Risk of Fracture with Thiazolidinediones: Disease or Drugs?

Article (PDF Available)inCalcified Tissue International 90(6):450-7 · April 2012with41 Reads
DOI: 10.1007/s00223-012-9591-8 · Source: PubMed
Abstract
The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996-2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06-1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20-1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13-1.18) and second (HR = 1.00, 95 % CI 0.96-1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account.
ORIGINAL RESEARCH
Risk of Fracture with Thiazolidinediones: Disease or Drugs?
Marloes T. Bazelier
Peter Vestergaard
Arlene M. Gallagher
Tjeerd-Pieter van Staa
Cyrus Cooper
Hubert G. M. Leufkens
Frank de Vries
Received: 16 January 2012 / Accepted: 27 February 2012 / Published online: 10 April 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract The use of thiazolidinediones (TZDs) has been
associated with an increased fracture risk. In addition, type
2 diabetes mellitus (T2DM) has been linked with fracture.
We evaluated to what extent the association between TZD
use and fracture risk is related to the drug or to the
underlying disease. We conducted a population-based
cohort study using the Danish National Health Registers
(1996–2007), which link pharmacy data to the national
hospital registry. Oral antidiabetic users (n = 180,049)
were matched 1:3 by year of birth and sex to nonusers. Cox
proportional hazards models were used to estimate hazard
ratios (HRs) of fracture. Time-dependent adjustments were
made for age, comorbidity, and drug use. We created a
proxy indicator for the severity of disease. The first stage
was defined as current use of either a biguanide or a sul-
fonyluerum, the second stage as current use of a biguanide
and a sulfonyluerum at the same time, the third stage as
patients using TZDs, and the fourth stage as patients using
insulin. The risk of osteoporotic fracture was increased 1.3-
fold for stages 3 and 4 compared with controls. Risk with
current TZD use (stage 3 HR = 1.27, 95 % CI 1.06–1.52)
and risk with current use of insulin (stage 4 HR = 1.25,
95 % CI 1.20–1.31) were similar. In the first (HR = 1.15,
95 % CI 1.13–1.18) and second (HR = 1.00, 95 % CI
0.96–1.04) stages risks were lower. Risk of osteoporotic
fracture was similar for TZD users and insulin users. When
studying fracture risk with TZDs, the underlying T2DM
should be taken into account.
The Department of Pharmacoepidemiology and Clinical
Pharmacology employing authors Marloes Bazelier, Arlene
Gallagher, Tjeerd-Pieter van Staa, Hubert Leufkens and Frank de
Vries has received unrestricted funding for pharmacoepidemiological
research from GlaxoSmithKline, Novo Nordisk, the private-public
funded Top Institute Pharma (www.tipharma.nl, includes co-funding
from universities, government, and industry), the Dutch Medicines
Evaluation Board, and the Dutch Ministry of Health.Tjeerd-Pieter van
Staa and Arlene Gallagher also work for the General Practice
Research Database (GPRD), UK. The GPRD is owned by the UK
Department of Health and operates within the Medicines and
Healthcare products Regulatory Agency (MHRA). GPRD is funded
by the MHRA, Medical Research Council, various universities,
contract research organisations and pharmaceutical companies.
M. T. Bazelier A. M. Gallagher T.-P. van Staa
H. G. M. Leufkens F. de Vries
Utrecht Institute for Pharmaceutical Sciences,
Utrecht University, Utrecht, The Netherlands
P. Vestergaard
The Osteoporosis Clinic, Aarhus University Hospital,
Aarhus, Denmark
A. M. Gallagher T.-P. van Staa
General Practice Research Database, Medicines and Healthcare
Products Regulatory Agency, London, UK
T.-P. van Staa C. Cooper F. de Vries
MRC Lifecourse Epidemiology Unit, University
of Southampton, Southampton, UK
C. Cooper
Institute of Musculoskeletal Sciences, University of Oxford,
Oxford, UK
F. de Vries
Department of Clinical Pharmacy and Toxicology, Maastricht
University Medical Centre, Maastricht, The Netherlands
F. de Vries (&)
Department of Pharmacoepidemiology and Clinical
Pharmacology, Utrecht Institute for Pharmaceutical Sciences,
Utrecht University, Universiteitsweg 99, 3584 CG Utrecht,
The Netherlands
e-mail: frank@fdevries.com
123
Calcif Tissue Int (2012) 90:450–457
DOI 10.1007/s00223-012-9591-8
Keywords Thiazolidinedione Type 2 diabetes mellitus
Fracture risk Osteoporosis
Thiazolidinediones (TZDs) improve insulin sensitivity
through activation of the nuclear receptor peroxisome prolif-
erator-activated receptor gamma (PPARc)[1]. Until recently,
both rosiglitazone and pioglitazone were frequently used in
the management of type 2 diabetes mellitus (T2DM). An
association of rosiglitazone with risk of cardiovascular out-
comes has caused withdrawal of the drug in Europe and
restricted access in the United States [2]. Pioglitazone is still
used in the management of later stages of T2DM and has ben-
efits in patients with a recent acute myocardial infarction [3].
