ANTIEPILEPTIC DRUGS AND BONE HEALTH: A COMPREHENSIVE REVIEW AND META-ANALYSIS

Abstract

Context

Epilepsy and osteoporosis are closely related. The detrimental effect on bone by older generation of antiepileptic drugs (AEDs) is well known, but newer AEDs can also cause a decline in bone health.

Objective

To provide a review on the impact of AEDs on bone mineral density, fractures and bone turnover markers and to analyze the effect of bone active treatments in epileptic patients.

Methods

Medline (PubMed) and EMBASE were searched for studies about AEDs and bone health. The PRISMA statement was used.

Results

Chronic use of AEDs is associated with alterations in bone metabolism, low bone mineral density values, and increased risk of fractures. These effects appear to be more associated to the use of enzyme-inducing AEDs. Supplements with vitamin D and bone active treatments may have benefits in terms of bone mineral density gain and of mortality risk. More studies are required to determine the impact of non-enzyme-inducing AEDs on bone health and to gather useful information about the management of osteoporosis therapy in epileptic patients.

Conclusion

Chronic AED use has a significant impact on bone health; it is therefore necessary to evaluate in such individuals the claim to vitamin D and calcium supplements and bone active treatments.

INTRODUCTION

Epilepsy is a chronic noncommunicable brain disease characterized by abnormal brain activity causing seizures, unusual behaviour, sensations and even loss of awareness and control of bowel or bladder function. It affects approximately 50 million people worldwide, about 4-10 per 1000 persons in the general population (1). Epilepsy is frequently treated with long-term mono- or polytherapy with antiepileptic drugs (AEDs) (2). Phenobarbital, introduced in 1912, became the first widely used AED and remained a cornerstone of treatment for many decades. The mid-20th century saw the development of several other key AEDs, including phenytoin in 1938 and valproate in 1967. These drugs revolutionized the management of epilepsy, shifting it from a largely untreatable condition to one that could be effectively controlled in many patients (3, 4). However, AEDs, besides being highly effective in preventing seizures, are associated with several adverse effects, including a greater risk of osteoporosis, fragility fractures and changes in bone turnover (2).

Osteoporosis is a systemic skeletal disease characterized by reduced bone mineral density (BMD) and deterioration of bone architecture, resulting in decreased bone strength and consequently an increased risk of fractures (5). The prevalence of osteoporosis, and therefore the risk of fragility fractures, continues to rise with advancing age (6). Setting aside the most common cause of osteoporosis, which is postmenopausal estrogenic deficiency, there are various pathological conditions and treatments that can have a detrimental effect on bone health (7). By referring to the latter, drugs may cause bone loss by lowering sex steroid levels, interfere with vitamin D levels, or directly by toxic effects on bone cells (7); among these drugs are antiepileptics (7, 8).

Osteoporosis affects between 11% and 31% of epileptic patients, who are estimated to have a two-fold to six-fold increased risk of fractures compared to the general population (9). The detrimental effect on bone by older generation AEDs is well known, but newer AEDs can also cause a decline in bone health (8). AEDs can affect bone mass and quality through many mechanisms that have been studied extensively but are still not completely understood to date.

Moreover, despite osteoporosis and fractures being a well-known side effect of AEDs, few epilepsy guidelines consider this issue (1), and endocrinological guidelines only address AEDs among risk factors without any recommendations on specific treatments or information on the effect of treatments in these patients (10). Therefore, the aims of the present paper are (1) to provide a comprehensive review on the impact of AEDs on bone mineral density, fractures and bone turnover markers and (2) to analyse the effect of bone active treatments in epileptic patients.

METHODS

Search strategy

A systematic review was designed according to the Preferred Reporting Items for Systematic reviews and Meta- Analyses (PRISMA) statement (11).

Medline (PubMed) and EMBASE were searched for studies published from 01 January 2000 to 31 December 2023.

The search string included multiple entries of: osteoporosis OR bone OR fracture OR bone density AND one of the following keywords, joined by the Boolean operator OR: epilepsy, antiepileptic, antiseizure, anticonvulsant, ASM, carbamazepine, valproate, valproic acid, topiramate, levetiracetam, lamotrigine, phenytoin, vigabatrin, gabapentin, ethosuximide, clozapine, oxcarbazepine, and phenobarbital.

Inclusion and exclusion criteria

The inclusion criteria were: 1) Articles written in English only; 2) Study had to be cross-sectional, case-control or longitudinal, either prospective or retrospective, with or without a control group; 3) Human data only; 4) Availability of either bone mineral density or bone marker or fragility fracture outcomes.

Reviews, meta-analyses, case reports, case series and basic science/animal studies were excluded.

After the final study selection was made, the references of each included study were screened for possible additional eligible studies.

Study selection

Two authors performed the different database searches independently in January 2024.

The initial search yielded a total of 862 papers from PubMed and 1,022 papers from Embase. The reference screening led to the addition of 34 studies. The elimination of duplicates reduced the total number to 378 records. Abstract and full-text screening led to the elimination of further studies, leaving 67 papers. Detailed selection process is available in the diagram shown in Fig. 1. After completing the selection process, the following data were collected in an electronic database: author, publication year, study type, number of cases and of controls (if available), age, type of medication, duration of medication (if available), bone parameters in terms of bone mineral density and fractures, biochemical data concerning bone metabolism, bone active medication. Phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ), oxcarbazepine (OXC), primidone, mephenytoin, phenobarbitone and felbamate were classified as enzyme-inducing antiepileptic drugs (EI-AED). Valproic acid (VPA), lamotrigine (LMT), clonazepam (CLZ), gabapentin (GBP), topiramate (TPM), eslicarbazepine (ESL), etosuximide, levetiracetam (LEV), vigabatrin (VGB), acetazolamide, clobazam, felbamate, lacosamide, pregabalin, zonisamide, divalproex sodium, methsuxime and tiagabine were considered non-enzyme-inducing antiepileptic drugs (NEI-AEDs).

Figure 1.

The attrition diagram depicting the screening process of study inclusion in the current systematic review.

The selected method used to assess the risk of bias in individual studies and the applicability to the review question was QUADAS-2, a tool for evaluating the quality of diagnostic test accuracy studies (12). Two reviewers assigned scores to the studies in the systematic review in four domains for risk of bias (patient selection, index test, reference standard, and flow and timing) and in three fields for applicability (patient selection, index test, and reference standard). Taking advantage of the data reported in each study, the Authors assessed the risk of bias and concerns about the applicability of the included papers based on the QUADAS-2 instruments. The results of the quality assessment are reported in Fig. 2.

Figure 2.

The results of quality assessment of included papers based on the QUADAS-2 instruments.

