Bone mineral density measured by dual-energy X-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs

Välimäki, Matti; Tiihonen, Mikko; Laitinen, Kalevi; Tähtelä, Riitta; Kärkkäinen, Merja; Lamberg‐Allardt, Christel; Mäkelä, Pekka; Tunninen, Riitta

doi:10.1002/jbmr.5650090507

Cited by 162 publications

(57 citation statements)

References 36 publications

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“…2,3 In contrast, other clinical studies have not found significant changes in BMD or abnormalities in mineral metabolism in patients receiving carbamazepine and thus are consistent with our results. [17][18][19] There were no demographic differences between the phenytoin and carbamazepine groups that could account for our observation, excepting that there were fewer white women in the phenytoin group. However, the racial composition of the phenytoin group was diverse and no racial group predominated.…”

mentioning

confidence: 58%

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Pack

Morrell²,

Randall³

et al. 2008

Neurology

151

102

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Objective-Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in pre-menopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin.Methods-Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year.Results-Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling.Conclusion-In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy.Antiepileptic drug (AED) treatment has adverse effects on bone and mineral metabolism that may ultimately increase the risk of fracture. 1 Most studies of AED effects on bone and mineral metabolism are cross-sectional. Of the few longitudinal studies, some revealed bone loss in children and adults as well as changes in indices of bone and mineral metabolism. [2][3][4][5] None have evaluated the effects of individual AEDs.We previously reported results of a cross-sectional study of bone mineral density (BMD) and indices of bone and mineral metabolism in premenopausal women with epilepsy taking Herein, we report our findings in women treated with one of four AEDs in monotherapy followed up for 1 year. Given the biochemical evidence of increased turnover at baseline in women receiving phenytoin, we hypothesized that there would be more bone loss in this group. METHODS SubjectsPremenopausal women with epilepsy (n = 147) aged between 18 and 40 years and with normal menstrual cycles participated in the study. Subjects were enrolled at Stanford University (n = 83) or Columbia University (n = 64) between September 1997 and January 2004. Baseline data on the first 93 subjects enrolled were published previously. 6 Of the 147 subjects, ...

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confidence: 58%

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Pack

Morrell²,

Randall³

et al. 2008

Neurology

151

102

View full text Add to dashboard Cite

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“…Previous studies assumed that one of the mechanism for bone loss by AEDs promoted the catabolism of 25(OH) D and 1,25(OH) D. [23][24][25] The resulting decrease in serum 25(OH) D and 1,25(OH) D levels leads to reduced calcium absorption, with consecutive secondary hyperparathyroidism, increased bone resorption, and accelerated bone loss. 26) In support of this hypothesis, several clinical studies have reported the elevation of serum PTH levels 27) and the reduction of serum 25(OH) D levels in patients treated with enzyme-inducing AEDs. 28) In contrast to this finding, several studies have observed no significant differences in these parameters.…”

Section: Discussionmentioning

confidence: 90%

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Kanda

Izumo

Kobayashi

et al. 2017

Biological & Pharmaceutical Bulletin

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Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a longterm administration of gabapentin should be regularly monitored for changes in bone mass.Key words gabapentin; levetiracetam; osteoblast; osteoclast; rat Epilepsy is a chronic neurological disorder characterized by recurrent seizures. 1) Pharmacotherapy with antiepileptic drugs (AEDs) is the mainstay of treatment for epilepsy and is effective in the prevention of seizures. Patients with epilepsy usually require long-term treatment with AEDs; thus, the prevention of side effects is important in the continuation of medication.The bone is a metabolically active organ that undergoes continuous remodeling from bone resorption by osteoclasts and bone formation by osteoblasts.2) Under healthy conditions, the balance between bone formation and bone resorption is always uniform; thus, bone strength and bone mass are maintained. Certain pathological states and drugs affect normal bone remodeling, which can induce skeletal disorders, such as osteopenia or osteoporosis.3) A serious side effect associated with long-term administration of AEDs is the elevated risk of bone fracture owing to a decrease in bone mass.4-7) Patients taking AEDs are approximately 2-6 times more at risk of bone fracture than healthy individuals are. 8,9) Previous studies have demonstrated that treatment with phenytoin decreased bone mineral density (BMD) owing to enhanced bone resorption.10,11) Currently, new...

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“…2 Evidence linking phenytoin (EIAED) [3][4][5][6][7] and phenobarbital (EIAED) 4,5 to lower bone mineral density (BMD) is generally consistent with this theory. However, carbamazepine (EIAED) [6][7][8][9][10] has not been associated with lower BMD, while valproic acid (nonenzyme-inducing AED [NEIAED]) 3,7-9 has been associated with lower BMD. Thus, multiple mechanisms underlying AEDrelated bone loss appear to exist, and all types of AED are potentially implicated.…”

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confidence: 89%

Antiepileptic drug use and rates of hip bone loss in older men

Ensrud¹,

et al. 2008

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Objective: To test the hypotheses that older community dwelling men taking non-enzymeinducing antiepileptic drugs (NEIAEDs) and those taking enzyme-inducing antiepileptic drugs (EIAEDs) have increased rates of hip bone loss. Methods:We ascertained antiepileptic drug (AED) use (interviewer-administered questionnaire with verification of use by containers) and measured hip bone mineral density (BMD) (using dual energy x-ray absorptiometry) at baseline and an average of 4.6 years later in a cohort of 4,222 older community-dwelling men enrolled in the Osteoporotic Fractures in Men study. Men were categorized as nonusers (no AED use at either examination, n ϭ 4060), NEIAED user (use of NEIAED only at either examination, n ϭ 100), or EIAED user (use of EIAED only at either examination, n ϭ 62). Results:After adjustment for multiple potential confounders (age, race, clinic site, health status, pain interfering with work or activity, physical activity, smoking status, alcohol use, total calcium intake, diabetes, chronic kidney disease, vitamin D supplement use, bisphosphonate use, selective serotonin reuptake inhibitor use, inability to rise from a chair, body mass index, and baseline BMD), the average rate of decline in total hip BMD was Ϫ0.35%/year among nonusers compared with Ϫ0.53%/year among NEIAED users (p ϭ 0.04) and Ϫ0.46%/year among EIAED users (p ϭ 0.31). Multivariable adjusted rate of loss was Ϫ0.60%/year among men taking NEIAED at both examinations, Ϫ0.51%/year among men taking NEIAED at one examination only, and Ϫ0.35%/ year among nonusers (p for trend ϭ 0.03). Findings were similar at hip subregions. Conclusion:Use of non-enzyme-inducing antiepileptic drugs was independently associated with increased rates of hip bone loss in this cohort of older community-dwelling men. Antiepileptic drug (AED) use may be associated with higher rates of bone loss because AED use may have adverse effects on bone metabolism. 1 On the other hand, AED use may be a marker of factors such as poor health, medical conditions, lifestyle behaviors, and neuromuscular impairments that are associated with greater rates of bone loss. Thus, an apparent association between AED use and bone loss might be due to these confounding factors rather than an effect of AED use.

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Bone mineral density measured by dual-energy X-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs

Cited by 162 publications

References 36 publications

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Antiepileptic drug use and rates of hip bone loss in older men

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