holesterol provitamin D3 24R-hydroxylase 24R 25(OH) % pg/ml 8.8 mg/ (PTH) dl 10.4 mg/dl 1α-hydroxylase 24R-hydroxylase 1,25(OH) 4.

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1 3 (vitamin -binding protein) IU 50 phenytoin phenobarbital IU 3 5-hydroxylase 5 (OH) carbamazepine ng/ml 4R-hydroxylase 4R 5(OH) 1 98% 1,5 (OH) 0.5% pg/ml 8.8 mg/ (PTH) dl 10.4 mg/dl 1α-hydroxylase 4R-hydroxylase 1,5(OH) 4.8 mg/dl PTH 5-hydroxylase 1,5(OH) 1 g/dl ( 4 g/dl) 0.8 mg/dl 1,5(OH) (vitamin receptor, VR) VR steroid VR 1,5(OH) (parathyroid hormone, PTH) retinoid acid X (RXR) VR- RXR NA (vitamin response element, VRE) teopontin Alkaline phosphate 1,5(OH) 3 7- PTH osteoblast RANK dehydroxycholesterol 7-dehydroxycholesterol cholesterol ligand immature osteoclast RANK immature osteoclast ( 90 nm 315 nm) 7-dehydroxyc- (osteoid) (mineralization) holesterol provitamin 3 5(OH) 1α-hydroxylase 1,5(OH) ( ) osteocalcin os

2 hydroxylase cytochrome P450 (CYP450) P450C1 P450C5 1,5(OH) P450C4 1,5(OH) BM BM 3 3 CYP450 BM (oateoporosis) BM (osteomalacia) phenytoin phenobarbital [1,,3,4] cohort 48 phenytoin phenobarbital [5] 19% 33% 5 (OH) (alkaline phosphatase, ALP) [9,10,11] 5(OH) Hahn et al. [6] phenytoin phenobarbital 19% 33% 56 phenytoin phenobarbital [7] (OH) ( ng/ml 5(OH) 10 (osteopenia) (bone mass density, BM) BM ( ) [1, 13] phenytoin phenobarbital ng/ml) PTH -sensitive adenylate cyclase ALP PTH [8] 4 ( 33 ) -I (insulin-like 9 ( 11 ) 6 growth factor I, IGF-I) Pack et al. [14] 80 ng/ml 5(OH) CYP450 IGF-I 10 0 ng/ml IGF -3 (IGFBP-3) phentoin phenobarbital CYP450 IGF-I IGFBPprimidone carbamazepine 3 vaprolic acid lamotrigine clonazepam IGF-I gabapentin topiramate 34% 10 ng/ml K K 59% naphthoquinone γ-glutamyl

3 carboxylase cofactor Gla-contain protein glutamine carboxylation Glaprotein [6] phenytoin [15] Gla-protein osteoblast osteocalcin protein S matrix Gla protein (MGP) osteocalcintransforming growth factor (TGF) 0% mrna MGP IGF-1 IGFBP-3,-4,-5 (PGF) osteocalcin phenytoin TGF- type I α mrna MGP TGF- 1 [16] Gla K Gla Phenytoin K high turn- phenytoin [19] high turnover K [17,18] over phenytoin BM osteocalcin (trabecular bone) menatetrenone ( K high turnover osteopenia osteoporosis ) phenytoin BM osteomalacia ricket osteocalcin osteosarcoma phenytoin [18] osteocalcin phenytoin 1,5(OH) ketogenic acetazolamide calcitonin [0] phenytoin calcitonin [1] [8] C-cell calcitonin ( ) ( osteoclast [,3] phenytoin IU phenytoin ( 000 IU ) collagen lysosomal [4] 5(OH) [5] osteoblast- 3 PTH BM like phenytoin Hahn et al. Nakade et al. [7] phenytoin phenytoin 1 1 ALP

