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or specific drug classes. Given the now huge number of available drugs/drug combinations,
this is perhaps not surprising. Using a surrogate marker of cumulative drug burden (the total
duration of epilepsy multiplied by the number of AEDs), one cross-sectional from a tertiary
population, all of whom had an established diagnosis of osteoporosis64, did conclude that
cumulative drug load was the dominant factor in predicting fracture risk, but this has yet to be
evaluated in larger/more general populations.

Studies in children and adolescents are generally smaller, with an inevitably bigger spread of
data reflecting various growth stages. Several well controlled earlier studies have not found
any significant reduction in DEXA Z scores in children taking CBZ43,65-68 or lamotrigine69,70.
Others have found BMD reductions associated with treatment, especially polytherapy and long
duration, though often without adequate controls for potential confounders71-73. 72. Similarly
there are conflicting reports for VPA34,43,65-68,71,74. Whether the more inconsistent nature of
reports in children reflects purely methodological difficulties, shorter duration of AED therapy,
that there is simply more spare capacity in younger bones that will be unmasked in later life,
or that young skeletons are better able to tolerate metabolic challenges remains unclear.

As for biochemical markers, prospective longitudinal studies (Table 1) offer the greatest
potential. Despite the methodological limitations (most are underpowered, and/or inadequately
controlled for confounders) the message is at least consistent in supporting that AEDs probably
do contribute to reduced bone health, including reduced BMD, though it is notable that despite
the fact that all these prospective studies included a broad range of biochemical parameters the
mechanisms remain uncertain, and correlation between biochemical changes and BMD is
generally absent. This may of course reflect different mechanisms with different drugs.

Attributable risk
In addition to epilepsy-based studies, prevalence data from various populations consistently
report AED use as an independent risk factor for markers of bone disease: AED use is
associated with increased fracture rates amongst ITU patients75, increased hip fracture rates in
Caucasian women in the community76, and hypovitaminosis D in medical inpatients14. Thus
overall, even allowing for confounders, the consistency of the message across different studies
using different methodologies suggests this is a real association. What is more difficult to
ascertain is how significant this is in clinical terms. In one study (men only) to include
sequential scans two years apart, bone loss of an estimated 1.8% per year was attributable to
AED use, and this was a more important risk factor than either smoking or alcohol38.

A prospective community-based study of osteoporotic fractures in over 9000 women over 65
has recently reported on AED use and BMD (hip and calcaneus DEXA) with an average of 5.7
years between scans77. With careful adjustment for confounders, the average rate of decline in
total hip BMD increased from 0.7%/year in non-AED users (ever), to -0.87%/year in ‘partial
users’ (AEDs at some time during the study, but not throughout), to -1.16%/year in continuous
users (P for trend 0.015). Whilst these numbers sound small, such is the importance of BMD,
this translates to a nearly 30% increase in the risk of hip fracture over five years, associated
with AED use. Phenytoin looked the worst offender, but was also the most commonly used
AED, and smaller changes with other AEDs in this study may have been masked by smaller
numbers. As would be expected, the AED users were also different in other respects, e.g. as a
group having less good general health, being thinner and more depressed. HRT and exercise
also came through as protective factors, independent of AED usage. Across mixed-sex
populations, sex and hormonal status almost certainly have a larger influence, and AED use
has been estimated to contribute to only 5% of the total variation in BMD at the femoral neck63.
However, this does not mean men should be complacent: the same group78 have also reported
a community-based prospective BMD study in 4000 men over 65. As expected, all rates of
decline were lower, but men taking notable non-enzyme inducing AEDs at both visits, an