Review

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The problem of osteoporosis in epileptic patients taking antiepileptic drugs 1.

Introduction

2.

AEDs and bone disease

3.

Polytherapy and bone health

4.

Treatment duration

5.

Possible mechanisms of AEDs related to their negative effects on bones

6.

Risk factors of AED-associated bone loss

7.

Prevention and treatment of bone problems

8.

Conclusion

9.

Expert opinion

Barbara Miziak, Barbara Błaszczyk, Magdalena Chros´cin´ska-Krawczyk, Grzegorz Danilkiewicz, Ewa Jagiełło-Wo´jtowicz & Stanisław J Czuczwar† †

Medical University, Department of Pathophysiology, Lublin, Poland

Introduction: Epilepsy is a common neurological disorder associated with recurrent seizures. Therapy with antiepileptic drugs (AEDs) helps achieve seizure remission in approximately 70% of epileptic patients. Treatment with AEDs is frequently lifelong and there are reports suggesting its negative influence on bone health. This is especially important in terms of general occurrence of osteoporosis, affecting over 50 million people worldwide. Areas covered: This study refers to two main groups of AEDs: hepatic enzyme inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and topiramate) and non-inducers (clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, valproate, vigabatrin and zonisamide). Some reports indicate that enzyme inducers may exert a more negative influence on bone mineral density (BMD) compared to non-inducers. Bone problems may appear in both sexes during AED therapy, although women are additionally burdened with postmenopausal osteoporosis. Supplementation of vitamin D and calcium in patients on AEDs is recommended. Expert opinion: Apart from enzyme inducers, valproate (an even enzyme inhibitor) may also negatively affect BMD. However, the untoward effects of AEDs may depend upon their doses and duration of treatment. Although the problem of supplementation of vitamin D and calcium in epileptic patients on AEDs is controversial, there are recommendations to do so. Keywords: antiepileptic drugs, calcium supplementation, fractures, osteoporosis, vitamin D supplementation Expert Opin. Drug Saf. (2014) 13(7):935-946

1.

Introduction

Osteoporosis affects over 50 million people around the world, and over 80% of all fractures after the age of 60 occur as a result of osteoporosis [1]. Other data show that approximately 70 -- 80% of fractures in women and 50% in men are caused by osteoporosis [2]. Worldwide, 9 million osteoporotic fractures were registered in 2000, of which 34.8% was in Europe. This shows that Europe is in the lead in this regard [3]. The countries of high-population risk of hip fractures include those with a high developmental level, that is, Sweden, Denmark, Norway, The United Kingdom or Germany [4]. There are many secondary reasons, which increase the danger of osteoporosis [5,6]. Available evidences show that one of the reasons is using antiepileptic drugs (AEDs), which cause a considerable decrease in bone mass in people, especially over 65 years of age [7]. In 1960, dysfunctions in bone structures were linked to AED treatment, both in children and adults [8,9]. The consequences of using AEDs include osteopenia/ osteoporosis, osteomalacia, fractures, severe chronic pain, and disability. The most cases of bone-mass decrease and the connected skeletal dysfunctions were noted in 10.1517/14740338.2014.919255 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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Over 50 million people worldwide suffer from osteoporosis, which is responsible for millions of osteoporotic fractures each year. Antiepileptic drugs (AEDs) are prescribed to epileptic and non-epileptic patients (mainly for bipolar disorder, migraine and chronic pain) and, in some instances, may be used for a lifetime. Some reports indicate that AEDs inducing hepatic enzymes (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and topiramate) may exert more negative impact on bone mineral density than non-inducers (clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine (LTG), levetiracetam, pregabalin, tiagabine, valproate, vigabatrin and zonisamide). Probably LTG has the lowest negative impact upon the bone health. Supplementation with calcium and vitamin in epileptic patients on AEDs is recommended. Whether to apply a bisphosphonate in epileptic patients to prevent osteoporosis is a matter of dispute.

This box summarizes key points contained in the article.

the groups of elderly, women after menopause, and children [8]. Historically, bone problems in epileptic patients were associated with the chronic use of AEDs in high doses, disturbances in vitamin D metabolism, reduced exposure to sunlight, and limited physical activity [10]. It has been proved that treatment with AEDs results in the development of secondary osteoporosis, along with a drop in bone mineral density (BMD) and accelerated bone-mass loss, whereas in the case of children, secondary to poor bone accrual has been observed [11]. Around 80% of subjects had low BMD and 51.9% comprised people aged 18 -- 50 years. Additionally, it was demonstrated that in the abovementioned 80, 48.2% of patients were diagnosed with osteopenia and 31.8% with osteoporosis [12]. In epilepsy, fracture rates are two- to threefold those encountered in the general population, although the influence of gender and age seems not well defined [13]. Other sources indicate that the risk of fractures and bone-structure damage in patients with epilepsy is 2 -- 6 times higher compared to the general population, and most often femur or hip fracture occurs [14,15]. Long-term studies [12-20] confirm a higher morbidity of osteoporosis in AED-treated patients, and a drop of BMD in the hip joint by ‘0.70%/year in nonusers to -0.87%/year in partial AED users to -1.16%/year in continuous AED users’ [16]. The drugs contributing to modifications in the bone structure, in case of monotherapy, most often include phenytoin (PHT), primidone and phenobarbital (PB) [8]. Other sources claim that applying carbamazepine (CBZ), valproate (VPA), PB or PHT monotherapy is associated with a higher risk of fracture [21,22], whereas until 2001, there was no information available concerning the change in bone 936

