bone density - epilepsy
densidade óssea - epilepsia
Neurologic disorders are the most prevalent genetic disorders in Egypt, accounting
for 31.38% of all genetic disorders[1]. Epilepsy is a neurological disorder that requires lifelong treatment. Unfortunately,
the treatment usually affects both bone and mineral metabolism and may increase the
risk of fractures[2].
Many studies have found a link between antiepileptic drugs (AEDs) and bone disease[3]. Old AEDs, such as phenobarbital and phenytoin-induced hepatic (CYP-450) enzymes,
led to an increase of catabolism of vitamin D, and this subsequently decreased the
absorption of calcium[4]. However, this proposed mechanism has failed to explain the same condition reported
in patients receiving valproate (VPA), an inhibitor of the CYP-450 enzyme[5].
Bone remodeling is a lifelong process in which the skeleton is continuously being
resorbed and replaced to maintain skeletal integrity. Serum markers of bone formation
are bone-specific alkaline phosphatase, osteocalcin and carboxy-terminal propeptide
of type I procollagen. Markers of bone resorption are serum carboxy-terminal telopeptide
of type 1 collagen, urinary N-telopeptide of type 1 collagen bone and hydroxypyridinium
cross-links collagen (pyridinoline and deoxypyridinoline)[6].
Serum osteocalcin is a specific marker of osteoblast function, as its levels correlate
with the bone formation rate. The major advantages of using osteocalcin are its tissue
specificity, its wide availability, and its relatively low within-person variation[7].
The hydroxypyridinium cross-links collagen, deoxypyridinoline, is formed during the
extracellular maturation of collagens and released upon the degradation of mature
collagens. Its major advantages are that its measurement dose is not influenced by
degradation of newly-synthesized collagens and is independent of dietary sources.
Deoxypyridinoline is found only in bone and dentin and may be derived from the cancellous
and cortical compartments of bone. The presence of deoxypyridinoline in urine can
be regarded as a specific marker of bone turnover[8].
New generations of AEDs such as lamotrigine (LTG), topiramate and levetiracetam (LEV)
are approved to be used as antiepileptic monotherapy or adjuvant therapy[9]. Few studies have investigated the adverse effects of new AEDs on bone mineral density
and bone turnover. Some of these studies demonstrated a negative influence of these
drugs on bone health status, and other studies have shown contradictory effects[10],[11].
These previously-reported conflicting findings warrant further studies to evaluate
the possible adverse effects of novel antiepileptic drugs on bone health. In this
context, our study aimed to evaluate and compare the effects of old and new generations
of monotherapy AEDs on both biochemical markers of bone turnover and on bone mineral
density in Egyptian adult patients with epilepsy.
METHODS
Participants
In this case-control study, 68 adult patients with a recently-diagnosed epilepsy were
recruited from the Epilepsy Clinic of the Neuropsychiatric Department, Alexandria
Main University Hospital, Alexandria, Egypt between January 2013 and November 2016.
The diagnosis of epilepsy was made in accordance with the criteria of the International
League Against Epilepsy. The patients had different generalized tonic-clonic, myoclonic
and absence seizure types. Exclusion criteria were mental retardation, postmenopausal
women, immobilization, diseases that affect the skeleton (Paget disease, multiple
myeloma), and those taking glucocorticoids and excessive doses of vitamins. The ethical
committee of Alexandria University approved the study. A written informed consent
for participation was obtained from each patient or his/her legal representative.
Thirty healthy subjects were included as a control group, and their selection criteria
matched the patients’ age, gender, body mass index, and social economic state. The
recruited participants periodically visited the Alexandria Regional Centre for Health
and Development for checkups.
Of the 68 patients, 20 were excluded for the following reasons: patients had to change
to a different AED (n = 5); patients moved and were lost to follow-up (n = 6); patients
got pregnant (n = 5); and patients with coincidental endocrinological diseases (n
= 4).
Eventually, 30 healthy subjects and 48 patients were included in this study. Each
patient in this study underwent a full medical examination and family history, including
menarchal age and reproductive history. Patients were treated with mono- and polytherapy
AEDs (with doses within therapeutic range) including VPA (Depakine® 500 mg tablets, Sanofi Aventis, Berlin, Germany), LTG (Larogen® 100 mg tablets, Delta Pharm, Egypt) and LEV (Tiratam® 500 mg tablets, Al Andalous Egypt). During the six month follow-up period, patients
visited the epilepsy clinic monthly for follow-up and dispensing of their AEDs, and
this information was recorded on their dispensing card.
