Content uploaded by Amy Theresa Page
Author content
All content in this area was uploaded by Amy Theresa Page on Dec 06, 2023
Content may be subject to copyright.
Regular Research Article
Prospective Association Between the
Dispensing of Antidepressants and
of Medications to Treat Osteoporosis
in Older Age
Osvaldo P. Almeida, Ph.D., Amy Page, Ph.D., Frank M. Sanfilippo, Ph.D.,
Christopher Etherton-Beer, Ph.D.
ARTICLE INFO
Article history:
Received August, 11 2023
Revised September, 15 2023
Accepted October, 4 2023
ABSTRACT
Background: Osteoporosis is a common condition associated with fragility frac-
tures, especially in older individuals and women. Antidepressants have emerged
as a potential risk factor, but their association with bone fragility remains uncer-
tain because the results of past studies are difficult to generalize. We aimed to
investigate the association between antidepressant exposure and subsequent
treatment for osteoporosis in a nationally representative sample of Australians.
Methods: Cohort study using a 10% random sample of the Pharmaceutical Bene-
fits Scheme (PBS) data for 2012, that included 566,707 individuals aged older
than or equal to 50 years not dispensed osteoporosis medications. The effect of
exposure to antidepressants during 2012 (prevalent or incident) or later (up to
2022) was examined using Cox regression models adjusted for age, sex, comorbid-
ities and other psychotropic medications. Results: Over 10 years, 73,360 (12.94%)
received osteoporosis medications; 16,216 (22.10%) had been dispensed antide-
pressants in 2012. The hazard of osteoporosis medication dispensing was higher
among those exposed to antidepressants (HR = 1.16, 99% CI = 1.14
−
1.18; average
duration of follow up: 8.0 §3.1 years, range: 1
−
10 years). The hazard of osteopo-
rosis medication diminished with increasing age, and the effect of antidepressants
was 37%
−
76% more pronounced among men in the 50s and 60s. Different classes
of antidepressants had a similar risk profile. Conclusion: The dispensing of antide-
pressants in older age is associated with higher hazard of subsequent dispensing of
medications for osteoporosis, and this association is more marked for young older
adults, particularly men. Clinicians should monitor the bone health of older indi-
viduals treated with antidepressants in order to decrease the morbidity associated
with fragility fractures. (Am J Geriatr Psychiatry 2023; &&:&&−
&&)
Key Words:
Antidepressants
SSRI
tricyclics
monoamine oxidase inhibitor
osteopenia
osteoporosis
fractures
cohort study
From the Medical School (OPA, CE-B), University of Western Australia, Perth, Australia; School of Allied Health (AP), University of Western
Australia, Perth, Australia; and the School of Population and Global Health (FMS), University of Western Australia, Perth, Australia. Send cor-
respondence and reprint requests to Osvaldo P. Almeida, Ph.D., WA Centre for Health & Ageing (M577), University of Western Australia, 35
Stirling Highway, Perth WA 6009, Australia. e-mail: osvaldo.almeida@uwa.edu.au
© 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jagp.2023.10.004
Am J Geriatr Psychiatry &&:&&,&& 2023 1
ARTICLE IN PRESS
Am J of Geriatric Psychiatry &&:&& (2023) &&−&&
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.ajgponline.org
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
Highlights
What is the primary question addressed by this study?
Does exposure to antidepressants increase the risk of osteoporosis treatment in the general population?
What is the main finding of this study?
Antidepressants are independently associated with subsequent treatment for osteoporosis and this effect is
more pronounced for men than women.
What is the meaning of the finding?
The bone health of older adults dispensed antidepressants should be monitored regularly because of
increased risk of osteoporosis and fragility fractures.
INTRODUCTION
Osteoporosis is a major cause of health burden
and morbidity associated with fragility frac-
tures, most noticeably among individuals older than
50 years and women.