Various studies have found that TZD use leads to
decreased bone mineral density (BMD) and an elevated
risk of fracture [410]. TZDs affect the differentiation of
mesenchymal stem cells, leading to increased adipogenesis
at the expense of the formation of osteoblasts [4, 5]. The
use of TZDs in rodents has been linked with adverse
skeletal effects [6, 7]. In humans, TZD use has also been
associated with adverse skeletal outcomes, at least in
women with T2DM: women who were exposed to TZDs
for 3–4 months had significantly reduced BMD at the
lumbar spine and hip in two randomized controlled trials
[8, 9]. Moreover, a meta-analysis from ten randomized
controlled trials showed that rosiglitazone and pioglitazone
significantly increased the risk of fractures [odds ratio
(OR) = 1.45, 95 % confidence interval (CI) 1.18–1.79]
[10]. In observational studies, the relationship between
TZD use and fracture risk has also been reported [1114].
Not only the use of TZDs but also underlying T2DM has
been associated with fracture [15, 16]. Among the potential
mechanisms are direct effects of high glucose levels on
bone turnover [17], increased urine calcium loss [18],
changes in vitamin D metabolism [19], and alterations in
glycosylation of collagen caused by hyperglycemia [20]. In
addition, complications of diabetes such as renal failure,
neuropathy, and micro- and macro-angopathy may con-
tribute to fracture risk [2124].
At present, it is unclear to what extent the association
between TZD use and fracture risk is related to the drug or to
the underlying disease. The aim of this study was to estimate
risk of fracture in diabetic patients compared with controls,
stratified by the use of TZDs and by disease severity.
Methods
Data Source
In Denmark, separate registers of computerized medical
records on all contacts to hospitals and on the use of drugs
can be linked for the entire population (approximately 5.5
million inhabitants). The Ministry of the interior keeps
records of all inhabitants, including their migrations and
dates of birth and death. Information on hospital admis-
sions comes from the National Hospital Discharge Register
[25], which covers all inpatient contacts from 1977
onwards and from 1995 also all outpatient visits to hospi-
tals, outpatient clinics, and emergency rooms. Upon dis-
charge, the physician codes the reason for the contact using
the ICD system. The register has an almost 100 % capture
of contacts, and the validity of registrations is high [26].
The Danish Medicines Agency keeps a nationwide register
of all prescription drugs sold at pharmacies throughout the
country from 1996 onward, the National Pharmacological
Database (www.dkma.dk). All prescriptions are registered
with ATC code, dosage, and date. As all sales are regis-
tered to the individual who redeems the prescription, the
capture and validity are high. All registers can be linked
through the use of a person-specific code (the civil person
number) given to all inhabitants and can be used for all of
the registrations mentioned.
Study Population
The exposed cohort consisted of all patients (aged 18?)
with at least one prescription of oral antidiabetic (OAD)
medication between 1996 and 2007. Each OAD drug user
was matched to up to three patients by exact year of birth
and sex. Controls did not have an antidiabetic (OAD or
insulin) prescription any time during follow-up. The date of
the first OAD prescription defined the index date, and
controls were assigned the same index date as their mat-
ched OAD drug user. All participants were then followed
from their index date to the end of data collection, emi-
gration, or the patient’s death, whichever came first.
Exposure
The total period of follow-up for each patient was divided
into periods of current exposure and past exposure, with
patients moving between current and past use. Each period
of current exposure started with an OAD or insulin pre-
scription and ended 3 months after the expected duration of
antidiabetic (AD) therapy or on the date that a new AD
drug was prescribed within this period. The expected
duration of OAD therapy was defined as the median
expected duration of treatment, based on all OAD pre-
scriptions. For insulin treatment, the median time between
two insulin injections (based on all insulin prescriptions)
was taken as the expected duration of use.
