Journal: Pediatric Drugs
Effects of Antiepileptic Drugs on Bone Health and Growth Potential in Children with Epilepsy – a Systematic Review
Peter Vestergaard
Professor, consultant
Departments of Clinical Medicine and Endocrinology
Aalborg University Hospital
Mølleparkvej 4
DK-9100 Aalborg
Denmark
E-mail:
Table 1: Studies on bone mineral density in children and adolescents. All of the studies were cross-sectional in design.
Study / Study population / Country / N / Age / GenderM/F / Drugs and duration / Measurements / BMD
Patients Controls / Result
Akin 1998
[1] / Children with primary epilepsy. Children with mental or motor retardation, neurological deficits or abnormal cerebral imaging were excluded, along with children who had used other drugs / Turkey / 25 on VPA
28 on CBZ
26 controls / 8 yr 10 mo6 mo
9 yr 6 mo4 mo
8 yr 11 mo6 mo / 14/11
15/13
15/12 / VPA or CBZ for >1 year / Lumbar spine L2-L4 in g/cm2 / 0.5740.02/0.5680.02
0.6110.01/0.5680.02
The serum levels of calcium and phosphorus inall groups were normal / NS
Aksoy 2011
[2] / Prepubertal children with epilepsy / Turkey / 53 VPA
23 CBZ
50 controls / No difference in BMD. Serum ALP and CTx levels were higher in the CBZ group than in the VPA group and the control group. Serum osteocalcin and ALP levels were lower in the VPA group than in the control group / NS
Babayigit 2006
[3] / Children with idiopathic epilepsy treated for more than 1 year / Turkey / 23 CBZ
31 VPA
14 OXC
30 controls / Serum ALPlevels were higher in the patient group as compared with the control subjects. In patients receiving AEDs, BMD values were significantly lower than the healthy control group / P<0.05
Cansu 2008
[4] / Newly diagnosed pediatric patients (18 prepubertal, and 16 pubertal) with idiopathic partial epilepsy / Turkey / 34 OXC / Pre-treatment
After 18 months / Z-score / -0.06±0.19
-0.14±0.20
Levels of 25-OHD levels
were significantly decreased after therapy compared with baseline values. Levels of -glutamyl transferase, phosphorus, ALP, osteocalcin, PTH, and calcitonin had increased. However, only changes in osteocalcin and -glutamyl transferase levels were statistically significant compared with baseline values / NS
Chou 2007
[5] / Children with uncomplicated epilepsy treated for more than 6 months. All subjects were 5 to 18 years of age, seizure-free for 5 months or more, with normal daily activity, and normal diet / Taiwan / 21 CBZ
21 VPA / Spine BMD L2-L4 Z-score / 33% ≤-1.5 Z-score
0% ≤-1.5 Z-score
The serum levels of calcium and phosphate were normal. The serum level of ALP was significantly higher in the CBZ group than in the VPA group / P<0.05
NS
Chung 1994
[6] / Children with epilepsy. The children were ambulatory and participated in outdoor activities. No signs of rickets were present based on X-ray and vitamin D supplementation. Children with metabolic bone disease, physical handicap, growth impairment, malnutrition, or psychomotor retardation were excluded. / South Korea / 78 patients
78 controls / 8.53.3 yr
8.53.3 yr / 48/30 / <12 mo
12-24 mo
>24 mo
<12 mo
12-24 mo
>24 mo
>24 mo / Total body BMD
(g/cm2)
Spine BMD
(g/cm2)
