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Vitamin D and Bone Health Among Children With Epilepsy
Review Article
Vitamin D and Bone Health Among Children With Epilepsy Rene´e A. Shellhaas, MD, MS and Sucheta M. Joshi, MD, MS The lay media and scientific literature have focused increasing attention on vitamin D deficiency and insufficiency in recent years. Low vitamin D levels confer increased an risk of abnormal bone mineralization, and are linked to poor bone health in epilepsy patients. However, vitamin D is not the only determinant of bone health in children with epilepsy. Anticonvulsant medications, in addition to features and comorbidities of epilepsy and coexisting neurologic diseases, are important factors in this complex topic. We review the basic metabolism of vitamin D in terms of bone health among children with epilepsy. We also discuss the literature regarding vitamin D and bone mineral density in this population. Finally, we suggest algorithms for screening and treating vitamin D insufficiency in these patients. Ó 2010 by Elsevier Inc. All rights reserved. Shellhaas Rene´e A, Joshi SM. Vitamin D and bone health among children with epilepsy. Pediatr Neurol 2010;42: 385-393.
Introduction Much attention has focused recently on the impact of vitamin D on various aspects of health, both in the medical and lay press. Besides rickets and reduced bone mineral density, vitamin D has been linked to an array of health conditions, e.g., diabetes mellitus, stroke, autoimmune diseases, and cancer (reviewed by Holick [1]). The association between vitamin D, antiepileptic drugs, and bone health in individuals with epilepsy has been recognized for more than 30 years (e.g., by Offermann et al. [2]). Although few data are available for children, adults with epilepsy are known to be at significantly increased risk for bone fractures, compared with the general population, and increasing age and duration of treatment are important risk factors [3-5].
The issue of bone health in children with epilepsy is particularly important, because these patients are often treated for many years, including the time of highest bone mineral accrual. Seizures themselves can pose a risk for injury, including fractures, and the added comorbidity of poor bone health increases this risk, especially in children with major motor manifestations of their seizures, as well as in those with impaired motor function and coordination. We review the literature on vitamin D and bone health in children with epilepsy, including data on antiepileptic drugs and bone health. We suggest strategies for monitoring vitamin D levels in children on chronic antiepileptic drug therapy, and for treating vitamin D insufficiency. Vitamin D Metabolism Vitamin D is a fat-soluble vitamin. Dietary sources of vitamin D include milk and dairy products, eggs, certain fish, and vitamin D-fortified foods. Food, however, accounts for less than 10% of vitamin D requirements [6]. The major source of this vitamin is cutaneous synthesis. Vitamin D is synthesized photochemically in the skin from 7-dehydrocholesterol, after exposure to specific ultraviolet spectra in sunlight. Exposure to sunlight for 10-15 minutes in the daytime (between 10 AM and 3 PM) in the spring, summer, and fall results in adequate vitamin D synthesis in fair-skinned people. Persons with darker skin require a much longer duration of sun exposure [7]. Lack of sun exposure, as occurs in Northern climates, reduces the amount of vitamin D synthesized in the skin, increasing the risk of insufficient vitamin D levels. Impact of Vitamin D Insufficiency on Bone Health Vitamin D and parathyroid hormone levels are inversely related, so that as vitamin D levels rise, parathyroid hormone levels drop. Parathyroid levels reach a nadir
From the Division of Pediatric Neurology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
Communications should be addressed to: Dr. Shellhaas; L3215 Women’s Hospital; 1500 East Medical Center Drive; Ann Arbor, MI 48109-5203. E-mail: [email protected] Received July 2, 2009; accepted December 8, 2009.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.12.005 0887-8994/$—see front matter
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 385
when 25-hydroxyvitamin D serum levels are between 30-40 ng/mL. When 25-hydroxyvitamin D levels fall below this level, the intestinal absorption of calcium decreases, and parathyroid hormone levels begin to increase [6]. The secretion of parathyroid hormone then enhances the tubular reabsorption of calcium, promotes the urinary loss of phosphorus, and stimulates the kidneys to produce 1,25-dihydroxyvitamin D (the active vitamin D metabolite), facilitating intestinal calcium absorption. Parathyroid hormone also activates osteoblasts, which stimulate the transformation of preosteoclasts into mature osteoclasts. Osteoclasts dissolve the mineralized collagen matrix in bone, which can result in osteopenia and osteoporosis. Although there is no consensus on optimal vitamin D levels, recent studies suggest that 25-hydroxyvitamin D should ideally exceed 30 ng/mL, because lower levels result in increased levels of parathyroid hormone [7,8]. However, these definitions are based on adult data, and no such data are available for children. Prevalence of Vitamin D Deficiency in the General Pediatric Population The prevalence of vitamin D deficiency is difficult to estimate. This is partly attributable to variation in definitions. Data from 2955 12-19-year-old American adolescents from the National Health and Nutrition Examination Survey revealed striking differences in prevalence, depending on the cutoff levels of vitamin D used to define deficiency [9]. When the definition of vitamin D deficiency was changed from <11 ng/mL to <20 ng/mL, the prevalence increased from 2% to 14%. This range of general population prevalence should be kept in mind as we review the literature related to children with epilepsy. Vitamin D levels are also affected by age, gender, geographic location, use of supplements, and body mass index, making it still more complex to define deficiency or insufficiency, and to estimate prevalence [10]. The American Academy of Pediatrics recently revised its recommended daily intake of vitamin D [11], for the prevention of rickets in children. The American Academy of Pediatrics Committee on Nutrition recommended that children and adolescents receive at least 400 IU of vitamin D daily. Children taking antiepileptic drugs were identified in this report as being at high risk for vitamin D deficiency.
D <15 ng/mL [2]. Levels manifested seasonal variability, and were highest in June and lowest in December. Since that time, several cross-sectional studies examined the prevalence of vitamin D insufficiency among children with epilepsy. One clinical trial attempted to determine the effect of vitamin D supplementation on bone mineral density among children with epilepsy. These data are summarized below. In several areas, the literature is contradictory, suggesting that vitamin D and bone health are complex issues for children with epilepsy, and many gaps in knowledge remain. Verrotti et al. [13] demonstrated the importance of a detailed reading of this literature. They studied 60 Italian children with epilepsy (6-19 years old, drug-naı¨ve, with idiopathic localization-related epilepsy) who commenced carbamazepine and became seizure-free, compared with 60 control patients, stratified by pubertal status. Verrotti et al. [13] reported that all subjects exhibited ‘‘normal’’ vitamin D levels. However, the mean level of 25-hydroxyvitamin D was <30 ng/mL in all groups. Because there are metabolic consequences of vitamin D levels at less than approximately 30 ng/mL [14], these results suggest that, as a group, these subjects’ vitamin D status was indeed insufficient. Effect of Ambulatory Status on Vitamin D Levels in Children With Epilepsy Most studies specifically exclude patients who are nonambulatory, because of concerns about confounding results. However, Baer et al. [15] studied vitamin D levels in relation to ambulatory status in a large sample of 3-9-year-old children who lived at home. Two hundred and twenty-six subjects were ambulatory and did not receive antiepileptic drugs, 23 were ambulatory and taking antiepileptic drugs, 43 were nonambulatory but not taking antiepileptic drugs, and 46 were nonambulatory and taking antiepileptic drugs. Baer et al. [15] observed that the risk of vitamin D deficiency among nonambulatory children was about twice that of ambulatory children (c2 statistic, 20.9; P < 0.001), even after adjusting for confounders. They also found lower z-scores for bone mineral density among nonambulatory patients, independent of antiepileptic drug status. Other studies reported no effects of ambulatory status on 25hydroxyvitamin D levels among noninstitutionalized children with intractable epilepsy, but these studies may have been underpowered to detect such a difference [16].
Vitamin D Status Among Children With Epilepsy The diets of children with intractable epilepsy often lack adequate protein, vitamins, and minerals [12]. However, vitamin D insufficiency is also quite prevalent among ambulatory children whose epilepsy is well-controlled on monotherapy. The association between epilepsy, antiepileptic drugs, and vitamin D status has been recognized for more than 30 years. In 1979, Offerman et al. reported that 72% of 83 children aged 10-16 years with epilepsy vs 50% of 16 control subjects exhibited 25-hydroxyvitamin
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Vitamin D Status Among Children With Intractable Epilepsy Children with intractable epilepsy are at risk of poor nutritional status [12], and were reported to manifest a high prevalence of vitamin D insufficiency. Bergqvist et al. [16] studied children with intractable epilepsy, taking new-generation antiepileptic drugs, before and during treatment with the ketogenic diet. Before the initiation of the diet, 4% of 45 subjects exhibited vitamin D deficiency
(defined as 25-hydroxyvitamin D levels of <11 ng/mL), whereas 51% exhibited insufficient 25-hydroxy vitamin D levels (<32 ng/mL). The levels of 1,25-dihydroxyvitamin D were normal in all cases. No effects of age or gender were detectable, but vitamin D levels declined during treatment with the ketogenic diet. Bergqvist et al. [16] observed an important effect of polypharmacy, with a 25-hydroxyvitamin D decrease of approximately 7 ng/mL for each additional antiepileptic drug. An adequate dietary intake of vitamin D, fewer antiepileptic drugs, and generalized seizures were associated with higher levels of 25-hydroxyvitamin D.
cussed here, children with metabolic or other diseases that could affect bone health were excluded. To our knowledge, no study has specifically compared the effects of antiepileptic drugs on bone health in children with idiopathic vs symptomatic epilepsy syndromes, or in those with wellcontrolled vs intractable epilepsy. Below, we review studies designed to look specifically at the effects of individual drugs, and most of these studies included only subjects with idiopathic epilepsy syndromes or very well-controlled seizures.
