Epilepsy&

Epilepsy & Behavior 5 (2004) S36–S40

Behavior

www.elsevier.com/locate/yebeh

Fractures, epilepsy, and antiepileptic drugs

Richard H. Mattsona,* and Barry E. Gidalb

a Department of Neurology, Yale University, 15 York Street, P.O. Box 208010, New Haven, CT 06520, USAb University of Wisconsin School of Pharmacy and Department of Neurology, Madison, WI, USA

Received 21 November 2003; accepted 21 November 2003

Abstract

The risk for skeletal fractures in patients with epilepsy is two to six times greater than in the general population. Fractures may be

caused by seizures themselves or by falls, with or without seizures. Side effects of antiepileptic drugs (AEDs), such as ataxia, and

coexisting neurological deficits contribute to the risk for falls. The effects of older AEDs on bone mineral density probably increase

the risk for fractures associated with seizures and falls. Preventive measures include optimal control of seizures and supplementation

with calcium and vitamin D. Whether newer AEDs prove to be without adverse effects on bone mineral metabolism remains to be

determined.

� 2003 Elsevier Inc. All rights reserved.

Keywords: Epilepsy; Seizures; Fractures; Antiepileptic drugs; Bone mineral density

1. Introduction

The occurrence of skeletal fractures in people with

epilepsy is increased compared with the general popula-

tion, although the risk varies with a number of factors

[1–8]. The fractures can result from the seizures them-

selves [9–18] or from falls associated with or independent

of seizures [19–22]. Fractures are probably more likely to

occur as a consequence of decreased bonemineral densitycaused by antiepileptic drug (AED) therapy [23]. These

injuries are doubly costly, because their consequences

include pain and suffering as well as loss of time at school

or work [24–27]. Fractures of the hip or vertebrae, es-

pecially in the elderly, may lead to nursing home place-

ment and risk for phlebitis, pneumonia, and death.

Decreased bone mineral density and overt osteoma-

lacia have been well documented in patients with epi-lepsy, and especially those taking phenobarbital,

phenytoin, or primidone, since the late 1960s; however,

the evidence of an increased frequency of fractures was

not reported until Vasconcelos [12], in 1973, and Pe-

dersen et al. [10], in 1976, called attention to the high

incidence of vertebral fractures in patients with epilepsy.

* Corresponding author. Fax: 1-203-785-5694.

E-mail address: Richard.Mattson@yale.edu (R.H. Mattson).

1525-5050/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2003.11.030

2. Incidence of fractures in patients with epilepsy

No prospective studies have been performed to define

the frequency of fractures in patients with epilepsy.

Systematic reviews of the literature, however, have

suggested that use of AEDs is indeed a significant risk

factor for the development of fractures related to loss of

bone mass [28]. The available publications are case

reports, retrospective analyses, and, at best, case–controlstudies. The populations studied differ widely as well.

Some studies were conducted in institutions for persons

with other handicaps, such as intellectual disability, in

addition to epilepsy [8], whereas others included out-

patients with relatively normal function [6].

Fractures were described in 1977 by Lidgren and

Walloe [4]. They reported a study of 87 adult patients

with long-standing epilepsy who lived in apartments buthad mild handicaps. The patients were evaluated from

1969 through 1975. Most had been treated with phe-

nytoin. Analysis for fractures revealed a sixfold increase

compared with an age-matched normal population. The

bones affected included the femur, radius, and ankle.

The increase was particularly marked for fractures of

the femur. Interestingly, 22 of 35 fractures seemed not to

be related to a seizure. Allen and Oxley [1] conducted a5-year retrospective survey of fractures at the Chalfont

R.H. Mattson, B.E. Gidal / Epilepsy & Behavior 5 (2004) S36–S40 S37

Centre for Epilepsy in England. They reported on 67patients who had 118 fractures, comparing them with an

epilepsy control group that did not experience fractures.

The two groups differed only in that tonic seizures were

significantly more frequent in the fracture group.

