Bone Mineral Changes in Epilepsy Patients During Initial Years of Antiepileptic Drug Therapy

doi:10.1016/j.jocd.2016.07.008

Journal of Clinical Densitometry

Volume 19, Issue 4, October 2016, Pages 450-456

https://doi.org/10.1016/j.jocd.2016.07.008 Get rights and content

Abstract

Antiepileptic drug (AED) therapy is associated with decreased bone mineral density; however, the time course for this development is unclear. The aim of this study was to evaluate bone mineral changes during the initial years of AED therapy in AED-naive, newly diagnosed epilepsy patients compared with non-AED users. In 49 epilepsy patients newly started on AEDs and in 53 non-AED users of both genders, bone mineral density (BMD) and bone mineral content were measured using dual-energy X-ray absorptiometry at baseline (within the first year of therapy) and at least 1 yr later. Bone changes between the 2 assessments, adjusted for age, height, and weight, were calculated as the annual rate of change. The median duration of AED therapy was 3.5 mo at baseline and 27.6 mo at follow-up. No overall difference was found in mean BMD and bone mineral content measures between user and nonuser cohorts in both cross-sectional baseline and the annual rate of change (p > 0.05). However, users on carbamazepine monotherapy (n = 11) had an increased annual rate of total hip (−2.1% vs −0.8%, p = 0.020) and femoral neck BMD loss (−2.1% vs −0.6%, p = 0.032) compared to nonusers. They also had a marginally higher rate of femoral neck BMD loss (−2.1%, p = 0.049) compared with valproate (−0.1%, n = 13) and levetiracetam users (+0.6%, n = 13). During the initial years of AED treatment for epilepsy, no difference was found in bone measures between AED users as a group and nonuser cohorts. However, the data suggested that carbamazepine monotherapy was associated with increased bone loss at the hip regions, compared to users of levetiracetam or valproate and nonusers. Larger studies of longer duration are warranted to better delineate the bone effects of specific AEDs, with further consideration of the role of early dual-energy X-ray absorptiometry scanning and careful AED selection in potentially minimizing the impact on bone health in these patients.

Introduction

Associations between antiepileptic drug (AED) therapy, bone disease, and increased fracture rates are well recognized 1, 2. Associations have also been reported between AED use and changes in bone mineral measures 3, 4, 5, but bone changes in the initial years of therapy (6) have had little research focus.

Some AEDs, particularly older drugs (7) and perhaps enzyme inducers 3, 8, may affect bone measures more than others, although the evidence is inconsistent and lacking direct comparative studies (9). Several different mechanisms that have been invoked for the adverse bone effects of AEDs may be relevant, including hepatic cytochrome P450 enzyme induction, direct effects on bone cells, and impaired calcium absorption 10, 11.

When, and at which sites, AED therapy may begin to exert a measurable effect on bone metabolism is unclear. Measuring bone mineral density (BMD) at the clinically important sites for fracture risk in axial or peripheral bones in new AED users is needed to obtain this information. Moreover, any differences in early bone effects between various AED types could be important in guiding AED treatment choices.

Importantly, researching newly diagnosed epilepsy patients may potentially minimize confounding effects of related comorbidities, lifestyle factors, and multiple drug exposures associated with longer-term epilepsy 12, 13. The present study aimed to evaluate a cohort of newly diagnosed epilepsy patients recently started on AEDs compared to AED nonusers by comparing longitudinal changes in bone measures using dual-energy X-ray absorptiometry (DXA).

Section snippets

Protocol Approval and Patient Consent

Melbourne Health Human Research Ethics Committee (HREC) approved the study (HREC 2002.232). All participants provided written informed consent.

Newly Treated AED Users

Patients attending the “First Seizure Clinic” at the Royal Melbourne Hospital who were diagnosed by a neurologist to have epilepsy, confirmed by investigations including electroencephalography, and within the first year of AED therapy initiation (any type) were invited to participate upon being referred by clinicians not otherwise involved in the study

Cohort

Sixty-seven AED users and 57 nonusers participated at baseline, and of these, 49 (73%) users and 53 (93%) nonusers completed the follow-up, with 18 (27%) users and 4 (7%) nonusers failing to complete the follow-up.

Eighteen users did not complete the follow-up for the following reasons: pregnancy (1), untraceable (2), discontinued AED use or history of AED-free interval between assessments (7), death (1), migration overseas (1), withdrawal from or failure to attend the follow-up visit (5), and

Discussion

The present study of epilepsy patients newly treated with AEDs and of AED nonusers is one of the few prospective investigations into a potential association between early AED use and changes in bone measures.

