol on bone or if the hypercortisolemia
is simply a physiologic reflection of the severity of the un-
derlying eating disorder.
Lastly, oxytocin has been shown to induce osteoblast
formation and to inhibit osteoclast activity in mice.[38]
Oxytocin concentrations are decreased in patients with
AN,[39] but return to normal with weight gain.[40] De-
creased oxytocin concentrations in these patients predict
lower BMD even after correction for BMI [41] but no stud-
ies have evaluated the effect of oxytocin administration on
bone health in AN.
4. Role of exercise
A tendency toward excessive exercise is seen in 31% to
80% of patients with AN [42] and typically presents with a
compulsion to exercise regardless of weight or physical
state. While exercise is beneficial to bone health in the gen-
eral population,[43] it might be deleterious in the case of a
patient with active AN whose body is already in a low en-
ergy state.[42] A recent study by Waugh et al.[44] showed
that exercising while ill from AN decreases BMD, while high
bone loading activities when AN is in remission (defined as
BMI >18 and recovery of menstrual cycles) leads to an in-
crease in BMD, suggesting exercise is beneficial when ap-
propriately timed.
Based on the physiologic and hormonal alterations seen
in patients with AN described in the previous section, sev-
eral therapeutic approaches to improve bone health in
these patients have been studied and will be described
1. Weight restoration
Weight gain is generally considered the most effective
intervention to attenuate or reverse bone loss in patients
with AN. Several studies have assessed the effect of weight
restoration on BMD as summarized in Table 1 [19,30,45-57]
and many showed positive correlations between weight
gain and BMD. In a secondary analysis of patients random-
ized to alendronate or placebo, Golden et al.[51] compared
changes in BMD between patients who experienced weight
gain during the study to those who did not. Weight resto-
ration (defined as a weight at or above 85% of standard
body weight) was associated with an increase in BMD at
the hip and spine that was independent of both alendro-
nate administration and resumption of menses. Another
study by Miller et al.[53] showed that weight gain, inde-
pendent of oral contraceptive use or regulation of men-
strual cycles, improved BMD at the hip.
Most of these studies unfortunately did not provide a
detailed nutritional regimen or protocol to induce suffi-
cient weight gain in these patients. Only 3 studies provid-
ed rather limited information regarding their refeeding
protocols.[52,54,55] These generally included high dietary
protein,[54,55,58] graduated increases in daily caloric in-
take to a target of 2,500 to 4,000 kcal/day,[52,55,58] and a
daily calcium intake of around 1,500 to 2,000 mg.[54,55,58]
It is important to note here that while several other stud-
ies failed to demonstrate an increase in BMD in association
with weight restoration, none showed loss of BMD in asso-
ciation with weight gain.[30,46,48,49,52,54,55] In the set-
ting of AN where continued weight loss and malnutrition
might result in continued bone loss, stabilization of BMD
as a result of weight restoration may actually present a fa-
vorable outcome. Furthermore, many of these studies did
show favorable changes in markers of bone turnover, per-
haps suggesting early improvements in bone metabolism
not yet captured by BMD measurement.[47,49,52,55] For
example, Compston et al.[52] evaluated 21 young females
who experienced an average of 10 kg of weight gain over
a period of 1 year and did not observe improvements in
their BMD. However, they noted an increase in the concen-
trations of markers of bone formation and a decrease in
the concentrations of markers of bone resorption, suggest-
ing a positive effect of weight gain that likely had not yet
manifested as a change in BMD.[52]
It is important to note here that some of the positive
Jeremy Steinman, et al.
Table 1. Summary of studies showing effect of weight gain on bone mineral density and serological markers in patients with anorexia nervosa
References Year Study design Subjects Average age
Weight/BMI changes Subjective change in BMD Change in bone turnover
Bachrach et al.
1991 Prospective cohort 15 females with AN 16.7 13 At least 4.7 kg weight gain in
9 patients
Whole body BMD increased in 7 of
the 9 patients who gained weight
Kooh et al.[46] 1996 Prospective cohort 12 females with AN 16.7 14.1 Average 4.9 kg weight gain No change in lumbar spine BMD NA
seau et al.[47]
2000 Prospective cohort 9 females with AN 21 8 BMI improvement from 13.8
to 17.5
NA CTX: decreased from base-
line, osteocalcin: increased
from baseline
Jagielska et al.
2001 Prospective cohort 42 females with AN (only
11 at follow-up)
14.7 27.8 Average 17.6 kg weight gain;
BMI improvement from 14.7
to 19.8
No change in BMD NA
Soyka et al.[49] 2002 Prospective cohort 19 females with AN, 19
healthy female controls
AN: 15.4,
controls: 14.6
12 Weight restoration to BMI
>18 in 11 AN patients
No change in lumbar spine and total
body BMD in AN patients
Osteocalcin, BSAP, DPD, NTX
low at baseline and in-
creased to healthy control
Castro et al.[50] 2002 Prospective cohort 20 males with AN 15.4 12.4 9 males had BMI >19 (com-
plete), 6 had improved
weight but BMI <19 (par-
Increased if complete weight recov-
ery, decreased if partial weight
Golden et al.
2005 Randomized clinical
trial of alendronate
vs. placebo with
secondary analysis
of effect of weight
32 females with AN ran-
domized to alendronate
or placebo
AN: 16.9,
controls: 16.9
12 Average of 7.1 kg weight gain Femoral neck and lumbar spine BMD
increased with weight gain irre-
spective of alendronate administra-
Compston et al.
