Can Antiepileptics (Anticonvulsants) Increase the Risk of Osteoporosis?

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Q&A 122.5 Can antiepileptics (anticonvulsants) increase the risk of osteoporosis?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 2nd December 2014

Background Antiepileptics drugs (AEDs) are the most common treatment for epilepsy – a disease characterised by recurrent seizures (1). AEDs include the enzyme inducing antiepileptic drugs: phenytoin, phenobarbitone, primidone and carbamazepine, and the non-enzyme inducing antiepileptic drugs: lamotrigine, gabapentin, topiramate, tiagabine, valproate and levetiracetam (2).

Osteoporosis is a progressive, systemic, skeletal disease, which is characterised by a decrease in bone mineral density (BMD) and an increase in bone fragility and fracture risk. Osteoporosis is asymptomatic and usually presents only after a bone fracture, which commonly occurs after a fall from a height equal to, or less than, that of an ordinary chair (3). Treatment with AEDs has been associated with serious side effects on bone health although these appear difficult to confirm as other factors need to be considered e.g. fractures from falls during seizures; AEDs causing drowsiness and co- ordination problems, particularly in elderly patients, which can lead to falls and fractures; lack of exposure to sunlight, limited physical activity and poor nutrition in patients with epilepsy who are hospitalised or institutionalised (1).

Answer The Summary of Product Characteristics (SPC) for several AEDs highlight possible associations with bone related adverse events. There have been reports of decreased bone mineral density (BMD), osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine, eslicarbazepine, lamotrigine, oxcarbazepine, phenytoin, phenobarbital and sodium valproate. The mechanism for how this occurs has not been identified (4-10). Osteomalacia is regarded as a rare side effect of primidone (11). Chronic metabolic acidosis with topiramate and zonisamide increases the risk of renal stone formation and may potentially lead to osteopenia (12, 13). The effect of topiramate on bone-related sequelae has not been systematically investigated in paediatric or adult populations (12).

AEDs are thought to affect bone health through disturbance of mineral metabolism and acceleration of bone turnover mechanisms (14). Phenytoin, phenobarbitone, primidone, carbamazepine, oxcarbazepine, sodium valproate and topiramate may decrease serum calcium levels and cause other changes in calcium and bone formation leading to poor bone accrual in children and accelerated bone breakdown in adults (15). Enzyme inducing AEDs have been shown to reduce BMD (15) and may have a more of an effect on bone than non-enzyme inducing AEDs (1). Studies investigating the newer, non-enzyme inducing antiepileptic drugs (lamotrigine, gabapentin, topiramate and tiagabine) have shown either a reduction in BMD or no significant changes in bone health (1). Limited clinical study data for lamotrigine indicates that BMD is not affected (1, 15). The data for the effect of levetiracetam monotherapy on BMD are conflicting. One study indicates that osteoporosis and osteopenia can develop after chronic use (4.4 years) while two shorter studies (14 and 27 months) did not draw the same conclusion (15). Similarly with topiramate, small studies have shown either a reduction in BMD or no significant abnormalities (1).

Changes in BMD can occur after short term use e.g. 1 year with phenytoin and phenobarbitone (15). Generally the fracture risk increases with cumulative duration of AED use. Treatment with more than one AED is thought to have an increased detrimental effect on bone health compared to monotherapy, although results are conflicting. No specific combination of AEDs has a greater risk than others. There is a strong association for increased fracture risk with an exposure duration of 12 years or more (1).

Available through NICE Evidence Search at www.evidence.nhs.uk 1

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A retrospective cohort study has found that newer non-enzyme inducing AEDs (gabapentin, lamotrigine and topiramate) are less likely to be associated with osteoporosis at the lumbar spine, femoral neck and total hip (16).

A literature review on the relationship between AED therapy and bone disease in 2013 concluded that AEDs have been associated with increased fracture risk, rickets in children, decreased bone mineral density, osteopenia and osteoporosis. The relative risk of osteoporosis with AEDs varies from 1.7 to 3.8 (1).