Total body BMD (g/cm2)
PB
PHT
Spine BMD
PB
PHT / 0.8110.079/0.8540.085
0.8130.085/0.8350.159
0.8480.092/0.9600.099
0.7060.141/0.7620.119
0.6860.131/0.7520.127
0.7300.145/0.8160.145
0.8510.09/0.9620.108
0.8460.087/0.9600.146
0.7480.130/0.8180.123
0.7210.145/0.8150.141 / NS
NS
p<0.01
NS
NS
p=0.02
p<0.01
p<0.01
p=0.03
p=0.02
Coppola 2007
[7] / Patients with Angelman syndrome (17/18 on VPA) with or without antiepileptic therapy, and two control groups consisting of 18 epileptic and 24 healthy patients / Italy / 18 Angelman
18 epilepsy
24 control / 4.0-24.3 years (mean age, 10.1 years) / 9/9 / 17 VPA for years / Spine L1-L4 BMD / 0.65/0.75
0.73/0.75
1,25-dihydroxy-vitamin D, PTH, osteocalcin, ALP, calcium and phosphate were normal / P=0.04
NS
Ecevit 2004
[8] / Children with idiopathic epilepsy. No concomitant diseases, children with mental or physical disability school difficulties, abnormal neurologic signs, abnormal cerebral imaging findings or dietary restrictions were excluded / Turkey / 17 CBZ
16 VPA
31 controls / 10.22.5 yr
10.63.2 yr
11.52.6 yr / 13/20
14/17 / CBZ 3216 mo
VPA 2411 mo / Femoral neck (g/cm2)
CBZ
VPA
Greater troch. (g/cm2)
CBZ
VPA / 0.700.09/0.730.09
0.670.08/0.730.09
0.580.07/0.640.10
0.580.07/0.640.10 / NS
NS
NS
p=0.02
Erbayat 2001
[9] / Idiopathic generalised epilepsy. Children on CBZ or VPA for >1 yr. Children with mental or physical disability school difficulties, abnormal neurologic signs, abnormal cerebral imaging findings, dietary restrictions, or using other drugs were excluded / Turkey / 21 CBZ
15 VPA
22 controls / 12.8 yr
10.9 yr
10.7 yr / 16/5
10/5
14/8 / CBZ 3.72.4 yr
VPA 3.11.8 yr / Lumbar spine (g/cm2)
CBZ
VPA
Femoral neck (g/cm2)
CBZ
VPA / 0.7290.185
0.6290.218
0.8010.148
0.6620.152
Serum calcium was decreased and ALP was increased in the CBZ group. Urine calcium was decreased in both CBZ and VPA. Urine calcium was lower in the VPA than the CBZ group / NS
NS
NS
NS
Farhat 2002
[10] / Ambulatory epileptic patients on AED for >6 month. Various AEDs. Patients with metabolic bone disease or receiving bone active medications were excluded. / Lebanon / 29 patients / 11.33.8 yr / 17/12 / 54 yr / Lumbar spine (g/cm2) / 0.820.27
Over 50% of children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD / NS
Fuleihan 2008
[11] / 88 children with idiopathic (52%), cryptogenic/
congenital (38%), trauma (7%), and cerebrovascular (3%). 111 control children. / Lebanon / 88 patients / 13±2 yr / 55% were taking enzyme-inducing AEDs, and 33% were on multiple AEDs / Lumbar spine g/cm2
Subtotal body g/cm2
Subtotal body BMC, g / 0.77±0.17 0.76±0.15
0.84±0.12 0.85±0.11
1209±433 1231±400
Plasma vitamin D and calcium intake lower in children with epilepsy / NS
NS
NS
Gniatkowska-Nowakowska 2010
[12] / 126 epilepsy children in age 7–16 who were treated with AEDs in mono and add-on therapy during 5 years. In the control group were 132 children in age
7–16 / Poland / 126 patients
VPA 16
CBZ 7
LTG 26
TPM: 10
VPA+CBZ 19
VPA+LTG 32
VPA+TPM 13
LTG + TPM 3 / 7-16 years / 6 years / BMD (spine or hip) / 0.901±0.251 0.983±0.121
Decreased plasma calcium, plasma phosphate and urine calcium in the epilepsy group / P<0.01
