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Effect of phenytoin on bone and vitamin D metabolism.

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Effect of Phenytoin on Bone
and Vitamin D Metabolism
Rodney D. Bell, MD, Charles Y. C. Pak, MD, Joseph Zerwekh, PhD,
Donald E. Barilla, MD, and Michael Vasko, P h D
Calcium and vitamin D metabolism were evaluated in 5 adult epileptic patients before and during treatment with
phenytoin. Significant decreases occurred in serum concentrations of calcium, albumin, and 25-hydroxycholecalciferol. The decreases in serum calcium paralleled those in serum albumin. Significant increases occurred in serum alkaline phosphatase and la,25-dihydroxycholecalciferol,in urinary hydroxyproline, and in the
fractional gastrointestinal absorption of calcium. Urinary cyclic adenosine monophosphate and serum parathyroid
hormone did not change.
The results suggest that the bone disease resulting from phenytoin therapy may be associated with a deficiency of
25-hydroxycholecalciferoland not of la,25-dihydroxycholecalciferol,and that reduced gastrointestinal absorption
of calcium or changes in parathyroid function may not be necessary for the development of bone disease.
Bell RD, Pak CYC, Zerwekh J, et al: Effect of phenytoin on bone and vitamin D metabolism.
Ann Neurol 5:374-378, 1979
Epileptic drugs, particularly phenytoin, are known to
modify calcium metabolism and induce osteomalacia
in epileptic patients during long-term treatment [2,9,
10, 12, 22, 27, 28, 31-33, 36-38, 41, 431. The
pathophysiology of this form of osteomalacia is
poorly understood. Because of the clinical picture of
osteomalacia, an alteration in vitamin D metabolism
has been postulated [11, 26, 29, 441. It has been
proposed that epileptic drugs induce the hepatic microsomal Pd5,,system and facilitate the conversion of
vitamin D to more polar and presumably inactive
metabolites [ 12, 361. Although the hepatic conversion of vitamin D to 25-hydroxycholecalciferol (25OH-D) may be increased [30],
a reduction in serum
concentration of this metabolite has been generally
reported following therapy [17,18, 29, 421. However, it has recently been shown that the renal
metabolite, 1a,25-dihydroxycholecalciferol, or la,
2 5-(OH),D, increases in patients on long-term
epileptic therapy [24].Moreover, the effect of antiepileptic drugs on the gastrointestinal absorption of
calcium has been variable [ 13, 151.
In order to elucidate further the pathophysiology
of phenytoin-induced osteomalacia, the following
prospective study was performed. From simultaneous measurements of parathyroid function, vitamin
D status, and calcium metabolism in a controlled set-
From the Division of Neurology, The University of Texas Health
Science Center at San Antonio, and the Department of Neurology
and the Section on Mineral Metabolism, Department of Internal
Medicine, The University of Texas Health Science Center at Dallas Southwestern Medical School, Dallas, Tx.
ting, it was possible t o assess these interrelationships
critically.
Materials and Methods
Five ambulatory, nonalcholic adult patients with ages
ranging from 24 to 4 1 years were evaluated at the General
Clinical Research Center, Dallas, TX, shortly after the
diagnosis of epilepsy and prior to any drug therapy. Informed consent was obtained from each patient. The patients were not taking any drugs and had no evidence of
systemic disease. They had normal values for serum calcium, phosphorus, alkaline phosphatase, and liver enzymes; endogenous creatinine clearance was greater than
90 ml per minute. For three days the patients received a
liquid synthetic diet (Calcitest) containing 1,500 calories,
400 mg of calcium, 800 mg of phosphorus, 100 mEq of
sodium, and 195 gm of carbohydrate daily.
During the first three days of the diet, urine was collected daily in 24-hour pooled collections for determination of calcium, phosphorus, cyclic adenosine monophosphate (CAMP), hydroxyproline, and creatinine. Venous
blood was obtained daily before breakfast, without stasis,
for determination of calcium, magnesium, phosphorus,
total protein, albumin, alkaline phosphatase, and creatinine. On day 2, fasting venous blood was obtained to
assay serum immunoreactive parathyroid hormone (PTH),
25-OH-D, and la,25-(OH),D, fractional calcium absorption (a)and bone density were also determined.
Following oral administration of the isotope [341, a was
Accepted for publication Sept 5, 1978.
Address rep,.int requests to Dr Bell, Division of Neurology, The
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determined from the recovery of calcium 47 in the feces.
Serum immunoreactive PTH was measured as previously
described [l] using antiserum 21 1/32 (Wellcome Reagents,
Ltd), which predominantly recognizes the NH,- terminus of
the PTH molecule. Additional samples were sent to the
Mayo Clinic for assay, directed predominantly at the
carboxy- terminus of the PTH molecule [I]. Urinary cyclic
AMP was measured by the protein binding method of Gilman [ 161. 25-OH-D and la,25-(OH)*Dwere measured by
the method of Brumbaugh et a1 [7]. Bone density in the
distal third and distal end of the radius was measured by
iodine 125 photon absorptiometry (Norland-Cameron) [8].
