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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 23  |  Issue : 2  |  Page : 84-88

Serum calcium deficiency and bone mineral density in patients on long-term anti-epileptic therapy


1 Department of Medicine, GMC and JJ Group of Hospitals, Mumbai, India
2 Department of Medicine, GMC, Nagpur, Maharashtra, India

Date of Web Publication11-Oct-2018

Correspondence Address:
Dr. Parag Rahatekar
349, Gandhinagar, Nagpur - 440 010, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmgims.jmgims_45_16

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  Abstract 


Introduction: Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AEDs). AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment and the pathogenesis of AED-associated fractures. The fracture rate in patients with epilepsy is 2–6 times higher than the rate observed in the general population. Only a few studies in India have studied the prevalence of osteopenia in patients on long-term AEDs. Purpose of Study: The purpose of this study is to find out the prevalence of osteoporosis and osteopenia and to correlate serum calcium levels with bone mineral density (BMD) by bone densitometer in patients with epilepsy on long-term AED therapy. Materials and Methods: The study was carried out at Government Medical College and Hospital where 50 cases having epilepsy of more than or equal to 2 years duration and 50 age- and sex-matched healthy controls were taken by comparing BMD and associated parameters. Results: Mean BMD value was low in cases as compared to controls in all age groups with a significant decrease in young age group and as the duration of AED therapy increased the mean BMD decreased.

Keywords: Anti-epileptic drugs, bone mineral density, epilepsy


How to cite this article:
Rahatekar P, Khot R. Serum calcium deficiency and bone mineral density in patients on long-term anti-epileptic therapy. J Mahatma Gandhi Inst Med Sci 2018;23:84-8

How to cite this URL:
Rahatekar P, Khot R. Serum calcium deficiency and bone mineral density in patients on long-term anti-epileptic therapy. J Mahatma Gandhi Inst Med Sci [serial online] 2018 [cited 2018 Dec 18];23:84-8. Available from: http://www.jmgims.co.in/text.asp?2018/23/2/84/243137




  Introduction Top


Epilepsy is a neurological disorder that affects people in every country worldwide. It is characterized by a tendency to recurrent seizures and defined by two or more unprovoked seizures. “Epilepsy” is derived from the Greek word “epilambanein” which means “to seize or attack.” Seizures are the result of sudden, usually brief, excessive electrical discharges in a group of brain cells (neurons) and that different parts of the brain can be the site of such discharges. The clinical manifestations of seizures will therefore vary and depend on where in the brain the disturbance first starts and how far it spreads. Transient symptoms can occur, such as loss of awareness or consciousness and disturbances of movement, sensation (including vision, hearing, and taste), mood, or mental function.[1] Osteoporosis is a bone condition defined by low bone mass, increased fragility, decreased bone quality, and an increased fracture risk. Using the World Health Organization (WHO) criteria, the Third National Health and Nutrition Examination Survey (NHANES Ш, 1988–1991) reported that 34%–50% of postmenopausal white women have osteopenia (T-score 1 to −2.49) and ~17%–20% have osteoporosis (T-score ≤−2.5).[2] Both low bone mass conditions increase fracture risks, with osteopenia having the greater impact. Bone mineral density (BMD) is altered in patients with long-term anti-epileptic drugs (AEDs) therapy. The fracture rate in patients with epilepsy is 2–6 times higher than the rate observed in the general population. Several theories have been proposed to explain the link between AEDs and bone disease. Hepatic induction of the cytochrome P450 enzyme system leading to increased catabolism of Vitamin D is the principal mechanism reported. One of the reasons is calcium deficiency occurring after long-term AEDs therapy. Only a few studies in India have studied the prevalence of osteopenia in patients on long-term AEDs. Factors that influence the development of osteopenia in epileptics are not well established. Hence, it is essential to evaluate the prevalence and magnitude of osteopenia in patients on long-term AEDs and its association with clinical metabolic and biochemical variables.

We studied the BMD in patients on long-term AEDs therapy and compared it with clinical and biochemical variables such as serum calcium and serum phosphorous levels.

Aims and objectives

The aim of this study is to find out the prevalence of osteoporosis and osteopenia and to correlate serum calcium levels with BMD by bone densitometer in the patients with epilepsy on long-term AED therapy.


  Materials and Methods Top


A cross-sectional study was carried out over a period of 2 months at Medicine and Psychiatry Outpatient Department of Government Medical College and Hospital, Nagpur. A total of 50 patients having either primary or secondary epilepsy and receiving anti-epileptic medications regularly for more than 2 years and 50 age- and sex-matched healthy controls not receiving any anti-epileptic medication were recruited in the study. Ethics committee approved the study, and written informed consent of the cases and controls was taken. They were evaluated using a bone densitometer ultrasound machine [Figure 1] and [Figure 2]. Serum calcium and phosphorus levels were also measured. According to T-score (WHO criteria), the patients and controls were classified as normal (>−1), osteopenia (<−1 and ≥2.5), or osteoporosis (<−2.5). Data were analyzed by univariate analysis and multivariate logistic regression.
Figure 1: Patient undergoing bone mineral density testing at Medicine and Psychiatry Outpatient Department of GMCH, Nagpur

