50 Years Ago in TheJournalofPediatrics: Rickets and Antiepileptic Drugs: What Have We Learned?

Abstract

Borgstedt AD, Bryson MF, Young LW, Forbes GB. Long-term administration of antiepileptic drugs and the development of rickets. J Pediatr 1972;81:9-15. In 1972, Borgstedt et al reported 2 neurologically impaired children who developed rickets after years of antiepileptic drug therapy. The diagnosis was based on physical findings, radiographs, and serum calcium, phosphate, and alkaline phosphatase levels. Rickets resolved with daily doses of calcium and large amounts of vitamin D, despite continuance of the antiepileptic drugs. Missing were measures of vitamin D metabolites, presumably owing to a lack of available clinical assays at that time. Our knowledge of vitamin D metabolism has progressed far beyond the already established metabolic pathways of hepatic 25-hydroxylation and renal 1-hydroxylation of that era. As the authors suspected, antiepileptic drugs, and other drugs, cause rickets by increased hepatic vitamin D catabolism. Induction of catabolic enzymes leaves less vitamin D for eventual renal conversion to the active metabolite 1,25 dihydroxyvitamin D (1,25-D). With inadequate 1,25-D, calcium absorption is impaired, contributing to inadequate bone mineralization. As extracellular calcium decreases, parathyroid hormone responds, but this response causes phosphaturia, further under mineralizing bone. In vitamin D disorders, bone chondrocyte function is also altered, leading to metaphyseal abnormalities explaining many hallmark features of vitamin D rickets, such as widened wrists and rachitic rosary. Other bone health issues in children with epileptic disorders, not related to vitamin D deficiency, include seizure-associated trauma, nonambulatory status, and nutritional deficiencies. The measurement of the main circulating metabolite, 25-hydroxyvitamin D (25-D), is widely available. Problems remain, including assay variability and an inconsistent relationship of level to clinical impact; for example, a 25-D level of 12 ng/mL may cause rickets in 1 individual and no notable signs in another. The 25-D levels are, at best, a surrogate for potential 1,25-D production. Another issue is that 25-D is measured in nanograms per milliliter, with acceptable levels in children generally considered to be more than 20 ng/mL. However, 1,25-D is measured in picograms per milliliter, or a 1000-fold less concentration. Why is a 25-D level of 10 000 pg/mL (=10 ng/mL) not enough substrate to provide adequate 1,25-D production to the 20-80 pg/mL reference range? From their inference of vitamin D deficiency, Borgstedt et al helped to identify an important preventable complication of antiepileptic drug use in children. Incorporating these findings into clinical guidelines remains to be completed.