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June 7, 2004

Antiepileptic drug use increases rates of bone loss in older women
A prospective study

June 8, 2004 issue
62 (11) 2051-2057

Abstract

Objective: To test the hypothesis that older women with antiepileptic drug (AED) use have increased rates of bone loss.
Methods: AED use was ascertained and calcaneal and hip bone mineral density (BMD) measured in a cohort of 9,704 elderly community-dwelling women enrolled in the Study of Osteoporotic Fractures, and they were followed prospectively for changes in BMD. Current use of AED was assessed by interview, with verification of use from medication containers at baseline and follow-up examinations. Women were classified as continuous users, partial (intermittent) users, or nonusers. Rates of change in BMD were measured at the total hip and two subregions (average 4.4 years between examinations) and at the calcaneus (average 5.7 years between examinations).
Results: After adjustment for confounders, the average rate of decline in total hip BMD steadily increased from −0.70%/year in nonusers to −0.87%/year in partial AED users to −1.16%/year in continuous AED users (p value for trend = 0.015). Higher rates of bone loss were also observed among continuous AED users at subregions of the hip and at the calcaneus. In particular, continuous phenytoin users had an adjusted 1.8-fold greater mean rate of loss at the calcaneus compared with nonusers of AED (−2.68 vs −1.46%/year; p < 0.001) and an adjusted 1.7-fold greater mean rate of loss at the total hip compared with nonusers of AED (−1.16 vs −0.70%/year; p = 0.069).
Conclusions: Continuous AED use in elderly women is associated with increased rates of bone loss at the calcaneus and hip. If unabated, the rate of hip bone loss among continuous AED users is sufficient to increase the risk of hip fracture by 29% over 5 years among women age 65 years and older.

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References

1.
Ensrud KE, Blackwell TL, Mangione CM, et al. Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc. 2002; 50: 1629–1637.
2.
Ensrud KE, Blackwell TL, Mangione CM, et al. Central nervous system-active medications and risk for fractures in older women. Arch Intern Med. 2003; 163: 949–957.
3.
Tannirandorn P, Epstein S. Drug-induced bone loss. Osteoporos Int. 2000; 11: 637–659.
4.
Dent CE, Richens A, Rowe DJ, Stamp TC. Osteomalacia with long-term anticonvulsant therapy in epilepsy. Br Med J. 1970; 4: 69–72.
5.
Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, Fuleihan GE. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002; 58: 1348–1353.
6.
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.
7.
Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case controlled study. Seizure. 1999; 8: 339–342.
8.
Valimaki MJ, 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.
9.
Cummings SR, Black DM, Nevitt MC, et al., for the Study of Osteoporotic Fractures Research Group. Appendicular bone density and age predict hip fracture in women. JAMA. 1990; 263: 665–668.
10.
Veterans Affairs Medication Classification System. In: United States Pharmacopeia dispensing information (USPDI), vol. 1, appendix VII. 22nd ed. Greenwood Village, CO: Micromedix Thompson Healthcare, 2002: 3033–3050.
11.
Steiger P, Cummings SR, Black DM, Spencer NE, Genant HK. Age-related decrements in bone mineral density in women over 65. J Bone Miner Res. 1992; 7: 625–632.
12.
Ensrud KE, Palermo L, Black DM, et al. Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures. J Bone Miner Res. 1995; 10: 1778–1787.
13.
Cummings SR, Block G, McHenry K, et al. Evaluation of two food frequency methods of measuring dietary calcium intake. Am J Epidemiol. 1987; 126: 796–802.
14.
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986; 5: 165–173.
15.
Lohman TG, Roche AF, Mavtorell R. Anthropometric standardization reference manual. Champaign, IL: Human Kinetics Books, 1988: 177.
16.
Nevitt MC, Johnell O, Black DM, Ensrud KE, Genant HK, Cummings SR. Bone mineral density predicts non-spine fractures in very elderly women. Osteoporosis Int. 1994; 4: 325–331.
17.
Kubota F, Kifune A, Shibata N, et al. Bone mineral density of epileptic patients on long-term antiepileptic drug therapy: a quantitative digital radiography study. Epilepsy Res. 1999; 33: 93–97.
18.
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.
19.
Bohannon AD, Hanlon JT, Landerman R, Gold DT. Association of race and other potential risk factors with nonvertebral fractures in community-dwelling elderly women. Am J Epidemiol. 1999; 149: 1002–1009.
20.
Vestergaard P, Tigaran S, Rejnmark L, et al. Fracture risk is increased in epilepsy. Acta Neurol Scand. 1999; 99: 269–275.
21.
Cummings SR, Nevitt MC, Browner WS, et al., for the Study of Osteoporotic Fractures Research Group. Risk factors for hip fracture in white women. N Engl J Med. 1995; 332: 767–773.
22.
Heller HJ, Sakhaee K. Anticonvulsant-induced bone disease. Arch Neurol. 2001; 58: 1352–1353.
23.
Wasnich RD, Ross PD, Vogel JM, Davis JW. Bone mineral measurements. In: Osteoporosis critique and practicum. Honolulu: Banyan Press, 1989: 125.
24.
Hahn TJ, Birge SJ, Scarp CR, Avioli LV. Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest. 1972; 51: 741–748.
25.
Weinstein RS, Bryce GF, 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.
26.
Bell RD, Pak CYC, Zersekh J, Barilla DE, Vaski M. Effect of phenytoin on bone and vitamin D metabolism. Ann Neurol. 1979; 5: 374–378.
27.
Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002; 43: 1488–1492.
28.
Ohta T, Wergedal J, Gruber H, Baylink D, Lau K-HW. Low dose phenytoin is an osteogenic agent in the rat. Calcif Tissue Int. 1995; 56: 42–48.
29.
Nakade O, Baylink DJ, Lau K-HW. Phenytoin at micromolar concentrations is an osteogenic agent for human-mandible-derived bone cells in vitro. J Dent Res. 1995; 74: 331–337.
30.
Feldkamp J, Becker A, Witte OW, Scharif 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.
31.
Isojarvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllyla VV. Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol. 1990; 47: 670–676.
32.
Hauser WA. Epidemiology of seizures in the elderly. In: Rowan AJ, Ramsey RE, eds. Seizures and epilepsy in the elderly. Boston: Butterworth-Heinemann, 1997: 7–20.
33.
Lackner TE. Strategies for optimizing antiepileptic drug therapy in elderly people. Pharmacotherapy. 2002; 22: 329–364.
34.
Looker AC, Orwoll ES, Johnston CC, et al. Prevalence of low femoral bone density in older U. S. adults from NHANES III. J Bone Miner Res. 1997; 12: 1761–1771.
35.
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.