Influence of Monotherapy vs Polypharmacy
There are conflicting reports regarding bone mineral density among children with varying epilepsy syndromes, and treated with antiepileptic drugs. Direct comparisons between studies are often difficult, because some report site-specific bone mineral density results, whereas others use a total body measurement. The most recent recommendations involve evaluating whole-body Dexa scans, because differences may exist between trabecular and cortical bone density, and between weight-bearing and nonweight-bearing bone, limiting the generalizability of site-specific measurements. Some studies demonstrated no significant differences in bone mineral density among epilepsy patients compared with healthy control subjects [18-20]. However, many reported clinically significant reductions in bone mineral density among children with epilepsy [21-26]. Compared with monotherapy-treated patients, those treated with more than one antiepileptic drug appear to be at higher risk for low bone mineral density [20,22]. Younger and nonambulatory patients, and those with lower body mass indices, are also at high risk [22]. In addition, increasing durations of antiepileptic drug treatment may elevate the risk of osteopenia [24]. In two separate studies of normally ambulating children, Sheth et al. [24] and Sheth and Hermann [25] demonstrated lower bone mineral density among patients with generalized epilepsy syndromes compared with healthy control subjects, and those with symptomatic generalized epilepsy were at the highest risk. Even among those with normal ambulatory status, patients with both idiopathic and symptomatic epilepsy syndromes exhibited lower bone mineral density than did healthy control subjects. However, those with partial seizures had bone mineral density comparable with that of control subjects [25], and those with idiopathic generalized epilepsy exhibited lower bone mineral density than those with idiopathic localization-related epilepsy. Children with symptomatic generalized epilepsy syndromes appear to be at highest risk for low bone mineral density, and this risk increases with time [24,25]. The reasons for these findings are likely multifactorial, and could include dietary differences, possible subtle neuromotor abnormalities among those with symptomatic epilepsy syndromes, effects of medication, vitamin D levels, and the influence of seizures themselves on the pituitary-hypothalamic axis. No study has been powered to evaluate the
Several studies commented on the effect of polypharmacy on vitamin D status in children with epilepsy. A German cross-sectional study [17] included 38 children (aged 5-12 years) taking antiepileptic drugs (no restrictions on antiepileptic drug or epilepsy syndrome) and 44 healthy control subjects. More than 75% of patients were vitamin D-deficient (defined as <20 ng/mL), and 21% vitamin D-insufficient (20-30 ng/mL). Polytherapy patients demonstrated significantly lower 25-hydroxyvitamin D levels than patients treated with monotherapy (12.7 6.55 ng/mL S.D., n = 26, vs 18.1 8.29 ng/mL S.D., n = 12, P = 0.038). As previously mentioned, Bergqvist et al. [16] reported a decline of approximately 7 ng/mL in 25-hydroxyvitamin D for each additional antiepileptic drug in children with medically refractory epilepsy. In a Lebanese study, El-Hajj Fuleihan et al. [18] evaluated 88 children with epilepsy (mean age, 13 2 years S.D.) of varying types (52% idiopathic, 38% cryptogenic, and 10% symptomatic), treated for a mean duration of 4.7 4 years S.D. The authors did not comment on seizure control or on differences among epilepsy syndromes. Fifty-five percent were receiving enzyme-inducing antiepileptic drugs, and 33% were receiving multiple antiepileptic drugs. The type of antiepileptic drug exerted no effect on vitamin D status or bone mineral density, but polypharmacy exerted a negative impact on bone mineral density. Remarkably, the subjects’ 25-hydroxyvitamin D levels were insufficient, on average (i.e., 18.5 8.1 ng/mL S.D.; 57% had a 25-hydroxyvitamin D level of <20 ng/mL), but were actually higher than those of the 111 age-matched and gender-matched control subjects (15.3 6.8 ng/mL S.D., P = 0.004; 79% of control subjects had 25-hydroxyvitamin D levels of <20 ng/mL). Vitamin D Status Among Children With Idiopathic Epilepsy Syndromes or Seizure-Free Status To avoid the potentially confounding factors of polypharmacy, neuromotor disability, and symptomatic epilepsy syndromes, many studies include only children with idiopathic epilepsy syndromes whose seizures are well-controlled with a single antiepileptic drug. In all studies dis-
Bone Mineral Density Among Children With Epilepsy
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 387
influence of specific medications on bone mineral density among children with symptomatic generalized epilepsy. This task is difficult because these patients are often treated with multiple medications, and their regimens are adjusted frequently. Although it is clear that antiepileptic drugs or epilepsy are associated with a lower bone mineral density, at least in certain subgroups, several studies indicated no correlation between biochemical markers of bone health and bone mineral density [18,27], suggesting that the impact of antiepileptic drugs and epilepsy on bone mineral density is multifactorial. Below, we summarize studies investigating the specific antiepileptic drugs carbamazepine and valproic acid. The majority of studies demonstrated no significant decrease in bone mineral density among those treated with valproic acid [26,27-30], whereas five demonstrated no difference among patients given carbamazepine [26-30], and two demonstrated decreased bone mineral density in carbamazepine-treated patients [31,32]. Bone mineral density was also abnormal among children taking phenobarbital or phenytoin, compared with age-matched and sex-matched control subjects [23]. One study reported lower bone mineral density in patients treated with oxcarbazepine [33], whereas another found no difference [31]. Specific Antiepileptic Drugs Because many antiepileptic drugs induce hepatic CYP450 metabolism, they result in an increased metabolism of vitamin D, leading to declining 25-hydroxyvitamin D levels, increased parathyroid hormone levels, and abnormally enhanced bone turnover. However, even nonenzymeinducing medications were associated with poor bone health. Therefore, hepatic enzyme induction is only one component of the complex mechanisms by which antiepileptic drugs affect bone health. Most studies of bone density and of vitamin D status among children with epilepsy were not powered or designed to study the effects of specific drugs. However, several studies evaluated the effects of carbamazepine and valproic acid. Carbamazepine Nine published studies specifically examined the effects of carbamazepine on vitamin D or bone mineral density in children with epilepsy (Table 1). Three studies examined vitamin D levels in children treated with carbamazepine [13,31,34]. Two of these studies reported no statistically significant differences between 25-hydroxyvitamin D levels in control subjects and carbamazepine-treated children, refuting the theory of hepatic enzyme induction as the driving force for hypovitaminosis D among epilepsy patients. Conversely, Nicolaidou et al. [34] observed that 19 of 37 patients (37%) treated with either carbamazepine or valproic acid exhibited 25-hydroxyvitamin D levels of <10 ng/mL in the first year of treatment, and that the mean 25-hydroxyvitamin D level declined over
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the 36-month treatment period (25/51, or 49%, had a 25-hydroxyvitamin D level of <10 ng/mL during the 36-month study period). Nicolaidou et al. [34] did not observe differences between the valproic acid and carbamazepine groups. That study also reported a significant negative correlation between 25-hydroxyvitamin D and parathyroid hormone, as well as seasonal variation among 25-hydroxyvitamin D levels, but did not examine bone mineral density. Among studies that examined bone mineral density in relation to treatment with carbamazepine, five reported no significant difference [26-30], whereas one reported lower bone mineral density but unchanged 25-hydroxyvitamin D levels [31] compared with healthy control subjects, and another reported lower bone mineral density in children receiving carbamazepine compared with those receiving valproic acid [32]. Verrotti et al. [13] observed no difference in 25-hydroxyvitamin D levels among those treated with carbamazepine compared with control subjects, but the mean 25-hydroxyvitamin D levels were insufficient in both groups. Valproic Acid Because valproic acid is a hepatic enzyme-inhibiting antiepileptic drug, many postulate that it should have less effect than enzyme-inducers on bone health. The literature demonstrates that the effects of valproic acid on bone density and markers of bone health are complex (Table 2). Chou et al. [32] observed higher bone mineral density among those receiving valproic acid compared with those on carbamazepine. Conversely, Babayigit et al. [31] demonstrated no significant differences in 25-hydroxyvitamin D levels between children treated with valproic acid and healthy control subjects, but the valproic-acid group exhibited lower bone mineral density. One study found lower bone mineral density in subjects treated with valproic acid and/or lamotrigine [35] compared with control subjects in the literature, but five studies reported no significant difference in bone mineral density among children treated with valproic acid [26-30]. Effects of New Antiepileptic Drugs and the Ketogenic Diet on Bone Health in Children With Epilepsy Oxcarbazepine Because it is a less potent enzyme-inducer than carbamazepine, one may hypothesize that oxcarbazepine should have less of an effect on bone health than carbamazepine. Because recent guidelines suggest that oxcarbazepine is the initial treatment of choice for people with partial epilepsy syndromes [36], the study of this medication’s effects on bone health is vitally important. Two studies evaluated the effects of oxcarbazepine on bone health in children with epilepsy. Cansu et al. prospectively enrolled 34 newly diagnosed children with idiopathic localization-related epilepsy who were ambulatory and without other neurologic or medical diagnoses [33]. Patients were treated with
