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BsmI vitamin D receptors polymorphism and bone mineral density

in men and premenopausal women on long-term antiepileptic

therapy

I. Lambrinoudakia, G. Kaparosb, E. Armenia, A. Alexandrouc, C. Damaskosc, E. Logothetisb,

M. Creatsaa

, A. Antonioud

, E. Kouskounib

and N. Triantafylloue

a2nd Department of Obstetrics and Gynecology, University of Athens, Aretaion Hospital; bHormonal Laboratory, University of Athens,

Aretaieion Hospital; c1st Department of Surgery, University of Athens, Laiko Hospital; dRadiology Department, University of Athens,

Aretaieion Hospital; and eDepartment of Neurology, University of Athens, Aiginiteion Hospital, Athens, Greece

Keywords:

bone mineral density,

BsmI, epilepsy, VDR

Received 14 December 2009

Accepted 25 March 2010

Background: Utilization of antiepileptic drugs (AEDs) has long been associated with

bone deleterious effects. Furthermore, the BsmI restriction fragment polymorphism of

the vitamin D receptor (VDR) has been associated with reduced bone mineral density

(BMD), mostly in postmenopausal women. This study evaluates the association

between bone metabolism of patients with epilepsy and the BsmI VDRs polymor-

phism in chronic users of AEDs.

Methods: This study evaluated 73 long-term users of antiepileptic drug monotherapy,in a cross-sectional design. Fasting blood samples were obtained to estimate the cir-

culating serum levels of calcium, magnesium, phosphorus, parathormone, 25hydrox-

yvitamin D as well as the VDRs genotype. Bone mineral density at the lumbar spine

was measured with Dual Energy X-Ray Absorptiometry.

Results: Bone mineral density was significantly associated with the genotype of VDR

(mean BMD: Bb genotype 1.056 0.126 g/cm2; BB genotype 1.059 0.113 g/cm2;

bb genotype 1.179 0.120 g/cm2; P < 0.05). Additionally, the presence of at least

one B allele was significantly associated with lower bone mineral density (B allele

present: BMD = 1.057 0.12 g/cm2, B allele absent: BMD = 1.179 0.119 g/

cm2; P < 0.01). Patients with at least one B allele had lower serum levels of 25hy-

droxyvitamin D when compared with bb patients (22.61 ng/ml vs. 33.27 ng/ml,

P < 0.05), whilst they tended to have higher levels of parathyroid hormone.

Discussion: Vitamin D receptor polymorphism is associated with lower bone mass in

patients with epilepsy. This effect might be mediated through the vitamin D-para-

thormone pathway.

Introduction

Epilepsy is a common neurological disorder, knowing

to affect approximately 50 million people of all ages

worldwide [1]. It is estimated that 410 per 1000 people

of the general population are in need of antiepileptic

therapy at a certain time. Furthermore, there is an

increased utilization of antiepileptic drugs (AEDs) for

the treatment of several non-epileptic neurological

conditions such as neuropathic pain syndromes, tri-

geminal neuralgia, migraine and essential tremor as well

as psychiatric disorders [2].

Accumulating evidence has linked epilepsy with

osteoporosis. Osteoporosis in patients with epilepsy is a

multifactorial condition, related to the type of epilepsy,

falls, habitus, family history and to the presence of

conditions affecting bone metabolism. Amongst other

risk factors, AEDs-treatment may be one additional

cause of osteoporosis [3,4]. Long-term AED therapy is

an independent risk factor for reduced bone mineral

density (BMD), at least in some patients [3,58]. In

addition, AEDs users have an increased risk for frac-

tures [5,8,9], which can be an important cause of mor-

bidity and mortality. The fracture risk of the epileptic

population is approximately twice that of the general

population, independently of seizure-related falls,

whilst 35% of fractures may be related to seizure

[5,8,10].

Correspondence: E. Armeni, 8b, Nestou Street, Vrilissia, GR-15235

Athens, Greece (tel.: +30 210 6009726; fax: +30 210 7333310;

e-mail: elenaarmeni@hotmail.com).