In 2009 the Medicines Healthcare and Regulatory Agency (MHRA) highlighted the effects of AEDs on bone and advised all healthcare professionals that long term treatment with phenytoin, carbamazepine, primidone and sodium valproate are associated with decreased bone mineral density, which may lead to osteopenia, osteoporosis and increased fractures, particularly in the following at risk patients;

 those who are immobilised for long periods  those who have inadequate sun exposure  those with inadequate dietary calcium intake (17).

The National Institute for Clinical Excellence (NICE) clinical guideline for management of epilepsy recommends monitoring vitamin D levels and other measures of bone health and bone metabolism, including serum calcium and alkaline phosphatase every 2-5 years for all patients taking enzyme inducing drugs (18).

Vitamin D supplementation should be considered in at risk patients who receive long term treatment with primidone, phenytoin, carbamazepine, phenobarbital and sodium valproate (17, 18).

Summary  There have been reports of decreased bone mineral density (BMD), osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine, phenytoin, phenobarbital and sodium valproate.  The data for levetiracetam and topiramate is mixed so there is insufficient information to establish a definitive conclusion. Further studies are necessary with these agents. Lamotrigine does not appear to be associated with effects on bone.  AEDs are thought to affect bone health through disturbance of mineral metabolism and acceleration of bone turnover mechanisms.  The MHRA have advised all healthcare professionals that long term treatment with phenytoin, carbamazepine, primidone and sodium valproate are associated with decreased bone mineral density, which may lead to osteopenia, osteoporosis and increased fractures.  NICE recommends monitoring vitamin D levels and other measures of bone health and bone metabolism, including serum calcium and alkaline phosphatase every 2-5 years for all patients taking enzyme inducing drugs for epilepsy.  Vitamin D supplementation should be considered in all at risk patients who receive long term treatment with primidone, phenytoin, carbamazepine, phenobarbital and sodium valproate.

Limitations This document only considers the risk of osteoporosis in patients with epilepsy taking antiepileptics and does not consider other indications associated with antiepileptic drug use.

References (1) Beerhorst K, van der Kruijs SJM et al. Bone disease during chronic antiepileptic drug therapy: General versus specific risk factors. Journal of the Neurological Sciences 2013; 331: 19-25. (2) Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press; November 2014. Accessed 10/11/14 via http://www.medicinescomplete.com (3) NICE Technology appraisal guidance 160. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the primary prevention of osteoporotic fragility fractures in

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postmenopausal women. National Institute for Health and Clinical Excellence. October 2008, amended Jan 2011. Accessed via http://www.nice.org.uk/nicemedia/live/11746/47176/47176.pdf (4) Summary of Product Characteristics. Tegretol tablets 100mg, 200mg, 400mg. Novartis Pharmaceuticals UK Limited. Last updated 6 June 2014. (5) Summary of Product Characteristics. Zebinix 800mg tablets. Eisai Ltd. Last updated 6 Nov 2014. (6) Summary of Product Characteristics. Lamictal. GlaxoSmithKline UK. Last updated 8 April 2014. (7) Summary of Product Characteristics. Trileptal 150 mg, 300 mg, 600 mg Film-coated tablets. Novartis Pharmaceuticals UK Limited Last updated 1 August 2013. (8) Summary of Product Characteristics. Phenytoin Sodium Flynn Hard Capsules 25mg, 50mg, 100mg and 300mg. Flynn Pharma Limited. Last updated 30 April 2014 (9) Summary of Product Characteristics. Phenobarbital Actavis Tablets BP 60mg. Actavis UK Ltd. Last updated 14 Jan 2014. (10) Summary of Product Characteristics. Epilim 200 Gastro resistant tablets. Sanofi. Last updated 2 Oct 2014. (11) Summary of Product Characteristics. Primidone 250mg tablets. Serb Laboratories. Last updated 18 August 2014. (12) Summary of Product Characteristics. Topiramate 100 mg film-coated Tablets. Sandoz Limited. Last updated 5 Aug 2014. (13) Summary of Product Characteristics. Zonegran 25, 50, 100 mg Hard Capsules. Eisai Limited. Last updated 8 Oct 2013. (14) Hamed SA, Moussa EMM et al. Bone status in patients with epilepsy: relationship to markers of bone remodelling. Frontiers in Neurology 2015; 5: 142. doi; 10.3389/fneur.2014.00142 (15) Gaitatzis A, Sander JW. The long term safety of antiepileptic drugs. CNS Drugs 2013; 27: 435-55 (16) Salimipour H, Kazerooni S et al. Antiepileptic treatment is associated with bone loss: difference in drug type and region of interest. Journal of Nuclear Medicine Technology 2013; 41: 208-211. (17) Medicines Healthcare and Regulatory Agency (MHRA). Anti-epileptics: Adverse effects on bone. Drug Safety Update. April 2009; Volume 2: Issue 9. Page 2. (18) NICE Guidance. CG137: The Epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. January 2012. Accessed via http://www.nice.org.uk/nicemedia/live/13635/57779/57779.pdf

