Calcif. Tissue Int. 28, 99-102 (1979)
Calcified Tissue International c', 1979 by Springer-Verlag
Bone Mineral Content in Epileptics Lars Lidgren,
Bo E. Nilsson, and Anders
Wall6e
Departments of Orthopedic Surgery. University Hospital. Lund, Sweden. and Maim6, Sweden. S u m m a r y . T h e b o n e m i n e r a l c o n t e n t in t h e f o r e a r m s w a s m e a s u r e d in 71 e p i l e p t i c s , a d m i t t e d t o a n institution for epileptics. The mineral content was decreased in e p i l e p t i c s a s c o m p a r e d with agem a t c h e d n o r m a l c o n t r o l s . T h e d e c r e a s e w a s in t h e o r d e r o f 1 0 - 1 5 % e x c e p t in t h e d i s t a l e n d o f t h e f o r e a r m in w o m e n . A l s o , t h e s t r e n g t h o f t h e h a n d a n d f o r e a r m w a s d e c r e a s e d b y V3 a n d s i n c e t h e r e is a known relationship between strength and bone mineral content, the loss of bone mineral may be secondary to the loss of strength. Therefore, inactivity could be an important contributory factor to the b o n e m i n e r a l l o s s in t h e s e e p i l e p t i c s .
Key words: E p i l e p s i a - - B o n e m i n e r a l - - A n t i c o n vulsant drug -- Osteoporosis.
Introduction Biochemical abnormalities related to osteomalacia in e p i l e p t i c s o n a n t i c o n v u l s a n t d r u g s h a v e b e e n d e s c r i b e d b y s e v e r a l a u t h o r s in r e c e n t y e a r s [ I - 5 ] . R a diographic changes suggestive of this diagnosis h a v e b e e n d e s c r i b e d b y K r u s e [1] a n d S o t a n i e m i e t al. [5]. O t h e r s h a v e d e m o n s t r a t e d a l o w b o n e m i n e r al c o n t e n t ( B M C ) in e p i l e p t i c s w i t h a n d w i t h o u t b i o c h e m i c a l b l o o d c h a n g e s [6, 7]. I n a g r o u p o f e p i l e p tics, we have demonstrated six times the expected n u m b e r o f n o n s e i z u r e r e l a t e d f r a c t u r e s [8]. T h e a i m of the present study was to compare the bone mine r a l c o n t e n t a n d t h e m u s c l e s t r e n g t h in t h i s g r o u p o f epileptics with those of a normal control group.
Send reprint requests to Bo Nilsson at the above address. IAverage + I SD.
Materials and Methods The material comprises 71 epileptics, 38 women and 33 men. The age was 61 _+ 12 ~ years and 57 - 12 ~ years, respectively. The material has been described in detail by Lidgren and WallOe [8]. Most of these epileptics had suffered from the disease since childhood and had been on anticonvulsant drug therapy for considerable time. The median time of treatment was 49 years. The drugs most frequently used were diphenylhydantoin in dosages of 100-500 mg daily and/or phenobarbital 100 mg daily. Diphenylhydantoin was used in 41 cases and phenobarbital in 41 cases. Other drugs used were carbamazepin in 22 cases and primidone in 5 cases. Only 13 epileptics had diphenylhydantoin as the only drug. Five epileptics had no medication when the investigation was performed but had had prolonged periods of medication in the past. In these cases the medication was stopped 2-8 years before the present investigation. Serum concentration determination of diphenylhydantoin was not carried out routinely. The epileptics were debilitated to some degree but most had occupation therapy and lived in their own apartments in an institution for epileptics (Fogdar6dshernmet). None had been on steroid therapy. Two had diabetes and one had rheumatoid arthritis. None was on vitamin D or calcium therapy. There was no history of fractures during the past seven years in 41 of these epileptics. There were 37 fractures unrelated to epileptic seizures in 18 epileptics and 23 fractures related to epileptic seizures in 13 epileptics. The mean age was not significantly different between epileptics without fractures, epileptics with fractures related or not related to epileptic seizures. The alkaline phosphatase was increased in 25 epileptics, whereas the urinary calcium was decreased in 38. The blood and urinary chemistry of these patients has been described in great detail by Dymling et al. [9]. The data of the epileptics were compared with normative data obtained by the same method of measuring bone mineral content [10] and strength [11]. From these data age- and sex matched controls were drawn, two for each of the epileptics. The bone mineral content (BMC) was measured in the forearms of the epileptics using gamma absorptiometry. A continuous scan was perlbrmed across the forearms, radius plus ulna, on the levels l centimeter and 6 centimeters proximal to the tip of the ulnar styloid process. The data was obtained by a garnrna absorptiometer consisting of a scintillation detector and an Americium241 source (Figures 1 and 2). This method has been described in detail elsewhere [ 12]. The method has a precision of 4% or better for measurements on the proximal measuring site--in cortical bone, whereas the precision distally--in trabecular bone--is
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L. Lidgren et al.: Bone Mineral Content in Epileptics
Detector
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tU ~Ll.Lllllll[ik~JJ@ ~-
Bone - - -/I- - - Soft
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Source Fig. 1. Measuring apparatus for BMC.