Study design
Each participant completed a validated nutritional and physical activity questionnaire.
The nutrition questionnaire is a food frequency questionnaire that assesses daily
diet, meals and snacks, vitamin intake, tobacco, and alcohol[12]. The physical activity questionnaire evaluates the duration and frequency of specific
exercises and daily activities[13]. Patients were instructed to maintain the same dietary habits and level of physical
activity during the study period.
Fasting blood and urine samples were collected for measurement of biochemical bone
mineral parameters. All samples were coded and stored at -15 to -25 °C until use.
Serum calcium, phosphate and alkaline phosphatase were measured using the available
colorimetric method (Roche/Hitachi cobas (c 501) analyzers; Germany). Serum parathyroid
hormone and osteocalcin were measured with the ElectroChemiLuminescence Immuno Assay
kit (Elecsys and cobas (e 411) analyzers; Roche, Germany). Markers of bone resorption
urinary deoxypyridinoline were measured by the Enzyme Immunoassay EIA kit (Quidel
MicroVue DPD-Enzyme Immunoassay; Hannover, Germany). The results of urinary markers
were expressed in relation to urinary creatinine. Bone mineral density of the lumbar
spine, which consists mainly of trabecular bone and is a common site of compression
fracture, was measured using a dual energy X-ray absorptiometry scanner (DEXA, QDR-4500A,
Hologic, Waltham, MA) at the Alexandria Regional Centre for Women’s Health and Development.
Bone mineral density was assessed according to the World Health Organization guideline
that defined osteoporosis as a T-score less than -2.5 at any site and osteopenia as
a T-score between -1 and -2.5. All tests were measured at baseline and after six months[14],[15]
The follow-up period in this study was six months and this duration accounted for
two bone remodeling cycles considering that each cycle is approximately three months.
This period was chosen to ensure that the effects of prior AED exposure would have
been unlikely to influence bone turnover markers and rates of bone loss[14],[15].
Tests of measurement
Serum calcium levels were measured photometrically using the cobas c 501 analyzer
(Roche/Hitachi, Germany). Test principle: calcium ions react with 5-nitro-5.-methyl-BAPTA
under alkaline conditions to form a complex. This complex reacts in the second step
with EDTA. The change in absorbance is directly proportional to the calcium concentration
in the sample.
Serum phosphate levels were measured photometrically using the cobas c 501 analyzer
(Roche/Hitachi, Germany). Test principle: the phosphate concentration was measured
spectrophotometrically. Phosphate forms an ammonium phosphomolybdate complex with
ammonium molybdate in the presence of sulfuric acid. The concentration of phosphomolybdate
formed is directly proportional to the phosphate concentration in the provided samples.
Serum alkaline phosphatase levels were measured photometrically using the cobas c
501 analyzer (Roche/Hitachi, Germany). Test principle: in the presence of magnesium
and zinc ions, ρ-nitrophenyl phosphate is cleaved by alkaline phosphatase into phosphate
and ρ-nitrophenol. The ρ-nitrophenol released results in an increase of absorbance,
which is directly proportional to the catalytic alkaline phosphatase activity.
Serum parathyroid hormone and osteocalcin were measured by the ElectroChemiLuminescence
Immune Assay. Test principle: the sandwich technique.
First incubation of serum parathyroid hormone: 50μl of sample, a biotinylated monoclonal
parathyroid hormone-specific antibody, and monoclonal parathyroid hormone-specific
antibody labeled with a ruthenium complex form a sandwich complex.
First incubation of serum osteocalcin: 20μl of sample, a biotinylated monoclonal N-MID
osteocalcin-specific antibody, and monoclonal N-MID osteocalcin-specific antibody
labeled with a ruthenium complex form a sandwich complex.
Second incubation parathyroid hormone and osteocalcin: after addition of streptavidin-coated
microparticles, the complex becomes bound to the solid phase via interaction of biotin
and streptavidin. The reaction mixture is aspirated into the measuring cell where
the microparticles are magnetically captured onto the surface of the electrode. Unbound
substances are then removed with Pro Cell/Clean Cell. Application of a voltage to
the electrode then induces chemiluminescent emission, which is measured by a photomultiplier.
Urinary deoxypyridinoline was measured by enzyme immunoassay using the Quidel MicroVue
DPD-Enzyme Immunoassay Kit 30175 (Hannover, Germany). The urinary deoxypyridinoline
assay is a competitive enzyme immunoassay in a microtiter stripwell format utilizing
a monoclonal anti-deoxypyridinoline antibody coated on the strip to capture deoxypyridinoline.
