1 INTRODUCTION

Epilepsy is a common and chronic neurological disorder affecting ~ 60 million people worldwide.¹ The current body of research increasingly supports the phenomenon of declining bone health, resulting in an elevated risk of fractures in individuals with epilepsy. Factors contributing to the increased fracture risk in patients with epilepsy have been identified, including age, race, comorbidities, levels of physical activity, and seizure-related functional impairment.^{2, 3} Specifically, patients with epilepsy exhibit reduced levels of physical activity and a diminished motivation to exercise.³ Furthermore, patients with epilepsy often present comorbidities such as intellectual disability and emotional disorders, which are independent risk factors for the development of osteoporosis.^4-6 Additionally, a higher prevalence of pathological fractures has been documented among men aged 30–49 years and women aged 50–59 years and 70–79 years who have epilepsy.⁷

However, the use of antiseizure medications (ASMs) is one of the important causes of osteoporosis in patients with epilepsy.^8-11 The treatment of epilepsy relies mainly on the use of ASMs, and more than half of the people using these drugs must continue to do so for the rest of their lives.¹² Although later-generation ASMs are significantly safer than first-generation ASMs, the impact of new ASMs on bone health is still controversial. However, notably, no studies have focused on the effect of perampanel (PER) on the bone health of patients with epilepsy. PER is an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist with high selectivity and noncompetitive properties and has gained approval in numerous countries globally for its efficacy in managing diverse forms of seizures associated with different epileptic disorders. In animal studies, PER has been shown to regulate the expression of the proinflammatory cytokines TNF-α, IL-1β, and TGF-β1.^{13, 14} The impact of PER on BMD remains unexplored, despite extensive research on the regulatory effects of three cytokine types on osteoblasts and osteoclasts in relation to bone metabolism.^15-18

Therefore, the objective of this study was to assess bone metabolism and BMD in adult epilepsy patients treated with PER. BMD and related indicators (including hormone levels, serum electrolyte levels, and alkaline phosphatase [ALP] levels) were measured in adult epilepsy patients who received PER for 1 year and compared with untreated epilepsy patients. Additionally, we also examined the impact of PER on bone mineral density (BMD) in a subset of epilepsy patients before and after treatment to further validate the findings.

2 STUDY DESIGN

2.1 Patient recruitment

This study retrospectively and consecutively included patients who were admitted to the Epilepsy Center of Sichuan Provincial People's Hospital from January 2023 to June 2024. The diagnosis and categorization of epilepsy were conducted according to the guidelines suggested by the International League Against Epilepsy.^{19, 20} Patients who underwent PER monotherapy for 1 year were categorized into the PER group. Additionally, patients who were newly diagnosed with epilepsy and had not yet received any form of treatment were continuously included in the untreated group. The two groups were then studied cross-sectionally (Figure 1).

The inclusion criteria are listed below.

The PER group of patients.

1. Were > 16 years of age;
2. Had a diagnosis that was consistent with the guidelines suggested by the International League Against Epilepsy.
3. Had complete sociological and clinical data available for this study after 1 year of PER treatment.

The untreated group of patients.

1. Were > 16 years of age;
2. Had a diagnosis that was consistent with the guidelines suggested by the International League Against Epilepsy.
3. Had complete sociological and clinical data required for this study when ASMs were not used.

The exclusion criteria were as follows:

1. Individuals with a prior medical history of skeletal disorders, cancerous tumors, mental illness, diabetes, thyroid irregularities, PTH abnormalities, and other diseases.
2. Individuals taking medications that potentially impact bone metabolism, such as glucocorticoids, estrogen, Ca, and vitamin D supplements, vitamin A supplements or diuretics, any antineoplastic agents, or other medicines that should be considered;
3. Individuals with physical disabilities, neurological impairments, compromised cardiopulmonary function, and other conditions leading to reduced activity levels
4. Individuals consuming a ketogenic or vegan diet or having other dietary restrictions.

Second, we conducted a subgroup analysis of patients stratified by seizure frequency and type to evaluate the impact of PER treatment on bone metabolism and BMD in patients with epilepsy with identical seizure characteristics. Third, within the PER group, patients were further stratified according to their seizure frequency and seizure type to evaluate the impact of these factors on bone metabolism and BMD in patients with epilepsy receiving PER treatment. Finally, we performed a cohort study involving 10 PER-treated patients whose baseline data were available prior to initiating PER therapy.

This study was approved by the Research Ethics Committee of Sichuan Provincial People's Hospital, and the application for exemption from informed consent was approved.

3 RESULTS

A total of 631 patients with epilepsy underwent treatment with PER, 64 of whom received monotherapy with PER and had available data on bone metabolism and BMD. After applying the exclusion criteria, 25 subjects were excluded from the study. The reasons for exclusion included the following: 6 individuals who were taking vitamin D or Ca supplements; 2 individuals who were on diuretics; 7 individuals who had neurological deficits due to stroke, dementia, or Parkinson's disease; 3 individuals with psychiatric disorders; 2 individuals with hyperthyroidism; 1 individual with heart failure; 2 individuals with cancer; and 2 individuals following a ketogenic diet. Ultimately, 39 eligible subjects were included in this study.