Statistical analysis

The data from the included studies were utilized, considering each study’s relative importance, employing a random-effect statistical model. Furthermore, the study included the provision of 95% confidence interval values, which were subsequently visually represented through forest plots. The I-square (I2) index, also known as the inconsistency index, was employed to assess the level of statistical heterogeneity within the papers included in the analysis. Statistical heterogeneity was considered significant if the I-square index exceeded 50%. The software OpenMeta[Analyst]® (version 3.13), supported by the Agency for Healthcare Research and Quality (AHRQ) in Rockville, MD, USA, was utilized to calculate the pooled values of mean differences.

RESULTS

Chronic AED therapy and Biochemical Markers of Bone Metabolism

Several studies have analysed the effects of chronic AED therapy on the biochemical markers of bone metabolism. The results of these papers are reported in the Tables 1-5.

Table 1.

Chronic AED therapy and Biochemical Markers of Bone Metabolism - EI-AEDs versus controls

Study	Study design	subjects	calcium	phosphate	25OHD	PTH	total ALP – bone ALP	OC	Urinary markers
Feldkamp et al. 2000 (18)	case control	59 patients (CBZ, PHT) vs 55 controls	No difference	na	Lower in patients vs controls	No difference	higher in patients vs controls (tALP)	No difference	na
Filardi et al. 2000 (20)	case control	69 patients (PHB, PHT, CBZ) vs 30 controls	lower in patients vs controls	na	No difference	No difference	tALP higher in patients vs controls	na	na
Mintzer et al. 2006 (24)	case control	45 patients (24 OXC + 21 CBZ) vs 24 controls	No difference	na	Lower in patients vs controls	No difference	no difference (bALP)	Higher in CBZ vs controls	No difference (NTX)
Telci et al. 2000 (19)	case control	89 patients (PHT, PHB, CBZ) vs 39 controls	No difference	No difference	Lower in male patients vs controls	na	tALP higher in patients vs controls, no difference in bALP	No difference	na

Anti-epileptic drugs (AEDs); enzyme inducers of cytochrome P450 enzyme antiepileptic drugs (EIAEDs) including carbamazepine (CBZ), oxcarbazepine (OXC); phenytoin (PHT), and phenobarbital (PHB); Alkaline Phosphatase (ALP); bone Alkaline Phosphatase (bALP) and total Alkaline Phosphatase (tALP); 25-Hydroxy Vitamin D (25OHD); Parathyroid hormone (PTH); Osteocalcin (OC); Versus (vs); Not available (na).

Table 5.

Chronic AED therapy and Biochemical Markers of Bone Metabolism - Longitudinal studies

Study	Study design	subjects	calcium	phosphate	25OHD	PTH	total ALP – bone ALP	CTX	OC	Urinary markers
Bauer et al. 2013 (36)	prospective study, 3 months	31 patients (16 starting OXC, 15 starting VPA)	increase in OXC group, no changes in VPA from baseline	no changes from baseline	N/A	N/A	increase in OXC group, decrease in VPA group (ALP)	N/A	increase in OXC group, no changes from baseline in VPA group	N/A
Brämswig et al.2003 (40)	prospective study, 10 weeks	21 healthy volunteers starting CBZ	no changes from baseline	no changes from baseline	no changes from baseline	no changes from baseline	N/A	no changes from baseline	no changes from baseline	N/A
El-Haggar et al. 2018 (38)	prospective study, 6 months	48 patients (12 starting LMT, 12 LEV, 12 VPA+LMT, 12 VPA+LEV) vs 30 controls	decrease from patients in all treatment groups, greater in combined therapies	no changes from baseline	N/A	no changes from baseline	decrease in LEV group, increase in combined therapies, no changes from baseline in LMT group (ALP)	N/A	decrease in LEV group, increase in combined therapies, no changes from baseline in LMT group	no changes from baseline in LMT and LEV group, increase in combined therapies
Hakami et al. 2016 (42)	prospective study, 15 months	70 patients who “failed” initial monotherapy with older AED, 40 switched to LEV and 30 to another older AED (CBZ or VPA)	no changes from baseline and no difference between groups	N/A	no changes from baseline and no difference between groups	no changes from baseline and no difference between groups	N/A	no differences at baseline, decrease in both groups from baseline	N/A	N/A
Hirsch et al. 2023 (38)	prospective study, 12 months	26 patients starting ESL	no changes from baseline	no changes from baseline	no changes from baseline	no changes from baseline	no changes from baseline (ALP)		no changes from baseline	N/A
Kim et al. 2007 (26)	prospective study, 6 months	33 patients (10 starting CBZ, 15 VPA and 8 LMT)	no changes from baseline and no difference between groups	no changes from baseline and no difference between groups	decreased in CBZ group, no changes in other groups	increased in all groups	no changes from baseline and no difference between groups (ALP)	N/A	increased in VPA and LMT, no changes in CBZ	no changes from baseline and no difference between groups (U-pyrilinks)
Koo et al. 2013 (27)	prospective study, 14 months	61 patients naive starting LEV	no changes from baseline	no changes from baseline	no changes from baseline	no changes from baseline	no changes from baseline (ALP)	no changes from baseline	no changes from baseline	N/A
Koo et al. 2014 (37)	prospective study, 12 months	41 naive patients starting OXC	decrease from baseline	no changes from baseline	no changes from baseline	no changes from baseline	decrease from baseline (bALP)	no changes from baseline	no changes from baseline	N/A
Phabphal et al. 2013 (39)	prospective study, 2 years	90 patients taking PHT at baseline, 54 switched to LEV, 17 continued PHT, 19 stopped AED	N/A	N/A	decrease in PHT group, increase in LEV and no therapy group	N/A	N/A	N/A

Anti-epileptic drugs (AEDs); Enzyme inducers antiepileptic drugs (EI-AEDs) including phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ), oxcarbazepine (OXC), primidone, mephenytoin, phenobarbitone and felbamate; Non-enzyme inducers antiepileptic drugs (NEI-AEDs) including valproic acid (VPA), lamotrigine (LMT), clonazepam (CLZ), gabapentin (GBP), topiramate (TPM), eslicarbazepine (ESL), etosuximide, levetiracetam (LEV), vigabatrin, acetazolamide, clobazam, felbamate, lacosamide, pregabalin (PGB), zonisamide, divalproex sodium, methsuxime and tiagabine; Alkaline Phosphatase (ALP); bone Alkaline Phosphatase (bALP) and total Alkaline Phosphatase (tALP); 25-Hydroxy Vitamin D (25OHD); Parathyroid hormone (PTH); Osteocalcin (OC); C-terminal telopeptide (CTX); Versus (vs); Not available (na).

Table 2.