2006 Prospective cohort 26 females with AN 16.5 12 Average 9.6 kg weight gain No change in lumbar spine, total hip,
femoral neck and total body BMD
Osteocalcin, BSAP, NTX
increased from baseline
Miller et al.[53] 2006 Prospective cohort 75 females with AN 24.4 13.5 Average 13 kg weight gain in
35 patients
Lumbar spine BMD increased with
weight gain
Stone et al.[54] 2006 Retrospective cohort 45 females with AN AN: 14.6,
controls: 15.1
12 Average 3 kg weight gain No change in total body, lumbar spine
and femoral neck BMD
do Carmo et al.
2007 Retrospective cohort 15 females with AN 18.6 72 Average 12.5 kg weight gain Improvement in Z score at lumbar
spine and femoral necka)
Mika et al.[55] 2007 Prospective cohort 19 females with AN, 19
healthy female controls
AN: 14.4,
controls: 15.1
24 BMI improvement from 14.2
to 17.8
No change in lumbar spine and
femoral neck BMD
PICP, BASP, CTX: low at
baseline and increased
with weight gain to levels
of healthy controls, same
parameters decreased in
controls to young adult
(Continued to the next page)
Anorexia Nervosa and Osteoporosis 137
studies showed improvement in BMD as a function of wei-
ght gain alone,[45,50,51,53] while others suggested that
both weight restoration and resumption of menses were
essential for the BMD to increase.[56,57] Since traditional
estrogen replacement therapy with oral contraceptive pills
(OCPs) in patients with active AN does not seem to be con-
sistently effective at improving BMD (as will be discussed
in the next section), it is fair to assume that weight restora-
tion, with or without correction of hypogonadism, is an es-
sential intervention to stop or reverse bone loss.
1. Estrogen
Early observational studies suggested that OCP use [59]
or use of estrogen replacement [60] was associated with
improvement in BMD in adults with AN. However, prospec-
tive clinical trials using typical OCP doses (35-50 µg of oral
estradiol) for 1 and 2 years did not have any effect on BMD
in peripubertal AN patients.[53,61-63] Conversely, admin-
istration of estradiol at more physiologic doses to peripu-
bertal females with AN (100 µg transdermally in patients
with bone age >15 years, or escalating doses of 3.75-11.25
µg oral in those with bone age <15 years) led to near-nor-
malization of BMD after 18 months of therapy.[64] It is un-
clear whether this robust change was due to the route of
administration of estrogen which bypassed hepatic me-
tabolism or the more physiologic doses used. Further stud-
ies are needed to clarify this question.
2. Androgens
When 33 women with AN and low testosterone concen-
trations were treated with transdermal testosterone (150
or 300 µg daily patches) for 3 weeks, they experienced an
increase in CTX with no changes in osteocalcin and BSAP.
[65] A later study randomized 19 women to testosterone
alone (150-300 µg daily transdermal patch based on se-
rum testosterone concentrations), 20 to risedronate alone
(35 mg/week), 20 to dual therapy with testosterone and
risedronate, and 18 to placebo. After a 12-month follow-
up, no improvements in bone turnover markers or BMD
were observed in the testosterone monotherapy or place-
bo groups. Only patients who took risedronate (either alone
or in combination with testosterone) experienced an im-
provement in BMD. However, there was no difference in
References Year Study design Subjects Average age
Weight/BMI changes Subjective change in BMD Change in bone turnover
Misra et al.[56] 2008 Prospective cohort 34 females with AN, 33
healthy female controls
AN: 15.9,
controls: 15.0
12 BMI improvement from 16.7
to 20.4 with recovery of
menses in 14 AN patients,
BMI improvement from 16.5
to 17.3 with no recovery of
menses in 20 AN patients,
controls: BMI unchanged
With recovery of weight and men-
ses, spine and whole body BMD
increased, without menstrual
recovery, only whole body BMD in-
creased, BMD continued to decline
if no recovery of weight or menses
Schulze et al.
2010 Prospective cohort 52 females with AN 15.1 62.8 26 patients had BMI >17.5
with regular menses, 20
had BMI <17.5 or irregular
menses, 6 had both BMI
<17.5 and irregular menses
Whole body BMD increased with
weight gain only if menses resumed
Franzoni et al.
2014 Prospective cohort 46 females with AN 16.3 12 BMI Improvement from 16.3
to 17.6
No change in lumbar spine BMD NA
a)Unclear statistical significance as no P-values present for study.
AN, anorexia nervosa; BMI, body mass index; BMD, bone mineral density; NA, not applicable; CTX, C-terminal telopeptide of type I collagen; BSAP, bone-specific alkaline phosphatase; DPD, deoxypyridi-
noline; NTX, N-telopeptides; PICP, propeptide of type I procollagen.
Table 1. Continued
Jeremy Steinman, et al.
the observed benefit between patients who received rise-
dronate alone and those who received testosterone and
risedronate,[66] suggesting that testosterone supplemen-
tation is unlikely to be of benefit in the treatment of osteo-
porosis in women with AN.
Treatment of women with AN with DHEA at doses rang-
ing between 50 and 100 mg daily does not increase BMD
compared to baseline or to untreated controls according
to 2 randomized clinical trials.[67,68] When DHEA was giv-
en in combination with an OCP (DHEA 50 mg+20 µg ethi-
nyl estradiol/0.1 mg levonorgestrel) for 18 months, BMD
remained stable while untreated controls experienced a
drop in BMD,[69,70] suggesting that DHEA and OCPs may
attenuate bone loss when used in combination, though
there are still very limited data supporting this notion.