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As the report from Morrison et al. [11], many candi-

date genes have been associated with bone turnover,

bone density or fractures [12]. Amongst them, the vita-

min D receptor (VDR) gene is by far the most exten-

sively investigated, and more specifically, the BsmI

restriction fragment length polymorphism. Epileptic

treatment, on the other hand, can be characterized byvarying responses, unpredictable outcomes and adverse

effects. Treatment with phenytoin was reported to be

affected by genetic variability in drug metabolism more

than 25 years ago [13]. The principle of pharmacoge-

netics in the field of epilepsy is to test how a patient s

genotype might affect variation in response to AEDs

amongst individuals, in terms of different adverse

reactions or effectiveness of the drugs. Many drug-

metabolizing enzymes, transporters, and targets have

well-characterized functional variants. Therefore,

genetic variation can have a significant effect on the

efficacy of AEDs, provoking alterations in pharmaco-

kinetic and pharmacodynamic pathways [1315].

Even if many theories have been proposed, the

exact mechanisms for the adverse effect of AEDs on

bone health are not well known yet. Furthermore, no

data exist as to the possible association between

VDRs polymorphism and the AEDs induced bone

disease. The aim of this study was therefore to eval-

uate the association between the VDRs polymor-

phism BsmI genotypes and the individual responses

of bone metabolism after long-term utilization of

AEDs.

Methods

Subjects

Consecutive ambulatory patients with epilepsy, regu-

larly evaluated in the outpatient clinic of the tertiary

care center of the Aiginiteion Hospital in Athens

between January 2006 and December 2008, were

included in the study. A total of 73 subjects on long-

term anti-epileptic monotherapy were retrieved, of

which 41 patients were on valproic acid, 23 were on

oxcarbazepine and nine patients on levetiracetam; 31

subjects (42.47%) had generalized seizures, 12 (16.44%)

had partial seizures and 30 patients (41.09%) had par-

tial secondarily generalized seizures.

Before recruitment, patients had to complete a

questionnaire according to the presence of conditions

knowing to affect bone turnover and BMD. The ques-

tionnaire evaluated their medical history, smoking,

alcohol intake, dietary calcium intake, current and

prior drug intake, bone fractures, daily exercise and the

presence of regular menses. Subsequently, the subjects

underwent a laboratory evaluation, which included

thyroid ) liver renal ) parathyroid and gonadal

function.

Inclusion criteria were AED-monotherapy for a time

period 1 year and regular menses for women. Exclu-

sion criteria were intake of medications knowing to

affect bone metabolism (e.g. bisphosphonates, calcium

supplements, steroids, calcitonin, thiazides, glucocor-ticoids, or vitamin D), daily alcohol intake, smoking,

nutritional deficiency, thyroid liverrenal disorders,

hypogonadism or hyperparathyroidism. All patients

who fulfilled these criteria were invited to participate in

the study. Written informed consent was obtained by all

subjects. Institutional Review Board approval was

obtained by the Ethics Committee of Aretaieion Hos-

pital.

Protocol

Participants were evaluated in a cross-sectional design.

A detailed medical history was recorded for every

patient, which included category and dosage of the

antiepileptic therapy. Anthropometric parameters were

measured at 8:30 a.m. in light clothing, and the Body

Mass Index (BMI) was computed. The measurements

of height and weight were performed using an electronic

scale with height rod, and BMI was estimated using the

following equation: BMI = body weight (kg)/height2

(m). Subsequently, fasting venous blood samples were

collected and stored at )80C until assessment. The

BMD was evaluated the same morning.

Bone densitometry

Bone mineral density of the lumbar spine was mea-

sured using a Norland-Excell Plus-XR-36 densitometer

(Norland Medical Systems, Fort Atkinson, WI, USA)

by Dual Energy X-Ray Absorptiometry (DXA).

Within-subject coefficient of variation was 1.1%.

Using the Greek normative database [16], Z-scores

(number of SD below age and sex-matched controls)

were calculated. In young adults, bone density below

the expected range for age was determined according

to the International Society of Clinical Densitometry

definition for this term, as a BMD Z-score at one site

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25-hydroxyvitamin D3 30.074.0 ng/ml; PTHi 10

55 pg/ml.

