Calcif. Tissue Int. 28, 17-22, (1979)

Calcified Tissue International @ 1979 by Springer-Verlag

Disordered Mineral Metabolism Produced by Ketogenic Diet Therapy Theodore J. Hahn, Linda R. Halstead, and Darryl C. DeVivo Division of Bone and Mineral Metabolism. The Jewish Hospital of St. Louis, Departments of Pediatrics. Neurology, and Neurosurgery. Washington University School of Medicine. St. Louis. Missouri 63110. USA Summary. Vitamin D and mineral metabolism status was examined in five children maintained chronically on combined ketogeniz 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. K G 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.

Introduction Ketogenic diet therapy continues to be a useful adjuvant to anticonvulsant drug treatment in the management of intractable epilepsy [1]. Although the precise mechanism of action of this regimen remains obscure, various earlier speculations attributing the anticonvulsant action to associated waterSend offprint requests to

dress.

Theodore J. Hahn at the above ad-

mineral disturbances, systemic metabolic acidosis, or nonspecific sedative effects appear to be less tenable in light of recent studies which indicate that development of systemic ketosis is central to the anticonvulsant effect o f the ketogenic diet [1-3]. The observed elevation of the seizure threshold during maintenance of systemic ketosis has been recently suggested to correlate with an increased cerebral energy reserve and an elevated brain A T P / ADP ratio [2, 3]. It is well recognized that anticonvulsant drug therapy is associated with various disorders of mineral and vitamin D metabolism. Hypocalcemia, reduced serum 25-hydroxyvitamin D (25OHD) concentrations, elevated serum immunoreactive parathyroid hormone (iPTH) concentrations, reduced bone mass, and histologic evidence of osteomalacia have been reported in 10-60% of various anticonvulsant drug-treated populations [4-10]. Current evidence suggests that drug-induced alterations in the hepatic metabolism o f vitamin D play a major role in the pathogenesis of this disorder [11. 12]. It has also been demonstrated that chronic acidosis can derange mineral metabolism both by placing direct demands on bone mineral for required additional buffering capacity [13] and by impairing the renal conversion o f 25OHD to 1,25-dihydroxyvitamin D [l,25-(OH)2D] [14]. Therefore, it might be anticipated that the addition of ketogenic diet therapy to anticonvulsant drug regimens could result in a further deterioration of bone mineral status. The purpose of these studies was to evaluate the status of mineral and vitamin D metabolism in children receiving combined ketogenic diet-anticonvulsant drug therapy. Our findings indicate that combined ketogenic diet-anticonvulsant drug therapy appears to result in a reduction in bone mass more severe than that caused by anticonvulsant drug therapy alone, and that this loss can be partially reversed by moderate-dose vitamin D supple-

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m e n t a t i o n . A p r e l i m i n a r y a b s t r a c t o f t h e s e findings has b e e n r e p o r t e d p r e v i o u s l y [15].