1. Bisphosphonates
Two oral bisphosphonates, risedronate and alendronate,
have been studied in AN. In a randomized clinical trial of
32 adolescent girls with AN who took alendronate 10 mg
daily or placebo for 1 year, the end-of-study BMD was sig-
nificantly higher than baseline in the alendronate group
but not in the placebo group. However, the magnitude of
change in BMD from baseline between the 2 groups was
not statistically different (4.4% vs. 2.3% at the femoral neck
and 3.5% vs. 2.2% at the lumbar spine with alendronate
and placebo respectively).[51]
In a small study of 10 women with AN and low BMD, rise-
dronate 5 mg daily increased BMD at the spine by 4.1%
and 4.9% at 6 and 9 months, respectively.[71] A larger study
where 38 women were randomized to risedronate 35 mg
weekly or placebo showed a 3.2% increase in lumbar spine
BMD in the risedronate group after 12 months of treat-
ment compared to no change in the control group. This
study also assessed the effect of testosterone supplemen-
tation on bone density (both alone and in combination
with risedronate as described in a previous section) and
showed no improvement with testosterone.[66]
Based on these data, it appears that there may be a trend
toward improved BMD with bisphosphonates, but the evi-
dence is still insufficient at this point.
2. Denosumab
In a case report, denosumab use for 3 years (at 60 mg
subcutaneously every 6 months) in a woman with AN and
low BMD led to a 14.8% increase in BMD at the spine, a
1.4% increase at the hip, and a 5.7% increase at the femo-
ral neck.[72] In a separate report, treatment with deno-
sumab (same dosing) in 3 women was again associated
with an improvement in BMD at the hip by 20% and at the
lumbar spine by 17%.[73] The role of denosumab in the
treatment of AN-related osteoporosis has not been formal-
ly evaluated, and further studies are necessary to clarify
these anecdotal findings.
1. Teriparatide
In 2012, a case report of teriparatide treatment of a post-
menopausal woman with AN and osteoporosis showed im-
provement in BMD by 12% at the lumbar spine and 21% at
the femoral neck when administered in conjunction with vi-
tamin D supplementation and weight gain.[74] Later, a ran-
domized controlled trial of 21 women treated with teripara-
tide (20 µg subcutaneously daily) or placebo showed that
teriparatide increased BMD at the lumbar spine by 6% within
6 months,[75] even after correcting for baseline body weight.
2. IGF-1/Growth hormone
As IGF-1 concentrations are low in patients with AN, sev-
eral studies have assessed the effect of IGF-1 replacement
on BMD. In fact, women with AN and low BMD manifested
a dose dependent increase in markers of bone formation
when given recombinant human IGF-1 at either 60 or 200
mcg subcutaneously daily.[7] In another study, administra-
tion of recombinant human IGF-1 (60-80 µg daily) to ado-
lescents with AN increased markers of bone formation and
bone resorption.[76] Grinspoon et al.[77] randomized 60
osteopenic women with AN to four groups for 12 weeks:
IGF-1 monotherapy (30 µg/kg twice daily), OCP monother-
apy (35 µg ethinyl estradiol/0.4 mg norethindrone daily),
combination therapy with OCP and IGF-1 at the same dos-
es, or placebo. The patients in the IGF-1 monotherapy and
the IGF-1/OCP groups experienced an increase in bone
density at the lumbar spine of 1.1% and 1.8%, respectively,
while BMD was unchanged in the other 2 groups. The in-
crease in BMD from baseline in each of the IGF-1 and IGF-
Anorexia Nervosa and Osteoporosis 139
1/OCP groups were significant, but there was no difference
in the magnitude of the change between the 2 groups.
This suggests that IGF-1 may be modestly effective at in-
creasing BMD, but that OCPs may not augment the efficacy
of IGF-1.[77] However, it is important to note that the short
duration of the study may have been insufficient to fully
demonstrate changes in BMD.
Interestingly, in 21 adults with AN, treatment with re-
combinant GH (dose was titrated to achieve IGF-1 levels in
the upper quartile of the normal range) did not affect mark-
ers of bone turnover. These patients required GH doses 3
times higher than doses used in patients with GH deficien-
cy due to pituitary disease (15 vs. 5 µg/kg), which further
supports the theory of GH resistance in AN.[78]
1. Leptin
The correlation between higher leptin concentrations
and increased BMD makes leptin a promising therapeutic
target, but it has not been evaluated in patients with AN.
In patients with exercise-induced hypothalamic amenor-
rhea, its administration lead to an increase in markers of
bone formation (BSAP and osteocalcin) in one study [79]
and to a 4% to 6% improvement in lumbar spine BMD in
another.[80] However, patients who took leptin experi-
enced a small degree of weight loss,[79,80] an effect that
might preclude its safe use in patients with AN given the
baseline weight deficits in these patients.
2. Menatetrenone
Vitamin K stimulates osteoblast activity through vitamin
K dependent carboxylation of osteocalcin.[81] Menatetre-
none is a vitamin K analogue that works similarly to stimu-
late this pathway. A single study in 19 young women with
AN showed that treatment with menatetrenone for 1 year
attenuated BMD loss by 4% (2.9% BMD loss in treatment
arm versus 6.9% BMD loss in control arm).[82] Further re-
search with longer follow-up will be needed to better un-
derstand the role of menatetrenone on bone health in pa-
tients with AN.
Our review of the literature suggests that low body weight
and decreased gonadal function are the strongest predic-
tors of bone loss and fractures in patients with AN. While
other metabolic disturbances such as GH resistance, low
leptin concentrations, and hypercortisolemia have been
linked to bone loss, those correlations are less consistent
and lack evidence of causality.
