Objective: The prolonged usage of antiepileptic medicines has been linked to a reduction in bone mineral density (BMD), resulting in the risk of fracture. However, most evidence has been from western countries, predominantly in institutionalized patients. Furthermore, only a single antiepileptic drug (AED) has been evaluated. This study explores the impact of AEDs on bone health in ambulatory patients from North India. Methodology: A hospital-based observational study on sixty adult patients with epilepsy. All patients were already on AED (valproic acid [VPA], levetiracetam, and phenytoin) either as monotherapy or polytherapy. The serum levels of calcium, phosphorus, alkaline phosphatase, albumin, 25 (OH) Vitamin D, and intact parathyroid hormone were estimated. BMD was assessed at the lumbar spine and femur using a dual-energy X-ray absorptiometry scan. Results: The mean age of patients was 32.75 ± 5.9 years. 56.7% of subjects were female, and 43.3% were male. 40% of patients were taking VPA. Both cytochrome P450 inducing and noninducing AED resulted in a decline in T-score at the lumbar spine (P < 0.01). The BMD declined significantly as the duration of AED intake was prolonged (P < 0.001). Conclusions: In some patients, the intake of AEDs is prolonged, even lifelong. People living with epilepsy are predisposed to falls, and the adverse effects of AED on bone metabolism over time compound the risk of fractures. Thus, the physician needs to monitor all patients on AED for bone health and advise early intervention.
Keywords: Antiepileptic drugs, bone metabolism, bone mineral density
|How to cite this URL:|
Kumar DA, Zafar L, Ashraf H, Ansari AG. Alteration in bone metabolism and bone mineral density with chronic antiepileptic drug therapy. Apollo Med [Epub ahead of print] [cited 2022 Sep 27]. Available from: https://apollomedicine.org/preprintarticle.asp?id=355260
| Introduction|| |
Epilepsy contributes significantly to the burden of neurological diseases worldwide. It affects individuals of all ages, sex, race, social class, and geographical location. The incidence of epilepsy worldwide is 61.4 per 100,000 person-years, and the prevalence is 7.60 per 1000 population. The overall disease burden is 46 million people worldwide and 12 million in India.,
Although antiepileptic drugs (AEDs) are the cornerstone in managing these patients, they are riddled with adverse effects that may impact the quality of life and sometimes result in the discontinuation of therapy. The newer AEDs have better tolerability and safety profiles, but many patients still use conventional medications. All AED need to be prescribed for a prolonged duration resulting in bone abnormalities such as osteomalacia, rickets, osteoporosis, and increased chances of fracture. The most accepted theory attributing bone diseases to AED intake is the hepatic induction of the cytochrome P450 (CYP450) enzyme system, which results in increased catabolism of Vitamin D. In addition, osteocalcin inhibition and reduction of intestinal calcium transport contribute to the detrimental effect of AED. Thus, the harmful effects of AEDs on bone are complex and multifactorial. The enzyme-inducing AEDs such as phenytoin and carbamazepine are most commonly implicated in causing bone disorders. Still, the data on the consequences of noninducing AEDs on bone metabolism are scarce and contentious.
Most research on this aspect of AED has been conducted on the western population and children., The Indian subcontinent differs from the west in the lifestyle, dietary habits, sunlight exposure, ethnicity, and genetic composition. Therefore, it is worth exploring the impact of commonly used AEDs on bone turnover markers and bone mineral density (BMD) in patients of North India.
| Methodology|| |
The study was conducted to estimate the bone turnover markers and BMD (by dual-energy X-ray absorptiometry [DEXA] scan) in epilepsy patients on AED and to correlate them with the duration of AED intake.
It was an observational study conducted at the Department of Medicine and Rajiv Gandhi Centre for Diabetes and Endocrinology at a tertiary hospital in North India. The enrollment of patients began after obtaining Institutional Ethics Committee approval. The study was undertaken between January 2019 and December 2020.
The consecutive 60 patients fulfilling the inclusion criteria were enrolled in the study.
Adult (≥18 years) with epilepsy, on treatment with AEDs, and consent for the study.
Patients with hepatic and renal impairment, chronic smokers, alcoholics, malabsorption syndromes, malignancies, pregnant and postmenopausal females, males >70 years of age, history of glucocorticoid, oral contraceptive pills, and hormone replacement therapy intake. Patients already on calcium supplementation, Vitamin D supplementation, and bisphosphonate therapy were excluded.