VDR genotyping

Blood samples were drown by atraumatic venipuncture

into trisodium circle tubes. Genomic DNA was isolatedfrom leukocyte nucleids using High Pure PCR Tem-

plate Preparation kit (Roche). Real-time PCR was

performed in capillaries with a reaction volume of

10 ll, containing 2 ll of DNA (50100 ng), 0.3 lM

sence primer VDR bF (TAG GGG GGA TTC TGA

GGA ACT A) and antisense primer VDR bsm A (AGT

TTT GTA CCC TGC CCG C), 1.4 ll 25 mM MgCl2,

1 ll H2O, 1 ll of Light Cycler DNA Master HybProbe

(ready to use reactionmix for PCR containing Taq

DNA polymerase, reaction buffer, dNTP mix with

dUTP instead of dTTP and 10 mM MgCl2), 0.6 lM

Sensor b, 3 modified with fluorescein (AGT ATT GGG

AAT GCG CAG GCC-FL) and 0.6 lM Anchor b 5

labeled with Light Cycler Red 640 and 3 terminally

blocked by phosphorylation (Red 640-TCT GTG GCC

CCA GGA ACC CTG-pH). Sensor b covers the BsmI

restriction site.

The polymorphism was defined as BB (absence of

restriction site on both alleles), Bb (heterozygous) and

bb (presence of restriction site on both alleles).

Statistical analysis

Data analysis was performed using SPSS version 17.0.

(SPSS, Chicago, IL, USA). Data on qualitativecharacteristics are expressed as percent values, whilst

data on quantitative characteristics are expressed as

means SD. Non-parametric tests were used in cases

of deviation from normal distribution. Adjustments for

possible confounding factors were performed by mul-

tiple regression analysis. Statistical significance was set

at the 0.05 level.

Results

The baseline demographic and anthropometric char-

acteristics of the study population are presented in

Table 1. The mean levels of BMD, PTHi and 25hy-

droxyvitamin D3 did not differ regarding the sex of the

patients or the utilization of each individual AED.

Our analysis showed the following results (Table 2):

BMD was associated with the VDR genotype, and

specifically, patients with the unfavorable B allele

(homozygotes, heterozygotes) had lower BMD at sta-tistically significant levels (BMD: Bb genotype

1.056 0.126 g/cm2, BB genotype 1.059 0.113 g/

cm2, bb genotype 1.179 0.119 g/cm2, P < 0.05 for

linear trend; Fig. 1). In addition, the presence of at least

one B allele was associated with significantly lower

Table 2 Mean levels of hormones, biochemical parameters and BMD

according to the genotype of the vitamin D receptor

Characteristics

Ballele

BB+Bb bb P-value

BMD 1.06 0.12 1.18 0.12 0.012

Z-Score)

0.28 0.68 0.33 0.72 0.021Serologic test results

S erum Ca (mg /d l) 9.8 4 0.5 7 10. 09 0 .75 0. 39

Serum P (mg/dl) 3.65 0.59 3.62 0.56 0.73

S erum Mg (mg/dl) 1.9 7 0.1 7 1.9 9 0 .22 0. 69

25(OH)Vit.D3 (ng/dl) 19.64 6.58 22.5 4.28 0.028

P THi (pg/dl ) 4 4.8 7 22. 89 33. 46 1 4.0 2 0. 052

BMD, bone mineral density; PTHi, parathormone. Bold indicates

statistical significant (P < 0.05) associations.

Table 1 Baseline demographic and anthropometric characteristics of

the study population

Characteristics Mean Minimum Maximum SD

Age (years) 31.99 16.00 54.00 8.82

Weight (kg) 70.75 48.00 105.00 14.16

BMI (kg/m2) 24.89 17.63 36.51 4.00

Height (m) 1.68 1.50 1.88 0.09

AEDs do sa ge (g/day ) 1 610 .96 5 00. 00 35 00.0 0 562 .87

Duration of AEDsintake (years) 8.27 1.50 25.00 6.67

BMD (g/cm2) 1.07 0.81 1.42 0.13

Z-SCORE )0.18 )1.90 1.55 0.77

Serologic test results

Serum Ca (mg/dl) 9.86 8.70 11.50 0.64

Serum P (mg/dl) 3.62 2.20 5.10 0.58

Serum Mg (mg/dl) 1.96 1.57 2.33 0.18

25(OH)Vit.D3 (ng/ml) 19.73 5.30 40.70 6.29

PTHi (pg/ml) 44.09 13.20 128.00 23.13

BMD, Bone mineral density; PTHi, parathormone; AEDs, antiepi-

leptic drugs; 25(OH)Vit.D3 = 25-hydroxy-vitamin D3.