At the start of each interval, patients were classified as
current users of AD medication if they had an AD pre-
scription on that start date or in the 3 months before.
M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones 451
123
Current user status was determined for five different groups
of AD medication: biguanides, sulfonyluerum, TZDs,
insulin, and other ADs [including dipeptidyl peptidase-4
(DPP-4) inhibitors, glinides, glucagon-like peptide-1
(GLP-1) analogs and a-glucosidase inhibitors]. For con-
trols, the total period of follow-up was divided into periods
of 6 months.
We created a proxy indicator for the severity of disease
in diabetic patients. The first stage of disease was defined
as current use of either a biguanide or a sulfonyluerum, the
second stage comprised current users of a biguanide and a
sulfonyluerum at the same time, the third stage was
assigned to patients using TZDs (regardless of comedica-
tion), and the fourth stage was assigned to patients using
insulin (regardless of comedication and not exposed to
TZDs).
Study Outcomes
Patients were followed up for the occurrence of a first
fracture. Types of fracture were classified according to the
International Classification of Diseases (ICD-10) catego-
ries. These included skull (S02), neck (S12), ribs (S22),
pelvis (S32), shoulder (S42), forearm (S52), hand (S62),
hip/femur (S72), tibia/fibula/ankle (S82), foot (S92), or
unspecified (T02, T08, T10, T12). A clinical osteoporotic
fracture was defined as a fracture of the radius/ulna, ver-
tebrae, femur, hip, humerus, pelvis, or ribs.
Risk Factors
The presence of risk factors was assessed by reviewing the
computerized medical records for any evidence of risk
factors before the start of each interval. Potential con-
founders that were determined at baseline were sex and a
history of fracture. For a time-dependent analysis we
considered age, a history of chronic diseases (rheumatoid
arthritis, congestive heart failure, asthma, epilepsy, cere-
brovascular disease, noninfectious enteritis and colitis,
dementia, renal failure, diabetic retinopathy, hyperpara-
thyroidism), as well as a prescription for thiazide diuretics,
estrogen-containing hormone replacement therapy, statins,
oral glucocorticoids, bisphosphonates, calcium, vitamin D,
antipsychotics, antidepressants, antiarrhythmics, hypnotics/
anxiolytics, anticonvulsants, opioids, and asthma medica-
tion in the previous 6 months as potential confounders.
Statistical Analysis
Cox proportional hazards analysis was used. In the first
analysis, we compared fracture risk in users of TZDs with
that in control patients (without diabetes) and users of other
AD medication. In this analysis, calculations were adjusted
for all potential confounders that changed the hazard ratio
(HR) [1 % in an age-/sex-adjusted analysis. Secondly, we
studied the risk of osteoporotic fracture in current AD drug
users versus controls, using the proxy indicator for severity
of disease. To investigate whether a dose-response rela-
tionship was apparent, we stratified the risk of osteoporotic
fracture in current TZD users by number of TZD pre-
scriptions ever before. Wald tests were used to examine if
there were significant differences between differently
exposed groups. All data management and statistical ana-
lyzes were conducted using SAS 9.1/9.2 software (SAS
Institute, Cary, NC).
Results
Our study population included 180,049 diabetic patients
and 490,147 population-based controls. Mean age at index
date (first OAD prescription) was 62.6 years, and 47 % of
all patients were female. Mean duration of follow-up after
the index date was 5.3 years for diabetic patients and
6.2 years for controls. Further baseline characteristics are
shown in Table 1. During the study period, 4.2 % of dia-
betic patients were prescribed a TZD at least once
(Table 2). Of all diabetic patients, 12.8 % suffered from a
fracture after the index date. Hip fractures (3.1 %) and
radius/ulna fractures (2.2 %) were common.