metabolism caused by, for example, lamotrigine (LTG), topiramate (TPM), vigabatrin and gabapentin (GBP) [8]. There are also evidences pointing to no increased risk of bone damage when using CBZ, GBP, clonazepam, VPA, levetiracetam (LEV), primidone and TPM. Moreover, in patients using LTG, no fractures were reported [22]. In this review, we systematically searched the Englishlanguage literature (at least accompanied by an English abstract) in PUBMED databases. We limited our search to systematic reviews and research studies published between October 1970 and January 2014. The selection criteria (by using the combination of keywords) were as follows: osteoporosis, BMD, AEDs, fractures, bone turnover, changes in bone metabolism, parathyroid hormone (PTH), alkaline phosphatase (ALP) and calcium supplementation, vitamin D supplementation. 2.

AEDs and bone disease

CBZ, oxcarbazepine (OXC), PB, PHT, TPM and primidone are classified as hepatic enzyme inducers and according to many reports may exert more negative effects on bone health than non-inducers, which include clobazam, clonazepam, ethosuximide (ETX), GBP, lacosamide, LEV, LTG, pregabalin, tiagabine, VPA, vigabatrin and zonisamide. However, non-inducers may also share a negative impact on bones [19,23-29]. Inducers of the hepatic CYP 450 system trigger the emergence of smaller biologically active analogs of 25-hydroxy vitamin D (25-OHD). This results in reduced intestinal calcium absorption, increased calcium mobilization from the skeleton and decreased bone mineralization [8,11]. PHT is a potent CYP 450 enzyme inducer, which would explain its negative influence on the skeletal system in young women [30]. However, this group of drugs also incorporates CBZ, and it did not demonstrate any negative influence on the bone metabolism. The negative influence was also not exerted in this particular study by LTG or VPA [30]. Also, LTG did not reduce BMD or affect bone turnover markers in premenopausal women [23]. However, data concerning CBZ appear conflicting. Following treatment with CBZ in adolescents for 1 -- 2 years, bone turnover markers were significantly disturbed, which could result in deteriorating long-term effects on BMD. This was actually the case in patients receiving CBZ for 6 months, in whom significant BMD reductions were found [23,31]. Some disturbances in vitamin D metabolites and increased concentration of PTH were recorded in adults on OXC, which may behave as an enzyme-inducer at higher doses [32]. According to Va¨lima¨ki et al. [33], serum concentrations of 25-OHD and 1,25-dihydroxyvitamin D were reduced in 38 females taking CBZ or PHT [33]. However, only in women treated with PHT, BMD was significantly reduced, which may point to other mechanisms, than the enzyme induction, in the development of bone disease. VPA is an inhibitor of CYP-450 enzymes and yet some negative effects exerted by this AED on bones have

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The problem of osteoporosis in epileptic patients taking antiepileptic drugs

been reported. These included reduced BMD in children and adults at multiple sites and elevated bone turnover markers [23]. A considerable reduction in IGF-1 was discovered in PHT-treated patients in comparison to patients on LTG (p = 0.017). Bone-specific ALP test showed an increase in its level in PHT-treated patients [34]. The influence of this AED on bone metabolism and BMD in premenopausal women (aged 18 -- 40 years) was also tested [30]. Despite high consumption of calcium (> 1000 mg/day) and high physical activity, a huge reduction of BMD was observed -2.6% at the femoral neck after a year of treatment. The loss is over 8 times bigger than that observed in the cohort of young women. In this group, lower serum 25-OHD concentrations, ‘higher PTH, bone ALP, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling’ [30], were also observed. Hegedu¨s et al. [35] checked the thyroid volume in epileptic patients subject to, among others, PHT treatment. It was proved that in these patients, median thyroid volume was 26 ml (range 14 -- 57 ml) compared to 17 ml (range 8 -- 41 ml) in the controls (p < 0.01). It allowed the suggestion that this was a compensatory mechanism, a reaction to a low level of thyroid hormones in the serum [35]. On the other hand, it was demonstrated that low levels of PHT stimulated ‘cell proliferation, differentiation and mature osteoblastic activities to stimulate bone formation in human craniofacial bone cells’ [36]. However, Onodera et al. [37] examined the influence of long-term PHT (20 mg/kg/day for 5 weeks) in male rats. BMD was measured in femoral diaphysis, femoral metaphysis, mandibular head, tibial metaphysis and tibial diaphysis. Serum osteocalcin (a marker of bone formation) and BMD were markedly reduced. As regards serum calcium concentration, pyridinoline, 25-OHD and PTH, no significant differences were noted. In histomorphometric analysis, the medication caused a reduction in ‘trabecular bone volume and trabecular thickness, and increased osteoclast numbers per area of bone surface in the secondary trabecular bone of the tibia’ [37]. No significant difference in osteoid thickness was observed. Administration of either alfacalcidol or calcitriol with PHT throughout the period of experiments blocked the BMD reduction caused by PHT [37]. Nissen-Meyer et al. [38] carried out experiments, in which for 90 days (‘representing about 20 oestrous cycles in rats, corresponding to ca. 2 years of menstrual cycles in women’) PHT (50 mg/kg, daily) was administered to female rats. The experiments clearly showed that PHT reduced BMD [38]. Moreover, the influence of PHT on neonatal mouse calvaria was examined, revealing a significant bone resorption [39]. Human data also provided evidences on dysfunctions of skeleton in patients receiving PHT and PB. It was shown that in 29% of patients hypocalcemia occurred, and 27% of the patients were registered with higher levels of hypocalcemia [40], whereas other studies showed reductions in serum 25-OHD concentrations in

