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CNS Drugs. Author manuscript; available in PMC 2016 March 01.
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Published in final edited form as:

CNS Drugs. 2015 March ; 29(3): 245252. doi:10.1007/s40263-015-0231-5.

Serotonin-Norepinephrine Reuptake Inhibitor and Selective

Serotonin Reuptake Inhibitor Use and Risk of Fractures: A new-
user cohort study among US adults aged 50 and older
Amy Lanteigne1, Yi-han Sheu2, Til Strmer3, Virginia Pate3, Deb Azrael1, Sonja A.
Swanson2, and Matthew Miller2,4
1Department of Health Policy and Management, Harvard University, Harvard School of Public
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Health, 677 Huntington Ave, Boston, MA 02115, USA

2Department of Epidemiology, Harvard University, Harvard School of Public Health, 677
Huntington Ave, Boston, MA 02115, USA
3Department of Epidemiology, University of North Carolina at Chapel Hill, Gillings School of
Global Public Health, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, CB #7435, Chapel Hill,
NC 27599-7435, USA
4Department of Health Sciences, Northeastern University, 360 Huntington Ave, Boston, MA
02115, USA

Abstract
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BackgroundAntidepressants may increase the risk of fractures by disrupting sensory-motor

function, thereby increasing the risk of falls, and by decreasing bone mineral density and
consequently increasing the fall- or impact-related risk of fracture. Selective serotonin reuptake
inhibitor (SSRI) antidepressants appear to increase fracture risk relative to no treatment, while less
is known about the effect of serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants,
despite SNRIs being prescribed with increasing frequency. No prior study has directly examined
how fracture risk differs among patients initiating SNRIs versus those initiating SSRIs.

ObjectiveThe objective of this study was to assess the effect of SNRI vs. SSRI initiation on
fracture rates.

Data sourceData came from a PharMetrics claims database, 19982010, which is comprised
of commercial health plan information obtained from managed care plans throughout the US.
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MethodsWe constructed a cohort of patients aged 50 years or older initiating either of the two
drug classes (SSRI, N=335,146; SNRI, N=61,612). Standardized mortality weighting and Cox
proportional hazards regression were used to estimate hazard ratios for fractures by antidepressant
class.

ResultsIn weighted analyses, the fracture rates were approximately equal in SNRI and SSRI
initiators: hazard ratios for the first one and five-year periods following initiation were,

Corresponding Author: Matthew Miller, MD, MPH, ScD, Professor of Health Sciences and Epidemiology, Director, Undergraduate
Major in Health Sciences, Northeastern University, Bouv College of Health Sciences, Department of Health Sciences, Room 316
Robinson Hall, 360 Huntington Avenue, Boston, MA 02115-5000, USA, ma.miller@neu.edu, 617- 373-2087, 617-373-2968 (fax).
 Lanteigne et al. Page 2

respectively, 1.11 (95% CI: 0.921.36) and 1.06 (95% CI: 0.901.26). For the sub-group of
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patients with depression who initiated on either SNRIs or SSRIs, those initiating SNRIs had a
modestly, but not significantly elevated fracture risk, compared with those who initiated on SSRIs,
hazard ratio = 1.31 (95% CI: 0.951.79).

ConclusionsWe found no evidence that initiating SNRIs rather than SSRIs materially
influenced fracture risk among a cohort of middle-aged and older adults.

1. Introduction
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake
inhibitors (SNRIs) have become the mainstream pharmacological treatments for patients
with depressive disorders since the late 1990s [1, 2], due in part to the perception that SSRIs
and SNRIs have more favorable side-effect profiles than do older drugs such as tricyclic
antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) [36], with the possible
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exception of fracture risk, which is of particular concern among older adults [7].
Antidepressants have been hypothesized to increase fracture risk among older adults through
three mechanisms: 1) antidepressants can cause dizziness at initiation of the drug, increasing
the risk of falls and resulting fractures [8, 4]; 2) serotonin-affecting drugs, such as SSRIs,
down regulate osteoblast activity and thereby, in time, decrease bone mineral density,
increasing the risk of sustaining a fracture after a fall or other impact [8, 3, 9, 10]; and 3)
norepinephrine-affecting drugs, such as SNRIs, may play a role in osteoblast activity and
may result in reduced bone density by increasing bone resorption [11, 12].

