Prevention of bone loss and vertebral fractures in

FULL-LENGTH ORIGINAL RESEARCH
Prevention of bone loss and vertebral fractures in patients
with chronic epilepsy—Antiepileptic drug and osteoporosis
prevention trial
*†‡§¶#Antonio A. Lazzari, **Philip M. Dussault, ††Manisha Thakore-James, ‡‡§§David Gagnon,
¶¶Errol Baker, ##Samuel A. Davis, and ***Antoun M. Houranieh
Epilepsia, 54(11):1997–2004, 2013
doi: 10.1111/epi.12351
SUMMARY
Purpose: To evaluate whether use of a bisphosphonate (risedronate) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs (AEDs) long term can prevent the loss of bone mass (BMD,
bone mineral density) associated with AED use compared to patients who were treated with a placebo plus calcium
and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral
fractures.
Methods: Antiepileptic drug and osteoporosis prevention trial (ADOPT) was designed as a prospective 2-year doubleblind, randomized placebo controlled study involving 80 male veterans with epilepsy who were being treated with
AEDs such as phenytoin, phenobarbital, sodium valproate, or carbamazepine for a minimum of 2 years. All enrolled
participants received calcium and vitamin D supplementation, and were randomized to risedronate or matching placebo. Total body, bilateral proximal femora, and anteroposterior (AP) lumbar spine BMDs in addition to morphometric lateral vertebral assessments (LVAs) were evaluated by a dual energy x-ray absorptiometry (DXA) instrument.
Comparisons of BMDs were made between baseline, 1 year, and after 2 years of enrollment in the study. The incidence
of new vertebral and nonvertebral fractures was secondary end point.
Key Findings: Of the 80 patients initially enrolled in the study, 53 patients completed the study. Baseline characteristics
of the two groups were similar. At the end of the study, in the placebo plus calcium and vitamin D group, we observed
a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69% (18/26) of
the participants. In the risedronate plus calcium and vitamin D group, we observed significant improvement of BMDs
in 70% (19/27) of the participants. At the end of the study, the risedronate group experienced a significant increase of
BMD at the lumbar spine L1-4 (1.267–1.332 g/cm2), which was significantly larger than that seen in the placebo group)
(1.229 g/cm2 vs. 1.245 g/cm2; p = 0.0066).There were nonsignificant differences between the two groups regarding
changes of total body BMD or at the proximal bilateral femora. Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group.
Significance: Calcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69% of male veterans with epilepsy who were taking AEDs. In the group receiving
risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared
to the placebo group, which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort.
KEY WORDS: Epilepsy, Anti-epileptic drugs, Osteoporosis, Bisphosphonates, Fractures.
Accepted July 27, 2013; Early View publication September 6, 2013.
*Primary Care Service, †Osteoporosis Clinic, ‡Rheumatology Section, and §Department of Medicine, Boston VA Healthcare System, Boston, Massachusetts, U.S.A.; ¶Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, U.S.A.; #Department of Medicine, Harvard
Medical School, Boston, Massachusetts, U.S.A.; **Pharmacy Services, Boston VA Healthcare System Osteoporosis Clinic, Boston, Massachusetts,
U.S.A.; ††Neurology Department, Boston VA Healthcare System, Boston, Massachusetts, U.S.A.; ‡‡MAVERIC, Boston VA Healthcare System, Boston,
Massachusetts, U.S.A.; §§Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, U.S.A.; ¶¶Research and Development Department, Boston VA Healthcare System, Boston, Massachusetts, U.S.A.; ##Research and Development Department, Boston VA Healthcare
System Osteoporosis Clinic, Boston, Massachusetts, U.S.A.; and ***Pharmacy Services, Boston VA Healthcare System, Boston, Massachusetts,U.S.A.
Address correspondence to Antonio A. Lazzari, Boston VA Healthcare System, 120 South Huntington Avenue, Suite F2-29, Boston, Massachusetts
02130, U.S.A. E-mail: [email protected]
Wiley Periodicals, Inc.