In terms of treatment of AN-related bone disease, weight
gain has the most robust impact on BMD. In addition, res-
toration of gonadal function seems to augment this effect
and may independently improve BMD. Bisphosphonates,
IGF-1 supplementation, and teriparatide may also be rea-
sonable considerations, but still need long-term efficacy
and safety data. Most notable here is the inconsistency in
efficacy between risedronate and alendronate, despite the
fact these drugs have fairly similar mechanisms of action.
[83,84] Whether this discrepancy reflects a true difference
in clinical efficacy versus variability in study design is un-
clear, highlighting the fact that there is no sufficient evi-
dence at this time to support the universal use of bisphos-
phonates in AN-related bone disease.
Limitations of the studies reviewed include the rather
small size and short duration of follow up of most studies
and the significant heterogeneities in relation to subjects
(some studies were focused on either adolescents or adults,
while others included both age groups) and interventions
(for example, studies on OCPs used variable doses of estro-
gen). Furthermore, in 2013, the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition was published
and changed the definition of AN to no longer require amen-
orrhea for diagnosis,[24] which is especially critical in os-
teoporosis as menstrual status can affect bone health.
It is also important to note that all studies used surro-
gates of bone health as outcomes, namely BMD and bone
turnover markers, and that no studies looked at the effect
of interventions on fracture risk. While improvements in
these surrogate markers are generally assumed to imply
decreased fracture risk, direct correlation of interventions
with fracture risk will ultimately be essential to truly prove
Ethics approval and consent to participate
Not applicable.
Jeremy Steinman, et al.
Conflict of interest
No potential conflict of interest relevant to this article
was reported.
Jeremy Steinman
Amal Shibli-Rahhal
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... In AN, low nutrient intake, excessive physical activity and purging behaviours are associated with BMD loss [12,13]. Known risk factors are low weight, hypothalamic amenorrhoea, and longer illness duration [6,14,15], with low weight being one important predictor of osteoporosis and risk of fracture [12]. ...
... In AN, low nutrient intake, excessive physical activity and purging behaviours are associated with BMD loss [12,13]. Known risk factors are low weight, hypothalamic amenorrhoea, and longer illness duration [6,14,15], with low weight being one important predictor of osteoporosis and risk of fracture [12]. A previous meta-analysis showed lower BMD in individuals with BN than HC but only for those with a history of AN [14]. ...
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Background Lower bone mineral density (BMD) increases the risk of osteoporosis in individuals with eating disorders (EDs), particularly women with anorexia nervosa (AN), making them susceptible to pain and fractures throughout adulthood. In AN, low weight, hypothalamic amenorrhoea, and longer illness duration are established risk factors for low BMD, and in people with other EDs a history of AN seems to be an important risk factor for low BMD. Purpose To conduct a systematic review and meta-analysis of BMD in individuals with EDs, including AN, bulimia nervosa (BN), binge-eating disorder (BED) and other specified feeding or eating disorders (OSFED) compared to healthy controls (HC). Methods Following PRISMA guidelines, electronic databases were reviewed and supplemented with a literature search until 2/2022 of publications measuring BMD (dual-energy X-ray absorptiometry or dual photon absorptiometry) in females with any current ED diagnosis and a HC group. Primary outcomes were spine, hip, femur and total body BMD. Explanatory variables were fat mass, lean mass and ED clinical characteristics (age, illness duration, body mass index (BMI), amenorrhoea occurrence and duration, and oral contraceptives use). Results Forty-three studies were identified (N = 4163 women, mean age 23.4 years, min: 14.0, max: 37.4). No study with individuals with BED met the inclusion criteria. BMD in individuals with AN (total body, spine, hip, and femur), with BN (total body and spine) and with OSFED (spine) was lower than in HC. Meta-regression analyses of women with any ED (AN, BN or OSFED) (N = 2058) showed low BMI, low fat mass, low lean mass and being amenorrhoeic significantly associated with lower total body and spine BMD. In AN, only low fat mass was significantly associated with low total body BMD. Conclusion Predictors of low BMD were low BMI, low fat mass, low lean mass and amenorrhoea, but not age or illness duration. In people with EDs, body composition measurement and menstrual status, in addition to BMI, are likely to provide a more accurate assessment of individual risk to low BMD and osteoporosis.
... The etiology of low BMD in patients with eating disorders is multifactorial. The most commonly cited risk of BMD loss is the downregulation of the hypothalamic-pituitary-gonadal axis, often clinically evidenced in females by amenorrhea (134,138,140,141). This downregulation, which results in low estrogen and testosterone, directly and indirectly increases osteoclastic activity (134). ...
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As more accurate diagnostic tools and targeted therapies become increasingly available for pediatric metabolic bone diseases, affected children have a better prognosis and significantly longer lifespan. With this potential for fulfilling lives as adults comes the need for dedicated transition and intentional care of these patients as adults. Much work has gone into improving the transitions of medically fragile children into adulthood, encompassing endocrinologic conditions like type 1 diabetes mellitus and congenital adrenal hyperplasia. However, there are gaps in the literature regarding similar guidance concerning metabolic bone conditions. This article intends to provide a brief review of research and guidelines for transitions of care more generally, followed by a more detailed treatment of bone disorders specifically. Considerations for such transitions include final adult height, fertility, fetal risk, heritability, and access to appropriately identified specialists. A nutrient-dense diet, optimal mobility, and adequate vitamin D stores are protective factors for these conditions. Primary bone disorders include hypophosphatasia, X-linked hypophosphatemic rickets, and osteogenesis imperfecta. Metabolic bone disease can also develop secondarily as a sequela of such diverse exposures as hypogonadism, a history of eating disorder, and cancer treatment. This article synthesizes research by experts of these specific disorders to describe what is known in this field of transition medicine for metabolic bone diseases as well as unanswered questions. The long-term objective is to develop and implement strategies for successful transitions for all patients affected by these various conditions.
