Bone Consequences of

Epilepsy and Antiepileptic Medications

Edgar A. Samaniego, MD, and Raj D. Sheth, MD

Childhood and adolescence are critical periods of skeletal mineralization. Peak bone
mineral density achieved by the end of adolescence determines the risk for later patho-
logical fractures and osteoporosis. Chronic disease and medication often adversely affect
bone health. Epilepsy is one of the most common neurological conditions occurring in
persons under the age of 21. Epilepsy may affect bone in a number of ways. Restrictions
of physical activity imposed by seizures, cerebal palsy or other coexisting comorbidities
adversely affect bone health. It has been observed that treatment with phenytoin and
phenobarbital can be associated with rickets. More recently, established agents such as
carbamazepine and valproate have been shown to be associated with decreased bone
mineral density. The literature related to bone health in pediatric epilepsy is reviewed.
Semin Pediatr Neurol 14:196-200 © 2007 Elsevier Inc. All rights reserved.

C hildhood and adolescence are critical periods of skeletal

mineralization. There is very little bone mineralization
at birth. This rapidly increases to reach peak bone mass peaks
between the second and third decade of life. Peak bone min-
eral density achieved by the end of adolescence determines
the risk for later pathological fractures and osteoporosis.
Chronic disease and medications that interfere with bone
mineralization or adversely affect bone health can have sig-
nificant long-term implications for bone health.
Epilepsy is one of the most common neurologic conditions
occurring in persons under 21 years of age. Patients with
epilepsy frequently experience trauma resulting from sei-
zure-related falls.1,2 Fractures are between 2 and 6 times
more common in patients with epilepsy than in the general
population, with fracture rates in the United States of 2,205
per 100,000 person-years.3,4 The fracture rate in epilepsy
remains to be defined, although the rate is estimated to be
similar to those patients taking steroids.5
Antiepileptic-induced bone disease has a heterogeneous
spectrum of severity.6 In mild cases, patients are asymptom-
atic and have normal bone mass, although they have elevated
parathyroid hormone levels suggestive of a high turnover
state. Patients using antiepileptics (AEDs) for ⬎2 years, in
particular those taking enzyme-inducing AEDs and those
older than 40 years, have a significant lower bone mineral
From the Department of Neurology, University of Wisconsin-Madison,
Madison, WI.
Address reprint requests to Raj D. Sheth, MD, Department of Neurology,
600 Highland Ave, H6/574 CSC, Madison, WI 53792-5132. E-mail:
sheth@neurology.wisc.edu
density (BMD) at clinically relevant fracture risk sites.7 Addi-
tionally, AED-related osteopenia may increase the suscepti-
bility to fractures, particularly in women.1,2 Unfortunately,
the data in children are scarce. Appleton8 reported a small
series of 198 children in which 12.6% suffered injuries before
being diagnosed with epilepsy.
Henderson et al9 described osteopenia in the femur of most
nonambulatory children with cerebral palsy by 10 years of
age. Fractures occurred in more than one fourth of the se-
verely involved children who were older than 10 years at the
time of their evaluation. The clinical and nutritional factors
that most directly correlated with low BMD were severity of
impairment, difficulty feeding the child, use of anticonvul-
sants, and lower triceps skinfold z scores (in decreasing order
of importance). The issue of bone health in patients using
AEDs is of even more interest because exposure to AEDs is
growing because of the increasing use of AEDs in patients
with neuropsychiatric disorders other than epilepsy.
Childhood Epilepsy
Childhood-onset seizures have a profound long-term impact.
In a prospective cohort study of 245 patients with epilepsy
diagnosed before the age of 16 and followed up over a 30-
year period, epilepsy was found to have a severe negative
impact on quality of life.10 Eighteen percent of the cohort
died, with most of those who died (39/44) being patients
whose seizures could not be controlled. Even when seizure
control was achieved, physical activity, social adaptation, and
economic condition were adversely affected. Accordingly,

196 1071-9091/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.spen.2007.08.006
Bone consequences 197

