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evidence81, epilepsy and AED treatment per se are now recognised as secondary risks.
Qfracture also has the advantage, for clinical use, in producing a helpful Cates plot82 to
facilitate shared patient decision-making.

The risk from AEDs is almost certainly substantially lower than, for example, that with steroid
treatment, which is presumably why epilepsy/AEDs are still not included in what after all is an
international, WHO-backed consensus guideline for osteoporosis updated as recently as
201012. For example, the odds ratio (OR) for fracture risk in patients on long-term
glucocorticoid treatment83 ranges from around 2 (hip) to over 5 (spine) after as little as six
months’ treatment, compared to the ~1.4 OR that might be attributable to AEDs (excluding
seizure-related fractures) after many years. Importantly, the cost, clinical effectiveness and
service implications of including epilepsy patients as a high-risk group have also barely been
evaluated, though perhaps are deserving of further research to inform future practice and
guidelines.

Calcium and vitamin D supplements
The argument for ensuring adequate vitamin D levels in all patients on AEDs, notwithstanding
that there are undoubtedly vitamin D independent mechanisms37, is far stronger than for DEXA
scanning. As previously discussed, hypovitaminosis D appears to be a widespread problem,
not just in epilepsy patients, and is an independent risk factor for fracture. Vitamin D is cheap,
well tolerated, and supplementation is of proven efficacy in community-based studies of high-
risk groups (principally the elderly), both with calcium13 and alone84, irrespective of vitamin D
status. Two randomised controlled trials of vitamin D supplementation in ambulatory children
and adults on AEDS have now been reported together85. In adults, in whom the baseline BMD
was lower than in control populations consistent with other studies, after one year of
supplementation only high-dose (4000 IU/day), and not low-dose (400 IU/day), vitamin D was
effective as assessed by BMD increases. In children, baseline BMD was normal, but increased
in both low- and high-dose treatment groups. Reflecting this, national guidance now exists
recommending that vitamin D supplementation should be considered for at-risk patients taking
long-term enzyme-inducing AEDs or valproate86. ‘At risk’ and ‘long-term’ are however not
defined, there is no guidance on dose or what levels to aim for in this population, and the
exclusion of those on newer non-enzyme-inducing AEDs may well reflect absence of evidence,
rather than evidence of safety.

Although the standard recommended daily vitamin D intake is 400 IU/day, and this is the most
readily available form in combination with calcium, most published trials (not specific to
epilepsy) use doses equal to 8001100 IU/day, either daily or as a three-monthly bolus. There
is also data supporting that patients on AEDs probably require higher doses, perhaps up to 4000
IU/day87-89 or in some instances over 50 times the normal daily dose of vitamin D to overcome
the enzyme inducing effects of phenytoin90, and in the epilepsy trials cited above, it was only
the high dose (4000 IU in adults) which was effective. Ongoing international debate about
‘normal’ ranges, limits and recommended daily intakes further confuse the picture, with a
growing expert body pushing for an increase in the acceptable lower level and recommended
intakes91. There is additionally no consensus on when such supplementation might be most
beneficial. While a pragmatic view might be only to provide supplements to older patients most
at risk, some studies have suggested that the young adult skeleton, particularly in men, is most
at risk of AED-induced bone loss38,73, and from the one trial in epilepsy, even low doses might
be enough in children85. Even high doses of vitamin D alone (i.e. without similarly high doses
of calcium) are generally considered safe, with the minimal risk of unmasking untreated
hyperparathyroidism almost certainly outweighed by the benefits. Annual costs (BNF 2010)
per patient vary from £25 (standard 400 IU and calcium supplement) to £250 or more for higher
doses of some formulations of vitamin D alone, many of which are less readily available and
licensed only for confirmed insufficiency. For comparison, a vitamin D serum level costs