00 000

20 000

40 000

60 000

80 000

100 000

120 000

140 000

160 000

BMDL2-L

4(g/cm2)

VDR Genotypes

bb Bb BB

P-value = 0.033

Figure 1 Mean levels of bone mineral density in lumbar spine

(L2L4) according to vitamin D receptors genotype.

BsmI VDR and bone disease in epilepsy 95

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BMD, and lower z-scores. Bone density below the

expected range for age (4.1% of subjects) correlated

positively with the presence of the BB genotype

(P = 0.031). This association remained significant after

adjusting for the daily drug dosage, duration of ther-

apy, sex, age and BMI. The presence of at least one B

allele was associated with lower levels of serum 25hy-droxyvitamin D3 (bb genotype: 22.5 4.28 ng/ml vs.

19.64 6.58 ng/ml, P = 0.028). Furthermore, patients

having at least one B allele tended to have higher levels

of PTHi compared to patients with bb genotype

(P = 0.052).

Regression analysis revealed that the presence of at

least one unfavorable B allele was a significant predictor

of BMD, independently of age, sex, BMI, daily dosage

and duration of therapy (b = )0.149; P = 0.001).

Discussion

The results of this study support the existence of a

significant association between BMD of the lumbar

spine, measured by DXA, and VDR genotype in men

and premenopausal women on AEDs. The presence of

the BB genotype correlated positively with BMD below

the expected range for age in this sample of young

adults. The presence of the unfavorable B allele was an

independent predictor of lower BMD.

Vitamin D plays a central role in bone biology and

mineral homeostasis. Its actions are mediated through

the active metabolite 1,25 dihydroxyvitamin D3, pro-

duced after the hydroxylation of vitamin D3 to its

active form in liver and kidney [17]. The effects of 1,25dihydroxyvitamin D3 on bone mineral homeostasis are

mediated by the nuclear VDR, a ligand-activated

transcription factor [18]. Chromosome 12cen-q12 is the

location of the VDR-encoding gene, in which at least 22

unique mutations have been reported. Restriction site

polymorphisms in the VDR gene associated with BMD

changes are mainly the FokI, the TaqI, the BsmI, the

ApaI and the EcoRV [17,18]. The BsmI polymorphism

occurs in the intron between exons VIII and IX in the 3

region of the hVDR gene and is in linkage with two of

the other polymorphic sites (ApaI and TaqI) [19]. The

frequency of the unfavorable BB genotype was found to

be as high as 17% amongst Caucasians [18].

The association between BMD and the BsmI

restriction fragment polymorphism of VDR has been

subject of many studies. Recent reports have identified

an association between the presence of the B allele and

spinal BMD in postmenopausal women [20], which

appears to be similar between black and white pre-

menopausal women [21]. In addition, this polymor-

phism has been strongly associated with an increased

risk of fractures, independent of BMD levels in

postmenopausal women [22], as well as with stress

fractures amongst healthy men and women [23]. Other

studies proposed that homozygotes for the B allele had

a more than twofold increased risk of hip fracture

compared with the wild type [24]. Furthermore, the

BsmI polymorphism has been related to lumbar spine

BMD in healthy adolescent girls [25]. On the contraryto the above, some studies have failed to corroborate

these findings [10,26].

Data relating VDR polymorphism with PTHi and

25-hydroxyvitamin D3 is relatively limited. One study

suggests that baseline 1,25dihydroxyvitamin D levels

are higher in premenopausal women with the BB

genotype than in those with the wild type, a finding

suggesting lower receptor activity of the BB genotype

[27]. In addition, evaluating patients with chronic re-

nal failure, another study proposed that the BsmI

polymorphism may affect circulating levels of PTHi

[28].

Beyond healthy subjects and osteoporotic postmen-

opausal women, the potential role of the BsmI restric-

tion fragment polymorphism of VDR as a determinant

of BMD has been evaluated in patients with thalasse-

mia, thyroid disorders and renal failure. The homozy-

gous BB genotype has been suggested as an additional

risk factor for the development of bone disease in

patients with homozygous beta thalassemia [29] and

hyperthyroidism [30]. Furthermore, renal failure

patients with the bb genotype, who underwent renal

transplantation, have been considered as being

protected to some extent against bone loss after the

procedure [31]. AEDs-induced bone disease, however,has not been investigated yet, regarding the BsmI

restriction fragment length polymorphism of VDR.