the impact of epilepsy and its associated social and physical persons with epilepsy, seizure-related fractures accounted for
burden on bone health is likely to be additive to the indepen- 33.9% of all fractures (95% confidence interval, 25.3%-
dent effect of AEDs on future osteoporosis and fracture risk. 43.5%). Fractures of the spine, forearms, femurs, lower legs,
and feet and toes were significantly increased after the diag-
Pathophysiology of Bone Disorders in Epilepsy
nosis of epilepsy. Phenytoin use was also associated with an
At birth, bone is minimally mineralized. With development,
increased fracture risk in this study. In a case-control study
bone becomes progressively more mineralized until a plateau
evaluating fractures in patients with epilepsy taking AEDs,
is attained in the third decade of life. In otherwise healthy
risk factors for fracture were prolonged seizures, long-term
people, at the sixth decade of life bone lost is a result of
AED use (either enzyme-inducing AEDs or nonenzyme-in-
involutional osteoporosis.11 Reduced bone accumulation in
ducing AEDs), AED polypharmacy, and female gender.24
children, adolescents, and young adults with epilepsy as well
Therefore, seizure control is of clear importance in prevent-
as progressive bone loss may increase fracture susceptibility.
ing fracture in persons with epilepsy. However, because
A lower peak bone mass in adolescence is associated with
emerging evidence indicates an adverse effect of AEDs on
greater involutional osteoporosis and increased fracture risk
bone metabolism, in particular the enzyme-inducing AEDs,
during adulthood.12
the choice of an AED to both prevent seizures and to protect
Chronic illness, particularly renal disease and other dis-
bone health is important. The most critical decision is at the
eases that impair constitutional development, adversely af-
initiation of therapy because AEDs are likely to be a long-
fects the mineralization process. Furthermore, many of the
term therapy.
medications used in the treatment of chronic disease also
Generally, there are 3 main situations that predispose pa-
adversely affect bone mineralization. There is increasing ev-
tients with epilepsy to fractures.1 Another factor is incoordi-
idence suggesting that epilepsy and comorbid conditions that
nation associated with either a coexisting comorbid condi-
frequently coexist, such as cerebral palsy, a hypoactive state,
tion or AED drug-induced ataxia. Other factor is
and depression, may adversely affect bone mineralization in
incoordination associated with either a coexisting comorbid
childhood. Cerebral palsy, which frequently is associated
condition or AED drug-induced ataxia.25,26 Thus, fractures
with epilepsy, is a powerful predictor of muscular and skel-
result from the interplay between accidental trauma, seizure-
etal hypoplasia.13 A study performed at our institution found
related falls, and bone strength.13
that children treated for epilepsy for more than 1 year had
significant lower BMD than controls. These findings suggest
AED and BMD Relationship
that children with epilepsy may be more vulnerable to frac-
Bone density reduction has been found in patients using
tures.14
enzyme-inducing AEDs. Phenytoin, phenobarbital, and car-
Bone is a complex dynamic tissue that responds to external
bamazepine appear to be associated with reductions in bone
and internal forces. Accordingly, body weight, exercise, and
mineralization by virtue of their enzyme-inducing proper-
calcium homeostasis can alter bone structure and architec-
ties.27 Induction of the CYP450 enzyme system results in in-
ture.15 These changes are complex and involve osteoclast and
creased clearance of vitamin D, which results in secondary
osteoblast dynamics, vitamin D, calcium, and phosphorous
hyperparathyroidism and consequent increased bone turn-
homeostasis as well as connective tissue arrangements. Tra-
over and reduced bone density. Although enzyme-inducing
becular bone comprises about 20% of all bone and is meta-
AEDs have often been associated with increased bone turn-
bolically more active because of a larger surface area. Regions
over, nonenzyme AEDs can also produce osteopenia.18,28
rich in trabecular bone such as the hip and spine are partic-
Souverein et al24 did not find a difference in fracture risk
ularly susceptible to fractures.
between hepatic enzyme-inducing and non– enzyme-induc-
Enzyme-inducing antiepileptics alter vitamin D concentra-
ing AEDs. This finding is in agreement with a recent Danish
tions and may predispose to reduced bone mass,16 although
case-control study including 124,655 fracture cases in which
nonenzyme-inducing AEDs may also affect bone density by
it was concluded that liver-inducing potential per se was not
possibly altering osteoblastic function.17,18 Premenopausal
responsible for the increased fracture risk.29 Also, no differ-
women treated with enzyme-inducing AEDs had lowered
ence in bone density was found between users of inducing
vitamin D concentrations as well as increased markers of
and noninducing AEDs in a case-control study in Scotland
bone turnover.16,19
among men and women aged 47 years and older.30 It has
Pathological Fractures in Epilepsy been described that sodium valproate, the main nonenzyme-
Patients with epilepsy frequently experience injuries result- inducing AED drug, can also affect bone metabolism.31
ing from seizure-related falls20 or trauma occurring in the Therefore, hepatic enzyme-inducing properties of AEDs are
