Oseo y Epilepsia

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Medicamentos anticonvulsivos y enfermedades óseas.

AUTORES: Alison M Pack, MD, Elizabeth Shane, MD
EDITORES DE SECCIÓN: Deborah E Sellmeyer, MD, Steven C Schachter, MD
EDITOR ADJUNTO: Katya Rubinow, MD
Todos los temas se actualizan a medida que hay nueva evidencia disponible y nuestro proceso de revisión por pares se
completa.
Revisión de la literatura vigente hasta: enero de 2024.

Este tema se actualizó por última vez: 09 de febrero de 2023.
INTRODUCCIÓN
La epilepsia es una enfermedad crónica que afecta a más de dos millones de personas en los
Estados Unidos, aproximadamente el 1 por ciento de la población [ 1 ]. Los medicamentos
anticonvulsivos (ASM) siguen siendo la base del tratamiento de la epilepsia. Además, estos
agentes tienen ahora muchas otras indicaciones, incluido el tratamiento de las migrañas, el
trastorno bipolar y el dolor crónico.
Tanto la epilepsia como los ASM se asocian con efectos adversos sobre la salud ósea. Las
personas con epilepsia tratadas con ASM tienen mayores tasas de pérdida ósea y anomalías en
el metabolismo óseo y mineral [ 2,3 ]. Estos efectos adversos pueden contribuir a un mayor
riesgo de fractura [ 4 - 7 ].
Este tema revisará la asociación entre las MAPE y los trastornos del metabolismo óseo y
mineral, incluida la osteomalacia/raquitismo y la osteoporosis o baja masa ósea. Además, se
discutirá la detección, el tratamiento y la prevención de las enfermedades óseas relacionadas
con la MAPE.
La osteopenia, la osteoporosis y las fracturas óseas también son una preocupación para los
niños con epilepsia intratable que siguen dietas cetogénicas. Este tema se analiza por separado.
(Consulte "Terapias dietéticas cetogénicas para el tratamiento de la epilepsia", sección sobre
"Efectos adversos comunes" .)
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ENFERMEDAD ÓSEA METABÓLICA
Los primeros informes que vinculan la terapia con medicamentos anticonvulsivos (ASM) con
enfermedades esqueléticas se publicaron a finales de la década de 1960 [ 8 ]. Los pacientes
afectados tenían una enfermedad ósea florida con anomalías clínicas, bioquímicas e
histológicas compatibles con raquitismo y osteomalacia. Sin embargo, estos primeros informes
incluyeron en su mayoría pacientes institucionalizados.
Los estudios de pacientes ambulatorios con epilepsia que viven en la comunidad y que reciben
terapia con ASM generalmente describen anomalías radiográficas y bioquímicas más sutiles,
incluida una disminución de la densidad mineral ósea (DMO), un metabolismo anormal de la
vitamina D y evidencia bioquímica de una mayor actividad de remodelación ósea [ 9-11 ]. . Cada
una de estas anomalías se asocia con una menor resistencia ósea y un mayor riesgo de
fracturas en comparación con las personas que no tienen epilepsia y no toman ASM. Los
pacientes con epilepsia tienen un riesgo aún mayor de sufrir fracturas, debido al mayor riesgo
de caídas y trauma físico asociado con las propias convulsiones, la enfermedad neurológica que
subyace a la epilepsia (accidente cerebrovascular, parálisis cerebral) y los efectos de ciertos ASM
que alteran la marcha. estabilidad. Por tanto, la identificación de individuos con epilepsia que
están predispuestos a sufrir fracturas debido a la disminución de la resistencia ósea es un
aspecto importante de su tratamiento.
Osteoporosis : la osteoporosis se define como un trastorno esquelético caracterizado por una

disminución de la resistencia ósea que conduce a un mayor riesgo de fractura. La fuerza ósea
representa la integración de la cantidad de hueso presente (masa o densidad ósea) y la calidad
de ese hueso [ 12 ]. Aunque las fracturas son el único síntoma clínico de la osteoporosis, la
osteoporosis se puede diagnosticar radiográficamente antes de que se produzcan las fracturas
midiendo la cantidad de hueso presente (densidad mineral ósea o DMO). (Ver "Manifestaciones
clínicas, diagnóstico y evaluación de la osteoporosis en mujeres posmenopáusicas" y
"Manifestaciones clínicas, diagnóstico y evaluación de la osteoporosis en hombres" .)
La osteoporosis, ya sea que se manifieste por una DMO baja o por fracturas, es más común en
mujeres posmenopáusicas y hombres mayores, en quienes los efectos del envejecimiento
(deficiencia de estrógenos y testosterona) causan que el hueso se pierda más rápidamente de
lo que se puede restaurar. Esto conduce al deterioro de la microarquitectura ósea y a la
reducción asociada de su resistencia.
However, osteoporosis can also develop as a result of a host of underlying medical conditions
and medications, in which case it is termed secondary osteoporosis. Concomitantly occurring

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secondary causes of osteoporosis can increase the severity of osteoporosis in postmenopausal

women and older men and can cause osteoporosis in young men, women, and children. ASMs
are one of the classes of medications associated with secondary osteoporosis ( table 1) [13].
In a murine study of untreated chronic temporal lobe epilepsy, there was no evidence of overt
bone abnormalities due to epilepsy itself [14]. (See "Clinical manifestations, diagnosis, and
evaluation of osteoporosis in postmenopausal women" and "Etiology of osteoporosis in men"
and "Epidemiology and etiology of premenopausal osteoporosis".)
Fracture — Fracture is the most important manifestation of osteoporosis. Several studies have
reported that fracture rates are higher in patients with epilepsy than in control populations, and
among patients with epilepsy, fractures are more common in postmenopausal women and
older men [4-7,15-20].
In a report from the Women's Health Initiative (WHI) study, which included 1385 users of ASMs
and 137,282 nonusers aged 50 to 79 years followed for a mean of 7.7 years, use of ASMs was
associated with a significantly increased risk of total fractures (annualized percentage 3.35
versus 2.10 percent, hazard ratio [HR] 1.44, 95% CI 1.30-1.61) and site-specific fractures,
including hip fracture (0.29 versus 0.15 percent, HR 1.51, 95% CI 1.05-2.17) and clinical vertebral
fracture (0.48 versus 0.22 percent, HR 1.60, 95% CI 1.20-2.12) [21]. Both the number of ASMs
used in a patient (more than one ASM compared with one) and type (enzyme inducing versus
non-enzyme inducing) were significantly associated with fracture risk. (See 'Effect of ASM type'
below.)
Other factors associated with higher fracture risk in adults with epilepsy in some [16,22], but
not all [23,24], studies include older age, female sex, greater severity of epilepsy, and duration
of ASM use. Children and young adults may also have an increased risk of fractures compared
with controls [25]. For example, a case-control study of 23 pairs of siblings aged 5 to 18 years
who were within two years of age and who were ASM exposure-discordant found that the
siblings taking ASMs reported more fractures (15 fractures in 8 subjects treated with ASMs
compared with 4 fractures in 3 controls) and had reductions in tibial volumetric BMD and lower
limb muscle force compared with their matched controls [26]. Another study found an age
effect among new ASM users with increased nontraumatic fracture incidence in a younger age
group peaking at 11 to 13 years then decreasing with older age group [27].
Several observations indicate that the increase in fracture rate is related to seizure-related
injuries and the effects of certain ASMs that impair gait stability, as well as the adverse effects of
ASMs on bone strength:

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● Patients with generalized tonic-clonic seizures are at higher risk for fracture than patients
with partial seizures, suggesting that seizure-related injuries contribute [24].
● The observation that epilepsy was associated with an even higher relative risk (RR) of hip
versus forearm fracture (5.3 versus 1.7) suggests a possible preponderance of falls
occurring in patients unable to use their hand to break the fall, a situation that might
occur during a seizure [10,16,28].
● In the WHI study, there was a significant association between ASM use and the risk of falls
(HR 1.6, 95% CI 1.5-1.7) [21].
● In a longitudinal study of balance measures and lower limb strength in 26 sibling pairs,
chronic ASM users had poorer balance compared with nonusers [29]. There was no
difference in quadriceps muscle strength.
Bone mineral density — Some ASMs alter bone and mineral metabolism. Several studies have
reported low BMD at multiple sites in adult patients receiving ASMs, with measurements
generally ranging between 10 and 16 percent below controls [9,19,30-34]. Men and women
appear to be affected similarly [34]. A meta-analysis of 12 studies measuring BMD in patients
with epilepsy found an overall significant deficit of BMD in both hip and spine with mean Z-
score deviations of -0.56 and -0.38, respectively [10]. (See "Overview of dual-energy x-ray
absorptiometry", section on 'DXA technology'.)
In contrast, however, a cross-sectional study of premenopausal women found BMD to be

normal despite ASM monotherapy for an average of 8 to 13 years [35]. In children, reduced
BMD at axial and appendicular sites has been described but not as consistently as in older
adults [32,36-45]. Increasing age is associated with decreased BMD among patients using ASMs,
perhaps contributing to these discrepancies [30,33]. Other potential confounders include body
mass index (BMI), number and type of ASMs, and duration of treatment [32,46]. (See 'Effect of
ASM type' below.)
Most [36,37,44,47], but not all [30], cross-sectional studies demonstrate that duration of ASM
treatment is associated with the degree of BMD loss. In some prospective studies, progressive
bone loss occurred over time [9,33,48]. As examples:
● In a prospective study of 81 men aged 25 to 54 years, followed for 12 to 29 months, there

was a 1.8 percent annualized loss of BMD by dual-energy x-ray absorptiometry (DXA),
much higher than would be expected in men of this age [33].

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● In a cohort of older women followed prospectively for an average of 4.4 years, the rate of
bone loss at the total hip (after adjusting for confounders) was -0.70 percent per year in
4094 non-ASM users, -0.87 percent per year in 61 intermittent ASM users, and -1.16
percent per year in 41 continuous ASM users [48].
In contrast, in the subset of ASM users (84 women) in the WHI study who had BMD measured
prospectively, there was no significant difference in three-year change in BMD of the hip, spine,
or total body between users and nonusers of ASMs [21]. The small number of women who had
BMD measured, combined with the fact that many ASM users were taking hormone therapy,
may have reduced the ability of the study to show an association between ASM use and change
in BMD. Alternatively, these observations may indicate that the increase in fracture rate may be
due to seizure-related injuries and the effects of certain ASMs that impair gait stability rather
than the adverse effects of ASMs on bone strength alone.
Markers of bone turnover — Markers of bone formation and resorption, measured in the
serum and urine, may be elevated in adults with epilepsy receiving ASMs. Elevated levels have
been reported during long-term ASM therapy [31,40,48,49], and increases have been reported
to occur after initiation of ASM therapy [31,35,40,48-51]. Elevated bone turnover markers are
considered to reflect increased bone remodeling activity, are associated with higher rates of
bone loss, and are independent predictors of fracture. (See "Use of biochemical markers of
bone turnover in osteoporosis".)
Findings in adults with epilepsy include:
● Increased serum alkaline phosphatase activity in adults receiving some ASMs [49,50,52-
54]. In those studies that measured isoenzymes of alkaline phosphatase, the increase in
total alkaline phosphatase activity appeared to be related to increases in the bone
isoenzyme fraction [35,55,56]. Phenytoin has been associated with the most consistent
and marked elevations of alkaline phosphatase. However, increases have also been
reported with carbamazepine. (See 'Effect of ASM type' below.)
● High serum levels of other bone formation markers. High levels of osteocalcin and C-
terminal extension peptide of type I procollagen (PICP) have been described in persons
receiving ASMs [31,40,49-51].
● Elevated markers of bone resorption. C-terminal telopeptide of human type I collagen

(CTX) and cross-linked N-terminal telopeptides of type I collagen (NTX) are also elevated in
patients treated with ASMs [31,49-51].

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While bone turnover markers are not used to diagnose osteoporosis because values overlap
substantially in normal subjects and patients with osteoporosis, the collective data suggest that
bone remodeling activity is higher in patients taking ASMs. (See "Use of biochemical markers of
bone turnover in osteoporosis".)
Osteomalacia and rickets — Osteomalacia is a disorder of bone mineralization in which the

deposition of calcium and phosphate into newly formed bone matrix (osteoid) at sites of bone
remodeling or periosteal or endosteal apposition is either insufficient or completely absent. On
histologic examination, thickened layers of unmineralized osteoid cover a higher than normal
proportion of the bone surface.
Clinically, patients with osteomalacia complain of bone pain, which is particularly prominent in
the lower extremities and is exacerbated by weightbearing. They may also notice muscle
weakness, particularly of the upper arms and thighs. Physical examination often reveals
tenderness to pressure over the anterior tibiae, an antalgic gait, and proximal muscle
weakness. Although there are many causes of osteomalacia, when osteomalacia occurs in
association with ASM treatment, it is generally associated with profound vitamin D deficiency.
Serum calcium and phosphorous and serum 25-hydroxyvitamin D (25[OH]D) may be low, and
parathyroid hormone (PTH) levels and total alkaline phosphatase activity may be elevated. (See
"Epidemiology and etiology of osteomalacia".)
Rickets, a failure of or delay in mineralization of cartilage at growth plates, occurs only in