1,2
Other factors associated with
decreased bone density and osteoporosis include low
body mass index, smoking, risky alcohol use, diabe-
tes, and the use of medications such as oral glucocor-
ticoids, immunosuppressants, thyroid hormones,
drugs that affect gonadal hormone production, and
some antiepileptics.
3
More recently, several studies
have suggested that treatment with antidepressants
may also lead to loss of bone mass and increased risk
of fractures. A review of observational studies found
that antidepressant use is associated with decreased
bone mineral density,
4
while findings from the Pre-
scribed Drugs Register of Sweden’s National Board of
Health and Welfare showed that adults aged 65 years
or older exposed to antidepressants sustain twice as
many hip fractures over one year as non-users.
5
How-
ever, hip fractures in later life are frequently associ-
ated with poor balance and falls, which increase in
frequency with older age, depression, and exposure
to antidepressants,
6
so that it is difficult to disentangle
the individual contribution of these factors to bone
fragility.
5,7,8
Moreover, a prospective analysis of data
from the Women’s Health Initiative Study found
no difference in bone mineral density over 7 years
among women exposed and not exposed to
antidepressants.
9
Data from randomized controlled trials are consistent
with the hypothesis that exposure to antidepressants
increase the risk of fractures compared with placebo in
high-risk populations. A recent systematic review and
meta-analysis showed that exposure to treatment with
the selective serotonin reuptake inhibitors fluoxetine or
citalopram more than doubles the risk of fractures over a
period of 6 months compared with placebo among
stroke survivors, with 1 fracture occurring for every 56
adults treated with an antidepressant.
10
However, only 4
trials were available for analysis, and findings that are
relevant for stroke survivors may not necessarily be
applicable to the general population of older people liv-
ing in the community.
10
The possible association between exposure to anti-
depressants and bone fragility is concerning, as an
increasing proportion of the population is exposed to
antidepressants every year (over 13% of the Austra-
lian population in 2021−2022, about 20% of older
adults).
11,12
One possible approach to investigate if
this association applies for older individuals living in
the community would be to examine if exposure to
an antidepressant increases the risk of bone fragility,
as inferred by the subsequent introduction of medica-
tions for the management of osteoporosis. We
designed this study to test this hypothesis.
METHODS
Study Design, Setting, and Participants
This cohort study used data from the 10% random
sample of the Pharmaceutical Benefits Scheme (PBS)
for the year 2012−2022. Services Australia maintains
the PBS database, which contains information on
medicines dispensed by all community pharmacies,
ARTICLE IN PRESS
Antidepressants and Osteoporosis
2 Am J Geriatr Psychiatry &&:&&,&& 2023
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
as well as private and PBS public hospitals across the
country, including the age and sex of the recipient,
the medicines dispensed, dispensing dates, and date
of death. The structure and content of the PBS data-
base have been described in detail elsewhere.
13
Briefly, the Australian government subsidizes the
cost of approved medicines dispensed to Australian
citizens, residents and eligible foreign nationals. Med-
icines listed under the PBS are initially approved for
clinical use by the Therapeutic Goods Administration
(TGA) and subsequently reviewed for comparative
cost-effectiveness before a recommendation for listing
is made for a particular clinical use (e.g., treatment of
depressive episodes). The dispensing of medicines
outside the PBS structure is uncommon.
As osteoporosis is a condition that affects predomi-
nantly older adults,
14
the study was limited to
566,707 individuals aged 50 years or over who were
alive and were dispensed a PBS medication in 2012
for the management of a health condition other than
osteoporosis (36,882 individuals dispensed medica-
tions for osteoporosis were excluded). We followed
participants until the dispensing of medications for
the management of osteoporosis, death, or the 31st
December 2022, whichever occurred first.
The Human Research Ethics Committee of the Uni-
versity of Western Australia reviewed and approved
this project (2022/ET000372).
Study Measures
The outcome of interest for this study was the
dispensing of medications commonly used for
the management of osteoporosis from 2013 to 2022.