children and adults [4,41,42] as well as hypocalcemia in a rat model [43]. In their first study, Tjellesen et al. [44] found reduced serum 25-OHD concentration, elevated serum ALP, and hypocalcemia in 9 patients on CBZ. These changes were more pronounced in patients on PHT. In their next study [45], the number of patients receiving CBZ was increased to 30 and the results were quite similar differing in that serum 25-OHD concentration was normal. After all, the patients’ bone mass was in the control range [45]. Patients on PHT (n = 19) had a mild generalized osteomalacia, which was not the case in patients on CBZ [45]. Verrotti et al. [46] also demonstrated elevated ALP concentration, accompanied with other markers suggesting enhanced bone formation or resorption, vitamin D levels being normal and BMD not significantly affected. No significant reductions of BMD in patients using CBZ were also found by Sheth et al. [47]. Further, Kim et al. [27] examined the influence of CBZ on changes in BMD in Koreans with diagnosed epilepsy. The tests were conducted before and after 6 months of monotherapy with this AED. In this case, CBZ caused a considerable drop in BMD, including a decrease in vitamin D concentration. It was also noted that there were no gender differences [27]. Subsequent studies showed that CBZ decreased 25-OHD levels in adult patients to the same degree as OXC did [48], and also produced increases in bone turnover [49]. Ecevit et al. [50] noted that 17.6% of CBZ-treated children were diagnosed with hypocalcemia and 35.3% with hypophosphatemia -- however, a 20%, decrease in BMD at the femoral neck area was not statistically significant [50], whereas, according to Kumandas et al. [51], BMD values at lumbar spine were significantly lower than those of the control group in children. In turn, PHT levels and serum ALP were significantly higher in the treatment group [51-53]. There have also been results available indicating that CBZ does not negatively influence the patients’ bone metabolism after at least a year-long therapy [54]. OXC, the 10-keto analog of CBZ, is metabolized by reduction, rather than oxidation, and might not induce the oxidative P450-enzyme system [55]. However, OXC at higher doses can bring about the induction of liver enzymes [56]. Biochemical markers of bone metabolism (serum calcium, phosphate, bone ALP, PTH, osteocalcin, IGF-1, C-telopeptide, vitamin D3 levels) along with BMD were studied in 41 patients with epilepsy prior to and after a chronic OXC monotherapy [32]. Most markers were not modified but serum calcium and bone-specific ALP were reduced, following OXC monotherapy. BMD measured at the lumbar spine (L2 -- L4) was even increased but this effect was only significant in female patients [32]. Enzyme-inducing AEDs can cause a decline in serum 25-OHD levels, which in turn may lead to bone-mass loss and destruction of the bone structure [57]. Indeed, patients treated with CBZ or OXC had decreased serum 25-OHD concentration. This reduction was significant for the OXC group

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B. Miziak et al.

(p < 0.05) [57]. The influence of OXC monotherapy was examined (for 18 months) on bone turnover in prepubertal and pubertal children. Concentration of 25-OHD was significantly reduced in comparison to the level before the therapy. The levels of ALP, calcitonin, g-glutamyl transferase, osteocalcin, PTH and phosphorus rose [48]. Changes in osteocalcin and g-glutamyl transferase levels proved to be statistically significant. Three pediatric patients (two prepubertal children and one pubertal child) were noted to have drug-induced osteopenia symptoms. Summing up, the authors noted that the examined drug had a slightly negative impact on the skeletal system. Nonetheless, in children with a correct BMD mass, the occurring effect seems insignificant [48]. VPA, an AED-inhibiting liver enzyme, may exert negative effects on bone health, although earlier studies revealed no significant changes in calcium and 25-OHD concentrations. There are data suggesting that this AED may actually elevate serum calcium level, probably due to increased bone resorption, and reduce metabolites of vitamin D. However, both reduced or unchanged BMD in children on VPA were reported [23,58-61]. Other authors showed that VPA caused a decline in BMD and serum 25(OH)D3 concentration as well as PTH level was higher than that of the control group [51,53]. Ecevit et al. [50] examined epileptic children, treated with CBZ or VPA. In the case of the VPA group, 25% of the tested were diagnosed with hypocalcemia and one child (6% of the tested) with an increased level of ALP, and in 50% of the children, hypophosphatemia was evident. Moreover, a drop of BMD by 31.9% in the femoral neck area (p < 0.05) was observed in this group [50]. VPA-treated patients exhibited statistically significant declines in BMD, 52% were diagnosed with osteopenia and 16% with osteoporosis [61]. Experimental studies with VPA (300 mg/kg) by Nissen-Meyer et al. [38] (administered for 90 days) to female rats showed that VPA decreased BMD and caused increased bone turnover. Possible mechanisms responsible for the negative effects of VPA on bone health were evaluated in in vitro studies. The results obtained from these studies indicate that VPA reduced the concentration of two essential bone proteins -- collagen 1 and osteonectin. Pro-collagen 1 was also diminished by 48% and osteonectin by 25%, following 24-h exposure of cultured bone cells to a therapeutic concentration of VPA [59,62]. Newer AEDs, LTG, LEV, GBP and tiagabine seem neutral as regards BMD and vitamin D. Kim et al. [27] (in adults) as well as Sheth and Hermann [63] (in children) found that LTG did not affect either BMD or vitamin D following 6 months of therapy. This result was confirmed by other investigators [22,34,63]. However, Zhang et al. [64] proved that TPM reduced BMD in children and also observed alterations in serum contents of calcium and phosphorus. Heo et al. [65] revealed that long-term TPM administration might have a negative influence on bones. Their data indicate that the concentration of calcium in serum was much lower in patients treated with TPM or CBZ in comparison to the group 938