children and results in profusion of disorganized, nonmineralized, degenerating cartilage and
consequent widening of the epiphyseal plates with flaring or cupping and irregularity of the
epiphyseal-metaphyseal junctions. If untreated, the disorder may progress to include bowing of
the lower extremities. In adults, joint enlargement due to the profusion of cartilage and
ultimate formation of excess but undermineralized bone is sometimes evident [57]. (See
"Overview of rickets in children".)
As noted above, early reports of bone disease in patients with epilepsy describe osteomalacia
[8,58,59]. However, these reports primarily included institutionalized patients, and in
ambulatory, community-dwelling persons with epilepsy, osteomalacia is rarely seen today.
Bone biopsy studies in patients taking ASMs found normal osteoid seam width and
mineralization rates that were consistently normal or increased [60,61]. These results are not
consistent with osteomalacia and suggest that bone disease associated with ASM use is a
disorder of increased remodeling (consistent with bone turnover markers data) rather than
abnormal mineralization, resulting in osteoporosis rather than osteomalacia. Similarly, while
rickets has been reported in older studies of children treated with ASMs, most of the subjects

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were institutionalized, and the findings likely reflect the additive effects of ASM and lack of sun
exposure on vitamin D metabolism [62]. More recent studies of ambulatory, community-
dwelling children taking ASMs do not report clinical rickets [36-39].
EFFECT OF ASM TYPE
The relationship between antiseizure medication (ASM) type and fracture risk remains
uncertain. In a systematic review of 13 observational studies in patients with epilepsy that
compared treatment with ASMs that induce the cytochrome P450 system versus ASMs that do
not induce, five studies showed decreased bone mineral density (BMD) in users of ASMs that
induce the cytochrome P450 system, whereas five studies showed no effect on BMD [63]. Two
studies showed an increased risk of fracture in patients treated with enzyme-inducing ASMs,
whereas one study showed no difference in fracture risk. In the largest study, a prospective
study of over 63,000 patients with epilepsy, there was an increased risk of hip fracture with use
of enzyme-inducing compared with non-enzyme-inducing ASMs for both men (hazard ratio [HR]
1.53, 95% CI 1.10-2.12) and women (HR 1.49, 95% CI 1.15-1.94) [64].
Induction of the cytochrome P450 system by ASMs leads to increased catabolism of vitamin D to
inactive metabolites and a subsequent rise in parathyroid hormone (PTH), which increases the
mobilization of bone calcium stores and subsequent bone turnover [52,65-67]. However, this
mechanism does not account for the studies that have shown accelerated bone turnover or
bone loss independent of vitamin D deficiency [32,33,35,49-51,61].
Other mechanisms that have been implicated in the pathogenesis of ASM-induced bone disease
include:
● A cytochrome P450-induced increase in metabolism of sex steroids, resulting in lower

estrogen levels [68]
● A direct inhibitory effect of phenytoin on intestinal absorption of calcium [69,70]
● Hyperparathyroidism with normal serum 25-hydroxyvitamin D (25[OH]D) level [49]
● Direct effects of phenytoin to stimulate osteoclastic bone resorption [71]
● Direct effects of phenytoin and carbamazepine to inhibit proliferation of human
osteoblast-like cells at concentrations equivalent to therapeutic doses for the treatment of
epilepsy [47]
● Vitamin K deficiency [72]
● Calcitonin deficiency [73]
● Elevated homocysteine levels [74]

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● Suppression of long bone growth by valproate by inhibiting cartilage formation and

accelerating ossification of the growth plate [75]
● Genetic factors [76,77]
Enzyme inducing — The ASMs most commonly associated with altered bone and mineral
metabolism and decreased bone density are those that induce the cytochrome P450 enzyme
system [35-37,48-53]. The ASMs that induce the cytochrome P450 enzyme system are
phenytoin, primidone, carbamazepine, and phenobarbital ( table 2) [31,35,37,48,49,52,53].
(See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
Induction of the cytochrome P450 system by ASMs leads to increased catabolism of vitamin D to
inactive metabolites [52,65-67]. Decreased availability of active vitamin D metabolites leads, in
turn, to decreased gastrointestinal absorption of calcium, hypocalcemia, and a rise in circulating
PTH. PTH increases the mobilization of bone calcium stores and subsequent bone turnover. This
mechanism is the one most often purported to underlie the bone disease associated with ASM
use.
Laboratory findings in patients taking these drugs often, but not consistently, include
hypocalcemia, hypophosphatemia, reduced serum 25(OH)D levels, elevated PTH levels, and
elevated markers of bone formation and resorption. All of these have been described in adults
taking enzyme-inducing ASMs [52,53,55,56,78-82].
Basic studies have evaluated the effect of these ASMs on the expression of specific cytochrome
P450 isoenzymes involved in vitamin D metabolism [83,84]. Phenobarbital, phenytoin, and
carbamazepine are among a class of drugs known as xenobiotics. Xenobiotics activate a nuclear
receptor known as either the steroid and xenobiotic receptor (SXR) or pregnane X receptor
(PXR):
● One study found that xenobiotics upregulate 25(OH)D3-24-hydroxylase (CYP24) in the

kidney through activation of PXR [84]. This enzyme catalyzes the conversion of 25(OH)D to
its inactive metabolite (24,25-dihydroxyvitamin).
● Other investigators found that xenobiotic activation of PXR did not upregulate CYP24 but
did increase expression of a different isoenzyme, CYP3A4, in the liver and small intestine
[83]. This enzyme converts vitamin D to more polar inactive metabolites. They also found
that xenobiotic activation of PXR represses CYP24 expression in the liver and intestine,
suggesting a dual role in mediating vitamin D metabolism.
Studies that have compared ASM regimens often find that phenytoin is associated with the
most marked increases in bone turnover markers and decreases in BMD [31,35,48,49,85]. In a