The medications considered indicative of treatment
for osteoporosis are listed in eTable1 and included the
following Anatomical Therapeutic Chemical (ATC)
codes: M05BA (bisphosphonates), M05BB (combina-
tion of bisphosphonates), M05BX03 (strontium
ranelate) and M05BX04 (denosumab), G03XC01 (ral-
oxifene) and H05AA02 (teriparatide).
Antidepressants dispensed during 2012, or later,
were the primary exposures of the study: ACT codes
N06AA (non-selective monoamine reuptake inhibi-
tors, NSMRI), N06AB (selective serotonin reuptake
inhibitors, SSRI), N06AF/G (monoamine oxidase
inhibitors, MAOI), and N06AX (other antidepres-
sants). Other study measures included age (in years),
sex (male/female), death (between 2013 and 2022),
and exposure to antipsychotics (N05A), anxiolytics
(N05B) and hypnotics (N05C) in 2012. We also calcu-
lated the unweighted Rx-Risk Comorbidity Index,
which is a measure of health burden and mortality
risk measured from medications dispensed.
15,16
(See
original publication for list of medications used to
produce the index.
15
) For this study, we excluded
from the Index inferred anxiety, bipolar, depressive,
psychotic and osteoporotic illnesses, and considered a
total score greater than or equal to 5 out of the 37
remaining conditions indicative of high comorbidity
burden in 2012 (a score ≥5 is consistent with increas-
ing frailty).
17
The exclusion of anxiety, bipolar,
depressive and psychotic disorders inferred from the
dispensing of medicines was due to the significant
overlap in the dispensing of these medicines,
18
which
would result in collinearity and overadjustment of
the analyses. Osteoporosis was excluded because it
was the outcome of interest of the study.
Statistical Analyses
We used the statistical package Stata version 18.0
to manage and analyze the data. Descriptive statistics
were used for discrete data (counts and percentages).
We used cross-tabulation and Pearson chi-squared
statistic to examine the association between the dis-
pensing of antidepressants during 2012 and sociode-
mographic and clinical characteristics of the
population, and Cox regression with the Breslow
method for ties to examine the independent associa-
tion between exposure to antidepressants and the
subsequent dispensing of medications for the man-
agement of osteoporosis. The additional measures
included in these analyses were age group (reference
age 50−54 years), sex (reference male), Rx-Risk
Comorbidity Index greater than or equal to 5, and the
dispensing of antipsychotics, anxiolytics and hyp-
notics during 2012. The results were summarized by
the hazard ratio (HR) and respective 99% confidence
interval (99%CI). Additional models examined the
interaction between exposure to antidepressants, age,
and sex. As people not exposed to antidepressants
during 2012 could be exposed at a later date, they
were included in these analyses as non-exposed con-
trols until that date, and as exposed antidepressant
cases thereafter using the “stsplit”command of Stata
(time-dependent analysis). These analyses were
repeated to examine the impact of specific classes of
ARTICLE IN PRESS
Almeida et al.
Am J Geriatr Psychiatry &&:&&,&& 2023 3
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
antidepressants (NSMRI, SSRI, other antidepressants)
on the subsequent dispensing of medications for the
management of osteoporosis. For this post-hoc analy-
ses we excluded individuals dispensed any other
class of antidepressants between 2012 and 2022 to
decrease the risk of contamination (e.g., individuals
exposed to a SSRI who were subsequently exposed to
another class of antidepressant were excluded). Alpha
was set at 1% and all probability tests were two-
tailed.
RESULTS
The study sample consisted of 566,707 people aged
50 years or over who had not been dispensed a medi-
cation for the management of osteoporosis during
2012. Of the 566,707 participants, 293,436 (51.8%)
were women and 111,426 (19.7%) were dispensed an
antidepressant in 2012. The age of participants ranged
from 50 to over 95 years (individuals aged >95 years
were recorded as aged 95 years to minimize risk of
identification of the very old). Table 1 summarizes the
demographic and clinical characteristics of partici-
pants. There were more individuals in the 50s and 80s
dispensed antidepressants, as well as more women
(63.5%), and people with five or more inferred medi-
cal morbidities (simplified Rx-Risk Index ≥5). A
larger proportion of people dispensed antidepres-
sants were also dispensed antipsychotics, anxiolytics,
and hypnotics. During the 10 years of follow up,
73,360 (12.9%) received medications for the manage-
ment of osteoporosis, and of these 16,216 (22.1%) had
been dispensed antidepressants during 2012. Another
135,055 individuals were dispensed antidepressants
at least once between 2013 and 2022. There were
108,494 (19.1%) deaths between 2013 and 2022, and
these were more frequent among individuals who
had been dispensed an antidepressant.