receiving VPA or the control group. What is more, other biomarkers were also altered in TPM patients: decreased levels of PTH and higher levels of bone-specific ALP and osteocalcin as well as serum bicarbonate concentrations were significantly reduced, when compared with controls [65]. There are also data pointing to a better profile of TPM [66]. No dysfunctions of the skeletal system were registered in patients treated with LEV (for a period of a year), which means that LEV may not negatively influence bone strength and metabolism [67,68]. These results were supported by Fekete et al. [69], as regards LEV monotherapy. However, experimental data obtained from experiments on female rats showed that low doses of LEV caused a decline in the biomechanical strength of the femoral neck (mainly the trabecular bone) and decreased the level of osteocalcin [38]. 3.

Polytherapy and bone health

In a study carried out on children with epilepsy, short stature associated with low BMD and reduced bone formation were found, particularly in patients on long-term combined treatment with VPA and LTG. However, the authors are of opinion that these effects might mainly result from low physical activity [70], whereas Winnacker et al. [71] showed a significant reduction in phosphorus, 25-OHD concentrations and hypocalcemia as well as a significant increase in serum ALP values when compared to the control group. According to Gniatkowska-Nowakowska [31], the incidence of fractures is higher in patients on polytherapy compared to monotherapy patients. The most severe biochemical changes were also noted in patients on polytherapy [72]. Some authors observed only a tendency for polytherapy to increase a risk for bone disease and fractures [72-75]. No significant changes, as regards mono- and polytherapy with a variety of classical or newer AEDs, were noted in respect of the frequency of BMD reduction among the evaluated groups [19]. 4.

Treatment duration

Duration of AED therapy was taken into consideration as a probable risk factor for fractures. Actually, fracture risk would increase over treatment duration for 12 years and more [76]. It has been proven that even short-term OXC or VPA therapy in children destabilizes the functioning of the thyroid [77]. Also, Vestergaard et al. [78] confirmed a connection between a long-term AED therapy and an increased risk of bone fractures. He particularly took note of the following drugs: OXC, VPA, CBZ, clonazepam and PB, which were significantly associated with risk of fractures [78]. Falls in thyroid hormone level in serum have also been observed in adult men in long-term CBZ or OXC therapies, whereas in VPA group no essential changes in the level of hormones have been observed. However, the possibility that the decrease in hormone level was connected with liver enzyme induction or the activation of immunologic

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The problem of osteoporosis in epileptic patients taking antiepileptic drugs

mechanisms was discarded, whereas it is possible that there is a role for the hypothalamic regulation of thyroid function by CBZ and OXC [79].

Possible mechanisms of AEDs related to their negative effects on bones

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5.

In healthy bone tissue, two interconnected processes occur: bone formation and bone resorption. Bone resorption always occurs to the same degree as the other process -- bone formation. Both processes are based on the activity of osteoclasts (resorption), osteoblasts (formation) and osteocytes (maintenance). The whole mechanism is regulated by the hormone system, including other steroid hormones, the PTH, vitamin D and local mediators such as cytokines and growth factors [51,80]. It has been proved that both PHT and PB participate in bone resorption processes, evaluated in fetal rat bone in vitro [81]. Both AEDs significantly inhibit basal, PTH-stimulated and 1,25-(OH)2D-stimulated resorption. PHT has much greater inhibiting characteristics [81]. Moreover, an impact of 1,25-(OH)2D3 (1 -- 25 ng/ml) was examined (for a period of 2.5 -- 60 min) on bone cells isolated from periosteum-free rat calvaria, or in cells isolated from rat periosteal tissues. The experiment demonstrated that 1,25-OH2-D3 does not change the level of cAMP in cells and cannot modify the acute increases in cAMP elicited by PTH (10 ng/ml -- 1 µg/ml) [82]. A decline in vitamin D leads to a considerable reduction in calcium absorption in the intestine, which leads to the development of hypocalcemia and an increase in circulating PTH, which in turn increases the release of Ca from bones [27]. There are many mechanisms taken into consideration to explain the influence of drugs on the skeletal system. Direct AED effects on bone cell functions (especially when using CBZ, PHT and VPA), interference with vitamin K metabolism -- especially in case of PHT, and resistance to PTH (in case of CBZ) have been considered [83,84]. Other mechanisms include the direct reaction/influence of an AED on the organism, for example, hormonal changes (the decline of bioactive testosterone in males as a result of increases in sex hormone binding globulin levels), or increase in serum lipids and C-reactive protein. Such reactions were noted in case of CBZ, PB and PHT. Another reaction of the organism to AEDs include a fall in IGF-1 concentration or an increase in the homocysteine level [83,85]. TPM, in turn, may cause the development of mild to moderate metabolic acidosis, which might result in osteomalacia, osteoporosis or even kidney stones [20]. 6.

