Antiepileptic Drugs and Bone Health: Current Concepts

Abstract

Chronic use of antiepileptic drugs (AEDs) can induce the development of adverse effects on bone metabolism. In epileptic patients treated with AED, the monitoring of biochemical markers of bone turnover, such as the measurement of serum 25 (OH) vitamin D, bone mineral density, before the beginning of the treatment and during the follow-up is not routinely required. In the future, monitoring of biochemical markers in epileptic patients treated with AED may help us for adequate prevention therapy.

Introduction

In epileptic patients, the chronic treatment with antiepileptic drugs (AEDs), can induce the onset of metabolic bone disorders ranging from the alteration of bone metabolism^1–3 to the bone mineral density (BMD) decrease and risk of fractures increase (about 2–3 fold),^4,5 particularly in patients > 50 years.⁵

An increased risk of osteoporosis has been also reported in disabled elderly patients receiving AEDs⁶ while Fernandez et al.⁷ described reduced levels of serum 25 (OH) D in both adults and children treated with AED.

In a meta-analysis, in 1492 children treated with AED, Zhang et al.⁸ observed a reduction in BMD in particular in the lumbar spine, trochanter, femoral neck. In another meta-analysis of nine studies Tosun et al.⁹ was documented an association between AEDs use and both the decrease in 25-OH D levels and the increase in alkaline phosphatase (a marker of bone turnover formation), with a significant reduction in BMD.

Bone loss associated with AEDs use is generally insidious and asymptomatic in the beginning; therefore, it is not diagnosed and not treated.¹⁰ Pack et al.¹¹ documented an association between the use of AEDs and both the decrease of calcium, phosphate, vitamin D and the increase of parathyroid hormone (PTH), in blood levels. Krishnamoorthy et al.¹² described an increase of alkaline and serum total bone phosphatase in blood of outpatients correctctly exposed to the sun about 90 days after the beginning of carbamazepine or valproic acid treatment. More recently Meier et al.⁴ reported, in blood of patients treated with AEDs, an alteration of alkaline phosphatase, osteocalcin and of the markers of bone turnover (i.e., C-terminal extension peptide of type I procollagen) and of bone reabsorption (i.e., cross-linking C-terminal telopeptide of type I collagen (CTX-1) and hydroxyproline).

Several radiological studies in adult patients documented a significant decrease in rib and spine BMD¹³ neck of the femur and hip,^1,2 particularly during chronic treatment with AED.^1,3 Regarding AEDs therapy, several factors can increase the risk of bone alterations: 1) age 2) dose used 3) duration of therapy; 4) polytherapy; 5) female gender; 6) sun exposure (Figure 1). The consideration of these factors may represent a possible prevention strategy for bone alterations deriving from the use of AED.^14–16 Clinical studies have described that the effects of AEDs on bone can depend from their activity on cytochrome P450 (CYP450) enzymes. In fact, AEDs inductor activity of CYP450 enzymes (EI-AEDs); e.g., phenytoin (PTH), phenobarbital (PB), carbamazepine (CBZ), oxcarbamazepine (OXC), valproic acid (VPA) and primidone (PRM) accelerate the metabolism of vitamin D and therefore decrease plasma levels of both 25 (OH) D and 1 alpha, 25 (OH) 2D;^3,7,15–18 AEDs without activity on CYP450 enzymes (NEI-AEDs) (e.g., lamotrigine (LTG), clonazepam (CPZ), gabapentin (GPB), topiramate (TPM) and etosuximide (ETS) induce hypocalcaemia and stimulate the release of PTH, which restores the serum calcium levels^3,16,18 (Table 1). Additional proposed mechanisms for AED-induced bone loss include calcitonin deficiency, hyperhomocysteinemia (associated with changes in bone microarchitecture and increased bone fragility), vitamin K and carnitine deficiency, decreased sex hormones and direct effect on osteoclasts. AEDs have also a direct effect on chondrocytes growth, particularly in children, with effects on vitamin D and calcium.^19–21 Therefore, the treatment of vitamin D levels in epileptic patients receiving some AEDs may represents reasonable prevention of bone loss. In this manuscript we reviewed the effects of AEDs on bone metabolism.

Figure 1.