Out of 92 patients screened, 13 patients did not give consent, and 19 did not fulfill the criteria. The remaining 60 eligible patients participated in the study.
Fasting peripheral venous blood samples were collected from all participants without a tourniquet. The samples were processed, and serum calcium, phosphorus, alkaline phosphatase (ALP), and albumin were estimated on the same day. The serum sample of 25 (OH) Vitamin D and intact parathyroid hormone (PTH) was stored at 4°C and analyzed within 72 h. BMD was estimated at the level of the femur and lumbar spine by DEXA scan. It was graded as per the WHO classification: T-score ≥−1.0: normal, −1.0 to − 2.5: osteopenia, and ≤−2.5: osteoporosis.
The data were analyzed using IBM SPSS Statistics for Windows, version 26.0 (Armonk, NY, USA).
Numerical variables were reported as the mean ± standard deviation. The Chi-square test analyzed the qualitative variables. The Student's t-test was used to analyze quantitative variables. Pearson's correlation was used to determine the correlation of Vitamin D, serum calcium, serum phosphorous, ALP, PTH, and BMD with types of AED and duration of AED intake. P < 0.05 was considered significant.
| Results|| |
Out of the 60 participants enrolled in the study, there was a female preponderance (56%). The mean age of the subjects was 32.75 ± 5.9 years. The most commonly used (40%) AED was valproic acid (VPA) [Table 1].
Relation of valproic acid intake with laboratory markers and bone mineral density
The serum level of calcium, phosphorus, and 25(OH) Vitamin D was significantly decreased in patients taking VPA for more than 5 years compared to <5 years of VPA intake. The serum levels of calcium, phosphorus, and 25(OH) Vitamin D had a negative correlation with the duration of VPA intake (r = −0.827, −0.839, and − 0.642, respectively, P < 0.01 in all groups). Furthermore, the T-score at the lumbar spine and VPA duration were negatively correlated (r = −0.809, P < 0.01). The PTH and alkaline phosphate levels were positively associated with the duration of VPA intake (r = 0.660 and 0.717, respectively, P < 0.01) [Table 2].
|Table 2: Relation of valproic acid intake with laboratory markers and bone mineral density|
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Relation of levetiracetam intake with laboratory markers and bone mineral density
The T-score at the lumbar spine was − 0.52 ± 0.07, −1.22 ± 0.22, and − 2.35 ± 0.35 in the participants taking levetiracetam (LEV) for <3 years, 3–5 years, and more than 5 years, respectively. Thus, BMD decreased with the duration of LEV intake (correlation coefficient-0.963, P < 0.01). Serum levels of calcium, phosphorus, and 25(OH) Vitamin D negatively correlated (r = −0.808, −0.685, and − 0.905 respectively, P < 0.01 for all) and iPTH, ALP levels positively correlated (0.800 and 0.822, respectively, P < 0.01 for both) with the duration of LEV intake [Table 3].
|Table 3: Relation of Levetiracetam intake with laboratory markers and bone mineral density|
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Relation of phenytoin intake with laboratory markers and bone mineral density
In the study, only seven participants took phenytoin, and none took it for more than 5 years. The mean 25(OH) Vitamin D levels were 21.45 ± 4.50 ng/ml and 20.00 ± 2.16 ng/ml in subjects on phenytoin for <3 years and 3–5 years, respectively. The serum calcium and phosphorus levels negatively correlated with the intake duration (r = −0.840, P < 0.01 and r = −0.806, P < 0.05, respectively).
Relation of combination therapy of antiepileptic drug with laboratory markers and bone mineral density
Similar observations were made in the participants taking a combination of AED. The calcium, phosphorus, and 25(OH) Vitamin D levels declined as the duration of drug intake increased (correlation coefficient − 0.810, −0.664, and − 0.807, respectively, P < 0.01). Furthermore, a negative correlation was observed between the lumbar spine T-score and the therapy duration (correlation coefficient − 0.886, P < 0.01) [Table 4].