Chronic AED therapy and Biochemical Markers of Bone Metabolism - NEI-AEDs vs controls

Study	Study design	subjects	calcium	phosphate	25OHD	PTH	total ALP – bone ALP	CTX
Albaghdadi et al. 2016 (25)	case control	50 patients (VPA) vs 50 controls	Lower in patients vs controls	No difference	Lower in patients vs controls	No difference	No difference (tALP)	na
Boluk et al. 2004 (21)	case control	50 patients (VPA) vs 60 controls	No difference	Higher in patients vs controls	na	Higher in patients vs controls	tALP higher in patients vs controls	na
Zare et al. 2013 (88)	case control	62 patients (VPA) vs 40 controls	No difference	No difference	na	na	No difference (tALP)	No difference

Anti-epileptic drugs (AEDs); Non-enzyme inducers antiepileptic drugs (NEI-AEDs) including valproic acid (VPA); Alkaline Phosphatase (ALP); bone Alkaline Phosphatase (bALP) and total Alkaline Phosphatase (tALP); 25-Hydroxy Vitamin D (25OHD); Parathyroid hormone (PTH); C-terminal telopeptide (CTX); Versus (vs); Not available (na).

Table 3.

Chronic AED therapy and Biochemical Markers of Bone Metabolism - AEDs (both EI and NEI) vs controls

Study	Study design	subjects	calcium	phosphate	25OHD	PTH	total ALP – bone ALP	CTX
Ashjazadeh et al. 2009 (22)	case control	90 patients vs 90 controls	No difference	No difference	No difference	No difference	Higher in patients vs controls (tALP)	na
El-Hajj Fuleihan et al. 2018 (15)	case control	137 patients vs 212 controls	na	na	Lower in patients vs controls	na	na	na
Hamed et al. 2014 (14)	case control	75 patients vs 40 controls	Lower in patients vs controls	na	Lower in patients vs controls	na	Higher in patients vs controls (tALP)	na
Heo et al. 2011 (23)	case control	104 patients vs 36 controls	lower in CBZ vs VPA and lower in TPM vs VPA	na	no difference between different AEDs and controls	lower in TPM vs CBZ and VPA	bALP higher in TPM and CBZ vs controls	higher in TPM vs CBZ or VPA, no difference vs controls
Kulak et al. 2004 (13)	case control	58 patients vs 29 controls	No difference	No difference	Lower in patients vs controls	No difference	No difference	na
Lyngstad-Brecha et al. 2008 (17)	case control	26 patients vs 26 controls	na	na	no differences, except for CBZ (lower vs controls)	na	tALP and bALP higher in patients vs controls	no difference
Pedrera et al. 2000 (16)	case control	30 patients vs 30 controls	na	na	Lower in patients vs controls	Higher in patients vs controls	na	na

Anti-epileptic drugs (AEDs); Non-enzyme inducers antiepileptic drugs (NEI-AEDs) and enzyme inducers antiepileptic drugs (EI-AEDs); valproic acid (VPA); carbamazepine (CBZ); topiramate (TPM); Alkaline Phosphatase (ALP); bone Alkaline Phosphatase (bALP) and total Alkaline Phosphatase (tALP); 25-Hydroxy Vitamin D (25OHD); Parathyroid hormone (PTH); C-terminal telopeptide (CTX); Versus (vs); Not available (na).

Almost all case-control studies show lower serum 25-Hydroxy Vitamin D (25OHD) (13-17) and higher serum alkaline phosphatase (ALP) levels (14, 17-23) in epileptic patients taking AEDs compared to controls. Reduced 25OHD is found in patients taking EI-AEDs (CBZ, PHT, PHB, OXC) (18, 19, 24) whereas conflicting results are reported in patients taking NEI-AEDs (23, 25-27).

In addition, conflicting results were also found for other markers of bone metabolism (28). Few studies have shown significantly lower serum calcium levels (14, 20, 23, 25, 29) and higher parathyroid hormone (PTH) levels (16, 21) in patients taking AEDs versus controls.

Table 4 reports the studies directly comparing NEI-AEDs and EI-AEDs (30-34). Apparently, no difference in 25OHD levels and other biochemical markers (PTH, ALP) was found, except for Teagarden et al. (35).

Table 4.

Chronic AED therapy and Biochemical Markers of Bone Metabolism - EI-AEDs vs non EI-AED

Study	Study design	subjects	calcium	phosphate	25OHD	PTH	total ALP – bone ALP
Farhat et al. 2002 (33)	cross sectional	42 patients (PHT, PHB, CBZ, primidone vs VPA, LMT, CLZ, GBT, TPM, ethosuximide)	na	na	no difference	na	na
Mikati et al. 2006 (89)	prospective (laboratory exams at baseline)	72 patients (PHT, PHB, CBZ, primidone vs VPA, LMT, CLZ, GBT, ethosuximide, vagabatrin)	na	na	no difference	na	na
Pack et al. 2005 (30)	Cross sectional	93 patients (CBZ, PHT vs LMT, VPA)	no difference		no difference	no difference	no difference (bALP)
Rahimdel et al. 2016 (31)	cross sectional	81 patients (CBZ vs VPA)	lower in CBZ vs VPA	lower in CBZ vs VPA	na	no difference	no difference (ALP)
Teagarden et al. 2014 (35)	cross sectional	596 patients (CBZ, PHT, PHB, primidone vs weak EI as OXC, TPM vs non-EI as GBP, LMT, LEV)	na	na	difference between EIAEDs, weak EIAEDs and non-EIAEDs	na	na
Winterhalder et al. 2022 (34)	prospective (laboratory exams at baseline)	102 patients (CBZ, ESL, PHB, PHT, TPM>200 mg vs clobazam, CLN, GBP, lacosamide, LMT, LEV, PGB, VPA, TPM <200 mg)	na	na	no difference	no difference	no difference (ALP)

Anti-epileptic drugs (AEDs); Enzyme inducers antiepileptic drugs (EI-AEDs) including phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ), oxcarbazepine (OXC), primidone, mephenytoin, phenobarbitone and felbamate; Non-enzyme inducers antiepileptic drugs (NEI-AEDs) including valproic acid (VPA), lamotrigine (LMT), clonazepam (CLZ), gabapentin (GBP), topiramate (TPM), eslicarbazepine (ESL), etosuximide, levetiracetam (LEV), vigabatrin, acetazolamide, clobazam, felbamate, lacosamide, pregabalin (PGB), zonisamide, divalproex sodium, methsuxime and tiagabine; Alkaline Phosphatase (ALP); bone Alkaline Phosphatase (bALP) and total Alkaline Phosphatase (tALP); 25-Hydroxy Vitamin D (25OHD); Parathyroid hormone (PTH); Versus (vs); Not available (na).