Existing literature examining the link between antidepressant use and fractures largely
focuses on three antidepressants classes: SSRIs, TCAs, and MAOIs [8, 13, 3, 14, 15]. SSRIs
have been weakly linked with an increased risk of fracture when compared to both TCAs
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and MAOIs [8, 14]. Excess fracture risk has been shown in users of SSRIs and SNRIs when
compared to non-users [9, 3, 4, 16].

SSRIs risk profile has been studied extensively, but SNRIs safety concerns are currently
less well-studied, especially as the drugs relate to risk of fractures and bone fragility [8, 13,
3, 14, 4]. To our knowledge, the current study is the first to directly compare the risk of
fractures between SSRIs and SNRIs.

2. Methods
2.1 Data Source and Patients
The PharMetrics Claims Database used in this study was purchased from IMS Health and is
comprised of commercial health plan information obtained from managed care plans
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throughout the United States. The database includes medical and pharmaceutical claims for
over 61 million unique patients from over 98 health plans (approximately 16 million covered
lives per year). The database includes inpatient and outpatient diagnoses (in International
Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] format) and
procedures (in Current Procedure Terminology [CPT-4] and Health Care Common
Procedure Coding System [HCPCS] formats) as well as both retail and mail order records of
all reimbursed dispensed prescriptions. Available data on prescriptions include the National

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Drug Code (NDC) as well as the quantity, number of days supplied, and the date of
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dispensing. Additional data elements include demographic variables (age, gender,

geographic region), provider specialty, and start and stop dates of health-plan enrollment.
Only health plans that submit data for all members are included in the database.

The current cohort study involves commercially-insured US patients 50 years of age or older
who initiated use of SSRIs or SNRIs between January 1, 1998 and December 31, 2010 (the
most recent data set available from the PharMetrics Claims Database.) Initiation was defined
as filling an SSRI or SNRI antidepressant prescription without evidence of having filled a
prescription for any class of antidepressants in the preceding 12 months. Such initiators are
referred to throughout as new users. Primary analyses focused on the first treatment
episode initiated during the study period. Subjects were required to be actively enrolled in a
health plan with prescription benefits that contributed data to our claims database (see
below) during the 15 months prior to initiation (i.e., 12 months for baseline covariate
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assessment and an additional 3 months to allow uniform assessment of all patients based on
a 60 day grace period and a usual antidepressant supply of 30 days).

2.2 Medication Exposure

Medications were classified as SSRIs or SNRIs. SSRIs studied were citalopram
hydrobromide, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride,
and sertraline hydrochloride; SNRIs studied were venlafaxine hydrochloride and duloxetine
hydrochloride. Patients initiating more than one antidepressant agent on the same day were
excluded.

2.3 Follow-up
Exposure status was assigned based on the initiated medication and carried forward. Study
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follow-up began on the day after initiation of the first antidepressant therapy. For each
patient we created a record of drug coverage by listing consecutive prescription fills, based
on dispensing dates and reported days supply. When a dispensing occurred before the
previous prescription should have run out, use of the new prescription is assumed to begin
the day after the end of the old prescription. Since users of any prescription medicine,
especially chronic users, may experience relatively brief episodes without a supply of
medicine or may skip taking the medicine some days, our primary analyses allowed for up
to 60 extra days to elapse beyond the provided days supply before censoring (i.e., we use a
60 day grace period, twice the most common days supply). Note, a person contributes
information, and is thus included in the number of patients contributing to any post-initiation
interval, if they are eligible to contribute time for the given analysis. Therefore, for the as
treated analysis, the person must still be on their initial treatment at the start of the time
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period; for the first treatment carried forward analysis, the person must only continue to be
enrolled in the health care plan at the start of the time period.

Patients were also censored at the date they switched agents (including when switching
occurred within antidepressant class), added other antidepressant agents to the initiated
regimen (i.e., treatment augmentation), ended enrollment in their health insurance plan, or
the end of the study period, whichever came first. Our rationale for censoring was based on

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the knowledge that because more SSRI drugs exist than do SNRI drugs, switching agents
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even within classes had the potential to introduce differential bias and thus introduce
asymmetry into our analyses. New users were not allowed to become new users again;
patients who were prevalent users at the start of their enrollment were allowed to become
new users later during the study period.