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Figure 2: X-ray hand of the epileptic patient on long-term anti-epileptic drugs developing osteoporosis

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  Results Top


The mean age of patients in our study was 33.94 ≥ 11.8 years [Chart 1] and [Table 1] with a male:female = 1.17:1 [Chart 2] and [Table 2]. Mean BMD in cases was −2.108 ≥ 1.01 versus −0.948 ≥ 0.96 in controls. The difference was statistically significant (P = 0.03) [Table 3]. Osteopenia was observed in 50% and osteoporosis in 32% of patients [Chart 3] and [Table 4]. The prevalence of osteopenia was 50% and osteoporosis 32%. Osteopenia was significantly higher in cases as compared to controls (34%) (P = 0.04). A significant decrease in BMD values was seen in cases in the age groups 20–29 and 30–39 years (P < 0.001) [Chart 4] and [Table 5]. There was no significant gender difference. As the duration of AED therapy increased the mean BMD decreased [Chart 5] and [Table 6]. Mean BMD was low for phenobarbitone (PB), phenytoin (PHT), and carbamazepine (CBZ) [Chart 6] and [Table 7]. Serum calcium and serum phosphorous levels were below normal in patients with epilepsy than controls [Table 8] and [Table 9]; however, the difference was not statistically significant. On multivariate analysis, age and duration of AEDs therapy were found to be independent factors for low BMD [Table 10].
Table 1: Age distribution of patients

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Table 2: Sex distribution

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Table 3: Bone mineral density and epilepsy

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Table 4: Epilepsy and prevalence of osteoporosis and osteopenia

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Table 5: Bone mineral density and age

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Table 6: Duration of anti-epileptic drug therapy and mean bone mineral density

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Table 7: Drug treatment and bone mineral density

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Table 8: Bone mineral density and serum calcium

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Table 9: Bone mineral density and serum phosphorous

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Table 10: Logistic regression table

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  Discussion Top


Epilepsy is a major public health problem affecting nearly 50 million people worldwide.[3] Treatment with (AEDs) is generally chronic, if not lifelong and may be associated with significant metabolic effects including decreased bone mass and increased fractures.[4],[5] The AEDs most commonly associated with altered bone metabolism and decreased bone density are inducers of the cytochrome P450 enzyme system, including PHT, CBZ, primidone (PRM), and PB. The effect of valproate (VPA) on bone metabolism and bone density has received limited study.

Several theories have been proposed to explain the link between AEDs and bone disease. Hepatic induction of the cytochrome P450 enzyme system leading to increased catabolism of vitamin D is the principal mechanism reported.[6],[7] However, it does not explain the findings described in patients receiving other medications, such as VPA, an inhibitor of the cytochrome P450 enzyme system. In addition, the finding of Vitamin D deficiency has not been demonstrated in all studies, and evidence of bone turnover is found independent of Vitamin D deficiency.[6],[8],[9] Other possible mechanisms include a direct effect on bone cells including impaired absorption of calcium and inhibition of response to PTH, hyperparathyroidism, and calcitonin deficiency.[7]

AEDs that induce hepatic cytochrome P450 enzymes may cause increased conversion of Vitamin D to polar inactive metabolites in the liver microsomes, reducing bioavailable Vitamin D. Decreased biologically active Vitamin D leads to decreased absorption of calcium in the gut, resulting in hypocalcemia, and an increase in circulating PTH. PTH then increases the mobilization of bone calcium stores and subsequent bone turnover.

AEDs may interfere with intestinal absorption of calcium. Impaired absorption would lead to hypocalcemia and feedback hypersecretion of PTH. Markedly decreased calcium absorption was found in rats treated with PHT but not with PB.[10] These results suggest that in patients treated with PHT, impaired calcium absorption may play a role.

Evidence also exists for inhibition of the cellular response to PTH. Fetal rats treated with PHT or PB demonstrated an impaired response to PTH.[11] Inhibition of the bone resorptive response to PTH could lead to hypocalcemia, a frequent finding in patients taking AEDs.

Hyperparathyroidism also has been suggested as a possible mechanism. Both male patients with normal Vitamin D status[6] and participants who were Vitamin D repleted had evidence of hyperparathyroidism.[8] Hyperparathyroidism can primarily activate bone resorption and through a coupling phenomenon, secondarily activate bone formation.

A final postulated mechanism is calcitonin deficiency. Calcitonin is a hormone produced by the thyroid gland that inhibits osteoclast-mediated bone resorption. Calcitonin deficiency may, therefore, accelerate bone turnover. This deficiency has been demonstrated both in vitro and in vivo.[12],[13]

Andress et al.[14] conducted a study of 81 men in the age group of 25–54 years. The mean age of the study population was 45 (7) years. Significant declines in femoral neck BMD (annualized loss 1.8%; P < 0.003) were observed in those in the youngest age group (25–44 years), suggesting that effect of AEDs may be more pronounced in the younger rather than older age group. This is a particularly concerning as AEDs are typically used for long periods of time and may be used for life.