Table 1. Effect of carbamazepine on vitamin D levels and bone mineral density N (Epilepsy Patients/Control Subjects)
Mean Mean 25-Hydroxyvitamin D, 25-Hydroxyvitamin D, Epilepsy Patients Control Subjects
Epilepsy Syndrome
Duration of AED Treatment
Akin et al. [28] 28/26 Altay et al. [29] 21/22 Babayigit et al. [31] 23/30 Chou et al. [32] 21 CBZ, 21 VPA
Varied Seizure-free IGE Idiopathic ‘‘Uncomplicated’’
>1 yr >1 yr >1 yr >6 mo
NA NA 20.47 11.60 S.D.* NA
NA NA 22.3 7.12 S.D.* NA
Kafali et al. [30] Sheth et al. [26] Tekgul et al. [27]
Idiopathic Idiopathic Varied
>6 mo >6 mo 2 yr
NA NA NA
NA NA NA
Drug-naı¨ve baseline and >2 yr treatment
P = NS
P = NS
Reference
Verrotti et al. [13]
6/57 13/27 11 CBZ 13 VPA 60/60
Idiopathic LRE
BMD (AED vs Control) No difference No difference Y Y compared with VPA No difference No difference No difference NA
* P > 0.05 (not significant). Abbreviations: Y = BMD decreased, compared with healthy control subjects AED = Antiepileptic drug BMD = Bone mineral density CBZ = Carbamazepine IGE = Idiopathic generalized epilepsy LRE = Localization-related epilepsy N = Number of subjects NA = Not applicable or not studied P = NS/Difference did not meet statistical significance VPA = Valproic acid
oxcarbazepine for 18 months. Mean vitamin D levels were <30 ng/mL at baseline and at 18 months for both prepubertal and pubertal subjects, and were statistically lower for the group as a whole at 18 months compared with baseline (25.14 6.11 ng/mL S.D. vs 27.92 8.76 ng/mL S.D., respectively, P = 0.016). No change in bone mineral density z-scores occurred over 18 months, and there was no correlation between 25-hydroxyvitamin D and bone mineral density. Babayigit et al. [31] compared patients with idiopathic epilepsy syndromes treated with oxcarbazepine (n = 14), carbamazepine (n = 23), or valproic acid (n = 31) with 30 healthy control children, and observed that although vitamin D levels were not lower in treated patients, total bone mineral density was lower in those on antiepileptic drugs. In the only other study designed specifically to evaluate oxcarbazepine, Mintzer et al. [37] evaluated adult patients taking carbamazepine or oxcarbazepine compared with control subjects, and then switched those on carbamazepine to oxcarbazepine monotherapy. Levels of 25-hydroxyvitamin D were significantly lower in the oxcarbazepine and carbamazepine subjects, compared with control subjects, but were not significantly different between the oxcarbazepine and carbamazepine groups, suggesting that the newer agent may also exert an important impact on bone health. Lamotrigine Guo et al. [35] evaluated the effects of valproic acid and lamotrigine, alone and in combination, on growth and bone
mass in children with epilepsy. Fifty-three patients taking one or both antiepileptic drugs and who were without bone or metabolic disease, other bone-altering medications, or a family history of osteoporosis, were studied. Twentythree subjects (43%) were below the 10th percentile for height, and nine (24.3%) had a bone mineral density z-score of less than 1.5, without significant differences between those treated with valproic acid or lamotrigine. Low physical activity scores corresponded to worse bone-health markers, including lower 25-hydroxyvitamin D levels. The combination of dual therapy with valproic acid and lamotrigine, along with low activity scores, was associated with the highest risk of low bone mineral density and short stature. Ketogenic Diet Bergqvist et al. [22] measured changes in bone mineral density among children treated with the ketogenic diet for 15 months. On average, height and weight status were low at baseline, and declined while on the ketogenic diet. Those at highest risk for poor bone mineral density were younger patients who were nonambulatory and who had a low body mass index. These patients were treated with new antiepileptic drugs (lamotrigine, n = 13; topiramate, n = 9; zonisamide, n = 7; levetiracetam, n = 4; and oxcarbazepine, n = 2) as well as older antiepileptic drugs (valproic acid, n = 6; phenytoin, n = 4; and chlorazepate, n = 5). Because antiepileptic drug use was variable and changed
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 389
Table 2. Effect of valproic acid on vitamin D levels and bone mineral density
Author Akin et al. [28] Altay et al. [29] Babayigit et al. [31] Chou et al. [32] Guo et al. [35]
Kafali et al. [30] Sheth et al. [26] Tekgul et al. [27] Verrotti et al. [13]
N (Epilepsy Patients/Control Subjects) 25/26 15/22 31/30 21 CBZ 21 VPA 28 VPA 16 LTG 4 VPA + LTG 6/57 13/27 11 CBZ 13 VPA 60/60
Epilepsy Syndrome
Duration of AED Treatment
Varied Seizure-free IGE Idiopathic ‘‘Uncomplicated’’
>1 yr >1 yr >1 yr >6 mo
NA NA 20.5 11.6 S.D.* NA
NA NA 22.3 7.1 S.D.* NA
Varied
>2 yr
NA
NA
Idiopathic Idiopathic Varied
>6 mo >6 mo 2 yr
NA NA NA
NA NA NA
Drug-naı¨ve baseline and >2 yr treated
P = NS
P = NS
Idiopathic LRE
Mean Mean 25-Hydroxyvitamin D, 25-Hydroxyvitamin D, Epilepsy Patients Control Subjects
BMD (AED vs Control Subjects) No difference No difference Y [ compared with CBZ All Y compared with literature control subjects No difference No difference No difference NA
* P = NS. Abbreviations: Y = BMD decreased compared with healthy control subjects AED = Antiepileptic drug BMD = Bone mineral density CBZ = Carbamazepine IGE = Idiopathic generalized epilepsy LRE = Localization-related epilepsy LTG = Lamotrigine N = Number of subjects NA = Not applicable or not studied P = NS/Difference did not meet statistical significance VPA = Valproic acid
during the 15 months of ketogenic-diet treatment, analyses of specific medication effects could not be performed. The same authors [16] evaluated vitamin D status among children with intractable epilepsy, and taking newer antiepileptic drugs, before and during treatment with the ketogenic diet. Details of this study were presented above in the discussion of vitamin D levels in children with intractable epilepsy. Levels of 25-hydroxyvitamin D were lower in winter and spring, compared with summer and fall, and declined by approximately 0.5 ng/mL per month during the 15 months of treatment with the ketogenic diet. Treatment With Vitamin D Supplements: Clinical Trial There is one reported clinical trial of vitamin D supplementation in children with epilepsy. Mikati et al. [19] described the results for 78 Lebanese 10-18-year-olds treated with antiepileptic drugs for >6 months (mean, 5.2 4.6 years S.D.). These subjects were given 400 IU or 2000 IU of vitamin D per day for 1 year. The mean baseline level of 25-hydroxyvitamin D was in the insufficient range (18.1 8.1 ng/mL S.D.), with 15% deficient (<10 ng/mL), 44% insufficient (10-20 ng/mL), and 41% normal (defined by the study’s authors as >20 ng/mL), and was not different between high-dose and low-dose supplementation groups.
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After 1 year of vitamin D supplementation, vitamin D levels rose marginally (low dose, 18.2 7.1 S.D. to 21.3 8.54 S.D.; high dose, 18.0 9.1 S.D. to 22.9 8.4 S.D.; P = 0.4), but overall, 6% remained deficient, and 44% remained insufficient. Bone mineral density after 1 year was the same in both groups, and was comparable to a group of healthy girls from the same region. The authors speculated that no difference in bone mineral density was detected because of the relatively brief duration of treatment and the modest increases in vitamin D levels, which remained well below the target value of >30 ng/mL. Importantly, the study did not control for diet or exercise, and compliance with the vitamin D supplementation was not explicitly documented. That study highlighted some of the difficulties in designing and conducting a clinical treatment trial in this population. Improving bone health in children with epilepsy seems intuitively important, because children are treated with antiepileptic drugs for years at a time, including periods of highest bone mineralization. Avoidance of osteoporosis and osteopenia in these patients should, in theory, reduce the risk of fractures later in life. However, to prove this effect requires a large sample size and an extensive follow-up period, during which it would be unethical to avoid adjustments in medication or to prohibit vitamin D and calcium supplementation.