Guo 2001
[13] / Children or adolescents on long-term treatment with VPA and/or LTG. Patients with diseases that could alter growth or bone metabolism, who used bone active drugs other than calcium or vitamin D or had a family history of osteoporosis were excluded / Canada / 28 VPA
16 LTG
9 VPA+LTG / 9.30.7
7.51.1
8.51.2 / 27/26 / Lumbar spine (g/cm2) / Z-score (too few for analysis)
Active epilepsy: 0.4
Inactive epilepsy: -1
1,25 dihydroxy-vitamin D was normal. Osteocalcin was decreased in the VPA+LTG group.The inactive group had lower 25-OHD and PTH than the active group / NS
Hahn 1979
[14] / Children on ketogenic diet (KG)+AED for epilepsy and children on PHT+PB / USA / 5 KG+PHT*
15 PHT+PB
15 controls / 10.41.5
11.21.3
11.01.6 / 3/2
7/11
6/9 / 7.43 yr
6.80.8 yr / Non dominant forearm BMC (% of normal) / 84.92.6
91.31.6
100.51.8
KG patients exhibited biochemical findings of vitamin D deficiency osteomalacia: decreased serum25-OHD and calcium concentrations, elevated serum ALP and PTH concentrations, decreased urinary calcium and increased urinary hydroxyproline excretion / p<0.01
p<0.01
NS
Kafali 1999
[15] / Outpatients with idiopathic epilepsy. Otherwise healthy. Children with mental or physical disability school difficulties, abnormal neurologic signs, abnormal cerebral imaging findings, dietary restrictions, or using other drugs were excluded. / Turkey / Patients
9 girls
10 boys
Controls
28 girls
29 boys / 8.41.7
8.81.7
9.21.9
8.81.7 / 9
10
28
29 / 1.80.68 yr
1.70.82 yr / All patients (g/cm2)
Distal radius
Mid radius
Proximal radius
Spine L1-L4
Middle radius (g/cm2)
VPA
CBZ / 0.2510.03/0.2610.04
0.2900.03/0.3140.04
0.3710.05/0.3990.05
0.5170.07/0.5480.07
0.2870.03/0.3120.04
0.2980.01/0.3120.04
Serum ALP was increased in the treatment group / NS
P<0.05
P<0.05
NS
P<0.04
NS
Koo 2013
[16] / 61 patients with recent onset epilepsy on monotherapy with LEV. Forty-six subjects had partial epilepsy and 15 had idiopathic generalized epilepsy. Of 46 patients with partial epilepsy, 6 had hippocampal sclerosis,5 had cortical dysplasia or heterotopias, and 4 hadforeign tissue lesions. After LEV therapy, 32 (52.5%) became seizure free and 7 (11.5%) had ≥50% reduction in seizure frequency / Korea / 61 LEV / 31.0±13.1 / 37/24 / 14.16±3.36 months / Lumbar spine L1-L4
Total hip / 0.987±0.127 before,
1.010±0.124 after
0.962±0.110 before
0.977±0.150 after
25-OHD, PTH, osteocalcin, ALP, CTx were normal / NS
NS
Kumandas 2006
[17] / Ambulatory, prepubertal children with normal activity and nutritionally adequate diets / Turkey / 33 VPA
33 CBZ
22 controls / 8.82.0
9.71.6
8.92.3 / 17/16
20/13
13/9 / 33.715.0 m
35.512.8 m / Spine Z-score / -1.280.80 -0.230.87
-1.690.85 -0.230.87
Serum ALP and PTH levels were significantly higher in CBZ than VPA and control Serum 25-OHD was lower in CBZ than VPA and controls / P<0.05
p<0.05
Lambrinoudaki 2011
[18] / 73 long-term users of antiepileptic drug monotherapy,
in a cross-sectional design / Greece / 41 VPA
23 OXC
9 LEV / 16-54 / Spine Z-score / BB+Bb allele -0.28±0.68
bb allele 0.33±0.72
On average -0.18±1.90
