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Bone and calcium metabolism and antiepileptic drugs

November 2009
Clinical Neurology and Neurosurgery 112(1):1-10

DOI:10.1016/j.clineuro.2009.10.011

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PubMed

Authors:

Alberto Verrotti

Università degli Studi di Perugia

Giangennero Coppola

Università degli Studi di Salerno

Pasquale Parisi

Sapienza University of Rome

Mohn Angelika

Università degli Studi G. d'Annunzio Chieti e Pescara

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There is increasing evidence suggesting that epilepsy and its treatment can affect bone mineralization and calcium metabolism. Many studies have shown a significant reduction in bone mineral density in patients treated with classic (phenobarbital, carbamazepine, valproate, etc.) and with new (oxcarbazepine, gabapentin) antiepileptic drugs. In spite of data about the possible effects of the antiepileptic drugs on calcium metabolism, the mechanisms of this important side effect remain to be defined. The abnormalities of calcium metabolism were thought to result from the cytochrome P450 enzyme-inducing properties of some antiepileptic drugs and the resultant reduction in vitamin D levels, but the effect of many medications (e.g., valproate) cannot be readily explained by vitamin D metabolism. In this article, the literature related to the effects of classic and new antiepileptic drugs on bone health and calcium metabolism is reviewed.

Main effects of classic and new AEDs on bone and calcium metabolism.

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Clinical Neurology and Neurosurgery 112 (2010) 1–10

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Review

Bone and calcium metabolism and antiepileptic drugs

Alberto Verrottia,∗, Giangennaro Coppolab, Pasquale Parisic, Angelika Mohna, Francesco Chiarellia

aDepartment of Pediatrics, University of Chieti, Italy

bDepartment of Child Neuropsychiatry, University of Naples, Italy

cII University of Rome “La Sapienza”, Italy

article info

Article history:

Received 2 April 2009

Received in revised form 21 August 2009

Accepted 10 October 2009

Available online 12 November 2009

Keywords:

Bone mineral density

Calcium

Vitamin D

Parathyroid hormone

Valproate

Carbamazepine

Phenobarbital

abstract

There is increasing evidence suggesting that epilepsy and its treatment can affect bone mineralization

and calcium metabolism. Many studies have shown a signiﬁcant reduction in bone mineral density

in patients treated with classic (phenobarbital, carbamazepine, valproate, etc.) and with new (oxcar-

bazepine, gabapentin) antiepileptic drugs. In spite of data about the possible effects of the antiepileptic

drugs on calcium metabolism, the mechanisms of this important side effect remain to be deﬁned. The

abnormalities of calcium metabolism were thought to result from the cytochrome P450 enzyme-inducing

properties of some antiepileptic drugs and the resultant reduction in vitamin D levels, but the effect of

many medications (e.g., valproate) cannot be readily explained by vitamin D metabolism.

In this article, the literature related to the effects of classic and new antiepileptic drugs on bone health

and calcium metabolism is reviewed.

Contents

1. Introduction .......................................................................................................................................... 2

2. Classic antiepileptic drugs ........................................................................................................................... 2

2.1. Benzodiazepines.............................................................................................................................. 2

2.2. Carbamazepine ............................................................................................................................... 2

2.3. CBZ and BMD ................................................................................................................................. 2

2.4. CBZ and bone metabolism.................................................................................................................... 3

2.5. Phenytoin ..................................................................................................................................... 3

2.6. Phenobarbital................................................................................................................................. 4

2.7. Primidone..................................................................................................................................... 4

2.8. Valproic acid .................................................................................................................................. 5

2.9. VPA and BMD ................................................................................................................................. 5

2.10. VPA and bone metabolism .................................................................................................................. 5

3. Newer AEDs .......................................................................................................................................... 6

3.1. Gabapentin ................................................................................................................................... 6

3.2. Lamotrigine ................................................................................................................................... 6

3.3. Levetiracetam................................................................................................................................. 7

3.4. Oxcarbazepine ................................................................................................................................7

3.5. Topiramate ................................................................................................................................... 7

3.6. Zonisamide ................................................................................................................................... 7

4. Conclusion............................................................................................................................................ 8

References ........................................................................................................................................... 8

∗Corresponding author at: Department of Pediatrics, University of Chieti, Poli-

clinico Universitario, Colle dell’Ara Via dei Vestini 5, 66100 Chieti, Italy. Tel.: +39

0871 358015; fax: +39 0871 574831.

E-mail address: averrott@unich.it (A. Verrotti).

doi:10.1016/j.clineuro.2009.10.011

2A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10

1. Introduction

The adverse effects of antiepileptic drugs (AEDs) on bone health

were ﬁrst reported nearly four decades ago, and, since then, a grow-

ing body of literature indicates that patients taking AEDs are at

increased risk for low bone mineral density and metabolic bone dis-

ease including changes in bone turnover, osteoporosis, alterations

in bone quality, and, most importantly, fracture.

First of all, it can be useful to focus on the basic bone physiology.

Maintenance of optimal bone health depends on an adequate sup-

ply of calcium and on the effects of some hormones. Parathyroid

hormone (PTH) is a peptide hormone that can alter serum calcium

via actions on three target organs: bone, intestinal mucosa and

kidney. PTH increases bone turnover and causes loss of calcium

from bone through increases in osteoclast number and activ-

ity. This hormone also increases intestinal calcium absorption

and acts in the kidney on the distal tubule to promote calcium

reabsorption and on the proximal tubule to decrease phosphate

absorption.

Vitamin D is metabolized in the liver to 25-hydroxyvitamin

D (25OHD), which is in turn metabolized in the kidney to 1,25-

dihydroxyvitamin D (1,25-(OH)2D), the biologically active form.

Drugs that increase liver hydroxylases can reduce the amount of

25OHD. 1,25-(OH)2D synthesis is stimulated by hypocalcemia, PTH

and hypophosphataemia. Vitamin D stimulates intestinal calcium

absorption and promotes mineralization of the skeleton.

Bone remodeling is a lifelong process by which skeleton is being

continuously resorbed and replaced to maintain skeletal integrity;

serum markers of bone formation are serum bone speciﬁc alkaline

phosphatase (bALP), osteocalcin (OC), carboxy-terminal propep-

tide of type I procollagen (PICP), amino-terminal propeptide of type

III procollagen (PIIINP), and markers of bone resorption are serum

carboxy-terminal telopeptide of type 1 collagen (ICTP) and urinary

N-telopeptide of type 1 collagen bone (NTx).

Several studies which assessed bone metabolism status and

bone mineral density (BMD) in adults and children on AEDs have

shown rather controversial results.

This review analyzes the main data of literature in order to sum-

marize the principal side adverse effects on bone induced by the

most frequently used AEDs.

2. Classic antiepileptic drugs

2.1. Benzodiazepines

The most common benzodiazepines (BZP) used are clonazepam,

diazepam and lorazepam. These are distinct allosteric binding

sites on the GABAa receptor chloride ionophore to enhance GABA-

mediated increases in chloride conductances [1–3].

Some studies have demonstrated a limited increase in the risk

of fractures, even at very low doses, for several types of BZPs. There

was a trend toward increasing fracture risk with increasing dose

[8–10], especially in the spine [8]. Also, a trend toward higher frac-

ture risk was seen with increasing half-life of the drugs. BZPs with

a shorter half-life may thus be preferred to reduce the risk of frac-

tures, but it should be noted that lower half-life may not completely

abolish the increased risk of fractures, although the relative risk is

rather limited [9].

A few studies investigate effects of BZP on bone metabolism.

Kulak et al. evaluating 58 young adults with epilepsy on chronic

AEDs therapy, have demonstrated signiﬁcant abnormalities of bone

metabolism, characterized by reduced BMD, reduced 25OHD and

increased alkaline phosphatase (ALP). Mean results of routine

biochemical testing, such as total calcium (Ca), phosphorus (P),

magnesium and PTH, were normal and did not differ statistically

[4]. Similarly, Farhat et al. have determined the effect of AED on

vitamin D levels and bone density in ambulatory patients and to

compare the effects of enzyme-inducing and noninducing AED

(such clonazepam) of single vs. multiple therapy on bone density.

No signiﬁcant difference in 25OHD levels was observed between

patients on enzyme-inducing and noninducing AED. In this study

a signiﬁcant proportion (>50%) of patients in both age groups had

low 25OHD levels and low BMD in adults of both sexes, indepen-

dent of vitamin D levels [5]. In contrast, in another study, BZPs did

not seem to have an effect on BMD [6] and thus did not induce

the modest increase in fracture risk observed in a prior study [7].In

conclusion, BZP can adversely affect bone health with a consequent

risk of fractures.

2.2. Carbamazepine

Carbamazepine (CBZ) is one of the front line AEDs for treat-

ment of partial seizures as well as secondary generalized seizures in

adults and children. It mainly acts on voltage-gated sodium chan-

nels that are stabilized in their inactivated state [11,12].

2.3. CBZ and BMD

Several studies on adults and children have shown that CBZ

treatment induces a state of decreased BMD in the lumbar spine

[5,13–19], femoral neck [5,19–21], forearm [19,22] and calcaneus

[23], but there have been some conﬂicting results, especially in

children.

Two recent studies by Kumandas et al. [15] and Kim et al. [23]

showed that the decrease in BMD was related to reduced levels of

vitamin D secondary to the property of the drug to activate spe-

ciﬁc cytochrome P450 (CYP-450) isoenzymes, which are involved

in vitamin D catabolism [24].

The work by Kumandas et al. was a cross-sectional, retrospective

study that examined the effects of at least 2 years of CBZ therapy

on bone mineral density in 33 preadolescent patients. They showed

that these patients had reduced BMD in the lumbar spine [15].

The report by Kim et al. was a longitudinal study that showed

a signiﬁcant reduction in BMD in the right calcaneus in 10 adult

patients after 6 months of CBZ monotherapy [23]. In both studies,

reduced BMD was associated with lower levels of 25(OH)D.

In contrast, 6 other cross-sectional studies [5,14,16,19,20,25]

and 2 longitudinal studies [13,21] have demonstrated a lack of

correlation between serum levels of vitamin D and reduced BMD,

suggesting that the loss of bone mass observed in patients treated

with CBZ may not be explained by an effect of drug on vitamin D

metabolism. Rather, it may be due at least in part to direct effects of

CBZ on bone cell proliferation, leading to reduced growth of human

bone cells [20,26]. Among these studies, the largest and most recent

was a study by El-Hajj Fuleihan et al. [19], who studied 225 ambu-

latory patients (137 adults and 88 children) treated with different

AEDs, including CBZ monotherapy. The results indicated that the

adult patients on enzyme-inducing drugs such as CBZ tended to

have lower BMD in the lumbar spine and total hip compared to

those on noninducers; BMD was negatively correlated with the

duration of treatment in adults and with polytherapy in children.

In agreement with these results, 2 previous studies [5,20]

demonstrated that the duration of CBZ therapy is an independent

predictor of BMD in adults.

Gender differences in the effects of CBZ on bone mineral density

have been analyzed. In several studies, the effect was more marked

in female patients [27–29]. In contrast, 2 studies [14,21] showed

that the incidence of osteopenia was signiﬁcantly greater in males

than in females. Other studies did not show a sex-related difference

[13,19,23].

A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10 3

We must underline that some studies have not shown a sig-

niﬁcant effect of CBZ monotherapy on bone mineral density

[28,30–33].

In conclusion, most evidence has shown that long-term treat-

ment with CBZ has a negative effect on BMD, which may be

a contributing factor to the increased fracture risk observed in

patients with epilepsy, postmenopausal women and older men, and

which may accelerate aging-related osteoporosis [8,34]. Therefore,

BMD screening with dual-energy X-ray absorptiometry (DEXA),

with intervals varying depending on the fracture risk of the indi-

vidual patient, is recommended.

2.4. CBZ and bone metabolism

Different biochemical alterations of bone metabolism have

been reported in association with CBZ treatment, both in adults

[5,20,23,35,36] and in children [15,31,37–39].

These alterations include reduced serum levels of biologically

active vitamin D metabolites, hyperparathyroidism and elevated

levels of markers of bone turnover, such as markers of bone forma-

tion and bone resorption. Serum levels of Ca and P were normal in

most of the studies.

Low levels of biologically active vitamin D in patients on CBZ

have been demonstrated in many [23,15,40,35,38,19,41], but not

in all [13,24,31,37,42–44] studies. This effect has been attributed

to changes in metabolism of vitamin D thought CYP-450 in the

liver [45,46]. Vitamin D deﬁciency associated with the use of CBZ

is likely mediated through the orphan nuclear receptor pregnane

X receptor (PXR), which can increase the expression of the CYP-

24. This enzyme catalyzes the conversion of 25OHD to its inactive

metabolite (calcitroic acid) [47]. This hypothesis is supported by the

recent cross-sectional, retrospective study by Kumandas et al. [15],

who found signiﬁcantly decreased lumbar BMD and serum levels

of 25OHD in a group of children who had received CBZ therapy for

at least 2 years. Furthermore, these patients had serum ALP and

PTH levels signiﬁcantly higher than those of the control groups. L1-

4BMDz-scores were negatively correlated with serum PTH levels

and positively correlated with serum levels of 25OH-vitamin D. In

this and other studies [13–16,23,42,43], no signiﬁcant alterations

in serum levels of Ca and P were observed.