Deoxypyridinoline in the sample competes with conjugated deoxypyridinoline-alkaline
phosphatase for the antibody and the reaction is detected with a ρ-nitrophenyl phosphate
substrate. The deoxypyridinoline results are corrected for urinary concentration by
creatinine using the formula; deoxypyridinoline = deoxypyridinoline / urinary creatinine
x 0.088
Urinary creatinine was measured photometrically using the Roche/Hitachi cobas c 501
analyzer. The test principle was based on the conversion of creatinine with the aid
of creatininase to creatine. This creatine, with the action of creatinase, is converted
to sarcosine. The sarcosine, through the action of sarcosine oxidase, is convert to
glycine, formaldehyde and hydrogen peroxide. This liberated hydrogen peroxide is catalyzed
by peroxidase and then reacts with 4-aminophenazone and 2,4,6-triiodo-3-hydroxybenzoic
acid to form a quinoneimine chromogen. The color of the quinoneimine chromogen formed
is directly proportional to the creatinine concentration in the samples.
RESULTS
Of the 48 patients aged between 18–42 years who completed the six-month follow-up
period, the mean age was 21.33 ± 3.03; there were not significantly more females than
males; and the generalized tonic-clonic type was the more prevalent seizure type.
Dietary intake of calcium, exposure to sunlight hours, amount of exercise, age of
menarche and number of pregnancies did not differ among groups ([Table 1]).
Table 1
Demographic data and biochemical parameters for all participants at baseline.
|
Characteristics
|
Healthy
|
LTG
|
LEV
|
VPA+LTG
|
VPA + LEV
|
p
|
|
Age (mean ± SD)
|
21.33 ± 3.03
|
19.92 ± 2.43
|
20.17 ± 2.72
|
21.00 ± 2.83
|
20.67 ± 2.87
|
0.421
|
|
Sex
|
|
Male (n, %)
|
10 (33.3 %)
|
2 (16.7%)
|
6 (50.0 %)
|
4 (33.3 %)
|
6 (50.0 %)
|
0.105
|
|
Female (n, %)
|
20 (66.7 %)
|
10 (83.3 %)
|
6 (50.0 %)
|
8 (66.7 %)
|
6 (50.0 %)
|
|
|
Seizure type
|
|
GTC (n, %)
|
-
|
6 (50.0 %)
|
7 (58.3 %)
|
8 (66.7 %)
|
8 (66.7 %)
|
0.336
|
|
Myoclonic (n, %)
|
-
|
3 (25.0 %)
|
3 (25.0 %)
|
3 (25.0 %)
|
3 (25.0 %)
|
|
|
Absence (n, %)
|
-
|
3 (25.0 %)
|
2(16.7 %)
|
1 (8.3 %)
|
1 (8.3 %)
|
|
|
Questionnaire
|
|
Dietary calcium, mg/day
|
1,032 ± 0.11
|
1,258 ± 0.20
|
1,095 ± 0.20
|
989 ± 0.76
|
1,105 ± 0.18
|
0.581
|
|
Exposure to sunlight (hr)
|
1.28 ± 0.40
|
1.09 ± 0.42
|
1.45 ± 0.53
|
1.28 ± 0.66
|
1.17 ± 0.68
|
0.352
|
|
Physical activity (hr)
|
3.36 ± 14.21
|
3.45 ± 12.86
|
2.18 ± 15.01
|
2.91 ± 12.42
|
3.16 ± 16.27
|
0.216
|
|
No. of pregnancies
|
1.57 ± 0.47
|
1.82 ± 0.69
|
1.91 ± 13.70
|
1.55 ± 0.36
|
1.27 ± 0.45
|
0.221
|
|
Age of menarche
|
13.00 ± 0.11
|
12.00 ± 0.21
|
12.00 ± 0.31
|
13.00 ± 0.81
|
12.00 ± 0.21
|
0.242
|
|
Bone parameters
|
|
Ca mg/dl
|
4.93 ± 0.11
|
4.95 ± 0.20
|
4.87 ± 0.20
|
4.83 ± 0.17
|
4.88 ± 0.18
|
0.233
|
|
PO4 mg/dl
|
3.96 ± 0.40
|
4.58 ± 0.42
|
4.45 ± 0.53
|
4.28 ± 0.66
|
4.17 ± 0.68
|
0.352
|
|
ALP U/L
|
56 ± 14.21
|
50.18 ± 13.93
|
61.55 ± 8.08
|
45.91 ± 12.42
|
55.36 ± 16.27
|
0.216
|
|
PTH pg/ml
|
47.57 ± 8.47
|
46.82 ± 7.69
|
43.91 ± 13.70
|
46.55 ± 11.36
|
45.27 ± 8.45
|
0.221
|
|
OC ng/ml
|
20.50 ± 5.11
|
24.09 ± 5.17
|
31.45 ± 2.21
|
21.73 ± 6.69
|
21.68 ± 6.52
|
0.262
|
|
U.DPD, nmol/mmol
|
5.68 ± 0.94
|
6.30 ± 0.57
|
6.31 ± 0.74
|
6.35 ± 0.73
|
6.25 ± 0.75
|
0.356
|
|
BMD (T-score)
|
-0.49 ± 0.48
|
-0.51 ± 0.98
|
-0.49 ± 1.07
|
-0.45 ± 0.21
|
-0.53 ± 0.11
|
0.326
|