Figure 1 shows the cumulative proportion of indi-
viduals dispensed medications for the management
of osteoporosis between 2013 and 2022 according to
their exposure to antidepressants. The proportion of
people dispensed medications for osteoporosis
increased with time, and this increase was more
marked among those dispensed than not dispensed
antidepressants (HR = 1.16, 99%CI = 1.14−1.18;
adjusted for age group, sex, Rx-Risk Index, and for
the dispensing of antipsychotics, anxiolytics, and
hypnotics in 2012). Figure 2 shows the hazard ratios
for the dispensing of medications for osteoporosis
according to age, sex, and exposure to antidepres-
sants. Medications for osteoporosis were dispensed
more frequently for women than men, and the dis-
pensing of these medications increased with age for
both men and women. Individuals dispensed
TABLE 1. Basic Demographic and Clinical Characteristics of Older Persons According to Whether or Not They Were Dispensed an
Antidepressant in 2012 (Study Entry)
No Antidepressant
N= 455,281
n(%)
Antidepressant
a
N= 111,426
n(%) p-Value
Age in years 50-54 84,451 (18.5) 21,789 (19.5) <0.001
55-59 82,086 (18.0) 20,315 (18.2)
60-64 80,449 (17.7) 18,523 (16.6
65-69 71,695 (15.7) 16,303 (14.63)
70-74 52,816 (11.6) 11,723 (10.5)
75-79 37,878 (8.3) 9,452 (8.5)
≥80 45,906 (10.1) 13,321 (12.0)
Female 222,654 (48.9) 70,782 (63.5) <0.001
Rx-Risk Index ≥5 62,429 (13.7) 28,574 (25.6) <0.001
Antipsychotics 6,406 (1.4) 9,011 (8.1) <0.001
Anxiolytics 21,070 (4.63) 19,342 (17.4) <0.001
Hypnotics 26,589 (5.8) 16,118 (14.5) <0.001
Medications for osteoporosis during follow up 57,144 (12.5) 16,216 (14.5) <0.001
Died during follow up 81,203 (17.8) 27,291 (24.5) <0.001
a
A total of 55,382 (49.70%) individuals were dispensed a selective serotonin reuptake inhibitor (SSRI), 29,810 (26.75%) a tricyclic antidepres-
sant, 1,254 (1.13%) a monoamine oxidase inhibitor, and 36,153 (32.45%) another antidepressant. Among those dispensed antidepressants,
100,993 received one class of antidepressant only (90.58%), 9,824 (8.82%) received 2, 658 (0.59%) received 3, and 11 (0.01%) received all 4.
ARTICLE IN PRESS
Antidepressants and Osteoporosis
4 Am J Geriatr Psychiatry &&:&&,&& 2023
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
antidepressants had greater hazard of being dis-
pensed medications for osteoporosis, but the effect of
antidepressants decreased progressively with increas-
ing age for both sexes (see details in eTables 2,3, and
4). The hazard of medications for osteoporosis in
association with exposure to antidepressants was
more pronounced for men than women, particularly
for the younger age-groups.
We completed a series of additional analyses to
examine whether the association between exposure to
antidepressants and the subsequent dispensing of
medications for the management of osteoporosis was
specific to certain classes of antidepressants. For these
analyses, we excluded individuals exposed to classes
of antidepressants other than the one under investiga-
tion (e.g., SSRIs) at any point between 2012 and 2022.