Table 3 shows that current TZD users had an increased
risk of fracture versus nondiabetic patients (HR = 1.29,
95 % CI 1.13–1.49) but no increased risk of fracture versus
patients who were exposed to other AD drugs (HR = 1.11,
95 % CI 0.97–1.27). When compared with other AD drug
users, the risk of fracture with current TZD use was, how-
ever, increased in women (HR = 1.30, 95 % CI 1.10–1.54)
and risks of foot/ankle fractures (HR = 1.54, 95 % CI
1.17–2.04) and tibia/fibula fractures (HR = 1.70, 95 % CI
1.22–2.37) were significantly increased. No increased risk of
hip fracture was apparent for current users of TZDs.
When we stratified current AD drug users by the proxy
indicator of disease severity, we found that the risk of
osteoporotic fracture was 1.3-fold increased for stages 3
and 4 compared with nondiabetic patients (Table 4).
Patients who were currently using TZDs (stage 3 HR =
1.27, 95 % CI 1.06–1.52) had a similar risk of osteoporotic
fracture as patients who were currently using insulin (stage
4HR= 1.25, 95 % CI 1.20–1.31). In women only, we
found a similar result using the proxy indicator of disease
severity. The risk in stage 3 was slightly higher than that in
stage 4, but this difference was not significant based on a
Wald test (stage 1 fully adjusted HR = 1.11, 95 % CI
1.07–1.14; stage 2 HR = 0.98, 95 % CI 0.93–1.04; stage 3
HR
= 1.34, 95 % CI 1.07–1.67; stage 4 HR = 1.17, 95 %
CI 1.10–1.23). In men only, the risk in stage 3 was not
452 M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones
123
significantly increased (stage 1 fully adjusted HR = 1.25,
95 % CI 1.20–1.31; stage 2 HR = 1.02, 95 % CI
0.94–1.10; stage 3 HR = 1.13, 95 % CI 0.82–1.57; stage 4
HR = 1.41, 95 % CI 1.31–1.52). In men, the risk in stage 3
was not significantly different from the risk in stage 4
either.
Stratification of current TZD users by the number of
TZD prescriptions ever before showed a cumulative dose–
response relationship (Table 5). Current TZD users with 30
or more TZD presciptions ever before had a threefold
increased risk of osteoporotic fracture compared with other
AD drug users (HR = 3.03, 95 % CI 2.03–4.52).
Discussion
This study showed a 1.3-fold increased risk of fracture in
current TZD users versus nondiabetic patients. Overall,
current TZD users had no significantly increased risk of
fracture compared with users of other AD drugs. The risk
of fracture with current TZD use was, however, increased
in women, among prolonged users of TZDs, and risks of
foot/ankle and tibia/fibula fractures were significantly
increased.
Our finding of an increased risk of fracture in women
using TZDs versus other AD drug users is in line with
previous studies. In a meta-analysis from randomized
controlled trials [10], the pooled data from the five trials
that reported fracture risk by sex showed a significantly
increased risk of fractures among women (OR = 2.23,
95 % CI 1.65–3.01) but not among men (OR = 1.00, 95 %
CI 0.73–1.39). Another recent trial on rosiglitazone use
presented a similar result: there was an increased fracture
risk in women (RR = 1.82, 95 % CI 1.37–2.41) but not in
men (RR = 1.23, 95 % CI 0.85–1.77) [27]. In observa-
tional studies, the use of TZDs has also been linked with an
increase in fracture risk [1214]. Habib et al. [12] found in
their cohort study that TZD use was associated with a 1.6-
fold increased risk of fracture in women but not in men.
