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The effect of antiepileptic drugs in monotherapy on bone mineral density in children

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The effect of antiepileptic drugs in monotherapy on bone mineral density

in children

Wpływ leków przeciwpadaczkowych stosowanych w monoterapii na mineralizację tkanki

kostnej u dzieci

Anna Masztalerz

1

, Grażyna Sergot-Martynowska

1

, Beata Stępień-Jaszowska

2

1 Oddział Neurologii Dziecięcej Wojewódzkiego Szpitala Dziecięcego w Bydgoszczy 2 Pracownia Densytometrii Klinicznej Wojewódzkiego Szpitala Dziecięcego w Bydgoszczy

ABSTRACT

Among many factors causing reduced bone mineralization, the chronic use of antiepileptic drugs (AEDs). May be one of them. Aim. The aim of the study was to asses the effect of carbmaazepine (CBZ), its derivative oxcarbazepine(OXC) and valproic acid (VPA) on bone mineral density (BMD) in children with epilepsy. Materials and Methods. The study comprised of 70 children (girls and boys) over five years of age who receiv-edlong-term AEDs therapy ( longer than 2 years). Control group consisted of children without any pharmacologic treatment. Densitometry of the osseous system and the lumbar section of spine were done. Results. The group treated with car-bamazepine and oxcarbazepine comprised 34 patients, treated with valproic acid 36 and the control group 42 patients. Reduc-tion in BMD was found in 41.2% of CBZ/OXC-treated patients, 38.9% of patients who were receiving VPA, and in the control group 23.8% of respondents. Moreover, the reduced BMD was not significantly different in groups of treated children, but it is statistically higher compared with the control group. Analysis of the determinants of osteopenia and osteoporosis showed that statistically the reduced bone mineral density was often observed in children treated with long-term therapy and with a lower BMI. In addition, no relation to age, gender, develop-mental period and type of epilepsy has been established.

Con-clusion. 1. Carbamazepine, oxcarbazepine and valproic acid

decrease at a comparable level the bone mineral density (BMD). 2. Reduction of bone mineral density occurs more frequently in children who received long-term AEDs therapy. 3. Densytom-etry examination is helpful in assessing adverse effects on long-term treatment of AEDs.

Key words: children, antiepileptic drugs, bone mineral density

STRESZCZENIE

Spośród wielu czynników przyczyną obniżonej mineralizacji kości może być przewlekłe stosowanie leków przeciwpadacz-kowych (LPP). Cel. Badano wpływ karbamazepiny(CBZ) i jej pochodnej okskarbazepiny (OXC) oraz kwasu walproinowego (VPA) na mineralizację kości u dzieci z padaczką. Materiał

i metody. Badaniem objęto 70 dzieci obojga płci, powyżej

5 r.ż., leczonych w monoterapii ponad 2 lata. Wykluczono dzieci niesprawne ruchowo, przewlekle chore, leczone diete-tycznie, przyjmujące leki i suplementy wpływające na układ kostny. Grupę kontrolną stanowiły dzieci z wadami postawy oraz obserwowane w kierunku astmy przed włączeniem ste-rydów.Wykonywano densytometrię całego układu kostnego i dodatkowo odcinka lędźwiowego kręgosłupa. Wyniki. Grupa leczonych CBZ/0XC liczyła 34, VPA – 36, grupa kontrolna – 42. Grupy leczonych i kontrolna były porównywalne pod względem płci, wieku, aktywności fizycznej, BMI; u dzieci z padaczką nie stwierdzono istotnej statystycznie różnicy w odniesieniu do czasu trwania padaczki i jej rodzaju. Obniżenie mineralizacji kości stwierdzono u 41,2% leczonych CBZ, u 38,9% leczonych VPA, w grupie kontrolnej u 23,8% badanych. Częstość występowania obniżenia mineralizacji kości nie różniła się istotnie w grupach dzieci leczonych, ale była statystycznie wyższa w porównaniu z grupą kontrolną. Analiza czynników warunkujących osteope-nię i osteoporozę wykazała,że statystycznie częściej obniżoną mineralizację tkanki kostnej wykazywały u dzieci dłużej leczone i z niższym wskaźnikiem BMI. Nie stwierdzono zależności od wieku, płci, okresu rozwojowego, rodzaju padaczki. Wnioski. 1. Karbamazepina oraz kwas walproinowy w porównywalnym stopniu obniżają mineralizację kości. 2. Obniżenie mineraliza-cji kości występuje częściej u dzieci leczonych dłużej LPP. 3. Densytometria jest badaniem pomocnym w ocenie objawów niepożądanych przy długotrwałym leczeniu LPP.