Thus, there were 385,085 individuals available for the
analysis of selective serotonin reuptake inhibitors
(SSRIs), 373,178 for nonselective monoamine reuptake
inhibitors, and 363,626 for other antidepressants.
SSRIs were associated with an independent adjusted
HR = 1.06 (99%CI = 1.02−1.10), nonselective
monoamine reuptake inhibitors with HR = 1.16
(99%CI = 1.12−1.21), and other antidepressants with
HR = 1.11 (99%CI = 1.05−1.16). Figure 3 summarizes
these results. The dispensing of vitamin D was not
captured reliably (only 2269 of 566,707 individuals),
but we re-ran the main analysis to examine whether
this could potentially affect the results −there was no
change (adjusted HR = 1.16, 99%CI = 1.14−1.18).
DISCUSSION
Our analyses showed that men and women aged
50 years or over who are exposed to antidepressant
medications are more likely to be dispensed treatment
for the management of osteoporosis than non-
exposed individuals. In addition, our results indicate
that this association is stronger for men than women
and decreases progressively with advancing age.
SSRIs, nonselective monoamine reuptake inhibitors,
and other antidepressants were all associated with a
small increase in the hazard of subsequent dispensing
of medications for the management of osteoporosis,
with SSRIs having the lowest observable group effect.
FIGURE 1. Cumulative proportion of adults aged older than or equal to 50 years dispensed medications for the management of
osteoporosis from 2013 to 2022 according to their exposure to antidepressants from 2012. Individuals who started using
antidepressants during follow up, but before the dispensing of medications for osteoporosis, were counted twice −they were
included in the no antidepressant group until the time they were dispensed an antidepressant.
ARTICLE IN PRESS
Almeida et al.
Am J Geriatr Psychiatry &&:&&,&& 2023 5
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
Access to a large community-representative sam-
ple of older adults is an obvious strength of this
study, as is the access to a reliable source of informa-
tion about the medications dispensed to the general
population.
13
While the dispensing of medications
cannot be assumed to imply appropriate use, existing
evidence suggests that agreement between these
measures is good to very good,
19
so that it seems rea-
sonable to infer from these data that individuals dis-
pensed antidepressants were actually consuming
them. We are also aware that other medications could
have confounded the association between exposure
to antidepressants and the subsequent use of medica-
tions for the management of osteoporosis, and we
attempted to address this issue by including in our
models the age of participants, as well as their expo-
sure to other psychotropic medications that could
decrease bone density,
20-22
and the Rx-Risk Comor-
bidity Index.
15
Our analysis took into account death
during 10 years of follow up, and the possible intro-
duction of antidepressants during this period (as a
time-dependent variable in the models), so that the
results are likely to reflect dynamic and real associa-
tions. However, we acknowledge that our proxy-mea-
sure of osteoporosis is not gold-standard,
23
and that
other factors, such as smoking, physical activity, diet,
body mass, exposure to sun light, and over-the-
counter use of vitamin D could have affected the
results. Moreover, our analyses did not allow us to
examine the potential effect of dosage and duration of
antidepressant treatment. Thus, confounding by
unmeasured factors and residual error cannot be dis-
missed. It is also possible that depression, and related
conditions, lead to behavioral and physiological
changes that facilitate the onset of osteoporosis, so
that the dispensing of antidepressants could be a
marker rather than the driver of such changes.
Furthermore, it is conceivable that people with
conditions that lead to the prescription and dispens-
ing of an antidepressant use health services more
regularly,
24,25
which may afford them greater oppor-
tunity of being investigated and treated for
FIGURE 2. Hazard ratio (HR) of being dispensed medication for osteoporosis according to age, sex (men/women), and use of
antidepressants (no/yes). The lines indicate the HR and the whiskers the 99% confidence interval of the HR. The analyses were
adjusted for the dispensing of antipsychotics, anxiolytics, hypnotics, and for the simplified Rx-Risk score. Men aged 50−54 are the
reference group for the depicted hazard ratios.