Conversely, Douglas et al. [13] reported an increased risk
of fracture in both women and men who were exposed to
TZDs. In a nested case–control study [11] an increased risk
of fracture with TZD use was only apparent in the group
with cumulative exposure of 15 TZD prescriptions or more
(HR = 2.86, 95 % CI 1.57–5.22). This result is in line with
Table 1 Baseline characteristics of diabetic patients and controls
Characteristic Diabetic patients (%) Controls (%)
(n = 180,049) (n = 490,147)
Mean duration of follow-up
after index date, years
5.3 6.2
Sex female 84,665 (47.0) 232,373 (47.4)
Age at index date
Mean 62.6 62.5
By category
18–29 4,064 (2.3) 10,174 (2.1)
30–39 8,164 (4.5) 21,029 (4.3)
40–49 18,887 (10.5) 50,622 (10.3)
50–59 39,944 (22.2) 111,053 (22.7)
60–69 47,288 (26.3) 133,197 (27.2)
70–79 40,586 (22.5) 111,448 (22.7)
80? 21,116 (11.7) 52,624 (10.7)
History of comorbidity
Fracture 30,631 (17.0) 80,127 (16.3)
Asthma 5,706 (3.2) 9,126 (1.9)
Rheumatoid arthritis 2,232 (1.2) 5,188 (1.1)
Cerebrovascular disease 15,084 (8.4) 22,155 (4.5)
Epilepsy 2,615 (1.5) 5,960 (1.2)
History of drug use
Statins 24,014 (13.3) 24,649 (5.0)
Antiarrhythmics 1,517 (0.8) 2,563 (0.5)
Antidepressants 26,774 (14.9) 52,861 (10.8)
Antipsychotics 13,232 (7.3) 21,813 (4.5)
Anxiolytics/hypnotics 51,984 (28.9) 119,634 (24.4)
Anticonvulsants 6,078 (3.4) 12,410 (2.5)
Opioids 41,930 (23.3) 78,901 (16.1)
Oral glucocorticoids 26,645 (14.8) 54,170 (11.1)
Bisphosphonates 1,668 (0.9) 6,368 (1.3)
Table 2 Use of AD medication and patients with fractures during
follow-up
Characteristic Diabetic
patients (%)
Controls (%)
(n = 180,049) (n = 490,147)
Use of AD medication any time
during follow-up
Biguanide 122,751 (68.2)
sulfonyluerum 137,326 (76.3)
TZD 7,603 (4.2)
Insulin 42,525 (23.6)
Other 17,865 (9.9)
Any fracture 22,978 (12.8) 66,401 (13.5)
Foot/ankle 3,180 (1.8) 8,003 (1.6)
Tibia/fibula 2,274 (1.3) 5,552 (1.1)
Hand/wrist 2,694 (1.5) 8,187 (1.7)
Osteoporotic 14,910 (8.3) 44,031 (9.0)
Hip 5,642 (3.1) 15,166 (3.1)
Vertebral 1,221 (0.7) 3,341 (0.7)
Radius/ulna 3,884 (2.2) 15,138 (3.1)
Humerus 2,926 (1.6) 7,121 (1.5)
Ribs 772 (0.4) 2,087 (0.4)
TZD thiazolidinedione, AD antidiabetic
M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones 453
123
our finding of a significantly increased risk of osteoporotic
fracture for current TZD users in the stratum with highest
cumulative exposure.
The association between TZD use and fracture risk may
be explained by the drug itself but also by the underlying
disease because both T2DM and the use of TZDs seem to
be independently associated with an increased risk of
adverse skeletal effects. There is substantial evidence from
in vitro studies that activation of PPARc, which is stimu-
lated by TZDs, causes a predominant formation of adipo-
cytes from mesenchymal stem cells, while the development
of osteoblasts is suppressed [4, 5]. Moreover, BMD was
Table 3 Risk of fracture in current TZD users compared with nondiabetic patients and with other AD drug users, by type of fracture and sex
Current TZD users versus nondiabetic patients Current TZD users versus other AD drug users
Fracture, n Age-/sex-adj. HR
(95 % CI)
Fully adj. HR
(95 % CI)
Fracture, n Age-/sex-adj. HR
(95 % CI)
Fully adj. HR
(95 % CI)
No TZD use 66,401 21,202
Current TZD use
Any fracture 213 1.24 (1.09–1.42) 1.29 (1.13–1.49)
a
213 1.03 (0.90–1.18) 1.11 (0.97–1.27)
h
Foot/ankle 52 1.96 (1.49–2.58) 1.84 (1.38–2.44)
b
52 1.50 (1.14–1.98) 1.54 (1.17–2.04)
i
Tibia/fibula 36 2.18 (1.57–3.03) 2.14 (1.52–3.02)
c
36 1.64 (1.17–2.28) 1.70 (1.22–2.37)
i
Hand/wrist 22 0.83 (0.55–1.27) 0.82 (0.54–1.24)
d
22 0.76 (0.50–1.16) 0.79 (0.52–1.20)
i
Osteoporotic 116 1.21 (1.01–1.45) 1.28 (1.06–1.54)
a
116 0.98 (0.81–1.18) 1.07 (0.89–1.29)
j
Hip 19 0.80 (0.51–1.26) 0.89 (0.57–1.39)
e
19 0.53 (0.34–0.84) 0.61 (0.39–0.96)
k
Femur 2
n
2–
n
Vertebral 11 1.44 (0.80–2.61) 1.67 (0.92–3.03)