Słowa kluczowe: dzieci, leki przeciwpadaczkowe,

mineraliza-cja kości

Os�eoporos�s �s a d�sease of bo�e �ha� leads �o a� ��creased r�sk of frac�ure. I� os�eoporos�s �he bo�e m��eral de�s��y �s reduced a�d bo�e m�cro arch��ec�ure �s d�srup�ed. O�e of

r�sk fac�ors �s a���ep�lep��c drug �rea�me��. Ma�y s�ud�es �� rece�� 40 years have show� a s�g��f�ca�� reduc��o� �� bo�e m��eral de�s��y �� pa��e��s �rea�ed w��h a���ep�lep��c drugs.

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The frac�ure r�sk �� ep�lep��c pa��e��s �s 2-6 ��mes grea�er �ha� �� o�hers. I� �s caused bo�h by �he ��jur�es dur��g �he epileptic attack and the treatment which deteriorates motor coord��a��o� a�d d�rec�ly �he bo�e m��eral de�s��y. The a�m of scree���g for os�eope��a a�d os�eoporos�s �s �o �de���fy �he respo�s�ble a���ep�lep��c drug a�d �o �de���fy �he popula��o� �� �eed of ���erve���o� �.e. d�e� mod�f�ca��o�, l�fes�yle cha�ge or a drug �rea�me�� �o decline the risk of fracture and �mprove �he qual��y of l�fe.

AIM

The a�m of �he s�udy was �o asses �he effec� of carbama�ep��e �C�Z�, ��s der�va��ve oxcarba�ep��e�OXC� a�d valpro�c ac�d �V�A� o� bo�e m��eral de�s��y��MD� �� ch�ldre� w��h ep�lepsy.

pATIENTS AND METHODS

The s�udy compr�sed 70 ch�ldre� �g�rls a�d boys� over f�ve years of age who rece�ved lo�g-�erm a���ep�lep��c drug mo�o�herapy �lo�ger �ha� 2 years� w��hou� a�y add���o�al chro��c d�sease a�d w��h modera�e phys�cal ac��v��y. The group �rea�ed w��h carbama�ep��e a�d oxcarba�ep��e compr�sed 34 ch�ldre�: 14 g�rls a�d 20 boys �age ra�ge 5,5-19 years, mea�11,7�. The group �rea�ed w��h V�A compr�sed 36 ch�ldre�: 18 g�rls a�d 18 boys �age ra�ge 6,2-19,8 years, mea� 13,5�. Co��rol group co�s�s�ed of 42 ch�ldre� w��h posture defects or asthma before the steroid treatment: 18 g�rls a�d 24 boys �age ra�ge 5–17,8 years, mea� 11,8 years�.

De�s��ome�ry of �he osseous sys�em a�d �he lumbar sec��o� of sp��e was do�e us��g GE Lu�ar �rod�gy U�A densitometer.

Photo 1. Densitometer Ge Healthcare Lunar Prodigy Advance

USA Densytometr Ge Healthcare Lunar Prodigy Advance USA Accord��g �o gu�del��es of I��er�a��o�al �oc�e�y for Cl���cal De�s��ome�ry�I�CD� os�eope��a was def��ed w��h �-score ≤ -1, os�eoporos�s ��� ch�ldre� �s recomme�ded �o use �erm “low age spec�f�c bo�e mass”� w��h �-score≤2,0 �� at least one from measured z-scores.