© 2013 International League Against Epilepsy
1997
1998
A. A. Lazzari et al.
It is well recognized that chronic use of antiepileptic drugs
(AEDs), both cytochrome P450 (CYP) enzyme-inducing
such as phenytoin, phenobarbital, carbamazepine, and primidone or non–enzyme-inducing AEDs such as valproate, are
known to be associated with accelerated rate of bone loss and
development of secondary osteoporosis and consequently
osteoporotic fractures (Kruse, 1968; Dent et al., 1970;
O’Hare et al., 1980; Chung & Ahn, 1994; Cummings et al.,
1995; Sheth et al., 1995; Aboukasm & Smith, 1997; Vestergaard et al., 1999; Sato et al., 2001; Lotfizadeh & Montouris,
2004; Carbone et al., 2010). Although some studies have
suggested that the increased prevalence of fractures in this
population was related to the seizure activity (Aboukasm &
Smith, 1997; Persson et al., 2002), other studies have suggested that chronic use of AEDs was an independent risk
factor for fractures (Nilsson et al., 1986; Cummings et al.,
1995; Vestergaard et al., 2004; Vestergaard, 2005). Clinical
studies have confirmed that >50% of adults on AEDs have
decreased bone density of either the hip or the spine (Farhat
et al., 2002; Lotfizadeh & Montouris, 2004); however,
another cross-sectional study suggested that the increased
prevalence of vertebral and nonvertebral fractures could not
be directly correlated with changes in bone mineral density
(BMD) over time but was associated with the number and
type of AEDs used (Carbone et al., 2010).
Other unique risk factors, including the use of AEDs with
sedative effect, have been described as playing important
roles in increasing the risk of fractures in the epileptic population (Gidal & Sheth, 2004; Mattson & Gidal, 2004). Lack
of sun exposure, excessive alcohol and tobacco use, and
poor dietary habits, are also considered to be responsible for
the increased prevalence of osteoporosis in both the male
and female epileptic population (Ensrud et al., 2004, 2008).
In a retrospective study of 750 patients with epilepsy who
sustained a fracture over a period of 7 years, the authors
concluded that age and gender played a role in the incidence
of pathologic or traumatic fractures in that population
(Sheth et al., 2006).
Although evidence-based clinical guidelines do not exist,
several authors recommend supplementation with calcium
and vitamin D in this population. In a randomized study,
Mikati et al. (2006) studied two different doses of vitamin
D and concluded that high-dose vitamin D (4,000 units)
resulted in increased bone density at several skeletal sites in
adults.
However, in a retrospective study, calcium and vitamin D
supplementation did not appear to influence the prevalence
of fractures in 3,303 veterans who were receiving AEDs
(Espinosa et al., 2011).
To the best of our knowledge no randomized clinical
trials have been published on the use of a bisphosphonate in
the prevention of osteoporosis and osteoporotic fractures
in male veterans with epilepsy who were taking anticonvulsants (Ali et al., 2004; Gidal & Sheth, 2004; Pack &
Morrell, 2004; Lee et al., 2010).
Epilepsia, 54(11):1997–2004, 2013
doi: 10.1111/epi.12351
We hypothesized that treatment with a bisphosphonate
(risedronate) would prevent accelerated bone loss in male
patients with epilepsy who underwent long-term AED treatment.
Methods
Study design
Anti-Epileptic Drug and Osteoporosis Prevention Trial
(ADOPT) was designed as a 2-year, longitudinal, randomized, double-blind placebo-controlled phase IV trial
(Clinicaltrials.gov number registration # NCT00869322)
involving male veterans with epilepsy who were taking
AEDs for more than 2 years prior to enrollment. This study
was conducted at the Veteran Affairs Boston Healthcare
System (VABHS) Outpatient Osteoporosis Prevention and
Treatment Clinic at the Jamaica Plain, Boston campus, and
approved and overseen by and monitored by the safety subcommittee of the local research and development and institutional review board committees.