Souverein et al.[15] conducted a case–control study of the population comprising 1018 cases and 1842 matched controls. The risk of fractures increased with cumulative duration of exposure (P for trend < 0.001), with the strongest association for >12 years of use: Adjusted odds ratios 4.15 (95% confidence interval 2.71–6.34).

Farhat et al.[16] conducted a cross-sectional evaluation of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months. They found that participants on enzyme-inducing drugs such as PHT, PB, CBZ, and PRM tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topiramate, and ethosuximide.

Bartl[17] found that a patient on long-term treatment with AEDs has a 2–3-fold risk of sustaining a fracture. On average, 50% of patients (ranging from 4% to 70% in different studies) have osteopathy. Bone loss has been noted with or even without evidence of Vitamin D deficiency among the enzyme-inducing drugs, especially PHT, PRM, PB, and carbamazepine.

von Borstel Smith et al.[18] determined the effects of several AEDs on intestinal epithelial calcium transport using Caco-2 cells, a model transport system for study of the function of the intestinal epithelium. PHT and CBZ dose-dependently inhibit active calcium transport from the apical to basolateral side of Caco-2 cells under physiologic calcium conditions.

There is serum calcium deficiency in patients on long-term anti-epileptic therapy; however, the difference concerning controls was not statistically significant in our study. The population in our study had the majority of controls with low calcium levels due to various dietary and other causes of calcium deficiency. However, the BMD showed a statistically significant difference between our patients and control groups thus emphasizing the calcium deficiency is not a statistically significant factor for low BMD.

In summary, it is clear that there is an increased risk for low BMD and increased risk particularly for fractures in patients on long-term anti-epileptic therapy.


  Conclusion Top


There is a significant decrease in BMD in the patients of epilepsy on long-term AED therapy. Serum calcium levels are relatively low in these patients and calcium deficiency is not a statistically significant factor for low BMD.

Thus, implications of our study are that all the patients of epilepsy using AED therapy especially PB, PHT, and CBZ for a duration of >2 years should be screened for the presence of osteopenia and osteoporosis and other biochemical markers so that prompt treatment can be instituted and risk of fracture in the future can be minimized.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
WHO. Epilepsy: Aetiogy, Epidemiology and Prognosis. Fact Sheet N°165; February, 2001. Available from: http://www.idealibrary.com. [Last accessed date 2018 Jun 21].  Back to cited text no. 1
    
2.
Looker AC, Orwoll ES, Johnston CC Jr. Lindsay RL, Wahner HW, Dunn WL, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761-8.  Back to cited text no. 2
    
3.
Scott RA, Lhatoo SD, Sander JW. The treatment of epilepsy in developing countries: Where do we go from here? Bull World Health Organ 2001;79:344-51.  Back to cited text no. 3
    
4.
Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63:S24-9.  Back to cited text no. 4
    
5.
Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleve Clin J Med 2004;71 Suppl 2:S42-8.  Back to cited text no. 5
    
6.
Välimäki MJ, Tiihonen M, Laitinen K, Tähtelä R, Kärkkäinen M, Lamberg-Allardt C, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994;9:631-7.  Back to cited text no. 6
    
7.
Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: Epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001;15:633-42.  Back to cited text no. 7
    
8.
Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal Vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984;58:1003-9.  Back to cited text no. 8
    
9.
Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol 2000;47:385-8.  Back to cited text no. 9
    
10.
Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972;13:829-34.  Back to cited text no. 10
    
11.
Hahn TJ, Hendin BA, Scharp CR, Haddad JG Jr. Serum 25-hydroxy calciferol levels and bone mass in children on chronic anti-epileptic therapy. N Engl J Med 1975;292:550-4.  Back to cited text no. 11
    
12.
Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteocalcin secretion from osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone 1990;11:309-12.  Back to cited text no. 12
    
13.
Kruse K, Süss A, Büsse M, Schneider P. Monomeric serum calcitonin and bone turnover during anticonvulsant treatment and in congenital hypothyroidism. J Pediatr 1987;111:57-63.  Back to cited text no. 13
    
14.
Andress DL, Ozuna J, Tirschwell D, Grande L, Johnson M, Jacobson AF, et al. Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol 2002;59:781-6.  Back to cited text no. 14
    
15.
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.  Back to cited text no. 15
    
16.
Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002;58:1348-53.  Back to cited text no. 16
    
17.
Bartl R. Antiepileptic drug-induced osteopathy. Subtypes, pathogenesis, prevention, early diagnosis and treatment. Dtsch Med Wochenschr 2007;132:1475-9.  Back to cited text no. 17
    
18.
von Borstel Smith M, Crofoot K, Rodriguez-Proteau R, Filtz TM. Effects of phenytoin and carbamazepine on calcium transport in caco-2 cells. Toxicol In Vitro 2007;21:855-62.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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