|Table 4: Relation of combination therapy with laboratory markers and bone mineral density|
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Bone mineral density and duration of antiepileptic drug
The study participants were divided into three subgroups depending on the duration of AED intake, irrespective of the type of AED. The lumbar spine T score was categorized into normal, osteopenic, and osteoporotic. The duration of AED intake was compared with the T score. It was observed that 4 out of 6 participants on AED for >5 years had a T score <−2.5, whereas none of the patients in other groups had osteoporosis. In addition, only 1 out of 28 patients in <3, 19 out of 26 patients in the 3–5 years group, and 2 out of 6 patients in >5 years group had T-scores between − 1.0 and − 2.5 in the lumbar region. The correlation of BMD with the duration of AED intake was significant (P < 0.001) [Table 5].
|Table 5: Association of the duration of antiepileptic drug with T-score (lumbar spine)|
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Along with the duration of AED, reduction in BMD was also related to significantly elevated levels of PTH, ALP, and age across the three categories of BMD. Reduced BMD was also associated with a decline in serum calcium, phosphorus, and Vitamin D. There was no significant difference in the gender distribution in the BMD categories [Table 6].
|Table 6: Difference between normal bone mineral density, osteopenia and osteoporosis|
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| Discussion|| |
In the past few years, there has been mounting evidence that antiepileptic medications can negatively affect bone mineralization and calcium homeostasis. Our study evaluated the effect of multiple AEDs, both enzyme inducers and noninducers, on bone metabolism. Few studies conducted in the past have not delineated the type of AED used and have taken all AEDs as a single group. This is perhaps a pioneer study from Northern India that has comprehensively explored this aspect of prescribed AEDs.
Of the 60 participants, 24 were taking VPA, followed by polytherapy in 16 patients, LEV in 13, and phenytoin in 7 patients. Most patients were on monotherapy (73.3%) rather than multiple AED. The choice of AED depends on factors such as the type of epilepsy, comorbid conditions, side effect profile, affordability, availability, and physicians' discretion.
VPA is a broad-spectrum AED widely prescribed for other neurological diseases like migraine. In our study, in epileptic patients, VPA was observed to reduce levels of Vitamin D with prolonged use (r = −0.642, P < 0.01). The serum iPTH and ALP levels positively correlated with the duration of VPA intake (r = 0.660, P < 0.01 and r = 0.717, P < 0.01, respectively). The T-score at the lumbar spine was suggestive of osteoporosis in participants on VPA therapy for >5 years. The BMD was observed to decline as the years of VPA intake increased (r = 0.809, P < 0.01). Boluk et al. also observed that VPA monotherapy increased serum PTH and ALP levels and reduced BMD for more than a year in young adults. In a meta-analysis by Fan et al., to assess the effect of VPA on BMD and bone metabolism, it was observed that the BMD at the lumbar spine and femoral neck significantly decreased in epileptic patients on VPA. Although there was an elevation in the serum PTH levels and decline in 25-(OH) vitamin D levels in children, they were unaffected in adults. Although VPA is not a CYP450 enzyme inducer, it is associated with bone loss and reduced BMD. Its effect on bone is mediated by decreased osteoblast proliferation, altered collagen synthesis, and induction of Vitamin D metabolism. Furthermore, it is postulated that VPA leads to an array of endocrinological alterations which may indirectly affect the bone.
LEV is one of the most widely prescribed antiepileptics due to its efficacy and safety profile. It acts through synaptic vesicle protein 2A (SV2A), which is responsible for calcium-mediated neurotransmitter release. Thus, the binding of LEV to SV2A decreases neurotransmitter release. The effect of LEV on bone is being investigated extensively but remains controversial. In our study, the participants taking LEV had a decline in serum calcium and 25-(OH)-D3 levels with increased duration (r = −0.896, P < 0.01, and r = −0.905, P < 0.01, respectively). The BMD at the lumbar region decreased with the duration of LEV intake (r = −0.963, P < 0.01). In their study to evaluate the consequences of LEV monotherapy on bone metabolism and BMD, they observed insignificant alteration in BMD and T-score in the participants. However, the mean duration of the study was 14.16 ± 3.36 months only. In an open-label randomized comparative trial, LEV was compared with older AEDs, namely carbamazepine and VPA, regarding adverse effects on bone. Both the groups demonstrated bone loss at 1 year at a clinically relevant fracture site and decreased bone turnover. The patients often receive multiple AEDs, due to poor seizure control on monotherapy, even at maximally tolerated doses. A subgroup of our study included these patients, and it was observed that combination therapy had a detrimental effect on BMD and T-score negatively correlated with the duration (r = −0.886, P < 0.01). The exact AEDs in combination were not evaluated, and it may be a combination of CYP450 inducer and noninducer.