2.4 Outcome
The occurrence of hip, humerus, radius, and ulna fractures during follow-up was our
outcome of interest. These fractures were defined as a medical claim with an International
Classification of Diseases, Ninth Revision (ICD-9) external cause of injury code (E-code) of
hip (733.14 or 820.xx), humerus (733.11 or 812.xx) or radius/ulna (733.12 or 813.xx)
fracture diagnosis.
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2.5 Patient Characteristics

Patient characteristics considered as potential confounders were age, sex, and several
indicators of past year medical comorbidity based on inpatient, outpatient, and pharmacy
claims, including the number of acute hospitalizations for non-psychiatric reasons, number
of outpatient visits, constituents of the Charlson Comorbidity Index score, and number of
distinct generic drugs filled. Psychiatric risk factors studied were the number of acute
psychiatric hospitalizations, the number of acute hospitalizations for substance abuse,
psychiatric comorbidity, and suicide ideation/attempts. Drug initiators were also sub-
categorized as having or not having a depression diagnosis in order to parse out any
potential effect modification on fracture risk. For drug initiators with a depression diagnosis,
a hierarchy of depression severity was constructed for each patient as a function of the
proximity of the most recent depression diagnosis to antidepressant initiation (i.e., within 30
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days of antidepressant initiation vs. within 31360 days of initiation) and whether the
diagnosis was an inpatient or outpatient diagnosis. For inpatient diagnoses, depression
diagnosis was further characterized as to whether the diagnosis was the primary or
secondary diagnosis of record. For outpatient diagnoses, persons with a single depression
diagnosis were distinguished from those with multiple depression diagnoses in the year prior
to initiation of antidepressant therapy. Other psychiatric disorders were defined as the
presence of at least one inpatient or outpatient diagnostic code. The disorders studied were
anxiety or sleep disorders, substance abuse, attention deficit hyperactivity disorder,
cognitive impairment or dementia, bipolar disorder, schizophrenic disorder, and personality
disorders. In addition to psychiatric comorbidities, we measured a number of general
medical comorbidities, including malignant neoplasms, opiate use, stroke and transient
ischemic attack, and Parkinson disease, all of which are listed in Table 1. Risk factors for the
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outcome of interest were diagnostic codes for fractures or medical procedures performed on
the hip, humerus, and/or radius/ulna.

2.6 Statistical Analyses

We estimated the propensity for initiating SNRIs versus SSRIs using multivariable logistic
regression including all of the covariates outlined above. Standardized mortality weighting
[17] was applied to weight the SNRI cohort by the propensity score odds to achieve a

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similar distribution of patient characteristics in SNRI initiators as in SSRI initiators. We

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chose to weight SNRI patients to SSRI patients because, by current prescribing patterns,
individuals are most commonly prescribed SSRIs as first-line antidepressant medications.
Thus, our study examines what the fracture risk differential would be among patients who
started on SNRIs (the less common practice) as opposed to SSRIs, and if this would be
beneficial in terms of alleviating fracture risk. Fracture rates were calculated for patients
exposed to SNRI vs. SSRI over the entire exposure period using weighted Poisson
regression. Robust methods were used to calculate 95% confidence intervals. We also used
weighted Cox proportional hazard models to estimate hazard ratios of medication class on
fracture stratified by 1 and 5-year time periods.

3. Results
3. 1 Description of cohort
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Between January 1, 1998 and December 31, 2010, 335,146 patients initiated SSRI
antidepressants and 61,612 patients initiated SNRI antidepressants. As shown in Table 1,
baseline characteristics, including comorbidities, severity level of depression diagnosis (if a
diagnosis existed at all), and measures of health care utilization, largely reflect the
characteristics of the original SSRI cohort, which indicates a well-matched SNRI weighted
cohort.