Study drugs
Patients were assigned randomly to receive either a
risedronate 35 mg tablet or matching placebo tablet to take
weekly according to manufacturer’s package insert. All
enrolled patients received calcium supplementation (1,000–
1,500 mg) and vitamin D (500–750 IU) daily. For patients
who had 25-hydroxy vitamin D levels <20 ng/ml, a loading
dose of ergocalciferol 50,000 IU weekly for 12 weeks was
prescribed before those patients being enrolled and
randomized into the study.
Participants and inclusion and exclusion criteria
Participants were included if they were male; had a diagnosis of epilepsy; were actively taking phenytoin, carbamazepine, phenobarbital, or sodium divalproex for 2 years
prior to enrollment, and had normal calcium levels
(8.5–10.5 mg/dl) and vitamin D levels (>20 ng/ml). Subjects were excluded if they were female; were treated with
glucocorticoids; were organ transplant recipients; had an
estimated glomerular filtration rate (EGFR) of <30 ml/min;
did not have a diagnosis of epilepsy or seizure disorder;
were treated previously with miacalcin, bisphosphonate,
teriparatide, or testosterone; had severe swallowing disorder or esophagitis; were osteoporotic at baseline (BMD
T-score < 2.5 at AP spine or femoral neck or total proximal femur or forearm), or were unable to follow instructions for taking medications.
Women were excluded from this study owing to the low
number of female veterans followed in our epilepsy/seizure
clinic.
Based on power calculations from previous studies
(Stephen et al., 1999; Andress et al., 2002; Farhat et al.,
2002), our own clinical data (A. A. Lazzari, P. M. Dussault,
and S. A. Davis, unpublished data), and assuming a drop-out
1999
Antiepileptic Drug and Osteoporosis Prevention Trial
rate of 30–35%, we recruited a total of 80 participants with
40 patients assigned by a randomization without replacement procedure into each treatment arm. The final cohort
who completed the study was 27 patients in the risedronate
group (67.5%) and 26 patients in the placebo group (65%).
Randomization and blinding
For randomization we utilized QM for Windows Version
1.41 to run a simulation to randomize 80 patients in a 1:1
ratio. Assignment of active versus placebo was placed in an
alphabetical placeholder prior to run (Weiss, 1996).
Study design and assessments of efficacy
The primary goal of this study was to determine the
effects of treatment with bisphosphonates in preventing
further bone loss and possibly improving BMD as measured
by the same DXA instrument in patients who were taking
long-term AEDs.
We also determined the rate of new verterbral fractures
that were identifed in the cohort by serial lateral vertebral
assessment (LVA) scans and changes in 25-hydroxy vitamin D levels during the study period.
Patients were monitored for up to 2 years, with clinic visits scheduled at 0, 3, 6, 12, 18, and 24 months. At the initial
visit, patients were assessed for existence of modifiable risk
factors such as smoking, alcohol consumption, sedentary
lifestyle, poor nutrition, and the presence of hypogonadism.
Education and counseling were provided to all patients with
respect to nutrition, weight-bearing exercises, smoking
cessation, and alcohol intake.
BMD evaluations were performed at baseline, and at 12
and 24 months. All studies were performed on the same GE
Lunar Prodigy DXA instrument, performed by the same
research radiology technician, and analyzed with the same
enCore software version 13.6 (GE Medical Systems Lunar,
Madison, WI, U.S.A.). Positioning of patients for imaging
and analysis was undertaken according to recommended
instrument protocol (GE Medical Systems Lunar). BMD
assessment was performed at the bilateral proximal femora,
AP lumbar spine (AP), lateral spine including morphometric evaluation (LVA), and forearm. All densitometric studies were analyzed by an International Society of Clinical
Densitometry certified clinical densitometrist (AAL). Standard dual-energy LVA imaging was performed in the lateral
decubitus position as described previously (Binkley et al.,
2005). Assessment of vertebral fractures using DXA morphometry is known to provide an excellent specificity, with
moderate sensitivity (Duboeuf et al., 2005). All morphometric vertebral fractures were confirmed by two independent nonradiologist clinicians who were blind to study
participants; both are certified and trained densitometrists
(AAL, PD).