Finally, in Table 5, we report the longitudinal studies, which showed discordant results. Kim et al. found a decrease in 25OHD levels after 6 months of CBZ therapy and an increase in osteocalcin (OC) after 6 months of VPA and LMT therapy (26). Bauer et al. found an increase in total ALP and OC levels after 3 months of OXC therapy and a decrease in total ALP levels after 3 months of VPA therapy (36). Koo et al. reported data for 41 naïve patients starting OXC; after 12 months of therapy, a significant reduction in calcium and bone-ALP levels was reported, with no significant changes in phosphate, 25OHD, PTH, telopeptide (CTX), and OC (37). El-Haggar et al. included in their study 48 patients starting NEI-AEDs in single or combined schemes; after 6 months of therapy, they found a decrease in calcium levels in all patients (particularly in combined therapies), a decrease of total ALP and OC levels in patients taking LEV, an increase of total ALP and OC in patients taking combined therapies, and an increase in urinary markers only in combined therapies (38). Phabphal et al. included 90 patients taking PHT at baseline, 54 of whom were switched to LEV, 17 continued PHT, and 19 stopped AEDs. After 2 years, 25OHD levels significantly decreased in the PHT group and increased in the LEV and no-therapy group (39). The remaining longitudinal studies showed no changes in biochemical parameters during AED treatment (27, 40-42).

To evaluate any serum 25OHD differences among patients on chronic AED treatment and controls sixteen studies (13-16, 18-20, 23-27, 37, 40, 41, 43) encompassing 16122 subjects were pooled. The meta-analysis showed that patients on AED treatment had lower serum 25OHD compared to controls (SMD= -3.976 ng/mL, CI 95%: -10.280 to 2.328) with a significant heterogeneity across studies (I2=99%, p<0.001) (Fig. 3). To assess any serum 25OHD differences among patients taking EI-AEDs and NEI-AEDs and controls, the available data retrieved respectively from 10 (BIBLIO) and 4 studies (BIBLIO) were pooled using the fixed effect model. A total of 15401 subjects (15102 for EI-AEDs and 398 for NEI-AEDs) wereincluded. The meta-analysis showed that patients taking EI-AEDs displayed lower serum 25OHD levels (SMD=-2.160 ng/mL, CI 95%: -4.608 to 0.287) with a significant heterogeneity across studies (I2=75%, p<.001), whereas no differences was observed in NEI-AEDs patients (SMD=0.116 ng/mL, CI 95%: -2.091 to 2.324) with a very low heterogeneity across studies (I2=37%, p=0.189) (Fig. 4a and Fig. 4b).

Figure 3.

Forest plot of the meta-analysis on serum concentrations of 25OH vitamin D in patients on chronic antiepileptic treatment compared with healthy controls.

Figure 4.

A. Forest plot of the meta-analysis on serum concentrations of 25OH vitamin D in patients on enzyme-inducing antiepileptic drugs (a) and non-enzyme-inducing antiepileptic drugs (b) compared with healthy controls. B. Forest plot of the meta-analysis on serum concentrations of 25OH vitamin D in patients on enzyme-inducing antiepileptic drugs (a) and non-enzyme-inducing antiepileptic drugs (b) compared with healthy controls.

Chronic AED therapy and Bone Mineral Density

The studies focusing on the correlation between chronic AED therapy and BMD are reported in Table 6. Most of the studies, cross-sectional, cohort studies and prospective ones found lower BMD values in patients in chronic AED therapy compared to controls and reference populations (13-15, 17, 18, 25, 33, 43-48), also showing an increased rate of BMD loss during treatment (21, 26, 28, 32, 38, 39, 42, 49-53). Indeed, the duration of treatment (15, 18, 22, 33, 54), the type of AIDs adopted (15, 17, 44) and cumulative drug load (55) seem to be negatively correlated to BMD. PHT and CBZ were significantly associated with BMD loss (26, 49, 51, 52). Conversely, NEI-AEDs (such as VPA, LEV, LMT, GBP, ESL) appear to have less effect on bone health (26, 27, 31, 38, 39, 41, 49, 56, 57).

Table 6.

