Calcified Tissue International

, Volume 28, Issue 1, pp 17–22 | Cite as

Disordered mineral metabolism produced by ketogenic diet therapy

  • Theodore J. Hahn
  • Linda R. Halstead
  • Darryl C. DeVivo
Clinical Investigations


Vitamin D and mineral metabolism status was examined in five children maintained chronically on combined ketogenic diet-anticonvulsant drug therapy (KG), and the results compared to those obtained in 18 patients treated with anticonvulsant drugs alone (AD) and 15 normal controls. KG patients exhibited biochemical findings of vitamin D deficiency osteomalacia: decreased serum 25-hydroxyvitamin D (25OHD) and calcium concentrations, elevated serum alkaline phosphatase and parathyroid hormone concentrations, decreased urinary calcium and increased urinary hydroxyproline excretion, and decreased bone mass. Although the KG and AD groups demonstrated similar reductions in serum 25OHD concentration, the KG patients exhibited a significantly greater reduction in bone mass. In response to vitamin D supplementation (5000 IU/day), mean bone mass in the KG group increased by 8.1±0.9% (P<0.001) over a 12-month period. These results suggest that ketogenic diet and anticonvulsant drug therapy have additive deleterious effects on bone mass and that these effects are partially reversible by vitamin D treatment.

Key words

Anticonvulsant Ketogenic diet Calcium Vitamin D Bone 


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  1. 1.
    Huttenlocher, P.R.: Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy, Pediatr. Res.10:536–540, 1976PubMedCrossRefGoogle Scholar
  2. 2.
    DeVivo, D.C., Leckie, M.P., Ferrendelli, J.A., McDougal, D.B., Jr.: Chronic ketosis and cerebral metabolism, Ann. Neurol.3:331–337, 1978PubMedCrossRefGoogle Scholar
  3. 3.
    DeVivo, D.C., Malas, K.M., Leckie, M.P.: Starvation and seizures: Observations on the electroconvulsive threshold and cerebral metabolism of the starved adult rat, Arch. Neurol.32:755–760, 1975PubMedGoogle Scholar
  4. 4.
    Bouillion, R., Reynault, J., Claes, J.G., Lissens, W., DeMoor, P.: The effect of anticonvulsant therapy on serum levels of 25-hydroxyvitamin D calcium and parathyroid hormone, J. Clin. Endocrinol. Metab.41:1130–1135, 1135, 1975Google Scholar
  5. 5.
    Dent, C.E., Richens, A., Rowe, D.J.F., Stamp, T.C.B.: Osteomalacia with long-term anticonvulsant therapy in epilepsy, Br. Med. J.4:69–72, 1970PubMedGoogle Scholar
  6. 6.
    Hahn, T.J., Hendin, B.A., Scharp, C.R., Boisseau, V.C., Haddad, J.G., Jr.: Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy, N. Engl. J. Med.292:550–554, 1975CrossRefGoogle Scholar
  7. 7.
    Jubiz, W., Haussler, M.R., McCain, T.A., Tolman, K.: Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs, J. Clin Endocrinol. Metab.44:617–621, 1977PubMedGoogle Scholar
  8. 8.
    Lifshitz, F., Maclaren, N.K.: Vitamin D-dependent rickets in institutionalized, mentally retarded children receiving long-term anticonvulsant therapy: I. A survey of 288 patients, J. Pediatr.83:612–620, 1973PubMedCrossRefGoogle Scholar
  9. 9.
    Richens, A., Rowe D.J.F.: Disturbance of calcium metabolism by anticonvulsant drugs, Br. Med. J.3:73–76, 1970Google Scholar
  10. 10.
    Tolman, K.G., Jubiz, W., Sannella, J.J., Madsen, J.A.: Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children, Pediatrics56:45–51, 1975PubMedGoogle Scholar
  11. 11.
    Hahn, T.J., Birge, S.J., Scharp, C.R., Avioli, L.V.: Phenobarbital-induced alterations in vitamin D metabolism, J. Clin. Invest.51:741–748, 1972PubMedGoogle Scholar
  12. 12.
    Silver, J., Neale, G., Thompson, G.R.: Effect of phenobarbitone treatment on vitamin D metabolism in mammals, Clin. Sci. Mol. Med.46:433–448, 1974PubMedGoogle Scholar
  13. 13.
    Lemann, J., Jr., Litzow, J.R., Lennon, E.J.: The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis, J. Clin. Invest.45:1608–1614, 1966PubMedGoogle Scholar
  14. 14.
    Lee, S.W., Russell, J., Avioli, L.V.: 25-Hydroxycholecalciferol to 1,25-dihydroxycholecalciferol conversion impaired by systemic acidosis, Science195:994, 1977PubMedGoogle Scholar
  15. 15.