In our study, all the participants on AED for <3 years had normal T-scores (at the lumbar spine), except one who had osteopenia and none had osteoporosis. In contrast, 4 out of 6 patients on AED for more than 5 years had osteoporosis, and the association was significant (P < 0.001). Souverein et al., in their study, reported that the fracture risk escalates with the duration of AED exposure, and the most significant correlation is observed with AED intake for more than 12 years. Farhat et al. made similar observations in patients on anticonvulsant therapy for more than 6 months. A progressive decline in femoral neck BMD has been noticed in patients taking AED for more than 1 year.
Along with the duration of AED, reduction in BMD was also associated with significantly elevated levels of PTH, ALP, and age across the three categories of BMD. Reduced BMD was also associated with a significant decline in serum calcium, phosphorus, and vitamin D., The sex of the subject, did not have a substantial effect on BMD. Recently a similar report was published from Egypt.
Apart from the biochemical abnormalities such as hypocalcemia, hypophosphatemia, hypovitaminosis D, and hyperparathyroidism that were observed in our study, other markers of bone turnover (Osteocalcin and type I procollagen C-terminal peptide) and bone resorption (hydroxyproline and carboxy-terminal telopeptide of type I collagen (ICTP) are also raised in patients on AED. Various mechanisms have been postulated for AED-induced bone abnormalities. The most widely established is the increased catabolism of Vitamin D due to induction of the CYP450 system through the pregnane X receptor, an orphan nuclear receptor. It is present in the intestine, kidney, and liver. The reduced level of active Vitamin D leads to diminished calcium absorption from the intestine, resulting in hypocalcemia, which increases the serum PTH. This activates the resorption of bone, thereby decreasing BMD. The reduced Vitamin D levels may directly affect osteoblast through the aromatase pathway. Furthermore, the androgen substrate for the aromatase pathway may be reduced by AED. VPA is not an enzyme inducer but leads to bone loss and decreases BMD. Its effect on bone is direct as well as indirect. VPA decreases the proliferation of osteoblasts and the synthesis of collagen type 1 and osteonectin. It also mediates catabolism of 1,25 (OH) Vitamin D. Hence, bone formation and mineralization by mature osteoblast decrease. The indirect effect of VPA is mediated through numerous endocrinal dysfunctions such as hypogonadism, hypothyroidism, and hypercortisolemia induced by its chronic use.
Limitations of the study
The study is a hospital-based study that can induce inclusion bias and a small sample size. The baseline bone parameters and BMD of the participants are not known. There is a lack of long-term follow-up of the participants.
| Conclusions|| |
AED therapy results in many metabolic derangements in bone and decreases BMD. Prolonged intake of old and novel AED can have a detrimental effect on bone. A lot of evidence is available to establish the adverse effect of AED, but this aspect is often overlooked by the treating physician. There is a lack of guidelines regarding supplementation of calcium and vitamin D in a patient with epilepsy or whether baseline parameters of bone metabolism are mandatory before initiation of AED. The consequences of AED on bone remain subclinical for a prolonged duration and may manifest later as osteopenia, osteoporosis, osteomalacia, rickets, and pathological fractures. Therefore, it is recommended that regular monitoring of bone health using laboratory markers and DEXA should be done during AED therapy, and treatment modification or supplementation should be advised to circumvent bone-related complications.
Conflicts of interest
There are no conflicts of interest.
The final manuscript has been read and approved by all the authors.
Institutional ethical committee approval
The study has been approved by the Institutional Ethics committee (D. No. 248/FM). The study was conducted by the ethical principles mentioned in the Declaration of Helsinski (2013).
Dr Lubna Zafar: Concept and design of the study, data analysis and drafting of the manuscript Dr Damera Achyuth Kumar: Data collection, data analysis and writing manuscript Dr Hamid Ashraf: Concept of study and critical revision of the manuscript Dr Ahmad Ghayas Ansari: Data collection and analysis
Financial support and sponsorship
| References|| |
Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, et al.
Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017;88:296-303.
GBD 2016 Epilepsy Collaborators. Global, regional, and national burden of epilepsy, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:357-75.