GTC: generalized tonic-clonic seizure; hr: hours; VPA: valproate; LTG: Lamotrigine;
LEV: Levetiracetam; Ca: calcium; PO4; Phosphate; ALP: alkaline phosphatase; PTH: parathyroid
hormone; OC: osteocalcin; U.DPD: urinary deoxypyridinoline; BMD: bone mineral density;
SD: standard deviation. Data are expressed by mean ± standard deviation; Level of
significance was set at p-value < 0.05.
The mean dose and serum drug levels were found to be in therapeutic range for all
AEDs studied. Group 1 comprised patients taking monotherapy LTG 191.67 ± 79.3 mg/day,
and Group 2 comprised patients taking monotherapy LEV 1,250 ± 452.3 mg/day. Group
3 comprised patients who were being treated with polytherapy VPA 1,125 ± 226.13 mg/day
and LTG 316.67 ± 83.5 mg/day. Group 4 comprised patients who were being treated with
polytherapy VPA and 1,250 ± 452.3 mg/day and LEV 758.3 ± 334.2 mg/day.
Bone mineral density and biochemical markers of bone and mineral metabolism
The statistical analyses revealed that there were no significant differences between
all groups at the baseline. The healthy participants group showed no significant differences
before and after six months.
Regarding the biochemical parameters, as shown in [Table 2], after six months of treatment there was a significant decrease in serum calcium
concentrations in all treated groups with no significant change in phosphate and parathyroid
hormone parameters. Serum calcium was decreased significantly more in subjects receiving
VPA+LEV polytherapy than in those receiving VPA+LTG polytherapy (p = 0.04).
Table 2
Changes in bone biochemical parameters and bone turnover markers in all treatment
groups.
|
Parameters/ Groups
|
LTG n = 12
|
LEV n = 12
|
VPA + LTG n = 12
|
VPA + LEV n = 12
|
|
|
|
|
|
|
Baseline
|
6 months
|
Baseline
|
6 months
|
Baseline
|
6 months
|
Baseline
|
6 months
|
|
Ca mg/dl
|
4.95 ± 0.20
|
4.50 ± 0.08*
|
4.87 ± 0.20
|
4.30 ± 0.19*
|
4.83 ± 0.17
|
4.46 ± 0.11*
|
4.88 ± 0.18
|
3.89 ± 0.27*b
|
|
PO4 mg/dl
|
4.58 ± 0.42
|
4.40 ± 0.59
|
4.45 ± 0.53
|
4.05 ± 0.75
|
4.28 ± 0.66
|
4.11 ± 0.60
|
4.17 ± 0.68
|
4.07 ± 0.64
|
|
ALP U/L
|
50.18 ± 13.93
|
47.45 ± 12.86
|
61.55 ± 8.08
|
45.18 ± 15.0*
|
45.91 ± 12.42
|
62.45 ± 14.91*d
|
55.36 ± 16.27
|
70.64 ± 18.56*c
|
|
PTH pg/ml
|
46.82 ± 7.69
|
52.55 ± 8.63
|
43.91 ± 13.70
|
46.36 ± 6.04
|
46.55 ± 11.36
|
48.36 ± 5.57
|
45.27 ± 8.45
|
47.82 ± 4.51
|
|
OC ng/ml
|
24.09 ± 5.17
|
21.09 ± 3.14
|
31.45 ± 2.21
|
21.71 ± 5.19*
|
21.73 ± 6.69
|
43.36 ± 7.59*d
|
21.68 ± 6.52
|
42.00 ± 8.12*c
|
|
U.DPD nmol/mmol
|
6.30 ± 0.57
|
6.74 ± 0.66
|
6.31 ± 0.74
|
6.68 ± 0.81
|
6.35 ± 0.73
|
8.02 ± 0.83*d
|
6.25 ± 0.75
|
8.42 ± 0.68 *c
|
|
BMD (T-score)
|
-0.51 ± 0.98
|
-0.46 ± 0.31
|
-0.49 ± 1.07
|
-0.19 ± 0.30*a
|
-0.45 ± 0.21
|
-0.09 ± 0.65*d
|
-0.53 ± 0.11
|
-0.12 ± 0.42*
|
VPA: valproate; LTG: lamotrigine; LEV: levetiracetam; Ca: calcium; PO4: phosphate;
ALP: alkaline phosphatase; PTH: parathyroid hormone; OC: osteocalcin; U.DPD: urinary
deoxypyridinoline; BMD: bone mineral density; SD: standard deviation. Data are expressed
as mean ± standard deviation. Level of significance was set at p-value < 0.05. * Within-
drug group change from baseline (paired t-test). aComparing LTG with LEV monotherapy
groups after 6 months of treatment; bComparison between (VPA+LTG and VPA+LEV) polytherapy
groups after 6 months of treatment; cComparing LEV with (VPA+LEV) treated groups after