Recently, an increase in the markers of bone turnover correlated

with use of CBZ has been demonstrated in a number of small studies

[15,16,29,31,35,39,48,49], and this increase has even been seen in

the presence of normal vitamin D and PTH levels [42,43]. Increased

bone turnover may be an important contributing mechanism for

bone disease in epileptic patients [20]. It is known that AEDs such

as CBZ, which induce P-450 enzymes, can accelerate vitamin D

catabolism. This acceleration could lead to decreased absorption

of Ca in the gut. The onset of an intermittent hypocalcemia could

result in compensatory hyperparathyroidism and consequently

increase bone turnover and loss of cortical bone. In severe cases,

this could lead to long-term loss of bone mass [50]. This hypoth-

esis is consistent with some studies [35,39], but not with others

[13,24,29,42,43].

Currently, few studies have evaluated effects of AEDs on bone

metabolism by concurrently measuring the markers of bone for-

mation and resorption. We previously reported the results of a

prospective longitudinal study of bone mineral status in epileptic

patients before and after treatment with CBZ [42]. We found higher

values of serum markers of bone formation such as bALP, OC, PICP,

PIIINP, and markers of bone resorption such as ICTP and NTx in

patients than in controls. CBZ treatment increases bone turnover,

and these changes are independent of the serum levels of vitamin

D metabolites and PTH.

More recently, we showed that markers of bone formation

were signiﬁcantly higher in male than in female patients; on

the contrary, serum levels of ICTP were signiﬁcantly higher in

female patients [43]. These data are in agreement with a previous

study by Välimäki et al. [29], who suggested that these differences

may be partly explained by lower serum 1,25-dihydroxyvitamin

D (1,25-(OH)2D) levels found in their female patients treated with

CBZ.

Four other studies carried out on ambulatory epileptic chil-

dren [16,31,39,49] showed an increase of bALP, which is a marker

that is considered to be highly sensitive and speciﬁc to increased

bone turnover [51]. In particular, a recent longitudinal study [39]

showed that epileptic patients using CBZ monotherapy had their

metabolism altered early, as indicated by the elevated activities of

serum bALP isoenzyme after 3 months of treatment, because this

effect was independent of the length of therapy.

In conclusion, CBZ cause decreased serum levels of 25OHD,

secondary hyperparathyroidism and increased bone turnover. The

mechanisms by which CBZ determines such alterations of bone

metabolism may be multiple: increased catabolism of vitamin D, a

direct effect on function of bone cells [20] and direct inhibition of

intestinal calcium transport through a mechanism not mediated by

vitamin D [52]. Therefore, regular screening for hypovitaminosis

and monitoring of biochemical markers of bone turnover during

the treatment period are advisable. Additionally, prophylaxis with

calcium supplements and the use of vitamin D supplementation

could be considered for all patients with epilepsy upon initiation

of CBZ therapy.

2.5. Phenytoin

Phenytoin (PHT) was introduced for the treatment of epilepsy

in 1938 by Merritt and Putnam [53].

This drug plays a major role in altering sodium ion movements

across nerve cell membranes [54,55] and is indicated for treat-

ing generalized tonic–clonic seizures [56,57] and status epilepticus

[58,59].

Cross-sectional studies in adults have shown that epileptic

patients treated with PHT experience reduced BMD at the lumbar

spine [5,27,29,7], femur [5,17,20,27,29,7] and hip [5].

Among these reports, the most recent is a longitudinal study by

Pack et al. [17]. In this study, the authors reported reduced BMD

in their patients that was not related to the duration of therapy.

These results are in agreement with 2 previous studies [27,29].In

contrast, 2 other studies showed a signiﬁcant negative correlation

between duration of phenytoin use and BMD [5,20].

Multiple biochemical abnormalities of bone metabolism have

been reported in association with PHT treatment.

Several studies reported hypocalcemia and hypophosphatemia

[36,40,60–66]; hepatic induction of the CYP-450 enzyme system,

leading to increased catabolism of vitamin D is the principal mech-

anism reported [47,67]. Indeed, many reports revealed reduced

levels of serum 25OHD in both adults and children taking PHT

[5,17,20,29,7,61,68]. Evidence also exists for inhibition of the cel-

lular response to PTH, caused by the inhibitory effect of PHT on

hormone-sensitive adenylate cyclase activity [69,70]. Fetal rats

treated with PHT demonstrated an impaired osteoblastic response

to PTH [71].

It has also been shown that PHT interferes with cation trans-

port in many tissues, thereby directly inhibiting intestinal calcium

absorption in rats [72]. This effect might also exist in humans, and

it would lead to lower Ca levels in serum, a frequent ﬁnding in

patients taking PHT.

In addition, elevated levels of markers of bone turnover are

found in the serum, such as markers of bone formation and

bone resorption [17,20,29,61,73,74]. One of the mechanisms that

may determine the amount of bone turnover is secondary hyper-

parathyroidism, which activates bone resorption and secondarily,

4A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10

through the coupling phenomenon, bone formation. This hypoth-

esis is supported by the results of Pack et al. [17], who reported

that epileptic patients treated with PHT had lower serum concen-

trations of 25OHD. This is associated with a biochemical pattern

consistent with hyperparathyroidism that includes higher PTH,

bALP, and urine NTx. In a bone biopsy study [75], osteomalacia was

found in 53% of patients, along with evidence of increased bone

resorption (secondary hyperparathyroidism).

Primary hyperparathyroidism has also been suggested as a pos-

sible mechanism because male patients with normal vitamin D

status had evidence of elevated levels of PTH [29]; hyperparathy-

roidism can primarily activate bone resorption.

However, direct action of PHT on bone resorption and bone

formation has also been suggested [61]. The latter hypothesis is

supported by animal studies [71,76] and experiments on human

osteoblast-like bone cells [20], where PHT has been demonstrated

to inhibit the proliferation of human osteoblast-like cells at con-

centrations equal to therapeutic doses. Signiﬁcant bone resorption

was found in the calvaria of neonatal mice treated with PHT, as

demonstrated by signiﬁcantly increased calcium in the medium as

compared with controls [76]. These results suggest that both bone

resorption and formation may be affected by PHT.

A ﬁnal postulated mechanism of increased bone turnover is cal-

citonin deﬁciency. Animal studies suggest a direct inhibitory effect

of PHT on calcitonin secretion [77,78]. This deﬁciency has been

demonstrated both in vitro and in vivo [79–81].

Additionally, PHT can cause an increase in vitamin K

metabolism, resulting in deﬁciency [26]. Vitamin K is an essential

cofactor for post-translational carboxylation of glutamine residues

on ␥-carboxylase (Gla)-containing proteins, including osteocalcin.

Gla proteins play an important role in the structure and function of

the skeleton. Thus, inducing deﬁciency in Gla proteins can poten-

tially cause alterations in bone structure, resulting in osteopenia

and fractures [78].

In conclusion, PHT can be associated with adverse effects on

bone mineralization and an increased risk of fractures, especially

in postmenopausal women and older men [8,34]. Therefore, moni-

toring of BMD by DEXA is recommended for patients at high risk for

fracture. PHT can induce several abnormalities in bone metabolism

including hypocalcemia, hypophosphatemia, reduced serum levels

of biologically active vitamin D metabolites, hyperparathyroidism

and elevated levels of markers of bone turnover.

These ﬁndings suggest that prophylactic therapy with vitamin

D given beginning in the earliest phases of anticonvulsant therapy

could prevent the possible development of bone disease.

2.6. Phenobarbital

Phenobarbital (PB) is an effective anticonvulsant for many kinds

of seizures such as tonic–clonic and focal seizures, and certain clin-

ical epilepsy sub-syndromes [82].

Like other barbiturates, PB enhances ␥-aminobutyric acid

(GABA)-mediated increases in chloride conductance by prolonging

the duration of channel opening [83].

Studies performed during the early 1970s provided the ﬁrst sug-

gestion of the adverse effects of PB on bone with consequent high

risk of fractures [84–87].

These studies showed that PB was involved in causing rick-

ets, which was the result of a decrease in vitamin D levels due to

the CYP-450 enzyme-inducing properties of this antiepileptic drug.

These changes led to impaired intestinal calcium transport result-

ing in hypocalcemia, and increased PTH levels mobilized Ca from

bone. Consequently, bone mineralization was reduced.

More recent studies also show that PB causes induction of

hepatic microsomal enzymes, resulting in increased catabolism of

25OHD and the classic bone changes of osteomalacia [4,88].

Abnormalities in Ca and bone metabolism can also be associated

with direct inhibition of intestinal calcium absorption [86].

Several studies evaluating vitamin D levels in ambulatory

patients produced conﬂicting results [5,74,89–93].

Mosekilde et al. showed that chronic PB therapy was associated

with a mild degree of osteomalacia, which was inversely correlated

with dietary vitamin D intake. Serum 25-hydroxycholecalciferol

(25-HCC) was reduced in epileptic patients compared with a con-

trol group, and this reduction was positively correlated with dietary

vitamin D intake but not with the severity of bone changes, indicat-

ing that factors other than circulating 25-HCC are responsible for

the development of anticonvulsant osteomalacia [89]. In contrast,

Weinstein et al. demonstrated that hypocalcemia and osteopenia

occurred in spite of normal mean levels of serum 25OHD and 1,25-

(OH)2D. The indirect relationship between serum concentrations

of antiepileptic drug and the serum ionized Ca level, and the lack

of correlation with vitamin D metabolite levels, suggested that

hypocalcemia was independent of the effect of the drug on vitamin

D metabolism. Bone biopsies revealed increased osteoid but nor-

mal calciﬁcation front formation, accelerated mineralization rate,

and decreased mineralization lag time, which were indicative of

increased skeletal turnover rather than osteomalacia [90].Inthe

same way, Farhat et al. found that over 50% of adults and chil-

dren/adolescents receiving long-term PB therapy had low 25OHD

levels, but these levels did not correlate with BMD [5]. In par-

ticular, Gissel et al. have observed that BMD reduction is more

evident only among those who had used PB for more than 2 years

[93].

Aysegül et al. evaluated differences in markers of bone forma-

tion and bone resorption between control patients and epileptic

patients receiving chronic anticonvulsant therapy. They found that

only the resorption phase of bone turnover is affected by chronic

administration of PB [94].

bALP isoenzyme levels are found to be higher in children receiv-

ing antiepileptic drugs such as PB. Therefore, Voudris et al. suggest

that the bALP isoenzyme could be used as a marker to monitor bone

metabolism [49].

Moreover, in a recent trial, a laboratorial evaluation of bone and

mineral metabolism, including measurements of bALP and ICTP,

showed an increase of ICTP in patients treated with PB compared

to those not receiving this drug. This increase led to a reduction of

BMD, as measured by DEXA [95].

Finally, in a recent cross-sectional study of 130 epileptic patients

treated with PB, BMD was measured by DEXA and a decrease in

bone mineralization was also found [96].

In conclusion, a down-regulation of 25-hydroxylation in

patients receiving long-term PB therapy may be responsible

for an increased risk of osteomalacia, bone loss and fractures

[8,88], despite no reported alteration in calcium and phosphorus

metabolism [13,49,97].

Therefore, vitamin D supplementation should be used routinely.

2.7. Primidone

Primidone (PRM), classiﬁed as an enzyme-inducing antiepilep-

tic drug, was ﬁrst synthesized and used as an anticonvulsant in

1952 [98].

It is a desoxyphenobarbital differing from PB in the absence of

the carbonyl group in position 2 of the pyrimidine ring. Thus, it is

not a true barbiturate but clinically it is considered to be in that

group [99].

The likelihood of fractures seems to be minimal, although sev-

eral studies have shown that PRM, such as PHT and PB, affects bone

and mineral metabolism indirectly since the induction of CYP-450

increases vitamin D metabolism, thereby causing vitamin D insuf-

ﬁciency or deﬁciency [6,73,100,101].

A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10 5

Another mechanism involves direct action on bone cells, thereby

increasing bone resorption and formation. In this way, PRM may

inﬂuence bone turnover [29,43,74].

Both mechanisms can be associated with a reduction in BMD

[6,21,30,74].

In contrast, Filardi et al. led a study to assess BMD and vitamin D

metabolism in patients receiving chronic anticonvulsant therapy,

including PRM therapy, and did not ﬁnd any signiﬁcant differences

between patients and controls [97].

Despite the introduction of several newer drugs for the treat-

ment of epilepsy, primidone is still a drug that should be considered

in certain patients [99].

2.8. Valproic acid

Valproic acid (VPA) is a broad-spectrum antiepileptic drug that

has been in use as a ﬁrst line agent for both generalized and partial

seizures [102,103]. VPA blocks voltage-dependent sodium chan-

nels and modiﬁes calcium and potassium conductance [104,105].

Administration of VPA increases the activity of the GABA-synthetic

enzyme glutamic acid decarboxylase and acts as an inhibitor of

GABA transaminase [106].