Chronic AED therapy and Bone Mineral Density

Study	Study design	Subjects	AED	Results
Albaghdadi et al. 2016 (25)	cross-sectional study	50 patients vs 50 controls	VPA monotherapy	Chronic VPA therapy is associated with lower BMD measurements in young patients. No correlation was found between duration or dosage of VPA and BMDs.
Andress et al, 2002 (28)	prospective study, 29 months	81 young male veterans (54 patients with DEXA repeated over time)	PHT, CBZ, VPA, LMT, GBP, PHB	Age and time receiving AEDs were risk factors associated with low femoral neck BMD. Longitudinal analysis of femoral neck BMD revealed that only those in the youngest age group (25-44 years) showed significant declines in femoral neck BMD
Ashjazadeh et al. 2009 (22)	cross-sectional study	90 patients vs 90 controls	VPA, PHB, PHT, LMT, CLZ	BMD in patients treated was lower at the spine and femoral sites compared to the control group. Independent risk factor for osteopenia at the lumbar spine was polytherapy and for osteopenia at the femoral neck was duration of therapy
Beerhorst et al. 2013 (55)	cross-sectional study	205 patents with refractory EP from a residential unit of a tertiary epilepsy centre	N/A	In this high-risk population was obtained a prevalence of 80% of low BMD. Cumulative drug load was confirmed as the dominant factor correlating with the T-score of the femur neck.
Beniczky et al. 2012 (46)	cross-sectional study	160 patients taking AEDs	CBZ, OXC, VPA, LMT, TPM and LEV.	Patients on long-term treatment with LEV and OXC have a higher risk for affection of bone density
Berkvens et al. 2021(47)	retrospective cohort study, 7 years	205 institutionalized patients with EP and intellectual disability	EI-AEDs and NEI-AEDs both	Patients had low BMD: 92 patients (44.9%) were diagnosed with osteopenia and 65 (31.7%) with osteoporosis.
Boluk et al. 2004 (21)	prospective study, 6 months	50 patients vs 60 controls	VPA (at least 1 year of therapy before enrolment)	Lumbar and femur BMD values of patients were significantly lower than those of control group. The second DEXA measurement revealed a continual osteoporotic process when compared to the first measurement.
Carbone et al. 2010 (58)	prospective study, 3 years	84 patients vs 8677 controls (postmenopausal women)	EI-AEDs and NEI-AEDs	Users of AEDs had no significant differences in percentage change from baseline to year 3 BMD of the hip, spine, or total body.
DeShazo et al. 2023 (48)	retrospective study, 20 years	35936 patients taking PHT vs 109335 patients with EP taking no AED	PHT	Patients on PHT therapy were at significantly higher risk for osteoporosis (risk ratio 3,6).
El-Haggar et al. 2018 (38)	prospective study, 6 months	48 patients starting AED vs 30 controls	LMT (12 patients), LEV (12), VPA+LMT (12), VPA+LEV (12)	BMD after six months of treatment revealed a significant decrease in all treated groups except for the LMT monotherapy group.
El-Hajj Fuleihan et al. 2008 (15)	cross-sectional study	137 adult patients vs 212 controls	EI-AED and NEI-AED	Ambulatory adults on chronic AED therapy had lower BMD. Independent predictors of BMD were duration of treatment and use of EIAEDs in adults.
Ensrud et al. 2003 (59)	prospective study (only 1 BMD measurement available)	123 women aged >65 y-o using AEDs vs 6720 controls	PHT, PHB, CBZ, other	The average bone density is decreased among AEDs users.
Ensrud et al. 2004 (51)	prospective study, 3 years	cohort of 9704 elderly community-dwelling women classified as continuous AED users, partial users and nonusers	PHT, CBZ, PHB, primidone, VPA	The average rate of decline in total hip BMD was 0.70%/year in nonusers, 0.87%/year in partial AED users and 1.16%/year in continuous AED users .Continuous phenytoin users had an adjusted 1.7-fold greater mean rate of loss at the total hip compared with nonusers of AED.
Ensrud et al. 2008 (53)	prospective study, 4.6 years	62 patients taking AEDs vs 4060 nonusers (men at least 65 years old)	EIAEDs and NEIAEDs	Use of NEI-AEDs was independently associated with increased rates of hip bone loss in this cohort of older community-dwelling men.
Farhat et al. 2002 (33)	cross-sectional study	42 patients vs age-matched controls	EI-AEDs	BMD was lower compared with controls. There was a significant negative correlation between duration of AED use and BMD.
Study	Study design	Subjects	AED	Results
Feldkamp et al. 2000 (18)	cross-sectional study	59 patients in CBZ and/or PHT vs 55 controls	CBZ, PHT	BMD in the lumbar spine region was significantly lower in the patient group as compared to controls. Decrease in BMD was dependent on the duration of therapy.
Filardi et al. 2000 (20)	cross-sectional study	69 patients vs 30 controls	single or combined AED (PHB, PHT, CBZ) for at least 5 years	AEDs chronic users did not show a reduction in BMD
Hakami et al. 2016 (42)	prospective study, 15 months	70 patients who failed initial monotherapy, 40 switched to LEV and 30 to CBZ or VPA	Newer AED (LEV) or older AED (CBZ or VPA)	Use of both LEV and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites
Hamed et al. 2014 (14)	cross-sectional study	75 patients vs 40 controls	CBZ and VPA (mono or polytherapy)	Patients had significantly lower BMD at the femoral neck and lumbar spine
Hirsch et al. 2023 (41)	prospective study, 1 year	26 patients starting ESL	Eslicarbazepine acetate (ESL) as adjunctive treatment or monotherapy	After 1 year of treatment with ESL there was no significant group effect on osteodensitometry parameters.
Kim et al. 2007 (26)	prospective study, 6 months	33 drug naive patients starting AED	CBZ (10 patients), VPA (15), LMT (8) monotherapy	BMD Z score at calcaneus significantly decreased in patients after 6 months of CBZ treatment, but not with VPA or LMT.
Kinjo et al. 2005 (43)	cross-sectional study	78 patients taking AEDs vs 14360 controls	N/A	Total hip BMD of AED users was significantly lower than nonusers
Koo et al. 2013 (27)	prospective study, 14 months	61 naive patients starting LEV	LEV monotherapy	T score in lumbar spine was significantly increased across LEV monotherapy.
Koo et al. 2014 (37)	prospective study, 1 year	41 drug naïve patients starting OXC	OXC monotherapy	Long-term OXC monotherapy does not appear to have harmful effect on bone health in drug naïve epilepsy patients
Kulak et al. 2004 (13)	cross-sectional study	598 patients vs 29 controls	CBZ, phenobarbitone, PHT, VPA, LMT, clobazan, CLZ (mono or politherapy)	Lumbar spine BMD and total femur BMD were lower in patients than in controls. There was no correlation between BMD and the time of treatment with AED. Total femoral BMD was significant lower in those patients who had used phenobarbitone.
Lee et al. 2012 (57)	retrospective cohort study, 4 years	560 veterans in AED vs 1219 controls	Traditional AEDs (PHT, CBZ, VPA) and newer AEDs (GBP, LEV, LMT).	Higher duration of use of traditional AEDs was correlated to a lower total hip T-score. Newer anticonvulsant medications are not associated with lower BMD.
Lyngstad-Brechan et al. 2008 (17)	cross-sectional study	26 patients (post-menopausal women) taking AED monotherapy vs 26 controls	EI-AEDs and NEI-AEDs	Patients had significantly lower BMD, particularly those treated with EI-AEDs
Mikati et al. 2006 (89)	prospective randomized study (BMD available only at baseline)	72 patients vs young controls	EI-AEDs and NEI- AEDs	BMD was decreased vs normal young controls as provided by the manufacturer’s database. Except at the femoral neck, BMD was not different between patients on EI-AEDs and those on NEI-AEDs.
Pack et al. 2003 (90)	cross-sectional study	153 patients	EI-AEDs	Patients with epilepsy who are receiving EI-AEDs have an increased risk for bone loss, regardless of age, gender, and duration of therapy.
Pack et al. 2008 (49)	prospective study, 12 months	93 pre-menopausal women starting a single AED	single AED (CBZ, LMT, PHT or VPA)	Significant loss was seen at the femoral neck in the PHT group. BMD remained stable in the other AED groups.
Petty et al. 2005 (44)	cross-sectional study	35 twins and siblings pairs discordant for AED use (70 subjects, 35 taking AED)	EI-AEDs and EI-AEDs	Patients using AEDs for at least 2 years (in particular those taking EI-AEDs and those older than 40 yo) had significantly lower BMD.
Study	Study design	Subjects	AED	Results
Phabphal et al. 2009 (45)	cross-sectional study	123 young adults taking AEDs	EI-AEDs and non EIAEDs	Chronic use of AED in young adult patients is associated with low BMD. Multivariate analysis identified BMI and male gender to be independent risk factors.
Phabphal et al. 2013 (39)	prospective study, 2 years	90 patients taking PHT at baseline, 54 switched to LEV, 19 stopped AED and 17 continued PHT	PHT, LEV	All patients who switched to LEV and those who stopped PHT had significant improvement of BMD over those who continued PHT. Patients who continued taking PHT had significant worsening of BMD.
Rahimdel et al. 2016 (31)	cross-sectional study	82 patients vs general population	CBZ or VPA	Lumbar spine BMD was not significantly different between CBZ and VPA and was significantly higher than normal population. Femoral neck BMD in CBZ group was lower than VPA group.
Shiek Ahmad et al. 2016 (52)	prospective study, 1 year	49 patients who recently started AED vs 53 non users	N/A	No evidence was found of a longitudinal association between AED use (all types combined) and the rate of BMD change. Analysis of specific monotherapy showed that by comparison with nonusers, CBZ was associated with an increased annual rate of BMD loss at the total hip and femoral neck.
Shiek Ahmad et al. 2017 (54)	prospective study, 3 years	24 twins and siblings pairs discordant for AED use (48 subjects, 24 taking AED)	EI-AEDs and NEI-AEDs	AED users, compared to non-users, at baseline and follow-up had reduced BMD. EI-AED users had greater BMD loss than non-users at the total hip and whole body regions, which was not found in NEI-AED discordant pairs. AED use >20 years predicted higher BMD loss.
Triantafyllou et al. 2010 (91)	cross-sectional study	41 patients vs age-matched controls	VPA monotherapy for at least 2 years	BMD did not differ between patients and age-matched controls.

