Influence of antiepileptic drugs on bone mineral density and bone metabolism in adults: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

FAN Danyang , Miao Jie , HOU Yuli ,  SUN Meizhen

The First Hospital of Shanxi Medical University, Taiyuan, 030001, P.R.China;

Corresponding author：

SUN Meizhen, Email: sunmeizhen213@126.com

Keywords：

Epilepsy; Antiepileptic drugs; Bone mineral density; Bone metabolism; Adults; meta-analysis; Systematic review

DOI：

10.7507/1672-2531.201809077

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Objectives To systematically review the influence of antiepileptic drugs on bone mineral density and bone metabolism in adults.Methods PubMed, EMbase, CNKI, CBM, VIP and WanFang Data databases were electronically searched to collect studies on the influence on antiepileptic drugs on the bone mineral density and bone metabolism in adults from inception to April 1^st, 2018. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed by using RevMan 5.3 software.Results A total of 14 studies were included. The results of meta-analysis showed that: VPA could decline the bone mineral density of lumbar spine (SMD=–0.39, 95%CI –0.65 to –0.13, P=0.003); CBZ (SMD=–0.71, 95%CI –1.08 to –0.33, P=0.000 2) and VPA (SMD=–0.3, 95%CI –0.58 to –0.02, P=0.03) could decline the bone mineral density of femoral neck; CBZ could decline the bone mineral density of total hip (SMD=–0.47, 95%CI –0.84 to –0.10, P=0.01). Serum 25-hydroxy vitamin D₃ was decreased in OXC group (SMD=–0.67, 95%CI –1.28 to –0.05, P=0.03); serum calcium was decreased in CBZ (SMD=–0.49, 95%CI –0.78 to –0.20, P=0.000 8), LEV (SMD=–0.83, 95%CI –1.15 to –0.51, P<0.000 01) and OXC (SMD=–0.48, 95%CI –0.90 to –0.05, P=0.03) group; serum phosphorus was decreased in LEV group (SMD=–11.36, 95%CI –12.97 to –9.76, P<0.000 01). Serum alkaline phosphatase was increased significantly in LEV (SMD=6.79, 95%CI 5.78 to 7.80, P<0.000 01) and CBZ (SMD=1.90, 95%CI 1.35 to 2.44, P<0.000 01) group.Conclusions Current evidence shows that treatment with antiepileptic drugs may be associated with an decreasing bone mineral density and influence bone metabolism in epileptic adults. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusion.

Citation： FAN Danyang, Miao Jie, HOU Yuli, SUN Meizhen. Influence of antiepileptic drugs on bone mineral density and bone metabolism in adults: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2019, 19(2): 189-198. doi: 10.7507/1672-2531.201809077 Copy