All measurements of each participant BMD were compared to their baseline measurements. The least significant
change (LSC) calculated for the GE Lunar densitometer
instrument utilized in this study and for the technician
(SAD) is 0.012 g/cm2 for the proximal femur and 0.010
g/cm2 for lumbar spine and total body. LSC is calculated
using a 95% confidence interval. LSC is the least amount of
BMD change measured by the DXA instrument that can be
considered statistically significant (Hind et al., 2010).
Comparisons of BMDs were performed at lumbar spine,
total mean bilateral proximal femora, and total body owing
to better precision at those sites.
Statistical analysis
Statistical tests were conducted on demographic data
to determine the existence of any subtle selection bias.
Quantitative measures (e.g., age) were tested by unpaired
t-test; qualitative measures (e.g., ethnicity) were tested
by the chi-square test. All data for the primary outcome
was analyzed on an intent-to-treat basis. Each patient’s
BMD at each specific site was compared to his own
baseline BMD at year 1 and year 2 after enrollment.
Increases or losses of BMD above the LSC for the
instrument and our technician were considered significant. Means within groups and differences in BMD were
calculated from baseline to year 1 and then baseline to
year 2. The differences of BMD between the individuals
that completed the study were compared using a paired
t-test. A p-value of <0.05 was considered statistically significant. Differences in BMD between risedronate and
placebo over time were tested using a mixture model
(SAS v. 9.2, PROC MIXED, SAS Institute, Inc., Cary,
NC, U.S.A.), where an exchangeable matrix was used to
model within-subject correlations over time and where
ethnicity was entered into the model as a confounder.
Least squared means were calculated, giving ethnicity
adjusted mean estimates of bone density for each treatment group at each of the three observation times. To
test for the effect of risedronate on fractures compared to
placebo, Fisher’s exact test was used to test for significant differences between the two groups.
Results
Baseline characteristics of the participants
Eighty patients provided informed consent to participate in the study (Table 1). Forty patients each were randomized to risedronate 35 mg per week or to a matching
placebo tablet. All participants received supplementation
with calcium and vitamin D. Baseline characteristics
including alcohol and smoking history were similar
between groups, with the exception of a greater number
of vertebral fractures identified at baseline by LVA in
the risedronate group compared to placebo (Table 1;
37% vs. 22%). Mean baseline vitamin D level in the
risedronate group was 29.10 ng/ml and in the placebo
group was 29.31 ng/ml (p = 0.57). The two groups had
similar baseline characteristics in terms of prevalence of
Epilepsia, 54(11):1997–2004, 2013
doi: 10.1111/epi.12351
2000
A. A. Lazzari et al.
Table 1. Baseline demographics and characteristics of
enrolled participants
Risedronate
(n = 40)
Demographics
Age
Race or ethnic group
White (%)
Black (%)
Body mass index
Current smoker (%)
Consumption of alcohol
drinks >1 per day (%)
Weight – mean (kg)
Seizure type and AED use
Grand mal (%)
Other types (%)
Refractory epilepsy (%)
Controlled epilepsy (%)
Antiepileptic drug use (%)
One AED (%)
Two or more AEDs (%)
Length of use of AEDs (years)
Baseline BMD
AP lumbar spine BMD – L1–L4
Bilateral total proximal
femur BMD
Lowest femoral neck BMD
Total body BMD
Vertebral fracture at
baseline (%)
One vertebral fracture
Two or more vertebral
fractures
Baseline – 25-hydroxy
vitamin D
Baseline – urinary
N telopeptide
Placebo
(n = 40)
63 (13)
58 (13)
95
5
29 (3.9)
72.5
30
92.5
7.5
29 (5.4)
70
40
85.0 (11.8)
84.7 (19)
47.5
52.5
25
75
55
45
22.5
77.5
90
10
28 (16)
90
10
22 (12)
1.246 (0.189)
0.990 (0.144)
1.244 (0.162)
1.018 (0.144)
0.882 (0.121)
1.204 (0.092)
15 (37.5%)
0.924 (0.139)
1.229 (0.107)
9 (22.5%)
7/15
8/15
7/9
2/9
29.10 (18.95)
29.31 (15.65)
39.24 (26.30)
37.18 (16.79)
Values are given as means (1 SD). Values of BMD are expressed in g/cm2
(1 SD). Values for 25-hydroxy vitamin D are given as ng/ml. Values for
urinary N telopeptide of collagen type I are expressed in nmol bone collagen
equivalents/nmol creatinine.