Table 3. Suggested vitamin D supplementation, based on 25-hydroxy vitamin D level 25-Hydroxyvitamin D Level (ng/mL)
Cholecalciferol Dose
Repeat Laboratory Examinations
30+ 15-29
400 IU per day* 2000 IU per day in divided doses
<15
2000-4000 IU per day in divided doses, in consultation with dietician
Annually Every 4 weeks until 25-hydroxyvitamin D >30† Every 3-4 weeks until 25-hydroxyvitamin D >30†
Additional Laboratory Examinations
Phosphorus, magnesium, calcium Parathyroid hormone, calcium, magnesium, phosphorus, consider Dexa scan
* In accordance with American Academy of Pediatrics recommendations, we suggest that all children treated for epilepsy be given a daily multivitamin with 400 international units of vitamin D3. † After 25-hydroxyvitamin D levels rise to normal range, we halve the vitamin D supplement dose. If level remains normal, recheck in 3-6 months. Abbreviation: IU = International units
Gaps in Knowledge Despite increasing interest in the comorbidities of epilepsy, along with an expanding literature on the effects of epilepsy and its treatment on bone health, as well as the high prevalence of vitamin D deficiency in persons with epilepsy, significant gaps in knowledge persist. Debate persists in the medical literature about the optimal vitamin D level in the general population, even after a recent upward revision of the recommended daily vitamin D intake [6,11]. Until the most advantageous vitamin D level is defined for children, questions will remain about the correct approach to children with epilepsy. Most studies evaluate the ‘‘healthiest’’ epilepsy patients (i.e., those treated with monotherapy who are ambulatory and seizure-free). If these patients have significant abnormalities in bone health, the effect may be even more pronounced in the ‘‘sicker’’ patients (i.e., those with uncontrolled seizures and requiring polypharmacy, or with neuromotor deficits). In addition, all studies cited in this review examined bone health among school-age children. The impact of epilepsy and antiepileptic drugs on bone health in infants and toddlers has not been studied. There are practical barriers to conducting such studies, yet it is an important subject for this population. Although many studies evaluated the impact of older antiepileptic drugs on bone health, the results were mixed, and few examined the effects of specific newer antiepileptic drugs. Future studies should be designed to evaluate the impact of individual new-generation antiepileptic drugs on bone health in children. The mixed results discussed here demonstrate that the effects of antiepileptic drugs on bone health are not as simple as the hepatic enzyme induction theory would suggest. Even drugs that do not induce CYP450 enzymes can be associated with abnormal bone mineral density or inadequate vitamin D status. Despite hopes that the newer antiepileptic drugs, which are less potent enzyme-inducers, would exert a minimal impact on bone health, the literature suggests otherwise. The role of vitamin D supplementation in this population is not clear. Only one treatment trial of vitamin D supple-
mentation has been undertaken among children with epilepsy [19], and it demonstrated no significant difference between high-dose and low-dose vitamin D, and no impact on bone mineral density after 1 year of treatment. Therefore, no evidence-based treatment guide exists yet for children with epilepsy who manifest vitamin D insufficiency or reduced bone mineral density. Additional well-designed and well-controlled studies are required. These trials must take into account the high prevalence of vitamin D insufficiency in the general population, as well as multiple potential confounders. Before the results of such studies can be generalized to specific epilepsy patient populations, factors such as geography and seasonal variation must also be taken into account, e.g., can a study conducted in a sunny or tropical country be applicable among patients treated in northern climates, who have much more limited sun exposure? Suggestions for Clinical Practice Vitamin D and bone health among children with epilepsy is a complex topic. We lack the experimental data to support universal screening and specific interventions for those with low vitamin D levels. Nonetheless, the data are sufficient to suggest that vitamin D insufficiency may be important for people with epilepsy, testing is readily available, and supplementation with vitamin D is inexpensive and without significant risk. We recognize that future work may dictate revisions in our practice, but until such literature becomes available, we offer suggestions for the screening and treatment of insufficient vitamin D levels (Table 3). In our practice, all children with epilepsy are screened annually with a 25-hydroxyvitamin D level assay. Like Bergqvist et al. [16], we found that 1,25 dihydroxyvitamin D levels are almost always normal in our patient population, and so we do not check that level routinely. Recommended vitamin D supplementation depends on the level of 25-hydroxyvitamin D. Because cholecalciferol (vitamin D3) is better absorbed than ergocalciferol (vitamin D2), we recommend using cholecalciferol rather than ergocalciferol in
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 391
children with normal kidney function. Cholecalciferol is available in tablet, capsule, liquid, and ‘‘gummy’’ formulations, and is relatively inexpensive. Some pediatric epilepsy practices routinely screen high-risk patients with Dexa scans. There is no current evidence base for this recommendation, and we suggest pursuing bone density measurements on a case-by-case basis. Measurement of bone mineral density should be considered if there is a history of bone fractures or vitamin D deficiency.
Conclusions The potential impact of epilepsy and antiepileptic drugs on bone health has been recognized for more than 30 years, but some of the literature remains contradictory. By inducing the CYP450 system, many antiepileptic drugs (phenytoin, phenobarbital, and carbamazepine in particular) result in an accelerated metabolism of vitamin D. Lower vitamin D levels then result in hyperparathyroidism, ultimately leading to abnormally enhanced bone turnover and subsequent decreased bone density. However, even nonenzyme-inducing antiepileptic drugs (e.g., valproic acid) and less potent enzyme-inducers (e.g., oxcarbazepine) may exert adverse effects on bone mineralization. Clearly, hepatic enzyme induction is not the only mechanism by which antiepileptic drugs affect bone mineralization. The literature demonstrates a high prevalence of vitamin D insufficiency not only among children with epilepsy, but also among apparently health control subjects. Despite some contradictory results, pediatric neurologists, who care not only about seizures but also about patients’ overall well-being, should attend to this potentially important aspect of patients’ health. Studies exhibited conflicting results among children with idiopathic epilepsy syndromes treated with carbamazepine or valproic acid. Some demonstrated an association with lower 25-hydroxyvitamin D levels and lower bone mineral density, whereas others did not. Children with intractable epilepsy who are treated with multiple antiepileptic drugs appear to be at high risk of poor bone mineralization, and this problem is likely multifactorial, including the impact of the seizures themselves, diet, antiepileptic drugs, and neuromotor disability. Although there is increasing recognition of the probable negative effects of epilepsy and its treatment on bone health, a survey of pediatric neurologists indicated that only 41% screened for bone disease among their patients, and only 3% routinely monitored parathyroid hormone or 25-hydroxyvitamin D levels [38]. If further studies demonstrate a beneficial effect of interventions such as vitamin D or calcium supplementation on bone health in our pediatric epilepsy patients, we hope that these numbers, and the interest of pediatric neurologists in this important aspect of epilepsy care, will rise. While we await evidence-based treatment guidelines, we suggest screening for vitamin D insufficiency and supplementation with cholecalciferol, to maintain levels of vitamin D in the optimal range.
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References [1] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357: 266-81. [2] Offermann G, Pinto V, Kruse R. Antiepileptic drugs and vitamin D supplementation. Epilepsia 1979;20:3-15. [3] Vestergaard P. Epilepsy, osteoporosis and fracture risk—A metaanalysis. Acta Neurol Scand 2005;112:277-86. [4] Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts ACG. Use of antiepileptic drugs and risk of fractures: Case-control study among patients with epilepsy. Neurology 2006;66:1318-24. [5] Sheth RD, Gidal BE, Hermann BP. Pathological fractures in epilepsy. Epilepsy Behav 2006;9:601-5. [6] Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: Review of current knowledge and recommendations. Pediatrics 2008; 122:398-417. [7] Rovner AJ, O’Brien KO. Hypovitaminosis D among healthy children in the United States: A review of the current evidence. Arch Pediatr Adolesc Med 2008;162:513-9. [8] Holick MF. Vitamin D status: Measurement, interpretation, and clinical application. Ann Epidemiol 2009;19:73-8. [9] Saintonge S, Band H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: The National Health and Nutrition Examination Survey III. Pediatrics 2009;123: 797-803. [10] Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr 2008;88(Suppl):S558-64. [11] Wagner CL, Greer FR. Section on Breastfeeding and Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-52. [12] Volpe SL, Schall JI, Gallagher PR, Stallings VA, Bergqvist AGC. Nutrient intake of children with intractable epilepsy compared with healthy children. J Am Diet Assoc 2007;107:1014-8. [13] Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia 2002;43:1488-92. [14] Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-83. [15] Baer MT, Kozlowski BW, Blyler EM, Trahms CM, Taylor ML, Hogan MP. Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status. Am J Clin Nutr 1997;65:1042-51. [16] Bergqvist AGC, Schall JI, Stallings VA. Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet. Epilepsia 2007;48:66-71. [17] Nettekoven S, Strohle A, Trunz B, et al. Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy. Eur J Pediatr 2008;167:1369-77. [18] El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati MA. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone 2008;43:149-55. [19] Mikati MA, Dib B, Yamout B, Sawaya R, Rahi AC, el-Hajj Fuleihan G. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone. Neurology 2006;67:2005-14. [20] Tekgul H, Dizdarer G, Demir N, Ozturk C, Tutuncuoglu S. Antiepileptic drug-induced osteopenia in ambulatory epileptic children receiving a standard vitamin D3 supplement. J Pediatr Endocrinol Metab 2005;18:585-8. [21] Tsukahara H, Kimura K, Todoroki Y, et al. Bone mineral status in ambulatory pediatric patients on long-term anti-epileptic drug therapy. Pediatr Int 2002;44:247-53. [22] Bergqvist AGC, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr 2008;88:1678-84. [23] Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994;16: 382-5.