After the initial evaluation was completed, the patients
were given phenytoin (5 mg per kilogram per day) and seen
at monthly intervals or as clinically necessary. N o additional epileptic medication was required. Therapeutic
blood levels of phenytoin (10 to 20 p g per milliliter) were
achieved.
After 4 to 21 months, the patients were readmitted to
the General Clinical Research Center, Dallas, TX, and the
initial studies were repeated while the patients were taking
phenytoin. Analysis of the data was performed by paired t
test.
Results
Tables 1 and 2 and the Figure show the results of the
prospective study. During phenytoin treatment,
statistically significant increases occurred in serum
alkaline phosphatase-63 f 8 (SD) to 89 ? 5 IU; la,
25-(OH),s3.23 2 1.00 (SD) to 4.95 +- 1.39 ng
per deciliter; fractional calcium absorption4.466
Table 1 . Serum Laboratory Changes in Epileptic Patients Treated with Phenytoin
Patient
No.
1
2
Phenytoin
Treatment
(mo)
0
5
0
4
3
0
4
4
0
4
14
5
0
9
21
Calcium
(mddl)
9.82 f 0.15
9.10 f 0.17”
10.20 t 0.26
9.43 ? 0.23”
9.33 f 0.32
8.96 2 0.20”
9 . 6 0 t 0.11
9.33 f 0.40”
9.30 f 0.10”
9.76 f 0.25
9.00 t 0.0“
9.10 t 0.26“
Alkaline
Phosphatase
Phosphorus
(mddl)
(IU)
3.37 f 0.20
3 . 5 6 t 0.30
3.23 f 0.50
2 . 9 0 f 0.26
4.00 f 0.17
3.73 f 0.51
3.93 f 0.30
3.80 2 0.70
3.96 f 0.05
3.33 f 0.28
3.15 f 0.49
3.23 ? 0.25
55 f 4
85 f 3”
70 f 2
92 f 8
66 t 3
96 2 2a
70f 1
90 f 4”
87 2 4”
53 2 3
72 f 2a
84 2 3“
PTH
(jdEq/ml)
25-
Ia,25-
Albumin
(gddl)
a
b
OH-D
(nglml)
(0H)ZD
(ngldl)
a
3.9 f 0.1
3.3 t 0.1“
4.8 t 0.4
4 . 0 t 0.1”
4.5 f 0.2
3.9 ? O.Oa
4 . 2 f 0.1
3.8 ? 0.1”
3.9 t 0.1”
4.2 ? 0.1
3.9? O.la
3.8 t 0.0”
9
5
UD
UD
13
9
UD
UD
6
42
48
50
. ..
35.9
17.7”
25.3
13.8”
16.3
19.4
31.2
7.6”
12.2”
17.8
9.9”
10.5”
1.84
4.15”
3.99
6.79b
3.15
3.62”
4.39
4.92”
4.12”
2.80
5.92”
6.08b
0.404
0.520”
0.295
0.480”
0.767
0.873”
0.461
0.483”
0.484”
0.406
0.411
0.455”
UD
UD
11
10
UD
UD
12
12
50
38
61
This table shows serum values (mean f SD) for calcium, phosphorus, alkaline phosphatase, albumin, PTH, 25-OH-D, lc~,25-(OH)~D,
and
fractional calcium absorption prior to and following treatment with phenytoin. PTH assay a used antiserum 21 1/32,and assay b was obtained
from the Mayo Clinic; it is expressed as microliter-equivalents per milliliter.
Statistical significance by paired t test: “p < 0.01; ”p < 0.05.
UD = undetectable.
Table 2. Urinary Laboratory Changes in Epileptic Patient.[ Treated with Phenytoin
Patient
No.
Phenytoin
Treatment
(mo)
1
0
2
5
0
4
3
0
4
4
0
4
14
5
0
9
21
Calcium
(mdday)
Cyclic AMP
( p m o l / p Cr)
Hydroxyproline
(mdday)
174 f 11
136 ? 14
83 t 34
5 0 f 11
188 t 57
156 t 40
74 ? 27
125 f 23
8.46 f 1.36
7.21 f 0.24
1.90 0.61
3.16 f 0.50
1.88 f 0.64
3.68 ? 1.67
4.02 f 1.13
3.25 f 0.25
3.47 f 1.24
4.68 f 2.30
3.86 ? 0.77
3.15 f 0.35
25.4 f 14.6
87 2 10
89f 5
1 1 9 t 52
145 f 25
*
36.3 c 28.8“
27.0 5 11.5
28.7 ? 3.2“
31.9 t 10.3
60.4 t 23.8“
30.6 t 12.0
39.5 f 23.3“
31.3 f 1.0
25.5 f 2.8
. . .