Table 2. Mean baseline BMDs in patients with vertebral
compression at baseline compared to patients with no
vertebral fractures
Compression
fracture (n)
Lowest femoral
neck BMD
Bilateral total
proximal femora
BMD
AP lumbar
spine BMD
No (56)
Yes (24)
p-Value
0.925 (0.129)
0.827 (0.152)
0.02
1.024 (0.130)
0.897 (0.195)
0.04
1.240 (0.168)
1.309 (0.103)
0.7
Values are given as means g/cm2 (1 SD). p-Values were calculated using a
Student’s t-test – two-sample assuming unequal variance.
controlled or refractory seizures or in the number of
patients receiving one or more AEDs or on the length of
AEDs treatment (p = 0.158; Table 1). In the placebo
Epilepsia, 54(11):1997–2004, 2013
doi: 10.1111/epi.12351
Table 3. BMD placebo group
Site
Baseline
Year 1
Year 2
Bilateral
proximal
femora
L1–L4 AP spine
Total body
1.009 (0.150)
0.989 (0.161)*
0.999 (0.174)*
1.229 (0.153)
1.216 (0.108)
1.231 (0.143)*
1.211 (0.101)*
1.245 (0.154)*
1.192 (0.127)**
Values are given as means g/cm2 (1 SD).
*p > 0.05 using the paired T-test as compared to baseline values.
**p < 0.05 using the paired T-test f as compared to baseline values.
Table 4. Mean BMD risedronate group
Site
Baseline
Year 1
Year 2
Bilateral
proximal
femora
L1–L4 AP spine
Total body
1.007 (0.118)
1.042 (0.109)**
1.025 (0.111)*
1.267 (0.204)
1.204 (0.092)
1.334 (0.242)**
1.230 (0.088)**
1.332 (0.221)**
1.205 (0.096)*
Values are given as means g/cm2 (1 SD).
*p > 0.05 using the paired T-test as compared to baseline values.
**p < 0.05 using the paired T-test f as compared to baseline values.
group, 58% were using phenytoin, 38% were taking carbamazepine, and 8% were taking divalproex, whereas in
the risedronate group 78% were taking phenytoin; 7%
carbamazepine, 11% divalproex, and 4% phenobarbital.
At the end of the study period (2 years after enrollment),
65% of patients in the placebo group and 65% patients
in the risedronate group completed the protocol, having
at least one scan after baseline.
At baseline it was observed that subjects who had compression fractures had lower BMD at the femoral neck and
bilateral proximal femora as compared to those who did not
have compression fractures (p = 0.02 and 0.04, respectively) (Table 2).
Changes in BMD
In the first follow-up DXA study after 1 year of enrollment for the patients who completed the study (Table 3),
the mean total bilateral proximal femora BMD decreased
nonsignificantly in the placebo group (1.009–0.989 g/cm2;
p = 0.44), whereas in the risedronate group, the mean
BMD increased significantly by 3% (1.007–1.042 g/cm2;
p = 0.02). The mean BMD at the AP lumbar spine as
measured at L1 to L4 did not change significantly in the
placebo group (1.229–1.231 g/cm2; p = 0.8), whereas the
BMD significantly increased in the risedronate group
(Table 4) (1.267–1.334 g/cm2; p ≤ 0.005). Total body
BMD in the placebo group decreased nonsignificantly
(1.216–1.211 g/cm2; p = 0.10), whereas in the risedronate
group total body bone density increased significantly
(1.204–1.230 g/cm2; p = 0.001).