2.9. VPA and BMD

Some studies of VPA therapy in children and adults found no dif-

ferences in mean BMD values at both the femur neck and lumbar

spine [13,17,23,31,33,36], while many authors noticed a signiﬁ-

cant reduction of BMD in epileptic patients who used VPA for a

prolonged period [15,16,18,21,28,74,107]. In particular, studies in

epileptic children found a lower BMD compared with matched con-

trols at multiple sites including the femoral neck, radius and lumbar

spine [5,15,16,108–110]. Similar results have been described in

adults [107,111]. One study carried out by Farhat et al. [8] found

that in adults, BMD at all skeletal sites was lower compared with

young adults; in children, BMD was lower in the spine but higher

in the total body. Among these studies, Sheth et al. [18] measured

axial (second, third, and fourth lumbar vertebrae) and appendic-

ular (distal third of radius) BMD in children with uncomplicated

idiopathic epilepsy who had been treated with VPA for more than

18 months. After correction for gender and age, children treated

with VPA had a 14% and 10% reduction in BMD at the axial and

appendicular sites, respectively, and showed a possible increase

in their risk of osteoporotic fractures. In this study, the reduction

in BMD increased with the duration of VPA therapy. In another

study [37], children receiving VPA monotherapy had a mean BMD

reduction of 31.9% at the femoral neck region compared with the

untreated group. The patients had been receiving VPA monother-

apy for more than 6 months. Thus, decreased BMD was observed

in children with epilepsy who had been treated with VPA, even

though treatment was for a rather short time [28,37]. In one study,

children with epilepsy who had been receiving VPA and/or LTG

therapy for more than 2 years had overall reduced stature, low bone

mass, and reduced bone formation; these outcome measures were

particularly compromised in those children whose physical activ-

ity was low and who received a combined therapy of VPA and LTG

[112]. In conclusion, long-term antiepileptic treatment with VPA

may cause osteopenia in both sexes [5,14,16,74,108,111]. A very

limited increased fracture risk for osteoporotic-related trauma can

be present in users of VPA [37].

2.10. VPA and bone metabolism

Reports of abnormalities in Ca and P associated with VPA use

are controversial and difﬁcult to interpret because of widely vary-

ing study designs [108]. Ca and P concentrations are essential

components of bone metabolism. In most studies, there were no

statistically signiﬁcant differences between groups in the mean

values of Ca and P. None of the patients had hypocalcemia or

hypophosphatemia [15,16,23,28,33,38]; similarly, ratios of uri-

nary Ca to serum creatinine, and urinary P to serum creatinine

stayed within normal ranges [15]. On the other hand, some

studies found results suggesting that serum Ca concentrations

can be signiﬁcantly lower in subjects receiving VPA [13,14,36].

Furthermore, Ecevit et al. [37] compared healthy subjects and

patients receiving VPA therapy, and in the VPA-treated group,

one-fourth of the patients manifested hypocalcaemia and half of

the patients manifested hypophosphatemia. Tsukahara et al. [14]

found that one patient was hypercalciuric (deﬁned as urinary

Ca > 0.21mg/mg Cr). Tubular resorption of P was within the normal

range. Hypercalciuria is at present best explained by an imbal-

ance of Ca intake and mineral deposition during skeletal growth

[14].

Serum 25OHD concentration is the most commonly used index

of vitamin D status. In patients receiving VPA therapy, biologi-

cally active vitamin D levels within the normal range have been

demonstrated in a number of studies [14,16,17,21,23,36,109,111].

Conversely, in a cross-sectional evaluation conducted on 71

patients (adults and children) who had received anticonvulsant

therapy for at least 6 months, the mean 25OHD level was in the

insufﬁcient range. Over one-half of the children in the study had

low vitamin D levels [12]. Furthermore, Tekgul et al. and Nico-

laidou et al. [13,38] noticed a decreasing trend in all seasons in

serum 25OHD concentrations from class 0 (before any anticonvul-

sant therapy) to class 3 (third year of therapy) patients receiving

VPA monotherapy. In many studies, serum levels of intact PTH were

within the normal ranges [13,14,16,17,31,36,109,111,112].Inone

study, compared with reference values, plasma intact PTH was in

the lower limits [14]. In contrast with those results, a few studies

have shown markedly increased PTH levels [15,23,38]. Increases

in serum levels of total ALP have been reported in several studies.

Babayigit et al. studied healthy children and children with idio-

pathic epilepsy who had been treated with VPA for more than

1 year. They found that mean serum ALP concentration was sig-

niﬁcantly higher in the treated patient group as compared to the

control subjects [16]. Similar ALP values were seen in other studies

[28,31,109]. Voudris et al. reported an increase in bALP isoenzyme

values that correlated with the duration of treatment in children

receiving VPA, without a concomitant signiﬁcant elevation of total

ALP values. This result suggests that VPA administration does have

an impact on bone mineral metabolism in ambulatory children

and that normal total ALP levels could not exclude the possibil-

ity that the respective bone fraction may be high. This isoenzyme,

but not total ALP values, could therefore be used as a marker for

the selection of patients who could beneﬁt from an evaluation of

their bone metabolism proﬁle [49]. In contrast with those results,

Elliott et al. [107] found lower serum ALP. Also, serum ALP was neg-

atively correlated with serum homocysteine in patients receiving

VPA.

OC is a noncollagenous protein synthesized by osteoblasts and

is speciﬁc for bone and dentin. In two studies, the OC levels

of the patient group were signiﬁcantly higher than the control

group [23,74,108]. Another study demonstrated OC levels at the

upper limits of the normal range [31]. In contrast, Tsukahara et

al. have shown lower values of intact OC [14,109], PICP and ICTP

in pediatric patients receiving long-term VPA monotherapy [14].

Similarly, Song et al. [110] stated that serum OC in children who

took VPA was lower relative to normal control patients. Urine val-

ues of deoxypyridinoline showed no signiﬁcant difference between

epileptic and healthy children [23,110]. Sato et al. [74] noticed that

ICTP, a bone resorption marker, signiﬁcantly exceeded control val-

ues. They also reported that high ICTP was positively correlated

6A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10

with ionized Ca. In this case, they indicated that the rate of resorp-

tion may be more than that of formation, thus leading to a reduction

in bone density.

Recently, Kumandas et al. [15] investigated the effect of VPA

and CBZ monotherapies on insulin-like growth factor (IGF)-1 and

IGF binding protein (IGFBP)-3 levels, which are known to affect

bone metabolism and BMD. There were no differences in the serum

concentrations of IGF-1 and IGFBP-3 between the patients taking

antiepileptic drugs and control children.

Long-term use of VPA is associated with bone metabolism

abnormalities, which include reduced BMD and changes in bone

turnover. VPA displayed a dose–response relation. However, a

recent study found that subjects receiving VPA monotherapy had

less negative effects on bone markers and improved bone density

compared to those receiving PHT or CBZ monotherapy [107]. The

effect of VPA cannot be readily explained by vitamin D metabolism,

since VPA is not an inducer of the CYP-450 system; it is instead

thought to act by stimulating osteoclast activity and may cause an

imbalance between bone formation and resorption, thereby con-

tributing to bone loss [74].

Finally, in an experimental study, oral administration of VPA to

epileptic rats for 6 months resulted in a signiﬁcant increase of bALP,

OC and NTx relative to the control group. There were increases in

receptor activator of NFkB ligand (RANKL) and TNF-␣, and there

was a decrease in osteoprotegrin compared with normal controls.

The authors postulated that the increase in bone formation markers

was caused by increased osteoblast number or activity in order to

compensate for increased osteoclastic activity. The high turnover

state may be also caused by the increase in PTH caused by VPA [113].

Effects of VPA on bone may occur as a result of this agent’s effect on

IGF-I, as suggested by Rattya et al. The mechanism remains to be

more robustly deﬁned. However, a recent study found that subjects

receiving VPA monotherapy had fewer negative effects on bone

markers and improved bone density compared to those receiving

phenytoin and CBZ monotherapy [107].

In conclusion, long-term antiepileptic drug treatment with VPA

has detectable adverse effects on bone turnover and induces a state

of decreased BMD. Therefore, routine monitoring of BMD and bio-

chemical markers of bone turnover are warranted.

3. Newer AEDs

3.1. Gabapentin

Gabapentin (GBP) was formed by adding a cyclohexyl group

to GABA, which allowed it to cross the blood–brain barrier [114].

Despite its structure, GBP does not bind to GABA receptors in the

central nervous system [115]. It appears to have an inhibitory effect

on voltage-gated calcium channels containing the alpha 2-delta

subunit [116,117]. It is not metabolized, and it does not induce

or inhibit hepatic enzymes [118]. GBP, in clinical use since 1993,

is indicated as an adjunctive AED for treatment of partial seizure,

with or without secondary generalization, in patients over 12 years

of age [119]. Side effects of GBP are generally mild and transient

[120]; adverse effects on sexual function [121] and weight gain

[122] are reported at higher doses.

There is no study that has examined the relationship between

bone metabolism and GBP monotherapy. However, there are three

papers [5,19,21] that have studied a group of adult epileptic

patients treated with different AEDs, including GBP. From their

data, there was evidence that long-term GBP therapy may cause

bone loss at the hip and lumbar spine. More recently, Ensrud et al.

[123] conﬁrmed, in a prospective study, that this AED can cause a

signiﬁcant hip bone loss in older men, suggesting that GBP is not

free from this important adverse effect.

To date, no changes in biochemical parameters of bone

metabolism have been associated with GBP treatment.

3.2. Lamotrigine

The principal mechanism of action of lamotrigine (LTG) appears

to involve inhibition of voltage-activated sodium channels, result-

ing in increased inhibition of action potential-ﬁring activity [124].

LTG also inhibits high voltage-activated calcium channels that are

located presynaptically, and consequently it inhibits the release of

neurotransmitters such as glutamate [125].

LTG is used in monotherapy or as an add-on treatment for refrac-

tory partial [126] and generalized epilepsies [127–129].

There are no data about a direct association between LTG and

fractures but some studies have assessed LTG in relation to its effect

on BMD [23,24,130,111].

Sheth and Hermann [130] examined the effects of LTG

monotherapy on 13 children by measuring total z-scores of BMD.

The patients were compared with 40 patients receiving polyther-

apy, as well as 36 control subjects. They showed that the z-scores

for BMD for LTG and control subjects were similar and were higher

than for those receiving polytherapy. Furthermore, increased dura-

tion of therapy was a predictor of lowered bone mineral density for

polytherapy, but not for lamotrigine monotherapy. These ﬁndings

suggest that LTG is not a drug that alters bone mineralization during

childhood.

A recent longitudinal study of premenopausal women with

epilepsy receiving AED monotherapy compared a group of 23

patients receiving LTG treatment with a group of 15 patients taking

PHT [24]. All enrolled subjects were between 18 and 40 years old

and were receiving a single AED at least 6 months before enroll-

ment; after 1 year of observation, the BMD of the proximal femur

and lumbar spine was measured. There was signiﬁcant femoral

neck bone loss over 1 year in the group that received PHT. In con-

trast, patients treated with LTG did not lose bone mass at any

site.

Interestingly, Guo et al. [112] reported that LTG and/or VPA

therapy lasting more than 2 years was associated with low total

body BMD, reduced bone formation (reduced plasma OC) and short

stature in children with epilepsy aged 3–17. In fact, these anoma-

lies were more evident in those children who had lower physical

activity and were receiving a combined therapy (VPA and LTG).

The authors concluded by afﬁrming that the observed abnormali-

ties were related to reduced physical activity rather than the direct

effect of drug therapy, because patients who had the need for com-

bination therapy were also those who had more severe seizures

and, consequently, reduced physical activity.

Currently, there are few studies that have assessed markers of

bone metabolism in epileptic patients receiving LTG monotherapy.

Using a cross-sectional study, Pack et al. [36] studied 19 women

with epilepsy who received LTG monotherapy for an average

period of 21 months. They measured indices of mineral metabolism

(25OHD, PTH, Ca, IGF-I, and IGFBP-III), markers of bone forma-

tion (bALP, OC) and urinary NTx, a bone resorption marker. This

study demonstrated that premenopausal women receiving LTG

monotherapy had no signiﬁcant reductions in Ca and 25OHD or

increased bone turnover. These ﬁndings are in agreement with

those reported by a previous study by Stephen et al. [27].

A recent longitudinal study [23] prospectively evaluated the

alterations in BMD and biochemical markers of bone metabolism

in 8 patients with newly diagnosed epilepsy, aged between 18 and

50, before and after 6 months of LTG monotherapy. In this study,

there were no abnormalities in BMD, Ca, P, vitamin D or urinary

Pyrilinks both before and after 6 months of LTG treatment. Instead,

PTH and OC levels increased. The authors suggested that LTG may

affect bone metabolism, inducing the development of resistance to

A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10 7

PTH, but this drug can compensate for bone loss by increasing bone

formation.

In summary, the data now available indicate that LTG monother-

apy does not lead to osteopenic effects or signiﬁcant alterations in

bone metabolism.

3.3. Levetiracetam

Levetiracetam (LEV) is an enantiomer of the ethyl analog of

piracetam that has the ability to facilitate cholinergic transmission

[131]. LEV seems to have several modes of action, such as sup-

pression of negative allosteric modulators of neuronal GABA- and

glycine-gated currents [132], inhibition of voltage-gated calcium

channels [133], reduction of voltage-operated potassium currents

[134] and binding to synaptic vesicle protein 2A (SV2A) [135].It

has been proven effective in treatment-resistant partial seizures in

adults [136]. LEV is safe and well tolerated, but has been scarcely

studied. A study carried out by Nissen-Meyer et al. [137] evalu-

ated the effect of AEDs on bone mass, biomechanical strength and

bone turnover in rats. LEV did not affect BMC or BMD at either

low or high dose. In the femoral neck, predominantly trabecular

bone, low-dose LEV signiﬁcantly decreased bone biomechanical

strength parameters. However, high-dose LEV treatment seemed to

affect these parameters of bone strength to any signiﬁcant extent.