Markers of abnormal calcium metabolism were evident

in both groups. Subsequently, multiple publications

have confirmed these early observations of an increased

incidence of fractures in patients with epilepsy.Desai and colleagues [3] performed a retrospective

evaluation of fracture frequency in 202 institutionalized

patients with epilepsy and compared this with expected

rates in a normal population. Overall, there was an

apparent fivefold increase in femoral neck fractures as

well as a nearly tenfold increase in ankle fractures. The

occurrence of fractures of the humerus was increased

fourfold. In this population, the apparent fracture ratewas 1 in every 14 person-years. Similarly, Lidgren and

Walloe [4] reported the incidence of fractures to be 1 in

every 8.7 person-years.

In another study of developmentally disabled patients

with epilepsy, Jancar and Jancar [8] found that fractures

occurred in 26% of patients with epilepsy as compared

with 15% of nonepileptic patients.

Persson and co-workers [6] evaluated the incidence ofextremity fractures in a group of patients with epilepsy

seen in an outpatient epilepsy clinic. Relative risk of

fracture was calculated by comparing fracture rates in

the general population in the same geographic area.

These authors found that the incidence of fractures was

1 in every 42 person-years, representing a standardized

morbidity ratio (observed minus expected for the pop-

ulation) of 2.39. The relative risk for fractures involvingthe humerus, forearm, hands, and fingers, as well as the

hips, legs, and feet, was apparently most increased in

patients older than 45 years. Fractures in older men may

be particularly more common.

In a questionnaire study of noninstitutionalized pa-

tients with epilepsy, Vestergaard et al. [7] found an in-

creased fracture rate in patients with epilepsy as

compared with a normal control group that was ran-domly selected from a geographically similar popula-

tion. In this study, the relative risk for fractures of the

spine, forearm, femur, feet, and toes was significantly

increased as compared with controls. Patients with epi-

lepsy were also more likely to be hospitalized for frac-

tures. The overall fracture rate was calculated to be 194

per 10,000 person-years, representing a relative risk of

2.0 as compared with controls. Not unexpectedly, therelative risk of fractures in the epilepsy group appeared

to increase with advancing age. In addition, among the

AEDs reported to be used by this patient group (in-

cluding carbamazepine, valproate, primidone, barbitu-

rates, vigabatrin, tiagabine, oxcarbazepine, lamotrigine,

gabapentin, and clonazepam), only phenytoin use was

associated with an increased fracture rate.

Annegers et al. [2] found that the incidence of hipfracture was higher in patients with seizures as com-

pared with the general population. Similarly, in an as-

sessment of more than 9000 Caucasian women older

than 65 years, Cummings et al. [20] found that post-

menopausal women who had ever received AEDs were

at elevated risk for hip fracture.

In addition to an apparent increase in the risk for

extremity fractures, the incidence of vertebral fracturealso appears to be increased. In a case–control study,

Scane et al. [29] found that the relative risk for vertebral

fracture in patients receiving AEDs as compared with

controls was 6.1 (95% confidence interval, 1.3–28.4), an

increase comparable to that seen in patients receiving

steroid agents. Pedersen et al. [10] performed radiogra-

phy on 87 asymptomatic patients with epilepsy and

found that 14 (16%) had compression fractures, con-firming the findings of Vasconcelos. In none of the re-

ported cases was a neurological deficit found.

Not surprisingly, the precise risk for fractures in pa-

tients with epilepsy is not clearly defined. Nonetheless,

all reports indicate an increased frequency of fractures,

ranging from two to six times greater than that expected

in an otherwise comparable nonepileptic population.

3. Relationship of seizures to fracture rate

Seizures themselves can infrequently cause fractures.

Seizures were first recognized as a cause of vertebral

compression fracture almost a century ago in a patient

with tetanus [12]. Electroconvulsive therapy, when in-

troduced in the 1930s, also caused vertebral fractures. Itwas theorized that the extreme muscular contractions

led to hyperflexion that caused compression of the spine.