4 DISCUSSION

For both traditional and new ASMs, negative reports regarding BMD have emerged.^21-25 The incidence of vertebral fracture can reach 16.7% when liver enzyme-inducing ASMs, such as carbamazepine, phenobarbital, phenytoin, and valproic acid, are administered for a duration exceeding 2 years.²⁶ Levetiracetam, either alone or in combination with other agents, has been found to have adverse effects on BMD in adults with epilepsy.²¹ Similarly, oxcarbazepine has been associated with disturbances in bone metabolism among children with epilepsy.²⁷ Controversy arises when considering the use of certain new ASMs, such as oxcarbazepine, levetiracetam, and lamotrigine, because they have been documented to have no impact on bone health; however, other studies have revealed that their use is associated with adverse effects on BMD.^{21, 25, 27-29} ASMs can affect BMD through a variety of mechanisms, such as hepatic cytochrome P450, parathyroid dysfunction, and vitamin D deficiency.^{1, 30}

Regardless of the method used, our assessments of the impact of PER on bone health revealed no discernible effect on BMD in our study. Consequently, the short-term use of PER does not appear to have any effect on bone health in patients with epilepsy. Several potential reasons for this finding exist. First, PER exhibits high specificity for AMPA receptors located primarily within the central nervous system,³¹ suggesting minimal influence on the peripheral tissues or organs responsible for the secretion of hormones related to bone metabolism, such as the parathyroid and thyroid glands.³² Our results confirm this hypothesis through the analysis of BMD-related hormones, such as thyroxine, PTH, and CT, which revealed no significant differences or minimal differences following 1 year of PER usage. Furthermore, two animal experiments revealed notable changes in cytokine levels in rats after a PER intervention, with reduced expression levels of IL-1β and TNF-α and increased expression levels of IL-10 and TGF-β1.^{13, 14} The proliferation and differentiation of osteoclasts, which contribute to bone resorption, can be stimulated by IL-1β and TNF-α.^{33, 34} Conversely, inhibiting the expression levels of these factors increases the BMD.³⁵ Additionally, IL-10 and TGF-β1 enhance the tissue microenvironment, stimulate stem cell proliferation, and promote osteogenic differentiation, facilitating accelerated bone regeneration.³⁶ Therefore, the observation that PER may not confer potential harmful effects on the bone health of patients with epilepsy is plausible.

The majority of the bone metabolism parameters did not differ significantly in this study; however, the Mg and FT4 levels were slightly elevated among the epilepsy patients who were treated with PER. In a subgroup analysis, patients with annual seizures who were treated with PER presented higher levels of FT4. In subgroup analyses focusing on patients with focal epilepsy, both FT4 and TT4 levels were elevated in patients receiving PER. Conversely, in the subgroup categorized as unknown, TT4 levels were lower in patients treated with PER. However, reduced TT4 levels in patients with unclassified seizure types may reflect the limited statistical power due to the small subgroup sample sizes.

These differential outcomes underscore potential pathophysiological interactions between the PER mechanism of action and neuroendocrine regulation specific to focal epilepsy. Current evidence highlights substantial interdrug variability in the thyroid-modulating effects of ASMs. Nonenzyme-inducing ASMs, such as levetiracetam, cause negligible thyroid disruption,²⁷ whereas enzyme-inducing agents, such as oxcarbazepine, reduce FT4 levels through hepatic cytochrome P450 activation.³⁷ As a selective AMPA receptor antagonist, PER diverges pharmacodynamically from conventional ASMs, potentially influencing hypothalamic–pituitary–thyroid (HPT) axis activity by modulating glutamatergic signaling. Preclinical models have revealed that thyroid hormone imbalances (e.g., developmental hypothyroxinemia) impair hippocampal synaptic plasticity through AMPA receptor subunit GluR1 dephosphorylation,³⁸ suggesting a bidirectional regulatory relationship between PER-mediated AMPA receptor inhibition and thyroxine homeostasis. Notably, Mendelian randomization analyses have refuted causal associations between thyroid dysfunction and epilepsy subtypes,³⁹ reinforcing the hypothesis that the thyroid effects of PER are pharmacologically driven rather than secondary to disease pathology. Nevertheless, current conclusions remain constrained by short-term observational data and insufficient mechanistic validation.

Mg deficiency has been suggested to be associated with a decreased BMD and increased fracture risk, whereas Mg supplementation contributes to improved bone health.^{40, 41} For example, multiple meta-analyses have consistently demonstrated a positive correlation between Mg intake and BMD at the hip and femoral neck.⁴² Therefore, an increase in Mg levels may mitigate bone loss. Thyroid hormones play crucial roles in maintaining bone health; however, the impact of FT4 on BMD remains controversial. Specifically, certain groups have proposed that elevated FT4 levels are associated with increased BMD in adults and exert a more favorable effect on cortical bone.⁴³ Conversely, another study reported that increased FT4 levels contribute to adult bone loss.⁴⁴ Furthermore, some studies have indicated no correlation between FT4 levels and BMD in women of childbearing age.⁴⁵ The correlation between TT4 levels and BMD appears to be relatively weak. In one study, TT4 levels were weakly negatively associated with BMD in postmenopausal women and young men, whereas no significant associations were observed in other populations.⁴⁶ Consequently, the impact of PER on bone metabolism in patients with epilepsy remains ambiguous, with no definitive evidence indicating whether it exerts a positive or negative effect.

Finally, this study has several limitations. (1) Notably, the limited observation time or small sample size in this study might have hindered the detection of a significant effect of PER treatment. (2) Full matching of the dietary and behavioral patterns of the enrolled patients was not possible. For example, vegetarian diets can induce changes in BMD, and effective means to intervene and verify patient diets for achieving dietary matching between groups are lacking. (3) Although no differences in seizure frequency were observed between groups, the severity and duration of seizures might also influence BMD; however, in the present study, quantifying this impact effectively proved challenging.

5 CONCLUSIONS

Our findings suggest that PER treatment does not adversely affect bone health in patients with epilepsy over a one-year period.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose.

ETHICS STATEMENT

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.