Medicines Q&As
Q&A 122.4
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: 28th June 2012
Background
Osteoporosis is a progressive, systemic, skeletal disease, which is characterised 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, which commonly occurs after a fall
from standing height or less [3]. Patients with epilepsy are at high risk of fractures due to falls caused
by seizures, 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) include, the enzyme inducing antiepileptic drugs; phenytoin,
phenobarbitone, primidone and carbamazepine, and the non-enzyme inducing antiepileptic drugs:
lamotrigine, gabapentin, topiramate, tiagabine, valproate and levetiracetam [5].
Answer
Antiepileptic 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 [6-11]. 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].
The Summary of Product Characteristics (SPC) for several AEDs highlight possible associations with
bone related adverse events; carbamazepine has been associated rarely with disturbances in bone
metabolism and osteomalacia [12]; phenytoin and sodium valproate have been associated with
decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long term
treatment [13, 14], osteomalacia has been reported with primidone and phenobarbital [15, 16]. The
SPC for primidone suggests that vitamin D supplementation may be needed during long term
treatment, since vitamin D catabolism may increase [15].
Several small studies have assessed the impact of AED use on vitamin D levels, bone turnover
markers and bone mineral density (BMD). Phenytoin, phenobarbitone, carbamazepine,
oxcarbazepine and valproate have been associated with changes in bone turnover markers, reduction
in serum vitamin D levels and decreased bone mineral density [17-32].
There have been no adequate studies and only a few anecdotal reports of reduced BMD with the
newer AEDs such as lamotrigine, levetiracetam and topiramate. [30-37]. Lamotrigine and
levetiracetam do not appear to be has been associated with effects on bone [30-35]. Topiramate did
not affect bone turnover markers when compared with placebo in a small study involving 29 obese
subjects [36]. In another study, topiramate treatment was associated with mild hypocalcaemia and
increased bone turnover but no change in BMD from baseline, in 36 women receiving topiramate for
longer than 1 year [37]. A definite conclusion cannot be established from this limited data [30-37].
Progressive bone deficit and an increased risk of developing osteopenia and osteoporosis has been
linked with both childhood use and long term use of anti-epileptics. [38-47]. 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 [45]. In the first case, a 36 year old women, who
developed epilepsy at the age of 10 and had received AEDs for 28 years, including phenobarbitone,
ethosuximide, valproate monotherapy, oxcarbazepine monotherapy and lamotrigine monotherapy,
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
developed severe back pain after a seizure. A subsequent 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, including phenobarbitone, phenytoin,
carbamazepine, and valproate therapies, until the age of 21 years when he stopped AED treatment
completely. He then went on to develop severe osteopenia at 31 years [45].
Five young males with intellectual disability and epilepsy, aged 19-38 years, who had received
between 1 and 4 AEDs for between 14-34 years, sustained one or more fractures with osteoporosis
(T score-3.3 to-2.4) being diagnosed [46]. In another report, the medical examination of 3 young
males aged 21, 27 and 44 years, with a history of long term AED use, who on examination had low
serum vitamin D levels, consistent with vitamin D deficiency as well as low bone T scores consistent
with osteoporosis [47].
In 2 large studies, carbamazepine, oxcarbazepine, clonazepam, phenytoin, phenobarbitone and
valproate were associated with a very limited increased fracture risk, whilst ethosuximide, lamotrigine,
primidone, tiagabine, topiramate and vigabatrin were not. However the total number of patients taking
non-enzyme inducing AEDs, such as lamotrigine was small and limited by short observational periods
and a definitive conclusion regarding the incidence of fractures with the newer agents cannot be
drawn [48].
The authors of smaller study, involving 52 subjects (26 receiving either oxcarbazepine,
phenobarbitone, phenytoin; valproate and lamotrigine and 26 controls), noted there was a tendency
towards an increased prevalence of fracture with increasing duration of AED treatment after 13
patients and 9 control subjects experienced low energy fractures [49].
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 [50].
The exact mechanism of bone effects is not completely understood. Some evidence suggests that
antiepileptics 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 [6, 51-53]. The mechanism by which sodium valproate, a non enzyme inducing drug causes
decreased BMD is unclear [51].
No definitive guidelines for the evaluation, prevention and treatment of AED induced bone disease
have been determined [50-53].
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 for all patients taking enzyme inducing drugs [54].
The Medicines Healthcare and Regulatory Agency (MHRA) have highlighted the effects of AEDs on
bone and 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;



those who are immobilised for long periods
those who have inadequate sun exposure
those with inadequate dietary calcium intake [55].
Vitamin D supplementation should be considered in at risk patients who receive long term treatment
with primidone, phenytoin, carbamazepine, phenobarbital and sodium valproate [54, 55].
The role of bisphosphonates, selective estrogen receptor modulators or calcitonin is of unknown
value in the management of AED bone loss [50].
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
Summary
 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. Levetiracetam does not appear to be associated
with effects on bone; however there is insufficient data to establish a definitive conclusion. Further
studies are necessary with these agents.
 The exact mechanism of AED associated bone disease is not fully known.
 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.
 Vitamin D supplementation should be considered in all 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 unknown 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.
References
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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
28th June 2012
Checked by
Sarah Cavanagh, East Anglia Medicines Information Service
Date of check
11th July 2012
Search strategy.
 Martindale The complete drug. Search terms. Epilepsy, antiepileptics
 BNF online No 63 March. Antiepileptics
 NHS Evidence. Search terms. Searched Epilepsy/osteoporosis.
 National electronic Library for Medicines (NeLM) http://www.nelm.nhs.uk. Searched
osteoporosis, antiepleptics
 Drugdex. Searched carbamazepine, phenytoin, Phenobarbital,primidone, gabapentin,
lamorigine, valproate, sodium valproate, levetiracetam, topiramate, vigabatrin, ethosuximide,
oxcarbazepine.
 Meyler’s Side Effects of Drugs. 15th ed;
 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/
 Embase: anticonvulsive agent + bone or osteoporosis.
 Medline: anticonvulsant + bone or bones..
 IDISweb osteoporosis +
antiepileptics/carbamazepine/phenytoin/valproate/lamotrigine/oxcarbazepine/phenobarbital/to
piramate/vigabatrin/gabapentin/pregabalin/levetiracetam.
From the NHS Evidence website www.evidence.nhs.uk
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