In rats treated with low-dose LEV, serum OC levels were signiﬁ-

cantly reduced relative to controls, whereas RatLaps (a resorption

marker) levels were unaltered, indicating an effect of this drug

primarily on bone formation. In contrast, neither OC nor RatLaps

levels were signiﬁcantly affected by high-dose LEV under these

experimental conditions. There were no signiﬁcant differences in

serum Ca levels induced by the different treatments compared

to controls. Ali et al. [138] studied the effects of LEV monother-

apy on BMD, vitamin D and OC levels in 16 adult patients. They

found no signiﬁcant decrease in vitamin D levels or BMD; eleva-

tion of OC levels was noted in 4 patients but all 4 had previous

prolonged exposure to other AEDs known to cause increased bone

turnover, such as PHT, CBZ and VPA. In conclusion, it remains to

be determined whether LEV does not affect BMD, but it seems to

reduce bone strength and bone formation without altering bone

mass. Based on these few results, epidemiological studies on bone

turnover in patients treated with LEV are needed, and these patients

should be evaluated regularly to identify possible bone-related side

effects.

3.4. Oxcarbazepine

Oxcarbazepine (OXC) is a new AED and is indicated for the treat-

ment of partial and secondarily generalized tonic–clonic seizures

as both a monotherapy and as part of combination therapy in adults

and children with epilepsy [139,140]. The mechanism of action of

OXC is similar to that of CBZ, with comparable efﬁcacy but supe-

rior safety, according to controlled clinical trials [141]. OXC and its

active metabolite, monohydroxy derivative (MHD), have effects on

sodium channels [142] and possibly potassium [143] and calcium

channels [144].

To date, few studies in the literature have assessed the effect

of OXC on BMD [16,145]. Babayigit et al. [16] measured BMD and

determined the changes in biochemical markers of bone miner-

alization in 14 patients with idiopathic epilepsy who had received

OXC for more than 1 year. They showed that patients had decreased

BMD and increased serum alkaline phosphatase concentrations

compared with controls. There were no signiﬁcant differences in

the serum concentration of Ca, P, PTH and 25OHD.

Recently, Cansu et al. [145] reported a slight decrease in lumbar

and femoral BMD in 8% of epilepsy patients studied after receiving

18 months of OXC monotherapy. There was no correlation between

decreased 25OHD levels and decreased BMD, although a signiﬁcant

reduction of 25OHD was found.

Mintzer et al. [35] demonstrated that OXC monotherapy induced

signiﬁcant reductions in 25OHD, with a pattern of changes in other

bone biomarkers suggestive of secondary hyperparathyroidism

such as higher PTH and bALP. This suggested that this drug had sim-

ilar effects on bone and 25OHD metabolism as CBZ. These ﬁndings

were unexpected because OXC is only a limited enzyme inducer.

An explanation could be that OXC may have some dose-dependent

CYP-450 induction property [146]; in this latter study, OXC dosage

was found to have a signiﬁcant correlation with bALP. An alterna-

tive hypothesis is that OXC may have a direct effect on osteoblast

proliferation, as has been proposed for CBZ [20].

In summary, OXC seems to be associated with reduced 25OHD

levels and elevated biomarkers that are consistent with increased

bone turnover. Because this AED has been shown to possess mech-

anisms that might affect bone, patients with osteopenia diagnosed

before the initiation of OXC therapy should be followed carefully,

especially in long-term treatment.

3.5. Topiramate

Topiramate is a sulfamate-substituted derivative of the

monosaccharide d-fructose. Although the precise mechanisms of

action are unknown, it is considered to produce its antiepilep-

tic effects primarily through enhancement of GABAergic activity,

inhibition of kainite/alfa-amino-3-hydroxy-5-methyllisoxazole-

4-proprionic acid-type glutamate receptors and inhibition of

voltage-sensitive sodium and calcium channels. It also inhibits

most of the carbonic anhydrase isozymes (except I and III). Top-

iramate as monotherapy or adjunctive therapy was effective in

reducing the frequency of seizures in patients with primary gener-

alized tonic–clonic seizures, partial seizures or seizures associated

with Lennox-Gastaust syndrome [147].

Carbonic anhydrase is a ubiquitous zinc enzyme. One isozyme

(II) catalyzes the reversible hydration of carbon dioxide to give

bicarbonate and proton ions. These proton ions provide an acidic

environment during the bone resorption phase of the bone cycle

and, thus, carbonic anhydrase is implicated in osteoclast differen-

tiation. Moreover, the majority of topiramate recipients developed

mild to moderate metabolic acidosis. As chronic metabolic acidosis

may result in an increased risk of renal calculi, osteomalacia and/or

osteoporosis.

However, it has been reported, in a double-blind, placebo-

controlled study in obese adults, that bone turnover was similar

in topiramate placebo groups during long-term exposure [148].

In conclusion topiramate seems not to be associated with bone

metabolism alterations but there is a lack of clinical information.

3.6. Zonisamide

Zonisamide is a 1,2-benzisoxazole compound with a sulfon-

amide side chain that is structurally different from other AEDs. Its

exact mechanism of action is not known; however, current experi-

mental evidence suggests that the major mechanisms of action are

the blocking of repetitive ﬁring of voltage-gated sodium channels

[149] and the reduction of T-type calcium channel currents [150].

This drug has been shown to be an effective AED in patients with

refractory partial [151,152] and generalized tonic–clonic seizures

[153,154].

Currently, there is only one study that showed that administra-

tion of zonisamide can decrease BMD signiﬁcantly [155] in epileptic

patients.

Interestingly, an animal study [156] found signiﬁcantly

decreased BMD at the tibial metaphysis and diaphysis and

increased serum pyridinoline level (PYD), a marker of bone resorp-

8A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10

Table 1

Main effects of classic and new AEDs on bone and calcium metabolism.

Drug BMD 25-OHD Ca/P PTH Bone turnover

Classic AEDs

Benzodiazepines ↓↓ NN↑bALP ↑OC ↑ICTP ↑NTx

Carbamazepine ↓↓ N↑↑bALP ↑OC ↑ICTP ↑NTx

Phenytoin ↓↓ ↓↑↑bALP ↑NTx

Phenobarbital ↓↓ N–↑bALP ↑ICTP

Primidone ↓↓ N––

Valproic acid ↓NNN↑ALP ↑OC

New AEDs

Gabapentin ↓––––

Lamotrigine N N N ? N

Levetiracetam N N N – ?

Oxcarbazepine ↓↓ N↑↑bALP

Zonisamidea↓–––↑PYD

aResults from animal studies.

tion, in rats after chronic administration of zonisamide. On the

contrary, there was no signiﬁcant alteration in OC level. These

results suggest that zonisamide may cause bone loss by accelerat-

ing bone resorption. The same study demonstrated that combined

administration of alfacalcidol with zonisamide could prevent this

bone loss.

Zonisamide has been found to inhibit carbonic anhydrase in

human erythrocytes [157]; as suggested for topiramate, we spec-

ulate that this inhibition may be a potential cause of reduction of

BMD.

4. Conclusion

The treatment of epilepsy can adversely affect bone health and

calcium metabolism. The main abnormalities induced by classic

and new AEDs are reported in Table 1. These adverse effects of the

older AEDs (PHT, PB, CBZ and VPA) have been studied in depth and

appear to have been demonstrated. The effects of the new AEDs on

bone and calcium metabolism need to be better deﬁned because

the number of studies is limited and more evidence is needed on

the safety of these new AEDs.

References

[1] Gavish M, Snyder SH. Benzodiazepine recognition sites on GABA receptors.

Nature 1980;87:651–2.

[2] MacDonald RL, Barker JL. Enhancement of GABA-mediated post-

synaptic inhibition in cultured mammalian spinal cord neurons:

a common mode of anticonvulsant action. Brain Res 1979;167:

323–36.

[3] Olsen RW. GABA–benzodiazepine–barbiturate receptor interactions. J Neu-

rochem 1981;37:1–13.

[4] Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of

antiepileptic drugs. Epilepsia 2004;45:1330–7.

[5] Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics and sedatives

and risk of fractures: effects of half-life. Calcif Tissue Int 2008;82:

34–43.

[6] Ensrud KE, Walczak TS, Blackwell T, Ensrud ER, Bowman PJ, Stone KL.

Antiepileptic drug use increases rates of bone loss in older women: a prospec-

tive study. Neurology 2004;62:2051–7.

[7] Kulak CA, Borba VZ, Bilezikian JP, Silvado CE, Paola L, Boguszewski CL. Bone

mineral density and serum levels of 25 OH vitamin D in chronic users of

antiepileptic drugs. Arq Neuropsiquiatr 2004;62:940–8.

[8] Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G.

Effects of antiepileptic drugs on bone density in ambulatory patients. Neurol-

ogy 2002;58:1348–53.

[9] Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH. Bone mineral density

in subjects using central nervous system-active medications. Am J Med

2005;118:1414.

[10] Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al.

Risk factors for hip fracture in white women. Study of Osteoporotic Fractures

Research Group. N Engl J Med 1995;332:767–73.

[11] Talwar D. Mechanisms of antiepileptic drug action. Pediatr Neurol

1990;6:289–95.

[12] Kuo CC. A common anticonvulsant binding site for phenytoin, carbamazepine,

and lamotrigine in neuronal Na+channels. Mol Pharmacol 1998;54:

712–21.

[13] Tekgul H, Serdaroglu G, Huseyinov A, Gökben S. Bone mineral status in

pediatric outpatients on antiepileptic drug monotherapy. J Child Neurol

2006;21:411–4.

[14] Tsukahara H, Kimura K, Todoroki Y, Ohshima Y, Hiraoka M, Shigematsu Y, et

al. Bone mineral status in ambulatory pediatric patients on long-term anti-

epileptic drug therapy. Pediatr Int 2002;44:247–53.

[15] Kumandas S, Koklu E, Gümüs H, Koklu S, Kurtoglu S, Karakukcu M, et al. Effect

of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-

3. J Pediatr Endocrinol Metab 2006;19:529–34.

[16] Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of

antiepileptic drugs on bone mineral density. Pediatr Neurol 2006;35:

177–81.

[17] Pack AM, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young

women with epilepsy after one year of antiepileptic drug monotherapy. Neu-

rology 2008;29:1586–93.

[18] Sheth RD, Wesolowski CA, Jacob JC, Penney S, Hobbs GR, Riggs JE, et al.

Effect of carbamazepine and valproate on bone mineral density. J Pediatr

1995;127:256–62.

[19] El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati MA. Predictors of

bone density in ambulatory patients on antiepileptic drugs. Bone 2008;43:

149–55.

[20] Feldkamp J, Becker A, Witte OW, Scharff D, Scherbaum WA. Long-term anti-

convulsant therapy leads to low bone mineral density—evidence for direct

drug effects of phenytoin and carbamazepine on human osteoblast-like cells.

Exp Clin Endocrinol Diabetes 2000;108:37–43.

[21] Andress DL, Ozuna J, Tirschwell D, Grande L, Johnson M, Jacobson AF, et

al. Antiepileptic drug-induced bone loss in young male patients who have

seizures. Arch Neurol 2002;59:781–6.

[22] Petty SJ, Paton LM, O’Brien TJ, Makovey J, Erbas B, Sambrook P, et al.

Effect of antiepileptic medication on bone mineral measures. Neurology

2005;65:1358–65.

[23] Kim SH, Lee JW, Choi KG, Chung HW, Lee HW. A 6-month longitudinal study

of bone mineral density with antiepileptic drug monotherapy. Epilepsy Behav

2007;10:291–5.

[24] Pack A. Bone health in people with epilepsy: is it impaired and what are the

risk factors? Seizure 2008;17:181–6.

[25] Chou IJ, Lin KL, Wang HS, Wang CJ. Evaluation of bone mineral density in

children receiving carbamazepine or valproate monotherapy. Acta Paediatr

Taiwan 2007;48:317–22.

[26] Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvul-

sant therapy. Epilepsy Behav 2004;5 Suppl 2:S3–15.

[27] Stephen LJ, McLellan AR, Harrison JH, Shapiro D, Dominiczak MH, Sills GJ,

et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure

1999;8:339–42.

[28] Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone min-

eral density in children between ages 6 and 12 years. Clin Pediatr (Phila)

1999;38:93–8.

[29] Välimäki MJ, Tiihonen M, Laitinen K, Tähtelä R, Kärkkäinen M, Lamberg-

Allardt C, et al. Bone mineral density measured by dual-energy X-ray

absorptiometry and novel markers of bone formation and resorp-

tion in patients on antiepileptic drugs. J Bone Miner Res 1994;9:

631–7.

[30] Pack AM, Olarte LS, Morrell MJ, Flaster E, Resor SR, Shane E. Bone mineral

density in an outpatient population receiving enzyme-inducing antiepileptic

drugs. Epilepsy Behav 2003;4:169–74.

[31] Erbayat Altay E, SerdaroÄ ¨

Ylu A. Evaluation of bone mineral metabolism in

children receiving carbamazepine and valproic acid. J Pediatr Endocrinol

Metab 2000;13:933–9.

[32] Hoikka V, Alhava EM, Karjalainen P, Keränen T, Savolainen KE, Riekkinen

P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand

1984;70:77–80.

[33] Akin R, Okutan V, Sarici U, Altunbas A, Gökc¸ ay E. Evaluation of bone

mineral density in children receiving antiepileptic drugs. Pediatr Neurol

1998;19:129–31.

[34] Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic

drugs and risk of fractures: case–control study among patients with epilepsy.

Neurology 2006;66:1318–24.

[35] Mintzer S, Boppana P, Toguri J, DeSantis A. Vitamin D levels and bone

turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilep-

sia 2006;47:510–5.

[36] Pack AM, Morrell MJ, Marcus R, Holloway L, Flaster E, Do ˜

ne S, et al. Bone mass

and turnover in women with epilepsy on antiepileptic drug monotherapy.

Ann Neurol 2005;57:252–7.