4 osteopenia osteoporosis ALP 5(OH) PTH osteocalcin pyridinium crosslink excretion BM 7. Collins et al [9] IU 5 (OH) 5(OH) [3] IU/ BM BM osteoporosis K osteomalacia osteopenia novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994; 9: Harris M, Jenkins MV, Wills MR. Phenytoin inhibition of parathyroid hormone induced bone resorption in vitro. Br J Phar- osteoporosis macol 1974; 50: ( ) osteomalacia PTH ALP 5(OH) IU [33] ALP / BM mg 3 4 PTH hydroxyproline [30,31] osteomalacia [34] BM 1. Richens A, Rowe FJ: isturbance of calcium metabolism by anticonvulsant drugs. Br Med J 1970; 4: ent C Richen A, Rowe, Stamp T: Osteomalacia with longterm anticonvulsant therapy in epilepsy. Br Med J 1970; 4: Kruse R: Osteopathien bei antiepileptischer Langzeittherapie. Monatasschr Kinderheilkd 1968; 116: Hunter J, Maxwell J, Stewart A, Parsons V, William R: Altered calcium metabolism in epileptic children on anticonvulsants. Br Med J 1971; 4: Hahn TJ, Birge SJ, Scharp CR, Avioli LV: Phenobarbitalinduced alternation in Vitamin metabolism. J Clin Invest 197; 51: Hahn TJ, Hendin BA, Scharp CR, Haddad JGJ: Effect of chronic anticonvulsant therapy on serum 5-hydroxycalciferol level in adult. N Engl J Med 197; 87: Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad Jr JG: Serum 5-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med 1975; 9: Farhat G, Yamout B, Mikati MA, emirjian S, Sawaya R, ElHajj Fuleihan G: Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 00; 58: Weinstein RS, Bryce GF, Sappington LJ, King W, Gallagher BB: ecreased serum ionized calcium and normal vitamin metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58: Andress L, Ozuna J, Tirschwell, et al. Antiepileptic druginduced bone loss in young male patients who have seizure. Arch Neurol 00; 59: Valimaki MJ, Tiihonen M, Laitinen K, et al: Bone mineral density measured by dual-energy X-ray absorptiometry and 13. Jenkins MV, Harris M, Wills MR. The effect of phenytoin on parathyroid extract and 5-hydroxycholecalciferol-induced bone resorption: adenosine 3, 5-cyclic monophosphate production. Calc Tiss Res 1974; 16: Pack AM, Morrell MJ, Flynn KL, et al: Possible mechanisms of bone disease in women receiving antiepileptic drug(ae) monotherapy. Epilepsia 001; 4(suppl. 7): Zittermann A: Effect of vitamin K on calcium and bone metabolism. Curr Opin Clin Nutr Metab Care 001; 4: ucy P, esbois C, Boyce B, et al: Increased bone formation in osteocalcin-deficienct mice. Nature 1996; 38: Scott AK, Haynes BP, Schinkel K, Ohnhaus EE, Park BK: Hepatic enzyme induction and vitamin K elimination in man. Eur J Clin Pharmacol 1987; 33: Vernillo AT, Rifkin BR, Hauschka PV: Phenytoin affects osteocalcin secretion from osteoblastic rat osteosarcoma 17/. 8 cells in culture. Bone 1990; 11: Onodera K, Takahashi A, Sakurada S, Okano Y: Effect of phenytoin and/or vitamin K(menatetrenone) on bone mineral density in the tibiae of growing rats. Life Sci 00; 70: Pento JT, Glick SM, Kagan A: iphenylhydantoin inhibition of calcitonin secretion in the pig. Endocrinology 1973; 9:

5 1. Kruse K, Kracht U: Inhibition of calcitonin secretion/synthesis by anticonvulsant drugs. Acta Endocrinol 1981; 96: Koch HC, raft, von Herrath : Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 197; 13: Harrison HC, Harrison HE: Inhibition of vitamin -stimulated active transport of calcium of rat intestine by diphenylhydantoin-phenobarbital treatment. Proc Soc Exp Biol Med 1976; 153: ietrich JW, uffield R: Effects of diphenylhydantoin on synthesis of collagen and noncollagen protein in tissue culture. Endocrinology 1980; 38: Feldkamp J, Becker A, Witte OW, Scharff, Scherbaum WA: Long-term anticonvulsant therapy leads to low bone mineral density: evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol iabetes 000; 108: Hahn TJ, Scharp CR, Richardson CA, Halstead LR, Kahn AJ, Teitelbaum SL: Interaction of diphylhydantoin(phenytoin) and phenobarbital with hormonal mediation of fetal rat bone resorption in vitro. J Clin Invest 1978; 6: Nakade O, Baylink J, Lau KH: Osteogenic actions of phenytoin in human bone cells are mediated in part by TGF-beta 1. J Bone Miner Res 1996; 11: Hahn TJ: Steroid and drug-induced osteopenia. In Favus MJ editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. nd ed. New York: Raven Press; p Collins N, Maher J, Cole M, Baker M, Callaghan N: A prospective study to evaluate the dose of vitamin required to correct low 5-hydroxyvitamin levels, calcium and alkaline phosphatase in patients at risk of developing antiepileptic drug induced osteomalacia. Q J Med 1991; 78: Bardens HS, Mazess RB, Rose PG, McAweeney W: Bone mineral status measured by direct photon absorptiometry in institutionalized adults receiving long-term anticonvulsant therapy and multivitamin supplementation. Calc Tiss Int 1980; 31: Peterson P, Gray P, Tolman KG: Calcium balance in drug induced osteomalacia: response to vitamin. Clin Phamacol Ther 1976; 19: Stamp TC, Round JM, Rowe J, Haddad JG: Plasma levels and therapeutic effect of 5-hydroxycholecalciferol in epileptic patients taking anticonvulsant drugs. Br Med J 197; 4: Kruse K: Pathophysiology of calcium metabolism in children with vitamin -deficiency rickets. J Pediatr 1995; 16: Rao S: Metabolic bone disease in gastrointestinal, hepatobiliary and pancreatic disorder. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 3rd ed. Philadelphia: Lippincott-Raven; p

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