Information & Authors

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Published In

Neurology®
Volume 62Number 11June 8, 2004
Pages: 2051-2057
PubMed: 15184613

Publication History

Received: June 24, 2003
Accepted: January 12, 2004
Published online: June 7, 2004
Published in issue: June 8, 2004

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Authors

Affiliations & Disclosures

K. E. Ensrud, MD MPH
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.
T. S. Walczak, MD
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.
T. Blackwell, MA
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.
E. R. Ensrud, MD
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.
P. J. Bowman, MPH
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.
K. L. Stone, PhD
From the Department of Medicine and Center for Chronic Disease Outcomes Research (Dr. K.E. Ensrud), VA Medical Center, and Division of Epidemiology (Dr. K.E. Ensrud, P.J. Bowman), School of Public Health, University of Minnesota, Minnesota Comprehensive Epilepsy Program (Dr. Walczak), and Noran Neurological Clinic (Dr. E.R. Ensrud), Minneapolis, MN; and Department of Epidemiology and Biostatistics (T. Blackwell and K.L. Stone), University of California, San Francisco.

Notes

Address correspondence and reprint requests to Dr. K.E. Ensrud, Department of Medicine 111-0, VA Medical Center, One Veterans Dr., Minneapolis, MN 55417; e-mail: [email protected]

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Cited By
  1. Aging, Menopause, and Bone Health in Women with Epilepsy, Women with Epilepsy, (306-321), (2024).https://doi.org/10.1017/9781009006903.019
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  2. Chapter 7. Depression: A Major, Unrecognized Risk Factor for Osteoporosis?, Medical and Psychiatric Comorbidity Over the Course of Life, (129-153), (2024).https://doi.org/10.1176/appi.books.9781615377671.lg07
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  3. Phenytoin regulates osteogenic differentiation of human bone marrow stem cells by PI3K/Akt pathway, Regenerative Therapy, 24, (201-210), (2023).https://doi.org/10.1016/j.reth.2023.06.015
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  4. Assessment of bone mineral density in epileptic patients with long-term antiepileptic therapy: pilot data, V.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY, 57, 4, (75-89), (2023).https://doi.org/10.31363/2313-7053-2023-859
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  5. Liver enzyme inducing anticonvulsant drug use is associated with prevalent vertebral fracture, Osteoporosis International, 34, 10, (1793-1798), (2023).https://doi.org/10.1007/s00198-023-06820-9
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  8. Prevalence of anticonvulsant-induced vitamin D deficiency, Epilepsy and paroxysmal conditions, 14, 3, (304-315), (2022).https://doi.org/10.17749/2077-8333/epi.par.con.2022.117
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  9. Analysis of trends and factors determining initial antiseizure medication choice for epilepsy in Taiwan, Seizure, 93, (145-153), (2021).https://doi.org/10.1016/j.seizure.2021.10.020
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  10. The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density, Drugs, 81, 16, (1831-1858), (2021).https://doi.org/10.1007/s40265-021-01625-8
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