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prospective study of premenopausal women with epilepsy receiving a single ASM, treatment
with phenytoin for one year was associated with a 2.6 percent decrease in femoral neck BMD,
whereas treatment with other ASMs (carbamazepine, lamotrigine, valproate) did not have such
an adverse effect on BMD [85]. In a prospective cohort study of 90 young Thai adults, patients
who stopped or switched phenytoin to levetiracetam had a significant increase in BMD at
multiple sites as well as an increase in 25(OH)D concentrations [86]. In contrast, patients who
continued phenytoin had a significant decrease in BMD at multiple sites and a decrease in
25(OH)D concentrations. Animal studies suggest that phenytoin may also have direct toxicity on
bone [47,71].
Carbamazepine appears to be less commonly associated with bone disease than phenytoin.
While hypocalcemia, hypophosphatemia, decreased vitamin D metabolites, and elevated
markers of bone turnover have all been reported with carbamazepine, these findings have not
been observed as consistently [11,36,41,42,50,51]. One short-term (10-week) study of normal,
young men found that carbamazepine was not associated with any change in markers of bone
turnover [87]. In contrast, significant increases in markers of bone turnover were documented
in children and adolescents after initiation of carbamazepine treatment for epilepsy [50,51].
Bone mass has been reported to be normal or decreased in children and young adults treated
with long-term carbamazepine therapy [32,42,49,88,89]. In a prospective study of
premenopausal women with epilepsy receiving a single ASM, treatment with carbamazepine
was not associated with any changes in markers of bone turnover or BMD [85]. However,
fracture risk has been reported to be increased in adults treated with carbamazepine [5].
In a meta-analysis of 87 studies evaluating bone health indices in carbamazepine-treated

persons compared with controls, vitamin D levels as well as calcium were significantly lower and
alkaline phosphatase was higher in carbamazepine-treated persons with epilepsy. Interestingly,
there was no difference in BMD [90].
Non-enzyme inducing
Valproate — In contrast to phenytoin, primidone, carbamazepine, and phenobarbital,

valproate is an inhibitor of the cytochrome P450 enzyme system. (See "Antiseizure medications:
Mechanism of action, pharmacology, and adverse effects".)
Although studies published in the 1980s did not find any association with bone disease [52,78],
subsequent studies have consistently reported bone loss, abnormal biochemical indices of bone
and mineral metabolism, and higher fracture rates with valproate in both children and adults
[5,31,36,39,40]. Both dose and duration of valproate therapy have been associated with
increased rates of bone loss and higher incidence of fracture [5,40].
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Three meta-analyses support negative effects of valproate on children and adults with epilepsy
[91-93]. BMD reductions and increased serum alkaline phosphatase were seen in children and
adults. Reduced vitamin D and calcium levels and increased PTH occurred in children and not
adults with epilepsy.
In cell-culture studies, valproate has been shown to suppress longitudinal bone growth by
inhibiting cartilage formation and accelerating ossification of the growth plate [75]. Similarly,
valproate-treated rats have decreased bone volume fraction and decreased apparent density
[94]. Perhaps consistent with this effect, short stature has been reported in children treated
with valproate [39]. In the same study, low BMD, short stature, and elevated markers of bone
turnover were more pronounced in children treated with valproate in combination with
lamotrigine [39]. In this study, physical inactivity was identified as a possible confounder.
Other ASMs — Few studies have evaluated the effect of newer antiseizure medications (ASMs)
on bone and mineral metabolism and BMD:
● Lamotrigine – Lamotrigine is increasingly used to treat epilepsy. A study of

premenopausal women on ASM monotherapy (phenytoin, carbamazepine, valproate, or
lamotrigine) found no significant effect of lamotrigine on BMD, calciotropic hormones, or
bone turnover markers [35,85]. Although treatment duration was shorter for patients on
lamotrigine, there was no association between duration of therapy and BMD or any
marker of bone and mineral metabolism. Similarly, 32 adults with newly diagnosed
epilepsy treated with lamotrigine had no changes in markers of bone turnover after two
years [95] and eight Korean men and women did not have any changes in BMD after six
months of treatment with lamotrigine [89]. In contrast, children treated with lamotrigine
were significantly shorter and had lower BMD and higher markers of bone turnover
compared with children not receiving ASMs [39]. These findings were most pronounced in
children treated with both lamotrigine and valproate.
● Oxcarbazepine – A large case-control study found that oxcarbazepine (and clonazepam)

were among the ASMs associated with small increases in the relative risk (RR) of fracture
after controlling for epilepsy diagnosis [5].
A study of 45 patients found reduced serum 25(OH)D and slightly elevated osteocalcin
levels among patients taking oxcarbazepine [11]. A retrospective claims-based study found
that initiating oxcarbazepine among 4 to 13 year olds was associated with an elevated risk
of fragility fracture [96]. Among children with new-onset focal epilepsy treated with
oxcarbazepine, serum calcium was reduced and parathyroid hormone levels were
increased [97].
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● Levetiracetam – A study of 61 patients (mean age 31 years) initiating levetiracetam found

no adverse effect on BMD or in biochemical markers (25[OH]D, calcium, phosphorus, PTH,
markers of bone remodeling) after 14 months of treatment [98]. Among 25 children with
new-onset focal epilepsy treated with levetiracetam, there was no effect of levetiracetam
on bone metabolism [97]. Similarly, 47 adults with newly diagnosed epilepsy treated with
levetiracetam had no changes in markers of bone turnover after two years [95]. In another
study, there was improvement in BMD two years after switching from phenytoin to
levetiracetam [86]. A retrospective claims-based study found that initiating levetiracetam
among 4 to 13 year olds did not increase the risk of fragility fracture [96].
● Topiramate and zonisamide – Topiramate and zonisamide are carbonic anhydrase

inhibitors. As carbonic anhydrase inhibitors are potent inhibitors of osteoclastic bone
resorption, one might expect lower rates of bone loss to be associated with their use [99].
Limited data suggest no effect on BMD. As an example, in a cross-sectional study in
premenopausal women with epilepsy, there were no differences in BMD Z-scores or
vitamin D metabolites in women taking topiramate compared with control women and
compared with women taking carbamazepine or valproic acid [100]. Topiramate was
associated with lower PTH, bicarbonate, and calcium concentrations as well as higher
biochemical markers of bone turnover compared with the other groups. In a prospective
study in 59 adults with new onset epilepsy, there were no changes in BMD or biochemical
markers of bone turnover after 13 months of treatment with zonisamide [101].
SCREENING
Osteoporosis screening is typically recommended in postmenopausal women and older men

with risk factors for fracture ( table 3) (see "Screening for osteoporosis in postmenopausal
women and men"). For patients with epilepsy, we consider the risk factors for bone disease
related to antiseizure medication (ASM) use in addition to more general risk factors for
osteoporosis and fracture.
Clinical risk factor assessment — Risk factors for bone disease in ASM users include high-
dose, multidrug regimens; long-term therapy; inadequate intakes of vitamin D; limited sunlight
exposure; chronic illness; old age; institutionalization; low physical activity; adjuvant therapy to
induce chronic metabolic acidosis (acetazolamide or ketogenic diets); and concomitant therapy
with other drugs that induce hepatic enzymes (rifampin, glutethimide).
Risk factors for osteoporosis and fractures include female sex, postmenopausal status, old age,
poor balance, tobacco, low body mass index (BMI), and low dietary calcium and vitamin D intake

