ANTICONVULSANT THERAPY AND THE RISK OF OSTEOPOROSIS IN WOMEN OF CHILDBEARING AGE

107 ActaCAMU № 4 (12) 2025 ISSN: 2181-4155 ANTICONVULSANT THERAPY AND THE RISK OF OSTEOPOROSIS IN WOMEN OF CHILDBEARING AGE ПРОТИВОСУДОРОЖНАЯ ТЕРАПИЯ И РИСК ОСТЕОПОРОЗА У ЖЕНЩИН ФЕРТИЛЬНОГО ВОЗРАСТА TUG'ISH YOSHIDAGI AYOLLARDA ANTIKONVULSANT TERAPIYA VA OSTEOPOROZ XAVFI Yusupova Dilnoza Yusupovna https://orcid.org/0009-0001-0278-5580 Muratov Fakhmitdin Khayritdinovich https://orcid.org/0000-0003-4587-0301 Tashkent State Medical University, Uzbekistan Abstract. Epilepsy is one of the most prevalent neurological disorders, affecting approximately five million people worldwide, which accounts for 0.5–1% of the global population. Many patients require long-term or even lifelong anticonvulsant therapy to manage seizures effectively. However, beyond their primary therapeutic benefits, these drugs can have significant long-term side effects. Prolonged use of antiepileptic drugs (AEDs) has been linked to metabolic disturbances, including impaired bone metabolism, alterations in calcium and vitamin D levels, and an increased risk of osteoporosis, especially in women of reproductive age. Given these risks, modern research focuses on developing safer and more effective AEDs with fewer adverse effects, minimal drug interactions, and lower enzyme induction. Understanding the broader impact of AEDs on systemic health is essential for optimizing treatment approaches and improving patients' overall wellbeing. Keywords: epilepsy in women, bone metabolism, anticonvulsant therapy, side effects. Аннотация. Эпилепсия — одно из наиболее распространенных неврологических заболеваний, поражающее около пяти миллионов человек во всем мире, что составляет 0,5– 1% населения планеты. Многим пациентам требуется длительная или даже пожизненная противосудорожная терапия для эффективного купирования приступов. Однако, помимо основных терапевтических преимуществ, эти препараты могут иметь значительные долгосрочные побочные эффекты. Длительное применение противоэпилептических препаратов (ПЭП) связано с метаболическими нарушениями, включая нарушение метаболизма костной ткани, изменения уровня кальция и витамина D, а также повышенный риск остеопороза, особенно у женщин репродуктивного возраста. Учитывая эти риски, современные исследования сосредоточены на разработке более безопасных и эффективных ПЭП с меньшим количеством побочных эффектов, минимальным лекарственным взаимодействием и меньшей индукцией ферментов. Понимание более широкого влияния ПЭП на системное здоровье имеет важное значение для оптимизации подходов к лечению и улучшения общего самочувствия пациентов. Ключевые слова: эпилепсия у женщин, метаболизм костной ткани, противосудорожная терапия, побочные эффекты. Xulosa. Epilepsiya eng keng tarqalgan nevrologik kasalliklardan biri bo'lib, butun dunyo bo'ylab taxminan besh million kishiga ta'sir qiladi, bu dunyo aholisining 0,5-1% ni tashkil qiladi. Ko'pgina bemorlar tutqanoqlarni samarali nazorat qilish uchun uzoq muddatli yoki hatto umrbod 108 ActaCAMU № 4 (12) 2025 ISSN: 2181-4155 antikonvulsant terapiyaga muhtoj. Biroq, ularning asosiy terapevtik foydalaridan tashqari, bu dorilar uzoq muddatli sezilarli yon ta'sirga ega bo'lishi mumkin. Antiepileptik dorilarni (AED) uzoq muddatli qo'llash metabolik buzilishlar, jumladan, suyak metabolizmining buzilishi, kaltsiy va D vitamini darajasining o'zgarishi va osteoporoz xavfining ortishi bilan bog'liq, ayniqsa reproduktiv yoshdagi ayollarda. Ushbu xavflarni hisobga olgan holda, hozirgi tadqiqotlar kamroq yon ta'sirga ega, minimal dori ta'siriga ega va ferment induksiyasining pasayishiga ega xavfsizroq va samaraliroq AEDlarni ishlab chiqishga qaratilgan. AEDlarning tizimli sog'liqqa kengroq ta'sirini tushunish davolash usullarini optimallashtirish va bemorlarning umumiy farovonligini yaxshilash uchun juda muhimdir. Kalit so'zlar: ayollarda epilepsiya, suyak metabolizmi, antikonvulsant terapiya, yon ta'sirlar. Introduction (Heading 1). Patients with epilepsy often suffer from concomitant chronic diseases requiring additional medications. As a result, the combination of different drugs can lead to complex pharmacologic interactions and have a negative impact on bone mineral metabolism [1]. Studies show that more than half of adult patients with epilepsy on long-term ADS’s have reduced bone mineral density (BMD) at the spine or hip [2]. Specifically, these patients have a 1.3-3.8-fold, 1.7-3.8-fold, and 1.7-6.1-fold increased risk of osteopenia, osteoporosis, and pathologic fractures, respectively. Osteoporosis is a chronic metabolic disease of the bone system characterized by decreased bone mass and impaired bone microarchitecture, resulting in increased bone fragility and increased fracture risk [3]. Prolonged intake of ADS’s, especially in high doses, may