Risk factors of AED-associated bone loss

The general risk factors for the development of osteopenia or osteoporosis include malnutrition, reduced exposure to sunlight, low body weight, female gender, family history of bone disease and race. As regards race, White, Asian, Hispanic

and Native American women are more prone to osteoporosis than African Americans. Such a conclusion is based on the difference in the BMD levels in different races [86]. African Americans have the highest BMD level, whereas the Asians have the lowest [87]. However, African-American women have lower vitamin D levels [86]. To additional risk factors, connected to chronic epilepsy, belong decreased physical mobility and possible institutionalization [23]. Also, some specific risk factors exist and these include type of AED, effective AED dose and duration of AED therapy [23]. Deformations of the skeletal system in the case of AED therapy apply to both sexes, but female patients show a greater risk of bone fractures, especially due to the fact that women are additionally burdened with postmenopausal osteoporosis [88]. In AED-treated patients, imbalances of bone biochemical parameters were noted, and 32% of patients were diagnosed with hypocalcemia. Only women showed a drop in BMD levels in comparison to the control group. Moreover, histomorphometric analysis showed an increase in the amount of osteoid, but no changes were noted in the trabecular bone in comparison of the non-AED group [89]. Liverenzyme--inducing AEDs might increase the risk of bone fractures in patients suffering from epilepsy, with an even greater risk noted in women [24]. Age may be a quite important factor when considering treatment with AEDs and bone health. The level of osteocalcins in the serum increases in children (especially within the first three years), and in puberty, which means that in this period a fast bone turnover occurs, and also quicker physical growth in the organism [90-92]. It was proved that until the end of the period of puberty the skeletal mass increases its volume nearly twofold [93]. That is why the increases in bone mass and any bone metabolism disorders in puberty are very important [48,91,92]. Erbayat et al. [94] examined the influence of VPA or CBZ (given for at least a year) on the skeletal system (rating lumbar spine [L2 -- L4] and femoral neck) in children with diagnosed generalized idiopathic epilepsy. The value of BMD did not vary much, either in the case of CBZ or VPA in comparison with the control group. In the case of CBZ, the level of calcium was lower and the level of ALP was higher. Urinary calcium levels were significantly reduced in both groups: CBZ and VPA (p £ 0.05), especially in the VPA group (significantly lower). The results show that VPA and CBZ monotherapies have no critical influence on the bone metabolism in the case of pediatric patients [94]. Other investigators measured BMD at the lumbar vertebrae (L1 -- L4) and the radius-ulna in children who were CBZ- or VPA-treated [95]. After 6 months, it was shown that ALP concentration was higher in patients compared to the control group. While BMD was lower in girls, a drop was not registered in boys. In the VPA-treated group, BMD was reduced by 8%, and in CBZ-treated group by 4.5% (no statistical significance) [95]. It is also vital to mention the group of children and adolescents with cerebral palsy. Disabled children suffering from epilepsy are additionally at an increased risk of sustaining

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Table 1. Influence of classic and new antiepileptic drugs on bone metabolism and risk of fracture.

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Phenytoin

Carbamazepine

Abnormal bone mineral density Children + [72] + [51,64, 72,103] Adults + [17,20,30,33, + [17,27,72] 37R,38R,72] Hypocalcemia Children + [71P] + [49,63,93] Adults + [17,20,33, + [17,30, 34,44] 34,64] Lower serum 25(OH)D3 concentration Children + [41,71P] + [51,53] Adult + [17,20, + [17,27, 33,34] 33,47,56] Increased parathyroid hormone Children N.A. + [51,53] Adult + [20,30] + [27] Higher ALP Children + [71P] + [44,51,52, 93,94,103] Adult + [34,40] + [45] Higher bone turnover Children N.A. [23,31] Adult + [34] + [48] Changes in bone metabolism Children N.A. - [93] + [52] Adult + [34] + [17] Increased risk of fractures Children N.A. N.A. Adult + [6,21,22] + [6,21,22,78]

Oxcarbazepine

Valproate

Lamotrigine

Levetiracetam

Phenobarbital

+ [103]

+ [49,51,103]

- [63]

N.A.

+ [72]

+ [19]

+ [38R,60]

- [20]

+ [19,67,69R] - [20,38R]

+ [20,72]

N.A. - [20]

+ [49] + [34]

N.A. - [20,30,34]

N.A. - [20]

N.A. + [40,43R]

+ [47] + [56]

+ [53] - [20]

N.A. - [20,27]

N.A. - [20,68]

+ [41] + [42]

+ [47] + [20]

+ [49,53] + [27]

N.A. + [27]

N.A. N.A.