    DeVivo, D.C., Dahn, T.J.: Calcium-vitamin D metabolism and the ketogenic diet. Child Neurology Society Meeting, Charlottesville, Virginia-October 6–8, Ann. Neurol.2:255, 1977 (abst.)Google Scholar
  16. 16.
    Huttenlocher, P.R., Wilbourn, A.J., Signore, J.M.: Medium-chain triglycerides as a therapy for intractable childhood epilepsy, Neurology (Minneap.)21:1097–1103, 1971Google Scholar
  17. 17.
    Haddad, J.G., Jr., Chyu, K.G.: Competitive protein-binding radioassay for 25-hydroxycholecalciferol, J. Clin. Endocrinol. Metab.33:992–995, 1971PubMedGoogle Scholar
  18. 18.
    Slatopolsky, E., Cagbar, S., Pennell, J.P., Taggard, D.D., Canterbury, J.M., Reiss, E., Bricker, N.: On the pathogeneses of hyperparathyroidism in chronic experimental renal insufficiency in the dog, J. Clin. Invest.50:492–499, 1971PubMedGoogle Scholar
  19. 19.
    Prockop, D.J., Udenfriend, S.: A specific method for the analysis of hydroxyproline in tissues and urine, Anal. Biochem.1:228–239, 1960PubMedCrossRefGoogle Scholar
  20. 20.
    DeVivo, D.C., Haymond, M.W., Leckie, M.P., Bussmann, Y.L., McDougal, D.B., Jr., Pagliara, A.S.: The clinical and biochemical implications of pyruvate carboxylase deficiency, J. Clin. Endocrinol. Metab.45:1281–1296, 1977PubMedGoogle Scholar
  21. 21.
    Hahn, T.J., Boisseau, V.C., Avioli, L.V.: Effect of chronic corticosteroid administration on diaphyseal and metaphyseal bone mass, J. Clin. Endocrinol. Metab.39:274–282, 1974PubMedCrossRefGoogle Scholar
  22. 22.
    Snedecor, G.W.: Analyses of variance. In G.W. Snedecor (ed.): Statistical Methods, 5th Ed., pp. 237–290. Iowa State University Press, Ames, Iowa, 1956Google Scholar
  23. 23.
    Lassiter, W.E., Gottschalk, C.W., Mylle, M.: Micropuncture study of renal tubular reabsorption of calcium in normal rodents, Am. J. Physiol.204:771–775, 1963Google Scholar
  24. 24.
    Klein, L., Lafferty, F.W., Pearson, O.H., Curtiss, P.H., Jr.: Correlation of urinary hydroxyproline, serum alkaline phosphatase and skeletal calcium turnover, Metabolism13:272–284, 1964PubMedCrossRefGoogle Scholar
  25. 25.
    Haddad, J.G., Jr., Couranz, S., Avioli, L.V.: Nondialyzable urinary hydroxyproline as an index of bone collagen formation, J. Clin. Endocrinol. Metab.30:282–287, 1970PubMedCrossRefGoogle Scholar
  26. 26.
    Sjoerdsma, A., Udenfriend, S., Deisser, H., LeRoy, H.C.: Hydroxyproline and collagen metabolism. Clinical implications, Ann. Intern. Med.63:672–694, 1965.Google Scholar
  27. 27.
    Glorieux, F.H., Delvin, E.E., Dussault, M.: Evaluation of liver hydroxylation of vitamin D by simultaneous measurement of circulating cholecalciferol and 25-hydroxycholecalciferol. Trans. 22nd Annual Meeting, Orthop. Res. Soc.1:123–128, 1976Google Scholar
  28. 28.
    Koch, H.V., Kraft, D., von Herrath, D., et al.: AL.: Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat, Epilepsia13:829–841, 1972PubMedGoogle Scholar
  29. 29.
    Jenkins, M.V., Harris, M., Willis, M.R.: The effect of phenytoin on parathyroid extract and 25-hydroxycholecalciferol-induced bone resorption: adenosine 3′5′ cyclic monophosphate production, Calcif. Tissue Res.16:163–167, 1974PubMedCrossRefGoogle Scholar
  30. 30.
    Hahn, T.J., Scharp, C.R., Richardson, C.A., Halstead, L.R., Kahn, A.J., Teitelbaum, S.L.: Interaction of diphenylhydantoin and phenobarbital with hormonal mediation of fetal rat bone resorptionin vitro, J. Clin. Invest.62:406–414, 1978PubMedCrossRefGoogle Scholar
  31. 31.
    Christiansen, C., Rodbro, P., Lund, P.: Incidence of anti-convulsant osteomalacia and effect of vitamin D: controlled therapeutic trial, Br. Med. J.4:695–701, 1973PubMedCrossRefGoogle Scholar
  32. 32.
    Christiansen, C., Rodbro, P., Nielson, C.T.: Iatrogenic osteomalacia in epileptic children. A controlled therapeutic trial, Acta Paediatr. Scand.64:219–224, 1975PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • Theodore J. Hahn
    • 1
    • 2
  • Linda R. Halstead
    • 1
    • 2
  • Darryl C. DeVivo
    • 1
    • 2
  1. 1.Division of Bone and Mineral MetabolismThe Jewish Hospital of St. LouisSt. LouisUSA
  2. 2.Departments of pediatrics, Neurology, and NeurosurgeryWashington University School of MedicineSt. LouisUSA

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