Vasconcelos first described these findings in patients

with epilepsy [12]. Fifteen of 1487 patients with epilepsy

underwent radiography because of complaints of back

pain, and all 15 exhibited thoracic compression frac-

tures. Many of the fractures occurred during sleep ra-

ther than when the patient was up and about, makingtrauma from a fall an unlikely explanation. Another

group was selected, comprising 70 patients with grand

mal seizures who did not have symptoms of fracture,

and radiography was performed. These studies revealed

that 11 patients (16%) had unrecognized fractures. The

fractures had occurred early in the course of their epi-

lepsy. Subsequent cases were reported of seizure-in-

duced fractures occurring in sleep or during statusepilepticus, without a history of a fall or evidence of

external trauma [9–12]. Less frequently, vertebral burst

fractures have occurred and caused neurological deficits

[17,18]. Rarely, compression fractures may be the pre-

senting sign of undiagnosed epilepsy [9].

Another complication associated with seizures is

shoulder dislocation/fracture. This commonly produces

S38 R.H. Mattson, B.E. Gidal / Epilepsy & Behavior 5 (2004) S36–S40

an unusual bilateral posterior dislocation and fracture ofthe humerus, a finding considered highly indicative of a

seizure even if no seizure was witnessed or reported [13–

16]. The dislocation is believed to be due to strong

muscular contractions that cause internal rotation and

adduction. These occurrences have been reported pri-

marily in men, perhaps because of the more powerful

male musculature [13].

Not surprisingly, many fractures, as well as otherinjuries associated with seizures, result from the trauma

of a fall [1,4–7,24–27]. These fractures are usually seen in

the context of a tonic–clonic, tonic, or atonic attack.

Generalized tonic–clonic seizures pose a substantial risk

for fractures. The fractures often occur early in the

course of epilepsy, suggesting that control of the more

severe attacks with AED therapy may contribute to a

decreased incidence later in life. The fractures associatedwith these seizures commonly involve the hip, foot/an-

kle, humerus, and wrist [1,3,6,7]. Many studies did not

assess vertebral fracture, presumably because of the

common occurrence of asymptomatic vertebral frac-

tures, as well as the difficulty of radiological diagnosis.

Traumatic vertebral fractures often affect the lumbar

spine, rather than the thoracic spine, as is seen in cases

of seizure-induced compression.While it is commonly assumed that most fractures

occur as a consequence of a seizure, the available data

suggest a marked increase in the fracture rate that is

independent of specific seizure events. Large epidemio-

logical studies [14–17] indicate an approximate doubling

of fracture incidence among people taking AEDs, even

in the absence of seizures. Desai et al. [3] noted that of

323 fractures recorded, only approximately 35% wereknown to have occurred during a seizure. As noted

previously, the overall fracture rate in this study was 1 in

every 14 person-years. For fractures apparently not

occurring during a seizure, the rate was 1 in every 21.4

person-years. Persson and colleagues [6] reported that

43% of fractures were definitely, or most probably, as-

sociated with a seizure, while 22% were clearly not sei-

zure-related. Causality could not be adequatelydetermined in the remaining cases. In the questionnaire

study by Vestergaard et al. [7], of fractures that occurred

after a diagnosis of epilepsy was made, approximately

34% were reported to have been associated with seizures,

a figure similar to that noted by Lidgren and Walloe [4].

With respect to hip fracture, Cummings et al. [20] also

noted that none of the hip fractures reported in older

women receiving AEDs appeared to be associated witheither a seizure or other loss of consciousness.

4. Antiepileptic drugs, epilepsy, and falls

Although the injuries associated with falls can be

secondary to seizures, many patients are at risk for falls

because of incoordination, ataxia, clumsiness, or weak-ness resulting from coexisting neurological deficits or

medication side effects. Interestingly, increased fracture

risks have also been associated with the use of ben-

zodiazepines, antidepressants, and antipsychotics, sug-

gesting that underlying brain disease or adverse effects

of the medication were responsible for the falls and

injuries.