3.2 Risk of fractures

In our primary (as-treated, 60-day grace period, 360 days follow-up) analysis (Table 2), the
rate of fractures was approximately equal in both the SSRI and SNRI cohorts (SNRI: 7.5 per
1,000 person-years, 95% CI: 6.29.0; SSRI: 6.7 per 1,000 person-years, 95% CI: 6.37.1).
Follow up through 5-years (1800 days) after initiation (Table 2) also showed that patients
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filling prescriptions for SNRIs showed a fracture rate of 6.9 per 1,000 person-years (95%
CI: 5.98.2) while patients filling prescriptions for SSRIs showed a very similar fracture rate
of 6.5 per 1,000 person-years (95% CI: 6.26.8). Over the first year after initiating therapy,
those starting SNRIs, relative to those initiating with SSRIs, were not significantly more
likely to suffer a fracture (hazard ratio = 1.11, 95% CI: 0.921.36) (Table 3). A similarly
null finding was observed over the first five years after beginning therapy (hazard ratio =
1.06, 95% CI: 0.901.26.) Additionally, for a cohort of patients with a depression diagnosis
who initiated on either SNRIs or SSRIs, those initiating on SNRIs had a slightly elevated,
though not statistically significantly elevated, rate of fracture (hazard ratio = 1.31, 95% CI:
0.951.79) (Table 4). For a cohort of patients without a depression diagnosis who initiated
on either SNRIs or SSRIs, those initiating on SNRIs had essentially the same rate of fracture
as those initiating on SSRI (hazard ratio = 1.04, 95% CI: 0.801.34) (Table 4).
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4. Discussion
Our study is the first of which we are aware to directly examine the differences in the risk of
fracture associated with initiating SNRI compared to SSRI among subjects aged 50 years or
older. In our study, there was no statistically significant differential in fracture risk between
initiators of SNRIs vs. initiators of SSRIs during our follow-up period. Our finding that, on
balance, SSRIs and SNRIs are correlated with similar fracture rates is consistent with the

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notion that both SSRIs and SNRIs may contribute to fracture risk through different, though
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related pathways. It is possible, for example, that the extent to which serotonin-affecting
drugs down regulate osteoblast activity and, in time, decrease bone mineral density[8, 3, 9,
10], is similar to the effect of norepinephrine-affecting drugs, such as SNRIs [11, 12][18].

Although depression is known to be an independent risk factor for fracture, no prior work of
which we are aware point to effect modification by depression status. Future work is needed
to examine whether our secondary finding of a non-significant and modest increase in
fracture risk among depressed patients initiating SNRIs, compared with those initiating
SSRIs, can be replicated, or whether our finding in this regard is due to chance or residual
confounding that is attenuated in our larger cohort of initiators both with and without
depression.

There are several methodological issues to be considered regarding the current study. First,
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as depression itself has been shown to be a risk factor of osteoporosis [1922], incomplete
elimination of the impact of disease severity (or other potential confounders) during the
matching process could affect our findings, especially in our cohort with depression
diagnoses. Another limitation comes from our assessment of medication exposure. While we
used the best-available data to define duration of exposure to the drug (longitudinal
information on prescription refills) this may not accurately reflect the reality of drug-
adherence among SSRI and SNRI patients. It has been shown that non-adherence to
antidepressants is a prevalent phenomenon [23, 24], but whether there are differences in
adherence between SSRIs and SNRIs has not been reported in the previous literature to our
knowledge. Nevertheless, our findings are similar for grace periods from 7 days to 60 days,
suggesting that to the extent that antidepressant persistence is a reasonable proxy for
antidepressant adherence, our findings may not be largely affected by differential adherence.
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Because there are many reasons people stop antidepressant therapy, including some side-
effects that would not be measured in administrative data but might be related to underlying
fracture risk, we did not perform analyses on the effects of drug discontinuation as this
would have opened up our findings to more unmeasured confounding. We do not have
information on the magnitude of patients obtaining prescriptions outside of the PharMetrics
claims database, but we have no reason to believe that SSRI initiators are any more likely or
less likely to purchase medication out of plan than are SNRI initiators. Due to limitation in
numbers of subjects and events, we did not have sufficient statistical power to report
findings that are stratified under specific risk factors, for example, age of the subjects, or to
parse fractures by type. Finally, we did not perform dose-response analyses as our study was
not powered to do so; further, doses across drug classes (SNRI vs. SSRI) are not directly
comparable.
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Conclusions
Despite the stated limitations, our null findings with respect to fracture rates comparing
SNRI and SSRI antidepressant initiators suggest that although mechanically plausible,
SSRIs do not materially increase fracture risk any more than do SNRIs, the class of
antidepressants next most likely to be prescribed today. Given the frequency with which

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antidepressant medications are prescribed, more research is needed to fully understand the
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relative risks and benefits of prescribing these classes of antidepressants.