[37] Ecevit C, AydoÄ ¨

Yan A, Kavakli T, AltinÃ z S. Effect of carbamazepine

and valproate on bone mineral density. Pediatr Neurol 2004;31:

279–82.

[38] Nicolaidou P, Georgouli H, Kotsalis H, Matsinos Y, Papadopoulou A,

Fretzayas A, et al. Effects of anticonvulsant therapy on vitamin D sta-

tus in children: prospective monitoring study. J Child Neurol 2006;21:

205–9.

[39] Voudris KA, Attilakos A, Katsarou E, Garouﬁ A, Dimou S, Skardoutsou A, et

al. Early alteration in bone metabolism in epileptic children receiving carba-

mazepine monotherapy owing to the induction of hepatic drug-metabolizing

enzymes. J Child Neurol 2005;20:513–6.

[40] Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A com-

parative study of the relative inﬂuence of different anticonvulsant drugs, UV

A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10 9

exposure and diet on vitamin D and calcium metabolism in out-patients with

epilepsy.QJMed1986;59:569–77.

[41] Zerwekh JE, Homan R, Tindall R, Pak CY. Decreased serum 24,25-

dihydroxyvitamin D concentration during long-term anticonvulsant therapy

in adult epileptics. Ann Neurol 1982;12:184–6.

[42] Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic

patients treated with carbamazepine. Ann Neurol 2000;47(3):385–8.

[43] Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover

in prepubertal, pubertal, and postpubertal patients receiving carbamazepine.

Epilepsia 2002;43:1488–92.

[44] Brämswig S, Zittermann A, Berthold HK. Carbamazepine does not alter bio-

chemical parameters of bone turnover in healthy male adults. Calcif Tissue

Int 2000;73:356–60.

[45] Samaniego EA, Sheth RD. Bone consequences of epilepsy and antiepileptic

medications. Semin Pediatr Neurol 2007;14:196–200.

[46] Myllynen P, Pienimäki P, Raunio H, Vähäkangas K. Microsomal metabolism

of carbamazepine and oxcarbazepine in liver and placenta. Hum Exp Toxicol

1998;17:668–76.

[47] Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepileptic drugs and bone

metabolism. Nutr Metab 2006;3:36.

[48] Pack AM. The association between antiepileptic drugs and bone disease.

Epilepsy Curr 2003;3:91–5.

[49] Voudris K, Moustak M, Zeis PM, Dimou S, Vagiakou E, Tsagris B, et al. Alkaline

phosphatase and its isoenzyme activity for the evaluation of bone metabolism

in children receiving anticonvulsant monotherapy. Seizure 2002;11:377–80.

[50] Sheth RD. Metabolic concerns associated with antiepileptic medications. Neu-

rology 2004;63:S24–9.

[51] Looker AC, Bauer DC, Chesnut CH, Gundberg CM, Hochberg MC, Klee G, et al.

Clinical use of biochemical markers of bone remodeling: current status and

future directions. Osteoporos Int 2000;11:467–80.

[52] von Borstel Smith M, Crofoot K, Rodriguez-Proteau R, Filtz TM. Effects of

phenytoin and carbamazepine on calcium transport in Caco-2 cells. Toxicol

In Vitro 2007;21:855–62.

[53] Delorenzo RJ, Sun DA. Phenytoin and other hydantioins mechanisms of action.

In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs,

vol. 57. Philadelphia: Lippincott Williams & Wilkins Publishers; 2002. p.

551–64.

[54] Delgado-Escueta AV, Horan MP. Phenytoin: biochemical membrane studies.

Adv Neurol 1980;27:377–98.

[55] Segal MM, Douglas AF. Late sodium channel openings underlying epilepti-

form activity are preferentially diminished by the anticonvulsant phenytoin.

J Neurophysiol 1997;77:3021–34.

[56] DeLorenzo RJ. The epilepsies. In: Bradley WG, Daroff RB, Fenichel GM, Penry

JK, Glaser JH, editors. Neurology in clinical practice: principles of diagnosis

and management. 4th ed. Philadelphia: Butterworth-Heinermann; 2004.

[57] DeLorenzo RJ, Bowling AC, Taft WC. A molecular approach to the development

of anticonvulsants. Ann N Acad Sci 1986;477:238–46.

[58] DeLorenzo RJ. Status epilepticus: concepts in diagnosis and treatment. Semin

Neurol 1990;10:396–405.

[59] DeLorenzo RJ. Regulation of neuronal excitability: molecular foundations for

the study of alcohol withdrawal. In: Porter RJ, Mattson RH, Cramer JA, Taft

WC, Glaser GH, editors. Alcohol and seizures basic mechanism and clinical

concepts. Philadelphia: FA Davis; 1990. p. 47–54.

[60] Telci A, Cakatay U, Kurt BB, Kayali R, Sivas A, Akcay T, et al. Changes in bone

turnover and deoxypyridinoline levels in epileptic patients. Clin Chem Lab

Med 2000;38:47–50.

[61] Lau KH, Nakade O, Barr B, Taylor AK, Houchin K, Baylink DJ. Phenytoin

increases markers of osteogenesis for the human species in vitro and in vivo.

J Clin Endocrinol Metab 1995;80:2347–53.

[62] Richens A, Rowe DJ. Disturbance of calcium metabolism by anticonvulsant

drugs. Br Med J 1970;4:73–6.

[63] Schmitt BP, Nordlund DJ, Rodgers LA. Prevalence of hypocalcemia and

elevated serum alkaline phosphatase in patients receiving chronic anticon-

vulsant therapy. J Fam Pract 1984;18, 873-.

[64] Winnacker JL, Yeager H, Saunders JA, Russell B, Anast CS. Rickets in children

receiving anticonvulsant drugs. Biochemical and hormonal markers. Am J Dis

Child 1977;131:286–90.

[65] Reunanen MI, Sotaniemi EA, Hakkarainen HK. Serum calcium balance during

early phase of diphenylhydantoin therapy. Int J Clin Pharmacol Biopharm

1976;14:15–9.

[66] Silver J, Davies TJ, Kupersmitt E, Orme M, Petrie A, Vajda F. Prevalence and

treatment of vitamin D deﬁciency in children on anticonvulsant drugs. Arch

Dis Child 1974;49:344–50.

[67] Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone struc-

ture: epidemiology, mechanisms and therapeutic implications. CNS Drugs

2001;15:633–42.

[68] Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients

treated with 2 different anti-convulsants. Acta Neurol Scant 1982;66:335–41.

[69] Harris M, Jenkins MV, Wills MR. Phenytoin inhibition of parathyroid hormone

induced bone resorption in vitro. Br J Pharmacol 1974;50:405–8.

[70] Jenkins MV, Harris M, Wills MR. The effect of phenytoin on parathyroid extract

and 25-hydroxycholecalciferol-induced bone resorption: adenosine 3,5 cyclic

monophosphate production. Calcif Tissue Res 1974;16:163–7.

[71] Hahn TJ, Scharp CR, Richardson CA, Halstead LR, Kahn AJ, Teitelbaum SL. Inter-

action of diphenylhydantoin (phenytoin) and phenobarbital with hormonal

mediation of fetal rat bone resorption in vitro. J Clin Invest 1978;62:406–14.

[72] Koch HU, Kraft D, von Herrath D, Schaefer K. Inﬂuence of diphenylhydan-

toin and phenobarbital on intestinal calcium transport in the rat. Epilepsia

1972;13:829–34.

[73] Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad JG. Serum 25-

hydroxycalciferol levels and bone mass in children on chronic anticonvulsant

therapy. N Engl J Med 1975;292:550–4.

[74] Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased

bone mass and increased bone turnover with valproate therapy in adults with

epilepsy. Neurology 2001;57:445–9.

[75] Bell RD, Pak CY, Zerwekh J, Barilla DE, Vasko M. Effect of phenytoin on bone

and vitamin D metabolism. Ann Neurol 1979;5:374–8.

[76] Takahashi A, Onodera K, Shinoda H, Mayanagi H. Phenytoin and its metabolite,

5-(4-hydroxyphenyl)-5-phenylhydantoin, show bone resorption in cultured

neonatal mouse calvaria. Jpn J Pharmacol 2000;82:82–4.

[77] Pento JT, Glick SM, Kagan A. Diphenylhydantoin inhibition of calcitonin secre-

tion in the pig. Endocrinology 1973;92:330–3.

[78] Scott AK, Haynes BP, Schinkel KD, Ohnhaus EE, Park BK. Hepatic enzyme

induction and vitamin K1 elimination in man. Eur J Clin Pharmacol

1987;33:93–5.

[79] Bogliun G, Beghi E, Crespi V, Delodovici L, d’Amico P. Anticonvulsant drugs

and bone metabolism. Acta Neurol Scand 1986;74:284–8.

[80] Ohta T, Wergedal JE, Gruber HE, Baylink DJ, Lau KH. Low dose phenytoin is an

osteogenic agent in the rat. Calcif Tissue Int 1995;56:42–8.

[81] Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteocalcin secre-

tion from osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone

1990;11:309–12.

[82] Olsen RW. Phenobarbital and other barbiturates. In: Levy RH, Mattson RH,

Meldrum BS, Perucca E, editors. Antiepileptic drugs, vol. 50. Philadelphia:

Lippincott Williams & Wilkins Publishers; 2002. p. 489–95.

[83] Beghi E. Phenobarbital and other barbiturates. In: Levy RH, Mattson RH,

Meldrum BS, Perucca E, editors. Antiepileptic drugs, vol. 54. Philadelphia:

Lippincott Williams & Wilkins Publishers; 2002. p. 522–7.

[84] Hahn TJ, Birge SJ, Schrp CR, Avioli LV. Phenobarbital-induced alterations in

vitamin D metabolism. Clin Invest 1972;51:741–8.

[85] Lifshitz F, Maclaren N. Vitamin D-dependent rickets in institutionalized, men-

tally retarded children receiving long-term anticonvulsant therapy. I. A survey

of 228 patients. J Pediatr 1973;83:612–20.

[86] Foss MC, Meneghelli UG, Tolosa Verìssimo JM. The effect of the anticon-

vulsants phenobarbital and diphenylhydantoin on intestinal absorption of

calcium. Acta Physiol Lat Am 1979;29:223–8.

[87] Weisman Y, Fattal A, Eisenberg Z, Harel S, Spirer Z, Harell A. Decreased serum

24,25-dihydroxy vitamin D concentrations in children receiving chronic anti-

convulsant therapy. Br Med J 1979;2:521–3.

[88] Hosseinpour F, Ellfolk M, Norlin M, Wikvall K. Phenobarbital suppresses

vitamin D325-hydroxylase expression: A potential new mechanism for drug-

induced osteomalacia. Biochem Biophys Res Commun 2007;357:603–7.

[89] Mosekilde L, Christensen SC, Lund B, Sorensen OH, Melsen F. The inter-

relationships between serum 25-hydroxychocalciferol, serum parathyroid

hormone and bone changes in anticonvulsant osteomalacia. Acta Endocrinol

1977;84:559–65.

[90] Weinstein RS, Bryce FG, Sappington LJ, King DW, Gallagher BB. Decreased

serum ionized calcium and normal vitamin D metabolite levels with anticon-

vulsant drug treatment. J Clin Endocrinol Metab 1984;58:1003–9.

[91] Ala-Houhala M, Korpela R, Koivikko M, Koskinen T, Koskinen M, Koivula T.

Long-term anticonvulsant therapy and vitamin D metabolism in ambulatory

pubertal children. Neuropediatrics 1986;17:212–6.

[92] Holloway L, Paulson A, Seale C, Morell MJ, Marcus R. Skeletal status of women

with epilepsy. J Bone Miner Res 2000;15(Suppl. 1):SA302 (Abstract).

[93] Gissel T, Poulsen CS, Vestergaard P. Adverse effects of antiepileptic drugs on

bone mineral density in children. Expert Opin Drug Saf 2007;6:267–78.

[94] Ays¸egül T, C¸ akatay U, Kurt BB, Kayali R, Sivas A, Akc¸ ay T, et al. Changes in

bone turnover and deoxypyridinoline levels in epileptic patients. Clin Chem

Lab Med 2000;38:47–50.

[95] Kulak CAM, Borba VZC, Silvado CE, de Paola L, Seibel MJ, Bilezikian JP, et

al. Bone density and bone turnover markers in patients with epilepsy on

chronic antiepileptic drug therapy. Arq Bras Endocrinol Metabol 2007;51:

466–71.

[96] Lado F, Spiegel R, Masur JH, Boro A, Haut NY. Value of routine screening

for bone demineralization in an urban population of patients with epilepsy.

Epilepsy Res 2008;78:155–60.

[97] Filardi S, Guerreiro CAM, Magna LA, Neto JFM. Bone mineral density, vitamin

D and anticonvulsant therapy. Arq Neuropsiquiatr 2000;58:616–20.

[98] Goodman LS, Swinyard EA, Brown WC, Schiffman DO, Grawal MS, Bliss EL.

Anticonvulsant properties of 5-phenyl-ethylhexahydropyridine-4,6-dione, a

new antiepileptic. J Parmacol Exp Therapeut 1953;108:428–36.

[99] Fincham RW, Schottelius DD. Primidone. In: Levy RH, Mattson RH, Meldrum

BS, Perucca E, editors. Antiepileptic drugs, vol. 65. Philadelphia: Lippincott

Williams & Wilkins Publishers; 2002. p. 621–35.

[100] Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacea

and effect of vitamin D; controlled therapeutic trial. Br Med J 1973;4:695–701.