... Studies involving bone health in individuals with eating disorders have primarily focused on people with AN, revealing relatively consistent bone deficits in these patients [17,25,26]. Individuals with AN-R and AN-A have bone deficits when compared to non-AN healthy controls, with AN-R typically having lower BMD compared to those with AN-A [27]. ...
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Plain English summary An extensive body of evidence reports threatened bone health in people with eating disorders, focusing primarily on people with anorexia nervosa. The Diagnostic and Statistical Manual of Mental Disorders (DSM) Fifth Edition reclassified and expanded upon the DSM-IV diagnosis of “feeding disorder of infancy or early childhood,” introducing a new diagnostic term, avoidant/restrictive food intake disorder (ARFID). This has led to an increased need to understand effects of ARFID on bone health. Among the studies that have reported bone health outcomes in people with ARFID, authors have reported shorter stature and lower bone mineral density (BMD) in children and adults with ARFID compared to reference datasets. Malnutrition resulting in under-consumption of energy and/or nutrients that are integral to bone health can also cause conditions that impact the musculoskeletal system, including low body weight, scurvy due to vitamin C deficiency, and rickets due to vitamin D deficiency. Research in individuals with ARFID focusing on longitudinal changes in BMD, bone micro-structure, and bone strength during clinical intervention are required. These efforts will help identify long-term health risks in people with ARFID, inform comprehensive medical assessment, improve long-term health outcomes, and provide a benchmark for assessing treatment outcomes over time.
... 15,16 Adolescents who engage in disordered eating behaviors (e.g., patients with anorexia nervosa) are at increased risk for severe nutrient and/or caloric deficiencies and menstrual irregularities. 17 Elite athletes can also experience significant caloric deficits without disordered eating, given their extreme levels of energy expenditure via exercise. The combination of menstrual irregularity, low energy availability, and subsequent low BMD is known as the female athlete triad (recently expanded and named the Relative Energy Deficiency in Sport, RED-S Syndrome)-a disorder that often goes unrecognized and may have irreversible consequences. ...
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Osteoporosis is a common condition in which deteriorating bone tissue results in an increased risk of low trauma fracture. Influenced by the role of estrogen in building and maintaining bone mineral density, women have different patterns of bone accrual and loss compared with men, resulting in a lower peak bone mass and a greater lifetime fracture risk. Moreover, fracture risk increases significantly in postmenopausal women who have depleted estrogen levels. Osteoporotic fractures pose serious consequences-ranging from an inability to perform basic tasks and an increased risk of repeat fracture to the need for assisted living and even death. There is also a large economic toll associated with the health care costs required for post-fracture care. The Society for Women's Health Research (SWHR) convened an interdisciplinary Bone Health Working Group to review the current state of science and practice concerning women's bone health and osteoporosis care and to explore strategies to address gaps in screening, diagnosis, and treatment of bone disease in women. Women's bone health care must shift its paradigm from one of postmenopausal and post-fracture care to a preventive model that engages touchpoints throughout the lifespan. To achieve this paradigm shift, the Working Group recommends prioritizing efforts to build public awareness and clinical education of preventive bone health care for women, increase access to screening tools, improve patient-provider communication, and treat osteoporosis using a broader risk stratification approach.
... As previously mentioned, our register does not include non-prescription gastrointestinal medications that are readily available in Denmark, which could further increase the percentage of patients treated. The higher OR of mineral prescriptions, especially after AN diagnosis, likely reflects concerns about the impact of prolonged restrictive eating and low weight on osteoporosis, whereas the increased OR of bisphosphonate according to Danish practice reflects actual diagnosis of osteoporosis [23,24]. The increased use of antiinfective medication in patients may reflect the association between infections and eating disorders reported in several register based, clinical, and genetic studies [25][26][27]. ...
Objective No medications have been indicated for the treatment of anorexia nervosa (AN). Nonetheless, individuals with AN are frequently treated pharmacologically. The present study maps nationwide pharmacotherapy two years before to five years after first AN diagnosis. Methods We identified all medication prescriptions in a national register-based study of patients with a first diagnosis of AN between 1998 and 2011, and age and gender matched controls (1:10). Medication classes were compared using odds ratios (OR) between patients and controls; between patients below and above 15 years; between patients with and without comorbidity; and between those diagnosed before or after 2005. Results The odds of pharmacotherapy were increased in patients for all classes of medication except a small residual class. Highest odds were found for alimentary (OR 2.8, p < 0.001) and psychopharmacological (OR 5.5, p < 0.001) medication. The former peaked one year prior to first diagnosis and the latter one year after. Older patients had increased risk of almost all medication classes with cardiovascular medication showing a fivefold OR (p < 0.001). Patients with psychiatric comorbidity had a threefold OR for psychopharmacological medication (p < 0.001) compared to patients without psychiatric comorbidity. Calendar year showed few and small differences. Conclusion The extended use of all medication classes both prior to and after first diagnosis of AN highlights the severe cause and complexity of AN. The results encourage clinical caution of pharmacotherapy, highlight the need for pharmacotherapy guidelines for AN, and emphasize the urgency of research in pharmacotherapy in AN.
... This can lead to several medical complications including bone loss [228] with a 2-7-fold increased risk of fractures [229,230]. This is not only because of nutritional deficiencies but hormonal disturbances as well [231]. On the other hand, improving nutritional status corrects the endocrinological disorders and BMD in these patients [232]. ...
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Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.