Materials and Methods Five white children (3 girls and 2 boys) with a mean age of 10.4 years (range 7-13 years) were studied. The mean duration of anticonvulsant drug therapy was 7.4 years (range 4.5-11.5 years), and of medium-chain triglyceride ketogenic diet therapy [16], 2.5 years (range 1.3-3.0 years). All five patients were receiving diphenylhydantoin (mean dose 150 rag/day). Additionally, two patients were receiving trimethadione (mean dose 375 mg/day) and phenobarbital (mean dose 110 me/day/; one was receiving trimethadione (240 me/day) and ethosuximide (250 me/day), and one was receiving primidone (625 me/day). Initial studies were performed at the Clinical Research Center of the St. Louis Children's Hospital after a 1-week period of dietary equilibration. Informed consent was obtained from parents or guardians prior to initiating the studies. A detailed dietary history was obtained for each patient on admission, and the patient's customary ketogenic diet was continued throughout the hospitalization, with the exception that a hydroxyproline-free intake was instituted. Results in the study patients were compared to those in (a) 15 matched normal white controls, mean age 11 years (range 7-14 years), studied under similar conditions after a 3-day equilibration on their customary diet; and (b) 18 outpatients of similar age who had been receiving combined diphenylhydantoin (160 • 19 rag/day, mean _+ SEMI and phenobarbital (76 • 6 me/day) therapy for a mean of 6.8 • 0.8 years. The average level of customary physical activity was comparable in the ketogenic diet and anticonvulsant-drug-only patients. In the ketogenic diet, anticonvulsant-drug-only, and control groups, the mean percentile values for height were 54 • 10, 57 -- 5.55 • 4, and for weight were 48 _+ 7, 53 • 6, and 53 • 5, respectively. Blood samples in all patients were drawn after an overnight fast. Follow-up studies were performed on an outpatient basis under similar conditions. Calcium. phosphorus, and alkaline phosphatase were determined by Technicon Autoanalyzer [6]. Serum 25OHD was measured by the competitive protein-binding assay of Haddad and Chyu (normal range 10-30 ng/ml) [17]. serum iPTH by the radioimmunoassay technique of Slatopolsky et al. [I8] using Chicken9 antiserum, which recognizes primarily the carboxy terminal portion of the molecule (normal range 2-10/xl eq/ml), and urinary hydroxyproline by the method of Prockop and Udenfriend [19]. Aterial Poz, Pcoz, and pH were determined using a Coming 175 Automatic Blood Gas System (Corning Instrument Co., Medford, Mass.). Blood lactate, pyruvate, fl-hydroxybutyrate, and acetoacetate measurements were performed on perchloric acid extracts as described previously [20]. Bone mass was measured in the midshaft of the radius of the nondominant arm employing a Norland-Cameron Bone Mineral Analyzer (Norland Instrument Company, Fort Atkinson. Wisconsin) according to our previously described techniques [21]. A minimum of four scans of the radius were performed in each patient, and the measured bone mineral content in grams per centimeter was divided by bone width in centimeters to yield bone mass expressed as grams per square centimeter. The reproducibility of these measurements is approximately 2% and the accuracy approximately 4% [21]. Since bone mass varies with age, sex. and race, each patient's values were expressed as a percentage of normal mean

T.H. Hahn et al: Disordered Mineral Metabolism

values, based on a series of 450 normal subjects from the outpatient departments of St. Louis Children's Hospital and the families of medical personnel. Vitamin D supplementation was provided as vitamin D~ in propylene glycol, 5000 |U/day (Drisdoll (Winthrop Laboratories. N.Y.). The statistical significance of differences between group means was assessed using one-way analysis of variance [22]. For those parameters thus determined to be significantly altered by treatment, individual comparisons among group means were performed using a one-tailed Student's t test. The significance of differences of pre- and post-treatment values was determined by the paired t test.