context of seizure-related impairment of consciousness.21,22 likely to account for just a part of the association between
A retrospective 7-year analysis found a 61% of traumatic AED use and reduced BMD.
seizure-related fractures.23 Interestingly, traumatic fractures Children treated with valproate have a 10% or greater
were more likely to occur in men (55%), whereas patholog- reduction in BMD compared with controls.18 Considering
ical fractures were more likely in women (57%). that a 7% reduction of BMD in healthy adults is associated
Patients with epilepsy have an increased risk for fracture with a 50% increase in osteoporotic fractures,32,33 valproate
because of trauma injury incurred during seizures them- use in children might be expected to increase the risk of
selves. In the report by Vestergaard et al20 on fracture rates in future fractures.
198
The pathogenesis of valproate-associated reduction in
BMD remains undefined. Valproate has been associated with
reversible Fanconi syndrome,34,35 suggesting that valproate
may cause renal tubular dysfunction with increased urinary
loss of calcium and phosphorus. Sato et al28 found that 23%
of patients taking valproate for more than 1 year had a reduc-
tion in BMD in the osteoporotic range. This effect was present
despite increased weight, which is typically associated with a
protective effect on bone mineralization.
A 2-year longitudinal study performed by Verrotti et al27 in
60 adolescents taking carbamazepine compared serum
markers of bone formation and resorption after starting car-
bamazepine in normal subjects with epilepsy. Subjects
achieved typical serum concentrations of carbamazepine.
They were age and gender matched with controls and divided
by developmental status into 3 groups: prepubertal, puber-
tal, and postpuberty. After 2 years of carbamazepine treat-
ment, they found that several serum markers of collagen and
bone turnover were significantly increased. A urinary cross-
linked N-telopeptide of type 1 collagen excretion, a marker of
osteoclastic activity, was increased 10-fold. Interestingly, this
effect occurred despite a normal calcium intake and in the
face of similar parathyroid hormone and vitamin D serum
concentrations. Furthermore, pubertal stage did not influ-
ence the association. These findings suggest that increased
bone turnover occurred despite normal vitamin D levels.
Increased bone turnover during a critical period of miner-
alization can have long-lasting consequences on bone health.
A recent cross-sectional study of patients on AEDs under age
50 years showed that 40% were osteopenic, whereas 10%
had osteoporosis.36 These rates are considerably higher than
the incidence in the general population.
Other models attribute bone loss to the high-turnover state
that results from drug-induced interference with calcium ab-
sorption as well as direct effects on osteoclasts and osteo-
blasts. The resultant hypocalcemia can exacerbate seizures
that are treated with higher doses of anticonvulsants, which
sets up a vicious cycle.37 There might be other mechanisms
by which the use of AEDs leads to changes in bone compo-
sition, including effects on intestinal calcium absorption, in-
hibition of the cellular response to parathyroid hormone,
hyperparathyroidism, and calcitonin deficiency.38-40
Despite the emerging concern of epilepsy treatment on
bone health, few neurologists routinely screen for osteoporo-
sis.41 Earlier suggestions for vitamin D supplementation36
may not be enough to overcome the enzyme-inducing effects
of AEDs.6 The newer AEDs may be less likely to have a neg-
ative impact on bone, although this remains to be studied.
Unfortunately, this issue is even less well addressed in chil-
dren with epilepsy.
Of the newer AEDs used in the treatment of pediatric ep-
ilepsy, only lamotrigine has been evaluated regarding BMD.
Guo et al42 examined the effect of lamotrigine (16 children),
valproate (28 children), or a combination of the 2 (4 chil-
dren) on children aged 3 to 17 with epilepsy.42 They found
that treatment with valproate or lamotrigine for more than 2
years was associated with short stature, low bone mass, and
reduced bone formation. The major predictor of lowered
E.A. Samaniego and R.D. Sheth
bone mass was physical inactivity. However, only total BMD
was measured. This study design may account for the differ-
ences noted from other studies that used a more standardized
approach of measuring bone density in the distal third of the
radius, the lumbar spine, and the femoral neck. The authors
reasonably suggest that calcium homeostasis would be ex-
pected to be more generally linked with whole-bone miner-
alization rather than site-specific changes. A limitation of this
study is the presence of a lower range of body height (below
the 10th percentile) in 43% of the patients. This raises the
interesting issue of the role of growth in bone mineralization.
The authors suggest that lower physical activity in their co-
hort accounted for most of the observed reductions in BMD.
Growth stature and pubertal stage were studied in girls
receiving oxcarbazepine and carbamazepine.43 The authors
did not study bone mineralization directly but looked at body
height as an indirect measure of bone growth. The drugs
appeared not to affect linear growth or pubertal develop-
ment.
Dual-Energy Radiograph Absorptiometry
Dual-energy radiograph absorptiometry (DEXA) scans are a
cost-effective method of quantitatively evaluating BMD. The
hip and lumbar spine are the sites most frequently measured
for central mineralization and are most frequently involved in