[101] Bouillon R, Reynaert J, Claes JH, Lissens W, De Moor P. The effect of anti-

convulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and

parathyroid hormone. J Clin Endocrinol Metab 1975;41:1130–5.

[102] Bourgeois B, Beaumanoir A, Blajev B, de la Cruz N, Despland PA, Egli M, et

al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia

1987;28:S8–11.

10 A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10

[103] de Silva M, MacArdle B, McGowan M, Hughes E, Stewart J, Neville BG, et al.

Randomised comparative monotherapy trial of phenobarbitone, phenytoin,

carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy.

Lancet 1996;347:709–13.

[104] Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy:

clinical and pharmacological effects. Ann Neurol 1978;3:20–5.

[105] McLean MJ, Macdonald RL. Sodium valproate, but not ethosuximide, produces

use- and voltage-dependent limitation of high frequency repetitive ﬁring of

action potentials of mouse central neurons in cell culture. J Pharmacol Exp

Ther 1986;237:1001–11.

[106] Löscher W. Valproate induced changes in GABA metabolism at the subcellular

level. Biochem Pharmacol 1981;1:1364–6.

[107] Elliott JO, Jacobson MP, Haneef Z. Homocysteine and bone loss in epilepsy.

Seizure 2007;16:22–34.

[108] Oner N, Kaya M, Karasaliho˘

glu S, Karaca H, Celtik C, Tütüncüler F. Bone mineral

metabolism changes in epileptic children receiving valproic acid. J Paediatr

Child Health 2004;40:470–3.

[109] Rieger-Wettengl G, Tutlewski B, Stabrey A, Rauch F, Herkenrath P, Schauseil-

Zipf U, et al. Analysis of the musculoskeletal system in children and

adolescents receiving anticonvulsant monotherapy with valproic acid or car-

bamazepine. Pediatrics 2001;108:E107.

[110] Song XQ, Wang ZP, Bao KR, Zhang JM, Wu J, Yan CH, et al. Effect of car-

bamazepine and valproate on bone metabolism in children with epilepsy.

Zhonghua Er Ke Za Zhi 2005;43:728–32.

[111] Boluk A, Guzelipek M, Savli H, Temel I, OziÅ ¨

Yik HI, Kaygusuz A. The effect of

valproate on bone mineral density in adult epileptic patients. Pharmacol Res

2004;50:93–7.

[112] Guo CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treat-

ment may be a marker for reduced growth and bone mass in children with

epilepsy. Epilepsia 2001;42:1141–7.

[113] Elwakkad AS, El Elshamy KA, Sibaii H. Fish liver oil and propolis as

protective natural products against the effect of the anti-epileptic drug val-

proate on immunological markers of bone formation in rats. Epilepsy Res

2008;80:47–56.

[114] Petroff OA, Hyder F, Rothman DL, Mattson RH. Effects of gabapentin on

brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients. Epilepsia

2000;41:675–80.

[115] Goa KL, Sorkin EM, Gabapentin. A review of its pharmacological properties

and clinical potential in epilepsy. Drugs 1993;46:409–27.

[116] Striano P, Striano S. Gabapentin: a Ca2+ channel alpha 2-delta ligand far

beyond epilepsy therapy. Drugs Today 2008:44353–68.

[117] Bryans JS, Davies N, Gee NS, Dissanayake VU, Ratcliffe GS, Horwell DC, et

al. Identiﬁcation of novel ligands for the gabapentin binding site on the

alpha2delta subunit of a calcium channel and their evaluation as anticon-

vulsant agents. J Med Chem 1998;41:1838–45.

[118] LaRoche SM, Helmers SL. The new antiepileptic drugs: scientiﬁc review. JAMA

2004;291:605–14.

[119] Morris GL. Gabapentin. Epilepsia 1999;40:S63–70.

[120] McLean MJ, Morrell MJ, Willmore LJ, Privitera MD, Faught RE, Holmes GL,

et al. Safety and tolerability of gabapentin as adjunctive therapy in a large,

multicenter study. Epilepsia 1999;40:965–72.

[121] Dalal A, Zhou L. Gabapentin and sexual dysfunction: report of two cases.

Neurologist 2008;14:50–1.

[122] DeToledo JC, Toledo C, DeCerce J, Ramsay RE. Changes in body weight with

chronic, high-dose gabapentin therapy. Therpeut Drug Monit 1997;19:394–6.

[123] Ensrud KE, Walczak TS, Blackwell TL, Ensrud ER, Barrett-Connor E, Orwoll ES.

Antiepileptic drug use and rates of hip bone loss in older men: a prospective

study. Neurology 2008;71:723–30.

[124] Meldrum BS. Update on the mechanism of action of antiepileptic drugs.

Epilepsia 1996;37:S4–11.

[125] Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit

2007;13:1–7.

[126] Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A

placebo-controlled trial of lamotrigine add-on therapy for partial seizures

in children. Lamictal Pediatric Partial Seizure Study Group. Neurology

1999;53:1724–31.

[127] Gericke CA, Picard F, de Saint-Martin A, Strumia S, Marescaux C, Hirsch E.

Efﬁcacy of lamotrigine in idiopathic generalized epilepsy syndromes: a video-

EEG-controlled, open study. Epileptic Disord 1999;1:159–65.

[128] Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. Lamot-

rigine for generalized seizures associated with the Lennox-Gastaut syndrome.

Lamictal Lennox-Gastaut Study Group. N Engl J Med 1998;339:851–2.

[129] Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, et al. Lamictal

(lamotrigine) monotherapy for typical absence seizures in children. Epilepsia

1999;40:973–9.

[130] Sheth RD, Hermann BP. Bone mineral density with lamotrigine monotherapy

for epilepsy. Pediatr Neurol 2007;37:250–4.

[131] Wülfert E, Hanin I, Verloes R. Facilitation of calcium-dependent cholinergic

function by ucb L059, a new “second generation” nootropic agent. Psy-

chopharmacol Bull 1989;25:498–502.

[132] Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, et al. The anti-

epileptic drug levetiracetam reverses the inhibition by negative allosteric

modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol

2002;136:659–72.

[133] Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium

channels by levetiracetam. Epilepsia 2002;43:9–18.

[134] Madeja M, Margineanu DG, Gorji A, Siep E, Boerrigter P, Klitgaard H, et al.

Reduction of voltage-operated potassium currents by levetiracetam: a novel

antiepileptic mechanism of action? Neuropharmacology 2003;45:661–71.

[135] Gillard M, Chatelain P, Fuks B. Binding characteristics of levetiracetam to

synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing

the human recombinant protein. Eur J Pharmacol 2006;536:102–8.

[136] Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetirac-

etam for partial seizures: results of a double-blind, randomized clinical trial.

Neurology 2000;55:236–42.

[137] Nissen-Meyer LS, Svalheim S, Taubøll E, Reppe S, Lekva T, Solberg LB, et al.

Levetiracetam, phenytoin, and valproate act differently on rat bone mass,

structure, and metabolism. Epilepsia 2007;10:1850–60.

[138] Ali II, Herial NA, Horrigan T, Kellough L, Tietjen GE. Measurement of bone

mineral dendity in patients on levetiracetam monotherapy. Am Epilepsy Soc

Abstr 2006;2:150.

[139] Wellington K, Goa KL. Oxcarbazepine: an update of its efﬁcacy in the man-

agement of epilepsy. CNS Drugs 2001;15:137–63.

[140] Bang L, Goa K. Oxcarbazepine: a review of its use in children with epilepsy.

Paediatr Drugs 2003;5:557–73.

[141] Freidel M, Krause E, Kuhn K, Peper R, Vogel H. Oxcarbazepine in the treatment

of epilepsy. Fortschr Neurol Psychiatr 2007;75:100–6.

[142] Kalis MM, Huff NA. Oxcarbazepine, an antiepileptic agent. Clin Ther

2001;23:680–700.

[143] Herranz JL, Argumosa A. Characteristics and indications of oxcarbazepine. Rev

Neurol 2002;35:S101–9.

[144] Stefani A, Pisani A, De Murtas M, Mercuri NB, Marciani MG, Calabresi P. Action

of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal

system. II. Modulation of high-voltage-activated calcium currents. Epilepsia

1995;36:997–1002.

[145] Cansu A, Yesilkaya E, SerdaroÄ ¨

Ylu A, HirfanoÄ ¨

Ylu TL, Camurdan O, GÃ lbahar

O, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine.

Pediatr Neurol 2008;39:266–71.

[146] Patsalos PN, Zakrzewska JM, Elyas AA. Dose dependent enzyme induction by

oxcarbazepine? Eur J Clin Pharmacol 1990;39:187–8.

[147] Lyseng-Williamson KA, Yang LPH. Topiramate. A review of its use in the treat-

ment of epilepsy. Drugs 2007;67:2231–56.

[148] Ramsay ER, Leung AT. Effect of topiramate on bone resorption in adults.

Epilepsia 2006;47(S4):171.

[149] Schauf CL. Zonisamide enhances slow sodium inactivation in Myxicola. Brain

Res 1987;413:185–8.

[150] Suzuki S, Kawakami K, Nishimura S, Watanabe Y, Yagi K, Seino M, et al. Zon-

isamide blocks T-type calcium channel in cultured neurons of rat cerebral

cortex. Epilepsy Res 1992;12:21–7.

[151] Baulac M, Leppik IE. Efﬁcacy and safety of adjunctive zonisamide therapy for

refractory partial seizures. Epilepsy Res 2007;75:75–83.

[152] Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitenskyy V, Lucas C. Dose-

dependent safety and efﬁcacy of zonisamide: a randomized, double-blind,

placebo-controlled study in patients with refractory partial seizures. Epilepsia

2005;46:31–41.

[153] Leppik IE, Willmore LJ, Homan RW, Fromm G, Oommen KJ, Penry JK, et al.

Efﬁcacy and safety of zonisamide: results of a multicenter study. Epilepsy Res

1993;14:165–73.

[154] You SJ, Kang HC, Kim HD, Lee HS, Ko TS. Clinical efﬁcacy of zonisamide

in Lennox-Gastaut syndrome: Korean multicentric experience. Brain Dev

2008;30:287–90.

[155] Takahashi A. Effects of antiepileptics phenytoin, zonisamideand valproate on

bone metabolism in growing rats. Inter Congress Ser 2005;1284:87–8.

[156] Takahashi A, Onodera K, Kamei J, Sakurada S, Shinoda H, Miyazaki S, et al.

Effects of chronic administration of zonisamide, an antiepileptic drug, on

bone mineral density and their prevention with alfacalcidol in growing rats.

J Pharmacol Sci 2003;91:313–8.

[157] Masuda Y, Karasawa T. Inhibitory effect of zonisamide on human carbonic

anhydrase in vitro. Arzneimittelforschung 1993;43:416–8.

Effects of new antiseizure medication on bone metabolism and bone mineral density in children: A meta-analysis

Article

Full-text available

Nov 2022

Objective To explore the effect of new antiseizure medication on bone metabolism and bone mineral density in children.Methods The Chinese and English databases (PubMed, EMBASE, Cochrane Library, CNKI, Wanfang and VIP) were systematically searched for observational studies evaluating the effects of new antiseizure medication on bone metabolism and bone mineral density in children with epilepsy. The effects of new antiseizure medication on serum calcium, phosphorus, alkaline phosphatase, bone alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and bone mineral density in children were systematically evaluated.ResultsAfter systematic retrieval and screening, 12 studies with high literature quality (including 629 epileptic children and 627 control subjects) were included in the systematic evaluation. Meta-analysis showed that new antiseizure medication decreased bone mineral density (MD: −0.05, 95%CI, −0.09, −0.02; P = 0.004). From different kinds of antiseizure medication, levetiracetam can reduce blood phosphorus concentration in children (MD: −0.04; 95%CI, −0.07, −0.01). Oxcarbazepine increased serum alkaline phosphatase in children (MD:17.98; 95%CI, 10.43,25.53; P < 0.00001), and the increase intensity was significantly higher than that of levetiracetam (MD: 7.66; 95%CI, 0.29, 15.02; P = 0.04). In addition, oxcarbazepine can cause a significant increase in parathyroid hormone in children (MD: 7.52; 95%CI, 3.37,11.66; P = 0.0004), and 25 - hydroxyvitamin D was reduced, and the difference was statistically significant (MD:−2.18; 95%CI, −3.23, −1.13; P = 0.00006). However, the effects of new antiseizure medication on serum calcium and bone alkaline phosphatase in children were not statistically significantConclusion New antiseizure medication have different effects on bone metabolism and bone mineral density in children with epilepsy, and the effects of different types of new antiseizure medication are different.

Prenatal toxicity of gabapentin on bone development in rat offsprings

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Full-text available

Jun 2023

Background Gabapentin is a drug commonly prescribed to adult pregnant women with neuropathic pain and epilepsy. Since the effect of antiepileptic drugs used in pregnant women with epilepsy on prenatal bone development is controversial, this study was conducted to demonstrate the toxic effects of gabapentin use during pregnancy on the skeletal system. Methods In the study, pregnant Wistar albino rats were randomly selected and divided into 5 groups (n = 4) as control and 10 mg/kg/day, 30 mg/kg/day, 60 mg/kg/day and 120 mg/kg/day gabapentin groups. The pups were subjected to double skeletal staining (DSS) and the ossification lengths and areas of the fore and hind bones of the pups were measured. Immunohistochemistry (IHC) was used to evaluate the ossification sites and the levels of alkaline phosphatase (AP) and tartrate resistant acid phosphatase (TRAP) immunoreactivity in the pups' femurs. Results: According to the results, the weights and morphometric sizes of the pups were lower than those of the control group. It was found that ossification rates in the fore and hind bones were statistically significantly lower. It was revealed that AP and TRAP intensities which is metabolic markers for bone development were reduced in the experimental groups compared to the control group. Conclusions We have shown that continuous use of gabapentin during pregnancy in rats results in lower birth weight offspring, delayed ossification in the offspring and adverse effects on bone metabolism as the dose increases.