Results

Baseline Parameters A r t e r i a l b l o o d v a l u e s in the k e t o g e n i c diet p a t i e n t s d e m o n s t r a t e d a mild r e d u c t i o n in s e r u m p y r u v a t e c o n c e n t r a t i o n w i t h m a r k e d l y e l e v a t e d / 3 - h y d r o xyb u t y r a t e an d a c e t o a c e t a t e c o n c e n t r a t i o n s , a n d b l o o d gas v a l u e s t y p i c a l o f a partially c o m p e n s a t e d m e t a b o l i c a c i d o s i s (Table 1). T h e s e c h a n g e s are c h a r a c t e r i s t i c o f t h o s e o b s e r v e d in p a t i e n t s m aint a i n e d c h r o n i c a l l y on the k e t o g e n i c diet r e g i m e n [1, 16]. The combined anticonvulsant drug-ketogenic diet r e g i m e n ( K G ) , a n t i c o n v u l s a n t drug t h e r a p y ( A D ) , an d c o n t r o l g r o u p s w e r e similar with r e g a r d to age, s e x d i s t r i b u t i o n , an d e s t i m a t e d w e e k l y vitamin D ( T a b l e 2). M e a n s e r u m c a l c i u m and 2 5 O H D c o n c e n t r a t i o n s w e r e significantly r e d u c e d b e l o w c o n t r o l v a l u e s , an d s e r u m alkaline p h o s p h a t a s e c o n c e n t r a t i o n s w e r e significantly e l e v a t e d in b o t h the K G and A D g r o u p s . F r a n k h y p o c a l c e m i a ( s e r u m c a l c i u m c o n c e n t r a t i o n < 9.0 mg/dl) w a s not o b s e r v e d in e i t h e r g r o u p . O n e o f five K G p a t i e n t s an d t h r e e o f 18 A D p a t i e n t s h ad a s e r u m 2 5 O H D c o n c e n t r a t i o n o f less t h a n 10 ng/ml. M e a n s e r u m i o n i z e d c a l c i u m c o n c e n t r a t i o n s w e r e significantly l o w e r an d s e r u m i m m u n o r e a c t i v e p a r a t h y r o i d horm o n e c o n c e n t r a t i o n s significantly higher in the K G g r o u p t h a n in c o n t r o l s , i n d i c a t i n g a state o f mild c h r o n i c i n c r e a s e d P T H s e c r e t i o n , a finding prev i o u s l y r e p o r t e d in p a t i e n t s r e c e i v i n g c h r o n i c antic o n v u l s a n t d r u g t h e r a p y [4]. M e a n 24-h u r i n a r y calc i u m e x c r e t i o n w a s r e d u c e d in K G p a t i e n t s to app r o x i m a t e l y 58% o f c o n t r o l v a l u e s , p r e s u m a b l y reflecting both decreased intestinal calcium absorption s e c o n d a r y to r e d u c e d s e r u m v i t a m i n D m e t a b o lite l e v e l s an d the c a l c i u m - r e t a i n i n g effects o f P T H o n the p r o x i m a l renal t u b u l e [23]. U r i n a r y h y d r o x y p r o l i n e e x c r e t i o n w a s i n c r e a s e d in 52% in the K G p a t i e n t s as c o m p a r e d t o c o n t r o l s . T o t a l u r i n a r y hyd r o x y p r o l i n e e x c r e t i o n is an i n d e x o f b o n e c o l l a g e n t u r n o v e r [24] an d is e l e v a t e d in states o f i n c r e a s e d b o n e t u r n o v e r s u c h as o s t e o m a l a c i a and s e c o n d a r y

T.H. Hahn et al: Disordered Mineral Metabolism

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hyperparathyroidism [25, 26]. The increased hydroxyproline excretion in the KG patients therefore presumably reflects a state o f increased bone turnover in response to decreased availability of biologically active vitamin D metabolites and secondary hyperparathyroidism. Bone mass in the KG group was decreased by 16% below mean control values, representing a significantly greater degree o f loss than the 9% decrease (P < 0.05) observed in the AD group (Table 2). Both groups of patients had been receiving anticonvulsant drug therapy for a similar time period and had comparable decreases in serum 25OHD concentration. Moreover, the AD group was receiving a higher daily drug dose and had a significantly lower mean serum total calcium concentration than did the K G group. Hence it does not appear likely that the greater decrease in bone mass observed in the K G group could be attributed to differences in drug dose or duration. Therefore the relatively greater degree of bone mass reduction in the K G group suggests an additional deleterious effect o f the ketogenic diet regimen on mineral metabolism.

Response to Vitamin D Supplementation In order to determine whether the changes in mineral metabolism produced by combined ketogenic

Table 1. Arterial blood values in ketogenic diet patients Parameter

Ketogenic diet patients

Sodium (mEq/l) Potassium (mEq/l) Bicarbonate (mEq/l) Chloride (mEq/l) Po2 Pco~ pH Lactate (tzm/l) Pyruvate (#M/I) fl-Hydroxybutyrate

138.0 • 0.9 4.2 -+ 0.2 21.4 • 1.0 104.1 • 1.6 83.9 • 4.3 27.7 • 3.2 7.314 • 0.003 613 • 36 31 _+ 4 3,833 • 785

Normal range 136-143 4.0-5.0 22-28 98-106 80-105 35-45 7.35-7.45 500-1,120 42-88 30-200

(/zM/l) Acetoacetate (#M/I)