Anti-epileptic drugs (AEDs); Enzyme inducers antiepileptic drugs (EI-AEDs) including phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ), oxcarbazepine (OXC), primidone, mephenytoin, phenobarbitone and felbamate; Non-enzyme inducers antiepileptic drugs (NEI-AEDs) including valproic acid (VPA), lamotrigine (LMT), clonazepam (CLZ), gabapentin (GBP), topiramate (TPM), eslicarbazepine (ESL), etosuximide, levetiracetam (LEV), vigabatrin, acetazolamide, clobazam, felbamate, lacosamide, pregabalin (PGB), zonisamide, divalproex sodium, methsuxime and tiagabine; Bone mineral Density (BMD).

To evaluate any BMD differences among patients on chronic AED treatment and controls thirteen studies (13-15,18,20,21,25,27,37,54,58-60) encompassing 22351 subjects were pooled. The meta-analysis showed that patients on AED treatment had lower BMD compared to controls (SMD= -0.047 g/cm², CI 95%: -0.061 to -0.034) with a significant heterogeneity across studies (I2=94%, p<0.001) (Fig. 5).

Figure 5.

Forest plot of the meta-analysis on bone mineral density in patients on chronic antiepileptic treatment compared with healthy controls.

Chronic AED therapy and Fractures

Table 7 displays the studies concerning the correlation between chronic use of AEDs and fractures. Almost all the studies available in the literature agree that the use of AEDs in epileptic patients leads to an increased fracture risk; however, the extent of this increase is variable according to the study. A large cohort study including 124,655 subjects with fractures and 373,962 matched controls showed a very limited increased fracture risk in users of AEDs, in particular CBZ, OXC, VPA, CLZ and PHB (61). Another large retrospective study (121,455 subjects in total) found an overall risk of fractures nearly twice as high among patients with epilepsy compared with the general population (62). In different studies, the fracture risk due to chronic AED use is increased by cumulative drug dose (63, 64), number of AEDs (58, 64, 65), use of EI-AEDs (58, 61, 63) – in particular PHT (13,48), epilepsy severity (62, 66), and previous fracture history (67, 68). Interestingly, Jetté et al. observed in their cohort study that VPA is not associated with an increase in fracture risk, unlike other AEDs such as PHT, CBZ, CLZ, GBP, and PHB (69). The retrospective study published by Schelleman et al., however, found no significant difference in the rate of all-site fracture between the use of EI-AEDs and NEI-AEDs (70), deviating from the previously reported studies.

Table 7.