Acknowledgments
Research reported in this publication was supported by the National Institute of Mental Health of the National
Institutes of Health under Award Number R01 MH085021. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of Health. Dr. Strmer receives
investigator-initiated research funding and support as Principal Investigatory (R01 AG023178) and Co-Investigator
(R01 AG042845) from the National Institute on Aging (NIA), and as Co-Investigator (R01 CA174453) from the
National Cancer Institute (NCI) at the National Institutes of Health (NIH) and as Principal Investigator of a Pilot
Project from the patient Centered Outcomes Research Institute (PCORI). Dr. Strmer does not accept personal
compensation of any kind from any pharmaceutical company, though he receives salary support from the Center for
Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Merck) and research support from
pharmaceutical companies (Amgen, Merck) to the Department of Epidemiology, University of North Carolina at
Chapel Hill. Dr. Miller, Dr. Sheu, Dr. Azrael, Dr. Swanson, Ms. Lanteigne, and Ms. Pate have no conflicts of
interest.
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Key Points
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There is no statistically significant difference in rate of fracture among patients

who initiate SNRIs versus those who initiate SSRIs.

Future studies should examine whether the elevated fracture risk trend we
observe among patients with depression who initiate on SNRIs is present among
high fracture-risk populations.
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Table 1

Characteristics of the Study Cohort, SNRI vs SSRI Primary Analysis: 1 Rx Fill, Ages 50+
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SSRI SNRI
Characteristic N=335,146 N=61,612 SNRI Weighted to SSRI

Age
5054 95,920 (28.6%) 20,786 (33.7%) 28.2%

5559 80,093 (23.9%) 16,779 (27.2%) 24.4%

6064 59,918 (17.9%) 11,313 (18.4%) 18.0%

6574 50,208 (15.0%) 7,810 (12.7%) 14.5%

7584 33,072 (9.9%) 3,739 (6.1%) 9.7%

8599 15,935 (4.8%) 1,185 (1.9%) 5.2%

Sex, M 119,950 (35.8%) 18,379 (29.8%) 36.3%

Attention deficit hyperactivity disorder (ADHD) 1,407 (0.4%) 422 (0.7%) 0.4%
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Antipsychotics 14,004 (4.2%) 3,044 (4.9%) 4.4%

Anxiety 59,467 (17.7%) 7,897 (12.8%) 18.4%

Cardiac Arrhythmias 37,519 (11.2%) 5,239 (8.5%) 11.5%

Rheumatoid Arthritis 6,481 (1.9%) 1,786 (2.9%) 1.9%

Barbiturate 406 (0.1%) 62 (0.1%) 0.1%

Beta Blockers 71,810 (21.4%) 11,040 (17.9%) 21.6%

Benzodiazepine 82,224 (24.5%) 13,580 (22.0%) 25.0%

Bipolar Disorder 2,669 (0.8%) 816 (1.3%) 0.9%

History of Falls, Syncope or Gait Abnormality 41,229 (12.3%) 7,211 (11.7%) 12.6%

Suicidal Ideation 498 (0.1%) 106 (0.2%) 0.2%

Bone Mineral Density Scan 30,770 (9.2%) 6,956 (11.3%) 8.9%

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Cataracts 36,208 (10.8%) 6,038 (9.8%) 10.8%

Myocardial Infarction 9,544 (2.8%) 1,199 (1.9%) 3.0%

Paraplegia and Hemiplegia 1,429 (0.4%) 315 (0.5%) 0.5%

Moderate or Severe Liver Disease 902 (0.3%) 129 (0.2%) 0.3%

AIDS/HIV 431 (0.1%) 88 (0.1%) 0.1%

Peripheral Vascular Disease 21,215 (6.3%) 3,772 (6.1%) 6.5%

Peptic Ulcer Disease 4,014 (1.2%) 688 (1.1%) 1.3%

Congestive Heart Failure 19,523 (5.8%) 2,531 (4.1%) 6.1%

Asthma/Chronic Obstructive Pulmonary Disease (COPD) 51,384 (15.3%) 8,866 (14.4%) 15.7%

Cox-2 Inhibitors 20,816 (6.2%) 4,768 (7.7%) 6.3%

Crohn Disease/Gastroenteritis 11,037 (3.3%) 2,096 (3.4%) 3.4%

Alzheimer or Other Dementia 15,570 (4.6%) 1,586 (2.6%) 5.0%

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Diabetes 58,086 (17.3%) 11,721 (19.0%) 17.7%

Severity Level of Depression Diagnosis

T1: Primary Inpatient Diagnosis <=30 Days Pre-Index Date 866 (0.3%) 180 (0.3%) 0.3%

T2: Primary Inpatient Diagnosis 31360 Days Pre-Index Date 254 (0.1%) 91 (0.1%) 0.1%