Anorexia nervosa (AN) is the psychiatric disorder with the highest mortality rate, whose etiology remains largely unknown. It mainly concerns women and is characterized notably by a voluntary food restriction leading to a state of undernutrition often associated with excessive physical activity. Despite specialized care, relapse is common and affects approximately 40% of patients. AN is comorbid with several other psychiatric diseases such as depression, anxiety, or compulsivity. Patients suffering from AN also present autonomic, immune, metabolic, and neuroendocrine alterations that participate in the worsening of the disease. We describe here how the autonomic and hormonal systems, main contributors to the brain-body homeostasis, participate directly or indirectly in the modulation of the immune system in AN. The complexity of the interactions between these processes reflects the complexity of AN. The understanding of such complexity could help adjust procedures to personalize medical approaches, integrating the diversity of factors leading to AN manifestations.
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In the original definition by Klinefelter, Albright and Griswold, the expression “hypothalamic hypoestrogenism” was used to describe functional hypothalamic amenorrhoea (FHA). Given the well-known effects of estrogens on bone, the physiopathology of skeletal fragility in this condition may appear self-explanatory. Actually, a growing body of evidence has clarified that estrogens are only part of the story. FHA occurs in eating disorders, overtraining, and during psychological or physical stress. Despite some specific characteristics which differentiate these conditions, relative energy deficiency is a common trigger that initiates the metabolic and endocrine derangements contributing to bone loss. Conversely, data on the impact of amenorrhoea on bone density or microarchitecture are controversial, and reduced bone mass is observed even in patients with preserved menstrual cycle. Consistently, oral estrogen-progestin combinations have not proven beneficial on bone density of amenorrheic women. Low bone density is a highly prevalent finding in these patients and entails an increased risk of stress or fragility fractures, and failure to achieve peak bone mass and target height in young girls. Pharmacological treatments have been studied, including androgens, insulin-like growth factor-1, bisphosphonates, denosumab, teriparatide, leptin, but none of them is currently approved for use in FHA. A timely screening for bone complications and a multidisciplinary, customized approach aiming to restore energy balance, ensure adequate protein, calcium and vitamin D intake, and reverse the detrimental metabolic-endocrine changes typical of this condition, should be the preferred approach until further studies are available.
Zusammenfassung Die Anorexia nervosa ist eine psychische Erkrankung noch unbekannter Ätiologie, die durch eine reduzierte Nahrungsaufnahme, deutliche Gewichtsabnahme sowie Angst vor Gewichtszunahme charakterisiert ist. Sie verursacht eine Vielzahl endokrinologischer Veränderungen, wobei das Ausmaß dieser Veränderungen mit dem Grad der Unterernährung zusammenhängt. In Anpassung an diesen Hungerzustand kommt es zu einer deutlichen Veränderung einer Vielzahl von Hormonen und Signalpeptiden, wobei endokrinologische Achsen mit Beteiligung von Hypothalamus, Hypophyse, Gonaden bzw Nebenniere ebenso betroffen sind wie IGF-1 und die Adipokine Leptin, Ghrelin und PPY. Eine wesentliche Komorbidität ist die Reduktion der Knochendichte bis zur Entwicklung einer Osteoporose und die mit ihr verbundene Entwicklung eines erhöhten Frakturrisikos. Dabei sind sowohl der trabeculäre wie auch der corticale Knochen betroffen. Die Wiederherstellung des Gewichts und die Wiederaufnahme der Menstruation haben den stärksten Einfluß auf die Knochenmineraldichte. Zu den weiteren Behandlungsmöglichkeiten gehören neben der grundsätzlichen Psychotherapie die transdermale Therapie mit Östrogen bzw. die subcutane Gabe von Teriparatid.
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Adipose tissue (AT) is recognized as a complex organ involved in major home-ostatic body functions, such as food intake, energy balance, immunomodulation, development and growth, and functioning of the reproductive organs. The role of AT in tissue and organ homeostasis, repair and regeneration is increasingly recognized. Different AT compartments (white AT, brown AT and bone marrow AT) and their interrelation with bone metabolism will be presented. AT-derived stem cell populations - adipose-derived mesenchymal stem cells and pluripotent-like stem cells. Multilineage differentiating stress-enduring and dedifferentiated fat cells can be obtained in relatively high quantities compared to other sources. Their role in different strategies of bone and fracture healing tissue engineering and cell therapy will be described. The current use of AT- or AT-derived stem cell populations for fracture healing and bone regenerative strategies will be presented, as well as major challenges in furthering bone regenerative strategies to clinical settings.
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Purpose: Aim of this study is focusing on bone metabolism in AN patients with amenorrhoea and related estrogen deficiency effects. Methods: AN patients were compared both with healthy females and with postmenopausal women (reference model for estrogen deficiency). The study sample included 81 females with AN. Laboratory tests [25-OH vitamin D, bone turnover markers, intact parathyroid hormone, sclerostin (SOST) and dickkopf-related protein (DKK1)] and dual energy X-ray absorptiometry (DXA) were taken into account. Results: AN patients had higher levels of C-terminal telopeptide of type I collagen (CTX) than both control groups. AN adolescents had CTX higher than AN young adults. In postmenopausal women, intact N-propeptide of type I collagen was higher if compared with each other group. In AN groups, Dickkopf-related protein 1 was significantly lower than the two control groups. No differences were found in sclerostin except in adolescents. In AN adolescents, DXA values at femoral sites were higher than in AN young adults and a positive correlation was found with body weight (p < 0.01) and with fat mass evaluated using DXA (p < 0.01). Conclusions: AN women with amenorrhoea have an increased bone resorption like postmenopausal women but bone formation is depressed. The consequent remodeling uncoupling is considerably more severe than that occurring after menopause.
