Calcium metabolism and vitamin D metabolite levels in children receiving anticonvulsant drugs

Abstract

Abstract. Calcium metabolism and plasma concentrations of vitamin D metabolites were investigated in 27 children on long-term anticonvulsant therapy. Serum calcium was in the low normal range, phosphorus was normal, parathyroid hormone concentrations and alkaline phosphatase were elevated. Plasma 25-hydroxyvitamin D (25-OH D) and 24,25-dihydroxyvitamin D (24,25-(OH)2D) were decreased, but 1,25-dihydroxyvitamin D (1,25-(OH)2D) was normal when compared with a synchronous control group. The serum concentrations of all anticonvulsant drugs given were measured. The decreases in 25-OH D and 24,25-(OH)2D did not depend on the blood level of a single drug, or any combination of drugs given, or on the duration of therapy. The 25-OH D levels were negatively correlated with the number of different drugs used, which may reflect the severity of the neurologic disorder, and therefore with non-specific factors such as exposure to sunlight, nutrition, or physical activity.Our data do not support the hypothesis that anticonvulsant drugs act on vitamin D metabolism. Key words: Calcium metabolism -Vitamin D metabolites - Anticonvulsant drugsAnticonvulsant drugs, particularly diphenylhydantoin (DPH) and phenobarbital (PB), are known to affect calcium metabolism and to cause rickets or osteomalacia [1,2]. In vitro, in the rat, Caspary [3] and Koch et al. [4] found that intestinal absorption of calcium was depressed by DPH but not by PB. The amounts of the vitamin D dependent calcium binding were found to be normal [3].Since PB induces hepatic microsomal enzymes, it has been suggested that due to increased 25-hydroxylase activity PB may increase the availability of25-OH D and its conversion to more polar but less active vitamin D metabolites, thus enhancing plasma clearance of vitamin D and leading to reduced serum and tissue levels of active vitamin D metabolites [5][6][7]. Conversely, in patients receiving anticonvulsant therapy plasma levels of 24,25-(OH)2D were decreased [8], and levels of 1,25-(OH)2D were reported to be normal [9]. It was concluded that in the presence of PB the intestine is less responsive to 1,25-(OH)2D, or that other factors than vitamin D metabolites may impair intestinal calcium transport. [10] found that in epileptic patients on anticonvulsant therapy absorption of calcium from the digestive tract was moderately depressed but that small doses of 1,25-(OH)2D as well as 25-OH D enhanced calcium absorption. They concluded that the sensitivity of the intestine to vitamin D was not impaired in these subjects. These results may indicate that in patients on anticonvulsant therapy the serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) abnormalities are not caused by a defect in 1,25-(OH)2D metabolism or action on the intestine. As vitamin D metabolism is particularly influenced by external factors such as seasonal changes and differences in exposure to sunlight, physical activity and nutritional status, control data may be derived only from carefully matched subjects. This was also cons...

Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: A meta-analysis

“…AEDs are associated with significant side effects including, but not limited to, radiological evidence of rickets, decreased bone mineral density (BMD), altered bone turnover, and increased risk of fracture (Souverein et al, 2005;Karceski, 2007;Gniatkowska-Nowakowska, 2010;Verrotti et al, 2010;Meier and Kraenzlin, 2011). AEDs increase catabolism of 25-hydroxyvitamin D by induction of the hepatic P-450 enzyme system, leading to relative hypocalcemia, increased levels of parathyroid hormone (PTH), and subsequent low BMD (Dent et al, 1970;Keck et al, 1982;Chung and Ahn, 1994). However, some studies have suggested a significant reduction in BMD with non-enzymeinducing AEDs (Oner et al, 2004;Petty et al, 2005).…”

Vitamin D Status of Ambulatory and Nonambulatory Mentally Retarded Children with and without Carbamazepine Treatment

“…In com parison. Christensen et al [25], Keck et al [5] and Tjellesen et al [26]. who found low 25-OH-D concentrations in patients treated mainly with phenytoin, phénobarbital as compared to controls, found a significantly decreased serum 24,25-(OH)2-D concentra tion in the patients.…”

“…Most of the studies have been con cerned with patients treated with phenytoin and phénobarbital [3,[5][6][7]19] but some focused on carbamazepine therapy [8][9][10][11][12][13]. In animal experiments it has been shown that microsomal enzymes in the liver are activated by phénobarbital or phenytoin [20,21] and thus one reason for the low 25-OH-D concentration could be an increased turn over of 25-OH-D in the liver.…”

“…In the present study there was a trend towards lower 24,25-(OH)2-D concentra tions in the carbamazepine-treated patients, but due to a small number of subjects the difference between the carbamazepinetreated patients and those receiving no drugs was not significant. The serum l,25-(OH)2-Dj concentration was found to be normal [5] in patients treated with phenobarbital/phenvtoin [25. 26].…”

The effect of anticonvulsant use on bone mineral density in non-ambulatory children with cerebral palsy

“…21,22 Recent research on the effect of AED on BMD is inconclusive, and the results are often confounded by methodological flaws. In a crosssectional study, Farhat et al 5 measured the BMD in 71 ambulatory subjects who were prescribed AED for more than 6 months.…”