Oseo y Epilepsia
Oseo y Epilepsia
Oseo y Epilepsia
Todos los temas se actualizan a medida que hay nueva evidencia disponible y nuestro proceso de revisión por pares se
completa.
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" .)
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.
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
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:
● 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'.)
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 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".)
● 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].
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".)
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".)
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
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].
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:
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):
● 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
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].
Non-enzyme inducing
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:
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].
SCREENING
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
( table 3). ASMs are an accepted secondary cause of osteoporosis. (See "Osteoporotic fracture
risk assessment".)
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].
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
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 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).
● 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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Topic 2063 Version 19.0
GRAPHICS
Causes of osteoporosis
Parenteral nutrition
Reproduced with permission from: Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc 2002; 77:453. Copyright ©
2002 Mayo Foundation.
Enzyme or
Metabolism and Protein binding Half-li
transporter ¶
clearance (%) adults (
induction/inhibition*
Dose adjustment is
needed in hepatic
impairment
Dose adjustment is
needed in moderate
to severe hepatic
impairment
Dose adjustment is
needed for hepatic
impairment; not
recommended for
patients with severe
hepatic impairment
or end-stage renal
disease
Active metabolite is
primarily
metabolized by
CYP2C19
Dose adjustment is
needed in hepatic
impairment
Dose adjustment is
needed for renal
impairment; not
recommended in
patients with severe
hepatic impairment
Dose adjustment is
needed in renal
impairment
Dose adjustment is
needed in hepatic
and renal
impairment
Dose adjustment is
needed in moderate
to severe renal or
hepatic impairment
Dose adjustment is
needed in renal
impairment
Dose adjustment is
needed in severe
renal impairment
Dose adjustment is
needed in mild or
moderate hepatic
impairment
excreted renally as
unchanged drug
Dose adjustment is
needed in severe
renal or hepatic
impairment
Dose adjustment is
needed in severe
renal or hepatic
insufficiency;
monitoring of free
(unbound)
concentrations also
suggested
Dose adjustment is
needed in renal
impairment
Dose adjustment is
needed in moderate
and severe renal or
hepatic impairment;
close monitoring of
plasma levels
suggested
Dose adjustment is
needed in moderate
and severe renal or
hepatic impairment
other non-CYP
transformation
Dose adjustment is
needed in hepatic
impairment
Dose adjustment is
needed in renal
impairment
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.
Δ Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and active
metabolite of carbamazepine; refer to UpToDate topic.
Data from: Lexicomp Online. Copyright © 1978-2024 Lexicomp, Inc. All Rights Reserved.
Advancing age
Previous fracture
Glucocorticoid therapy
Rheumatoid arthritis
Data from: Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005; 16:581.
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
* 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
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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 .
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.