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Background: Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods: We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings: We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17·2 billion, 95% uncertainty interval [UI] 15·4–19·2 billion) and diarrhoeal diseases (2·39 billion, 2·30–2·50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2·36 billion (2·35–2·37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20–30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation: Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available.
Objective: Growth hormone (GH) and its main mediator, insulin-like growth factor-I (IGF-I) play a significant role in bone metabolism. The relations between IGF-I and bone mineral density (BMD) or osteoporosis have been assessed in previous studies but whether the associations are sex-specific remains uncertain. Moreover, only few studies examined bone quality assessed by quantitative ultrasound (QUS). We aimed to investigate these associations in the general population of northeast Germany. Design and measurements: Data from 1759 men and 1784 women who participated in the baseline examination of the Study of Health in Pomerania (SHIP)-Trend were used. IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations were measured on the IDS-iSYS multidiscipline automated analyzer (Immunodiagnostic Systems Limited). QUS measurements were performed at the heel (Achilles InSight, GE Healthcare). Sex-specific linear and multinomial logistic regression models adjusted for potential confounders were calculated. Results: Linear regression analyses revealed significant positive associations between IGF-I and IGF-I/IGFBP-3 ratio, a marker for free IGF-I, with all QUS parameters in men. Among women, we found an inverse association between IGF-I and the QUS-based fracture risk but no association with any other QUS parameter. There was no association between IGFBP-3 and the QUS-based fracture risk. Conclusions: Our data suggest an important role of IGF-I on bone quality in men. The observed association of IGF-I with the QUS-based stiffness index and QUS-based fracture risk in the present study might animate clinicians to refer patients with low IGF-I levels, particularly men, to a further evaluation of risk factors for osteoporosis and a detailed examination of the skeletal system. This article is protected by copyright. All rights reserved.
Anorexia nervosa (AN) is a psychiatric disorder associated with a high risk of decreased bone mineral density (BMD) and fractures. In recent years, the anti-osteoclastic agent denosumab has become widely adopted for primary and secondary osteoporosis, but the drug’s efficacy for osteoporosis in AN is uncertain. This retrospective, consecutive, case series investigated three osteoporotic cases of AN to examine the effects of denosumab on bone fragility and fracture prevention. Three female patients, respectively, aged 36, 37, and 42 years were diagnosed as having AN and began denosumab treatment for osteoporosis. Bone turnover markers and BMD of the lumbar 1–4 spine (L-BMD) and bilateral hips (H-BMD) were examined before and at 6, 12, 18, and 24 months of therapy. No fractures or severe side effects such as hypocalcemia were observed. All bone turnover markers were strongly decreased and both L-BMD and H-BMD were markedly augmented by denosumab over 24 months. These findings suggest that denosumab is a good option to treat osteoporosis in AN.
Context Oxytocin (OXT), an anorexigenic hypothalamic hormone anabolic to bone, may reflect energy availability. Basal serum OXT levels are lower in anorexia nervosa (AN, state of energy deficit) than healthy controls (HC) and negatively associated with spine bone density (BMD). However, reports are conflicting regarding OXT levels in overweight/obesity (OB, state of energy excess). Furthermore, relationships between OXT and BMD in OB and hip geometry across the weight spectrum are unknown. Objective To determine whether overnight serum OXT levels are (1) elevated in OB, and (2) associated with body composition, BMD, and hip geometry and strength across the weight spectrum. Design Cross-sectional Setting Clinical Research Center Participants 59 women, 18-45y: amenorrheic AN (N=16), eumenorrheic HC (N=24), eumenorrheic OB (N=19) Main Outcome Measures Serum sampled q20min 8PM–8AM and pooled for integrated overnight OXT levels. Body composition, BMD, and hip structural analysis (HSA) measured by DXA. Results OXT levels were lowest in AN, higher in HC, and highest in OB (p≤0.02). There were positive associations between OXT and 1) BMI (p=0.0004); 2) total, visceral, and subcutaneous fat (p≤0.0002); 3) BMD Z-scores at the spine and hip (p≤0.01); and 3) favorable hip geometry and strength, namely buckling ratio (p≤0.05). In a subset analysis of HC and OB, relationships between OXT and body composition, but not bone parameters, remained significant. Conclusions These data suggest that OXT is a marker of energy availability and may be a mediator of bone density, structure, and strength. OXT pathways may provide novel targets for obesity and osteoporosis treatment.