[24] Sheth RD, Binkley N, Hermann BP. Progressive bone deficit in epilepsy. Neurology 2008;70:170-6. [25] Sheth RD, Hermann BP. Bone in idiopathic and symptomatic epilepsy. Epilepsy Res 2008;78:71-6. [26] Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995;127:256-62. [27] Tekgul H, Serdaroglu A, Huseyinov A, Gokben S. Bone mineral status in pediatric outpatients on antiepileptic drug monotherapy. J Child Neurol 2006;21:411-4. [28] Akin R, Okutan V, Sarici U, Altunbas A, Gokcay E. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol 1998;19:129-31. [29] Altay EE, Serdaroglu A, Tumer L, Gucuyener K, Hasanoglu A. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab 2000;13:933-9. [30] Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr (Phila) 1999;38:93-8. [31] Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006;35: 177-81.
[32] Chou I-J, Lin K-L, Wang H-S, Wang C-J. Evaluation of bone mineral density in children receiving carbamazepine or valproate monotherapy. Acta Paediatr Taiwan 2007;48:317-22. [33] Cansu A, Ediz Y, Ayse S, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol 2008;39: 266-71. [34] Nicolaidou P, Georgouli H, Kotsalis H, et al. Effects of anticonvulsant therapy on vitamin D status in children: Prospective monitoring study. J Child Neurol 2006;21:205-9. [35] Guo C-Y, Ronene GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001;42:1141-7. [36] French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy. Neurology 2004;62:1252-60. [37] Mintzer S, Boppana P, Toguri J, DeSantis A. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia 2006;47:510-5. [38] Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol 2001;58:1369-74.
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 393
Vitamin D and Bone Health Among Children With Epilepsy Rene´e A. Shellhaas, MD, MS and Sucheta M. Joshi, MD, MS The lay media and scientific literature have focused increasing attention on vitamin D deficiency and insufficiency in recent years. Low vitamin D levels confer increased an risk of abnormal bone mineralization, and are linked to poor bone health in epilepsy patients. However, vitamin D is not the only determinant of bone health in children with epilepsy. Anticonvulsant medications, in addition to features and comorbidities of epilepsy and coexisting neurologic diseases, are important factors in this complex topic. We review the basic metabolism of vitamin D in terms of bone health among children with epilepsy. We also discuss the literature regarding vitamin D and bone mineral density in this population. Finally, we suggest algorithms for screening and treating vitamin D insufficiency in these patients. Ó 2010 by Elsevier Inc. All rights reserved. Shellhaas Rene´e A, Joshi SM. Vitamin D and bone health among children with epilepsy. Pediatr Neurol 2010;42: 385-393.
Introduction Much attention has focused recently on the impact of vitamin D on various aspects of health, both in the medical and lay press. Besides rickets and reduced bone mineral density, vitamin D has been linked to an array of health conditions, e.g., diabetes mellitus, stroke, autoimmune diseases, and cancer (reviewed by Holick [1]). The association between vitamin D, antiepileptic drugs, and bone health in individuals with epilepsy has been recognized for more than 30 years (e.g., by Offermann et al. [2]). Although few data are available for children, adults with epilepsy are known to be at significantly increased risk for bone fractures, compared with the general population, and increasing age and duration of treatment are important risk factors [3-5].
The issue of bone health in children with epilepsy is particularly important, because these patients are often treated for many years, including the time of highest bone mineral accrual. Seizures themselves can pose a risk for injury, including fractures, and the added comorbidity of poor bone health increases this risk, especially in children with major motor manifestations of their seizures, as well as in those with impaired motor function and coordination. We review the literature on vitamin D and bone health in children with epilepsy, including data on antiepileptic drugs and bone health. We suggest strategies for monitoring vitamin D levels in children on chronic antiepileptic drug therapy, and for treating vitamin D insufficiency. Vitamin D Metabolism Vitamin D is a fat-soluble vitamin. Dietary sources of vitamin D include milk and dairy products, eggs, certain fish, and vitamin D-fortified foods. Food, however, accounts for less than 10% of vitamin D requirements [6]. The major source of this vitamin is cutaneous synthesis. Vitamin D is synthesized photochemically in the skin from 7-dehydrocholesterol, after exposure to specific ultraviolet spectra in sunlight. Exposure to sunlight for 10-15 minutes in the daytime (between 10 AM and 3 PM) in the spring, summer, and fall results in adequate vitamin D synthesis in fair-skinned people. Persons with darker skin require a much longer duration of sun exposure [7]. Lack of sun exposure, as occurs in Northern climates, reduces the amount of vitamin D synthesized in the skin, increasing the risk of insufficient vitamin D levels. Impact of Vitamin D Insufficiency on Bone Health Vitamin D and parathyroid hormone levels are inversely related, so that as vitamin D levels rise, parathyroid hormone levels drop. Parathyroid levels reach a nadir
From the Division of Pediatric Neurology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
Communications should be addressed to: Dr. Shellhaas; L3215 Women’s Hospital; 1500 East Medical Center Drive; Ann Arbor, MI 48109-5203. E-mail: [email protected] Received July 2, 2009; accepted December 8, 2009.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.12.005 0887-8994/$—see front matter
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 385
when 25-hydroxyvitamin D serum levels are between 30-40 ng/mL. When 25-hydroxyvitamin D levels fall below this level, the intestinal absorption of calcium decreases, and parathyroid hormone levels begin to increase [6]. The secretion of parathyroid hormone then enhances the tubular reabsorption of calcium, promotes the urinary loss of phosphorus, and stimulates the kidneys to produce 1,25-dihydroxyvitamin D (the active vitamin D metabolite), facilitating intestinal calcium absorption. Parathyroid hormone also activates osteoblasts, which stimulate the transformation of preosteoclasts into mature osteoclasts. Osteoclasts dissolve the mineralized collagen matrix in bone, which can result in osteopenia and osteoporosis. Although there is no consensus on optimal vitamin D levels, recent studies suggest that 25-hydroxyvitamin D should ideally exceed 30 ng/mL, because lower levels result in increased levels of parathyroid hormone [7,8]. However, these definitions are based on adult data, and no such data are available for children. Prevalence of Vitamin D Deficiency in the General Pediatric Population The prevalence of vitamin D deficiency is difficult to estimate. This is partly attributable to variation in definitions. Data from 2955 12-19-year-old American adolescents from the National Health and Nutrition Examination Survey revealed striking differences in prevalence, depending on the cutoff levels of vitamin D used to define deficiency [9]. When the definition of vitamin D deficiency was changed from <11 ng/mL to <20 ng/mL, the prevalence increased from 2% to 14%. This range of general population prevalence should be kept in mind as we review the literature related to children with epilepsy. Vitamin D levels are also affected by age, gender, geographic location, use of supplements, and body mass index, making it still more complex to define deficiency or insufficiency, and to estimate prevalence [10]. The American Academy of Pediatrics recently revised its recommended daily intake of vitamin D [11], for the prevention of rickets in children. The American Academy of Pediatrics Committee on Nutrition recommended that children and adolescents receive at least 400 IU of vitamin D daily. Children taking antiepileptic drugs were identified in this report as being at high risk for vitamin D deficiency.
D <15 ng/mL [2]. Levels manifested seasonal variability, and were highest in June and lowest in December. Since that time, several cross-sectional studies examined the prevalence of vitamin D insufficiency among children with epilepsy. One clinical trial attempted to determine the effect of vitamin D supplementation on bone mineral density among children with epilepsy. These data are summarized below. In several areas, the literature is contradictory, suggesting that vitamin D and bone health are complex issues for children with epilepsy, and many gaps in knowledge remain. Verrotti et al. [13] demonstrated the importance of a detailed reading of this literature. They studied 60 Italian children with epilepsy (6-19 years old, drug-naı¨ve, with idiopathic localization-related epilepsy) who commenced carbamazepine and became seizure-free, compared with 60 control patients, stratified by pubertal status. Verrotti et al. [13] reported that all subjects exhibited ‘‘normal’’ vitamin D levels. However, the mean level of 25-hydroxyvitamin D was <30 ng/mL in all groups. Because there are metabolic consequences of vitamin D levels at less than approximately 30 ng/mL [14], these results suggest that, as a group, these subjects’ vitamin D status was indeed insufficient. Effect of Ambulatory Status on Vitamin D Levels in Children With Epilepsy Most studies specifically exclude patients who are nonambulatory, because of concerns about confounding results. However, Baer et al. [15] studied vitamin D levels in relation to ambulatory status in a large sample of 3-9-year-old children who lived at home. Two hundred and twenty-six subjects were ambulatory and did not receive antiepileptic drugs, 23 were ambulatory and taking antiepileptic drugs, 43 were nonambulatory but not taking antiepileptic drugs, and 46 were nonambulatory and taking antiepileptic drugs. Baer et al. [15] observed that the risk of vitamin D deficiency among nonambulatory children was about twice that of ambulatory children (c2 statistic, 20.9; P < 0.001), even after adjusting for confounders. They also found lower z-scores for bone mineral density among nonambulatory patients, independent of antiepileptic drug status. Other studies reported no effects of ambulatory status on 25hydroxyvitamin D levels among noninstitutionalized children with intractable epilepsy, but these studies may have been underpowered to detect such a difference [16].