A retrospective comparative fractal and radiomorphometric analysis of the effect of 3 generations of anti-epileptic drugs on the mandible

Article

Apr 2023

Objectives: The present study investigated the possible impacts of anti-epileptic drugs (AEDs) on trabecular and cortical bone in the mandible. Study Design: Fractal dimension (FD) and the radiomorphometric parameters of mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) were assessed on 497 dental panoramic radiographs (DPRs) of patients in the case group and controls. AEDs were compared according to 3 generations, duration of use, and patient age and gender. Results: FD of the angle and body of the mandible and MCW were significantly lower in the case group than in the control group (P<.001). FD values in the ramus and angle were lower in first-generation and third-generation AEDs than in second-generation drugs (P≤0.011). FD in the mandibular body was lower in first-generation and second-generation AED users than in third generation drugs (P=0.017). Drug use for at least one year resulted in significantly lower values for all FDs and MCW values and more Class 3 MCI assessments than shortduration use, but PMI was higher with more than one year of AED use (P≤ .020). Age and gender had no significant effects. Conclusion: AEDs caused significant changes in bone compared to controls in some FD values, MCW, and MCI. The effect of drug generations is pronounced in trabecular bone. AED use for more than 1 year had greater effect than short-term use.

The Eucalcemic Patient With Elevated Parathyroid Hormone Levels

Article

Full-text available

Jan 2023

Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.

Prognosticators of bone health in pediatrics with epilepsy using anti-epileptic drugs: A prospective interventional study

Article

Full-text available

Dec 2022

Introduction: Epilepsy is a common and long-lasting neurological disorder in children who require long-term treatment with Antiepileptic drugs (AED). Such long-term AED use may have negative effects on bone causing bone loss and osteoporosis, necessitating frequent monitoring. Data on the effect of AED on bone health in children is scarce compared to adults and hence this study was undertaken. Aim: To compare and quantify the effects of sodium valproate (SV), carbamazepine (CBZ), and levetiracetam (LEV) on bone health in children using specific bone biomarkers such as vitamin D, calcium, phosphorus, ALP, osteocalcin (OCN), and beta serum cross laps (CTx). Materials and methods: A prospective interventional study was carried out in Rajarajeswari Medical College and Hospital, Bangalore, between October 2019 to March 2022. A total of 79 confirmed cases of epilepsy within the age group of 1-18 years, receiving treatment with sodium valproate (SV), carbamazepine (CBZ), and levetiracetam (LEV) monotherapy for a period of minimum one month were enrolled. Serum samples of calcium (Ca), phosphorus (PO4), alkaline phosphatase (ALP), Vitamin D were analyzed at the time of initiation of study and these levels were considered as baseline levels.

Investigation of bone mineral density and the changes by enzyme replacement therapy in patients with Fabry disease

Article

Jun 2023
MOL GENET METAB

Background: Fabry disease (FD) is an inherited disorder that causes organ dysfunction. However, only a few studies have reported on bone mineral density (BMD) in FD patients, and the relationship between BMD and clinical factors such as globotriaosylsphingosine (lyso-Gb3) remains unclear. Therefore, the current study sought to investigate BMD in FD patients, the relationship between BMD and lyso-Gb3, and the effects of enzyme replacement therapy (ERT) on changes in BMD and lyso-Gb3. Methods: This single-center, observational study included 15 patients who visited our facility for FD between January 2008 and June 2021. We assessed BMD and clinical characteristics in study patients, including plasma lyso-Gb3 levels, and examined the relationship between BMD and plasma lyso-Gb3 levels, and changes in BMD after starting ERT. Results: Male patients' BMD had reduced, whereas female patients' BMD was preserved. Male patients had significantly higher plasma lyso-Gb3 levels than female patients. Moreover, plasma lyso-Gb3 levels were found to be significantly related to the lumbar spine and femoral BMD. These were strongly linked with plasma lyso-Gb3 levels in male patients, whereas no strong link was observed in female patients. Furthermore, BMD significantly increased only in male patients although plasma lyso-Gb3 levels significantly decreased by ERT in all patients. Conclusion: BMD decreased possibly due to Gb3 accumulation, and ERT could increase BMD in male FD patients.

Bone Turnover Markers: Basic Biology to Clinical Applications

Article

Full-text available

Dec 2022

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide; and commonly used resorption markers serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen and tartrate resistant acid phosphatase type 5b. BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable components (e.g., age, gender, ethnicity) and controllable components, particularly relating to collection conditions (e.g., fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics; and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget’s disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.

Myoclonic seizures and recurrent nonconvulsive status epilepticus in Dravet syndrome

Chapter

Nov 2012

Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.

Timing of medical and surgical treatment of epilepsy: a hemispherotomy that would have prevented disabling cerebellar atrophy

Chapter

Nov 2012

Jörg Wellmer

Cutaneous adverse reactions by AEDs: chance or predetermination?

Chapter

Nov 2012

Lamictal (Lamotrigine) Monotherapy for Typical Absence Seizures in Children

Article

Full-text available

Jul 1999

Purpose: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3–15 years, n = 45). Methods: A “responder-enriched” study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. Results: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. Conclusions: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.

Phenobarbital and other barbiturates: mechanism of action

Article

Jan 2002

R.W. Olsen

Phenytoin increases markers of osteogenesis for the human species in vitro and in vivo.

Article

Aug 1995

Gabapentin

Article

Sep 1993

Synopsis Gabapentin is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. The drug is not protein bound, is not metabolised and does not induce liver enzymes, diminishing the likelihood of drug interactions with other antiepileptic agents and drugs such as oral contraceptives. Although gabapentin is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA), which does not cross the blood-brain barrier, gabapentin penetrates into the CNS and its activity is seemingly distinct from GABA-related effects. Present clinical evaluation is largely restricted to proof of efficacy trials of gabapentin as addon therapy in patients with partial epilepsy resistant to conventional treatment. Gabapentin (usually 600 to 1800 mg/day) provides notable benefit, reducing seizure frequency by ⩾ 50% in 18 to 28% of patients with refractory partial seizures, as shown in 3 double-blind, placebo-controlled trials. Overall, seizure frequency decreased by 18 to 32% during 3-month treatment periods. Patients with complex partial seizures, and partial seizures secondarily generalised, are particularly likely to respond to gabapentin. Current experience with the drug in other seizure types, and as monotherapy, is limited. Mild adverse events, commonly somnolence, fatigue, ataxia and dizziness, have been reported in about 75% of gabapentin recipients. While the drug has been well tolerated when administered to a few patients for periods of up to 5 years, its long term tolerability profile has yet to be fully expounded. Thus, with its favourable pharmacokinetic profile, and efficacy in some refractory patients, gabapentin is poised to fill a niche as an adjunct to the treatment of partial epilepsy. Promising results obtained thus far warrant further work to clarify its long term tolerability, its possible efficacy in other seizure types, its position relative to other agents and its use as monotherapy. In the meantime, gabapentin is likely to provide a much-needed option in a therapeutic area requiring complex management.

Adverse Effects of Antiepileptic Drugs on Bone Structure

Article

Aug 2001

Antiepileptic drugs (AEDs) were first associated with disorders of bone in both adults and children in the late 1960s. The most severe manifestations of these disorders are osteopenia/osteoporosis, osteomalacia and fractures. Bone disease has been described in several groups of patients receiving AEDs. Groups identified as being more vulnerable to AED-associated bone disease include institutionalised patients, postmenopausal women, older men and children. Radiological and histological evidence of bone disease is found in patients taking AEDs. Numerous biochemical abnormalities of bone metabolism have also been described. The severity of bone and biochemical abnormalities is thought to correlate with the duration of AED exposure and the number of AEDs used. In monotherapy, the AEDs most commonly associated with altered bone metabolism are phenytoin, primidone and phenobarbital (phenobarbitone). To date there have been no reports of altered bone metabolism in individuals receiving the newer anticonvulsants (specifically lamotrigine, topiramate, vigabatrin and gabapentin). The mechanisms of AED-associated bone disease are not clearly elucidated; however, several theories have been proposed to explain the link. No definitive guidelines for evaluation or treatment have yet been determined.

Rickets in Children Receiving Anticonvulsant Drugs

Article

Mar 1977
Am J Dis Child

John L. Winnacker

• Forty-one epileptic children, aged 2 to 16 years, receiving combinations of phenobarbital, phenytoin, and primidone, and 39 control children were studied. The epileptics demonstrated slight but significant reductions in serum calcium, phosphorus, and 25-hydroxyvitamin D concentrations, and a significant increase in serum alkaline phosphatase values. No significant difference in serum immunoreactive parathyroid hormone levels was noted. Further analysis of the data revealed that patients whose drug therapy included primidone had the lowest serum levels of calcium and 25-hydroxyvitamin D. They had also received the largest number of drugs for the longest duration, and had serum phenobarbital levels that were significantly higher than those of other patients. The minimal degree of vitamin D deficiency in our epileptic children contrasts with the results of other investigations and warrants emphasis. The reasons for this difference are not apparent. (Am J Dis Child 131:286-290, 1977)