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( table 3). ASMs are an accepted secondary cause of osteoporosis. (See "Osteoporotic fracture
risk assessment".)
Bone mineral density — It is reasonable to recommend measuring bone mineral density

(BMD) in patients with epilepsy who have risk factors for osteoporosis and risk factors for ASM-
related bone disease, as well as in patients who have experienced a fragility fracture. Persons
treated with long-term (>5 years) enzyme-inducing ASMs or valproate are likely at risk and
therefore should be screened.
In a person with a normal baseline BMD, the frequency of testing should depend upon the age
and sex of the patient. More frequent testing (every two years) is appropriate in a
postmenopausal woman or older man and less frequent in a premenopausal woman or young
man. Because multiple risk factors further increase risk of fracture, earlier and more frequent
screening is prudent in such patients ( table 1) [6].
Laboratory evaluation — In patients with epilepsy who are taking ASMs, we typically measure
serum calcium, phosphate, and 25-hydroxyvitamin D (25[OH]D) levels [46,102-104].
TREATMENT AND PREVENTION
Few studies have rigorously evaluated strategies for prevention and treatment of bone disease
associated with antiseizure medications (ASMs).
Lifestyle measures — Patients with epilepsy who are taking ASMs should adopt the same
lifestyle measures that are recommended for all patients at risk for osteoporosis and fracture.
These include regular weightbearing exercise, smoking cessation, limiting alcohol intake, and
preventing falls. In one study, however, adults with epilepsy did not engage in higher level of
osteoprotective behaviors and were less physically active when compared with persons without
epilepsy [105]. (See "Overview of the management of low bone mass and osteoporosis in
postmenopausal women", section on 'Lifestyle measures to reduce bone loss' and "Treatment
of osteoporosis in men", section on 'Lifestyle measures'.)
Calcium and vitamin D — As a general rule, patients should achieve the reference calcium
intake for their age group ( table 4) through diet and supplements (if needed) and receive
supplemental vitamin D (400 to 800 international units/day).
Because studies have shown that much higher doses (up to 4000 international units) may be
necessary to normalize serum levels of 25-hydroxyvitamin D (25[OH]D) in some patients, we
typically measure serum 25(OH)D levels to determine whether vitamin D intake is sufficient to

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maintain levels above 30 ng/mL [106-108]. This is particularly important in the case of older
adults or institutionalized patients who may have limited access to sunshine.
There are limited data on the optimal doses of calcium and vitamin D for patients with epilepsy
who are taking ASMs. In a study that included both institutionalized and ambulatory individuals
receiving ASMs who had low baseline serum 25(OH)D levels, vitamin D supplementation was
titrated to achieve a normal serum 25(OH)D concentration [109]. All achieved normal 25(OH)D
levels over a period of 12 to 15 months. Dose requirements ranged from 400 to 4000
international units daily.
In two randomized trials in adults and children given either low-dose vitamin D (400
international units/day) or high-dose vitamin D (4000 international units/day in adults and 2000
international units/day in children), there were no significant differences in bone mineral
density (BMD) at one year between the adult groups, although BMD had increased from
baseline in the high-dose group only [106]. In children, both dose groups had comparable
increases in BMD after one year.
In a systematic review of nine studies evaluating vitamin D supplementation in adults with

epilepsy, vitamin D treatment increased serum calcium in three of eight studies, decreased
alkaline phosphatase in six of eight studies, and decreased parathyroid hormone (PTH) in two of
four studies [110]. All six studies that investigated BMD had significant findings; however, likely
due to varying methodologies employed by the studies, the impact of vitamin D on BMD was
not conclusive.
Pharmacologic therapy — In the absence of adequate data specifically targeting osteoporosis

in individuals treated with ASMs, treatment recommendations should follow other guidelines,
such as for postmenopausal women and men (see "Overview of the management of low bone
mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men").
However, it is of particular importance to make certain that individuals receiving ASMs are
vitamin D replete before initiating therapy for osteoporosis.
In a two-year, double-blind trial evaluating risedronate or placebo (all patients received calcium
and vitamin D supplementation) in 80 male veterans with epilepsy treated with either
phenytoin, phenobarbital, carbamazepine, or valproate, there was a greater increase in lumbar
spine BMD in the risedronate group (0.065 versus 0.016 g/cm2 in the placebo group) [111].
There were fewer new vertebral fractures in the risedronate group (none versus five in the
placebo group).

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SUMMARY AND RECOMMENDATIONS
● Fracture risk – Patients with epilepsy are at higher risk for fracture because of a higher
risk for falls and physical trauma related to seizures themselves, the neurologic disease
that underlies the epilepsy (stroke, cerebral palsy), and the effects of certain antiseizure
medications (ASMs) that impair gait stability and alter bone and mineral metabolism. (See
'Fracture' above.)
● Effect of ASM type on fracture risk and bone loss – The relationship between ASM type
and fracture risk remains uncertain. However, ASMs that induce the hepatic cytochrome
P450 enzyme system (phenytoin, phenobarbital, primidone, carbamazepine) are those
most commonly implicated as affecting bone and mineral metabolism ( table 2). The
most commonly implicated pathogenetic mechanism is via accelerated catabolism of
vitamin D. In addition, there is growing evidence to suggest that valproate, a cytochrome
P450 enzyme inhibitor, also affects bone and mineral metabolism. There are limited data
available on the skeletal effects of newer ASMs, such as lamotrigine. (See 'Effect of ASM
type' above.)
Several additional mechanisms for ASM-associated bone loss have been proposed,
including direct effects on intestinal calcium absorption and also on osteoblasts and
osteoclasts. It is likely that more than one mechanism contributes to ASM-associated bone
disease and that these are, to some extent, specific to the particular ASM. (See 'Effect of
ASM type' above.)
● Screening – For individuals with a history of prolonged use (>5 years) of ASMs, especially
those using enzyme-inducing ASMs or valproate, those with other risk factors for ASM-
induced bone disease (high-dose, multidrug regimens; low vitamin D intake; limited
sunlight exposure; chronically ill, older, or institutionalized patients; low physical activity
levels; exposure to drugs that induce chronic metabolic acidosis; and concomitant therapy
with other drugs that induce hepatic enzymes), and those with history of fragility fracture
or additional risk factors for osteoporosis, we suggest bone mineral density (BMD) testing
(Grade 2C). (See 'Screening' above.)
● Calcium and vitamin D intake – For patients receiving ASMs, we suggest calcium and
vitamin D supplementation (Grade 2C). Although the optimal intake (diet plus supplement)
has not been clearly established in this patient population, the age group-based reference
intake for calcium ( table 4) and 800 international units of vitamin D daily are the typical
doses used. However, patients receiving ASMs, particularly enzyme-inducing ASMs, may