25-OHD was lower with the BB+Bb allele / NS
Mikati 2006
[19] / 78 children and adolescents on long-term AED therapy:
generalized 23 (31%), focal 51 (69%) epilepsy;enzyme-inducing AED 41 (53%), non-enzyme inducing AED 37 (47%); monotherapy 50 (64%), multiple AEDs 28 (36%) / Lebanon / 78 patients / 10-18 / 41/37 / 5.2±4.6 yr / Lumbar spine
Subtotal body BMD
Subtotal body BMC / 0.77±0.17 0.76±0.15
0.84±0.12 0.85±0.11
1,217±480 1,231±400
Serum vitamin D higher in epilepsy than controls / NS
NS
NS
Oner 2004
[20] / Children with epilepsy on VPA monotherapy for >6 month. Children with uncontrolled seizures, physical handicaps, neurological impairment, dietary restrictions, or receiving bone active drugs were excluded. / Turkey / 33 patients
33 controls / 7.13.5
7.42.8 / 17/16
17/16 / 12.94.6 mo / Z-score (VPA)
Lumbar spine
Femoral neck / -0.36/-0.21
-0.36/0.00
Osteocalcin levels were significantly higher with VPA. ALP levels were normal. 25-OHD was not reported / P=0.04
P<0.01
Phabphal 2008
[21] / Epileptics who had been receiving long-term, antiepileptic drugs / Thailand / 130 patients
71 enzyme inducers, 28 non-enzyme inducers, 31 combination, 79 monotherapy, 51 combinations / 15-50 / 63/67 / >6 month / Hip Z-score
Spine Z-score / -0.15 ± 1.17
-0.56 ± 1.03
10% had low ALP levels / NS
p<0.05
Phabphal 2013
[22] / Adults with epilepsy on a stable dosage of PHT in the previous 9 months / Thailand / 94 PHT / 15-50 / 43/51 / Lumbar spine Z-score
Femoral neck Z-score / VDR wildtype 0.43 ± 1.09
Bsml -0.36 ± 0.84
On average 0.20
VDR wildtype 0.25 ± 0.95
Bsml -0.43 ± 0.15
On average 0.05
Vitamin D levels were normal / NS
NS
Rieger-Wettengl 2001
[23] / Ambulatory outpatients>6 years on VPA or CBZ for >1 yr. Patients with seizures secondary to structural brain defects or other diseases were excluded. / Germany / 19 VPA
20 CBZ / 12.53.7
13.03.3 / 9/10
13/7 / 3.72.5 yr
3.61.6 yr / pQCT of non-dominant forearm
VPA
CBZ / Z-score
-0.81.2
-0.50.9
25-OHD, PTH and ALP were normal. Urinary levels of deoxypyridinoline were significantly elevated above normal in the whole study population (1.35 2.00) and in both the VPA and the CBZ subgroups / P<0.01
NS
Sheth 1995
[24] / Children with uncomplicated idiopathic epilepsy seizure free for >18 month. On CBZ or VPA monotherapy. Children with either a mental or a physical disability, school difficulties, dietary restrictions, symptomatic or cryptogenic epilepsy, abnormal neurologic findings, abnormal cerebral imaging findings, or background abnormalities on an electroencephalogram were also excluded / Canada / 13 CBZ
13 VPA
27 controls / 13.24.1
15.43.3
13.42.8 / 3/10
6/7
15/12 / 3.92.3 yr
3.11.7 yr / Spine
VPA
CBZ
Distal 1/3 radius
VPA
CBZ / 14% reduction
5% reduction
10% reduction
5% reduction / P<0.01
NS
P<0.01
NS
Sheth 2008
[25] / 116 ambulatory children with epilepsy (79 idiopathic epilepsy and 37 symptomatic epilepsy), and 36 healthy controls / USA / 116 patients / 6-18 / 56/61 / Total body Z-score
Idiopathic epilepsy
Symptomatic epilepsy
Symptomatic generalized
epilepsy / 0.38±1 0.52±0.76
0.17±1 0.52±0.76
−0.15±1.1 / P<0.05
P<0.05
P<0.05
Sheth 2008