Factors Implicated in AED-induced bone Alteration

Table 1. AEDs Inductor Activity of CYP450 Enzymes (EI-AEDs) and no Inductor Activity of CYP450 Enzymes (NEI-AEDs).

EI-AEDS		NEI-AEDS
Phenytoin		Lamotrigine
Phenobarbital		Clonazepam
Carbamazepine		Gabapentin
Oxcarbazepine		Topiramate
Valproic acid		Etosuximide
Primidone

Methods

PubMed, Embase, Cochrane library and reference lists were searched for articles published until February 25, 2020, using the keywords “antiepileptic drugs”, “adult”, “children”, “bone health”, “vitamin D metabolism”, “bone metabolism vitamin D”, “calcium”, “bisphosphonates” and “epilepsy”. Secondary searches included articles cited in sources identified by the previous search. We enclosed randomized control trials (RCTs), open trials, case series, and case reports.

Mechanisms of Bone Loss with Antiepileptic Drugs

Multifactorial pathophysiological mechanisms are involved in bone alterations induced by AEDs [Figure 1]. Uncertain data has been published regarding a difference of EI-AED and NEI-AED, on bone metabolism and osteoporosis in terms of vitamin D, calcium and BMD.³

EI-AEDs accelerate the catabolism of vitamin D in its inactive polar metabolites, reducing the biologically active forms and causing a bone alteration. The decrease of biologically active forms of vitamin D causes a reduced intestinal absorption of calcium that is responsible of hypocalcaemia and hypersecretion of PTH with an increase in bone resorption and reduction of BMD. In clinical studies has been reported that AEDs influence bone metabolism through mechanisms not related to the induction of CYP450 enzymes,² e.g., direct effects on bone cells, direct inhibition of intestinal calcium absorption, inhibition of osteoblasts cell growth and inhibition of calcitonin secretion.^16,22,23 In human fetal osteoprogenitor cells, PHT compared to TPM, LEV, LTG and CBZ significantly reduced procollagen I, suggesting a direct effect of PHT on osteoblast-like cells through the decrease of synthesized COL1A1 protein that interferes with osteogenesis.²⁴ In experimental studies, PHT have been shown to have a direct effect on sodium currents affecting the function of osteoblasts and the bone metabolism, but without effect on biomechanical properties of bone.^25,26 Recently Wang et al.²⁷ in a translational study, reported that chronic use of PB increases the osteoclasts activity inducing the loss bone.

Finally, other authors suggested that genetic factors (e.g., gene polymorisms) can also influence the pathophysiological mechanism of AEDs-induced dysregulation of bone metabolism.^28,29

AEDs and bone metabolism

A retrospective study reported that chronic use of AED is an independent factor to reduce the plasma vitamin D levels, independently from the type of AEDs.³⁰ Epileptic patients treated with AEDs, particularly EI-AEDs, had lower levels of vitamin D respect to control ones.³¹ In 71 epileptic patients Farhat et al.² documented that subjects taking EI-AEDs have lower BMD respect to NEI-AEDs. Aksoy et al.³² reported in 48 epileptic patients that OXC, an EI-AED, but not LEV, a NEI-AED, reduced the plasma levels of calcium, ionized calcium and vitamin D and induced a bone loss with an increase risk of fractures. This study is in agreement with other clinical trials performed in children and adults that reported as OXC use reduces the plasma levels of 25 [OH] D³³ and BMD.³⁴

In an experimental study Nissen-Meyer et al.³⁵ reported that LEV at low-dose reduced the bone strength at the neck of the femur. In agreement, Fekete et al.³⁶ in an experimental study on 16 orchidectomised Wistar rats documented that the administration of LEV for 12 weeks induced a significant loss of BMD in the area of the left femur with decrease in the serum osteoprotegerin (marker of bone formation) levels and an increase in the serum CTXI (marker of bone resorption) levels, but without change in biomechanical bone strength.

In a clinical study perfomed in 33 children with idiopathic epilepsy Ecevit et al.³⁷ evaluated the effect of a chronic treatment (for more than 6 months) with CBZ (n = 17) or VPA (n = 17) on BMD and documented that VPA, but not CBZ, significantly reduces (about 31.9%) BMD values at the femoral neck area.