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require higher doses of vitamin D. We typically measure serum 25-hydroxyvitamin D

(25[OH]D) levels in such patients to determine whether vitamin D intake is sufficient to
maintain levels within the normal range. (See 'Calcium and vitamin D' above and "Calcium
and vitamin D supplementation in osteoporosis" and "Vitamin D deficiency in adults:
Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)
● Pharmacologic therapy – The pharmacologic treatment of osteoporosis and fracture in

patients taking ASMs is the same as the treatment of osteoporosis in individuals not on
ASM therapy. (See "Overview of the management of low bone mass and osteoporosis in
postmenopausal women" and "Treatment of osteoporosis in men" and "Evaluation and
treatment of premenopausal osteoporosis".)
Use of UpToDate is subject to the Terms of Use.
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Topic 2063 Version 19.0

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GRAPHICS
Causes of osteoporosis
Drugs Marrow-related disorders

Glucocorticoids Amyloidosis
Immunosuppressants (cyclosporine) Hemochromatosis
Antiseizure medications (particularly phenobarbital and Hemophilia

phenytoin)
Leukemia
Aromatase inhibitors
Lymphoma
GnRH agonists and antagonists
Mastocytosis
Heparin
Multiple myeloma
Cancer chemotherapy
Pernicious anemia
Endocrine disorders Sarcoidosis
Acromegaly Sickle cell anemia
Adrenal insufficiency Thalassemia
Cushing's syndrome
Organ transplantation
Eating disorders
Bone marrow
Endometriosis
Heart
Hyperparathyroidism
Kidney
Hyperprolactinemia
Liver
Hyperthyroidism
Lung
Hypogonadism (primary or secondary)
Miscellaneous causes
Diabetes mellitus
Ankylosing spondylitis
Gastrointestinal disease/nutritional disorders
Chronic obstructive pulmonary disease
Alcohol-related liver disease
Epidermolysis bullosa
Celiac disease
Idiopathic hypercalciuria
Chronic active hepatitis
Multiple sclerosis
Chronic cholestatic disease
Rheumatoid arthritis
Gastrectomy
Genetic disorders
Inflammatory bowel disease
Hypophosphatasia
Jejunoileal bypass
Osteogenesis imperfecta

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Malabsorption syndromes Homocystinuria due to cystathionine

deficiency
Pancreatic insufficiency
Parenteral nutrition
Primary biliary cholangitis
Severe liver disease
Vitamin D and/or calcium deficiency
GnRH: gonadotropin-releasing hormone.
Reproduced with permission from: Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc 2002; 77:453. Copyright ©
2002 Mayo Foundation.
Graphic 54926 Version 9.0

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Pharmacologic properties of antiseizure medications
Enzyme or
Metabolism and Protein binding Half-li
transporter ¶
clearance (%) adults (
induction/inhibition*
Brivaracetam Metabolized Inhibits epoxide ≤20 9

primarily by CYP- hydroxylase Δ
independent
hydrolysis (60%) and
CYP2C19 (30%)
Dose adjustment is
needed in hepatic
impairment
Cannabidiol Hepatic (primarily) Inhibits BCRP/ABCG2, >94 56 to 61

and gut by BSEP/ABCB11, CYP2C19
CYP2C19, CYP3A4, (moderate)
UGT1A7, UGT1A9,
May increase serum
and UGT2B7 to
concentration of
active metabolite 7-
clobazam and the active
OH-CBD and then to
metabolite(s) of clobazam
inactive metabolite
7-COOH-CBD
Dose adjustment is
needed in moderate
to severe hepatic
impairment
Carbamazepine >90% metabolized Potent and broad- 75 25 to 65 (in

by CYPs 3A4 (major) spectrum inducer of CYP, enzyme-ind
and 1A2/2C8 (minor) UGT-glucuronidation, and naive patie
to active (epoxide) P-gp
8 to 22 (afte
and inactive
weeks due
metabolites
induction)
Dose adjustment is
needed in severe
renal impairment;
use is not
recommended in
moderate or severe
hepatic impairment
Cenobamate Primarily May increase serum 60 50 to 60 ho

metabolized by concentrations of
glucuronidation via clobazam, phenobarbital,
16/2/24, 00:40 A hoy
UGT2B7 and to a phenytoin, and CYP2C19

lesser extent by substrates
UGT2B4, and by
May decrease serum
oxidation via
concentrations of
CYP2E1, CYP2A6,
carbamazepine,
CYP2B6, and to a
lamotrigine, and CYP2B6
lesser extent by
and CYP3A substrates
CYP2C19 and
CYP3A4/5
Dose adjustment is
needed for hepatic
impairment; not
recommended for
patients with severe
hepatic impairment
or end-stage renal
disease
Clobazam >90% metabolized Inhibits CYP2D6 (weak) 80 to 90 (clobazam, 36 to 42 (clo

by CYPs 3A4, 2C19, parent drug) parent drug
2B6 and non-CYP
70 (N- 71 to 82 (N-
transformations to
desmethylclobazam, desmethylc
active (N-
active metabolite) active meta
desmethylclobazam)
and inactive
metabolites
Active metabolite is
primarily
metabolized by
CYP2C19
Dose adjustment is
needed in hepatic
impairment
Eslicarbazepine Prodrug; <33% of Induces CYP3A4 <40 13 to 20 (pr

active form (moderate) in renal
undergoes UGT- insufficienc
Inhibits CYP2C19 (weak)
glucuronidation
(including <5%
metabolized to
oxcarbazepine); 66%
is excreted renally
as unchanged drug
Dose adjustment is
needed for renal
impairment; not

16/2/24, 00:40 A hoy
recommended in
patients with severe
hepatic impairment
Ethosuximide ~80% metabolized None <5 40 to 60

by CYP3A4 (major)
and non-CYP
transformations to
inactive metabolites
Felbamate 50% metabolized by Increases conversion of 25 13 to 22 (pr

CYPs 3A4, 2E1 carbamazepine to active in renal
(minor); ~50% epoxide metabolite; insufficienc
renally excreted as mechanism not
unchanged drug established
Dose adjustment is Inhibits CYP2C19 (weak)

needed in renal
impairment
Gabapentin >95% renally None <5 5 to 7 (prolo

excreted as renal insuff
unchanged drug (ie, >130 hours
does not undergo anuria)
hepatic metabolism)
Dose adjustment is
needed in renal
impairment
Lacosamide 40% renally excreted None <15 13

as unchanged drug;
30% metabolized by
non-CYP
transformations
(including
methylation) to
inactive metabolite
Dose adjustment is
needed in hepatic
and renal
impairment
Lamotrigine >90% metabolized May induce its own 55 12 to 62

by UGT- metabolism by UGT-
glucuronidation and glucuronidation (minor)
other non-CYP
transformations to