Vitamin D Status Among Children With Epilepsy The diets of children with intractable epilepsy often lack adequate protein, vitamins, and minerals [12]. However, vitamin D insufficiency is also quite prevalent among ambulatory children whose epilepsy is well-controlled on monotherapy. The association between epilepsy, antiepileptic drugs, and vitamin D status has been recognized for more than 30 years. In 1979, Offerman et al. reported that 72% of 83 children aged 10-16 years with epilepsy vs 50% of 16 control subjects exhibited 25-hydroxyvitamin
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Vitamin D Status Among Children With Intractable Epilepsy Children with intractable epilepsy are at risk of poor nutritional status [12], and were reported to manifest a high prevalence of vitamin D insufficiency. Bergqvist et al. [16] studied children with intractable epilepsy, taking new-generation antiepileptic drugs, before and during treatment with the ketogenic diet. Before the initiation of the diet, 4% of 45 subjects exhibited vitamin D deficiency
(defined as 25-hydroxyvitamin D levels of <11 ng/mL), whereas 51% exhibited insufficient 25-hydroxy vitamin D levels (<32 ng/mL). The levels of 1,25-dihydroxyvitamin D were normal in all cases. No effects of age or gender were detectable, but vitamin D levels declined during treatment with the ketogenic diet. Bergqvist et al. [16] observed an important effect of polypharmacy, with a 25-hydroxyvitamin D decrease of approximately 7 ng/mL for each additional antiepileptic drug. An adequate dietary intake of vitamin D, fewer antiepileptic drugs, and generalized seizures were associated with higher levels of 25-hydroxyvitamin D.
cussed here, children with metabolic or other diseases that could affect bone health were excluded. To our knowledge, no study has specifically compared the effects of antiepileptic drugs on bone health in children with idiopathic vs symptomatic epilepsy syndromes, or in those with wellcontrolled vs intractable epilepsy. Below, we review studies designed to look specifically at the effects of individual drugs, and most of these studies included only subjects with idiopathic epilepsy syndromes or very well-controlled seizures.
Influence of Monotherapy vs Polypharmacy
There are conflicting reports regarding bone mineral density among children with varying epilepsy syndromes, and treated with antiepileptic drugs. Direct comparisons between studies are often difficult, because some report site-specific bone mineral density results, whereas others use a total body measurement. The most recent recommendations involve evaluating whole-body Dexa scans, because differences may exist between trabecular and cortical bone density, and between weight-bearing and nonweight-bearing bone, limiting the generalizability of site-specific measurements. Some studies demonstrated no significant differences in bone mineral density among epilepsy patients compared with healthy control subjects [18-20]. However, many reported clinically significant reductions in bone mineral density among children with epilepsy [21-26]. Compared with monotherapy-treated patients, those treated with more than one antiepileptic drug appear to be at higher risk for low bone mineral density [20,22]. Younger and nonambulatory patients, and those with lower body mass indices, are also at high risk [22]. In addition, increasing durations of antiepileptic drug treatment may elevate the risk of osteopenia [24]. In two separate studies of normally ambulating children, Sheth et al. [24] and Sheth and Hermann [25] demonstrated lower bone mineral density among patients with generalized epilepsy syndromes compared with healthy control subjects, and those with symptomatic generalized epilepsy were at the highest risk. Even among those with normal ambulatory status, patients with both idiopathic and symptomatic epilepsy syndromes exhibited lower bone mineral density than did healthy control subjects. However, those with partial seizures had bone mineral density comparable with that of control subjects [25], and those with idiopathic generalized epilepsy exhibited lower bone mineral density than those with idiopathic localization-related epilepsy. Children with symptomatic generalized epilepsy syndromes appear to be at highest risk for low bone mineral density, and this risk increases with time [24,25]. The reasons for these findings are likely multifactorial, and could include dietary differences, possible subtle neuromotor abnormalities among those with symptomatic epilepsy syndromes, effects of medication, vitamin D levels, and the influence of seizures themselves on the pituitary-hypothalamic axis. No study has been powered to evaluate the
Several studies commented on the effect of polypharmacy on vitamin D status in children with epilepsy. A German cross-sectional study [17] included 38 children (aged 5-12 years) taking antiepileptic drugs (no restrictions on antiepileptic drug or epilepsy syndrome) and 44 healthy control subjects. More than 75% of patients were vitamin D-deficient (defined as <20 ng/mL), and 21% vitamin D-insufficient (20-30 ng/mL). Polytherapy patients demonstrated significantly lower 25-hydroxyvitamin D levels than patients treated with monotherapy (12.7 6.55 ng/mL S.D., n = 26, vs 18.1 8.29 ng/mL S.D., n = 12, P = 0.038). As previously mentioned, Bergqvist et al. [16] reported a decline of approximately 7 ng/mL in 25-hydroxyvitamin D for each additional antiepileptic drug in children with medically refractory epilepsy. In a Lebanese study, El-Hajj Fuleihan et al. [18] evaluated 88 children with epilepsy (mean age, 13 2 years S.D.) of varying types (52% idiopathic, 38% cryptogenic, and 10% symptomatic), treated for a mean duration of 4.7 4 years S.D. The authors did not comment on seizure control or on differences among epilepsy syndromes. Fifty-five percent were receiving enzyme-inducing antiepileptic drugs, and 33% were receiving multiple antiepileptic drugs. The type of antiepileptic drug exerted no effect on vitamin D status or bone mineral density, but polypharmacy exerted a negative impact on bone mineral density. Remarkably, the subjects’ 25-hydroxyvitamin D levels were insufficient, on average (i.e., 18.5 8.1 ng/mL S.D.; 57% had a 25-hydroxyvitamin D level of <20 ng/mL), but were actually higher than those of the 111 age-matched and gender-matched control subjects (15.3 6.8 ng/mL S.D., P = 0.004; 79% of control subjects had 25-hydroxyvitamin D levels of <20 ng/mL). Vitamin D Status Among Children With Idiopathic Epilepsy Syndromes or Seizure-Free Status To avoid the potentially confounding factors of polypharmacy, neuromotor disability, and symptomatic epilepsy syndromes, many studies include only children with idiopathic epilepsy syndromes whose seizures are well-controlled with a single antiepileptic drug. In all studies dis-
Bone Mineral Density Among Children With Epilepsy
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 387
influence of specific medications on bone mineral density among children with symptomatic generalized epilepsy. This task is difficult because these patients are often treated with multiple medications, and their regimens are adjusted frequently. Although it is clear that antiepileptic drugs or epilepsy are associated with a lower bone mineral density, at least in certain subgroups, several studies indicated no correlation between biochemical markers of bone health and bone mineral density [18,27], suggesting that the impact of antiepileptic drugs and epilepsy on bone mineral density is multifactorial. Below, we summarize studies investigating the specific antiepileptic drugs carbamazepine and valproic acid. The majority of studies demonstrated no significant decrease in bone mineral density among those treated with valproic acid [26,27-30], whereas five demonstrated no difference among patients given carbamazepine [26-30], and two demonstrated decreased bone mineral density in carbamazepine-treated patients [31,32]. Bone mineral density was also abnormal among children taking phenobarbital or phenytoin, compared with age-matched and sex-matched control subjects [23]. One study reported lower bone mineral density in patients treated with oxcarbazepine [33], whereas another found no difference [31]. Specific Antiepileptic Drugs Because many antiepileptic drugs induce hepatic CYP450 metabolism, they result in an increased metabolism of vitamin D, leading to declining 25-hydroxyvitamin D levels, increased parathyroid hormone levels, and abnormally enhanced bone turnover. However, even nonenzymeinducing medications were associated with poor bone health. Therefore, hepatic enzyme induction is only one component of the complex mechanisms by which antiepileptic drugs affect bone health. Most studies of bone density and of vitamin D status among children with epilepsy were not powered or designed to study the effects of specific drugs. However, several studies evaluated the effects of carbamazepine and valproic acid. Carbamazepine Nine published studies specifically examined the effects of carbamazepine on vitamin D or bone mineral density in children with epilepsy (Table 1). Three studies examined vitamin D levels in children treated with carbamazepine [13,31,34]. Two of these studies reported no statistically significant differences between 25-hydroxyvitamin D levels in control subjects and carbamazepine-treated children, refuting the theory of hepatic enzyme induction as the driving force for hypovitaminosis D among epilepsy patients. Conversely, Nicolaidou et al. [34] observed that 19 of 37 patients (37%) treated with either carbamazepine or valproic acid exhibited 25-hydroxyvitamin D levels of <10 ng/mL in the first year of treatment, and that the mean 25-hydroxyvitamin D level declined over
