Clinical Neurology and Neurosurgery 112 (2010) 1–10
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Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro
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
Received 2 April 2009
Received in revised form 21 August 2009
Accepted 10 October 2009
Available online 12 November 2009
Bone mineral density
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.
© 2009 Elsevier B.V. All rights reserved.
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: email@example.com (A. Verrotti).
0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
2A. Verrotti et al. / Clinical Neurology and Neurosurgery 112 (2010) 1–10
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
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
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 . 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 .
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
. 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 . In contrast, in another study, BZPs did
not seem to have an effect on BMD  and thus did not induce
the modest increase in fracture risk observed in a prior study .In
conclusion, BZP can adversely affect bone health with a consequent
risk of fractures.
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
, but there have been some conﬂicting results, especially in
Two recent studies by Kumandas et al.  and Kim et al. 
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 .
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 .
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 . 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. , 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
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
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) . This hypothesis is supported by the
recent cross-sectional, retrospective study by Kumandas et al. ,
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 . 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 . This hypoth-
esis is consistent with some studies [35,39], but not with others
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 . 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 . These data are in agreement with a previous
study by Välimäki et al. , 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
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 . In particular, a recent longitudinal study 
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  and direct inhibition of
intestinal calcium transport through a mechanism not mediated by
vitamin D . 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.
Phenytoin (PHT) was introduced for the treatment of epilepsy
in 1938 by Merritt and Putnam .
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
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 .
Among these reports, the most recent is a longitudinal study by
Pack et al. . 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 .
It has also been shown that PHT interferes with cation trans-
port in many tissues, thereby directly inhibiting intestinal calcium
absorption in rats . 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. , 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 , 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 ; hyperparathy-
roidism can primarily activate bone resorption.
However, direct action of PHT on bone resorption and bone
formation has also been suggested . The latter hypothesis is
supported by animal studies [71,76] and experiments on human
osteoblast-like bone cells , 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 . 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 . 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 .
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.
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 .
Like other barbiturates, PB enhances ␥-aminobutyric acid
(GABA)-mediated increases in chloride conductance by prolonging
the duration of channel opening .
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 .
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 . 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 .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 . 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
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 .
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
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 .
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 .
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
Therefore, vitamin D supplementation should be used routinely.
Primidone (PRM), classiﬁed as an enzyme-inducing antiepilep-
tic drug, was ﬁrst synthesized and used as an anticonvulsant in
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
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
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 .
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 .
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 .
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.  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.  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 , 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
. 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 .
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 . 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 . 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.  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. 
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
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 . 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 . 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 . 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 . In contrast with those results,
Elliott et al.  found lower serum ALP. Also, serum ALP was neg-
atively correlated with serum homocysteine in patients receiving
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 . 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 .
Similarly, Song et al.  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.  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.  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 . 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 .
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 .
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 .
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
Gabapentin (GBP) was formed by adding a cyclohexyl group
to GABA, which allowed it to cross the blood–brain barrier .
Despite its structure, GBP does not bind to GABA receptors in the
central nervous system . 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 . 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 . Side effects of GBP are generally mild and transient
; adverse effects on sexual function  and weight gain
 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.
 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.
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 .
LTG also inhibits high voltage-activated calcium channels that are
located presynaptically, and consequently it inhibits the release of
neurotransmitters such as glutamate .
LTG is used in monotherapy or as an add-on treatment for refrac-
tory partial  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  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
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 . 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
Interestingly, Guo et al.  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.  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. .
A recent longitudinal study  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
In summary, the data now available indicate that LTG monother-
apy does not lead to osteopenic effects or signiﬁcant alterations in
Levetiracetam (LEV) is an enantiomer of the ethyl analog of
piracetam that has the ability to facilitate cholinergic transmission
. LEV seems to have several modes of action, such as sup-
pression of negative allosteric modulators of neuronal GABA- and
glycine-gated currents , inhibition of voltage-gated calcium
channels , reduction of voltage-operated potassium currents
 and binding to synaptic vesicle protein 2A (SV2A) .It
has been proven effective in treatment-resistant partial seizures in
adults . LEV is safe and well tolerated, but has been scarcely
studied. A study carried out by Nissen-Meyer et al.  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.  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
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 . OXC and its
active metabolite, monohydroxy derivative (MHD), have effects on
sodium channels  and possibly potassium  and calcium
To date, few studies in the literature have assessed the effect
of OXC on BMD [16,145]. Babayigit et al.  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.  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.  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 ; 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 .
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.
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 .
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
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 .
In conclusion topiramate seems not to be associated with bone
metabolism alterations but there is a lack of clinical information.
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
 and the reduction of T-type calcium channel currents .
This drug has been shown to be an effective AED in patients with
refractory partial [151,152] and generalized tonic–clonic seizures
Currently, there is only one study that showed that administra-
tion of zonisamide can decrease BMD signiﬁcantly  in epileptic
Interestingly, an animal study  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
Main effects of classic and new AEDs on bone and calcium metabolism.
Drug BMD 25-OHD Ca/P PTH Bone turnover
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
Lamotrigine N N N ? N
Levetiracetam N N N – ?
Oxcarbazepine ↓↓ N↑↑bALP
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
Zonisamide has been found to inhibit carbonic anhydrase in
human erythrocytes ; as suggested for topiramate, we spec-
ulate that this inhibition may be a potential cause of reduction of
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