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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
INTRODUCTION
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
100,000.[2]
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
E-mail: Amal-rahhal@uiowa.edu
Received: June 12, 2019
Revised: July 6, 2019
Accepted: July 21, 2019
Review Article
J Bone Metab 2019;26(3):133-143
https://doi.org/10.11005/jbm.2019.26.3.133
pISSN 2287-6375 eISSN 2287-7029
Jeremy Steinman, et al.
134 http://e-jbm.org/ https://doi.org/10.11005/jbm.2019.26.3.133
AN. In this article, we provide an updated summary of ex-
isting data regarding the pathophysiology and treatment
of AN-related osteoporosis.
METHODS
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.
WHAT FACTORS CONTRIBUTE TO
AN-RELATED BONE DISEASE?
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
https://doi.org/10.11005/jbm.2019.26.3.133 http://e-jbm.org/ 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.
CAN AN-RELATED BONE DISEASE BE
STABILIZED OR REVERSED?
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
here.
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.
136 http://e-jbm.org/ https://doi.org/10.11005/jbm.2019.26.3.133
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
(year)
Average
follow-up
(month)
Weight/BMI changes Subjective change in BMD Change in bone turnover
markers
Bachrach et al.
[45]
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
NA
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
Caillot-Augus-
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.
[48]
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
levels
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-
tial)
Increased if complete weight recov-
ery, decreased if partial weight
recovery
NA
Golden et al.
[51]
2005 Randomized clinical
trial of alendronate
vs. placebo with
secondary analysis
of effect of weight
gain
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-
tion
NA
Compston et al.
[52]
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
NA
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
NA
do Carmo et al.
[19]
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)
NA
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
levels
(Continued to the next page)
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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.
SEX HORMONE REPLACEMENT
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
(year)
Average
follow-up
(month)
Weight/BMI changes Subjective change in BMD Change in bone turnover
markers
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
NA
Schulze et al.
[57]
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
NA
Franzoni et al.
[30]
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.
138 http://e-jbm.org/ https://doi.org/10.11005/jbm.2019.26.3.133
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.
ANTI-RESORPTIVE AGENTS
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.
ANABOLIC AGENTS
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
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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]
OTHER THERAPIES
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.
DISCUSSION
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
efficacy.
DECLARATIONS
Ethics approval and consent to participate
Not applicable.
Jeremy Steinman, et al.
140 http://e-jbm.org/ https://doi.org/10.11005/jbm.2019.26.3.133
Conflict of interest
No potential conflict of interest relevant to this article
was reported.
ORCID
Jeremy Steinman https://orcid.org/0000-0002-8419-3860
Amal Shibli-Rahhal https://orcid.org/0000-0003-2405-8963
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