2001
Antiepileptic Drug and Osteoporosis Prevention Trial
At the end of the study (Table 3), 2 years after enrollment, there was a 1% nonsignificant increase in the mean
BMD at AP lumbar spine in the placebo group (1.229–
1.245 g/cm2; p = 0.19), whereas the risedronate group
(Table 4) experienced a significant increase of BMD
(1.267–1.332 g/cm2; p = 0.004). In comparison, at the AP
lumbar spine as measured at L1 to L4, the increase in the
risedronate group (1.267 g/cm2 vs. 1.332 g/cm2) was significantly larger than that seen in the placebo group
(1.229 g/cm2 vs. 1.245 g/cm2; p = 0.0066). Over the
course of the study, the ethnicity-adjusted mean BMD of the
femur dropped slightly (1.043 g/cm2 vs. 1.041 g/cm2) in
the placebo group, whereas there was a small increase
(1.049 g/cm2 vs. 1.053 g/cm2) in the risedronate group.
There was no statistically significant difference in these
changes between the treatment groups (p = 0.2806). At the
end of the study, there was a significant decrease in total body
BMD in the placebo group (1.216 g/cm2 vs. 1.192 g/cm2;
p = 0.0066), whereas in the risedronate group there was a
nonsignificant change (1.204 g/cm2 vs. 1.205 g/cm2;
p = 0.454). At the end of the study, there was no statistically
significant difference in these measurements between
the treatment groups (p = 0.8477). In contrast, at the AP
lumbar spine as measured at L1 to L4, the increase in the
risedronate group (1.332 g/cm2 vs. 1.267 g/cm2) was confirmed to be significantly larger than that seen in the placebo
group (1.245 g/cm2 vs. 1.229 g/cm2; p = 0.0066).
At the end of the study period, of the 26 patients in the
placebo group who completed the protocol, 30% had a significant improvement of the BMD at the bilateral proximal
femora as determined by increases above LSC for the site
and instrument; 26% had no significant changes and 44%
had a decrease of BMD (lower than the LSC). At the same
site, in the 27 patients in the risedronate group who completed the protocol, 38% had significant gains in BMD,
27% had a significant decrease of BMD, and 35% had no
significant changes. In the placebo group, total body BMD
decreased in 69% of the patients, increased in 4%, and
there was no change in 27%. In the risedronate group 48%
had a significant decrease of total body BMD, 19%
gained, and 33% had no change. At the lumbar spine L1
to L4, for the entire study period, in the placebo group,
65% gained BMD, whereas 34% had a significant
decrease of BMD. In the risedronate group, from L1 to
L4, 88% gained BMD, whereas 11% had a significant
decrease in BMD.
Vitamin D levels
Mean vitamin D levels at baseline in the placebo group
were 30 ng/ml and at the final visit were 38 ng/ml. Mean
vitamin D levels in the risedronate group at baseline were
28 ng/ml and at the final visit were 29 ng/ml. These
changes in vitamin D levels did not differ significantly
(p > 0.05).
Fractures
Using semiquantitative methods as previously described
(Binkley et al., 2005), we found throughout the duration of
the study five new vertebral fractures in the placebo group
and none in the risedronate group (p = 0.0229). In addition,
one of the patients in the placebo group was found to have
had an upper arm fracture 1 year into the study. This patient
was withdrawn from the study as he was found to have
significant loss of BMD (T-score <2.5) at his proximal
femur. His results were not included in the final analysis.
Conclusions
To our knowledge, this study is the first longitudinal prospective randomized placebo controlled trial of prevention
and treatment of bone loss in male veterans with epilepsy
who underwent long-term AEDs treatment and had normal
or low bone mass.