involutional fractures. Measures of the distal third of the ra-
dius determine the “peripheral” mineral content. Between
30% and 40% of mineral content must be lost before a rou-
tine radiograph can shows osteoporosis. In contrast, DEXA
can detect 2% to 5% of bone mineral loss.
Standardized normative data are available for most bone
sites at risk of fractures. Patients with 1 to 2.5 standard devi-
ations below normal mineralization are considered to have
osteopenia, whereas 2.5 standard deviation below normal is
defined as osteoporosis.36 BMD measures are strongly corre-
lated with risk of osteoporotic fractures. For each decreased
standard deviation in BMD, there is a doubling of the fracture
rate.44
The National Osteoporosis Foundation cites the following
risk factors for the development of osteoporotic fractures in
the general population: a history of fracture as an adult, his-
tory of fragility fracture in a first-degree relative, low body
weight (⬍58 kg), current cigarette smoking, female gender,
estrogen deficiency at an early age (menopause before age 45
years or bilateral ovariectomy or prolonged premenopausal
amenorrhea [greater than 1 year]), white race, advanced age,
lifelong low calcium intake, alcoholism, inadequate physical
activity, recurrent falls, dementia, impaired eyesight despite
adequate correction, and poor health/frailty. Medical condi-
tions such as chronic obstructive pulmonary disease, gastrec-
tomy, hyperparathyroidism, hypogonadism, multiple my-
eloma, celiac disease, the use of glucocorticoid therapy for
more than 3 months, or the use of anticonvulsants are also
risk factors. Patients with any of these conditions are classi-
fied as high risk and should be screened with a DEXA scan.
Currently, it is not clear if children with epilepsy should
routinely be screened with DEXA scans; nevertheless, DEXA
is being used increasingly in children.45
Bone consequences
Bisphosphonates
Although bisphophonates are the major drugs used for the
treatment of bone diseases associated with excessive resorp-
tion, their use in children is controversial. In growing rats,
bisphosphonates block the removal of both bone and carti-
lage, thus retarding the modeling of the metaphysis, which
becomes club shaped and radiologically denser than normal.
This effect is also observed in children who are treated with
high doses of bisphosphonates.46 The use of biphosphonates
in children on chronic AED treatment is debatable. Case
reports on the induction of osteopetrosis-like lesions in chil-
dren who were treated with excessive doses of pamidronate
have been described.47
Vitamin D Supplementation
Vitamin D supplementation has been advocated as a poten-
tial therapy to counteract the negative effect of AEDs on bone.
However, there are few prospective trials of vitamin D sup-
plementation in patients on AEDs, and the found conflicting
results.48,49 There is evidence of an accelerated vitamin D
metabolism and decreased absorption in subjects taking
AEDs.39 Indeed, a recent study suggested that doses as high
as 50,000 IU of monthly vitamin D would be needed to
normalize vitamin D levels. It was recently recommended
that patients should be treated with an escalating regimen of
vitamin D, with doses varying between 400 and 15,000 IU/d,
depending on the type of AED-induced osteopathy.6 Doses
between 400 and 2,000 IU/d were proposed for prophylaxis
at the beginning of AED therapy, 2,000 to 4,000 IU/d for the
treatment of osteopenia/osteoporosis, and 5,000 to 15,000
IU/d for 3 to 4 weeks for the treatment of osteomalacia.50
Targets for optimal vitamin D levels have not been defined for
healthy children. However, the mean vitamin D levels
reached in a school study while consuming 2,000 IU/d of
vitamin D for 1 year were 38 ⫾ 31 ng/mL, levels well above
the achieved in children on AEDs.50
AED Evaluation
Patients who have already sustained a low-intensity fracture
should have their AED therapy evaluated. The change from
an enzyme-inducing agent or valproate to another AED
should be considered. This decision is at times difficult, es-
pecially for patients who have not experienced a seizure for
many years or are concerned about the cost of changing
AEDs. Once a low-intensity fracture has occurred, the chance
of further fractures increases. Patients with a BMD ⬍2.5
should have their AED regimen evaluated. The decision to
change AED therapy in patients with a BMD in the osteopenic
range (BMD of ⫺1 to ⫺2.5) should be discussed with the
patient. For patients with BMD in the normal range, no AED
change may need to be considered.
Patients with epilepsy appear to have an increased risk for
fracture because of trauma from both seizures and from fall-
related fractures that are not seizure related. Fractures in
persons with epilepsy not directly caused by seizures fre-
quently occur in the lower leg, ankles, and feet.2 These are
not typical sites of low bone density, and patients reported
that these fractures were caused by clumsiness, tripping, and
falling.2 The increased fracture rates in the legs, feet, and toes
199
are likely contributed by AED neurotoxicity and discoordi-
nation. This risk could be minimized by a careful manage-
ment of AEDs to avoid toxicity, limiting benzodiazepine use
and avoiding AEDs that can precipitously reach toxic levels,
in particular phenytoin. Notably, phenytoin use has been
identified as a risk factor for fractures.20 which is likely be-
cause of its narrow therapeutic window as well as its effect on
bone metabolism.
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