Medicines Q&As
Q&A 122.3
Can antiepileptics (anticonvulsants) increase the risk of
osteoporosis?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 30th April 2010
Background
Osteoporosis is a progressive, systemic, skeletal disease, which is characterized by a decrease in
bone mineral density (BMD) and an increase in bone fragility and fracture risk (1, 2). Osteoporosis is
asymptomatic and usually presents only after a bone fracture. The risk of falls and resulting trauma
are difficult to assess and predict.
Osteoporotic fractures are also called fragility fractures and commonly occur after a fall from standing
height or less (3). Patients with epilepsy are at high risk of fractures due to falls caused by seizures or
drowsiness and co-ordination difficulties caused by antiepileptic drugs (AEDs) (4).
Osteomalacia and osteoporosis may also contribute to the high fracture rate among people with
epilepsy (4).
Antiepileptic drugs (AEDs) can be divided into two groups; the enzyme inducing antiepileptic drugs
(EIAEDs) which includes phenytoin, phenobarbitone, primidone and carbamazepine and the nonenzyme inducing antiepileptic drugs (NEIAEDs) which include, lamotrigine, gabapentin, topiramate,
tiagabine, valproate and levetiracetam (5).
The Medicines Healthcare and Regulatory Agency (MHRA) have recently highlighted the effects of
AEDs on bone and have issued some guidance on the prevention of AED associated bone loss (6).
Answer
Anti-epileptic drugs have been associated with bone disorders since the late 1960s with an increased
incidence of hypocalcaemia, rickets, osteomalacia and fractures observed in epileptic patients on long
term AEDs, however the majority of these early cases were in institutionalised patients and inactivity,
inadequate diet and insufficient exposure to sunlight provide an alternative explanation for these
observations (7-11). A case controlled study in 2002, involving 231,778 adult patients found that
patients taking AEDs had the highest risk for fracture with an odds ratio of 2.1 compared to patients
with a past history of oral corticosteroid use who had an odds ratio of 1.4 (11).
Phenytoin, phenobarbitone and primidone are most commonly associated with altered bone
metabolism and decreased bone density (7, 10). There are conflicting results relating to
carbamazepine and there is inadequate data relating to valproate and the newer agents including
lamotrigine, topiramate, levetiracetam and gabapentin (7). The exact mechanism of AED induced
bone disease is not fully understood. A suggested possible mechanism is induction of hepatic
cytochrome P450 enzymes which can lead to increased breakdown of vitamin D and subsequent
hypocalcaemia, hyperparathyroidism and increased bone metabolism. Other mechanisms may
include decreased intestinal calcium absorption, inhibition of response to parathyroid hormone and
calcitonin deficiency (12, 13).
Several studies have assessed the impact of AED use on bone mineral density (BMD). A casecontrolled study involving 78 patients with epilepsy assessed the relationship between bone mineral
density and long term treatment with antiepileptic drugs. Males with epilepsy had significantly lower
BMD values at the lumbar spine and femoral neck than the control group whilst females with epilepsy
had significantly lower BMD at the femoral neck but not at the lumbar spine. There was no difference
in BMD between patients taking enzyme inducing drugs and those taking non-enzyme inducing drugs.
Both groups had lower BMD at the femoral neck and lumbar spine than controls (14).
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
A study comparing effects on BMD with antiepileptic use and non-use in twins and sibling pairs
reported a within pair difference for forearm BMD as 0.508 for AED users compared with 0.529 in
non-users (difference -3.8%). In subjects who had taken an enzyme inducing AED for greater than
two years, the BMD was 0.505 versus 0.531 in non AED users (difference -4.8%) (15).
In a one year, observational study, involving 93 pre-menopausal women with epilepsy, phenytoin was
associated with significant femoral neck bone loss over 1 year whilst carbamazepine, lamotrigine and
valproate did not have detectable adverse effects on bone turnover or bone mineral density (16).