f
11 1.00 (0.55–1.81) 1.12 (0.62–2.04)
e
Radius/ulna 43 1.11 (0.82–1.50) 1.10 (0.81–1.48)
d
43 1.23 (0.91–1.67) 1.27 (0.94–1.73)
i
Humerus 28 1.64 (1.13–2.38) 1.60 (1.09–2.36)
a
28 1.08 (0.75–1.58) 1.16 (0.80–1.69)
l
Pelvis 3
n
3–
n
Ribs 11 1.85 (1.02–3.35) 1.87 (1.01–3.48)
g
11 1.38(0.76–2.52) 1.47 (0.81–2.68)
m
By sex
Male
o
74 0.99 (0.79–1.24) 1.06 (0.84–1.34) 74 0.79 (0.63–1.00) 0.86 (0.68–1.09)
Female
p
139 1.43 (1.21–1.69) 1.46 (1.23–1.73) 139 1.22 (1.03–1.44) 1.30 (1.10–1.54)
TZD thiazolidinedione, AD antidiabetic, adj adjusted, HR hazard ratio, CI confidence interval
a
Adjusted for age; gender; use of statins, bisphosphonates, antidepressants, or opioids in the previous 6 months; history of fracture; and diabetic
retinopathy
b
Adjusted for age; gender; use of statins, antidepressants, or opioids in the previous 6 months; history of fracture; and diabetic retinopathy
c
Adjusted for age; gender; use of statins, antidepressants, anticonvulsants, or opioids in the previous 6 months; history of fracture; and diabetic
retinopathy
d
Adjusted for age, gender, use of antidepressants or opioids in the previous 6 months, and history of fracture
e
Adjusted for age; gender; use of statins, bisphosphonates, antidepressants, or opioids in the previous 6 months; history of fracture; and
cerebrovascular disease
f
Adjusted for age; gender; use of statins, bisphosphonates, antidepressants, or opioids in the previous 6 months; history of fracture; diabetic
retinopathy; and cerebrovascular disease
g
Adjusted for age; gender; use of statins, bisphosphonates, antidepressants, hypnotics/anxiolytics, anticonvulsants, or opioids in the previous
6 months; history of fracture; diabetic retinopathy; and cerebrovascular disease
h
Adjusted for age, gender, use of statins or antidepressants in the previous 6 months, history of fracture, and cerebrovascular disease
i
Adjusted for age, gender, use of statins in the previous 6 months, and history of fracture
j
Adjusted for age; gender; use of statins, antidepressants, or opioids in the previous 6 months; history of fracture; and cerebrovascular disease
k
Adjusted for age; gender; use of statins, antipsychotics, antidepressants, or opioids in the previous 6 months; history of fracture; cerebro-
vascular disease; and dementia
l
Adjusted for age; gender; use of statins, antipsychotics, or antidepressants in the previous 6 months; history of fracture; and cerebrovascular
disease
m
Adjusted for age, gender, use of statins or antidepressants in the previous 6 months, and history of fracture
n
Number of cases too low to estimate HR
o
Male TZD users versus male nonusers
p
Female TZD users versus female nonusers
454 M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones
123
significantly reduced at the lumbar spine and hip in women
exposed to TZDs in two randomized controlled trials [8, 9].
In addition, epidemiological studies suggest that T2DM
is an independent risk factor for adverse effects on the
skeleton [15, 16]. Even though patients with T2DM have
on average a higher BMI [28] as well as a higher BMD [16]
compared with the general population, which would in
theory protect them against fractures, previous studies have
found an increased risk of fractures in T2DM [15]. This
finding may be explained by different mechanisms. High
blood glucose might have a direct toxic effect on bone cells
[17, 29] and may cause a negative calcium balance by
increased urinary calcium excretion [18] and reduced
intestinal calcium absorption [30]. There is evidence that
vitamin D metabolism is altered in diabetic patients [19,
31], which may lead to bone loss. Further, functional
hypoparathyroidism may result in low bone turnover [32].
Complications of diabetes, such as neuropathy and angi-
opathy, may also contribute to an increased risk of fracture
as well as disease severity in general [2124].