[26] / 82 ambulatory children aged with epilepsy. Controls were 32 healthy children / USA / 82 patients / 6-18 (12.4±3.3) / 35/47 / <1 yr (18)
1-5 yrs (37)
>5 yrs (27) / Total body Z-score / 0.23±1.1 0.57±0.74
0.13±0.78 0.57±0.74
0.06±1.11 0.57±0.74 / NS
p=0.04
p=0.04
Sheth 2008
[27] / Ambulatory children with epilepsy. 35 healthy controls who were first-degree cousins
of patients / USA / 108 patients / 6-18 / 47/61 / Total body Z-score
Combined
Girls
Boys / 0.27±0.77 0.53±1.1
0.23±1.1 0.47±0.76
0.3± 1.1 0.8±0.5 / P<0.05
NS
NS
Suzuki 2007
[28] / 98 epilepsy patients with no intellectual or motor disorders or diseases affecting bone metabolism. All patients were taking one or a combination of VPA,CBZ and PB / Japan / 98 patients / 3-15 / Digital X-ray of forearm / Significant differences in BMD were observed regarding the administration periods in children taking multiple drugs, but not in children on VPA, CBZ, or PB monotherapy / P<0.05
Tekgul 2006
[29] / Children with primary epilepsy or febrile seizures. Ambulatory without neurologic deficit or metabolic diseases. / Turkey / 30 patients
15 VPA
11 CPZ
4 PHT / 7.753.68 / 15/15 / 2 yr / Spine (L1-L4) (g/cm2)
Start of therapy
After 2 years / 0.121.65
0.451.60
1,25-dihydroxy-vitamin D and calcitonin decreased, PTH increased during therapy / NS
P<0.05
Timperlake 1988
[30] / Children with epilepsy on PHT or PB. Children with metabolic bone disease, malnutrition or growth impairment were excluded. / USA / 20 patients
20 controls / 10.1 (5-20) yr / 51.4 (9-124) mo / Femoral neck (g/cm2)
Greater troch. (g/cm2) / 0.840.14/0.85/0.19
0.710.15/0.670.20 / P=0.76
P=0.32
Tsukahara 2002
[31] / Children with primary epilepsy and AED use>2 years, and seizure free for >6 month. Normally active outpatients without other diseases, did not use bone active drugs, had no fractures, no neurologic deficits, and normal cerebral imaging findings. / Japan / 18 patients
9 VPA
3 CBZ
3 VPA+CBZ
1 VPA+PHT+ET
1 CBZ+PHT
1 CBZ+ET+CLO / 10.73.3 / 7/11 / 5.42.7 yr / Spine (L2-L4) / 9113% of normal / P<0.05
Zhang 2010
[32] / Sixty-three epileptic children who received TPM or CBZ treatment and 36 epileptic children who did not receive any drug treatment (control group) / China / 63 patients / Spine L1-L4 / BMD was significantly reduced in both the TPM and the CBZ groups when compared to the control group. Serum calcium content was higher in the TPM group, but lower in the CBZ group than in the control group. Serum phosphorus content in both the TPM and the CBZ groups was significantly lower than that in the control group. There were no significant differences in the serum content of ALP between the groups / P<0.05
25OHD: 25-hydroxyvitamin D,AED: Antiepileptic drugs, ALP: alkaline phosphatase,BMD: bone mineral density, CBZ: Carbamazepine, CLO: Clonazepam, CTx: alkaline phosphatase, ET: Ethosuximide, KG: Ketogenic diet, LEV: Levetiracetam, LTG: Lamotrigine, OXC: Oxcarbazepine, PB: Phenobarbital, PHT: Phenytoin, PTH: parathyroid hormone, PR: Primidone, VPA: Valproate. * Two also received PB, 1 also PR, 1 also trimethadione+ethosuximide.
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