Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Bone Mineral Density and Bone Markers in the Children with Epilepsy Taking on Chronic Anticonvulsants

장기간 항경련제를 복용하고 있는 소아 간질 환아들의 골밀도 및 골대사 지표들

  • Lee, Soon Bum (Department of Pediatrics, College of Medicine, Dankook University) ;
  • Kang, So Young (Department of Pediatrics, College of Medicine, Dankook University) ;
  • Yu, Jeesuk (Department of Pediatrics, College of Medicine, Dankook University)
  • 이순범 (단국대학교 의과대학 소아과학교실) ;
  • 강소영 (단국대학교 의과대학 소아과학교실) ;
  • 유지숙 (단국대학교 의과대학 소아과학교실)
  • Received : 2004.12.02
  • Accepted : 2005.01.13
  • Published : 2005.05.15
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Abstract

Purpose : Long-term administration of anticonvulsants in children with epilepsy may cause short stature, hypocalcemia and low bone mineral density. This study was performed for the early detection of abnormal bone metabolism in children with epilepsy on taking anticonvulsants. Methods : Thirty children aged 5 to 16 years who were diagnosed with epilepsy were enrolled in this study. All had taken anticonvulsants for more than one year. Bone mineral density of lumbar vertebra was measured by dual-energy X-ray absorptiometry. Serum calcium, phosphorous, alkaline phosphatase, 25-hydroxycholecalciferol[$25(OH)D_3$], parathyroid hormone, and urine deoxypyridinoline were measured as biochemical bone markers. Bone age and body mass index were also calculated. Results : Bone minreal density, body mass index, bone age, and height were significantly decreased in two female patients who had taken two antiepileptic drugs for more than four years and they also had chronic diseases such as cerebral palsy with microcephaly, encephalomalacia, and microcephaly with atrial septal defect. Bone mineral density had significant positive correlations with body mass index(P<0.01) and bone age(P<0.01). Conclusion : This study showed chronic medication of anticonvulsants in children may cause low bone mineral density and short stature. Bone age and body mass index could be the important surrogate markers to find the population at risk. More studies, including a large study population and long term cohort study, will be required.

목 적 : 소아 간질 환아에서 장기간 항경련제를 투여시 저신장, 저칼슘혈증, 골밀도 저하가 올 수 있는 것으로 알려져 있다. 저자들은 골밀도 및 골표지자의 연구를 통해 항경련제 투여 환아의 골대사 질환의 위험을 조기 발견할 수 있는지 알아보고자 하였다. 방 법 : 간질로 단국대학교병원 소아과에서 12개월 이상 항경련제 치료를 받고 있는 환자들 중 5-16세의 환아 30명을 대상으로 2003년 7월부터 2004년 2월 사이에 본 연구를 시행하였다. 대상 환아들을 carbamazepine과 valproic acid를 단독 투여군과 2가지 이상의 항경련제를 병합투여한 군으로 나누었고, 요추부 골밀도, 체질량지수, 골연령 및 골표지자들을 측정한 후, 남녀별, 연령별로 분류하여 대조군과 비교하였다. 결 과 : 총 30명이었으며, 검사 당시 평균연령은 $10.4{\pm}3.1$세(5-16세)이었다. Carbamazpine 단독 투여군 10명, valproic acid 단독 투여군 6명, 2가지 이상의 약물을 투여 받은 복합 투여군이 14명이었고 복합 투여군 중에는 뇌성마비 2명, 소두증 2명, 뇌연화증 1명, 선천성심장병 1명이 포함되었다. 각 투여군 간에는 요추 골밀도, 칼슘, 인, 알칼리성 인산화효소, $25(OH)D_3$, 오스테오칼신, 부갑상선호르몬, deoxypyridinoline, 골연령 등의 차이는 없었다. 남녀별, 연령별로 나누었을 때 5세 및 15세 여아에서 -2.5 SDS 미만의 의미있는 골밀도의 감소를 보였으며, 체질량지수는 5 percentile 미만의 현저한 감소를 보이고 있었고, 골 연령 및 신장도 감소되어 있었다. 이러한 감소를 보인 두 명의 환아 중 5세 환아는 심방중격결손증 및 소두증을 가지고 있었으며 15세 여아는 뇌성마비 및 뇌연화증이 있었고 좌하지 골절의 기왕력이 있었으며 두 환아 모두 2가지 항경련제를 4년 이상 투약 받았다. 골밀도는 체질량지수 및 골연령과 통계적으로 의미있는 양의 상관관계를 보였다. 결 론 : 장기간 항경련제를 복용하는 소아환자들에 있어 특히, 신체활동이 제한되어 있거나 다른 만성질환을 동반한 경우에는 골대사에 대한 세심한 주의가 필요하며 주기적으로 키, 몸무게를 측정하여 체질량지수 및 신장의 SDS를 산출하는 것이 골대사에 대한 간단하면서도 중요한 검사가 될 수 있을 것으로 생각된다.