��a��s��cal a�alys�s was do�e w��h parame�r�c �es�s � ��ude��, Cochra�-Cox, F ��edecor a�d �o�parame�r�c �es�s �hap�ro-W�lk, Ma��-Wh���ey.

RESULTS

The s�udy a�d co��rol groups were comparable �� �erms of ge�der, developme��al per�od, phys�cal ac��v��y a�d �MI. I� �he ep�lep��c ch�ldre� group �he ��me of �rea�me�� a�d �he �ype of ep�lepsy were comparable. Ch�ldre� �rea�ed w��h V�A were a l���le older �ha� �hose �rea�ed w��h C�Z/OXC �13,5 vs 11,7�. I� �he C�Z/OXC group os�eope��a ��-score ≤ -1� was def��ed �� 35,3%, os�eoporos�s �w��h �-score≤2,0 � �� 5,9% ch�ldre�. I� V�A os�ope��a was d�ag�osed �� 30,6%, os�eoporos�s �� 8,3% ch�ldre�. I� co��rol group os�eope��a occurred �� 19%, os�eoporos�s �� 4,8% ch�ldre�. The s�a��-s��cal a�alys�s has proved �ha� bo�e m��eral��a��o� d�sorders occur more freque��ly �� ch�ldre� �rea�ed w��h a���ep�lep��c drug. We d�d �o� f��d a�y s�g��f�ca�� d�ffere�ces be�wee� �he V�A a�d C�Z/OXC groups.

Tab. I.ab. I. Częstość występowania osteopenii i osteoporozy

w badanych grupach. The incidence of osteopenia and

osteoporosis in the treated groups

The ��c�de�ce of �he bo�e m��eral de�er�ora��o� �s s�m�lar �� bo�h �rea�ed groups a�d �s s�a��s��cally lower compar��g �o co��rol. We a�aly�ed r�sk fac�ors for os�eope��a a�d os�eoporos�s �� �he �rea�ed groups. We d�v�ded �rea�ed popula��o� ���o 2 groups: w��h decreased a�d �ormal bo�e m��eral de�s��y ��MD�. We d�d �o� f��d a�y correla��o� be�wee� age, ge�der, developme��al per�od a�d os�eope��a or osteoporosis occurrence. All cases of osteoporosis were observed �� ch�ldre� w��h cryp�oge��c a�d symp�oma��c ep�lepsy �Da�dy-Walker sy�drome, chromosomopa�hy, arach�o�d cys��. Ch�ldre� w��h os�eoporos�s demo�s�ra�ed �ormal mo�or ac��v��y, al�hough �o� always d�rec�ed �hyperac��ve ch�ldre� a�d w��h moveme�� s�ereo�yp�es�. I� �he co��rol group os�eoporos�s was d�ag�osed �� 18-year old boy w��h a pos�ure defec� a�d back pa�� a�d 5-year old boy w��h as�hma ��o� �rea�ed w��h s�ero�ds�. Ch�ldre� w��h decreased �MD were �rea�ed lo�ger w��h a���ep�lep��c drug �4,5 vs 3,9 p=0.07� a�d had lower �MI �17,5 vs 19,5 �� Cochra�e-Cox �es� p=0.006�.

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Tab. II. Relationship between BMI and bone mineral density

(z-score) in children with epilepsy Diagram korelacyjny

DISCUSSION

Ep�lepsy �s a freque��, chro��c �eurolog�cal �ll�ess. I� occurs espec�ally of�e� �� ch�ldre� a�d older people, 1% of �hem �akes drugs for ma�y years. A���ep�lep��c drugs �AED� are used �o �rea� also m�gra��e, �d�opa�h�c �remor, psych�a�r�c d�sorders a�d �europa�h�c pa�� [3]. Ch�ldhood a�d adole-sce�ce are a cr���cal per�ods for bo�e m��eral��a��o� [4]. I� heal�hy people �he m��eral��a��o� process progressed gradu-ally up �o e�d �� �he �h�rd decade of l�fe. Chro��c d�seases �ur��ary �rac�, gas�roe��erolog�cal, e�docr��olog�cal a�d me�abol�c d�sorders �.e. homocys�y�ur�a� res�r�c��ve d�e� ��.e. ke�oge��c� may d�s�urb v��am�� D, calc�um a�d phospha�es homeostasis and influence on osteoclasts and osteoblasts bala�ce �� bo�e ma�r�x, decrease bo�e m��eral��a��o�, co�-seque��ly ��creas��g �he frac�ure r�sk [5].