The results suggest that a clinically significant association may exist. No cross-sectional or longitudinal differences in bone measures at the various bone regions examined were found for the AED user group compared to the nonuser group. However, greater bone loss at the hip regions was

Acknowledgments

The authors are grateful to all who have been involved with the University of Melbourne Bone and Epilepsy Research Program at the Department of Medicine, The Royal Melbourne Hospital. We would like to thank the research participants for their invaluable contributions throughout the study; Dr Raju Yera and other neurologists at the outpatient epilepsy clinic RMH who helped with participant recruitment; Dr Marian Todaro and Ms Mary Sakellarides who contributed to the baseline recruitment and

References (34)

S.H. Kim et al.
A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy
Epilepsy Behav
(2007)
R.H. Lee et al.
A review of the effect of anticonvulsant medications on bone mineral density and fracture risk
Am J Geriatr Pharmacother
(2010)
S. Khanna et al.
Insights into liaison between antiepileptic drugs and bone
Drug Discov Today
(2009)
R.M. Angus et al.
A simple method for assessing calcium intake in Caucasian women
J Am Diet Assoc
(1989)
D.L. Koo et al.
Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy
Epilepsy Res
(2013)
S.A. Beniczky et al.
Bone mineral density in adult patients treated with various antiepileptic drugs
Seizure
(2012)
N. Triantafyllou et al.
Effect of long-term valproate monotherapy on bone mineral density in adults with epilepsy
J Neurol Sci
(2010)
C. Ecevit et al.
Effect of carbamazepine and valproate on bone mineral density
Pediatr Neurol
(2004)
P.S. Espinosa et al.
Association of antiepileptic drugs, vitamin D, and calcium supplementation with bone fracture occurrence in epilepsy patients
Clin Neurol Neurosurg
(2011)
B. Shiek Ahmad et al.
Falls and fractures in patients chronically treated with antiepileptic drugs
Neurology
(2012)

S.J. Petty et al.

Effect of antiepileptic medication on bone mineral measures

Neurology

(2005)

A.M. Pack et al.

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

Neurology

(2008)

K.E. Ensrud et al.

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

Neurology

(2004)

L.D. Carbone et al.

Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the Women's Health Initiative (WHI)

J Bone Miner Res

(2010)

M.J. Valimaki 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)

M.J. Brodie et al.

Enzyme induction with antiepileptic drugs: cause for concern?

Epilepsia

(2013)

K.E. Ensrud et al.

Antiepileptic drug use and rates of hip bone loss in older men: a prospective study

Neurology

(2008)

Cited by (17)

