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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 58, Num. 2, 2010, pp. 175-176

Neurology India, Vol. 58, No. 2, March-April, 2010, pp. 175-176


Antiepileptic drugs and bone health: Dietary calcium and vitamin D the confounding factors

Chief of Neurology, The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India

Correspondence Address: J. M. K Murthy, Chief of Neurology, The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India,

Code Number: ni10050

PMID: 20508330

DOI: 10.4103/0028-3886.63773

There is a mounting body of evidence linking a variety of biochemical, metabolic and radiological abnormalities in bone to the use of antiepileptic drugs (AEDs). Although women are at particular risk, bone loss associated with AED use happens at all ages in both sexes. [1] However, the awareness of the effects of AEDs on bone health among the physicians dealing with patients with epilepsy is quite low. [2] Often the low bone mass associated with AED treatment is largely unrecognized, undetected, and untreated. [3],[4] Though the adverse effects on bone health are mostly seen with the use of enzyme-inducing AEDs, [1] these effects have also been shown with the use of non-enzyme-inducing AEDs including valproate [1] and newer AEDs. [5] Enzyme-inducing AEDs accelerate the metabolism of vitamin D3, resulting in inactive metabolites, leading to decreased fractional calcium absorption, secondary hyperparathyroidism with greater bone resorption, and higher rates of bone loss. [1] Valproate, a hepatic enzyme inhibitor, is thought to act by stimulating osteoclast activity. [6] Studies of valproate and calcium levels are contradictory. [7],[8] The possible mechanisms for the higher rates of bone loss with the use of non-enzyme-inducing newer AEDs have not yet been elucidated.

The study by Krishanmurthy and colleagues [9] documents that monotherapy with pheyntoin and valproate in Indian adult patients with epilepsy results in significant changes in calcium and vitamin D metabolism within few weeks of the initiation of AED treatment. The possible confounding effect of low dietary calcium intake and vitamin deficiency, for these early effects, needs consideration in patients with epilepsy on AEDs in India. Adequate nutrient intakes of calcium, vitamin D, and protein are of critical importance for bone health and help to maintain bone mineral mass attained at the end of growth period. The daily dietary calcium intake by the population in India [10],[11],[12],[13] is below that of the recommended daily allowance (RDA) suggested by the Indian Council of Medical Research (ICMR) [14] which is far lower than the Western data. [15] In a study in south India, the 25-hydroxyvitamin D levels of both the urban and rural children were low. [12] High prevalence of clinical and biochemical hypovitaminosis D has been documented in apparently healthy school children from north India, [16],[17] Studies form the Indian subcontinent also suggest low dietary calcium and 25-hydroxyvitamin D status in postmenopausal women [18],[19],[20] and pregnant women. [21] The study by Menon and colleagues [22] in this issue, documents that the dietary consumption of calcium is far below the RDA suggested by the ICMR in all the age groups of patients with epilepsy on AEDs. This study also shows that women aged between 15-45 years, the reproductive age group, and postmenopausal women are grossly deficient in their dietary calcium intake.

There are currently no evidence-based guidelines for diagnosis or treatment of bone disease associated with AED use. Periodic screening for vitamin D deficiency and dual-energy X-ray absorptiometry is likely beneficial. [1] In India there is a strong case for prophylactic supplementation with vitamin D and calcium for all patients on AEDs as the intake of dietary calcium is suboptimal and far below the recommended RDA dosage. Higher dose vitamin D therapy may be required in the presence of osteomalacia and rickets. In addition adequate sunlight exposure and physical activity are to be encouraged. The study by Krishnamurthy and colleagues also suggests that simultaneous co-administration of calcium and 25-OHD in RDA dosage is beneficial in limiting the changes in calcium and vitamin D metabolism in these patients. Thus there is an urgent need for nationwide well-designed prospective longitudinal studies to evaluate the effects of nutrient intakes of calcium, vitamin D, phytates and protein on bone health in patients with epilepsy on AEDs. Milk is not fortified with calcium or vitamin D in India and also most of the Indian diets are not rich in calcium