The frac�ure r�sk �� ep�lep��c pa��e��s �s 2-6 ��mes h�gher �ha� �� ge�eral popula��o� [6,7]. 25% of ep�lep��c ch�ldre� older �ha� 10 years �s suffer��g from bo�e frac�ures, wh�ch �s caused by ��jur�es freque��ly occurr��g dur��g ep�lep-��c se��ures a�d �he �rea�me�� wh�ch decreases �he move-me�� coord��a��o� a�d could d�rec�ly ��flue�ce �he osseous sys�em decreas��g bo�e m��eral��a��o� [2]. �p��e frac�u-res �� �o� �rea�ed os�eoporos�s cause sp��e deforma��o�, posture defects and short-stature.

The adverse effec�s of a���ep�lep��c drugs �AED�� o� bo�e heal�h were f�rs� repor�ed �early for�y years ago. I� �he old ha�dbooks os�eopa�hy was descr�bed o�ly “�� ��s���u-��o�al��ed ha�d�capped ch�ldre� a�d adolesce��s w��h drug res�s�a�� ep�lepsy �rea�ed w��h h�gh doses of a���ep�lep��c drugs”. I� 2007 we could read abou� e��ology a�d cl���cal �mpl�ca��o�s of “ep�lep��c os�eopa�hy” [1]. Ma�� fac�ors ��flue�c��g �he bo�e m��eral��a��o� �� ep�lep��c ch�ldre� are: u�bala�ced d�e�, v��am�� D def�c�e�cy, low phys�cal ac��v��y, geograph�c fac�ors a�d a���ep�lep��c drug �herapy [6,8]. The �mpac� AEDs o� bo�e sys�em �s �o� suff�c�e��ly ��ves��ga�ed [1,2,4,9].

AEDs ��duc��g fu�c��o� CY� 450 �C�Z, �HT� dec-rease 25�OH�D a�d ��cdec-rease bo�e �ur�over [3,10]. Co�se-cu��ve s�ud�es have proved �ha� V�A, a� e��yme ��h�b��or, ��creases �he r�sk of os�eope��a, os�eoporos�s a�d bo�e frac�ures [5,7,11,12,13].

�ome au�hors u�derm��e �hese resul�s [3,14-18]. I� our op���o� �he co��rovers�es could resul� from d�ffere�-ces �� de�s��ome�ry me�hodology. I� �he f�rs� s�ud�es o�ly d�s�a�� par�s of bo�e sys�em were evalua�ed, �-score was �o� a�aly�ed a�d �he pa��e�� groups were small. Curre�� recomme�da��o� �s �he whole body a�d lumbar sp��e de�s-��ome�ry [5].

I� our s�udy we a�aly�ed �he �mpac� of C�Z/OXC or V�A �rea�me�� o� bo�e m��eral de�s��y. �ecause of �he �de���cal effec� of carbama�ep��e a�d oxcarba�ep��e o� calc�um-phospha�e bala�ce, �he ch�ldre� �rea�ed w��h �h�s drugs were ��cluded �� o�e group. The s�udy a�d co��rol groups were comparable �� �erms of ge�der, age, develop-me��al per�od a�d �MI. I� AED �rea�me�� group we fou�d more os�eope��a a�d os�eoporos�s �C�Z/OXC 41,2%, V�A 38,9%, co��rol group 23,8%�.

��m�lar resul�s were repor�ed by o�her au�hors. Kuma�-das e� al [19] a�aly�ed 33 ch�ldre� �� pre puber�al per�od �rea�ed w��h C�Z �� mo�o�herapy for a� leas� 2 years. They fou�d �he decrease �� L1-L4 bo�e m��eral de�s��y a�d 25�OH�D �� blood. �abayg�� e� al [14] observed decrease �� bo�e m��eral de�s��y �� 68 ch�ldre� �rea�ed w��h valpro�c ac�d, carbama�ep��e a�d oxcarba�ep��e �� rela��o� �o co�-�rol group.