We conceived and designed the ADOPT study to determine if treatment with an oral bisphosphonate (risedronate)
compared to placebo resulted in an improvement in BMD in
this population. We observed that more than 65% of the
patients in the placebo group receiving supplementation of
calcium and vitamin D had a significant improvement of
their BMD at any studied site, this supports a beneficial
effect of this supplementation on the overall bone health in
this patient population. In the risedronate group, we
observed that a greater number of subjects sustained a significant increase in BMD at the lumbar spine and at the
bilateral proximal femora when compared to the placebo
group and to their own baseline BMDs. This significant
improvement in bone density at the lumbar spine in the
risedronate group may explain why no new compression
fractures were observed in this group during the study period. We observed five new vertebral fractures and one nonvertebral fracture only in the placebo group, even though
both groups were well matched for their baseline characteristics (Table 1) including the number of AEDs used, and
length of therapy and other cofactors such as age, body mass
index (BMI), and tobacco and alcohol use. The small sample size in both groups did not allow subanalyses of confounding factors, in particular; however, the statistical
analysis was performed as each subject was evaluated as
their own control. The overall baseline prevalence of vertebral fractures in the entire ADOPT cohort was 30%, (37.5%
were in the treatment group and 22.5% were in the placebo
group) (Table 2). This prevalence of vertebral compression
fractures is remarkable, since the ADOPT cohort was
selected based on T-scores above the threshold for defining
the diagnosis of osteoporosis. In this study cohort there was
a prevalence of tobacco use (71%) and alcohol use (35%),
which may have contributed to the remarkable prevalence
of baseline vertebral fractures of the participants, since
those habits are considered to be independent risk factors
Epilepsia, 54(11):1997–2004, 2013
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2002
A. A. Lazzari et al.
for osteoporosis and osteoporotic fractures (Kanis et al.,
2009; Buns, 2013).
The identification of subclinical vertebral fractures is
important because a previous fragility vertebral fracture is
considered to be a strong predictor for future vertebral and
nonvertebral fractures (Binkley et al., 2005; Holmberg
et al., 2006). The benefit of identification of subclinical
vertebral fractures and other risk factors for osteoporosis in
this population would be the initiation of treatment and
establishment of preventive measures, which may justify
the cost and the possible risk of the use of bisphosphonates
as demonstrated in other populations at risk (Little &
Eccles, 2010; Majumdar et al., 2013; National Osteoporosis Foundation, 2013). We also observed that BMD at the
bilateral total proximal femur at baseline in this cohort was
significantly lower in the group of subjects who had baseline compression fractures. We did not, however, when
comparing patients at baseline who had a previous compression vertebral fracture to patients with no vertebral
deformities, observe significant differences of BMD at the
AP spine (Table 2). This may because vertebral compression fractures falsely increase BMD of the spine, as
reported previously (Krege et al., 2006). The remarkable
frequent finding of baseline vertebral fractures in this
population supports the importance of screening epileptic
patients for subclinical vertebral fractures either by routine
traditional vertebral radiographs or by performing LVAs on
a DXA scanner. We believe that by performing an LVA at
the same exam as a central DXA scan is performed is time
and cost efficient and can disclose asymptomatic and not
previously diagnosed compression fractures (Binkley et al.,
2005). We also believe that the identification of asymptomatic compression fractures in a patient with epilepsy may
improve management and treatment of future bone loss in
patients at risk for future fractures. Furthermore, LVA scans
expose patients to a considerable lower level of radiation
than conventional spine x-rays (2–50 microsievert vs. 600–
800 microsievert, respectively, per exposure) (Damilakis
et al., 2010; Hind et al., 2010; Robinson et al., 2013).
Our results are in agreement with previously reported risk
reduction of vertebral and nonvertebral fractures in other
male populations at risk for osteoporotic fractures, supporting the paradigm that the addition of a bisphosphonate in
combination with calcium and vitamin D supplementation
for 2 years significantly reduced the incidence of new vertebral and possibly nonvertebral fractures (Orwoll et al.,
2000; Boonen et al., 2009; Ringe et al., 2009).
There were a number of limitations to our study. Although
enrolled patients were provided travel support, there was a
large percentage of dropouts owing to travel difficulties,
although the dropout rate (40%) was similar for both groups.
Although weight-bearing exercises have been shown to
improve BMD, we did not quantify the amount of exercises
in this ambulatory population; however, both groups were
instructed in all visits to improve their level of physical
Epilepsia, 54(11):1997–2004, 2013
doi: 10.1111/epi.12351
activity and instructed on the importance of weight-bearing
exercises during the initial and all the follow-up visits. Even
though the duration of AED use did not differ significantly
in this cohort, owing to the small numbers of patients we are
unable to determine whether one AED resulted in significant bone density changes when compared to the others.