ARTICLE IN PRESS
Antidepressants and Osteoporosis
6 Am J Geriatr Psychiatry &&:&&,&& 2023
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
osteoporosis than non-depressed individuals (for
example, antidepressants may increase the risk of falls
and bone fractures, and the opportunity for the diag-
nosis of osteoporosis to be made). Hence, bias could
have affected our results, although the prevalence of
osteoporosis in Australia is about 1.5 times higher
than what we observed in our study (i.e., increased
case-finding alone is not a compelling explanation).
26
Our findings are consistent with those of other
studies showing that osteoporosis becomes more fre-
quent with increasing age and is more common
among women than men.
2,26
We observed that indi-
viduals dispensed antidepressants were more fre-
quent recipients of medications to manage
osteoporosis, a result that is supported by the findings
of other studies.
5,27−30
The effect of antidepressants
on the dispensing of medications for osteoporosis
seems to be greatest for the lower age-group of older
adults, and is more pronounced for men than women.
This may be due to the fact that other competing risks
for osteoporosis are more prevalent in women than
men (such as hormonal changes during the meno-
pausal transition),
31
and these could override the
osteoporotic effect of antidepressants in women com-
pared with men. The physiological mechanisms that
support this association are not entirely clear, but
existing evidence suggests that antidepressants
inhibit osteoblastic proliferation, which in turn leads
to a relative enhancement of osteoclastic function.
This could be due, at least in part, to serotonin-
induced inhibition of the phosphorylation of CAMP-
responsive element binding protein (CREB) by
FIGURE 3. Hazard ratio (HR) of being dispensed medication for osteoporosis according to age, sex (men/women), and use of selec-
tive serotonin inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other antidepressants (no/yes). The lines indicate the HR
and the whiskers the 99% confidence interval of the HR. The analyses were adjusted for the dispensing of antipsychotics, anxio-
lytics, hypnotics, and for the simplified Rx-Risk score. Each of the analysis excluded participants who had used any other class of
antidepressant between 2012 and 2022. We used split data analyses (time-dependent), so that participants who were dispensed an
antidepressant for the first time during the follow up period were considered not-exposed until the relevant year and exposed
thereafter. The model for monoamine oxidase inhibitors (MAOIs) had very few men aged older than or equal to 60 years exposed
to MAOIs and, for this reason, is not shown. All analyses used men aged 50−54 years not exposed to antidepressants as the refer-
ence group. Men aged 50−54 are the reference group for the depicted hazard ratios.
ARTICLE IN PRESS
Almeida et al.
Am J Geriatr Psychiatry &&:&&,&& 2023 7
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
phosphokinase A, which in turn leads to reduced
expression of cyclin genes that mediate osteoblast
proliferation (see Wadhwa et al.
32
for review and
more detailed discussion). It is also remarkable that
the association between the dispensing of antidepres-
sants and the subsequent dispensing of medications
for osteoporosis varied only slightly for the different
classes of antidepressants. Our data cannot offer
insights into the mechanisms supporting these associ-
ations, but they could be due to prescription bias (for
example, the onset of osteoporosis in a person dis-
pensed a SSRI may lead to a change of antidepressant
class), or to physiological changes associated with the
use of all antidepressants that facilitate the develop-
ment of osteoporosis.
In summary, the results of this study show that
adults aged older than or equal to 50 years exposed to
antidepressants are more likely to receive medications
for the management of osteoporosis over the subse-
quent 10 years. SSRIs, nonselective monoamine reup-
take inhibitors, and other antidepressants show a
similar risk profile for men and women, with this
association being particularly pronounced for young
older men dispensed non-selective monoamine reup-
take inhibitors or other antidepressants. These find-
ings suggest that the bone mineral density of older
adults dispensed antidepressants should be moni-
tored regularly, as they constitute a population at
increased risk of fragility fractures.