Ca�su e� al [20] d�d �o� fou�d a�y s�g��f�ca�� cha�ge �� bo�e m��eral de�s��y �� �ew d�ag�osed �d�opa�h�c ep�lepsy �� ch�ldre� af�er 18-mo��h oxcarba�ep��e �rea�me��. Three cases of os�eoporos�s af�er �he 18-mo��h �rea�me�� were related to osteopenia before treatment.

��ud�es a�aly���g �he ��flue�ce of a���ep�lep��c drugs o� bo�e m��eral de�s��y af�er shor�er dura��o� of �rea�me�� �6-12 mo��h� repor�ed small or �o effec� of AEDs o� �he bo�e m��eral de�s��y. Vurucu e� al [21] d�d �o� f��d a�y effec� of oxcarba�ep��e o� bo�e m��eral��a��o� pa��e��s �rea�ed for s�x mo��hs. �os�a�c�oglou e� al. [8] s�ud�ed bo�e m��era-l��a��o� �� 61 ep�lep��c ch�ldre� before a�d af�er o�e year of �rea�me�� w��h V�A. They fou�d 2 cases of os�eoporos�s ��-score<2�. I� au�hors op���o� �he b�ochem�cal markers: 25�OH�D, calc�um, phospha�es, alkal� phospha�ase, cal-c��o���, para�hormo� are �o� suff�c�e�� ��d�ca�ors of bo�e heal�h as �he de�s��ome�ry should be do�e.

Ecev�� e� al. [23] proved �he decrease �� bo�e m��era-l��a��o� �� prox�mal par� of femur �� o�e-�h�rd of ch�ldre� �rea�ed w��h V�A for a� leas� 6 mo��hs.

O�er e� al. [24] fou�d �� 33 �d�opah��c ep�lepsy ch�ldre� �rea�ed w��h V�A over 6 mo��hs �he decrease �� �-score �MD �� lumbar sp��e �-0.36 vs 0.21 �� co��rol p=0.04�. I� �h�s s�udy 7 ch�ldre� w��h os�eope��a were �rea�ed lo�ger a�d �ook h�gher doses �ha� o�her ch�ldre�.

��m�lar observa��o�s were made by Verro��� [25] af�er a�aly���g 20 boys w��h �d�opa�h�c ep�lepsy �rea�ed w��h V�A �� �he puber�al per�od.

Ecev�� e� al.[23] d�d �o� f��d a�y ��flue�ce of C�Z �re-atment on bone mineralization (the distal parts of the osse-ous sys�em were evalua�ed, �-score was �o� calcula�ed� �� 17 ch�ldre� w��h �d�opa�h�c ep�lepsy �rea�ed lo�ger �ha� 6 months.

Tegkul e� al. [16] fou�d os�eope��a ��-score<1.5� af�er �he 2 -year a���ep�lep��c drugs �rea�me�� o�ly �� 6,7%

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ch�l-dre� ��he s�udy group compr�sed 30 ch�lch�l-dre�: 15 �rea�ed w��h valpro�c ac�d, 11 w��h carbama�ep��e, 4 w��h barb�-�ura�es�. The decrease �� bo�e m��eral��a��o� occurred �� 1 ch�ld �rea�ed w��h carbama�ep��e a�d �� 1 ch�ld �rea�ed w��h barb��ura�es. L�m��a��o� of �h�s s�udy �s �he lack of co��rol group a�d �he small �umber of �he s�ud�ed popu-lation.

R�eger-We��e�gl e� al. d�d �o� f��d a�y ��flue�ce of �he valpro�c ac�d or carbama�ep��e �rea�me�� o� ch�ldre�’s bo�e m��eral de�s��y. Th�r�y ���e ch�ldre� w��h �d�opa�h�c ep�lepsy �rea�ed over 1 year u�dergo�e rad�us bo�e de�s-��ome�ry. I� compar�so� �o co��rol, �he bo�e �ur�over was more ���e�s�ve, bu� �o �mpor�a�� cha�ges �� �MD were found.