5. Abnormal bone mineral metabolism

In addition to the trauma of seizures and falls, very

persuasive evidence has emerged that dysfunction of

bone leads to increased susceptibility to fractures [18].

The frequency of occurrence, the types of fractures en-

countered, the cause of the problem, the consequencesof the fractures, and their prevention and treatment are

important issues.

The occurrence of rickets and osteomalacia in pa-

tients with epilepsy was first reported in Germany in

1967 [23]. These observations were confirmed by others

over the next few years, and evidence indicated that the

problem was at least in part attributable to AED use

and probable interference with vitamin D metabolism[23]. Some interference with intestinal calcium absorp-

tion and inhibition of osteoblast function may also play

a role. It is quite probable that this decreased bone

mineral density makes the occurrence of a fracture much

more likely in the event of a seizure, with or without a

fall. The potential pathophysiological mechanisms un-

derlying AED-associated bone disorders are discussed in

a comprehensive review by Fitzpatrick [30].

6. Prevention of fractures

The most obvious measure for prevention of seizure-

related fractures is optimal control of seizures, especially

those of the tonic–clonic type, with optimal medical/

surgical treatment. When control is not possible, envi-ronmental modification to minimize risk is also impor-

tant. Avoidance of overtreatment with AEDs may

minimize dizziness, ataxia, visual changes, and cognitive

slowing, all of which can contribute to falls.

Supplemental calcium and vitamin D (a minimum of

1000 mg and 400 IU daily, respectively) probably should

be taken, especially by those patients taking phenobar-

bital, phenytoin, or primidone. Although evidence ofdisturbed bone mineral density is less consistent for

patients taking carbamazepine and valproate, supple-

mentation is probably advisable for these patients also.

Despite the known risk for fracture posed by low bone

mineral density, a survey of neurologists conducted by

Valmadrid et al. [31] revealed that only 7% prescribed

supplements for patients taking AEDs. The evidence

R.H. Mattson, B.E. Gidal / Epilepsy & Behavior 5 (2004) S36–S40 S39

that valproate, a non-enzyme-inducing AED, altersbone density [32] raises the possibility that the new

AEDs, many of which are also non-enzyme-inducing,

may also prove to be implicated in the problem and

should be tested for effects on bone density. Farhat et al.

[33] confirmed other studies showing changes in bone

mineral metabolism associated with use of AEDs, in-

cluding some effect of the newer AEDs. It can be as-

sumed that correction or prevention of low bone densitywould decrease susceptibility to fractures, but there are

few prospective studies to prove a benefit, although re-

mineralization can be accomplished. In an older study,

supplementation of the diets of patients with epilepsy

with 400 IU/day vitamin D for 2 years was followed by a

reduction in fracture incidence [34].

In patients with osteoporosis, higher doses of vitamin

D may be needed. The precise role of bisphosphonatetherapy is still unclear. For a further discussion of po-

tential treatment approaches to patients with AED-as-

sociated bone disorders, the reader is directed to the

review by Drezner [35].

Other measures, including adequate physical exercise

and, in women, low-dose hormone replacement, may

have a role.

7. Summary

The incidence of fractures is increased in patients with

epilepsy. Some fractures are directly due to seizures or to

falls, with or without associated seizures. The propensity

to fall is probably aggravated by adverse effects ofAEDs, such as ataxia. In addition, the likelihood of

fractures is increased by the effect of older AEDs on

bone mineral density, which can lead to osteopenia and

osteoporosis.

Fractures can have catastrophic effects on the lives of

patients with epilepsy, and measures are available to

minimize the risk for fractures, such as ensuring ade-

quate calcium and vitamin D supplementation and,potentially, using antiresorptive therapy. The doses of

vitamin D employed should be sufficient to normalize

biochemical markers of bone turnover. Clinicians

should recognize that relatively large doses of vitamin D

may be required to correct vitamin D deficiency in some

patients [35]. The evidence suggests that these measures

are not currently being taken. Whether newer AEDs will

prove to be without adverse effects on bone mineralmetabolism remains to be determined.

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