The association between reduced BMD and utiliza-

tion of AEDs remains controversial. The inducers of

the CYP450 are most commonly associated with bone

alterations, because they accelerate the hepatic micro-

somal metabolism of vitamin D to polar inactive

metabolites. Decreased biologically active vitamin D

leads to decreased absorption of calcium in the gut.

This results to hypocalcemia and increased circulating

PTH, and subsequently increased bone turnover [32].

Data, however, are still contradictory. Recent studies

demonstrate differing results regarding the effect of

carbamazepine, an inducer of the CYP450, on bones.

Valproate on the other hand, an inhibitor of the

CYP450, has only recently been associated with

increased bone resorption [8,32,33]. Furthermore,

Ensrud et al. [34] reported an independent association

between the use of non-enzyme-inducing AEDs and the

rate of bone loss in the hip ()0.53%/year; P = 0.04)

whilst the use of enzyme-inducing AEDs had no

significant effect on hip bone loss ()0.46%/year;

96 I. Lambrinoudaki et al.

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P = 0.31). Finally, the newer non-enzyme-inducing

AEDs have not been extensively investigated yet.

Beyond the use of AEDs, bone loss in the epileptic

population could be related to the disease itself.

Epilepsy is associated with recurrent falls, seizure-re-

lated injuries as well as with inactivity, which can pre-

dispose to bone loss. In addition, cerebral palsy,frequently associated with epilepsy, is related with

osteopenia [4].

Our study shows a statistically significant association

between BMD and the BsmI polymorphism of VDR.

Interestingly, all patients with bone density below the

expected range for age were of the BB genotype and

had lower circulating 25hydroxyvitamin D3 levels

compared to wild type. To our knowledge, this is the

first study to investigate this association in an epileptic

population. Only one study [35] tried to evaluate BMD

in patients with pediatric epilepsy examining the pres-

ence of the B allele as well, but the BB genotype was not

found amongst the study population.

The mechanism underlying the association of BsmI

VDR polymorphism and bone metabolism is yet

unclear. The presence of polymorphic variants of the

VDR gene can alter metabolic pathways and therefore,

affect the susceptibility to the osteopenic effects of

AEDs. Vitamin D receptor, which is found to be

present rather in osteoblasts than in osteoclasts, might

interact with AEDs and regulate thus the transcription

of target genes involved in bone metabolism, such as the

gene for osteocalcin, the induction of which is positively

related with new bone formation [36]. Equally possible,

this interaction may affect the gene of parathyroidhormone, which is normally down-regulated [37].

Our study bears certain limitations. The relative

small sample size may have not provided us with

enough statistical power to detect a clear association

between markers of bone metabolism and bone disease

in patients with epilepsy. Another limitation is the sin-

gle measurement of BMD in lumbar spine. In addition,

the number of patients with bone density below the

expected range for age was low. This might be related to

the fact that the subjects were slightly overweight that

may have affected bone metabolism positively. Even

though, the presence of a strong association between

VDRs genotype and bone metabolism in patients with

epilepsy is supportive of a synergistic role of this

polymorphism in the development of bone disease.

The impact of epilepsy on bone metabolism is con-

sidered as a type of secondary osteoporosis [3]. Physi-

cians awareness of epilepsy-associated bone disease

remains limited. Evidence suggests that bone pathology

related to epilepsy can be prevented or treated. Even

though, only few physicians recommend screening for

bone disorders and even fewer prescribe calcium and

vitamin D supplements [10,32]. The results of the cur-

rent study support the routine evaluation of patients

with epilepsy for bone loss. Furthermore, the potential

role of VDR polymorphism in the development of bone

disease in patients with epilepsy should be evaluated by

larger studies, as it might be helpful to ordinate patients

as high risk and low risk, regarding the development ofosteoporosis.

Acknowledgements

Funding for this study was provided by the Special

Account for Research Grants by the National and

Kapodistrian University of Athens, SARG 70/3/8259.

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