1.	Shiek AB, O'Brien TJ, Gorelik A, et al. Bone mineral changes in epilepsy patients during initial years of antiepileptic drug therapy. J Clin Densitom, 2016, 19(4): 450-456.
2.	Albaghdadi O, Alhalabi MS, Alourfi Z, et al. Bone health and vitamin D status in young epilepsy patients on valproate monotherapy. Clin Neurol Neurosurg, 2016, 146: 52-56.
3.	Aksoy D, Guveli BT, Ak PD, et al. Effects of oxcarbazepine and levetiracetam on calcium, ionized calcium, and 25-OH vitamin-D₃ levels in patients with epilepsy. Clin Psychopharmacol Neurosci, 2016, 14(1): 74-78.
4.	董翔. 妥泰对成人癫痫骨代谢的影响研究. 中国医药指南, 2014, 12(35): 112.
5.	陈雪军, 王辉. 左乙拉西坦治疗中老年癫痫全面强直阵挛发作的临床疗效及其对骨密度、骨代谢的影响. 中华医学杂志, 2014, (45): 3548-3551.
6.	Salimipour H, Kazerooni S, Seyedabadi M, et al. Antiepileptic treatment is associated with bone loss: difference in drug type and region of interest. J Nucl Med Tech, 2013, 41(3): 208-211.
7.	郭华爱. 癫痫病及抗癫痫药物对癫痫患者骨密度和骨代谢影响的相关性分析. 天津: 天津医科大学, 2013.
8.	鹿梁燕, 黄志凌. 丙戊酸钠对成年癫痫患者骨代谢的影响. 长治医学院学报, 2012, 26(4): 265-267.
9.	Heo K, Rhee Y, Lee HW, et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia, 2011, 52(10): 1884-1889.
10.	胡海霞. 托吡酯对癫痫患者骨质代谢的影响. 长春: 吉林大学, 2008.
11.	Mintzer S, Boppana P, Toguri J, et al. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia, 2006, 47(3): 510-515.
12.	董必能, 廖卫平, 潘英, 等. 抗癫痫药对成人骨密度的影响. 广州医学院学报, 2003, 31(3): 36-38.
13.	Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology, 2001, 57(3): 445-449.
14.	沈海, 卢宜. 长期服苯妥英钠癫痫患者的骨代谢研究. 中华内分泌代谢杂志, 1990, (2): 69-71.
15.	Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic drug- induced bone loss in young male patients who have seizures. Arch Neurol, 2002, 59(5): 781-786.
16.	Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology, 2002, 58(9): 1348-1353.
17.	Meier C, Kraenzlin ME. Antiepileptics and bone health. Ther Adv Musculoskelet Dis, 2011, 3(5): 235-243.
18.	Nakken KO, Taubøll E. Bone loss associated with use of antiep-ileptic drugs. Expert Opin Drug Saf, 2010, 9(4): 561-571.
19.	Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleve Clin J Med, 2004, 71(2): 42-48.
20.	Shellhaas RA, Joshi SM. Vitamin D and bone health among children with epilepsy. Pediatr Neurol, 2010, 42(6): 385-393.
21.	Pascussi JM, Robert A, Nguyen M, et al. Possible involvement or pregnane X receptor-enhanced CYP 24 expression in drug-induced osteomalacia. J Clin Invest, 2005, 115(1): 177-186.
22.	Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and druginduced osteomalacia. J Clin Invest, 2006, 116(6): 1703-1712.
23.	Cerveny L, Svecova L, Anzenbacherova E, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos, 2007, 35(7): 1032-1041.
24.	Kini U, Adab N, Vinten J, et al. Dysmorphic features: An important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed, 2006, 91(2): 90-95.
25.	Lee HS, Wang SY, Salter DM, et al. The impact of the use of antiepileptic drugs on the growth of children. BMC Pediatr, 2013, 13(1): 211.
26.	Wu S, Legido A, De LF. Effects of valproic acid on longitudinal bone growth. Child Neurol, 2004, 19(1): 26-30.
27.	More C, Bettembuk P, Bhattoa HP. The effects of pregnancy and lactation on bone mineral density. Osteoporos Int, 2001, 12(5): 732-737.
28.	陈艳艳,林卫红. 成人癫痫患者共患躯体疾病的抗癫痫药物选择. 癫痫杂志, 2018, 4(4): 344-350.
29.	冉俊哲, 慕洁. 抗癫痫药物与骨折风险. 癫痫杂志, 2017, 3(5): 401-405.
30.	Nissen-Meyer LS, Svalheim S, Tauboll E, et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia, 2007, 48(10): 1850-1860.
31.	Sayer JA, Pearce SH. Diagnosis and clinical biochemistry of inherited tubulopathies. Biochem, 2001, 38(5): 459-470.
32.	佴玉, 孙旭文. 左乙拉西坦、苯妥英、卡马西平及丙戊酸对骨质影响的风险评估. 中国药物警戒, 2009, 6(11): 648-653.

