Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy [RETRACTED]

Satō, Yoshihiro; Kondo, Izumi; Ishida, Shohei; Motooka, Hiromichi; Takayama, Kenji; Tomita, Yoshihito; Maeda, Hitoshi; Satoh, K.

doi:10.1212/wnl.57.3.445

Cited by 260 publications

(200 citation statements)

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“…A number of reports describe adverse effects in women receiving VPA, including reproductive (Isojarvi et al, 1993;Duncan, 2001;O'Donovan et al, 2002) and endocrine (Rattya et al, 2001) disorders, obesity (Luef et al, 2002) and a decrease in bone mass (Sato et al, 2001). We demonstrate that VPA and TSA, known deacetylase inhibitors, clear ERa from, and preclude oestrogen signalling in all ERa positive cell lines evaluated.…”

Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 55%

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

et al. 2005

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Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-a (ERa), resulting in subsequent clearance of ERa protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERa positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERa mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERa expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERa from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERa, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

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Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 55%

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

et al. 2005

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“…We have demonstrated significant abnormalities of bone metabolism, characterized by reduced BMD, reduced 25OHD, and increased AP. Previous studies have related these findings to chronic use of AEDs 5,6,11,12 . Serum levels of calcium and PTH were normal and similar to the control group.…”

Section: Discussionmentioning

confidence: 68%

“…The AED in common use are carbamazepine (CBZ), phenytoin (DPH), phenobarbitone (PB), sodium valproate (VPA), primidone (PRM), lamotrigina (LTG) and the benzodiazepines, clobazan (CLB) and clonazepan (CZP). The chronic use of AED can affect bone and mineral metabolism [2][3][4][5][6] . Studies indicate that 20 to 60% of AED users can develop rickets or osteomalacia, especially among older and institutionalized patients.…”

Section: Palavras-chave: Drogas Antiepiléticas Indutoras Hepáticas 2mentioning

confidence: 99%

“…The other mechanism of the AEDs involves a direct action on bone cells, increasing bone resorption and formation. In this way, the AED may influence bone turnover 4,5,13 . Both mechanisms can be associated with a reduction in bone mineral density (BMD) 5,6,11,12 .…”

Section: Palavras-chave: Drogas Antiepiléticas Indutoras Hepáticas 2mentioning

confidence: 99%

“…In this way, the AED may influence bone turnover 4,5,13 . Both mechanisms can be associated with a reduction in bone mineral density (BMD) 5,6,11,12 . Furthermore, DPH interferes with cation transport in many tissues, directly inhibits intestinal calcium transport and together with PB has been shown to inhibit vitamin D-mediated calcium absorption.…”

Section: Palavras-chave: Drogas Antiepiléticas Indutoras Hepáticas 2mentioning

confidence: 99%

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Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs

Kulak

Borba

Bilezikian

et al. 2004

Arq. Neuro-Psiquiatr.