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SSRI SNRI
Characteristic N=335,146 N=61,612 SNRI Weighted to SSRI
T3: Non-Primary Inpatient Diagnosis <=360 Days Pre-Index Date 5,968 (1.8%) 971 (1.6%) 1.9%
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T4: 2+ Outpatient Diagnosis <=360 Days Pre-Index Date 48,163 (14.4%) 8,869 (14.4%) 15.1%

T5: 1 Outpatient Diagnosis <=360 Days Pre-Index Date 45,774 (13.7%) 5,902 (9.6%) 14.2%

T6: No Diagnosis 234,121 (69.9%) 45,599 (74.0%) 68.4%

Glucocorticosteroids 47,435 (14.2%) 10,357 (16.8%) 14.2%

H-2 Antagonists 16,146 (4.8%) 2,306 (3.7%) 4.8%

Hip Fracture 2,253 (0.7%) 279 (0.5%) 0.7%

Humerus Fracture 1,360 (0.4%) 242 (0.4%) 0.4%

Hyperparathyroidism 1,313 (0.4%) 257 (0.4%) 0.4%

Hyperthyroidism 4,095 (1.2%) 783 (1.3%) 1.2%

Kyphosis 2,862 (0.9%) 786 (1.3%) 0.9%

Liver Disease 12,701 (3.8%) 2,405 (3.9%) 3.9%

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Malignant Neoplasm 39,968 (11.9%) 8,485 (13.8%) 11.5%

Other nonsteroidal anti-inflammatory drug (NSAIDs) 62,762 (18.7%) 13,904 (22.6%) 18.7%

# of Prescription Drugs
1 (antidepressant only) 16,279 (4.9%) 3,083 (5.0%) 4.9%

23 49,631 (14.8%) 8,304 (13.5%) 14.7%

45 55,563 (16.6%) 8,988 (14.6%) 16.5%

69 94,994 (28.3%) 16,521 (26.8%) 28.3%

10+ 118,679 (35.4%) 24,716 (40.1%) 35.7%

# of Hospitalizations, 1+ 60,258 (18.0%) 9,892 (16.1%) 18.3%

Number of Outpatient Visits

<5 53,861 (16.1%) 8,823 (14.3%) 16.1%
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59 61,093 (18.2%) 9,572 (15.5%) 18.1%

1019 92,445 (27.6%) 15,845 (25.7%) 27.6%

2039 81,406 (24.3%) 16,196 (26.3%) 24.4%

40+ 46,341 (13.8%) 11,176 (18.1%) 13.9%

Overweight or Obese 13,570 (4.0%) 3,007 (4.9%) 4.0%

Osteoporosis 20,431 (6.1%) 3,828 (6.2%) 6.0%

Other Fracture 12,291 (3.7%) 2,345 (3.8%) 3.8%

Antiparkinson Drug 7,281 (2.2%) 1,643 (2.7%) 2.2%

Personality Disorder 968 (0.3%) 211 (0.3%) 0.3%

PPI 54,090 (23.1%) 10,896 (23.9%) 23.6%

Radius/Ulna Fracture 1,889 (0.6%) 351 (0.6%) 0.6%

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Renal Disease 4,728 (1.4%) 664 (1.1%) 1.4%

Schizophrenic Disorder 908 (0.3%) 150 (0.2%) 0.3%

Ischemic Stroke 12,595 (3.8%) 1,631 (2.6%) 4.1%

Suicide Attempt 184 (0.1%) 34 (0.1%) 0.1%

Thiazides 31,528 (9.4%) 5,271 (8.6%) 9.3%

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SSRI SNRI
Characteristic N=335,146 N=61,612 SNRI Weighted to SSRI
Thyroid 43,939 (13.1%) 8,504 (13.8%) 13.1%
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Urinary Incontinence 7,974 (2.4%) 1,553 (2.5%) 2.4%

Vertebral Fracture 3,328 (1.0%) 648 (1.1%) 1.1%

SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor
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Table 2

Weighted fracture event rates by antidepressant class and time of follow-up

Period Drug Number Contributing Number of Events Total Person Time (years) Rate per 1,000 person-years
030 Days SNRI 336,949.7 193.9 26,758.35 7.3 (4.412.0)
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SSRI 335,146.0 192.0 26,596.29 7.2 (6.38.3)

3190 Days SNRI 313,478.2 284.7 47,917.74 5.9 (4.18.7)

SSRI 310,930.0 297.0 47,471.80 6.3 (5.67.0)