16/2/24, 00:40 A hoy
Dose adjustment is
needed in moderate
to severe renal or
hepatic impairment
Levetiracetam >65% renally None <10 6 to 8

excreted as
unchanged drug;
24% metabolized by
non-CYP
transformation
(including amidase
hydrolysis) to
Dose adjustment is
needed in renal
impairment
Oxcarbazepine Prodrug; 70% of Induces CYP3A4 (weak) 40 9 (active me

active (MHD) form and UGT-glucuronidation prolonged
undergoes UGT- but does not induce its insufficienc
glucuronidation; own metabolism
30% is renally
excreted as
unchanged active
drug
Dose adjustment is
needed in severe
renal impairment
Perampanel >70% metabolized Appears to induce 95 105

by CYPs 3A4, 3A5 metabolism of progestin-
and non-CYP containing hormonal
transformations to contraceptives
Dose adjustment is
needed in mild or
moderate hepatic
impairment
Phenobarbital 75% metabolized by Potent and broad- 55 75 to 110

CYPs 2C19, 2C9 spectrum inducer of CYP
(minor) and and UGT-glucuronidation
glucosidase
hydrolysis and 2E1
(minor) to inactive
metabolites; 25%

16/2/24, 00:40 A hoy
excreted renally as
unchanged drug
Dose adjustment is
needed in severe
renal or hepatic
impairment
Phenytoin >90% metabolized Potent and broad- 90 to 95 9 to >42 (do

by CYPs 2C9, 2C19, spectrum inducer of CYP dependent)
3A4 (minor) and and UGT-glucuronidation
non-CYP
transformations to
inactive
metabolites;
clearance is dose
dependent,
saturable, and may
be subject to
genetic
polymorphism
Dose adjustment is
needed in severe
renal or hepatic
insufficiency;
monitoring of free
(unbound)
concentrations also
suggested
Pregabalin >95% excreted None <5 6

renally as
unchanged drug
Dose adjustment is
needed in renal
impairment
Primidone 75% metabolized by Potent and broad- 0 to 20 10 to 15 (pa

CYPs 2C19, 2C9 spectrum inducer of CYP
29 to 100 (a
(minor) and 2E1
metabolite)
(minor) to active
intermediates; ~25%
excreted renally as
unchanged drug
Dose adjustment is
needed in moderate
and severe renal or

16/2/24, 00:40 A hoy
hepatic impairment;
close monitoring of
plasma levels
suggested
Rufinamide >90% metabolized Induces CYP3A4 (weak) 35 6 to 10

by non-CYP
transformations
(hydrolysis) to
Stiripentol Metabolized Inhibits CYP3A4, 99 4.5 to 13

primarily in the liver CYP2C19, P-gp, and BCRP
by CYP450 enzymes
CYP2C19, CYP3A4,
and glucuronidation
Tiagabine >90% metabolized None 95 7 to 9

by CYP3A4 and non-
2 to 5 (with
CYP transformations
inducing an
to inactive
medication
metabolites
Topiramate >65% excreted None 9 to 17 12 to 24

renally as
unchanged drug;
<30% metabolized
by non-CYP
transformations to
inactive
metabolites; extent
of metabolism is
increased ~50% in
patients receiving
enzyme-inducing
antiseizure
medications
Dose adjustment is
needed in moderate
and severe renal or
hepatic impairment
Valproate >95% undergoes None 80 to 95 7 to 16

complex
transformations
including CYPs 2C9,
2C19, 2A6, UGT-
glucuronidation and

16/2/24, 00:40 A hoy
other non-CYP
transformation
Dose adjustment is
needed in hepatic
impairment
Vigabatrin >90% excreted None 0 5 to 13 (unr

renally as duration of
unchanged drug
Dose adjustment is
needed in renal
impairment
Zonisamide >65% metabolized None 50 63

by CYPs 3A4, 2C19
(minor) and non-
CYP transformations
Dose adjustment
and/or slower
titration is needed
in mild renal
impairment or
hepatic impairment;
not recommended
in patients with
moderate or severe
renal impairment
CYP: cytochrome P450; MHD: monohydroxy derivative active form of oxcarbazepine; P-gp: membrane P-
glycoprotein multidrug resistance transporter; UGT-glucuronidation: metabolism by uridine
5'diphosphate-glucuronyltransferases.
* The inhibitors and inducers of CYP or UGT drug metabolism and P-gp transporters listed in this table
can alter serum concentrations of drugs that are dependent upon these enzymes or transporters for
elimination, activation, or bioavailability. Classifications are based on US Food and Drug Administration
guidance [4, 5]. Other sources may use a different classification system resulting in some agents being
classified differently. Specific interactions should be assessed using a drug interaction program such as
Lexicomp interactions included within UpToDate.
¶ Highly protein-bound antiseizure medications exhibit altered pharmacokinetics, including greater

therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum
albumin or protein-binding affinity (eg, due to nephrotic syndrome or acidosis). Dose alteration is needed
and monitoring of unbound (free) antiseizure medication serum concentrations is suggested. Refer to
UpToDate topic for additional information.
Δ Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and active
metabolite of carbamazepine; refer to UpToDate topic.

16/2/24, 00:40 A hoy
Data from: Lexicomp Online. Copyright © 1978-2024 Lexicomp, Inc. All Rights Reserved.
Additional data from:

1. Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756.
2. Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction.
Neurology 2006; 67:S28.
3. Anderson GD, Hakimian S. Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment. Clin
Pharmacokinet 2014; 53:29.
4. US Food and Drug Administration. Clinical drug interaction studies – Cytochrome P450 enzyme- and transporter-mediated
drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-
interactions (Accessed on June 5, 2020).
5. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers (Accessed on June 12, 2019).

16/2/24, 00:40 A hoy
Clinical risk factors for fracture independent of bone mineral density
Advancing age
Previous fracture
Glucocorticoid therapy
Parental history of hip fracture
Low body weight
Current cigarette smoking
Excessive alcohol consumption
Rheumatoid arthritis
Secondary osteoporosis (eg, hypogonadism or premature menopause, malabsorption, chronic liver

disease, inflammatory bowel disease)
Data from: Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005; 16:581.