1. Shiek AB, O'Brien TJ, Gorelik A, et al. Bone mineral changes in epilepsy patients during initial years of antiepileptic drug therapy. J Clin Densitom, 2016, 19(4): 450-456.
2. Albaghdadi O, Alhalabi MS, Alourfi Z, et al. Bone health and vitamin D status in young epilepsy patients on valproate monotherapy. Clin Neurol Neurosurg, 2016, 146: 52-56.
3. Aksoy D, Guveli BT, Ak PD, et al. Effects of oxcarbazepine and levetiracetam on calcium, ionized calcium, and 25-OH vitamin-D₃ levels in patients with epilepsy. Clin Psychopharmacol Neurosci, 2016, 14(1): 74-78.
4. 董翔. 妥泰对成人癫痫骨代谢的影响研究. 中国医药指南, 2014, 12(35): 112.
5. 陈雪军, 王辉. 左乙拉西坦治疗中老年癫痫全面强直阵挛发作的临床疗效及其对骨密度、骨代谢的影响. 中华医学杂志, 2014, (45): 3548-3551.
6. Salimipour H, Kazerooni S, Seyedabadi M, et al. Antiepileptic treatment is associated with bone loss: difference in drug type and region of interest. J Nucl Med Tech, 2013, 41(3): 208-211.
7. 郭华爱. 癫痫病及抗癫痫药物对癫痫患者骨密度和骨代谢影响的相关性分析. 天津: 天津医科大学, 2013.
8. 鹿梁燕, 黄志凌. 丙戊酸钠对成年癫痫患者骨代谢的影响. 长治医学院学报, 2012, 26(4): 265-267.
9. Heo K, Rhee Y, Lee HW, et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia, 2011, 52(10): 1884-1889.
10. 胡海霞. 托吡酯对癫痫患者骨质代谢的影响. 长春: 吉林大学, 2008.
11. Mintzer S, Boppana P, Toguri J, et al. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia, 2006, 47(3): 510-515.
12. 董必能, 廖卫平, 潘英, 等. 抗癫痫药对成人骨密度的影响. 广州医学院学报, 2003, 31(3): 36-38.
13. Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology, 2001, 57(3): 445-449.
14. 沈海, 卢宜. 长期服苯妥英钠癫痫患者的骨代谢研究. 中华内分泌代谢杂志, 1990, (2): 69-71.
15. Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic drug- induced bone loss in young male patients who have seizures. Arch Neurol, 2002, 59(5): 781-786.
16. Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology, 2002, 58(9): 1348-1353.
17. Meier C, Kraenzlin ME. Antiepileptics and bone health. Ther Adv Musculoskelet Dis, 2011, 3(5): 235-243.
18. Nakken KO, Taubøll E. Bone loss associated with use of antiep-ileptic drugs. Expert Opin Drug Saf, 2010, 9(4): 561-571.
19. Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleve Clin J Med, 2004, 71(2): 42-48.
20. Shellhaas RA, Joshi SM. Vitamin D and bone health among children with epilepsy. Pediatr Neurol, 2010, 42(6): 385-393.
21. Pascussi JM, Robert A, Nguyen M, et al. Possible involvement or pregnane X receptor-enhanced CYP 24 expression in drug-induced osteomalacia. J Clin Invest, 2005, 115(1): 177-186.
22. Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and druginduced osteomalacia. J Clin Invest, 2006, 116(6): 1703-1712.
23. Cerveny L, Svecova L, Anzenbacherova E, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos, 2007, 35(7): 1032-1041.
24. Kini U, Adab N, Vinten J, et al. Dysmorphic features: An important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed, 2006, 91(2): 90-95.
25. Lee HS, Wang SY, Salter DM, et al. The impact of the use of antiepileptic drugs on the growth of children. BMC Pediatr, 2013, 13(1): 211.
26. Wu S, Legido A, De LF. Effects of valproic acid on longitudinal bone growth. Child Neurol, 2004, 19(1): 26-30.
27. More C, Bettembuk P, Bhattoa HP. The effects of pregnancy and lactation on bone mineral density. Osteoporos Int, 2001, 12(5): 732-737.
28. 陈艳艳,林卫红. 成人癫痫患者共患躯体疾病的抗癫痫药物选择. 癫痫杂志, 2018, 4(4): 344-350.
29. 冉俊哲, 慕洁. 抗癫痫药物与骨折风险. 癫痫杂志, 2017, 3(5): 401-405.
30. Nissen-Meyer LS, Svalheim S, Tauboll E, et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia, 2007, 48(10): 1850-1860.
31. Sayer JA, Pearce SH. Diagnosis and clinical biochemistry of inherited tubulopathies. Biochem, 2001, 38(5): 459-470.
32. 佴玉, 孙旭文. 左乙拉西坦、苯妥英、卡马西平及丙戊酸对骨质影响的风险评估. 中国药物警戒, 2009, 6(11): 648-653.

Chinese Journal of Evidence-Based Medicine

Influence of antiepileptic drugs on bone mineral density and bone metabolism in adults: a meta-analysis

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