1,912 _+ 378

20-100

Values represent mean _+ SEM for 5 patients

diet-anticonvulsant drug therapy were reversible, we instituted a trial of vitamin D supplementation. Patients were maintained on their basic diets and were supplemented with an additional 5000 units of vitamin D per day. Serum calcium and 25OHD concentrations and forearm bone mass were measured at 3-month intervals for 1 year. Serum 25OHD concentrations rose rapidly, reaching a value significantly above control values by 3 months, and plateauing at a level approximately five times basal values by 9 months o f therapy (Fig. 1). Serum calcium concentration exhibited a slightly more de-

Table 2. Population characteristics, biochemical values, and bone mass Controls (15)

Combined anticonvulsant drugketogenic regimen

(5) Population characteristics Age(year) Sex (female/male) Vitamin D intake (IU/week) Serum values Total calcium (mg/dl) Ionized calcium (mg/dl) Inorganic phosphate (mg/dl) Alkaline phosphatase (B.U./ml/ 250HD(ng/ml) iPTH(/AEq/ml) Urinary values (24-h excretion) Calcium (mg/q creatinine) Hydroxyproline (mg/g creatinine) Bone mass (%age normalvalues) Figures in parentheses a Significantly different h Significantly different c Significantly different Significantly different

11.0 • 1.6 9/6 3670 • 380 10.44 • 0.07 4 . 5 5 -'- 0.09 4.34 +_ 0.12 8.04 • 0.44 23.1 • 1.7 5.0 +-0.4

10.4 • 1.5 3/2 3950 _+ 380 10.15 • 0.10~ 4.18 • 0.13 a 4.18 + 0.24 10.39 • 0.67 c 14.1 • 2.5" 7.3 • 0.9"

96.8 _+_ 8.2 74.7 • 7.1

56.1 • 10.6~" 113.7 • 8.2 c

100.5 _ 1.8

84.9 • 2.6 ~,d

indicate n u m b e r of subjects. N.D., not determined. Values are given as mean • SEM from controls at P < 0.05 from controls at P < 0.001 from controls at P < 0.01 from anticonvulsant drug therapy group at P < 0.05

Anticonvulsant drug therapy (18)

11.2 • 1.3 11/7 3590 • 360 9.89 • N.D. 4.16 11.98 • 13.3 • N.D.

0.88 b 0.10 0.53 ~ 1.2b

N.D. N.D. 91.3 • 1.6 b

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T.H. Hahn et ah Disordered Mineral Metabolism 10

ues, bone mass remained subnormal in the KG group.

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Fig. l. Serial changes in forearm bone mass, serum calcium concentration, and serum 250HD concentration in 5 ketogenic dietanticonvulsant drug-treated patients following initiation of vitamin D supplementation (5000 units/day). Vertical bars represent I SEM. *Significantlydifferent from original value at P < 0.05. **Significantlydifferent from original value at P < 0.01

layed response (Fig. 1). By 12 months the mean serum calcium concentration in the K G group was 10.51 -+ 0.16 mg/dl (mean + SEM), a value not significantly different from control levels. At this point serum iPTH had declined to 3.7 - 0.5 /zl eq/ml, a significant decrease from the original value of 7.3 + 0.9 #1 eq/ml (P < 0.02). Concomitant with these biochemical changes, forearm bone mass increased progressively, exhibiting an 8.1 -+ 0.9% increase over original values by 12 months (P < 0.001). At this point, forearm bone mass in the treated K G patients averaged 91.8 _+ 3.1% of age-sex normal values, still significantly below control subject values (P < 0.02). Thus, despite the return of serum calcium concentration to normal levels and the elevation of serum 25OHD concentration to approximately three times normal val-