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-The aim of this cross sectional study was to evaluate bone mineral density (BMD) and serum levels of 25-hydroxy vitamin D (25OHD) in a group of patients taking antiepileptic drugs (AED) for a seizure disorder. Between May-2001 and January-2003, we evaluated 58 patients (40 women/18 men), 34.4+6 years old living in Curitiba or in its metropolitan area, on antiepileptic therapy for 2 to 38 years (10 on monotherapy /48 on multiple drugs regime). The group was matched by age, gender, and bone mass index to 29 healthy subjects (20 women/ 9 men); 34.2+5.9 years old. Medical history and physical exam were performed on all subjects with particular information sought about fractures and risks factors for osteoporosis. Blood samples were collected for total serum calcium, albumin, phosphorus, creatinine, total alkaline phosphatase, and liver function tests. BMD of the lumbar spine, femur and forearm was determined by dual energy X-ray absorptiometry (DXA, Hologic QDR 1000). Between February and April-2003, other blood samples were collected to measure 25OHD, intact paratohormone (PTH) and calcium. Unemployment and smoking history were more frequent among patients than among controls (p<0.05). Fifteen patients had a fracture history, all of which occurred during a seizure. The BMD of the lumbar spine (0.975+0. 13 g/cm 2 vs. 1.058+0.1 g/cm 2 ; p<0.03) and of the total femur (0.930+0.1 g/cm 2 vs. 0.988+0.12 g/cm 2 ; p<0.02) was lower in patients than in controls. In 63.5% of patients and in 24.1 % of controls a T-score < -1.0 in at least one site was seen. The AED users had higher total alkaline phosphatase and lower 25OHD (p<0.02). No correlations between BMD and 25OHD were found. The use of phenytoin was correlated with a greater incidence of fractures (RR: 2.38). We conclude that patients on chronic use of AED have alterations in bone metabolism characterized in this study by lower BMD of the lumbar spine and total femur and lower serum concentrations of 25OHD.KEY WORDS: Enzyme-inducing antiepileptic drugs, 25OH vitamin D, osteomalacia. Densidade mineral óssea e níveis séricos de 25 OH vitamina D em usuários crônicos de drogas antiepilépticasRESUMO -O objetivo deste estudo transversal foi avaliar a densidade mineral óssea (DMO) e os níveis de 25hidroxi vitamina D (25OHD) em um grupo de pacientes com epilepsia e usuários crônicos de drogas antiepilépticas (DAE). Entre maio-2001 e janeiro-2003 avaliamos 58 pacientes (40 mulheres/18 homens) residentes em Curitiba ou região metropolitana da cidade, com média de idade 34,4+6 anos e tempo de tratamento entre 2 e 38 anos (10 em monoterapia/48 em politerapia). O grupo de pacientes foi emparelhado por idade, sexo e índice de massa corpórea com 29 indivíduos aparentemente sadios (20 mulheres/9 homens; 34,2+5,9 anos). Pacientes e controles foram submetidos a anamnese e exame clínico, com ênfase na história de fraturas e fatores de risco para osteoporose. Nas visitas foram coletadas amostras de sangue para dosagens de cálcio, albumina, fósforo, creatinina, fosfatase alcalin...

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Updates on the Treatment of Epilepsy in Women

et al. 2004

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Epilepsy is a condition of the central nervous system that is characterized by recurrent seizures. The goal of management is to make patients seizure free without intolerable adverse effects from treatment. Men and women differ in their physiologic makeup and therefore have different needs that must be considered when attempting to attain this goal. There are special concerns for women of child-bearing years with regard to contraception, pregnancy, and teratogenicity that should be considered during counseling and selection of appropriate treatment. There are also emerging concerns about the interaction of antiepileptic drugs and endocrine function that can affect ovarian function, induce polycystic ovary (PCO)-like syndrome, and threaten fertility. Systemic adverse effects can have a negative impact on weight, cosmetic appearance, sexual function, and bone health. Individualized treatment coupling antiepileptic drug use and the specific phase of impact of the reproductive cycle must be considered in treatment selection. Important concerns regarding long-term therapy are being raised as there are more treatment options to consider because of the plethora of new antiepileptic drugs that are available, often with more favorable pharmacokinetics and different adverse event profiles. Also, sex hormone fluctuations during maturation may exacerbate seizures at particular points during the life cycle for women, including menarche, during menses, during pregnancy, or later in the perimenopausal years, often presenting a uniquely challenging aspect to treatment. As the number of available treatment options for epilepsy increases, the optimal goal for primary care physicians is to work as a team with obstetricians, gynecologists, and neurologists in an effort to ensure the best treatment of women with epilepsy.

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Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy [RETRACTED]

Abstract: Long-term VPA monotherapy can increase bone resorption, leading to decreased BMD.

Cited by 260 publications

References 16 publications

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs

Updates on the Treatment of Epilepsy in Women

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