Fig. 3. Measuring of strength.
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Fig. 2. Measuring sites. about 5r Both forearms were m e a s u r e d and the average used for further calculation, except in patients with known fracture or other injury of one arm, in w h o m only the uninjured forearm was included. The force of the hand was m e a s u r e d by asking the patient to c o m p r e s s with full strength a rubber bulb connected with a man o m e t e r (Figure 3). The precision of this method was established to be 13~ in w o m e n and 5'7~ in men-'. Again. the average of the left and right hands was used in the calculations. The degree of physical activity was classified as follows: Active: 46 epileptics who m a n a g e d living in their own apartm e n t s within the institution and who regularly participated in occupational therapy. Less active: 25 epileptics who did not manage in these two respects.
Results The BMC was significantly decreased in the forearms of epileptics as c o m p a r e d with the normative control data, except in the distal measuring site in w o m e n (Table 1, Figure 4). There was a significant positive correlation between BMC and strength in both s e x e s ( r l o 2 w o . . . . = z Coefficient of variation, duplicate m e a s u r e m e n t s .
0.49, p < 0.001, rsr m e n = 0 . 5 1 , p < 0.001), in the epileptics as well as in the controls. The f o r e a r m strength was significantly decreased (p < 0.001) in epileptics as c o m p a r e d with controls (Table 2). When corrected for strength, assuming that there is a natural relationship between strength and BMC, there was no longer any difference between the two sets (analysis of covariance, with strength as the covariant factor). (Table 3). There was no significant difference in force or BMC b e t w e e n active and less active epileptics in either sex, nor between epileptics with and without phenobarbital or epileptics with and without diphenylhydantoin, nor between epileptics without fracture or with fracture, in connection with epileptic seizure or not.
Discussion The only quantitative data available on the bone mineral content in adult epileptics was reported by Christiansen et al. [13], who found a significant reduction soon after treatment with anticonvulsant drugs [14]. Hahn et al. [ 15] demonstrated a 10% reduction of the bone mass in epileptic children with anticonvulsant therapy. Sotaniemi et al. [5] showed with semi-quantitative methods a decrease of the bone mass in radiograms of epileptics on anticonvulsant drug therapy. Christiansen et al. [ 1311also suggested vitamin D., supplement as a routine measure in those epileptics who lost in BMC in the course of treatment. F r o m the present study it b e c o m e s apparent that even untreated, this loss will continue only to a certain point. There is no doubt that these epileptics are left with a bone mineral mass which is
L. Lidgren et al,: Bone Mineral Content in Epileptics
101
Table 1. BMC in epileptics (average _+ 1 SD) and age-matched controls (mg/cme). Men
Epileptics Controls
71 142
Women
Distal
Proximal
Distal
Proximal
375 -+ 85 4"15 • 95
566 -+ 112 656 • 91
258 + 74 239 • 73
397 • I11 466 ~ 92
BMC m g / c m 2, AV-+2 SO
J
t000
MEN PROXIMAL
900 8O0
BMC m g / c m 2, A V • 1000
700 x
9
O
60O
600
50O
500
4O0
400
300
100
0
MEN 01STAL
900 800
700
20O
$D
9 Fracture without seizure o Without fracture x Fracture during s e i z u r e
20
30
40
50
60
200 100
70
~r.o~ ~ -~.~o, o i~
o"..o-"---~
300
o
10
O
80
90
w,,h :.,zur. 9 Fracture9 without ;.e zure o Without f r a c t u r e x Fracture during s e i z u r e I
i
I
I
l
I
l
I
!
