Effect of antiepileptic drugs on bone density in ambulatory patients
Abstract
Background: Long-term antiepileptic drug (AED) use causes multiple abnormalities in calcium and bone metabolism that have been most extensively described in institutionalized patients. The objective is to determine the effect of AED on vitamin D levels and bone density in ambulatory patients and to compare the effects of enzyme-inducing and -noninducing AED and of single vs multiple therapy on bone density.
Methods: A cross-sectional evaluation was conducted of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months who presented to neurologists at a tertiary referral center. Bone mineral density (BMD) as well as serum 25 hydroxy–vitamin D (25-OHD) levels were measured. A detailed questionnaire assessing calcium intake as well as previous and current intake of antiepileptic medications was administered to all patients.
Results: Over 50% of adults and children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD. Antiepileptic therapy decreased BMD in adults. Generalized seizures, duration of epilepsy, and polypharmacy were significant determinants of BMD, more so at skeletal sites enriched in cortical bone. Subjects on enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primidone tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, and ethosuximide.
Conclusion: Epilepsy and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (farhat.doc)
- Download
- 29.00 KB
References
1.
Tolman KG, Jubiz W, Sannella JJ, et al. Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children. Pediatrics . 1975; 56: 45–51.
2.
Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad JG. Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med . 1975; 292: 550–553.
3.
Richens A, Rowe DJF. Disturbance of calcium metabolism by anticonvulsant drugs. BMJ . 1970; 4: 73–76.
4.
Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial. BMJ . 1973; 4: 695–701.
5.
Hahn TJ, Bridge SJ, Scarp CR, Avioli LV. Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest . 1972; 51: 741–748.
6.
Weinstein RS, Bryce FG, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab . 1984; 58: 1003–1009.
7.
Corradino R. Diphenylhydantoin: direct inhibition of the vitamin D3-mediated calcium absorptive mechanism in organ-cultured duodenum. Biochem Pharmacol . 1976; 25: 863–864.
8.
Mosekilde L, Christensen SC, Lund B, Sorensen OH, Melsen F. The interrelationships between serum 25-hydroxycholcalciferol, serum parathyroid hormone and bone changes in anticonvulsant osteomalacia. Acta Endocrinol . 1977; 84: 559–565.
9.
Sotaniemi EA, Hakkarainen HK, Puranen JA, Lahti RO. Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy. Ann Intern Med . 1972; 77: 389–394.
10.
Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr . 1995; 127: 256–262.
11.
Akin R, Okutan V, Sarici U, Altunbas A, Gokcay E. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol . 1998; 19: 129–131.
12.
Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure . 1999; 8: 339–342.
13.
Kubota F, Kifune A, Shibata N, et al. Bone mineral density of epileptic patients on long-term antiepileptic drug therapy: a quantitative digital radiographic study. Epilepsy Res . 1999; 33: 93–97.
14.
Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12. Clin Pediatr . 1999; 38: 93–98.
15.
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: 445–449.
16.
Valimaki MT, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual energy X-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res . 1994; 9: 631–637.
17.
McKenna MJ, Freaney R. Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D. Osteoporos Int . 1998; 8 (suppl): S3–S6.
18.
El-Hajj Fuleihan G, Testa M, Angell J, Porrino N, LeBoff MS. Reproducibility of DXA densitometry: a model for bone loss estimates. J Bone Miner Res . 1995; 10: 1004–1014.
19.
Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res . 1994; 9: 1137–1141.
20.
Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology . 2001; 56: 1445–1452.
21.
NIH consensus conference. Optimal calcium intake. NIH consensus development panel on optimal calcium intake. JAMA 1994;272:1942–1948.
22.
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: 212–216.
23.
Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. QJM . 1986; 59: 569–577.
24.
Holloway L, Paulson A, Seale C, Morell MJ, Marcus R. Skeletal status of women with epilepsy. J Bone Miner Res . 2000; 15 (suppl 1): SA302.Abstract.
25.
El-Hajj Fuleihan G, Nabulsi M, Choucair M, et al. Hypovitaminosis D in healthy school children. Pediatrics . 2001; 107: 1–7.
26.
El-Hajj Fuleihan G, Deeb M. Hypovitaminosis D in a sunny country. N Engl J Med . 1999; 340: 1840–1841. Letter.
27.
Feldkamp J, Becker A, Witte OW, Scharff D, Scherbaum WA. 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.
28.
Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med . 1990; 112: 352–364.
29.
Cohen A, Lancman M, Mogul H, Marks S, Smith K. Strategies to protect bone mass in the older patients with epilepsy. Geriatrics . 1997; 52: 70–81.
30.
Nashef L, Lamb E. Guidelines are needed for treating diseases of bone metabolism in epilepsy. BMJ . 1999; 318: 1285.Letter.
31.
Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol . 2001; 58: 1369–1374.
32.
Heller HJ, Sakhaee K. Anticonvulsant-induced bone disease. A plea for monitoring and treatment. Arch Neurol . 2001; 58: 1352–1353.
Information & Authors
Information
Published In
Neurology®
Volume 58 • Number 9 • May 14, 2002
Pages: 1348-1353
Copyright
© 2002.