Chronic AED therapy and fracture risk

Study	Study design	Subjects	AED	Results
Andress et al. 2002 (28)	prospective, 29 months	81 young male veterans	PHT, CBZ, VPA, LMT, GBP, PHB	The crude fracture rate was 1.9 fractures per 100 patient-years of observation and the non–seizure-related fracture rate was 1.4 fractures per 100 patient-years.
Babunovska et al. 2023 (65)	retrospective cohort study, 4 years	10919 patients using AEDs (age > 20) vs 58065 controls	N/A	Epileptic patients had higher fracture prevalence compared to the general population. Fracture risk was increased with the use of >2 AEDs and with the presence of comorbidities.
Beerhorst et al. 2012 (64)	cross-sectional study	261 patients with epilepsy living in a long-stay care facility	EI-AEDs and NEI-AEDs	In this high-risk population, the number of fractures correlated significantly with ambulatory status, cumulative drug load and current number of AEDs. Cumulative drug load was the dominant factor explaining the occurrence of fractures.
Beerhorst et al. 2013 (55)	cross-sectional study	205 patients with refractory epilepsy from a residential unit of a tertiary epilepsy centre	N/A	124 patients (63.6%) had history of previous fractures. 52 patients (28.1%) had radiological signs of one or more vertebral fractures.
Berkvens et al. 2020 (67)	prospective cohort study, 7 years	141 patients institutionalized patients with epilepsy and intellectual disability	EI-AEDs and NEI-AEDs	At baseline, 56 patients had at least one prevalent vertebral fracture (VF). After 7 years of follow-up, 38 new VFs occurred in 27 patients and 15 patients had a worsening VF, leading to an overall cumulative incidence of 27.0%. VF incidence was significantly higher in patients with at least one prevalent VF at baseline
Carbone et al. 2010 (58)	prospective study, 7.7 years	1385 patients AED users and 137282 nonusers (post-menopausal women)	EI-AEDs and NEI-AEDs	Use of AEDs was positively associated with total fractures (HR 1.44), all site-specific fractures (hip, clinical vertebral fractures, lower arm or wrist fractures and other clinical fractures) and two or more falls (HR 1.62) but not with baseline BMD or changes in BMD. Use of more than one and use of EI-AEDs were significantly associated with total fractures (HR 1.55, and HR 1.36, respectively).
DeShazo et al. 2023 (48)	retrospective study, 20 years	35936 epileptic patients using PHT vs 109335 epileptic patients using no AED	PHT	Epileptic patients on phenytoin therapy that were 18 - 55 years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions
Ensrud et al. 2003 (59)	prospective study, 8 years	123 patients taking AED vs 6720 controls (women, age > 65)	PHT, PHB, CBZ, others	Women taking AEDs were at increased risk for fractures (HR 1.88 for any non-spine fracture and HR 2.0 for hip fractures). This increased risk appeared to be partially explained by their lower femoral neck BMD. After adjustment for BMD and markers of frailty, the association between AEDs use and fracture were no longer significant.
Hadji et al. 2021 (68)	retrospective cohort study, 5 years	18354 osteoporotic patients aged >50 who experienced fracture (2469 with epilepsy / use of AEDs)	N/A	2918 patients (15.9%) suffered a subsequent fracture during the 1-year follow-up period. Epilepsy /use of AED was independently associated with subsequent fracture risk.
Jetté et al. 2011 (69)	retrospective cohort study, 9 years	15792 subjects > 50 yo with nontraumatic fractures (including 79 epileptic patients) vs 47289 matched controls with no fracture	EI-AEDs and NEI-AEDs	Most AEDs were associated with an increased risk of nontraumatic fractures in individuals aged 50 years or older (in particular CBZ, CLZ, GBP, PHB and PHT). The only AED not associated with increased fracture risk was VPA
Koppel et al. 2005 (92)	retrospective cohort study, 1 year	50 post-menopausal epileptic women (20 experienced fracture)	N/A	29 fractures occurred in 20 of the 50 interviewed subjects; 20 of these occurred on AEDs. AEDs may contribute more to the lifetime occurrence of fracture than seizures themselves.
Kulak et al. 2004 (13)	cross-sectional study	58 patients using AED vs 29 controls	EI-AEDs and NEI-AEDs	15 patients (25.8%) of the epilepsy group reported fractures related to a seizure episode. No significant difference was observed between the BMD of the patient with history of fracture than the patient without a fracture. The use of PHT was correlated with a greater incidence of fractures (RR: 2.38).
Persson et al. 2002 (66)	prospective study, 5 years	177 patients vs general population in the same geographic area	N/A	A significantly higher risk for fractures was found in patients with epilepsy. Risk factors were age 45 years or older, male sex, and occurrence of generalized seizures. Relative risk of fractures was higher during the first and second year compared with > 5 years after diagnosis.
Schelleman et al. 2011 (70)	retrospective cohort study, 13 years	4077 EI-AEDs initiators vs 6433 NEI-AEDs initiators	EI-AEDs and NEI-AEDs	The study found no statistically significant increased rate of all-site fracture during long-term exposure to EI-AEDs vs NEI-AEDs.
Sheth et al. 2006 (77)	retrospective cohort study, 7 years	750 epileptic patients who sustained fractures	N/A	293 patients (39%) had pathological fractures, which are a significant contributor across the life span, accounting for 20 to 40% of patients traditionally thought not to be at risk for involutional osteoporotic fractures. These findings suggest that epilepsy, and/or its treatment, may exacerbate the effects of aging-related involutional osteoporosis.
Souverein et al. 2006 (71)	retrospective cohort study, 8 years	1018 epileptic patients with a first fracture after cohort entry and 1842 EP controls with no fracture	EI-AEDs and NEI-AEDs	Risk of fractures increased with cumulative duration of exposure; each year of exposure to AEDs was associated with a 9% increase. There was a significant association between markers for epilepsy severity and the risk of fractures. There was no difference between EI-AEDs and NEI-AEDs.
Souverein et al. 2005 (62)	retrospective study, 3 years	40485 patients vs 80970 controls	EI-AEDs and NEI-AEDs	The overall risk of fractures was nearly twice as high among patients with epilepsy compared with the general population. The relative fracture risk was highest for hip and femur.
Spector et al. 2007 (93)	Prospective study, 1 year	N/A	N/A	Residents with epilepsy were found to have greater risk for fractures even when controlling for anticonvulsant use. Fractures in these cases generally result from a fall after a seizure. AEDs significantly increased the risk of a fracture (OR 2.2)
Tsiropoulos et al. 2008 (63)	retrospective cohort study, 9 years	7557 subjects with fractures (584 taking AED) vs 27575 matched controls (1105 taking AED)	EI-AEDs and NEI-AEDs	Fracture risk was increased with ever use of any AED. The risk was also increased with use of only EI-AEDs inducing, but not with use of only NEI-AEDs. Current and recent use, as well as high daily and cumulative dose increased fracture risk, but long treatment duration or previous use did not.
Tsiropoulos et al. 2008 (63)	retrospective cohort study, 7 years	205 institutionalized patients with epilepsy and intellectual disability	EI-AEDs and NEI-AEDs	40% of institutionalized adults with epilepsy and intellectual disability had at least one clinical fracture during seven years of follow-up, despite adequate anti-osteoporosis treatment. Thirty-eight patients (18.5%) had at least one major osteoporotic fracture. Overall, the IR was 11.6 fractures per 100 person-years.
Vestergaard et al. 2004 (61)	retrospective cohort study, 5 years	124655 subjects with fractures (3178 with epilepsy and 7091 using AED) vs 373962 matched controls	EI-AEDs and NEI-AEDs	A very limited increased fracture risk is present in users of CBZ, CZP, OXC, PB, and VPA. A limited significant increase cannot be excluded for the other AEDs because of the statistical power. Fracture risk was more increased by EI-AEDs than by NEI-AEDs

Anti-epileptic drugs (AEDs); Enzyme inducers antiepileptic drugs (EI-AEDs) including phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ), oxcarbazepine (OXC), primidone, mephenytoin, phenobarbitone and felbamate; Non-enzyme inducers antiepileptic drugs (NEI-AEDs) including valproic acid (VPA), lamotrigine (LMT), clonazepam (CLZ), gabapentin (GBP), topiramate (TPM), eslicarbazepine (ESL), etosuximide, levetiracetam (LEV), vigabatrin, acetazolamide, clobazam, felbamate, lacosamide, pregabalin (PGB), zonisamide, divalproex sodium, methsuxime and tiagabine; Bone mineral Density (BMD); vertebral fracture (VF); Incidence rate (IR); Hazard ratio (HR); Odds ratio (OR).

To evaluate any risk fracture differences among patients on chronic AED treatment and controls five studies (48, 58, 62, 65, 71) encompassing 493418 subjects were pooled. The meta-analysis showed that patients on AED treatment had an estimated odd risk of fracture of 3.594 (CI 95%: 1.424–9.073) with a significant heterogeneity across studies (I2 =100%, p<0.001) (Fig. 6).

Figure 6.

Forest plot of the meta-analysis on fracture risk differences in patients on chronic antiepileptic treatment compared with healthy controls.

Effectiveness of Osteoporosis Medication in Epileptic Patients Using AEDs

Few studies are available in the literature regarding the effectiveness of osteoporosis medication on attenuating fracture-risk among patients with epilepsy. As already described, it is assumed that one of the mechanisms by which AEDs cause bone damage is interference with calcium and vitamin D metabolism; for this reason, some authors have evaluated the effectiveness of calcium and vitamin D supplements as a preventive therapy.

Espinosa et al. included in their retrospective cohort study 3,303 epileptic veterans (of whom 162 were taking calcium and vitamin D supplements). This study suggests that the use of calcium and vitamin D in this setting of patients does not provide significant fracture prevention benefits. One possible reason for this result is that healthcare providers prescribed supplements only to patients considered to be at higher risk of fractures (72).

A prospective randomized trial, published by Mikati et al., investigated the effects of two doses of vitamin D (400 IU/day and 4000 IU/day given over 1 year) on BMD in 72 ambulatory patients on long-term AED therapy. High-dose vitamin D supplements increased BMD significantly at several skeletal sites but did not normalize it at one year; these results were not obtained with low-dose supplements (32).

Another prospective study evaluated the effect of a large oral dose of 120,000 IU of vitamin D on phalangeal bone ultrasound (Ad-SOS) values in 30 patients; one month after administration, Ad-SOS values increased nearly to the mean basal value of the control group (16).