16/2/24, 00:40 A hoy
Dietary Reference Intakes for calcium and vitamin D
Calcium Vitamin D
Estimated Recommende
Life stage Estimated Recommended Upper
average dietary
group average dietary level
requirement allowance
requirement allowance intake
(international (internationa
(mg/day) (mg/day) (mg/day)
units/day) units/day)
Infants 0 to 6 * * 1000 ¶ ¶
months
Infants 6 to 12 * * 1500 ¶ ¶
months
1 to 3 years old 500 700 2500 400 600
4 to 8 years old 800 1000 2500 400 600
9 to 13 years old 1100 1300 3000 400 600
14 to 18 years old 1100 1300 3000 400 600
19 to 30 years old 800 1000 2500 400 600
31 to 50 years old 800 1000 2500 400 600
51 to 70 year old 800 1000 2000 400 600

males
51 to 70 year old 1000 1200 2000 400 600

females
>70 years old 1000 1200 2000 400 800
14 to 18 years old, 1100 1300 3000 400 600

pregnant/lactating
19 to 50 years old, 800 1000 2500 400 600

pregnant/lactating
* For infants, adequate intake is 200 mg/day for 0 to 6 months of age and 260 mg/day for 6 to 12 months
of age.
¶ For infants, adequate intake is 400 international units/day for 0 to 6 months of age and 400
international units/day for 6 to 12 months of age.
Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Otten JJ, Hellwig JP, Meyers LD (Eds), The National
Academies Press, Washington, DC 2006. pp.530-541. Modified with permission from the National Academies Press, Copyright ©
2006, National Academy of Sciences.
Fuentes: Ingestas dietéticas de referencia de tiamina, riboflavina, niacina, vitamina B6 , folato, vitamina B12 , ácido pantoténico,
biotina y colina (1998); Ingestas dietéticas de referencia de vitamina C, vitamina E, selenio y carotenoides (2000); Informes de
16/2/24, 00:40 A hoy
ingesta dietética de referencia de la Junta de Alimentación y Nutrición, Instituto de Medicina (2010). Se puede acceder a estos
informes a través de www.nap.edu .
Gráfico 71669 Versión 18.0

16/2/24, 00:40 A hoy
Divulgaciones del colaborador

Alison M Pack, MD No hay relaciones financieras relevantes con empresas no elegibles para revelar.
Elizabeth Shane, MD Subvención/Investigación/Apoyo a ensayos clínicos: Amgen [osteoporosis
premenopáusica]. Todas las relaciones financieras relevantes enumeradas han sido mitigadas. Deborah E
Sellmeyer, MD Subvención/Investigación/Apoyo a ensayos clínicos: Amgen Inc [Algoritmo de predicción
de fracturas]. Todas las relaciones financieras relevantes enumeradas han sido mitigadas. Steven C
Schachter, MD Titular de la patente: Supernus Pharmaceuticals [Epilepsia]. Todas las relaciones
financieras relevantes enumeradas han sido mitigadas. Katya Rubinow, MD No hay relaciones
financieras relevantes con empresas no elegibles para revelar.
El grupo editorial revisa las divulgaciones de los contribuyentes para detectar conflictos de intereses.
Cuando se encuentran, estos se abordan mediante un proceso de revisión de varios niveles y mediante
requisitos de referencias que se deben proporcionar para respaldar el contenido. Se requiere que todos
los autores tengan contenido con las referencias adecuadas y deben cumplir con los estándares de
evidencia de UpToDate.
Política de conflicto de intereses

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16/2/24, 00:40 A hoy

Reimpresión oficial de UpToDate ®

Medicamentos anticonvulsivos y enfermedades óseas.

Revisión de la literatura vigente hasta: enero de 2024.

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 1/36

ENFERMEDAD ÓSEA METABÓLICA

Osteoporosis : la osteoporosis se define como un trastorno esquelético caracterizado por una

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 2/36

secondary causes of osteoporosis can increase the severity of osteoporosis in postmenopausal

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 3/36

In contrast, however, a cross-sectional study of premenopausal women found BMD to be

● In a prospective study of 81 men aged 25 to 54 years, followed for 12 to 29 months, there

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 4/36

Findings in adults with epilepsy include:

● Elevated markers of bone resorption. C-terminal telopeptide of human type I collagen

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 5/36

Osteomalacia and rickets — Osteomalacia is a disorder of bone mineralization in which the

Rickets, a failure of or delay in mineralization of cartilage at growth plates, occurs only in

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 6/36

EFFECT OF ASM TYPE

● A cytochrome P450-induced increase in metabolism of sex steroids, resulting in lower

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 7/36

● Suppression of long bone growth by valproate by inhibiting cartilage formation and

● One study found that xenobiotics upregulate 25(OH)D3-24-hydroxylase (CYP24) in the

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_r… 8/36

In a meta-analysis of 87 studies evaluating bone health indices in carbamazepine-treated

Valproate — In contrast to phenytoin, primidone, carbamazepine, and phenobarbital,

● Lamotrigine – Lamotrigine is increasingly used to treat epilepsy. A study of

● Oxcarbazepine – A large case-control study found that oxcarbazepine (and clonazepam)

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 10/36

● Levetiracetam – A study of 61 patients (mean age 31 years) initiating levetiracetam found

● Topiramate and zonisamide – Topiramate and zonisamide are carbonic anhydrase

Osteoporosis screening is typically recommended in postmenopausal women and older men

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 11/36

Bone mineral density — It is reasonable to recommend measuring bone mineral density

TREATMENT AND PREVENTION

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 12/36

In a systematic review of nine studies evaluating vitamin D supplementation in adults with

Pharmacologic therapy — In the absence of adequate data specifically targeting osteoporosis

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 13/36

SUMMARY AND RECOMMENDATIONS

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 14/36

require higher doses of vitamin D. We typically measure serum 25-hydroxyvitamin D

● Pharmacologic therapy – The pharmacologic treatment of osteoporosis and fracture in

Use of UpToDate is subject to the Terms of Use.

8. Kruse R. [Osteopathies in antiepileptic long-term therapy (preliminary report)]. Monatsschr

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https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 16/36

ncott, Williams and Wilkins, Washington, DC 2006. p.330.

60. Mosekilde L, Melsen F. Dynamic differences in trabecular bone remodeling between

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 19/36

72. Onodera K, Takahashi A, Sakurada S, Okano Y. Effects of phenytoin and/or vitamin K2

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 20/36

88. Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 21/36

Res 2013; 104:134.

https://www.uptodate.com/contents/antiseizure-medications-and-bone-disease/print?search=remodelacion osea y anticonvulsivos&source=search_… 22/36

Drugs Marrow-related disorders

Immunosuppressants (cyclosporine) Hemochromatosis