Quality Assurance Prepared by Katie Smith, East Anglia Medicines Information Service (based on earlier work by Vicky Gibson)

Date Prepared 2 December 2014

Checked by Sarah Cavanagh, East Anglia Medicines Information Service

Date of check 9 December 2014

Search strategy.  BNF online, November 2014, search terms = antiepileptics, osteoporosis  NHS Evidence, search terms = osteoporosis, antiepileptics  NICE, search term = osteoporosis  Cochrane library, search terms = antiepileptics, osteoporosis  Electronic Medicines Compendium http://emc/medicines.org.uk, search terms = carbamazepine, eslicarbazepine, oxcarbazepine, ethosuximide, gabapentin, pregabalin, lacosamide, lamotrigine, levetiracetam, perampanel, phenobarbitone, primidone, phenytoin, retigabine, rufinamide, tiagabine, topiramate, sodium valproate, vigabatrin, zonisamide  Embase: search terms = 1. exp ANTICONVULSIVE AGENT/ae [ae=Adverse Drug Reaction] 2. exp OSTEOPOROSIS/ 3. exp BONE DENSITY/

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4. 1 AND 2 [Limit to: Human and English Language and Publication Year 2012-2014]

5. exp ANTICONVULSIVE AGENT/ae AND exp OSTEOPOROSIS [Limit to: Human and English Language and Publication Year 2012-2014] 6. exp CARBAMAZEPINE/ae [Limit to: Human and English Language and Publication Year 2012- 2014] 7. exp ESLICARBAZEPINE/ae [Limit to: Human and English Language and Publication Year 2012- 2014] 8. exp OXCARBAZEPINE/ae [Limit to: Human and English Language and Publication Year 2012- 2014] 9. exp ETHOSUXIMIDE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 10. exp GABAPENTIN/ae [Limit to: Human and English Language and Publication Year 2012-2014] 11. exp PREGABALIN/ae [Limit to: Human and English Language and Publication Year 2012-2014] 12. exp HARKOSERIDE/ae [Limit to: Human and English Language and Publication Year 1312-2014] 14. exp LAMOTRIGINE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 15. exp ETIRACETAM/ae [Limit to: Human and English Language and Publication Year 2012-2014] 16. exp PERAMPANEL/ae [Limit to: Human and English Language and Publication Year 2012-2014] 17. exp PHENOBARBITAL/ae [Limit to: Human and English Language and Publication Year 2012- 2014] 18. exp PRIMIDONE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 19. exp PHENYTOIN/ae [Limit to: Human and English Language and Publication Year 2012-2014] 20. exp RETIGABINE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 21. exp RUFINAMIDE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 22. exp TIAGABINE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 23. exp TOPIRAMATE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 24. exp VALPROIC ACID/ae [Limit to: Human and English Language and Publication Year 2012- 2014] 25. exp VIGABATRIN/ae [Limit to: Human and English Language and Publication Year 2012-2014] 26. exp ZONISAMIDE/ae [Limit to: Human and English Language and Publication Year 2012-2014] 27. 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 [Limit to: Human and English Language and Publication Year 2012-2014] 28. 2 AND 27 [Limit to: Human and English Language and Publication Year 2012-2014] 29. 3 AND 27 [Limit to: Human and English Language and Publication Year 2012-2014]  Medline: search terms = 1. exp ANTICONVULSANTS/ae [ae=Adverse Effects] AND exp OSTEOPOROSIS/ [Limit to: English Language and Humans and Publication Year 2012-2014] 2. exp CARBAMAZEPINE/ae [Limit to: English Language and Humans and Publication Year 2012- 2014] 3. ESLICARBAZEPINE.ti,ab [Limit to: English Language and Humans and Publication Year 2012- 2014] 4. OXCARBAZEPINE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 5. exp ETHOSUXIMIDE/ae [Limit to: English Language and Humans and Publication Year 2012-2014] 6. GABAPENTIN.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 7. PREGABALIN.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 8. LACOSAMIDE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 9. LAMOTRIGINE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 10. LEVETIRACETAM.ti,ab [Limit to: English Language and Humans and Publication Year 2012- 2014] 11. PERAMPANEL.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 12. exp PHENOBARBITAL/ae [Limit to: English Language and Humans and Publication Year 2012- 2014] 13. exp PRIMIDONE/ae [Limit to: English Language and Humans and Publication Year 2012-2014] 14. exp PHENYTOIN/ae [Limit to: English Language and Humans and Publication Year 2012-2014] 15. RETIGABINE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 16. RUFINAMIDE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 17. TIAGABINE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014]