29.8 t 15.3”
”Significantdifference of values from the pretreatment (0 rno) values as determined by paired t test: p < 0.05.
Bell et al: Effect of Phenytoin o n Bone
375
0
A
s
1
7-OL
Control
B
Phtnytoin
Treotment
( A ) EfJect of phenytoin on 25-OH-D (open circles) a n d on
1 a,25-(OH),D (closed circles). Values represent mean % SD.
( B ) Ejlect of phenytoin on fractional calcitim absorption (a).
Values for indicidt4alpatients are presented.
0.174 (SD) to 0.562 5 0.175; and urinary
hydroxyproline-28.6
t 3.1 (SD) to 37.3 2 13.2 mg
per day.
Phenytoin produced significant decreases in serum
calcium- 9.75 5 0.31 (SD) to 9.17 -+ 0.18 mg per
deciliter; a l b u m i n A . 3 ? 0.3 (SD) to 3.7 t 0.3 gm
per deciliter; and 25-OH-D-25.3
k 8.4 (SD) to
14.2 t 3.7 ng per milliliter.
There were no significant changes in serum PTH,
phosphorus, or magnesium; in urinary calcium,
phosphorus, or cyclic AMP; or in bone density.
Discussion
Our study shows that during phenytoin treatment,
fractional calcium absorption increases, rather than
decreases, as determined by recovery of 47Cain feces
after oral administration of radioactive calcium. This
finding conflicts with the observations of other workers who have found no change or a decrease in calcium absorption. These workers employed a method
of determining calcium absorption based on measurement of blood radioactivity at time intervals after
oral administration of the isotope [15, 391. Such a
method may provide an inaccurate measure of calcium absorption because it does not account for variable accretion by bone, plasma distribution, o r renal
excretion of the isotope. Our finding of increased
376 Annals of Neurology Vol 5
No 4 April 1979
gastrointestinal absorption is consistent with the observation that in vitro phenytoin stimulates calcium
adenosine triphosphatase and calcium absorption
[ 131; it is also compatible with the observed increase
in la,25-(OH),D, the recognized active hormonal
metabolite of vitamin D involved in stimulation of
gastrointestinal calcium absorption [20, 2 11. Moreover, there is no evidence for secondary hyperparathyroidism, since urinary cyclic AMP and serum
PTH were not significantly altered by antiepileptic
therapy. This lack of evidence for secondary hyperparathyroidism further argues against the role of reduced calcium absorption in the pathogenesis of
osteomalacia.
Alternatively, the lower concentration of circulating 25-OH-D confirmed in this study may play an
important role in the development of bone disease.
There is evidence, albeit inconclusive, that 25-OH-D
or a further polar metabolite of 25-OH-D, and not
la,25-(OH),D, may be critical for bone mineralization [4-6, 14, 21, 23, 35, 451. Other simultaneous
actions of phenytoin on bone (e.g., direct inhibition
of membrane uptake of calcium or inhibition of bone
resorption) cannot be excluded by this study [ 191.
The exact cause for the rise in la,25-(OH),D
from anticonvulsant therapy is not known. It does
not result from parathyroid stimulation or hypophosphatemia, since serum PTH, urinary cyclic
AMP, and serum phosphorus were not significantly
altered. O n e may speculate that phenytoin alters the
renal intramitochondrial calcium pool by affecting
calcium transport [ 191 and thereby influences the
synthesis of la,25-(OH),D [31.
Although total serum calcium concentration decreased during antiepileptic therapy, there was a corresponding decrease in serum albumin. The assumption that ionized or ultrafilterable serum calcium
fraction may not have been significantly altered is
supported by the absence of a fall in urinary calcium
or of parathyroid stimulation. The cause of the fall in
serum albumin needs further clarification.
The increase that occurred in urinary hydroxyproline may represent heightened bone turnover [25]
or nonspecific stimulation of fibroblastic activity by
phenytoin, which has been reported in vitro [40].
We emphasize that the present study concerns the
effect of relatively short-term antiepileptic treatment. W e conclude, therefore, that the decrease in
serum 25-OH-D levels observed with phenytoin
therapy probably results from increased hepatic metabolism to inactive metabolites but that sufficient
25-OH-D is available to biosynthesize la,25(OH),D, which in turn produces an increase in gastrointestinal absorption of calcium. The fall in 25OH-D is noteworthy because a growing body of
evidence indicates that this metabolite is necessary
for adequate bone mineralization [4, 6, 14, 21, 2 3 ,
35, 441.
Supported by Grants ROI-AM16061, R01-RR00633, and 1P50-AM20543 from the US Public Health Service and by the
Epilepsy Foundation of America.
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