91360 Days SNRI 267,612.6 745.0 90,320.71 8.3 (6.510.5)

SSRI 266,836.0 583.0 87,228.48 6.7 (6.27.3)

0360 Days SNRI 336,949.7 1,223.6 164,996.80 7.5 (6.29.0)

SSRI 335,146.0 1,072.0 161,296.57 6.7 (6.37.1)

361720 Days SNRI 71,874.7 296.5 43,580.68 6.8 (4.710.0)

SSRI 67,855.0 261.0 40,979.64 6.4 (5.77.2)

7211080 Days SNRI 24,781.3 53.4 15,147.92 3.5 (1.96.4)

SSRI 23,874.0 81.0 15,089.71 5.4 (4.36.7)

10811440 Days SNRI 8,857.7 11.9 6,010.73 2.0 (0.66.6)

SSRI 9,292.0 35.0 6,437.72 5.5 (3.97.6)

14411800 Days SNRI 3,956.2 4.2 2,429.55 1.7 (0.212.4)

SSRI 4,333.0 9.0 2,744.35 3.3 (1.76.3)

>1800 Days SNRI 1,260.3 4.8 1,026.95 4.7 (0.634.3)

SSRI 1,460.0 7.0 1,435.70 4.9 (2.310.4)

CNS Drugs. Author manuscript; available in PMC 2016 March 01.

01800 Days SNRI 336,949.7 1,589.5 232,165.67 6.9 (5.98.2)

SSRI 335,146.0 1,458.0 226,548.00 6.5 (6.26.8)

SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor
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Table 3

SNRI vs. SSRI Fracture Hazard Ratios

Author Manuscript

Analysis 1-Year HR (95% CI) 5-Year HR (95% CI)

7-Day GP 1.01 (0.78, 1.30) 1.03 (0.82, 1.30)

14-Day GP 0.98 (0.78, 1.25) 1.01 (0.82, 1.24)

30-Day GP 1.02 (0.83, 1.26) 1.02 (0.85, 1.23)

60-Day GP 1.11 (0.92, 1.36) 1.06 (0.90, 1.26)

90-Day GP 1.12 (0.93, 1.36) 1.06 (0.90, 1.26)

180-Day GP 1.09 (0.90, 1.31) 1.04 (0.88, 1.22)

360-Day GP 1.03 (0.86, 1.24) 1.01 (0.87, 1.18)

First treatment carried forward 1.02 (0.87, 1.21) 0.98 (0.87, 1.10)

SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor GP = grace period; HR = hazard ratio; CI =
confidence interval
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Table 4

SNRI vs. SSRI Fracture Hazard Ratios, with vs. without depression diagnoses
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With Depression, Excluding Bipolar and Schizophrenic Without Depression

Disorders

Analysis 1-Year HR (95% CI) 5-Year HR (95% CI) 1-Year HR (95% CI) 5-Year HR (95% CI)
7-Day GP 1.34 (0.91, 1.96) 1.35 (0.95, 1.92) 0.83 (0.59, 1.17) 0.84 (0.62, 1.15)

14-Day GP 1.27 (0.88, 1.84) 1.26 (0.90, 1.76) 0.84 (0.62, 1.15) 0.87 (0.66, 1.13)

30-Day GP 1.22 (0.86, 1.72) 1.19 (0.88, 1.62) 0.92 (0.70, 1.21) 0.91 (0.72, 1.15)

60-Day GP 1.31 (0.95, 1.79) 1.22 (0.92, 1.60) 1.04 (0.80, 1.34) 0.98 (0.78, 1.22)

90-Day GP 1.30 (0.95, 1.77) 1.21 (0.92, 1.58) 1.05 (0.82, 1.34) 0.98 (0.79, 1.22)

180-Day GP 1.23 (0.91, 1.66) 1.15 (0.88, 1.50) 1.03 (0.81, 1.30) 0.97 (0.79, 1.19)

360-Day GP 1.17 (0.87, 1.57) 1.12 (0.87, 1.45) 0.98 (0.78, 1.23) 0.95 (0.78, 1.15)

First treatment 1.12 (0.86, 1.46) 1.06 (0.88, 1.29) 1.01 (0.82, 1.25) 0.94 (0.81, 1.09)
carried forward
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SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor GP = grace period; HR = hazard ratio; CI =
confidence interval
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CNS Drugs. Author manuscript; available in PMC 2016 March 01.