contribute to the development of osteoporosis and osteopenia, and increase the incidence of fractures, especially in the region of vertebral bodies and femoral neck [4-7]. Materials and research methods. This study examines the effects of carbamazepine (CBZ) on bone mineral density in patients on monotherapy with this drug for different times and doses. The analysis includes examining changes in biochemical indicators of bone metabolism such as levels of calcium, vitamin D, parathyroid hormone, osteocalcin and markers of bone resorption. The findings will help to better understand the potential risks of osteoporosis in patients taking CBZ and develop recommendations for the prevention of bone metabolism disorders in this patient group. This study was conducted from 2022 in the clinic of the Tashkent Medical Academy, with a duration of follow-up ranging from eight months to ten years. Inclusion criteria:  Age of participants between 18 and 50 years.  Diagnosis of epilepsy confirmed by clinical and electroencephalographic data.  At least 12 months of CBZ monotherapy.  No dosage changes in the last 6 months.  BMI within the range of 18.5-30 kg/m².  Absence of severe vitamin D deficiency (25-OHD level ≥ 20 ng/mL at the time of inclusion). Exclusion criteria:  Presence of concomitant neurologic diseases other than epilepsy.  History of fracture, osteoporosis, or other bone abnormalities.  Diabetes mellitus, chronic liver and kidney disease, gastrointestinal disorders affecting nutrient absorption.  Long-term use of drugs that can affect bone metabolism.  Postmenopausal, pregnant or breastfeeding women.  BMD below 18.5 or above 30 kg/m². As part of the study, all patients underwent a comprehensive neurologic and physical examination. At admission, parameters such as age, BMI, age of onset of epilepsy, duration and dosage of CBZ, and frequency and pattern of epileptic seizures were recorded. Laboratory investigations included determination of serum levels of 25-hydroxyvitamin D (25-OHD), total calcium, and parathormone. 109 ActaCAMU № 4 (12) 2025 ISSN: 2181-4155 Bone mineral density (BMD) was assessed in the lumbar vertebrae (L1-L4) and femoral neck, with subsequent analysis of the corresponding T-criteria. Statistical processing of the data was performed using IBM SPSS 22 (IBM SPSS) program, with the significance level set at p <0.05. The Shapiro-Wilks test was used to assess the distribution of numerical indices. Comparison of quantitative data between groups in the absence of normal distribution was performed using the Kraskell-Wallis criterion, and the Mann-Whitney U-test was used for pairwise analysis. Pearson correlation analysis was used to identify relationships between parameters having normal distribution. Result and discussion. The study included 50 patients divided into three groups according to the duration of HPA intake: group A (< 1 year, n = 12), group B (1-5 years, n = 28) and group C (> 5 years, n = 10). Bone mineral density (BMD) and blood biochemical parameters were analyzed. The mean age of the participants was 34.2 ± 12.8 years (19 to 55 years). There were 22 women (44%) and 28 men (56%) in the sample. BMI averaged 26.1 ± 4.1 kg/m² (19.5 to 34.7 kg/m²). The age of onset of epilepsy ranged from 12 to 42 years, averaging 29.4 ± 7.9 years. Among seizure types, generalized seizures predominated with 61.5% (including typical absences, myoclonic and generalized tonic-clonic seizures), whereas focal seizures accounted for 38.5% of cases. The mean duration of CBZ use was 3.1 ± 2.5 years (0.7 to 9.5 years), and the mean daily dose of the drug was 1085 ± 410 mg (450 to 2900 mg). The majority of patients (45 patients, 90%) were taking a dosage of 1000 mg/day or higher, whereas 5 patients (10%) were taking less than 1000 mg/day. Figure 1 Comparison of Calcium, Vitamin D, and PTH Levels in Different Therapy Duration Groups Mean calcium levels were 2.22 ± 0.08 mmol/L in group A, 2.28 ± 0.07 mmol/L in group B, and 2.24 ± 0.09 mmol/L in group C. The insignificant differences indicate that calcium homeostasis remains stable regardless of the duration of therapy. Vitamin D levels differed significantly between groups (p = 0.007). Mean values were 25.5 ± 4.2 nmol/L in group A, peaked at 30.8 ± 5.1 nmol/L in group B, and then decreased to 26.4 ± 4.7 nmol/L in group C. Post-hoc pairwise comparisons showed a significant difference between groups A and B (p = 0.009), whereas the difference between groups B and C did not reach statistical significance (p = 0.08). This pattern suggests an initial increase in vitamin D levels on therapy, but a possible long-term decrease, possibly due to metabolic changes. The PTH level showed no statistically significant difference between the groups (p = 0.21), with mean values of 45.2 ± 8.6 pg/mL in group A, 40.1 ± 7.9 pg/mL in