Our cohort was limited to a population of male veterans
with epilepsy with a T-score at any of the traditional sites
above 2.5; therefore, its application to a wider epileptic
population is to be determined.
In attempting to develop a treatment and preventive paradigm for patients with epilepsy regarding their skeletal
health, it is important to identify other primary risk factors
of bone loss and future fracture risk such as family history
of osteoporosis or hip fractures, personal history of fractures
and other conditions such as rheumatoid arthritis, and
chronic use of glucocorticoids. Well-established fracture
risk factors should be evaluated and calculated using the
“WHO Fracture Risk Assessment Tool” (FRAX (Kanis
et al., 2009; National Osteoporosis Foundation, 2013).
Pharmacologic intervention to prevent osteoporotic fractures in patients with epilepsy is indicated and justified with
an increased risk of fractures such as a previous fragility
fracture, for instance, a vertebral or a hip fracture, or if
patients are determined to have a 10-year increased risk of
hip fractures above 3% or of a major osteoporotic fracture
above 20% according to the FRAX calculator (Kanis et al.,
2009). Modifiable risk factors in this cohort included the
following: low vitamin D levels, tobacco use, alcohol use,
sedentary lifestyle, polypharmacy, and monitoring of
patients for central nervous system side effects from AEDs
(sedation, ataxia), which may increase fall risk.
The results of this present study suggest that treatment of
low bone mass and prevention of fractures in the epileptic
population not only can improve bone mass and possibly
reverse the progression of bone loss, but also may prevent
the development of new vertebral and possibly nonvertebral
fractures. Therefore, we believe that in order to address the
increased risk for the development of osteoporosis and osteoporotic fractures, clinicians providing care to patients with
epilepsy should focus on the following: (1) identification of
patients at an increased risk of fracture; (2) identification
and management of additional modifiable risk factors for
osteoporosis and falls; (3) provision of adequate seizures
prevention with as few AEDs or psychotropic medications
as possible and with minimal sedative effects; (4) use of
nonpharmacologic means of preventing falls and fractures,
such as improving physical activity, including but not limited to multifactorial interventions such as muscle strengthening and balance exercises such as tai chi; (5) home safety
evaluation should be considered to address environmental
factors that may contribute to a fall such as area carpets,
lighting, grab rails in bathroom; (6) physical therapy evaluation for gait, balance, and strength; (7) periodic evaluation
for BMD loss through DXA and LVA studies to be repeated
2003
Antiepileptic Drug and Osteoporosis Prevention Trial
at 1–2 year intervals; (8) ensure adequate calcium and
vitamin D supplementation; and (9) consider initiation of
antiosteoporotic drugs (antiresorptive agents such as bisphosphonates, receptor activator of nuclear factor kappa-B
ligand (RANK-L) inhibitors, selective estrogen receptor
modulators (SERMS), or drugs that improve bone formation
such as the parathyroid hormone (PTH) analogues in patients
at high risk for future fracture (National Osteoporosis
Foundation, 2013). Recently, concerns about the long-term
effects of bisphosphonates have been published (McClung
et al., 2013). In accordance with current recommendations,
we advise that all patients be asked about active dental
issues and potential invasive dental procedures prior to initiating therapy. If possible all extensive invasive dental work
should be performed before the patient starts taking a bisphosphonate. In addition, therapy should be limited to
5 years if possible, to possibly reduce the rare side effect of
atypical femoral fractures and other complications. Future
studies of long-term use of bisphosphonates in the epileptic
patient population should be encouraged.
Acknowledgments
We thank the following who have contributed to the design and statistical analysis or manuscript revision: Rachael Burns, RA; Roanna Bamford,
RNP; Kent Creamer, MD; and Jack Bukowski, MD. We also thank the
Boston VA Research Institute for their assistance and support and the VA
Boston Healthcare System.
Disclosure
This work was supported by a grant from the Alliance for Better Bone
Health, Boston VA Research Institute, and VA Boston Healthcare System.
The authors have no conflicts to disclose or affiliation with any commercial
entity. We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this report is consistent with
those guidelines.
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