A retrospective comparative fractal and radiomorphometric analysis of the effect of 3 generations of anti-epileptic drugs on the mandible
2023, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
The present study investigated the possible impacts of anti-epileptic drugs (AEDs) on trabecular and cortical bone in the mandible.
Fractal dimension (FD) and the radiomorphometric parameters of mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) were assessed on 497 dental panoramic radiographs (DPRs) of patients in the case group and controls. AEDs were compared according to 3 generations, duration of use, and patient age and sex.
FD of the angle and body of the mandible and MCW were significantly lower in the case group than in the control group (P < .001). FD values in the ramus and angle were lower in first-generation and third-generation AEDs than in second-generation drugs (P ≤ .011). FD in the mandibular body was lower in first-generation and second-generation AED users than in third-generation drugs (P = .017). Drug use for at least 1 year resulted in significantly lower values for all FDs and MCW values and more class 3 MCI assessments than short-duration use, but PMI was higher with more than 1 year of AED use (P ≤ .020). Age and sex had no significant effects.
AEDs caused significant changes in bone compared with controls in some FD values, MCW, and MCI. The effect of drug generation is pronounced in trabecular bone. Anti-epileptic drug use for more than 1 year had a greater effect than short-term use.
The effects of antiepileptic drugs on bone health: A systematic review
2021, Epilepsy Research
Citation Excerpt :
Some authors, however, have noted the possible association of diminished BMD loss with higher osteocalcin levels (known marker of bone formation) with LTG use (Kim et al., 2007). Two articles also showed that VPA (a NEIAED) had minimal BMD reduction with Z-scores similar to control groups (Salimipour et al., 2013; Triantafyllou et al., 2010) however, others conflicted (Hakami et al., 2016; Kumandas et al., 2006; Shiek Ahmad et al., 2016). Other individual AEDs were reported less often and with inconsistent data regarding BMD loss.
Epilepsy may be treated with antiepileptic drugs (AEDs), which have been reported to decrease bone mineral density (BMD). Current data is conflicting and variable, and little is known with regard to how duration of AED use or specific AEDs, such as CYP-450 enzyme-inducing (EIAEDs) versus non-enzyme inducing (NEIAEDs) drugs affect BMD. We sought to systematically review BMD changes due to AED use to identify trends in reporting.
A literature search via Medline (PubMed), EMBASE, and Cochrane databases was performed. Peer-reviewed articles were identified that reported on BMD measurements in conjunction with AEDs.
Twenty-six studies met inclusion criteria. Long-term therapy was shown across multiple, well-controlled studies to have the most significant BMD loss. Carbamazepine had the most frequent reporting of unfavorable effects on bone health and Lamotrigine seemed to show the most bone-protective qualities. Serum biochemical markers of bone turnover did not significantly correlate with measured BMD changes.
The present study provides evidence that long-term AED therapy is the most significant risk factor for BMD loss. Furthermore, there was little compelling evidence to support that EIAEDs, as a class, were more harmful to bone than NEIAEDs, which has been previously suggested in multiple studies. Early clinical concern for significant loss of BMD may not be warranted as lower BMD was less likely to be observed during the initial years of AED therapy. Furthermore, serum markers of bone turnover are not clinically reliable in assessing BMD changes in patients taking AEDs.
Micronutrient supplementation needs more attention in patients with refractory epilepsy under ketogenic diet treatment
2021, Nutrition
This study evaluated the adequacy of micronutrient intake from the ketogenic diet (KD) with and without micronutrient supplementation according to age in Brazilian children and adolescents with refractory epilepsy undergoing KD treatment.
This study enrolled children and adolescents with refractory epilepsy who were up to 19 y of age. Nutrient intakes were monitored using 3 d food records before introducing micronutrient supplementation and 3 mo after starting KD treatment. The prevalence of micronutrient inadequacy was estimated by sex and age according to the estimated average requirement cutoff values.
This study included 39 children and adolescents. The KD did not provide enough content of folate, calcium, and magnesium in all patients according to the dietary reference intake. Even after starting supplementation, calcium, phosphorus, and magnesium intake remained inadequate in the majority of patients. The supplementation effectively met the vitamin B₁₂ recommendation in all age groups.
KD treatment did not provide adequate levels of the monitored micronutrients. The supplementation improved but did not prevent the inadequacy of micronutrients such as calcium, magnesium, and phosphorus. The results highlight the importance of individual supplementation protocols and the need to monitor micronutrient intake according to age and sex.
Effects of valproic acid on bone mineral density and bone metabolism: A meta-analysis
2019, Seizure
Numerous studies have shown that the risk of fracture is increased by long-term antiepileptic drugs (AEDs). Valproic acid (VPA) is one of the most commonly used AEDs. In this meta-analysis, we aimed to assess the effects of VPA on bone mineral density (BMD) and bone metabolism.
PubMed, Embase, Cochrane and Web of Science databases were searched from inception to January 2019 for articles focusing on the effects of VPA on BMD and bone metabolism in adults or children. A meta-analysis was performed using RevMan 5. 3 software.
18 studies were included in the meta-analysis. The BMD of lumber spine (MD= −0.06, 95%CI: −0.09 to −0.03, P < 0.0001) and femoral neck (MD= −0.05, 95% CI= −0.08 to −0.01, P = 0.02) was markedly decreased in the VPA group compared to healthy controls. Serum bone-specific alkaline phosphatase (BALP) level (SMD = 0.85, 95% CI: 0.30–1.40, P = 0.002) was notably increased in the VPA group compared to healthy groups. In the child group, the serum parathyroid hormone (PTH) level was higher than in healthy groups (SMD= -0.22, 95% CI: −0.40 to −0.04, P = 0.02); besides, the serum 25-hydroxy vitamin D3 (25(OH)D3) level was decreased (SMD= -0.22, 95% CI: −0.40 to −0.04, P = 0.02), while no significant alteration of these parameters was noted in the adult VPA group (P ≥ 0.05).
VPA may reduce the BMD of lumbar spine and femoral neck in patients with epilepsy while increasing the serum BALP level. Serum PTH level are increased and serum 25(OH)D3 level decreased in children with epilepsy treated with VPA. These parameters were unaltered in adults.
The anti-epileptic drugs valproate, carbamazepine and levetiracetam cause bone loss and modulate Wnt inhibitors in normal and ovariectomised rats
2018, Bone
Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post-menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa β-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone.
Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients
2024, Journal of Bone and Mineral Metabolism

View all citing articles on Scopus

View full text

Original ArticleBone Mineral Changes in Epilepsy Patients During Initial Years of Antiepileptic Drug Therapy

Abstract

Introduction

Section snippets

Protocol Approval and Patient Consent

Newly Treated AED Users

Cohort

Discussion

Acknowledgments

Epilepsy Behav

Am J Geriatr Pharmacother

Drug Discov Today

J Am Diet Assoc

Epilepsy Res

Seizure

J Neurol Sci

Pediatr Neurol

Clin Neurol Neurosurg

Falls and fractures in patients chronically treated with antiepileptic drugs

Neurology

Effect of antiepileptic medication on bone mineral measures

Neurology

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

Neurology

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

Neurology

Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the Women's Health Initiative (WHI)

J Bone Miner Res

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

Enzyme induction with antiepileptic drugs: cause for concern?

Epilepsia

Antiepileptic drug use and rates of hip bone loss in older men: a prospective study

Neurology

Original Article
Bone Mineral Changes in Epilepsy Patients During Initial Years of Antiepileptic Drug Therapy