In young epileptic patients (mean age 26 ± 7.2-years) of both sexes with hypovitaminosis D, Albaghdadi et al.³⁸ documented that chronic VPA monotherapy is associated with lower BMD measurements. The authors failed to report an association between AED and low levels of vitamin D because Vitamin D deficiency (< 20 ng/mL) was highly prevalent (> 90%) in both epileptic patients and in control ones. In a cross sectional study in 82 epileptic patients (mean age 31.67 ± 10.69 years) Rahimdel et al.³⁹ compared the effect of at least 2-year of treatment with CBZ (n = 41), an EI-AED, or VPA (n = 41), a NEI-AED, on changes of both biochemical and BMD parameters. At the end of the study the authors, documented that patients enrolled in CBZ group showed a significant decrease in plasma levels of calcium and phosphorus and in BMD values at femoral neck compared to patients enrolled in VPA group.

Shiek Ahmad et al.⁴⁰ reported that a treatment with CBZ for 1 year significantly decreased the BMD values in the hip and femoral neck, respect to VPA and LEV.

In the same year, Artemiadis et al.⁴¹ evaluated, in epileptic patients (mean age: 35.7 years), the effect of 1-year therapy with LEV on bone health, and documented lower BMD values of the neck of the femur in all patients, and of lumbar spine in women but not in men, suggesting a a differential effect of LEV therapy duration in men and women, which could presumably account

Regarding the use of GBP, its use in adult patients can lead to hip and lumbar spine loss⁴² and at the neck of the femur,^43,44 with an increased risk of fractures.^2,5

In adult patients, TPM monotherapy causes mild to moderate metabolic acidosis resulting in the development of kidney stones, osteomalacia and/or osteoporosis,³⁴ as well as a decrease in PTH, mild hypocalcaemia and an increase of the turnover bone.⁴⁵ The use of TPM in children has also led to changes in the serum content of calcium, phosphorus and alkaline phosphatase, as well as decreases in BMD⁴⁶ In children and adolescents with epilepsy (mean age 9.2 ± 3.9, years), a chonic treatment (> 2 years) with LMG treatment alone or plus VPA reduced BMD, and bone formation.⁴⁷

Coclusions and directions for future research

Some clinical studies have shown that EI-AEDs have a greater impact on plasma vitamin D levels or BMD respect to NEI-AEDs,⁴⁸ although there are no conclusive data. However, chronic high dose of AEDs induces a dose-dependent increase in the risk of fractures particularly in children,⁴⁹ and in postmenopausal women.⁵⁰

To date, the monitoring of biochemical markers of bone turnover, before the beginning of the treatment and during the follow-ups is not recommended in clinical routine.⁵¹ The National Institute for Clinical Excellence (NICE) recommends bone metabolic tests every 2–5 years for adults taking EI-AED.^52,53 However, in AED-users non-pharmacological (e.g., regular physical activity, balanced diet, smoking cessation and decrease in alcohol intake) and pharmacological treatments (e.g., integration of calcium and vitamin D, the use of bisphosphonates, selective estrogen receptor modulators, hormone replacement therapy, recombinant forms of PTH and calcitonin) could be recommended.^4,54 However, to date, there are not recommendations on the administration of prophylactic doses of vitamin D and calcium, in patients treated with EI-AED and valproate and a meta-analysis of randomized controlled trials has reported that in healthy children with hypovitaminosis D, the vitamin D integration can be beneficial for bone health.^55,56 In these patients, data related to the dose of vitamin D, the type of vitamin D and the time of administration, are unconclusive.^7,57 A study on epileptic patients treated with AEDs reported that the integration of calcium and vitamin D with a bisphosphonate was associated with an improvement in BMD and a reduction in newly diagnosed vertebral fractures,⁵⁸ even if this effect could be related with the use of bisphosphonate.

However, we think that specific guidelines must be performed to monitoring the biochemical markers of bone turnover during the AEDs treatment in order to obtaine an appropriate treatment. Further cohort clinical trials or randomized controlled trials are needed to indicate an adequate and correct treatment strategy in patients treated with EI-AED and NEI-AED, respectively.

Conflicts of Interest and Source of Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.