6 months of treatment; dComparing LTG with VPA+LTG treated groups after 6 months of
treatment.
We noted changes in bone turnover markers between the monotherapy groups. In patients
in the LEV monotherapy group, we found a significant decrease in the bone formation
markers (serum alkaline phosphatase and serum osteocalcin levels) while the bone resorption
marker showed no significant change in urinary deoxypyridinoline levels. However,
in patients in the LTG monotherapy group, we found no significant changes in bone
turnover markers. On the other hand, both polytherapy groups showed significant increase
in the bone formation markers (serum alkaline phosphatase and serum osteocalcin levels)
and the bone resorption marker (urinary deoxypyridinoline levels).
Bone mineral density (T-score) after six months of treatment revealed a significant
decrease in all treated groups except for the LTG monotherapy group. The significant
decrease between monotherapy groups was more prevalent in the LEV monotherapy group
when compared with the LTG monotherapy group (p = 0.036). No significant difference
was shown between the LEV monotherapy group and the VPA+LEV polytherapy group.
To assess relationships between the bone mineral density and markers of bone turnover,
Pearson’s correlation coefficients were performed ([Table 3]). No significant relationships were detected in all the studied groups, except for
a positive significant correlation between urinary deoxypyridinoline level and bone
mineral density (T-score) in the LEV monotherapy group.
Table 3
Correlation between bone mineral density (T-score) and bone turnover markers in all
studied groups.
|
Parameter
|
LTG
|
LEV
|
|
|
|
|
r
|
p
|
r
|
p
|
|
Serum OC
|
0.380
|
0.224
|
0.320
|
0.312
|
|
Urinary DPD
|
0.391
|
0.209
|
0.197
|
0.04*
|
OC: osteocalcin (bone formation marker); U.DPD: urinary deoxypyridinoline (bone resorption
marker); LTG: lamotrigine; LEV: levetiracetam; r: Pearson’s correlation coefficient.
Level of significance was set at p-value < 0.05.
DISCUSSION
In the present study, patients on LEV monotherapy showed a significant decrease in
bone mineral density and levels of bone formation markers (alkaline phosphatase, osteocalcin).
The urine level of the bone resorption marker, urinary deoxypyridinoline, was not
significantly changed.
Beniczky et al.[16], in 2012, studied antiepileptic monotherapies: VPA, carbamazepine, LTG, oxcarbazepine,
topiramate and LEV. They postulated that there was a significant reduction of bone
mineral density in LEV monotherapy-treated patients. In a preclinical study in 2013,
Fekete et al.[17] demonstrated a significant loss of femoral bone marrow density following LEV therapy
and a decrease of osteoprotegerin serum levels (a marker of bone formation) with significant
elevation of C-terminal telopeptide of collagen type I (a marker of bone resorption).
In 2007, in a preclinical study, Nissen-Meyer et al.[11] demonstrated that LEV provoked a negative effect on bone marrow density.
In contrast to the previous studies, Anwar et al.[18] in 2014, compared the effects of three AEDs; phenytoin, VPA, and LEV on the lumbar
vertebrae of a Swiss strain of albino female mice and found that LEV did not provoke
any significant alterations in bone mineral density. As well, Lee et al.[19] in a 2012 clinical retrospective study, reported the absence of a deleterious effect
of newer AEDs including LEV on bone mineral density.