Osteopenia of widely varying degree is seen in premenopausal women who are amenorrheic. Osteoporosis is especially severe and complicated by fractures in women with anorexia nervosa (AN). In contrast, clinical fractures are rare in conditions such as hyperprolactinemia and hypothalamic amenorrhea (HA). Factors other than estrogen deficiency may be important in determining the extent of osteopenia. This study was designed to address whether more severe bone loss is found in women with AN independently of the duration of amenorrhea, possibly because of undernutrition. Bone loss was estimated by dual-energy x-ray absorptiometry in 30 amenorrheic women with AN and 19 age-matched women with HA. The two groups were similar with regard to the duration of amenorrhea, previous estrogen use, and age at menarche. Thirty healthy, age-matched women with normal menstrual function served as a control group. Body mass indices were significantly greater in women with HA than in those with AN, as were levels of insulin-like growth factor and percentages of body fat and lean body mass. Bone density of the lumbar spine, total hip, and total body was lowest in the AN group but was also reduced in women with HA compared with eumenorrheic women (Fig. 1). More than 85 percent of women with AN and fewer than 40 percent of those with HA had spinal bone density more than 1 standard deviation below the expected value. Differences in bone density remained significant after allowing for age at menarche, duration of amenorrhea, and previous estrogen use. In amenorrheic women in general and the group with AN in particular, lean body mass was most predictive of bone density at all sites on multivariate analysis. In women with HA, bone density measured at the lumbar spine correlated with body weight and duration of amenorrhea. FIGURE Fig. 1 Women with AN have more severe bone loss than those with HA, and the difference reflects a clinically relevant disparity in risk of fracture. Nutritional factors, especially lean body mass, seem to be a more important reason for these differences than estrogen deficiency. J Clin Endocrinol Metab 1999;84:2049–2055
More than half of the patients with anorexia nervosa (AN) have early bone loss and fractures. Despite the usual marked estrogen deficiency in young women with AN, hormone replacement therapy (HRT) has given mixed results at best. Because subnormal dehydroepiandrosterone (DHEA) levels may contribute to bone loss in AN, this study compared a 12-month course of oral DHEA (50 mg daily) with conventional HRT (20 μg ethinyl estradiol plus 0.1 mg levonorgestrel) in 61 females with AN (age range, 14-28 years). Among 51 women completing the study, those in both treatment groups gained significant body weight and had increased lean body and fat mass. Regular bleeding was reported by 58% of those taking DHEA and 80% of the HRT group. Lumbar bone mineral density (BMD) did not change significantly, but BMD at the hip did increase and correlated positively with increasing body weight in both treatment groups (Fig. 1). Increased BMD also correlated with elevations in insulin-related growth factor I and bone-specific alkaline phosphatase, a marker of bone formation, but only in the DHEA group (Fig. 2). No substantial effect on BMD was evident after controlling for weight gain. Daily caloric intake decreased 10% in the HRT group and 15% in patients given DHEA. Psychological ratings, including measures of body image, eating attitudes, and anxiety, indicated improvement in the DHEA group only. It seems that DHEA has both anabolic and antiresorptive effects on bone in young women with AN and that it may be preferable to standard HRT, in part because of favorable psychological effects.
Background Osteoporosis is a condition resulting in an increased risk of skeletal fractures due to a reduction in the density of bone tissue. Treatment of osteoporosis typically involves the use of pharmacological agents. In general it is thought that disuse (prolonged periods of inactivity) and unloading of the skeleton promotes reduced bone mass, whereas mechanical loading through exercise increases bone mass. Objectives To examine the effectiveness of exercise interventions in preventing bone loss and fractures in postmenopausal women. Search methods During the update of this review we updated the original search strategy by searching up to December 2010 the following electronic databases: the CochraneMusculoskeletal Group's Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 12); MEDLINE; EMBASE; HealthSTAR; Sports Discus; CINAHL; PEDro;Web of Science; Controlled Clinical Trials; and AMED. We attempted to identify other studies by contacting experts, searching reference lists and searching trial registers. Selection criteria All randomised controlled trials (RCTs) that met our predetermined inclusion criteria. Data collection and analysis Pairs of members of the review teamextracted the data and assessed trial quality using predetermined forms. For dichotomous outcomes (fractures), we calculated risk ratios (RRs) using a fixed-effect model. For continuous data, we calculated mean differences (MDs) of the percentage change from baseline. Where heterogeneity existed (determined by the I2 statistic), we used a random-effects model. Main results Forty-three RCTs (27 new in this update) with 4320 participants met the inclusion criteria. The most effective type of exercise intervention on bone mineral density (BMD) for the neck of femur appears to be non-weight bearing high force exercise such as progressive resistance strength training for the lower limbs (MD 1.03; 95% confidence interval (CI) 0.24 to 1.82). The most effective intervention for BMD at the spine was combination exercise programmes (MD 3.22; 95% CI 1.80 to 4.64) compared with control groups. Fractures and falls were reported as adverse events in some studies. There was no effect on numbers of fractures (odds ratio (OR) 0.61; 95% CI 0.23 to 1.64). Overall, the quality of the reporting of studies in the meta-analyses was low, in particular in the areas of sequence generation, allocation concealment, blinding and loss to follow-up. Authors' conclusions Our results suggest a relatively small statistically significant, but possibly important, effect of exercise on bone density compared with control groups. Exercise has the potential to be a safe and effective way to avert bone loss in postmenopausal women.
Objective: DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of "atypical AN" for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria. Method: Cross-sectional study of 168 women, 18 - 45y: (1) AN by DSM-IV (DSM-IV AN) (n = 37), (2) AN by DSM-5 but not DSM-IV criteria (DSM-5 AN) (n = 33), (3) atypical AN (ATYPICAL AN) (n = 77), (4) healthy comparison group (HC) (n = 21). Measurements included dual energy X-ray absorptiometry, Eating Disorder Examination-Questionnaire, Eating Disorder Inventory-2, Hamilton Depression and Anxiety Rating Scales. Results: BMD Z-score <-1.0 was present in 78% of DSM-IV, 82% of DSM-5, and 69% of ATYPICAL. Mean Z-scores were comparably low in DSM-IV and DSM-5, intermediate in ATYPICAL, and highest in HC. Lack of prior low weight or amenorrhea was, but history of overweight/obesity was not, protective against bone loss. Mean lean mass and percent fat mass were significantly lower in all AN groups than HC. DSM-IV, DSM-5, and ATYPICAL had comparable psychopathology. Discussion: Despite liberalizing diagnostic criteria, many women diagnosed with AN and atypical AN using DSM-5 criteria have low BMD. Presence or history of low weight and/or amenorrhea remain important indications for DXA. Loss of lean mass, in addition to fat mass, is present in all AN groups, and may contribute to low BMD. The deleterious effect of eating disorders on BMD extends beyond those with current low weight and amenorrhea. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016).