DISCLOSURES
Access to Services Australia data was supported by
infrastructure grants to OA, CEB, DP and FMS from the
University of Western Australia. CBE is a member of the
Drug Utilisation Sub-Committee of the Pharmaceutical
Benefits Advisory Committee. This publication’s content is
solely the responsibility of the authors. The authors declare
no other conflicts of interest with the published work.
AUTHOR CONTRIBUTIONS
OPA conceived the study, completed the analyses and
drafted the initial version of the paper. All authors contrib-
uted to the application to retrieve data from Services Aus-
tralia. AP and OPA managed and prepared the database
for analysis. All authors reviewed the paper critically, con-
tributed to its final format and content, and approved the
submission of its final version for publication.
DATA STATEMENT
The results of this study have not been presented
or published elsewhere. Data are available upon
request and approval from Services Australia (https://
www.servicesaustralia.gov.au).
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article
can be found in the online version at https://doi.org/
10.1016/j.jagp.2023.10.004.
References
1. US Department of Health and Human Services: Bone Health and
Osteoporosis: A Report of the Surgeon General. Rockville, MD:
US Department of Health and Human Services, Office of the Sur-
geon General, 2004 https://www.ncbi.nlm.nih.gov/pubmed/
20945569
2. Clynes MA, Harvey NC, Curtis EM, et al: The epidemiology of
osteoporosis. Br Med Bull 2020; 133:105–117
3. Gregson CL, Armstrong DJ, Bowden J, et al: UK clinical guideline
for the prevention and treatment of osteoporosis. Arch Osteo-
poros 2022; 17:58
4. Rizzoli R, Cooper C, Reginster JY, et al: Antidepressant medica-
tions and osteoporosis. Bone 2012; 51:606–613
5. Brannstrom J, Lovheim H, Gustafson Y, et al: Association
between antidepressant drug use and hip fracture in older
people before and after treatment initiation. JAMA Psychiatry
2019; 76:172–179
6. Kerse N, Flicker L, Pfaff JJ, et al: Falls, depression and antidepres-
sants in later life: a large primary care appraisal. PLoS One 2008;
3:e2423
7. Cizza G, Primma S, Csako G: Depression as a risk factor for osteo-
porosis. Trends Endocrinol Metab 2009; 20:367–373
8. Fernandes BS, Hodge JM, Pasco JA, et al: Effects of depression
and serotonergic antidepressants on bone: mechanisms and
implications for the treatment of depression. Drugs Aging 2016;
33:21–25
9. Spangler L, Scholes D, Brunner RL, et al: Depressive symptoms,
bone loss, and fractures in postmenopausal women. J Gen Intern
Med 2008; 23:567–574
ARTICLE IN PRESS
Antidepressants and Osteoporosis
8 Am J Geriatr Psychiatry &&:&&,&& 2023
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
10. Jones JS, Kimata R, Almeida OP, et al: Risk of fractures in
stroke patients treated with a selective serotonin reuptake
inhibitor: a systematic review and meta-analysis. Stroke 2021;
52:2802–2808
11. Australian Institute of Health and Welfare: Mental Health-Related
Prescriptions. Canberra: AIHW, 2023 https://www.aihw.gov.au/
mental-health/topic-areas/mental-health-prescriptions
12. deOliveira Costa J, Gillies MB, Schaffer AL, et al: Changes in anti-
depressant use in Australia: a nationwide analysis (2015-2021).