It should be noted that the range of daily doses of LEV and treatment duration were
different from the doses used in humans. These factors may explain the heterogeneity
of results between preclinical and human studies.
The underlying mechanisms through which LEV can affect bone remodeling is still unclear.
Levetiracetam might change the bone marrow density through disturbances in the bone
tissue maturation that concerns suboptimal mineralization of cartilage, secondary
to its direct negative effect on chondroclasts[20]. Nissen-Meyer et al.[11], in 2007, showed that LEV provoked a harmful effect on trabecular bones, which contain
more cartilage content than cortical bone.
Recently, several case reports have shown that LEV was found to be associated with
pancytopenia (bone marrow suppression) in epileptic patients[21],[22],[23],[24]. In another report, LEV induced hyponatremia and thrombocytopenia[25],[26]. The previously-mentioned information provides a logical justification for our result,
which showed a positive relationship between bone marrow density and bone resorption
marker urinary deoxypyridinoline using Pearson’s correlation coefficient.
In the current study, patients on LTG monotherapy showed no change in their bone mineral
density and only showed a significant reduction in calcium serum levels. This currently
seems to be in agreement with the results obtained by Kim Lee et al.[27] in 2007. In their prospective study of eight newly-diagnosed epileptic patients,
the authors reported that LTG monotherapy for a six-month duration resulted in no
abnormalities in bone mineral density, calcium, phosphate, vitamin D and urinary deoxypyridinoline
levels. Furthermore, it has been demonstrated that LTG monotherapy showed a nonsignificant
effect on bone turnover and on the indices of mineral metabolism, markers of bone
formation and bone resorption in premenopausal epileptic women who were stabilized
on LTG monotherapy for one year[28],[29],[30]. These aforementioned data may partially justify the results obtained in our study.
In general, the effect of LTG monotherapy on bone health is controversial and the
underlying mechanism through which LTG monotherapy may affect bone remodeling is still
unknown. However, it has been suggested that LTG monotherapy may affect bone metabolism,
inducing the development of parathyroid hormone resistance and compensating for bone
loss through increasing bone formation[27],[31].
In our study, both patients on LEV polytherapy (LEV+VPA combination) and those on
LTG polytherapy (LTG+VPA combination) showed a negative effect on bone. It has been
demonstrated that LTG and/or VPA therapies for more than two years were associated
with low bone mineral density, reduced bone formation (reduced plasma osteocalcin)
and short stature in children with epilepsy[31]. These previously-mentioned findings reported by Guo et al.[32] corroborate the results obtained in the current study concerning the effect of antiepileptic
polytherapy on bone health. However, a previously-reported cross-sectional study accomplished
with different groups of epileptic patients treated with six different AEDs including;
carbamazepine, oxcarbazepine, VPA, LTG, topiramate and LEV demonstrated that the patient
group treated with AED polytherapies showed nonsignificant changes in bone mineral
density[16].
Long-term antiepileptic treatment with VPA may cause osteopenia in both sexes[5],[28],[3]
[3],[34],[35],[36]. Many authors have noticed a significant reduction of bone marrow density[5],[28],[32],[3]
[4],[35]. Some studies found results suggesting that serum calcium concentrations may be
significantly lower in patients receiving VPA[28],[33],[34]. In many studies, serum levels of intact parathyroid hormone were within the normal
range[28],[30],[32],[34],[35],[36]. Increases in serum levels of total alkaline phosphatase have been reported in several
studies[28],[35],[37]. In two studies, the osteocalcin levels of the patient group were significantly
higher than the control group[5],[27],[36]. Urine values of deoxypyridinoline showed no significant difference between epileptic
and healthy children[27],[38],[39]. All the aforementioned prove that data on the effect of antiepileptic polytherapy
on bone health are still conflicting and require further investigation.
In this context, our study aimed to evaluate the effects of new AEDs on bone health.
The data obtained in our study revealed that LEV monotherapy showed harmful effects
on bone but LTD monotherapy did not. Even though antiepileptic polytherapy has been
associated with negative effects on bone, there was no difference between LEV in monotherapy
and polytherapy, while LTG polytherapy showed a decrease bone mineral density compared
with LTG monotherapy. However, this work needs further expansion through large scale,
longitudinal studies with different bone types in order to clarify and understand
which AEDs can affect bone health.