Our findings indicate that the combined effects of ketogenic diet therapy and anticonvulsant drug treatment produce a significantly greater degree of derangement in bone mineral metabolism than does anticonvulsant drug therapy alone. The effect of anticonvulsant drugs on mineral metabolism appears to be twofold. First, these agents have been postulated to impair hepatic conversion of vitamin D to 25OHD either by inducing hepatic microsomal enzyme systems which accelerate the conversion of vitamin D and 25OHD to polar, presumably biologically inactive products [11], or by directly inhibiting the hepatic 25-hydroxylation of vitamin D [27]. In support of both these hypotheses, it has been demonstrated that serum 25OHD levels are reduced in patients on chronic anticonvulsant drug therapy [4, 6, 7] in association with evidence of secondary hyperparathyroidism [4]. Of interest is the recent observation that evidence of deficient vitamin D biologic activity exists in these patients despite elevated levels of 1,25-dihydroxyvitamin D [1,25(OH)~D] [7]. Hence c o m p e n s a t o r y rises in 1,25(OH)2D production may not be sufficient to override the effects of decreased 25OHD availability, and the biologic role of 25OHD or metabolites other than 1,25(OH)2D may be therefore more central to mineral homeostasis than has been recently assumed. Secondly, diphenylhydantoin has been shown to have direct inhibitory effects on intestinal calcium transport [28] and bone metabolism [29, 30] independent of its effects on vitamin D metabolism. Hence it might be expected that supplementation with vitamin D would not completely restore normal mineral homeostasis in anticonvulsant drug-treated patients. It would be anticipated that the imposition of the additional burden of acidosis produced by institution of ketogenic diet therapy could accelerate the deleterious effects of anticonvulsant drugs on bone metabolism. It has been previously shown that chronic acidosis decreases bone mineral content directly by accelerating liberation of cations from bone in combination with bicarbonate to provide required additional buffering capacity [13]. More recently it has been reported that acidosis directly impairs the renal conversion of 25OHD to 1,25(OH)2D [14]. Thus the partially compensatory rise in 1,25(OH)zD production in anticonvulsant drugtreated patients may be blunted by regimens such as ketogenic diet therapy which result in the produc-

T.H. Hahn et al: Disordered Mineral Metabolism

tion o f s y s t e m i c a c i d o s i s . In the p r e s e n t s t u d y , b o n e m a s s in t h e k e t o g e n i c d i e t p a t i e n t s was d e c r e a s e d to a s i g n i f i c a n t l y g r e a t e r d e g r e e t h a n that o f p a t i e n t s treated with anticonvulsant drugs alone, suggesting an a d d i t i v e d e l e t e r i o u s effect o f k e t o g e n i c d i e t therapy. R e s u l t s o f the t h e r a p e u t i c trial o f v i t a m i n D ind i c a t e t h a t at least a p o r t i o n o f the d e r a n g e d m i n e r a l m e t a b o l i s m c a n be n o r m a l i z e d in k e t o g e n i c d i e t a n t i c o n v u l s a n t d r u g t r e a t e d p a t i e n t s . A f t e r 12 m o n t h s o f t r e a t m e n t w i t h v i t a m i n D2, 5000 units/ d a y , s e r u m t o t a l c a l c i u m w a s i n c r e a s e d to a v a l u e c o m p a r a b l e to that o f c o n t r o l s u b j e c t s , a n d s e r u m i P T H w a s s u p p r e s s e d to n o r m a l v a l u e s . It s h o u l d be n o t e d t h a t this n o r m a l i z a t i o n w a s a c h i e v e d at a t i m e when serum 25OHD concentrations were approxim a t e l y t h r e e t i m e s n o r m a l c o n t r o l levels, s u g g e s t i n g a r e s i s t a n c e to the b i o l o g i c effects o f 2 5 O H D in t h e s e p a t i e n t s . W h e t h e r this r e s i s t a n c e r e f l e c t s prev i o u s l y d e m o n s t r a t e d d i r e c t i n h i b i t o r y effects o f dip h e n y l h y d a n t o i n on the i n t e s t i n a l t r a n s p o r t o f calc i u m a n d the m o b i l i z a t i o n o f c a l c i u m f r o m b o n e , o r r a t h e r is the result o f a s u p p r e s s i v e effect o f a c i d o s i s o n r e n a l 1,25(OH)2D f o r m a t i o n r e m a i n s to be d e t e r mined. B o n e m a s s d e m o n s t r a t e d a significant i m p r o v e m e n t a f t e r v i t a m i n D t r e a t m e n t , i n c r e a s i n g b y 3.5 --1.6% o v e r initial v a l u e s at 3 m o n t h s a n d 8.1 • 0 . 9 % at 12 m o n t h s . In c o n t r o l l e d s t u d i e s o f the effects o f v i t a m i n D s u p p l e m e n t a t i o n in p a t i e n t s t r e a t e d with anticonvulsant drugs alone, Christiansen and cow o r k e r s [31, 32] h a v e d e m o n s t r a t e d a 3 % - 5 % inc r e a s e in b o n e m i n e r a l c o n t e n t a f t e r 3 m o n t h s ' t r e a t m e n t with v i t a m i n D in a d o s e o f 2000 units/ day. Thus although we employed a several-fold higher d o s e o f v i t a m i n D in o u r p a t i e n t s , the d e g r e e o f r e s p o n s e o f b o n e m a s s in the p r e s e n t s t u d y w a s c o m p a r a b l e to the r e s u l t s r e p o r t e d b y C h r i s t i a n s e n et al. [31, 32]. It is not c l e a r f r o m the p r e s e n t d a t a whether complete normalization of bone mineral content could have been achieved by more prol o n g e d v i t a m i n D t h e r a p y . In v i e w o f the f a c t o r s c i t e d a b o v e w h i c h p r e d i s p o s e to r e s i s t a n c e to the effects o f v i t a m i n D in t h e s e p a t i e n t s , the d e g r e e o f ultimate therapeutic response remains uncertain a n d s h o u l d be the s u b j e c t o f m o r e p r o t r a c t e d i n v e s tigation. A t the v e r y l e a s t , h o w e v e r , o u r findings ind i c a t e t h a t a l t h o u g h k e t o g e n i c diet t h e r a p y p r o d u c e s a d d i t i o n a l d e l e t e r i o u s effects on m i n e r a l met a b o l i s m in p a t i e n t s r e c e i v i n g c h r o n i c a n t i c o n v u l sant drug therapy, a considerable proportion of these c h a n g e s c a n be r e v e r s e d b y c h r o n i c m o d e r a t e dose vitamin D supplementation. T h e r e f o r e , it w o u l d a p p e a r a d v i s a b l e to i n s t i t u t e m o d e r a t e - d o s e v i t a m i n D s u p p l e m e n t a t i o n (eg, 5000 u n i t s / d a y ) in t h o s e k e t o g e n i c d i e t p a t i e n t s w h o m a n -