A study involving 93 pre-menopausal women with epilepsy, aged 18-40 years, receiving a single AED
for 6 months, assessed the impact of AED on bone turnover markers. All the women had been taking
either carbamazepine (n=37), lamotrigine (n=19), phenytoin (n=19) and valproate (n=18)
monotherapy for between 8 to 13 years. The average treatment duration for the lamotrigine group
was 21 months which was significantly shorter than the other groups; however the study authors
stated that this was a sufficient amount of time to affect the important markers of mineral metabolism
and bone turnover. BMD scores did not differ between the groups. Serum calcium concentrations
were significantly less in patients receiving carbamazepine, phenytoin, and valproate than in those
receiving lamotrigine (p=0.008). Phenytoin was associated with changes in bone metabolism and
increased bone turnover. Subjects receiving lamotrigine had no significant reductions in calcium or
increases in markers of bone turnover (16, 17).
A cross sectional retrospective study including 42 adults, assessed the effects of long term (>6
months) AED use on vitamin D levels and BMD. Twenty-five (59%) adults displayed signs of
osteopenia at the spine or hip (18). Adult patients taking enzyme-inducing AEDs, such as phenytoin
and phenobarbitone, had a lower BMD of the spine, total hip, femoral neck, trochanter and total body
than those taking non-enzyme inducing drugs such as valproate or lamotrigine, although the
differences were not significant. The study was not designed to show whether these changes in BMD
resulted in osteoporosis or fractures. This study did provide a small amount of data regarding the
impact of therapy duration on BMD and the effects on BMD in children.
A small study in 1995 involving 26 children with epilepsy concluded that carbamazepine did not
significantly reduce bone mineral density although valproate was associated with a 14% reduction in
BMD (19). Another study in 2000 showed that carbamazepine treatment could induce an increase in
bone turnover and potentially cause bone disease (20). The current Summary of Product
Characteristics (SPC) for Tegretol includes disturbances in bone metabolism and osteomalacia as a
very rare side effect (21).
Sato et al reported that 23% of patients taking valproate for longer than one year had a reduction in
BMD consistent with osteoporosis (22).
In a prospective, longitudinal study, BMD was measured before and after 6 months treatment of AED
monotherapy, in 33 drug naïve patients with newly diagnosed epilepsy. After 6 months the change in
BMD was -0.76; p=0.043 in the carbamazepine group; -0.55, p=0.068 in the valproate group and 0.12, p=0.100 in the lamotrigine group. This was accompanied by a statistically significant decrease in
serum vitamin D (25-0HD3) levels in the carbamazepine group (-10.9ng/ml, p=0.018) but not in the
valproate and lamotrigine groups (+3.4ng/ml, p=0.593 and -3.1ng/ml, p=0.668 respectively).
The change in serum osteocalcin levels was +7.3ng/ml, p=0.131 in the carbamazepine group,
+21.6ng/ml, p=0.002 in the valproate group and +15.1ng/ml, p=0.012 in the lamotrigine group. Serum
parathyroid hormone levels increased in all groups. No significant difference were observed in total
calcium (23)
Boluk et al studied the long term effect of valproate on BMD in 50 adult epileptic patients compared
with 60 control patients. At baseline, lumbar and femoral BMD values were significantly lower in
patient group than control group (0.814 ± 0.157 g/cm vs. 0.894 ± 0.102g/cm, P=0.003 and 0.824 ±
0.144 g/cm vs. 0.906 ± 0.104 g.cm; p=0.001 respectively. After 6 months treatment, all of the BMD
values had worsened compared to baseline (24).
A study by Ensrud et al, measured change in hip BMD from baseline, in men aged 65 or above, on
either NEIAEDs; including gabapentin, lamotrigine, valproic acid, levetiracetam, pregabalin and
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
tiagabine (n=100), and EIAEDs; including phenytoin, carbamazepine and phenobarbitone (n=62) or
non AED users (n=4022). Both EIAEDs users and NEIAEDS users appeared to have a higher
adjusted rate of bone loss at the total hip (-0.63%/year and -0.55%/year respectively; p=0.07 and The
patients taking NEIAEDs, when compared with non-AED users.(-0.35%/year). Findings were similar at
the femoral neck and trochanter. The results did not change significantly, if valproate users were
excluded. For gabapentin users only, BMD change at the hip was -0.62% vs. - 0.35% in non users,
p=0.005.). For phenytoin users only, the change in total hip BMD was -0.73%/year (25).