Publication History
Received: September 27, 2001
Accepted: January 20, 2002
Published online: May 14, 2002
Published in print: May 14, 2002
Authors
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Initial treatment of epilepsy with antiepileptic drugs, Neurology, 63, 10_suppl_4, (S30-S39), (2023)./doi/10.1212/WNL.63.10_suppl_4.S30
- Metabolic concerns associated with antiepileptic medications, Neurology, 63, 10_suppl_4, (S24-S29), (2023)./doi/10.1212/WNL.63.10_suppl_4.S24
- Effect of antiepileptic drugs on bone density in ambulatory patients, Neurology, 62, 2, (342-342), (2023)./doi/10.1212/WNL.62.2.342-a
- Menopause and bone density issues for women with epilepsy, Neurology, 61, 6_suppl_2, (S16-S22), (2023)./doi/10.1212/WNL.61.6_suppl_2.S16
- Progressive bone deficit in epilepsy, Neurology, 70, 3, (170-176), (2023)./doi/10.1212/01.wnl.0000284595.45880.93
- Epilepsy care in nursing facilities: Knowledge gaps and opportunities, Epilepsy & Behavior, 138, (108997), (2023).https://doi.org/10.1016/j.yebeh.2022.108997
- How do the top 10 known offending drug classes associated with decreased bone mineral density affect total shoulder arthroplasty outcomes?, Journal of Shoulder and Elbow Surgery, 32, 5, (1009-1015), (2023).https://doi.org/10.1016/j.jse.2022.11.006
- The Impact of Epilepsy on Complication Rates After Total Joint Arthroplasty: A Propensity Score–Matched Cohort Study, The Journal of Arthroplasty, 38, 2, (209-214.e1), (2023).https://doi.org/10.1016/j.arth.2022.08.022
- Drug-nutrition interactions, Encyclopedia of Human Nutrition, (79-92), (2023).https://doi.org/10.1016/B978-0-12-821848-8.00012-3
- Evaluation of the effect of antiepileptic drugs on mandibular bone quality by fractal analysis, Oral Radiology, 39, 3, (563-569), (2023).https://doi.org/10.1007/s11282-023-00671-0
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to get full access to it.
This article by Farhat et al [1] poses the question: Do antiepileptic drugs and in particular chronicity of use gave rise to an altered bone mineral density? The use of the American database as a control group may flaw this study and invaladate the implication set out in the conclusion; that the differences found are due to antiepileptic medication. The population in Beirut is very different to the Database and without firstly validating the database in Beirut we should be very cautious as to suggest differences found relate to epilepsy or antiepileptic drugs. Secondly you found a significant correlation between duration years of AED's and BMD. Was this corrected for age?, if not this alone could account for the difference.
References
1). Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients Neurology 2002; 58: 1348-1353.
One of the primary end-points chosen in our study is bone mineral density (BMD), because it is a very powerful predictor of fracture risk as demonstrated in many cross-sectional and longitudinal studies from the US and Europe. Although we have demonstrated in a population-based study that peak BMD is slightly lower in Lebanese compared to American subjects, we have warned against the use of the local database until validated. [1] It is for those reasons that we avoided the use of a local database in our study. [2]
Firstly, the WHO definition of osteoporosis using bone mineral density (BMD) derived T-scores only applies to Western Caucasian BMD databases [3], the database in which the WHO T-score cut-offs were established, and the population in whom the BMD-fracture relationship is validated. No such validation is yet available in our population, and although we are in the process of conducting such study, until its results are available, the use of local databases would be flawed. Indeed, it is for these reasons that the International Osteoporosis Foundation (IOF) recommends the use of established universal databases. [4]
Secondly, it is reasonable to expect the BMD-fracture relationship is the same in Caucasians whether they are American, European or Lebanese. In fact, the IOF recommends the American NHANES III database as an international reference for hip T-score calculation and fracture risk estimates. [4] Furthermore, we have demonstrated mean BMD in Lebanese and American patients with hip fractures to be very similar. [5]
Thirdly, let us consider applying the approach suggested by McCorry to the cholesterol-coronary artery disease analogy in our population. Lebanese subjects have higher mean cholesterol level than western counterparts. The argument presented by McCorry would imply that we should adjust the universally recognized NCEP cholesterol thresholds for intervention upwards taking into local "normative databases". This would be an unwarranted.
Contrary to what McCorry suggested, the inverse relationship in adults between BMD at the total body, total hip and trochanter and duration of anti-epileptic drug therapy is not due to age. The R values we reported between these variables varied between –0.38—0.45 and exceeded those known to correlate BMD and age, in the age range studied. In our study, the correlation between age and BMD was weaker and only significant at the trochanter. Finally, linear regression analyses revealed that duration of anti-epileptic drug use, and not age, was a significant correlate of BMD at the three skeletal sites.
The results and conclusions presented in our study are indeed solid and justified. However, as we discussed, the ultimate evidence for understanding the impact of epilepsy and antiepileptic drugs on skeletal health would only be attained by conducting randomized trials. [2]
References
1. El-Hajj Fuleihan G, Baddoura R, Awada H, Salam N, Salamoun M, Rizk P. Low peak bone mineral density in healthy Lebanese subjects. Bone 2002; 31:520-8.
2. Farhat G, Yamout B, Mikati MA, Demirjian S, Saway R, El-Hajj Fuleihan G. Effect of antiepilectic drugs on bone density in ambulatory patients. Neurology 2002;58: 1348-1353.
3. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis Report of a WHO study group. WHO technical report series 1994; 843:1-129.
4. Kanis JA, Gluer CC for the Committee of Scientific Advisors, International Osteoporosis Foundation. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporos Int 2000; 11: 192-202.
5. El-Hajj Fuleihan G, Badra M, Tayim A, Makari M, Salamoun M, Afeiche N, Baddoura O, Boulos S, Haidar R, Lakkis S, Musharrafieh R, Nsouli A, Taha A. Lebanese patients with hip fractures are relatively young, but have osteoporosis. J Bone Miner Res 2001; Suppl 1: Abstract M 337.