Oxcarbazepine

Article

Aug 2003

Oxcarbazepine (10,11 -dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a 10-keto analogue of carbamazepine with anticonvulsant activity. In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective as phenytoin and valproic acid at reducing generalised tonic-clonic and partial seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. The most commonly reported adverse events associated with oxcarbazepine monotherapy and/or adjunctive therapy in adults and/or children are somnolence, dizziness, headache, nausea and vomiting. Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults and children) and valproic acid (in adults), and although 75 to 90% of adult patients in 5 recent monotherapy studies reported adverse events while receiving oxcarbazepine, <8% withdrew from treatment because of them. Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of patients treated with oxcarbazepine. Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. Although oxcarbazepine does have a clinically significant interaction with some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for interactions than older antiepileptic drugs (AEDs) because its major metabolic pathway is mediated by noninducible enzymes. Conclusion: Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults and children. Furthermore, it is also effective as adjunctive therapy in the treatment of refractory partial seizures in both age groups. In addition, the drug is tolerated better than the older, established AEDs, and has a lower potential for drug interactions. These attributes make oxcarbazepine an effective component in the initial treatment of newly diagnosed partial and generalised tonic-clonic seizures, and also as an adjunct for medically intractable partial seizures in both adults and children. Pharmacodynamic Properties Oxcarbazepine is a 10-keto analogue of carbamazepine which appears to exert its anticonvulsant activity [as its major active metabolite, the monohydroxy derivative (MHD) 10-hydroxy-10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide] by blocking neuronal ion channels. In vitro studies in rodents showed that the drug blocks voltage-sensitive sodium channels, thereby stabilising neural membranes, inhibiting repetitive neuronal firing and reducing synaptic impulse activity. In vitro studies have also shown that MHD reduces high voltage-activated calcium currents in striatal and cortical neurons, thus reducing glutamatergic transmission at corticostriatal synapses. Cognitive function and saccadic and smooth-pursuit eye movements were minimally affected in newly diagnosed patients with epilepsy undergoing short term oxcarbazepine monotherapy. However, oxcarbazepine was found to stimulate some aspects of psychomotor functioning, such as focused attention and writing speed, in healthy volunteers after 2 weeks. Pharmacokinetic Properties Oxcarbazepine is rapidly absorbed after oral administration. Maximum plasma concentrations (Cmax; 1.05 to 1.74 mg/L) are reached within 2 hours after a single dose of oxcarbazepine 600mg taken after an overnight fast. The Cmax of MHD (5.44 to 8.85 mg/L) is reached after about 4 to 6 hours and the area under the plasma concentration-time curve ranges from 80 to 220 mg/L · h. Steady-state plasma concentrations of MHD are achieved within 2 to 3 days of implementing a twice daily regimen. Oxcarbazepine pharmacokinetics are linear and show dosage proportionality over the dosage range 300 to 2400 mg/day. Approximately 37 to 43% of MHD and 60 to 67% of oxcarbazepine is bound to plasma proteins. Once absorbed from the gastrointestinal tract, oxcarbazepine is almost immediately reduced by an hepatic cytosolic arylketone reductase to form the major active metabolite MHD. Hence, the metabolism of oxcarbazepine is not affected by autoinduction, as is the case with carbamazepine. The plasma elimination half-life of oxcarbazepine is 1 to 2.5 hours, illustrating its rapid conversion to MHD. The elimination half-life of MHD in healthy volunteers averages about 8 to 10 hours. The rate of renal clearance of MHD is 0.71 to 1.26 L/h in healthy volunteers. Plasma concentrations of MHD are higher in patients with renal dysfunction and in the elderly because of reduced renal clearance, and lower in healthy children aged between 2 and 5 years compared with older children and adults because of increased systemic clearance. Dosage adjustments for these 3 patient groups are recommended. Because the metabolism of oxcarbazepine to its active metabolite is mediated by noninducible enzymes, oxcarbazepine pharmacokinetics are largely unaffected by induction of the microsomal cytochrome P450 (CYP) system. As such, the potential for interactions with antiepileptic drugs (AEDs) that induce CYP isozymes is reduced. However, there are reports of clinically significant interactions between oxcarbazepine, phenytoin and lamotrigine. The efficacy of oral contraceptives may be reduced by oxcarbazepine because of significant reductions in serum ethinylestradiol and levonorgestrel concentrations reported in healthy women receiving oral contraceptives and oxcarbazepine concomitantly. Furthermore, switching to oxcarbazepine therapy from treatment with carbamazepine resulted in a 47 to 200% increase in plasma concentrations of haloperidol, chlorpromazine and clozapine, most probably due to the removal of the inducing effect of carbamazepine. Therapeutic Efficacy Adults. Early studies showed oxcarbazepine monotherapy to be equivalent in efficacy to carbamazepine in the treatment of generalised tonic-clonic seizures and partial seizures in adults. In a more recent study, oxcarbazepine 1200 mg/day significantly reduced seizure frequency by 89.1 vs 37.4% and increased the time to the first seizure compared with placebo in previously untreated patients. Two monotherapy trials showed oxcarbazepine to be as effective at reducing generalised tonic-clonic and partial seizure frequency as valproic acid and phenytoin in patients with newly diagnosed epilepsy. About 57 and 60% of patients with newly diagnosed epilepsy treated with oxcarbazepine were seizure-free during a 48-week maintenance treatment period. Furthermore, oxcarbazepine and the other 2 AEDs did not differ significantly in their effects on seizure frequency during the maintenance period, number of patients discontinuing treatment due to lack of efficacy, or overall physician and patient evaluation of treatment. Oxcarbazepine monotherapy has also proved effective in the treatment of refractory partial seizures. Oxcarbazepine 2400 mg/day significantly reduced seizure frequency and increased the time to the first seizure compared with placebo or a subtherapeutic dosage of the drug (300 mg/day), in patients with intractable seizures. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. Children. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of previously untreated children and adolescents with partial or generalised tonic-clonic seizures. In a well designed clinical trial, 60% of evaluable patients treated with oxcarbazepine 450 to 2400 mg/day were seizure-free during the maintenance period. Similarly, 60% of the patients treated with phenytoin 150 to 800 mg/day were also free of seizures. After accounting for baseline seizure frequencies, there was no significant difference in seizure frequency between the 2 treatment groups. Adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. Reductions in seizure frequency of 35% from baseline were reported for oxcarbazepine-treated patients compared with 9% for children receiving placebo. Tolerability Adults. The most commonly reported adverse events associated with oxcarbazepine monotherapy in adults (in ≥5% of patients) are somnolence, headache, dizziness, nausea, vomiting, fatigue, rash and diplopia. Although 75 to 90% of patients in 5 recent monotherapy studies who received at least one dose of oxcarbazepine reported adverse events, <8% withdrew from treatment because of them. Reasons for discontinuing treatment prematurely included rash, postictal psychosis, ataxia, oxcarbazepine intoxication, headache and dizziness. The time to premature discontinuation of treatment due to adverse events was significantly in favour of oxcarbazepine compared with phenytoin in one study, but there was no significant difference compared with valproic acid in another study. However, oxcarbazepine was better tolerated than phenytoin (particularly with respect to gum hyperplasia, tremor, diplopia and nystagmus), and valproic acid (particularly with respect to tremor, weight gain, alopecia and headache). The most commonly reported adverse events among adult patients receiving oxcarbazepine adjunctive therapy are dizziness, somnolence, sedation, headache, fatigue, nausea, vomiting, ataxia, nystagmus and abnormal gait. In 757 patients with severe partial and/or generalised seizures, as few as 110 adverse events were reported and only 1.3% of patients discontinued treatment because of them. The majority of these patients were treated for 2 to 6 years with a dosage of 150 to 3600 mg/day and along with dizziness, headache, nausea and vomiting, hyponatraemia was also a common adverse event. In 164 patients switched to oxcarbazepine (monotherapy and adjunctive therapy were not differentiated) from carbamazepine therapy because of adverse events and/or intolerability while receiving carbamazepine, 18% became free of adverse events, and in 60% of the patients, symptoms became tolerable. The adverse events most likely to resolve upon switching to oxcarbazepine were undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. In a large well designed clinical trial where oxcarbazepine 600, 1200 or 2400 mg/day was administered to patients taking up to 3 concomitant AEDs the highest dosage was associated with >65% of patients discontinuing treatment, mainly because of CNS-related adverse events. However, treatment was well tolerated in patients receiving oxcarbazepine 1200 mg/day. Children. Common adverse events in previously untreated children receiving oxcarbazepine monotherapy are similar to those in adults: somnolence, headache, dizziness, nausea, apathy and rash. Oxcarbazepine was tolerated better than phenytoin, particularly with respect to nervousness, dizziness, gum hyperplasia, hypertrichosis and ataxia. Furthermore, the time to premature discontinuation of treatment due to adverse events was significantly in favour of oxcarbazepine. The most common adverse events experienced by children and adolescents receiving oxcarbazepine adjunctive therapy were somnolence, headache, dizziness, vomiting, nausea, diplopia, fever and ataxia. Hyponatraemia. Acute hyponatraemia (serum sodium level <125 mmol/L), although usually asymptomatic, develops in 2.7% of patients receiving oxcarbazepine treatment. In a large retrospective evaluation of the records of 1966 patients who had been enrolled in 14 controlled monotherapy and adjunctive therapy trials conducted to date, and who were treated for about 20 months with oxcarbazepine 600 to 1800 mg/day, the incidence of acute hyponatraemia was found to be low (2.7%). Dosage and Administration In the US and the UK, orally administered oxcarbazepine is approved for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as adjunctive therapy in the treatment of partial seizures in children (aged ≥4 years in the US and ≥6 years in the UK). In the UK, the drug is also approved for use as monotherapy in children ≥6 years of age. The manufacturer recommends that initiation of monotherapy in adults should begin with a dosage of 600 mg/day and be titrated to 1200 mg/day. However, in practice a lower initial dosage may be better tolerated. Adult patients being switched to oxcarbazepine monotherapy from treatment with other AEDs can receive ≤2400 mg/day after a 4-week titration period starting at 600 mg/day. Adjunctive therapy with oxcarbazepine in adults should not exceed the recommended dosage of 1200 mg/day because of intolerability at higher dosages. Adjunctive therapy in children aged 4 to 16 years can begin with a daily dosage of 8 to 10 mg/kg (but not exceed 600 mg/day). The target maintenance dosage (median ≈30 mg/kg/day) should be reached within 2 weeks and is dependent upon patient bodyweight. Children <8 years of age have an increased clearance (by about 30 to 40%) compared with older children and adults and, therefore, may need higher maintenance dosages to achieve effective seizure control. During the titration phase, patients need to be observed closely and plasma concentrations of the concomitant AEDs should be monitored, as they may be altered, especially at oxcarbazepine dosages >1200 mg/day. The measurement of serum sodium levels should be considered during treatment with oxcarbazepine, especially if the patient is receiving concomitant medication known to decrease serum sodium levels or if the symptoms of hyponatraemia appear. There is a 25 to 30% chance that patients with a history of hypersensitivity to carbamazepine will also experience hypersensitivity reactions to oxcarbazepine. As such, oxcarbazepine treatment must be discontinued immediately if signs of hypersensitivity develop.

Serum 25-Hydroxycalciferol Levels and Bone Mass in Children on Chronic Anticonvulsant Therapy

Article

Mar 1975

Fifty-six children with epilepsy receiving chronic therapy with phenobarbital or diphenylhydantoin or both and 51 controls were studied to determine the effects of anticonvulsant therapy on mineral, vitamin D and bone metabolism. Combination therapy was associated with the greatest decreases in serum calcium (9.72 ± 0.06 vs. 10.40 ± 0.05 mg per 100 ml in controls; p < 0.001), serum 25-hydroxycalciferol (13.1 ± 1.0 vs. 23.6 ± 0.9 ng per milliliter in controls; p < 0.001), and bone mass by photon absorptiometry (90.5 ± 1.6 vs. 100.7 ± 1.0 per cent in controls; p < 0.001). Serum bone and liver alkaline phosphatase isoenzyme activity was increased in both treatment groups. Serum calcium concentration correlated with serum 25-hydroxycholecalciferol levels in both the single and combined drug groups. Serum 25-hydroxycholecalciferol correlated with vitamin D intake in all groups, but mean levels of the metabolite were lower for any given level of vitamin D intake in treated patients. Thus, vitamin D sup...

Oxcarbazepin in der Epilepsietherapie

Article

Nov 2007

Hintergrund: Oxcarbazepin (OXC; z. B. Timox®) ist ein dem Carbamazepin (CBZ) chemisch verwandtes, neues Antiepileptikum mit in kontrollierten Studien nachgewiesener, vergleichbarer Wirksamkeit bei besserer Verträglichkeit. In einer prospektiven Anwendungsbeobachtung (AWB) wurden Wirksamkeit und Verträglichkeit von OXC unter Praxisbedingungen untersucht. Methode: Über einen Beobachtungszeitraum von 8 Wochen wurde in 362 Zentren die Behandlung von 1385 männlichen und weiblichen Epilepsie-Patienten im Alter zwischen einem Monat und 94 Jahren dokumentiert, die auf OXC neu eingestellt oder von einem anderen Antiepileptikum umgestellt wurden. Wirksamkeit und Verträglichkeit wurden anhand der Anfallsfrequenz und des Auftretens unerwünschter Arzneimittelwirkungen (UAWs) sowie mit Globalurteilen von Ärzten und Patienten bewertet. Ergebnisse: 688 von 1385 Patienten (49,7 %) waren mit CBZ vorbehandelt, 342 (24,7 %) erhielten vor Beginn der AWB ein anderes Antiepileptikum und 355 (25,6 %) hatten vorher keine antiepileptische Medikation erhalten (initiale OXC-Monotherapie). Bei 161 der mit CBZ vorbehandelten Patienten (23,4 % von 688) erfolgte die Umstellung auf OXC „ad hoc” ohne Titration; die anderen Patienten wurden meist überlappend umgestellt. Das Umstellungsverhältnis CBZ zu OXC lag bei rund 21 % der Erkrankten im empfohlenen Bereich von 1 : 1,4 bis 1 : 1,6, bei knapp 60 % jedoch darunter. Die Erhaltungsdosis für OXC lag in der Altersgruppe 16 - 59 Jahren bei 1200 mg (Median), bei Patienten ab 60 Jahren bei 900 mg (Median). Während der Behandlung mit OXC verringerte sich die durchschnittliche Anfallsfrequenz pro 4 Wochen im Vergleich zu einer retrospektiv dokumentierten Vorphase im Gesamtkollektiv um durchschnittlich 76 %. 74 % der Patienten zeigten eine Verbesserung der Anfallssituation und 40,5 % wurden unter OXC anfallsfrei (bei initialer OXC-Monotherapie lag der Anteil anfallsfrei gewordener Patienten bei 62 %). 71 % der Patienten zeigten eine Reduktion der Anfallsfrequenz um ≥ 50 %. 10,8 % der Teilnehmer berichteten über UAWs (Inzidenz: 1 Ereignis je 459 Expositionstage; bei Patienten mit Ad-hoc-Umstellung von CBZ auf OXC 1 Ereignis je 1284 Tage). Die Behandlung mit OXC wurde lediglich von 2,5 % der Patienten wegen Unverträglichkeiten vorzeitig abgebrochen. 92 % der Patienten setzten die Einnahme von OXC über das Ende der AWB hinaus fort. Schlussfolgerungen: Die Ergebnisse unterstreichen die aus kontrollierten Studien bekannte, starke antiepileptische Wirksamkeit und gute Verträglichkeit von OXC. Beim Wechsel von CBZ auf OXC erwies sich eine „Ad-hoc”-Umstellung als günstig.

Gabapentin

Article

Aug 2005

George L. Morris

Gabapentin (GBP) is a antiepileptic drug (AED) indicated as adjunct therapy for treatment of partial seizures, with and without secondary generalization, in patients 12 and older with epilepsy. GBP (1-(aminomethyl) cyclohexaneacetic acid) is structurally related to γ-aminobutyric acid (GABA), which readily crosses the blood-brain barrier. Radiolabeled GBP binds throughout the central nervous system in anatomic areas important in treatment of seizures. Its precise mechanism of action is unknown. An open-label, dose-ranging study of doses up to 1,800 mg produced ≥50% seizure reductions [responder rate (RR)] in 29% of patients with partial seizures. Three double-blind, placebo-controlled, parallel add-on trials at doses of 300–1,800 mg have produced RR of up to 28%, with a placebo RR of 8–10%. An active controlled, parallel group comparison of 600 mg to 2,400 mg in monotherapy conversion design showed no significant difference among the 600 mg, 1,200 mg, and 2,400 mg groups compared to a placebo group. An inpatient, active-controlled comparison of 300 mg and 3,600 mg in a parallel-design monotherapy trial showed that time to exit from the study was significantly longer for the 3,600-mg group and the completion rate significantly higher (53% vs. 17%) for patients receiving 3,600 mg/day vs. 300 mg/day of GBP. Successful double-blind, placebo-controlled trials in refractory childhood partial seizures and benign childhood epilepsy with centrotemporal spikes have been recently concluded. Absence was not successfully treated in one small double-blind trial.

Bone and calcium metabolism and antiepileptic drugs

Abstract and Figures

Recommendations

Management of bone metabolism in epilepsy

Bone Mineral Changes in Epilepsy Patients During Initial Years of Antiepileptic Drug Therapy

Bone loss associated with use of antiepileptic drugs

Monitoring the risk of decreasing bone mineral density in children receiving valproate

A 12-month longitudinal study of calcium metabolism and bone turnover during valproate monotherapy

Bone Health

The Effects of Antiepileptic Drugs on Bone Density and Metabolism