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ifest b i o c h e m i c a l e v i d e n c e o f deficient v i t a m i n D a c t i v i t y . B i o c h e m i c a l i n d i c e s s h o u l d t h e n be m o n i t o r e d at 3 - m o n t h i n t e r v a l s until n o r m a l i z a t i o n is a c h i e v e d . A t t h a t p o i n t c h r o n i c m a i n t e n a n c e vitamin D s u p p l e m e n t a t i o n at a d o s e o f 1000-2000 units/ d a y [6] c a n be initiated.

References 1. Huttenlocher, P.R.: Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy, Pediatr. Res. 10:536-540, 1976 2. DeVivo, D.C., Leckie, M.P., Ferrendelli, J.A., McDougal, D.B., Jr.: Chronic ketosis and cerebral metabolism, Ann. Neurol. 3:331-337, 1978 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, 1975 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, 1975 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, 1970 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, 1975 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. 44:617621, 1977 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, 1973 9. Richens, A., Rowe D.J.F.: Disturbance of calcium metabolism by anticonvulsant drugs, Br. Med. J. 3:73-76, 1970 10. Tolman, K.G., Jubiz, W., Sannella, J.J., Madsen, J.A.: Osteomalacia associated wth anticonvulsant drug therapy in mentally retarded children, Pediatrics 56:45-51. 1975 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, 1972 12. Silver, J., Neale, G., Thompson, G.R.: Effect ofphenobarbitone treatment on vitamin D metabolism in mammals, Clin. Sci. Mol. Med. 46:433-448, 1974 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, 1966 14. Lee, S.W., Russell, J., Avioli, L.V.: 25-Hydroxycholecalciferol to 1,25-dihydroxycholecalciferol conversion impaired by systemic acidosis, Science 195:994, 1977 15. DeVivo, D.C., Hahn, 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.) 16. Huttenlocher, P.R., Wilbourn. A.J., Signore, J.M.: Medi-

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Received November 6, 1978 / Revised Januat3' 16, 1979 / Accepted JanuaO' 23, 1979