Other studies have examined the effectiveness of osteoporosis drugs in epileptic patients. Whitney D. published two observational cohort studies that evaluated the impact of osteoporosis medication on fracture risk and mortality risk in a cohort including epileptic and non-epileptic subjects. Osteoporosis medication is associated with significant attenuation of 12-month non-trauma fracture risk and with a 30% reduction in 3-year mortality risk (with effect noticeable by 6 months) among adults with epilepsy (56, 73). A prospective double-blind randomized placebo-controlled study published by Lazzari et al. evaluated whether the use of a bisphosphonate (risedronate) in addition to calcium and vitamin D can prevent the loss of BMD and the occurrence of fractures in a group of male veterans with epilepsy on AED therapy. More than 65% of the patients in the placebo group (receiving only calcium and vitamin D supplements) showed a significant increase in BMD, supporting the beneficial effects of these supplements in this population. However, in the risedronate group, a greater number of subjects showed significant improvement in BMD. New fractures (vertebral and non-vertebral) were observed only in the placebo group (74).

DISCUSSION

The detrimental effects of chronic AED therapy on bone health have been studied extensively, but the mechanisms behind bone damage are still poorly understood. The increased risk of fracture observed in epileptic patients cannot be attributed solely to the increased risk of falls associated with seizures. Studies have demonstrated that even after excluding seizure-related fractures, the overall fracture risk remains high (75, 76), particularly among individuals traditionally considered low risk for osteoporosis and fragility fractures, such as male and young patients (77).

The pathophysiological mechanisms behind bone fragility in epileptic patients are not fully understood. Diemar et al. have described the coexistence of multiple mechanisms influencing bone health in epilepsy. Some of these mechanisms are associated with the epileptic pathology itself, while others are related to chronic AED use (9).

These drugs are associated with an increased fracture risk mediated by different mechanisms. Firstly, they can decrease vitamin D serum levels. Indeed, EI-AEDs exert their effects on 25OHD status by inducing the liver's cytochrome P450 enzyme system (78). A variety of drugs can affect cytochrome P-450 activity, which is a key enzyme metabolizing endogenous and exogenous substances in the human body. In vitamin D metabolism, EI-AEDs accelerate the rate of 25OHD and 1α-25-dihydroxyvitamin D catabolism to inactive metabolites, leading to vitamin D deficiency (79). However, it remains controversial over the effects of NEI-AEDs, such as VPA, on the 25OHD levels. Some studies suggested that VPA monotherapy had a negative effect (80, 81), but others denied that 25OHD levels could be affected by VPA treatment (82).

In accordance, almost all case-control studies included in our review reported lower serum 25OHD and higher serum ALP levels in epileptic patients on AED therapy compared to controls. Our meta-analysis clearly showed in a large set of studies a significant 25OHD reduction (Fig. 3). The present review and meta-analysis confirmed that 25OHD deficiency is primarily caused by EI-AEDs (Fig. 4a and Fig. 4b). In other words, we confirmed the necessity to supplement with vitD all patients starting or taking EI-AEDs treatment. More conflicting results were found for other markers of bone metabolism (e.g., serum calcium, phosphate, urinary markers, etc.).

The alteration of calcium and vitamin D metabolism could be among the causes of the reduction in BMD values and the increased fracture risk, which are already reported in the literature (83, 84) and are confirmed by our review and meta-analysis (Fig. 5 and Fig. 6). Patients undergoing chronic AED therapy exhibit lower BMD values and a higher rate of BMD loss compared to the general population. Moreover, almost all studies included, and, above all, the present meta-analysis agree that the chronic use of AEDs leads to an increased risk of fractures, although the extent of this increase varies among studies from very limited to almost double compared to controls (Fig. 6).

Both BMD values and fracture risk in epileptic patients appear to be negatively affected by common factors such as cumulative AED load, number of AEDs, and use of EI-AEDs. NEI-AEDs (such as VPA, LEV, LMT, GBP, ESL) appear to have a less detrimental effect on bone health, although studies often show divergent results, in particular concerning VPA and LEV.

Additional well-designed studies with larger sample sizes would be required to confirm the hypothesis that EI-AEDs have more harmful effects on bone health than NEI-AEDs.

Our review also analysed the studies available in the literature regarding the use of vitamin D supplements and osteoporosis therapy in epileptic patients.

The retrospective study published by Espinosa et al. suggests that the use of calcium and vitamin D in patients using AEDs does not provide significant benefits in terms of preventing fractures (72); however, one possible reason for this result is that supplements were only prescribed for patients at higher risk of fractures. Two prospective studies suggest the usefulness of high-dose vitamin D supplements for preventive purposes; however, these trials also have limitations such as a small sample size and short observational period.

In addition, both EI-AEDs and NEI-AEDs are also thought to have a direct effect on bone cells, independent of alterations in vitamin D levels, as demonstrated by preclinical studies on animal models and cell cultures (9).

AED administration is also associated with adverse effects on the endocrine system, including increased catabolism of sex steroids, increased production of sex hormone-binding globulin, impaired thyroid function, alterations in vitamin K, leptin, homocysteine, and insulin-like growth factor 1 (85, 86). Another important and common adverse effect of AEDs is chronic hyponatremia (87), which is a well-known risk factor for osteoporosis and frailty fractures.

However, the BMD loss alone does not fully account for the increased fracture risk observed in these patients (75), as is the case with classical forms of secondary osteoporosis, suggesting an alteration in bone quality and structure.

Other common adverse effects of AEDs include confusion, dizziness, and unsteadiness [76], further increasing the already high risk of falls in epileptic patients.

Finally, only three studies concerning the effectiveness of osteoporosis medications met the criteria for inclusion in our review. These agree on the effectiveness of the therapy in improving BMD (with results higher than with calcium and vitamin D supplements alone) and even in reducing the 3-year mortality risk in epileptic patients. Again, more studies are needed to confirm these results and to obtain more useful information to guide the prescription of osteoporosis medications in this category of patients.

In conclusion, chronic use of AEDs is associated with alterations in bone metabolism, low BMD values, and an increased risk of fractures. These effects appear to be more closely linked to the use of EI-AEDs mainly due to a decrease in 25OHD levels; however, further studies are needed to determine the true impact of NEI-AEDs on bone health. Currently, there are few papers available on the prevention of bone damage in epileptic patients receiving chronic AED therapy. Vitamin D supplements alone seem to offer advantages in terms of improving BMD, although the limited studies on therapy for osteoporosis (e.g., bisphosphonates) demonstrate significant benefits in terms of increase in BMD and even a reduction in the 3-year mortality risk. However, more studies are required to gather useful information to guide the management of osteoporosis therapy in this patient population.

Conflict of interest

The authors declare that they have no conflict of interest.