Effects of Second-Generation Antiepileptic Drugs Compared to First-Generation Antiepileptic Drugs on Bone Metabolism in Patients with Epilepsy: A Meta-Analysis

Abstract

We conducted this meta-analysis to evaluate effects of second-generation anti-epileptic drugs (AEDs; levetiracetam, lamotrigine) compared to first-generation AEDs (valproic acid, carbamazepine) on bone metabolism in epilepsy patients. PubMed, Web of Science, Clinical trials.gov, Wanfang, and China national knowledge infrastructure databases were searched. Ten trials were included. Results showed: (1) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LEV versus first-generation AEDs were 1.00 (95% CI=0.23–1.77, Z=2.56, p=0.01), 0.98 (95% CI=− 0.05 to 2.01, Z=1.86, p=0.06), − 1.17 (95% CI=− 2.08 to − 0.25, Z=2.50, p=0.01), 0.07 (95% CI=− 0.14 to 0.27, Z=0.63, p=0.53), respectively. (2) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LTG versus first-generation AEDs were −0.16 (95% CI=− 0.47 to 0.16, Z=0.99, p=0.32), −0.05 (95% CI=− 0.55 to 0.44, Z=0.22, p=0.83), 0.10 (95% CI=− 0.53 to 0.73, Z=0.31, p=0.75), −0.05 (95% CI=− 0.52 to 0.42, Z=0.22, p=0.83), respectively. Overall, our results indicate that compared to first-generation AEDs, LEV has less adverse effects on blood bone metabolism markers in epilepsy patients, while LTG does not. However, due to small number of included studies, our results warrant additional research.