Keywords

Acknowledgement

Supported by : 단국대학교

References

  1. Riggs BL, Melton LJ 3rd. Involutional osteoporosis. N Engl J Med 1986;314:1676-86 https://doi.org/10.1056/NEJM198606263142605
  2. Cho YW, Lee IK, Seung HH. Adverse effects of antiepilep tic drugs on bone mineral density in women with epilepsy. Korean J Endocrinol 2002;17:218-25
  3. Suh YS, Kim YG, Lee JH, Yoo KH, Lee JW, Tockgo YC. The effect of long-term phenobarbital administration on the bone mineral density of children. J Korean Pediatr Soc 1994;37:368-75
  4. Kim TJ, Suh ES. Bone mineral density in epileptic children who received long-term anticonvulsant drugs. J Korean Child Neurol 1997;5:52-8
  5. Juhng WS, Kim SJ, Cho SC, Joo CU. Effect of antiepiletpic drugs on bone metabolism and growth in epileptic children. J Korean Pediatr Soc 1999:42:1078-85
  6. Oh HH, Jang YC, Choe BH, Park IH, Kwon SH. Effect of the chronic use of antivonculsants on bone mineral density in children with epilepsy. Korean J Pediatr 2004:47:965-9
  7. Timperlake RW, Cook SD, Thomas KA, Harding AF, Bennett JT, Haller JS et al. Effect of anticonvulsant drug therapy on bone mineral density in a pediatric population. J Pediatr Orthop 1988;8:467-70 https://doi.org/10.1097/01241398-198807000-00017
  8. Livingston S, Berman W, Pauli LL. Anticonvulsant drugs and vitamin D metabolism. JAMA 1973;224:1634-5 https://doi.org/10.1001/jama.224.12.1634
  9. Ala-Houhala M, Korpela R, Koivikko M, Koskinen T, Koskinen M, Koivula T. Long-term anticonvulsant therapy and vitamin D metabolism in ambulatory pubertal children. Neuropediatrics 1986;17:212-6 https://doi.org/10.1055/s-2008-1052532
  10. Hahn TJ, Hendin BA, Scharp CR, Haddad Jr. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972;287:900-4 https://doi.org/10.1056/NEJM197211022871803
  11. Hann TJ, Birge SJ, Scharp CR, Avioli LV. Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest 1972:51:741-8 https://doi.org/10.1172/JCI106868
  12. Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BE. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984:58:1003-9 https://doi.org/10.1210/jcem-58-6-1003
  13. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj F. Effect of antiepileptic durgs on bone density in ambulatory patients. Neurology 2002:58:1348-53 https://doi.org/10.1212/WNL.58.9.1348
  14. Matkovic V, Jelic T, Wardlaw GM, Llich JZ, Goel PK, Wright JK, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994;93:799-808 https://doi.org/10.1172/JCI117034
  15. Kim BY, Kim YG, Kim YJ, Yoo KH, Lee JW, Kim SK. A study of bone mineral density in korean children of normal growth and development. J Korean Pediatr Soc 1995;38: 612-8
  16. Boot AM, de Ridder MA, Pols HA, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab 1997;82:57-62 https://doi.org/10.1210/jc.82.1.57
  17. Schimid F. Osteopathien bei antiepileptischer daurbehandlung. Fortscher Med 1967;95:381-2
  18. Dent CE, Richens A, Rowe DJ, Stamp TC. Osteomalacia with long-term anticonvulsant therapy in epilepsy. BMJ 1970;4:69-72 https://doi.org/10.1136/bmj.4.5727.69
  19. Hunter J, Maxwell JD, Stewart DA, Parsons V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. BMJ 1971;4:202-4 https://doi.org/10.1136/bmj.4.5781.202
  20. Crosley CJ, Chee C, Berman PH. Rickets associated with long-term anticonvulsant therapy in a pediatric outpatient population. Pediatrics 1975:56:52 -7
  21. Jubiz W, Haussler MR, McCain TA, Tolman KG. Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs. J Clin Endocrinol Metab 1977;44:617-21 https://doi.org/10.1210/jcem-44-4-617
  22. Andress DL, Ozuna J, Tirschwell D, Grande L, Johnson M, Jacobson AF, et al. Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol 2002; 59:781-6 https://doi.org/10.1001/archneur.59.5.781
  23. Koch HV, Kratf D, von Herrath D. Influence of diphenylhydantion and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972;13:829-34 https://doi.org/10.1111/j.1528-1157.1972.tb05167.x
  24. Finsen V, Anda S. Accuracy of visually estimated bone mineralization in routine radiographs of the lower extremity. Skeletal Radiol 1988;17:270-5 https://doi.org/10.1007/BF00401810
  25. Paul LK, Donal EO, Banta D, Feinstein AR, Frazier HS, Hronick Richard, et al. Radiologic methods to evaluate bone mineral content. Health and Public Policy Committee, American College of Physicians. Ann Intern Med 1984;100: 908-11 https://doi.org/10.7326/0003-4819-100-6-908
  26. Delmas PD. Biochemical markers of bone turnover. J Bone Miner Res 1993;8:549-55
  27. Moss DW. Alkaline phosphatase isoenzymes. Clin Chem 1982;28:2007-16
  28. Tsutsumi H, Katagiri K, Morimoto M, Nasu T, Tanigawa M, Mamba K. Diurnal variation and age-related changes of bone turnover markers in female Gottingen minipigs. Lab Anim 2004;38:439-46 https://doi.org/10.1258/0023677041958864
  29. Eyre DR, Dickson IR, Van Ness K. Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues. Biochem J 1988;252:495-500 https://doi.org/10.1042/bj2520495
  30. Chung HY, Jang HC, Kim CJ, Min YK, Moon IG, Han IK.Urinary pyridinium cross links as bone markers in postmenopausal osteoporosis. J Korean Soc Bone Metabol 1994; 1:34-9
  31. Heller HJ, Sakhaee K. Anticonvulsant-induced bone disease: a plea for monitoring and treatment. Arch Neurol 2001;58:1352-3 https://doi.org/10.1001/archneur.58.9.1352
  32. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 2004;5:41-7 https://doi.org/10.1016/j.yebeh.2003.11.028