N.A. N.A.

+ [47,103]

+ [94,103]

N.A.

N.A.

N.A.

N.A.

+ [20]

- [20,34]

N.A.

+ [40]

N.A. + [20]

N.A. + [20,38R]

N.A. - [34]

N.A. N.A.

N.A. N.A.

N.A.

- [93]

N.A.

N.A.

N.A.

+ [20]

+ [20]

- [20,34]

- [68]

N.A.

N.A. + [78]

N.A. + [21,22,78]

N.A. N.A.

N.A. N.A.

N.A. + [6,21,22,78]

+: Present; -: Absent; ALP: Alkaline phosphatase; N.A.: Not available; P: Polytherapy; R: Model of rat.

fractures and developing osteoporosis due to reduced mobility and the resultant underdeveloped bone mass [96,97]. In addition, such patients are diagnosed with ‘long and fragile lever arms and stiffness in major joints, particularly the hips and knees’ [98], as well as low BMD (particularly in children with moderate to severe cerebral palsy), and also suffer from disequilibrium and, primarily, epileptic convulsions [97], which increase the risk of fractures. Children with cerebral palsy often sustain pathological fractures as a result of even minor impact [97,99,100]. It is also important to note that such patients often grow slowly [101] and ‘differences in linear growth become more accentuated over time compared with their typically growing peers,’ in whom ‘the accrual of peak bone mass follows peak height velocity’ [99]. Also, a number of studies have identified nutritional disorders (found to be the most frequent among the severely disabled pediatric patients) in as many as 50% of the studied children, of which 15% suffered from malnutrition [101]. The most frequent gastrointestinal disorders included constipation, problems with vomiting, chest infection, choking with food and prolonged feeding times [102]. Further studies have found a significant relation (p = 0.002) between the number of bone fractures in young people with 940

cerebral palsy and the fact of their using AEDs. Moreover, it has been observed that when supplemented with vitamin D, such patients demonstrate a substantial improvement in their clinical status and sustain fewer bone fractures [100]. Other studies, in turn, have revealed that severe mental retardation is correlated with abnormal BMD (p = 0.0005) [103]. As a matter of fact, Coppola et al. [103] evaluated a group of children, adolescents and young adults (aged 3 -- 25, average 11 years) with diagnosed epilepsy alone or in association with cerebral palsy and/or mental retardation and applied mono- or polytherapy with AEDs for at least 2 years. The results indicate that 58.3% of patients had incorrect BMD values, where osteopenia was diagnosed in 75% of the cases, and 25% had osteoporosis. Polytherapy with TPM has shown a significant correlation of the treatment with BMD. Polytherapies with VPA, PB and LTG have also shown correlations with abnormal BMD, but this was not significant [103]. Effects of AEDS on bone health are shown in Table 1. Babayigit et al. [104] conducted tests on a group of pediatric patients with diagnosed idiopathic epilepsy. Biochemical parameters were measured, such as calcium, ALP, PTH, phosphorus, 25-OHD and BMD from L1 to L4 (measured with the dual-energy x-ray absorptiometry method). The children

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The problem of osteoporosis in epileptic patients taking antiepileptic drugs

were treated with CBZ, OXC or VPA. It was demonstrated that the mean serum ALP concentration was significantly higher (p = 0.02) and BMD values were significantly lower in the AED group, in comparison with the control group. Taking the category of gender into consideration, it was demonstrated that there are some differences in both females and males (p = 0.08) [103]. Other results also confirmed changes in biochemical parameters in epileptic patients. In 22.5% of patients, a lower-level serum calcium was evident, and in 29% of subjects an increase in ALP was reported. Hypocalcemia was correlated with high doses of AEDs, combination therapy, and with individual AEDs with decreasing order of significance: primidone, PHT and PB [105]. Farhat et al. [73] examined the influence of AEDs (given for at least for 6 months) on bone metabolism in adults and children. In over 50% of cases, a drop in 25-OHD levels was shown, whereas in adults a decrease in BMD levels was demonstrated. Enzyme-inducing drugs, such as CBZ, PB, PHT and primidone, more often decrease the level of BMD than non-inducing AEDs, which include clonazepam, ETX, GBP, LTG, TPM and VPA [73]. Pack et al. [34] noted that young women (aged 18 -- 40 years), taking drugs such as CBZ, LTG and VPA, showed no negative influence on the skeletal system. High concentrations of calcium (after a year of testing) showed up only in patients using LTG [30]. The influence of AED was also examined in a group of young male patients with epilepsy (aged 25 -- 54 years) [106]. Multivariate linear regression analysis reveals that both age (p < 0.001) and the period of the treatment (p < 0.003) had an influence on a low femoral neck BMD. In a group of younger patients (25 -- 44 years), significant declines in femoral neck BMD occurred by 1.8%/year. No hypocalcemia was observed. However, 11% of patients showed vitamin-D deficiency and 40% had a higher concentration of PTH [106]. Moreover, the influence of AEDs on bone health of older men was brought about [107]. In patients receiving non--enzyme-inducing AEDs (GBP, VPA, LTG, LEV, pregabalin, tiagabine), the average rate of decline in total hip BMD amounted to 0.53%/year, whereas in patients receiving enzyme-inducing AEDs (PHT, PB, CBZ, OXC, TPM, primidone) 0.46%/year, in comparison to the control group 0.35%/year. Similar results were registered in the hip subregions [107], whereas in postmenopausal women, ‘markers for bone formation (ALP, bALP, osteocalcin) and bone resorption (Crosslaps) were elevated in the patient group compared with the controls.’ Also, BMD was significantly lowered in patients particularly treated with enzyme-inducing AEDs and an increased occurrence of osteoporosis was evident [7]. Valmadrid et al. [108] took a different perspective and noted that the potential negative influence on bone structure is less familiar to doctors prescribing AEDs. A survey was conducted in which 624 adult and 404 pediatric neurologists took part, and it showed that only 28% of adult and 41% of pediatric neurologists were aware of negative AED effects on bones. Where, among doctors who diagnose bone disease, 37% of