Key words

antiepileptic drugs - epilepsy - therapy - bone metabolism

• References

• 1 Stafstrom CE, Carmant L. Seizures and epilepsy: An overview for neuroscientists. Cold Spring Harb Perspect Med 2015; 5 pii a022426
• 2 Fisher RS, Acevedo C, Arzimanoglou A. et al. ILAE official report: A practical clinical definition of epilepsy. Epilepsia 2014; 55: 475-482
• 3 Guerreiro CA. Epilepsy: Is there hope?. Indian J Med Res 2016; 144: 657-660
• 4 Moshé SL, Perucca E, Ryvlin P. et al. Epilepsy: New advances. Lancet 2015; 385: 884-898
• 5 Zeng K, Wang X, Xi Z. et al. Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients. Clin Neurol Neurosurg 2010; 112: 291-295
• 6 Souverein PC, Webb DJ, Petri H. et al. Incidence of fractures among epilepsy patients: A populationbased retrospective cohort study in the General Practice Research Database. Epilepsia 2005; 46: 304-310
• 7 Lazzari AA, Dussault PM, Thakore-James M. et al. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy-Antiepileptic drug and osteoporosis prevention trial. Epilepsia 2013; 54: 1997-2004
• 8 Farhat G, Yamout B, Mikati MA. et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58: 1348-1353
• 9 Shiek Ahmad B, 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: 450-456
• 10 Koch HU, Kraft D, von Herrath D. et al. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972; 13: 829-834
• 11 Feldkamp J, Becker A, Witte OW. et al. Long‑term anticonvulsant therapy leads to low bone mineral density-Evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast‑like cells. Exp Clin Endocrinol Diabetes 2000; 108: 37-43
• 12 Fan HC, Lee HS, Chang KP. et al. The impact of anti-epileptic drugs on growth and bone metabolism. Int J Mol Sci 2016; 17 pii E1242
• 13 Abes M, Sarihan H, Madenci E. Evaluation of bone mineral density with dual X-ray absorptiometry for osteoporosis in children with bladder augmentation. J Pediatr Surg 2003; 38: 230-232
• 14 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
• 15 Zhang Y, Zheng YX, Zhu JM. et al. Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: A meta-analysis. J Zhejiang Univ Sci B 2015; 16: 611-621
• 16 Shen C, Chen F, Zhang Y. et al. Association between use of antiepileptic drugs and fracture risk: A systematic review and meta-analysis. Bone 2014; 64: 246-253
• 17 Fraser LA, Burneo JG, Fraser JA. Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review. Epilepsy Res 2015; 116: 59-66
• 18 Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother 2010; 10: 119-140
• 19 Abou-Khalil B. Benefit-risk assessment of levetiracetam in the treatment of partial seizures. Drug Saf 2005; 28: 871-890
• 20 Lee R, Lyles K, Sloane R. et al. The association of newer anticonvulsant medications and bone mineral density. Endocr Pract 2012; 1-22
• 21 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6: e1000097
• 22 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12
• 23 Fu J, Chen Y. The efficacy and safety of 5 mg/d Vortioxetine compared to placebo for major depressive disorder: A meta-analysis. Psychopharmacology (Berl) 2015; 232: 7-16
• 24 Wells G, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Health Research Institute 2010 Available at http://www.evidencebasedpublichealth.de/download/Newcastle_Ottowa_Scale_Pope_Bruce.pdf
• 25 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557-560
• 26 Hakami T, O'Brien TJ, Petty SJ. et al. Monotherapy with Levetiracetam Versus Older AEDs: A randomized comparative trial of effects on bone health. Calcif Tissue Int 2016; 98: 556-565
• 27 Li Wang, Lin Chen, Hui Zhao. et al. Effect of levetiracetam on bone metabolism and cognitive function in children with epilepsy. Guizhou Med J. 2017; 41: 722-724
• 28 Miao Liu, Rong Wang, Lilin Xie. et al. Effects of Valproic acid and Levetiracetam as a monotherapy on bone metabolism in preschoolers and school-age children with epilepsy. Chin J Appl Clin Pediatr 2017; 32: 944-946
• 29 El-Haggar SM, Mostafa TM, Allah HMS. et al. Levetiracetam and lamotrigine effects as mono- and polytherapy on bone mineral density in epileptic patients. Arq Neuropsiquiatr 2018; 76: 452-458
• 30 Li J, Liu W. Effects of carbamazepine and levetiracetam on blood lipid and bone metabolism in epilepsy patients. Neural Injury Funct Reconst 2018; 13: 260-262
• 31 Qiu H. Clinical efficacy of levetiracetam for the treatment of generalized tonic clonic seizures in elderly patients with epilepsy and its effect on bone mineral density and bone metabolism. Front Med 2017; 79: 131
• 32 Gao L, Wang L, Yan J. et al. Effects of levetiracetam and carbamazepine on quality of life and bone metabolism in newly diagnosed epilepsy patients. Chin J Integ Med Cardio/Cerebrovasc Dis 2017; 15: 3069-3072
• 33 Liu Y, Chen S, Liu L. et al. Effects of levetiracetam and carbamazepine on neurocognitive function and bone metabolism in newly diagnosed epilepsy patients. Modern J Integ Trad Chin Western Med 2016; 25: 1978-1979
• 34 Kim SH, Lee JW, Choi KG. et al. A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy. Epilepsy Behav 2007; 10: 291-295
• 35 Pack AM, Morrell MJ, Randall A. et al. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008; 70: 1586-1593
• 36 Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Clevel Clin J Med 2004; 71: S42-S48
• 37 Pack AM. The association between antiepileptic drugs and bone disease. Epilepsy Curr 2003; 3: 91-95
• 38 Petty SJ, O’Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos Int 2007; 18: 129-142
• 39 von Borstel Smith M, Crofoot K, Rodriguez-Proteau R. et al. Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells. Toxicol In Vitro 2007; 21: 855-862
• 40 Lee RH, Lyles KW, Colón-Emeric C. A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother 2010; 8: 34-46
• 41 Valsamis HA, Arora SK, Labban B. et al. Antiepileptic drugs and bone metabolism. Nutr Metab (Lond) 2006; 3: 36
• 42 Haria M, Balfour JA. Levetiracetam. CNS Drugs 1997; 7: 159-164
• 43 Nissen-Meyer LS, Svalheim S, Taubøll E. et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia 2007; 48: 1850-1860
• 44 Serin HM, Koç ZP, Temelli B. et al. The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine. Epilepsy Behav 2015; 51: 221-224
• 45 Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr (Phila) 1999; 38: 93-98
• 46 Shiek Ahmad B, 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: 450-456
• 47 Rahimdel A, Dehghan A, Moghadam MA. et al. Relationship between Bone Density and Biochemical Markers of Bone among Two Groups Taking Carbamazepine and Sodium Valproate for Epilepsy in Comparison with Healthy Individuals in Yazd. Electron Phys 2016; 8: 3257-3265
• 48 Andress DL, Ozuna J, Tirschwell D. et al. Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol 2002; 59: 781-786
• 49 Jette N, Lix LM, Metge CJ. et al. Association of antiepileptic drugs with nontraumatic fractures: A population-based analysis. Arch Neurol 2011; 68: 107-112
• 50 Guo CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001; 42: 1141-1147
• 51 Sheth RD, Hermann BP. Bone mineral density with lamotrigine monotherapy for epilepsy. Pediatr Neurol 2007; 37: 250-254
• 52 Pack AM, Morrell MJ, Marcus R. et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol 2005; 57: 252-257