I� our s�udy we compared ch�ldre� �rea�ed w��h AEDs with osteopenia and osteoporosis to those treated with AEDs w��h �ormal bo�e m��eral de�s��y. I� adul�s rece�-v��g AEDs �herapy �MD decl��e was assoc�a�ed w��h age a�d ge�der. I� wome�, ��creas��g age was s�g��f�ca��ly assoc�a�ed w��h a� ab�ormal �MD[26].I� our s�udy ch�l-dre� w��h ep�lepsy have lower �MD for bo�h females a�d males compared �o co��rols. ��m�lar observa��o�s were made by �he�h af�er a�aly���g 82 ch�ldre� rece�v��g AEDs �herapy [27].

I� has bee� es�abl�shed �ha� �he ��me of �he �rea�me�� decreases �MD. Th�s co�clus�o� correspo�ds w��h o�her repor�s [4,15,26,27]. Al�hough Fule�ha� e� al.[28] observed o�ly �� adul�s a pos���ve correla��o� be�wee� �he �rea�me�� ��me a�d �he decrease of bo�e m��eral de�s��y. I� our s�udy ch�ldre� w��hou� bo�e m��eral��a��o� d�sorders had h�gher �MI. The ch�ldre� w��h os�eope��a or os�eoporos�s had

s�g-��f�ca��ly lower �MI. �ayo e� al. repor�s �ha� �he body mass ��crease could pro�ec� bo�e m��eral��a��o� [29]. Accord��g �o s�ud�es co�duc�ed o� adul�s, �he obes��y does �o� pro�ec� from os�eoporos�s. Low body mass predes���a�es �o os�eo-poros�s [30]. ��m�lar resul� were ob�a��ed by Coppola e� al. [4] af�er a�alys��g 96 ch�ldre� w��h �d�opa�h�c a�d symp�o-ma��c ep�lepsy. The pos���ve correla��o� be�wee� �he �MI ��crease a�d �he �MD decrease was fou�d �� �he group of 92 Ch��ese ep�lep��c ch�ldre� [31]. �he�h e� al. [27] d�d �o� f��d a�y correla��o� be�wee� �MI a�d �MD.

Co�s�der��g ma�y co��rovers�es regard��g �he ��flu-ence of AEDs on BMD we need more multicenter studies o� lager groups of ch�ldre� �o f��d correla��o�s be�wee� a���ep�lep��c drugs a�d bo�e m��eral��a��o�.

CONCLUSIONS

1. Carbama�ep��e,oxcarba�ep��e a�d valpro�c ac�d decrease a� a comparable level �he bo�e m��eral de�s��y. 2. Reduc��o� of bo�e m��eral de�s��y occurs more

freque��ly �� ch�ldre� who rece�ved 3. lo�g-�erm AEDs �herapy.

4. De�sy�ome�ry exam��a��o� �s helpful �� assess��g �he adverse effec�s o� lo�g-�erm �rea�me�� of AEDs. Reference books for epileptic patients should contain diet ��d�ca��o�s [d�e� r�ch �� da�ry produc�s, mag�es�um – cacao, chocola�e, w��h l�m��ed supply of phospha�es a�d �a�r�um – coca-cola, �able sal�] a�d l�fe s�yle ��d�ca��o�s. I� �s �ecessary �o prov�de prophylax�s a�d ��forma��o� �o preve�� os�eope-��a a�d os�eoporos�s, �o decl��e frac�ure-r�sk a�d �mprove �he qual��y of l�fe lo�g-�erm �rea�ed ep�lep��c ch�ldre�.

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Correspondence:

Masztalerz Anna, Oddział Neurologii Dziecięcej Wojewódzkiego Szpitala Dziecięcego, ul Chodkiewicza 44, tel. 602 379 822go Szpitala Dziecięcego, ul Chodkiewicza 44, tel. 602 379 822 e-mail masztalerzm@wp.pl

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