To evaluate to what extent the association between TZD
use and fracture risk is related to the drug or to the underlying
disease, we created a proxy indicator of disease severity. We
defined four different stages based on a prescription scenario
that is often used in the treatment of T2DM. Patients who
were currently using insulin (stage 4) had a significantly
greater risk of osteoporotic fracture than patients in stages 1
and 2, which supports the hypothesis that the underlying
Table 4 Risk of osteoporotic fracture in current AD drug users compared with controls, by stage of disease
Fracture, n Age-/sex-adj. HR (95 % CI) Fully adj. HR (95 % CI)
a
No diabetes 44,031 1 1
Current AD drug use 13,989 1.21 (1.18–1.23) 1.14 (1.12–1.16)
By stage of disease
Stage 1: current use of biguanide or sulfonyluerum 8,866 1.23 (1.20–1.26)
b,c
1.15 (1.13–1.18)
b,c
Stage 2: current use of biguanide and sulfonyluerum 2,222 1.01 (0.97–1.05)
d
1.00 (0.96–1.04)
d,e
Stage 3: current use of TZD
f
116 1.20 (1.00–1.44) 1.27 (1.06–1.52)
Stage 4: current use of insulin
g
2,419 1.37 (1.32–1.43) 1.25 (1.20–1.31)
Unclassified stages 366 1.14 (1.03–1.26) 1.11 (1.00–1.23)
TZD thiazolidinedione, AD antidiabetic, adj adjusted, HR hazard ratio, CI confidence interval
a
Adjusted for age; gender; use of statins, antipsychotics, antidepressants, or opioids in the previous 6 months; history of fracture; diabetic
retinopathy; congestive heart failure; and cerebrovascular disease
b
Statistically significant difference (p \ 0.05) between current AD users in stage 1 and current AD users in stage 2, based on Wald test
c
Statistically significant difference (p \ 0.05) between current AD users in stage 1 and current AD users in stage 4, based on Wald test
d
Statistically significant difference (p \ 0.05) between current AD users in stage 2 and current AD users in stage 4, based on Wald test
e
Statistically significant difference (p \ 0.05) between current AD users in stage 2 and current AD users in stage 3, based on Wald test
f
Regardless of comedication
g
Regardless of comedication and not exposed to TZDs
Table 5 Risk of osteoporotic fracture in current TZD users compared with other AD drug users, by number of TZD prescriptions
Fracture, n Age-/sex-adj. HR (95 % CI) Fully adj. HR (95 % CI)
a
No TZD use 13,873
Current TZD use 116 0.98 (0.81–1.18) 1.07 (0.89–1.29)
By number of TZD prescriptions ever before
1–4 27 0.80 (0.55–1.17) 0.87 (0.59–1.26)
5–8 17 0.70 (0.44–1.13) 0.76 (0.47–1.23)
9–14 20 0.80 (0.52–1.24) 0.88 (0.57–1.37)
15–29 28 1.05 (0.72–1.52) 1.16 (0.80–1.68)
C30 24 2.70 (1.81–4.02) 3.03 (2.03–4.52)
b
TZD thiazolidinedione, AD antidiabetic, adj adjusted, HR hazard ratio, CI confidence interval
a
Adjusted for age; gender; use of statins, antidepressants, or opioids in the previous 6 months; history of fracture; and cerebrovascular disease
b
Statistically significant difference (p \ 0.05) between current TZD users with C30 TZD prescriptions ever before and all of the other
categories, based on Wald test
M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones 455
123
disease is involved. If the drug itself were strongly related to
fracture risk, we would expect a higher risk in patients who
were currently exposed to TZDs (stage 3). However, patients
in stage 3 had a similar risk of osteoporotic fracture as
patients in stage 4. Therefore, we would argue that the
association between TZD use and fracture is at least partially
confounded by the underlying disease.
Strengths of our study include a reasonable sample size
and duration of follow-up. Our source population included
the total Danish population, and controls were therefore
population-based. There was detailed longitudinal infor-
mation on drug prescribing.
There are several limitations. Data on smoking and body
mass index (BMI) were not available, and therefore,
unmeasured confounding may have biased our findings.