Aust N Z J Psychiatry 2023; 57:49–57
13. Mellish L, Karanges EA, Litchfield MJ, et al: The Australian phar-
maceutical benefits scheme data collection: a practical guide for
researchers. BMC Res Notes 2015; 8:634
14. Holroyd C, Cooper C, Dennison E: Epidemiology of osteoporosis.
Best Pract Res Clin Endocrinol Metab 2008; 22:671–685
15. Pratt NL, Kerr M, Barratt JD, et al: The validity of the Rx-Risk
Comorbidity Index using medicines mapped to the anatomical
therapeutic chemical (ATC) classification system. BMJ Open
2018; 8:e021122
16. Pratt NL, Kerr M, Barratt JD, et al: Correction: the validity of the
Rx-Risk Comorbidity Index using medicines mapped to the ana-
tomical therapeutic chemical (ATC) Classification System. BMJ
Open 2020; 10:e021122corr021121
17. Hyde Z, Flicker L, Almeida OP, et al: Low free testosterone pre-
dicts frailty in older men: the health in men study. J Clin Endocri-
nol Metab 2010; 95:3165–3172
18. Almeida OP, Etherton-Beer C, Kelty E, et al: Lithium dispensed
for adults aged >/= 50 years between 2012 and 2021: analyses of
a 10% sample of the Australian pharmaceutical benefits scheme.
Am J Geriatr Psychiatry 2023; 31:716–725
19. Richardson K, Kenny RA, Peklar J, et al: Agreement between
patient interview data on prescription medication use and phar-
macy records in those aged older than 50 years varied by thera-
peutic group and reporting of indicated health conditions. J Clin
Epidemiol 2013; 66:1308–1316
20. O’Keane V: Antipsychotic-induced hyperprolactinaemia, hypo-
gonadism and osteoporosis in the treatment of schizophrenia. J
Psychopharmacol 2008; 22:70–75
21. Vestergaard P, Rejnmark L, Mosekilde L: Anxiolytics, sedatives,
antidepressants, neuroleptics and the risk of fracture. Osteo-
poros Int 2006; 17:807–816
22. Bolton JM, Morin SN, Majumdar SR, et al: Association of mental
disorders and related medication use with risk for major osteopo-
rotic fractures. JAMA Psychiatry 2017; 74:641–648
23. Pisani P, Renna MD, Conversano F, et al: Screening and early
diagnosis of osteoporosis through X-ray and ultrasound based
techniques. World J Radiol 2013; 5:398–410
24. Prina AM, Huisman M, Yeap BB, et al: Association between
depression and hospital outcomes among older men. CMAJ
2013; 185:117–123
25. Luber MP, Meyers BS, Williams-Russo PG, et al: Depression and
service utilization in elderly primary care patients. Am J Geriatr
Psychiatry 2001; 9:169–176
26. Henry MJ, Pasco JA, Nicholson GC, et al: Prevalence of osteopo-
rosis in Australian men and women: Geelong osteoporosis study.
Med J Aust 2011; 195:321–322
27. Rauma PH, Honkanen RJ, Williams LJ, et al: Effects of antidepres-
sants on postmenopausal bone loss - a 5-year longitudinal study
from the OSTPRE cohort. Bone 2016; 89:25–31
28. Wu Q, Xu Y, Bao Y, et al: Tricyclic antidepressant use and risk of
fractures: a meta-analysis of cohort studies through the use of
both frequentist and bayesian approaches. J Clin Med 2020;
9:2584
29. Haney EM, Chan BK, Diem SJ, et al: Association of low bone min-
eral density with selective serotonin reuptake inhibitor use by
older men. Arch Intern Med 2007; 167:1246–1251
30. Diem SJ, Blackwell TL, Stone KL, et al: Use of antidepressants
and rates of hip bone loss in older women: the study of osteopo-
rotic fractures. Arch Intern Med 2007; 167:1240–1245
31. Ho-Pham LT, Nguyen HG, Nguyen-Pham SQ, et al: Longitudinal
changes in bone mineral density during perimenopausal transi-
tion: the Vietnam osteoporosis study. Osteoporos Int 2023;
34:1381–1387
32. Wadhwa R, Kumar M, Talegaonkar S, et al: Serotonin reuptake
inhibitors and bone health: a review of clinical studies and plau-
sible mechanisms. Osteoporos Sarcopenia 2017; 3:75–81
ARTICLE IN PRESS
Almeida et al.
Am J Geriatr Psychiatry &&:&&,&& 2023 9
Downloaded for Amy Page (amy.page@uwa.edu.au) at The University of Western Australia from ClinicalKey.com.au by Elsevier on
December 05, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