adult and 40% of pediatric neurologists prescribe calcium or vitamin D3, whereas 57% of adult and 54% of pediatric neurologists refer the patient to a specialist. Also, approximately 9% of adult and 7% of pediatric neurologists prescribe calcium and vitamin D3 supplementation in combination with AED as a prophylactic [108]. More recent studies show similar results [109].

Prevention and treatment of bone problems

7.

AED and osteoporosis prevention trial was carried out in 80 male epileptic veterans as a prospective 2-year doubleblind, randomized and placebo-controlled study designed to evaluate some preventive strategies to reduce bone problems [110]. The patients were administered for a minimum of 2 years the following AEDs: CBZ, PHT, PB and VPA and were also supplemented with calcium and vitamin D. Then, the patients were randomized to risedronate (a bisphosphonate) or placebo groups. Evaluations of BMD were made at baseline, 1 year and after 2 years from the onset of treatment. As a secondary end point, the incidence of new vertebral or nonvertebral fractures was chosen. The study was completed by 53 veterans. Both preventive strategies (with or without risedronate) led to an improvement of BMD in ca 69% of evaluated patients and the risedronate group was characterized by a better BMD at the lumbar spine compared to the placebo group, supplemented with calcium and vitamin D. The number of new fractures was also reduced [110]. However, also some negative data on this issue are available. It is of importance that this retrospective study was conducted on 7716 epileptic patients who were divided in a group taking AEDs and supplementation of calcium and vitamin D (3303 patients) and the control group on AEDs only [22]. The results clearly denied any beneficial effects of supplementation, pointing to a similar number of patients with fractures in both groups (11.7% in the supplemented group vs 9.9% in the control group) [22]. Among treatment methods of osteoporosis in postmenopausal women, the following are included: hormonereplacement therapy and bisphosphonate [111]. However, it was demonstrated that the estrogen component can increase seizure frequency in menopausal women with epilepsy and elevate the risk of breast cancer, stroke and dementia [112]. Some general principles for postmenopausal women to prevent osteoporosis refer to adequate nutrition, cessation or avoidance of alcohol and smoking, and regular physical exercise. Supplementation of vitamin D seems also of importance [113]. There are recommendations regarding vitamin D and calcium supplementation in patients with epilepsy starting AED treatment. According to Drezner [114], a daily dose of vitamin D should be in the range of 2000 IU and that of calcium -- 0.6 to 1.0 g daily. Patients with an osteopenic/ osteoporotic problem are advised to take 2000 -- 4000 IU per day [114]. Collins et al. [115] recommend using from

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400 to 4000 IU in both institutionalized and outpatients on AEDs in order to retain normal serum 25-OHD concentration. Ali et al. [116] are of opinion that the daily intake of calcium in epileptic patients, with no documented osteoporosis and on AEDs for more than 6 months, should be 1.0 -1.5 g/day.

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8.

Conclusion

Newer AEDs seem presumably safer than classical drugs in terms of bone health. For instance, LTG in a number of studies did not exert any negative effects upon BMD [20,63] or biochemical markers related to bone health [20,27,30,34], the only exception being increased PTH concentration in adult patients with epilepsy [27]. As regards LEV, some data on the reduction of BMD by this AED are available [19,67] although some authors are of opinion that LEV is neutral in this regard [20]. Also, experimental results obtained in rats on this issue provide controversial data [38,70]. Another newer AED, TPM, seems to possess less-beneficial profile -- the AED reduced BMD in children and disturbed numerous biomarkers [64,65]. By producing mild to moderate acidosis, TPM may lead to osteomalacia and osteoporosis [20]. However, as in the case of LEV there are reports available pointing to a better profile of TPM as regards a risk of bone damage [22,66]. Due to its enzyme-inducing properties, especially when given in high doses, OXC is likely to match rather classical than newer AEDs. This AED was reported to reduce BMD in children and adults [19,104]. Classical AEDs, especially hepatic enzyme inducers, have been proved to negatively affect bone health. There are many studies reporting on reduced BMD in patients using these AEDs -- PHT [17,20,30,33,74], CBZ [17,27,64,73,104,117], PB [20,73]. Reduced BMD was accompanied with substantial disturbances of bone health markers [17,20,30,31,33,34,40-42,44,45,48,51,52,57,65,94,103,104]. However, there are also results pointing to a better profile of CBZ in this respect [30]. The enzyme inhibitor, VPA, has been documented to exert negative effects in terms of BMD [51,60,61,104] and biochemical markers [20,38,42,50,95,104]. Preventive measures for patients taking AEDs have been suggested -- these include supplementation with calcium and vitamin D [114-116] and there are also data pointing to the beneficial effects of the bisphosphonate -- risedronate [110]. Whether to use hormone replacement therapy in general population of postmenopausal women is still a matter of controversy and this may also apply to postmenopausal women on AEDs [110] who are at particular risk for fractures when taking AED monotherapy [7]. 9.