group B, and 42.3 ± 9.2 pg/mL in group C. Although there was a slight decrease in group B and an increase in group C, these changes probably reflect compensatory mechanisms without a clear trend (Fig. 1). The findings suggest that long-term therapy with CBZ has no significant effect on calcium and PTH levels. However, vitamin D levels show a biphasic response with an initial increase and subsequent decrease in long-term users of the drug. Analysis shows that calcium and phosphorus have a weak positive correlation, which may indicate their relationship in mineral metabolism. Parathormone shows a moderately negative correlation with calcium levels, which is consistent with physiologic mechanisms: when calcium decreases, parathormone levels increase. Duration of therapy correlates weakly with calcium and 110 ActaCAMU № 4 (12) 2025 ISSN: 2181-4155 phosphorus levels, but tends to be positively correlated with parathormone, which may indicate compensatory mechanisms arising in response to prolonged use of anticonvulsants (Fig. 2). Figure 2. Correlation with calcium, phosphorus, PTH and therapy duration The mean BMD in the L1-L4 region, which was 0.99 ± 0.13 (range: 0.690-1.230), and the Tscore in this area was -0.79 ± 1.14 (range: -3.6 to 1.7). As a result, 27 subjects (58.7%) had normal values, 16 (34.8%) had osteopenia and 3 (6.5%) were diagnosed with osteoporosis. The mean BMD value in the femoral neck was 0.86 ± 0.13 (range: 0.590-1.230), and the Tscore was -0.32 ± 1.10 (range: -2.2 to 2.0). According to these parameters, 29 patients (63%) had normal bone density, whereas 17 (37%) had osteopenia. The total femoral bone mineral density was 0.97 ± 0.14 (range: 0.690 to 1.310) and the total T-score was -0.05 ± 0.88 (range: -2.2 to 1.9). In this group, 41 patients (89.1%) had normal values and 5 (10.9%) were diagnosed with osteopenia. Statistical analysis revealed significant differences in L1-L4 BMD, L1-L4 T-score, L2-L4 BMD and L2-L4 T-score according to the duration of CBZ intake (Table 1). According to pairwise analysis, the differences were statistically significant between group A (<1 year) and group C (>5 years) (Table 1). Table 1: Bone assessment according to the duration of CBZ application Bone assessment Group A Group B Group C p L1-L4 BMD (g/sm³) 0,91 1,01 0,98 0,041* L1-L4 T Score -1,5 -0,47 -0,80 0,052* BMD of femoral neck (g/sm³) 0,81 0,86 0,88 0,024 T-score of the femoral neck -0,73 -0,35 -0,28 0,031 Total femoral BMD (g/sm³) 0,96 0,99 1,02 0,075 p < 0,05. The results show that patients with shorter duration of CBZ intake (<1 year) have lower BMD values, especially in the lumbar spine (L1-L4). At the same time, patients taking the drug for more than 5 years have higher BMD and T-score values, which may indicate bone tissue adaptation mechanisms or a lesser effect of the drug on bone density in the long term. Analysis of BMD values in different zones revealed that the lumbar spine (L1-L4) is more susceptible to density reduction than the femur. This may be due to the different dynamics of bone metabolism in these zones, as well as the fact that the trabecular bone of the spine is more sensitive to metabolic changes. In contrast to the lumbar region, femoral neck BMD and total femoral bone 111 ActaCAMU № 4 (12) 2025 ISSN: 2181-4155 density did not show significant differences between the groups. This may mean that femoral bone tissue is less sensitive to the effects of BMD or that changes in it are manifested in the longer term (Fig. 3). Figure 3. BMD and T Score at different durations of therapy It has been previously shown that some antiepileptic drugs can cause a decrease in bone density by altering calcium, vitamin D, and parathormone metabolism. However, in the case of CBD, there is no clear evidence of its pronounced negative effects on bone, which is confirmed by the absence of critical changes in BMD in patients with long-term use of the drug. The findings emphasize the need to monitor bone metabolism in patients starting KBZ therapy, especially in the first year. Despite the lack of significant differences in femur, decreased BMD in lumbar BMD requires special attention, especially in patients with additional risk factors for osteoporosis. However, the study has several limitations. First, the relatively small sample may limit the generalizability of the results. Second, additional factors such as physical activity level, nutrition, and comorbidities that may affect bone density were not considered. Conclusions. Overall, the results indicate that patients taking CBZ for less than a year have lower bone mineral density, particularly in the lumbar spine. Long-term use of the drug is not associated with a significant decrease in BMD, which may indicate the presence of adaptive mechanisms. 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