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the 36-month treatment period (25/51, or 49%, had a 25-hydroxyvitamin D level of <10 ng/mL during the 36-month study period). Nicolaidou et al. [34] did not observe differences between the valproic acid and carbamazepine groups. That study also reported a significant negative correlation between 25-hydroxyvitamin D and parathyroid hormone, as well as seasonal variation among 25-hydroxyvitamin D levels, but did not examine bone mineral density. Among studies that examined bone mineral density in relation to treatment with carbamazepine, five reported no significant difference [26-30], whereas one reported lower bone mineral density but unchanged 25-hydroxyvitamin D levels [31] compared with healthy control subjects, and another reported lower bone mineral density in children receiving carbamazepine compared with those receiving valproic acid [32]. Verrotti et al. [13] observed no difference in 25-hydroxyvitamin D levels among those treated with carbamazepine compared with control subjects, but the mean 25-hydroxyvitamin D levels were insufficient in both groups. Valproic Acid Because valproic acid is a hepatic enzyme-inhibiting antiepileptic drug, many postulate that it should have less effect than enzyme-inducers on bone health. The literature demonstrates that the effects of valproic acid on bone density and markers of bone health are complex (Table 2). Chou et al. [32] observed higher bone mineral density among those receiving valproic acid compared with those on carbamazepine. Conversely, Babayigit et al. [31] demonstrated no significant differences in 25-hydroxyvitamin D levels between children treated with valproic acid and healthy control subjects, but the valproic-acid group exhibited lower bone mineral density. One study found lower bone mineral density in subjects treated with valproic acid and/or lamotrigine [35] compared with control subjects in the literature, but five studies reported no significant difference in bone mineral density among children treated with valproic acid [26-30]. Effects of New Antiepileptic Drugs and the Ketogenic Diet on Bone Health in Children With Epilepsy Oxcarbazepine Because it is a less potent enzyme-inducer than carbamazepine, one may hypothesize that oxcarbazepine should have less of an effect on bone health than carbamazepine. Because recent guidelines suggest that oxcarbazepine is the initial treatment of choice for people with partial epilepsy syndromes [36], the study of this medication’s effects on bone health is vitally important. Two studies evaluated the effects of oxcarbazepine on bone health in children with epilepsy. Cansu et al. prospectively enrolled 34 newly diagnosed children with idiopathic localization-related epilepsy who were ambulatory and without other neurologic or medical diagnoses [33]. Patients were treated with
Table 1. Effect of carbamazepine on vitamin D levels and bone mineral density N (Epilepsy Patients/Control Subjects)
Mean Mean 25-Hydroxyvitamin D, 25-Hydroxyvitamin D, Epilepsy Patients Control Subjects
Epilepsy Syndrome
Duration of AED Treatment
Akin et al. [28] 28/26 Altay et al. [29] 21/22 Babayigit et al. [31] 23/30 Chou et al. [32] 21 CBZ, 21 VPA
Varied Seizure-free IGE Idiopathic ‘‘Uncomplicated’’
>1 yr >1 yr >1 yr >6 mo
NA NA 20.47 11.60 S.D.* NA
NA NA 22.3 7.12 S.D.* NA
Kafali et al. [30] Sheth et al. [26] Tekgul et al. [27]
Idiopathic Idiopathic Varied
>6 mo >6 mo 2 yr
NA NA NA
NA NA NA
Drug-naı¨ve baseline and >2 yr treatment
P = NS
P = NS
Reference
Verrotti et al. [13]
6/57 13/27 11 CBZ 13 VPA 60/60
Idiopathic LRE
BMD (AED vs Control) No difference No difference Y Y compared with VPA No difference No difference No difference NA
* P > 0.05 (not significant). Abbreviations: Y = BMD decreased, compared with healthy control subjects AED = Antiepileptic drug BMD = Bone mineral density CBZ = Carbamazepine IGE = Idiopathic generalized epilepsy LRE = Localization-related epilepsy N = Number of subjects NA = Not applicable or not studied P = NS/Difference did not meet statistical significance VPA = Valproic acid
oxcarbazepine for 18 months. Mean vitamin D levels were <30 ng/mL at baseline and at 18 months for both prepubertal and pubertal subjects, and were statistically lower for the group as a whole at 18 months compared with baseline (25.14 6.11 ng/mL S.D. vs 27.92 8.76 ng/mL S.D., respectively, P = 0.016). No change in bone mineral density z-scores occurred over 18 months, and there was no correlation between 25-hydroxyvitamin D and bone mineral density. Babayigit et al. [31] compared patients with idiopathic epilepsy syndromes treated with oxcarbazepine (n = 14), carbamazepine (n = 23), or valproic acid (n = 31) with 30 healthy control children, and observed that although vitamin D levels were not lower in treated patients, total bone mineral density was lower in those on antiepileptic drugs. In the only other study designed specifically to evaluate oxcarbazepine, Mintzer et al. [37] evaluated adult patients taking carbamazepine or oxcarbazepine compared with control subjects, and then switched those on carbamazepine to oxcarbazepine monotherapy. Levels of 25-hydroxyvitamin D were significantly lower in the oxcarbazepine and carbamazepine subjects, compared with control subjects, but were not significantly different between the oxcarbazepine and carbamazepine groups, suggesting that the newer agent may also exert an important impact on bone health. Lamotrigine Guo et al. [35] evaluated the effects of valproic acid and lamotrigine, alone and in combination, on growth and bone
mass in children with epilepsy. Fifty-three patients taking one or both antiepileptic drugs and who were without bone or metabolic disease, other bone-altering medications, or a family history of osteoporosis, were studied. Twentythree subjects (43%) were below the 10th percentile for height, and nine (24.3%) had a bone mineral density z-score of less than 1.5, without significant differences between those treated with valproic acid or lamotrigine. Low physical activity scores corresponded to worse bone-health markers, including lower 25-hydroxyvitamin D levels. The combination of dual therapy with valproic acid and lamotrigine, along with low activity scores, was associated with the highest risk of low bone mineral density and short stature. Ketogenic Diet Bergqvist et al. [22] measured changes in bone mineral density among children treated with the ketogenic diet for 15 months. On average, height and weight status were low at baseline, and declined while on the ketogenic diet. Those at highest risk for poor bone mineral density were younger patients who were nonambulatory and who had a low body mass index. These patients were treated with new antiepileptic drugs (lamotrigine, n = 13; topiramate, n = 9; zonisamide, n = 7; levetiracetam, n = 4; and oxcarbazepine, n = 2) as well as older antiepileptic drugs (valproic acid, n = 6; phenytoin, n = 4; and chlorazepate, n = 5). Because antiepileptic drug use was variable and changed
Shellhaas and Joshi: Vitamin D in Childhood Epilepsy 389
Table 2. Effect of valproic acid on vitamin D levels and bone mineral density
Author Akin et al. [28] Altay et al. [29] Babayigit et al. [31] Chou et al. [32] Guo et al. [35]
Kafali et al. [30] Sheth et al. [26] Tekgul et al. [27] Verrotti et al. [13]
N (Epilepsy Patients/Control Subjects) 25/26 15/22 31/30 21 CBZ 21 VPA 28 VPA 16 LTG 4 VPA + LTG 6/57 13/27 11 CBZ 13 VPA 60/60
Epilepsy Syndrome
Duration of AED Treatment
Varied Seizure-free IGE Idiopathic ‘‘Uncomplicated’’
>1 yr >1 yr >1 yr >6 mo
NA NA 20.5 11.6 S.D.* NA
NA NA 22.3 7.1 S.D.* NA
Varied
>2 yr
NA
NA
Idiopathic Idiopathic Varied
>6 mo >6 mo 2 yr
NA NA NA
NA NA NA
Drug-naı¨ve baseline and >2 yr treated
P = NS
P = NS
Idiopathic LRE
Mean Mean 25-Hydroxyvitamin D, 25-Hydroxyvitamin D, Epilepsy Patients Control Subjects
BMD (AED vs Control Subjects) No difference No difference Y [ compared with CBZ All Y compared with literature control subjects No difference No difference No difference NA
* P = NS. Abbreviations: Y = BMD decreased compared with healthy control subjects AED = Antiepileptic drug BMD = Bone mineral density CBZ = Carbamazepine IGE = Idiopathic generalized epilepsy LRE = Localization-related epilepsy LTG = Lamotrigine N = Number of subjects NA = Not applicable or not studied P = NS/Difference did not meet statistical significance VPA = Valproic acid
during the 15 months of ketogenic-diet treatment, analyses of specific medication effects could not be performed. The same authors [16] evaluated vitamin D status among children with intractable epilepsy, and taking newer antiepileptic drugs, before and during treatment with the ketogenic diet. Details of this study were presented above in the discussion of vitamin D levels in children with intractable epilepsy. Levels of 25-hydroxyvitamin D were lower in winter and spring, compared with summer and fall, and declined by approximately 0.5 ng/mL per month during the 15 months of treatment with the ketogenic diet. Treatment With Vitamin D Supplements: Clinical Trial There is one reported clinical trial of vitamin D supplementation in children with epilepsy. Mikati et al. [19] described the results for 78 Lebanese 10-18-year-olds treated with antiepileptic drugs for >6 months (mean, 5.2 4.6 years S.D.). These subjects were given 400 IU or 2000 IU of vitamin D per day for 1 year. The mean baseline level of 25-hydroxyvitamin D was in the insufficient range (18.1 8.1 ng/mL S.D.), with 15% deficient (<10 ng/mL), 44% insufficient (10-20 ng/mL), and 41% normal (defined by the study’s authors as >20 ng/mL), and was not different between high-dose and low-dose supplementation groups.