Amudhan S, Gururaj G, Satishchandra P. Epilepsy in India I: Epidemiology and public health. Ann Indian Acad Neurol 2015;18:263-77.
] [Full text]
Park KM, Kim SE, Lee BI. Antiepileptic drug therapy in patients with drug-resistant epilepsy. J Epilepsy Res 2019;9:14-26.
Meier C, Kraenzlin ME. Antiepileptics and bone health. Ther Adv Musculoskelet Dis 2011;3:235-43.
Özemir Z, Yalçin AD. Effects of antiepileptic drugs on bone density and metabolism. Epilepsy 2017;23:1-6.
Serin HM, Koç ZP, Temelli B, Esen İ. The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine. Epilepsy Behav 2015;51:221-4.
Pack AM, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008;70:1586-93.
Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006;35:177-81.
Stephen LJ, Brodie MJ. Selection of antiepileptic drugs in adults. Neurol Clin 2009;27:967-92.
Romoli M, Mazzocchetti P, D'Alonzo R, Siliquini S, Rinaldi VE, Verrotti A, et al.
Valproic acid and epilepsy: From molecular mechanisms to clinical evidences. Curr Neuropharmacol 2019;17:926-46.
Boluk A, Guzelipek M, Savli H, Temel I, Ozişik HI, Kaygusuz A. The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res 2004;50:93-7.
Fan D, Miao J, Fan X, Wang Q, Sun M. Effects of valproic acid on bone mineral density and bone metabolism: A meta-analysis. Seizure 2019;73:56-63.
Lee R, Lyles K, Sloane R, Colón-Emeric C. The association of newer anticonvulsant medications and bone mineral density. Endocr Pract. 2012;14:1-22. doi: 10.4158/EP12119.
Salimipour H, Kazerooni S, Seyedabadi M, Nabipour I, Nemati R, Iranpour D, et al.
Antiepileptic treatment is associated with bone loss: Difference in drug type and region of interest. J Nucl Med Technol 2013;41:208-11.
Pitetzis DA, Spilioti MG, Yovos JG, Yavropoulou MP. The effect of VPA on bone: From clinical studies to cell cultures-The molecular mechanisms revisited. Seizure 2017;48:36-43.
Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat 2008;4:507-23.
Klitgaard H, Matagne A, Gobert J, Wülfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol 1998;353:191-206.
Kumar A, Maini K, Kadian R. Levetiracetam. In StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
Koo DL, Joo EY, Kim D, Hong SB. Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res 2013;104:134-9.
Hakami T, O'Brien TJ, Petty SJ, Sakellarides M, Christie J, Kantor S, et al
. Monotherapy with levetiracetam versus older AEDs: A randomized comparative trial of effects on bone health. Calcif Tissue Int 2016;98:556-65.
Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic drugs and risk of fractures: Case-control study among patients with epilepsy. Neurology 2006;66:1318-24.
Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002;58:1348-53.
Paticheep S, Chotipanich C, Khusiwilai K, Wichaporn A, Khongsaengdao S. Antiepileptic drugs and bone health in Thai children with epilepsy. J Med Assoc Thai 2015;98:535-41.
Osman NM, Abdel Aziz RA, Soliman GT, Mohamed AG. Bone mineral density evaluation of epileptic children on antiepileptic medications. Egypt J Radiol Nucl Med 2017;48:1083-90.
Baer MT, Kozlowski BW, Blyler EM, Trahms CM, Taylor ML, Hogan MP. Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status. Am J Clin Nutr 1997;65:1042-51.
Christakos S, Dhawan P, Porta A, Mady LJ, Seth T. Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol 2011;347:25-9.
Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav 2004;5 Suppl 2:S3-15.
Yanase T, Suzuki S, Goto K, Nomura M, Okabe T, Takayanagi R, et al.
Aromatase in bone: Roles of Vitamin D3 and androgens. J Steroid Biochem Mol Biol 2003;86:393-7.
Rättyä J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, et al.
Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001;56:31-6.
Wu S, Legido A, De Luca F. Effects of valproic acid on longitudinal bone growth. J Child Neurol 2004;19:26-30.
Xu Z, Jing X, Li G, Sun J, Guo H, Hu Y, et al.
Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure 2019;71:60-5.
Isojärvi JI, Taubøll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs 2005;19:207-23.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]