A study by Mintzer et al, measured the serum levels of vitamin D, parathyroid hormone, osteocalcin
and bone alkaline phosphatase in epilepsy patients taking either carbamazepine (n=21),
oxcarbazepine (n=24) and compared them with normal control subjects (n=24). Vitamin D levels were
lower in both AED treated groups; the difference was only statistically significant in the oxcarbazepine
group. Parathyroid hormone, bone alkaline phosphatase did not differ significantly among the groups.
Osteocalcin levels were raised in both the treatment groups (26).
In a small study involving 56 patients, the impact of oxcarbazepine on BMD and serum vitamin D3
levels in 28 adult patients was compared to 28 healthy control patients. After 1 year, there was little to
no change in BMD or biochemical parameters of bone metabolism and serum vitamin D3 levels. The
study authors concluded that oxcarbazepine had little or no effect on enzyme induction and did not
affect bone mineral metabolism (27).
Topiramate did not affect bone turnover markers when compared with placebo in a small study
involving 29 obese subjects (28).
In a study involving 16 patients aged 20-66 years who had been receiving levetiracetam for longer
than 6 months for the management of epilepsy, levetiracetam was not associated with a significant
decrease in vitamin D levels or bone mineral density (29).
Fracture risk
Two case control studies have assessed the impact of AEDs on fracture risk (30, 31). In the first
study, involving 498,617 patients; carbamazepine, oxcarbazepine, clonazepam, phenobarbitone and
valproate were all associated with a very limited increased fracture risk (30). Ethosuximide,
lamotrigine, phenytoin, primidone, tiagiabine, topiramate and vigabatrin were not significantly
associated with increased fracture risk. The second study assessed 40,485 patients with epilepsy of
which 3,478 experienced a fracture during the study period (31). An increased risk of fracture was
shown for monotherapy with carbamazepine, valproate, phenobarbitone and phenytoin but not
lamotrigine. The use of more than one AED was also associated with a higher risk of fracture. The
number of patients taking non-enzyme inducing AEDs in both studies was small and the studies were
also limited by short observational periods. Consequently the power of these studies to detect fracture
risk was low and a definitive conclusion regarding the incidence of fractures with the newer agents
cannot be drawn. The study authors concluded that a small fracture risk with newer agents could not
be excluded (30, 31).
Total z-score bone mineral density was measured in 13 children treated with lamotrigine monotherapy
who had never been exposed to other medications, and compared with 36 control subjects and 40
patients exposed to polytherapy. The z scores for lamotrigine and control subjects were similar (0.52
± 0.76 versus 0.49 ± 0.7) but higher that those receiving polytherapy for 1-5 years (0.14±0.8, P=0.12)
and ≥6 years (-0.27 ±1.15; p<0.003). The study authors concluded that lamotrigine may not interfere
with bone accrual (32).
Occurrence of osteoporosis and fracture was assessed in 26 postmenopausal women using AEDs,
including oxcarbazepine, phenobarbitone, phenytoin; valproate and lamotrigine compared with 26
individually matched healthy controls. There were significantly lower BMD values for the femoral neck
and the proximal forearm in the total patient group compared to controls with an increased incidence
of osteoporosis in postmenopausal women using EIAED including those on CBZ therapy. Thirteen
patients and 9 control subjects experience low energy fractures. None of the fractures in the patient
group were seizure related. The study authors noted that there was a tendency towards an increased
prevalence of fracture with increasing duration of AED treatment (33).
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
A report in 2005 of severe osteopenia and osteoporosis in 2 adults with epilepsy since childhood has
suggested a link between long term use of AEDs and reduction in BMD (35). In the first case, a 39
year women who developed epilepsy at the age of 10 had received AEDS for 28 years, including
phenobarbitone, ethosuximide, valproate monotherapy, oxcarbazepine monotherapy and lamotrigine
monotherapy. At the age of 36 she complained of severe back pain after a seizure and an x-ray
revealed two fractured thoracic vertebrae and severe osteopenia. In the second case, a 38 year old
male who had suffered from epilepsy since the age of 7, and had received numerous AEDs until the
age of 21 including phenobarbitone, phenytoin, carbamazepine, and valproate in single or combined
therapies developed severe osteopenia at 31 years (34).
No definitive guidelines for the evaluation, prevention and treatment of AED induced bone disease
have been determined (12-13, 35). A review published in 2010, concluded that an association
between the use of anticonvulsants, reduced bone mineral density and increased fracture risk is
suggested by the available data from observational studies, but that randomised clinical trials are
needed to guide the management of bone disease among those who use anticonvulsants (36).