Patients with T2DM have on average a higher BMI than
the general population [28], which is protective against
fracture [33]. In our study, this may have led to underes-
timation of a true association between T2DM/TZD use and
fracture. However, we did adjust our analyzes for the use of
statins, which is probably correlated with high BMI. Using
a proxy indicator of disease severity, we may have
underestimated the role of the underlying T2DM as a
confounder in the association between TZD use and frac-
ture. We used current treatment with insulin as a proxy
indicator for the highest level of disease severity (stage 4).
The risk of fracture for patients in this stage may be biased
by potential direct effects of insulin on bone. Although the
role of insulin on fracture risk is still unclear, it has been
suggested that higher insulin levels in T2DM may preserve
and increase bone density and bone strength [30, 34]. If
insulin were indeed protective against fractures, this may
have resulted in underestimation of a true association
between disease severity and fracture risk.
In conclusion, we found that patients who were currently
using TZDs had a similar risk of osteoporotic fracture as
patients who were currently using insulin. When observa-
tional studies assess the risk of fracture in patients using
TZDs, the underlying T2DM should be taken into account.
Acknowledgments This study was supported by a grant from the
European Calcified Tissue Society and by the Dutch Organization of
Scientific Research, Veni Grant 91696042.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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M. T. Bazelier et al.: Risk of Fracture with Thiazolidinediones 457
123
    • "According to Bazelier et al., risk of osteoporotic fracture was similar for TZD users and insulin users, but versus nondiabetic patients TZD users showed a 1.3-fold increased risk of fracture. In their opinion the underlying T2DM should be taken into account, when studying fracture risk with TZDs [46]. The results of a prospective, double-blind study did not demonstrate a causal relationship between pioglitazone treatment for 12 months and loss of bone mass or alteration of bone remodeling that would be expected to result in excessive bone fragility [50]. "
    [Show abstract] [Hide abstract] ABSTRACT: Type 2 diabetes mellitus is a serious, chronic, progressive and widespread disease. Metformin is the most commonly prescribed initial therapy, but combination with other antidiabetic agents usually becomes necessary due to the progression of the disease. Pioglitazone is recommended as a second-line therapy because of its strong antihyperglycemic effect and its ability to reduce insulin resistance. Treatment with pioglitazone is associated with a significantly lower risk of cardiovascular complications and hypoglycemia, while simultaneously improving the lipid profile and the symptomatic and histological changes in the liver. Gliptins (sitagliptin and vildagliptin) are a new class of oral antidiabetic drugs which reduce glycated hemoglobin by a different mechanism. Although the efficacy of sitagliptin and vildagliptin is close to that of pioglitazone, the lack of long-term safety data and the higher price question their predominant use. The objective of this review is to highlight the advantages of mono- and combination therapy with pioglitazone in comparison with gliptins and to underline the inconsistencies in the medicinal and reimbursement policy in Bulgaria.
    Full-text · Article · Aug 2015
    • "All participants were followed from the index date to the end of data collection, the patient’s transfer out of the registry, emigration, or the patient’s death, whichever came first. The study populations from PHARMO and Denmark have been described before (Bazelier et al., 2012a,b). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies. Methods: Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System, and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use.Results: In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 [1.37-1.60] in GPRD, HR 1.35 [1.15-1.58] in PHARMO and HR 1.22 [1.03-1.44] in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users (adj. HR 1.44 [1.35-1.53]). For men, there was no increased fracture risk (adj. HR 1.05 [0.96-1.14]). Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD presciptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users (HR 1.59 [1.46-1.74]).Conclusion: In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.
    Full-text · Article · Feb 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Since their approval, thiazolidinediones (TZDs) have been used extensively as insulin-sensitizers for the management of type 2 diabetes mellitus (T2DM). Activation of peroxisomal proliferator-activated receptor gamma (PPARγ) nuclear receptors by TZDs leads to a vast spectrum of metabolic and antiinflammatory effects. In the past decade, clinicians and scientists across the fields of metabolism, diabetes, liver disease (NAFLD), atherosclerosis, inflammation, infertility, and even cancer have had high hopes about the potential for TZDs to treat many of these diseases. However, an increasing awareness about undesirable "off-target" effects of TZDs have made us rethink their role and be more cautious about the long-term benefits and risks related to their use. This review examines the most relevant work on the benefits and risks associated with TZD treatment, with a focus on the only PPARγ agonist currently available (pioglitazone), aiming to offer the reader a balanced overview about the current and future role of TZDs in the management of insulin-resistant states and T2DM.
    Article · Apr 2013
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