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. 妥泰對成人癲癇骨代謝的影響研究. 中國醫藥指南, 2014, 12(35): 112.
5.	陳雪軍, 王輝. 左乙拉西坦治療中老年癲癇全面強直陣攣發作的臨床療效及其對骨密度、骨代謝的影響. 中華醫學雜志, 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.	郭華愛. 癲癇病及抗癲癇藥物對癲癇患者骨密度和骨代謝影響的相關性分析. 天津: 天津醫科大學, 2013.
8.	鹿梁燕, 黃志凌. 丙戊酸鈉對成年癲癇患者骨代謝的影響. 長治醫學院學報, 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. 托吡酯對癲癇患者骨質代謝的影響. 長春: 吉林大學, 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, 廖衛平, 潘英, 等. 抗癲癇藥對成人骨密度的影響. 廣州醫學院學報, 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, 盧宜. 長期服苯妥英鈉癲癇患者的骨代謝研究. 中華內分泌代謝雜志, 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, Taub?ll 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.	陳艷艷,林衛紅. 成人癲癇患者共患軀體疾病的抗癲癇藥物選擇. 癲癇雜志, 2018, 4(4): 344-350.
29.	冉俊哲, 慕潔. 抗癲癇藥物與骨折風險. 癲癇雜志, 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, 孫旭文. 左乙拉西坦、苯妥英、卡馬西平及丙戊酸對骨質影響的風險評估. 中國藥物警戒, 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. 妥泰對成人癲癇骨代謝的影響研究. 中國醫藥指南, 2014, 12(35): 112.
5. 陳雪軍, 王輝. 左乙拉西坦治療中老年癲癇全面強直陣攣發作的臨床療效及其對骨密度、骨代謝的影響. 中華醫學雜志, 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. 郭華愛. 癲癇病及抗癲癇藥物對癲癇患者骨密度和骨代謝影響的相關性分析. 天津: 天津醫科大學, 2013.
8. 鹿梁燕, 黃志凌. 丙戊酸鈉對成年癲癇患者骨代謝的影響. 長治醫學院學報, 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. 托吡酯對癲癇患者骨質代謝的影響. 長春: 吉林大學, 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, 廖衛平, 潘英, 等. 抗癲癇藥對成人骨密度的影響. 廣州醫學院學報, 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, 盧宜. 長期服苯妥英鈉癲癇患者的骨代謝研究. 中華內分泌代謝雜志, 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, Taub?ll 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. 陳艷艷,林衛紅. 成人癲癇患者共患軀體疾病的抗癲癇藥物選擇. 癲癇雜志, 2018, 4(4): 344-350.
29. 冉俊哲, 慕潔. 抗癲癇藥物與骨折風險. 癲癇雜志, 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, 孫旭文. 左乙拉西坦、苯妥英、卡馬西平及丙戊酸對骨質影響的風險評估. 中國藥物警戒, 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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