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18. TOPIRAMATE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 19. exp VALPROIC ACID/ae [Limit to: English Language and Humans and Publication Year 2012- 2014] 20. exp VIGABATRIN/ae [Limit to: English Language and Humans and Publication Year 2012-2014] 21. ZONISAMIDE.ti,ab [Limit to: English Language and Humans and Publication Year 2012-2014] 22. 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 [Limit to: English Language and Humans and Publication Year 2012- 2014] 23. MEDLINE; 1 AND 22 [Limit to: English Language and Humans and Publication Year 2012-2014]  IDISweb: search terms = "ANTICONVULSANTS 28120000" AND "OSTEOPOROSIS 733.0" "CARBAMAZEPINE 28122007" AND "OSTEOPOROSIS 733.0" "ESLICARBAZEPINE 28122041" AND "OSTEOPOROSIS 733.0" "OXCARBAZEPINE 28122011" AND "OSTEOPOROSIS 733.0" "ETHOSUXIMIDE 28121601" AND "OSTEOPOROSIS 733.0" "GABAPENTIN 28122020" AND "OSTEOPOROSIS 733.0" "PREGABALIN 28122016" AND "OSTEOPOROSIS 733.0" "LACOSAMIDE 28122045" AND "OSTEOPOROSIS 733.0" "LAMOTRIGINE 28122024" AND "OSTEOPOROSIS 733.0" "LEVETIRACETAM 28122040" AND "OSTEOPOROSIS 733.0" "PERAMPANEL 92000354" AND "OSTEOPOROSIS 733.0" "PHENOBARBITAL 28120405" AND "OSTEOPOROSIS 733.0" "PRIMIDONE 28120407" AND "OSTEOPOROSIS 733.0" "PHENYTOIN 28120805" AND "OSTEOPOROSIS 733.0" "EZOGABINE 28122039" AND "OSTEOPOROSIS 733.0" "RUFINAMIDE 28122002" AND "OSTEOPOROSIS 733.0" "TIAGABINE 28122034" AND "OSTEOPOROSIS 733.0" "TOPIRAMATE 28122035" AND "OSTEOPOROSIS 733.0" "VALPROIC ACID 28122015" AND "OSTEOPOROSIS 733.0" "VIGABATRIN 44100020" AND "OSTEOPOROSIS 733.0" "ZONISAMIDE 28122004" AND "OSTEOPOROSIS 733.0"