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After 1 year of vitamin D supplementation, vitamin D levels rose marginally (low dose, 18.2 7.1 S.D. to 21.3 8.54 S.D.; high dose, 18.0 9.1 S.D. to 22.9 8.4 S.D.; P = 0.4), but overall, 6% remained deficient, and 44% remained insufficient. Bone mineral density after 1 year was the same in both groups, and was comparable to a group of healthy girls from the same region. The authors speculated that no difference in bone mineral density was detected because of the relatively brief duration of treatment and the modest increases in vitamin D levels, which remained well below the target value of >30 ng/mL. Importantly, the study did not control for diet or exercise, and compliance with the vitamin D supplementation was not explicitly documented. That study highlighted some of the difficulties in designing and conducting a clinical treatment trial in this population. Improving bone health in children with epilepsy seems intuitively important, because children are treated with antiepileptic drugs for years at a time, including periods of highest bone mineralization. Avoidance of osteoporosis and osteopenia in these patients should, in theory, reduce the risk of fractures later in life. However, to prove this effect requires a large sample size and an extensive follow-up period, during which it would be unethical to avoid adjustments in medication or to prohibit vitamin D and calcium supplementation.
Table 3. Suggested vitamin D supplementation, based on 25-hydroxy vitamin D level 25-Hydroxyvitamin D Level (ng/mL)
Cholecalciferol Dose
Repeat Laboratory Examinations
30+ 15-29
400 IU per day* 2000 IU per day in divided doses
<15
2000-4000 IU per day in divided doses, in consultation with dietician
Annually Every 4 weeks until 25-hydroxyvitamin D >30† Every 3-4 weeks until 25-hydroxyvitamin D >30†
Additional Laboratory Examinations
Phosphorus, magnesium, calcium Parathyroid hormone, calcium, magnesium, phosphorus, consider Dexa scan
* In accordance with American Academy of Pediatrics recommendations, we suggest that all children treated for epilepsy be given a daily multivitamin with 400 international units of vitamin D3. † After 25-hydroxyvitamin D levels rise to normal range, we halve the vitamin D supplement dose. If level remains normal, recheck in 3-6 months. Abbreviation: IU = International units
Gaps in Knowledge Despite increasing interest in the comorbidities of epilepsy, along with an expanding literature on the effects of epilepsy and its treatment on bone health, as well as the high prevalence of vitamin D deficiency in persons with epilepsy, significant gaps in knowledge persist. Debate persists in the medical literature about the optimal vitamin D level in the general population, even after a recent upward revision of the recommended daily vitamin D intake [6,11]. Until the most advantageous vitamin D level is defined for children, questions will remain about the correct approach to children with epilepsy. Most studies evaluate the ‘‘healthiest’’ epilepsy patients (i.e., those treated with monotherapy who are ambulatory and seizure-free). If these patients have significant abnormalities in bone health, the effect may be even more pronounced in the ‘‘sicker’’ patients (i.e., those with uncontrolled seizures and requiring polypharmacy, or with neuromotor deficits). In addition, all studies cited in this review examined bone health among school-age children. The impact of epilepsy and antiepileptic drugs on bone health in infants and toddlers has not been studied. There are practical barriers to conducting such studies, yet it is an important subject for this population. Although many studies evaluated the impact of older antiepileptic drugs on bone health, the results were mixed, and few examined the effects of specific newer antiepileptic drugs. Future studies should be designed to evaluate the impact of individual new-generation antiepileptic drugs on bone health in children. The mixed results discussed here demonstrate that the effects of antiepileptic drugs on bone health are not as simple as the hepatic enzyme induction theory would suggest. Even drugs that do not induce CYP450 enzymes can be associated with abnormal bone mineral density or inadequate vitamin D status. Despite hopes that the newer antiepileptic drugs, which are less potent enzyme-inducers, would exert a minimal impact on bone health, the literature suggests otherwise. The role of vitamin D supplementation in this population is not clear. Only one treatment trial of vitamin D supple-
mentation has been undertaken among children with epilepsy [19], and it demonstrated no significant difference between high-dose and low-dose vitamin D, and no impact on bone mineral density after 1 year of treatment. Therefore, no evidence-based treatment guide exists yet for children with epilepsy who manifest vitamin D insufficiency or reduced bone mineral density. Additional well-designed and well-controlled studies are required. These trials must take into account the high prevalence of vitamin D insufficiency in the general population, as well as multiple potential confounders. Before the results of such studies can be generalized to specific epilepsy patient populations, factors such as geography and seasonal variation must also be taken into account, e.g., can a study conducted in a sunny or tropical country be applicable among patients treated in northern climates, who have much more limited sun exposure? Suggestions for Clinical Practice Vitamin D and bone health among children with epilepsy is a complex topic. We lack the experimental data to support universal screening and specific interventions for those with low vitamin D levels. Nonetheless, the data are sufficient to suggest that vitamin D insufficiency may be important for people with epilepsy, testing is readily available, and supplementation with vitamin D is inexpensive and without significant risk. We recognize that future work may dictate revisions in our practice, but until such literature becomes available, we offer suggestions for the screening and treatment of insufficient vitamin D levels (Table 3). In our practice, all children with epilepsy are screened annually with a 25-hydroxyvitamin D level assay. Like Bergqvist et al. [16], we found that 1,25 dihydroxyvitamin D levels are almost always normal in our patient population, and so we do not check that level routinely. Recommended vitamin D supplementation depends on the level of 25-hydroxyvitamin D. Because cholecalciferol (vitamin D3) is better absorbed than ergocalciferol (vitamin D2), we recommend using cholecalciferol rather than ergocalciferol in
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children with normal kidney function. Cholecalciferol is available in tablet, capsule, liquid, and ‘‘gummy’’ formulations, and is relatively inexpensive. Some pediatric epilepsy practices routinely screen high-risk patients with Dexa scans. There is no current evidence base for this recommendation, and we suggest pursuing bone density measurements on a case-by-case basis. Measurement of bone mineral density should be considered if there is a history of bone fractures or vitamin D deficiency.
Conclusions The potential impact of epilepsy and antiepileptic drugs on bone health has been recognized for more than 30 years, but some of the literature remains contradictory. By inducing the CYP450 system, many antiepileptic drugs (phenytoin, phenobarbital, and carbamazepine in particular) result in an accelerated metabolism of vitamin D. Lower vitamin D levels then result in hyperparathyroidism, ultimately leading to abnormally enhanced bone turnover and subsequent decreased bone density. However, even nonenzyme-inducing antiepileptic drugs (e.g., valproic acid) and less potent enzyme-inducers (e.g., oxcarbazepine) may exert adverse effects on bone mineralization. Clearly, hepatic enzyme induction is not the only mechanism by which antiepileptic drugs affect bone mineralization. The literature demonstrates a high prevalence of vitamin D insufficiency not only among children with epilepsy, but also among apparently health control subjects. Despite some contradictory results, pediatric neurologists, who care not only about seizures but also about patients’ overall well-being, should attend to this potentially important aspect of patients’ health. Studies exhibited conflicting results among children with idiopathic epilepsy syndromes treated with carbamazepine or valproic acid. Some demonstrated an association with lower 25-hydroxyvitamin D levels and lower bone mineral density, whereas others did not. Children with intractable epilepsy who are treated with multiple antiepileptic drugs appear to be at high risk of poor bone mineralization, and this problem is likely multifactorial, including the impact of the seizures themselves, diet, antiepileptic drugs, and neuromotor disability. Although there is increasing recognition of the probable negative effects of epilepsy and its treatment on bone health, a survey of pediatric neurologists indicated that only 41% screened for bone disease among their patients, and only 3% routinely monitored parathyroid hormone or 25-hydroxyvitamin D levels [38]. If further studies demonstrate a beneficial effect of interventions such as vitamin D or calcium supplementation on bone health in our pediatric epilepsy patients, we hope that these numbers, and the interest of pediatric neurologists in this important aspect of epilepsy care, will rise. While we await evidence-based treatment guidelines, we suggest screening for vitamin D insufficiency and supplementation with cholecalciferol, to maintain levels of vitamin D in the optimal range.
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