Expert opinion

When initiating therapy with AEDs, relevant variables and not only drug’s antiepileptic efficacy and effectiveness need to be taken into consideration [118]. However, if there are patients with obvious risk factors for the development of 942

bone problems, probably AEDs with lowest-documented negative impact on BMD and related biochemical markers should be introduced. Probably LTG would be the best choice in this regard. A problem appears when monotherapy is not effective and polytherapy must be considered. Then, an adjunctive AED would be expected to exert synergy with the AED used for the initial monotherapy with the lowest potential for the induction of adverse effects. From the preclinical point of view, a combined treatment of LTG with VPA fulfils this criterion, as anticonvulsant synergy and neurotoxic antagonism was evident for this AED combination [118]. Although VPA is associated with some negative impact on bone health [50,61,104,117], this combination might be quite promising in this respect. In contrast, when LTG is combined with CBZ, an apparent anticonvulsant antagonism occurs, accompanied with additive neurotoxicity [118]. Taking lower capacity of LEV to affect bone health, also combinations with this AED may seem beneficial to epileptic patients at risk of developing osteoporosis. Especially synergistic anticonvulsant interactions of LEV with TPM or vigabatrin should be considered [119]. Further combinations, encouraging from the preclinical point of view and based upon newer AEDs, could be recommended -- for example, pregabalin + tiagabine or pregabalin + GBP [120]. Generally, risk of fractures is more pronounced in patients taking enzyme inducers although some other AEDs also seem to affect this parameter. According to Vestergaard et al. [78], after adjustment for confounders, CBZ, OXC, clonazepam, PB and VPA significantly elevated risk of any fracture. In contrast, ETX, LTG, PHT, primidone, tiagabine, TPM and vigabatrin were not associated with this risk. Although Jette et al. [121] agree on the increased fracture risk in patients on CBZ, clonazepam and PB, they also add some more AEDs -- PHT and GBP, claiming VPA as the only AED without influence on the fracture risk. It is evident that the higher fracture risk may result from epilepsy itself and/or the negative impact of AEDs on the bone health. This indicates that the risk/benefit ratio for a given AED or an AED combination must be considered. Therefore, further studies are warranted to evaluate an impact of the newer AEDs on the fracture risk. However, the future results might be difficult to interpret, as the newer AEDs often follow the long-term use of conventional ones, so patients on monotherapy with a newer AED might be scarce. Also, such studies should possibly have no or at least reduced methodological limitations, as low statistical power, improper subject or control group selection, and failure to consider important confounding factors [122]. There is an obvious link between the number of fractures and the cumulative drug load (defined as total duration of epilepsy  number of AEDs used) in epileptic osteoporotic patients [123]. In such patients, the therapeutic use of bisposponates is out of question [123]. Whether to give a bisphosphonate as a preventive strategy against osteoporosis remains an open question, although initial results provided by Lazzari et al. [110] are encouraging in this regard.

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The problem of osteoporosis in epileptic patients taking antiepileptic drugs

Declaration of interest The authors acknowledge support of the Medical University of Lublin and Institute of Rural Health in Lublin, Poland. SJ Czuczwar and B Blaszczyk declare financial support from UCB pharmaceuticals and GlaxoSmith Kline for lectures. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.

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B Blaszczyk has also lectured for Bayer and Novartis. SJ Czuczwar has additionally lectured for Sanofi-Aventis and Janssen, and received an unrestricted grant from GlaxoSmithKline. B Miziak, M Chroscinska-Krawczyk, G Danilkiewicz and E Jagiello-Wojtowicz declare that they have no conflict of interest and have received no payment in relation to the manuscript.

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Affiliation Barbara Miziak1, Barbara Błaszczyk2, Magdalena Chros´cin´ska-Krawczyk3, Grzegorz Danilkiewicz1, Ewa Jagiełło-Wo´jtowicz4 & Stanisław J Czuczwar†1,5 † Author for correspondence 1 Medical University, Department of Pathophysiology, Jaczewskiego 8, PL 20-090 Lublin, Poland 2 Faculty of Health Sciences, High School of Economics, Law and Medical Sciences, Jagiellonska 109 A, PL 25-734 Kielce, Poland 3 Medical University of Lublin, Department of Pediatrics, Endocrinology and Neurology, Chodzki 2, PL 20-093 Lublin, Poland 4 Medical University of Lublin, Department of Toxicology, Chodzki 8, 20-093 Lublin, Poland 5 Institute of Rural Health, Department of Physiopathology, Jaczewskiego 2, PL 20-092 Lublin, Poland Tel: +48 81 718 7365; Fax: +48 81 718 7364; E-mail: [email protected]