There is limited understanding of the effects of anti-epileptics on bone. Some evidence suggests that
anti-epileptics induce the cytochrome P450 enzyme system which results in increased clearance of
vitamin D, leading to secondary hyperparathyroidism, increased bone turnover and reduced bone
density. The mechanism by which sodium valproate, a non enzyme inducing drug causes decreased
BMD is unclear (35). The role of bisphosphonates, selective estrogen receptor modulators or
calcitonin is of unknown value in the management of AED bone loss (35).
The National Institute for Clinical Excellence (NICE) in the United Kingdom recommends monitoring
vitamin D levels and other measures of bone health and bone metabolism, including serum calcium
and alkaline phosphatase every 2-5 years among adults taking enzyme inducing drugs (37).
The MHRA have advised all healthcare professionals that long term treatment with phenytoin,
carbamazepine, primidone and sodium valproate are associated with decreased bone mineral
density, which may lead to osteopenia, osteoporosis and increased fractures, particularly in the
following at risk patients (6)



those who are immobilised for long periods
those who have inadequate sun exposure
those with inadequate dietary calcium intake
Vitamin D supplementation should be considered in at risk patients who receive long term treatment
with primidone, phenytoin, carbamazepine, phenobarbital and sodium valproate (6).
Summary
 The MHRA have advised all healthcare professionals that long term treatment with phenytoin,
carbamazepine, primidone and sodium valproate are associated with decreased bone mineral
density, which may lead to osteopenia, osteoporosis and increased fractures, particularly in the at
risk patients (6)
 Phenytoin, phenobarbitone, carbamazepine and valproate have been associated with reduced
bone mineral density and increased fracture rates which are characteristic of osteoporosis.
 There have been no adequate studies and only a few anecdotal reports of reduced BMD with the
newer AEDs such as lamotrigine and topiramate and consequently there is insufficient data to
establish a definitive conclusion. Further studies are necessary with these agents.
 The exact mechanism of AED associated bone disease has not been fully elucidated.
 Vitamin D supplementation should be considered in at risk patients who receive long term
treatment with primidone, phenytoin, carbamazepine, phenobarbital and sodium valproate.
 The role of bisphosphonates, selective estrogen receptor modulators or calcitonin is of unknown
value in the management of AED bone loss.
Limitations
This document only considers the risk of osteoporosis in patients with epilepsy taking antiepileptics
and does not consider other indications associated with antiepileptic drug use.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
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From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
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Quality Assurance
Prepared by
Victoria Gibson, East Anglia Medicines Information Service
Date Prepared
30th June 2010
Checked by
Sarah Cavanagh, East Anglia Medicines Information Service
Date of check
23rd July 2010
Search strategy
 Embase: anticonvulsive agent + bone or osteoporosis, searched 25/03/2010.
 Medline: anticonvulsant + bone or bones, searched .25/03/2010.
 Pharmline: anticonvulsants + bone or osteoporosis, searched 25/03/2010.
 IDISweb osteoporosis +
antiepileptics/carbamazepine/phenytoin/valproate/lamotrigine/oxcarbazepine/phenobarbital/to
piramate/vigabatrin/gabapentin/pregabalin/levetiracetam. Searched 20/04/2010.
 Martindale The complete drug reference online 2010.Accessed via
www.medicinescomplete.com 13/05/2010.
 Meyler’s Side Effects of Drugs. 15th ed; accessed online via
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=&_xRefDocId=pii%23b0444510
052001480&_fmt=high&_orig=na&_cdi=40612&_refWorkId=367&view=c&_acct=C000058983
&_version=1&_urlVersion=0&_userid=5257210&md5=f4bc93dc256e25f07237af9b9d63622c#
s0005. Accessed 01/07/2010.
 Summaries of Product Characteristics (SPC) for Tegretol, Epanutin, Epilim, Sabril, Topamax,
Lamictal, Lyrica, Trileptal, Keppra, Zonegran, Gabatril, Zarontin, Neurontin accessed via
Electronic Medicines Compendium http://emc.medicines.org.uk/ accessed 23/03/2010.
From the NHS Evidence website www.evidence.nhs.uk
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