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2.Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mneral effects of antiepileptic drug theapy. Arch Neurol 2001;58:1369-74.   Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Seth RD. Metabolic concerns associated with antiepileptic medication. Neurology 2004;63:S24-9.   Back to cited text no. 3    
4.Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleve Clin J Med 2004;71:S42-8.   Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Ensrud KE, Walczak TS, Blackwell TL, Ensrud ER, Barrett-Connor E, Orwoll ES, et al. Antiepileptic drug use and rates of hip bone loss in older men: a prospective study. Neurology 2008;71:723-30.   Back to cited text no. 5    
6.Sheth RD, Wesolowski CA, Jacob JC, Penney S, Hobbs GR, Riggs JE, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995;127:256-62.   Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001;57:445-9.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Pack AM, Morrell MJ, Marcus R, Holloway L, Flaster E, Doρe S, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol 2005;57:252-7.  Back to cited text no. 8    
9.Krishnamurthy G, Nair R, Sundar U, Kini P, Shrivastava M. Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dasage: A prospective study. Neurol India 2010;58:213-9  Back to cited text no. 9    
10.Rajeswari J, Balasubramanian K, Bhatia V, Sharma VP, Agarwal AK. Aetiology and clinical profile of osteomalacia in adolescent girls in northern India. Natl Med J India 2003;16:139-42.  Back to cited text no. 10  [PUBMED]  
11.Mathew JT, Seshadri MS, Thomas K, Krishnaswami H, Cherian AM. Osteomalacia-Fifty five patients seen in a teaching institution over a 4-year period. J Assoc Physicians India 1994;42:692-4.  Back to cited text no. 11  [PUBMED]  
12.Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D, Srinivasarao PV, Sarma KV, et al. High prevalence of low dietary calcium high phytate consumption and vitamin D deficiency in health south Indians. Am J Clin Nutr 2007;85:1062-7.   Back to cited text no. 12  [PUBMED]  
13.Bhatia V. Dietary calcium intake - a critical appraisal. Indian J Med Res 2008;127:269-73.   Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Food composition table. In: Gopalan C, Sastri BV, Balasubramanyam SC, editors. Nutritive value of Indian foods. Hyderabad: India: National Institute of Nutrition ICMR; 1996: Appendix 1. p.92-4.  Back to cited text no. 14    
15.Report of the Joint FAO/WHO Expert Consultation on vitamin and mineral requirement in human nutrition: Bangkok 1998. 2 nd ed. FAO Rome, 2004. Available from: . [last cited on 2004].  Back to cited text no. 15    
16.Marwaha RK, Tandon N, Reddy DR, Aggarwal R, Singh R, Sawhney RC, et al. Vitamin D and bone mineral density status of healthy school children in northern India. Am J Clin Nutr 2005;82:477-82.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Marwaha RK, Sripathy G. Vitamin D and bone mineral density of healthy school children in north India. Indian J Med Res 2008;127:239-44.   Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Harinarayan CV. Prevalence of vitamin D insufficiency in postmenopausal south Indian women. Osteoporos Int 2005;16:397-402.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Harinarayan CV, Ramalakshmi T, Venkataprasad U. High prevalence of low dietary calcium and low vitamin D status in healthy south Indians. Asia Pac J Clin Nutr 2004;13:359-65.  Back to cited text no. 19  [PUBMED]  
20.Shatrugna V, Kulkarni B, Kumar PA, Rani KU, Balakrishna N. Bone status of Indian women from low income group and its relationship to the nutritional status. Osteoporos Int 2005;16:1827-35.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. High prevalence of vitamin D deficiency among pregnant women and their new borns in north India. Am J Clin Nutr 2005;81:1060-4.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Menon B, Hrinarayan CV, Raj N, Swapna V, Himabindu G, Afsana T. Prevalence of low dietary calcium intake in patients with epilepsy: a study from south India. Neurol India 2010;58:209-12.  Back to cited text no. 22  [PUBMED]  Medknow Journal

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