10
20
30
40
50
60
70
80
90
AGE
AGE
BMC m g / c m 2, AV-'!"2 SD
BMC r n g / c m z, A V + 2 SD 1000
WOMEN PROXIMAL
9OO
1000
80O
800
700
700
SO0
600
500
9
500
8
&00 30O 2OO 1O0
0
WOMEN DISTAL
900
400 300 Fracture e~ e e ~ 9 9 without l i e l z u r e oe o 9 Without fracture x Fracture during seizure |
!
!
I
!
!
!
!
10
20
:30
40
50
60
70
80
200 100 !
90 AGE
0
Fract u r e - ' - - " ~ oo 9 without s e l z u r ~ o o Without f r a c t u r e x Fracture during seizure
o e~
I
!
I
!
I
!
i
i
I
10
20
30
40
50
60
70
80
90 AGE
Fig. 4. BMC in the forearms in epileptics compared with normative data. The difference was significant in the proximal measuring site in both men and women (p < 0.001), whereas in the distal site there was a significant difference in men only (0.05 > p > 0.02) (t-test against age-matched controls drawn from the normative data).
102
L. Lidgren et al.: Bone Mineral Content in Epileptics
Table 2. Force in epileptics (average _+ 1 SD) and age-matched controls (kg/cm2).
Epileptics Controls
Men
Women
0.55 -+ 0.21 0.83 +- 0.26
0.33 + 0.18 0.55 +_ 0.22
Table 3. Analysis of covariance of bone mineral content (proximal) epileptics vs controls. Covariant factor = strength.
F scatter F slope F adjusted means
Men
Women
1.63 (p > 0.2) 0.08 (p > 0.2) 3.85(0.1 > p > 0.05)
1.93 (p > 0.2) 0.03 (p > 0.2) 2.30(0.2 > p > 0. l)
less than average and reduced to an extent which could produce fractures [ 16]. But what is the mechanism of this loss? In the past it has been suggested [2, 3, 17-19] that the bone mineral loss is due to osteomalacia, which in turn is caused by metabolic effecis of the anticonvulsant drugs. In the present study, it was not possible to demonstrate any difference b e t w e e n those epileptics who had for some time been without anticonvulsant drugs and those on continuous therapy nor between epileptics with diphenylhydantoin and those with phenobarbital. One possible explanation for the reduced BMC in our material is the physical inactivity of the epileptics, who are living in institutions. Even if there was no difference between more and less active epileptics in this study, it is more than likely that these epileptics have been less active o v e r the years than the healthy controls living outside institutions. It should be taken into account that the testing of muscle strength in these debilitated epileptics may not be completely reliable and that vitamin D deficiency has been d e m o n s t r a t e d to cause muscle weakness [20]. This should have introduced an increased scatter of the data on the epileptics as compared with the controls, which, however, was not seen. Therefore, it must be concluded that the muscle strength in the f o r e a r m was substantially decreased a m o n g the epileptics and that this decrease may relate to the loss of bone mineral, either directly or by interaction of the anticonvulsant treatment or of the disease itself. References 1. Kruse, R.: Osteopathien bei antiepileptischer Langzeittherapie. Mschr. Kinderheilk, 116:378-381 (1968) 2. Dent, C.E., Richens, A., Rowe, D.J.F., Stamp, T.C.B.: Osteomalacia with long-term anticonvulsant therapy in Epilepsy. Brit. Med. J, 4:69-72 (1970) 3. Richens, A., Rowe, D.J.D.: Disturbance of Calcium Metabolism by anticonvulsant drugs, Brit. Med. J. 4:73-76 (1970) 4. Hunter, J., Maxwell, J.D., Stewart, D.A., Parsons, V., Williams, R.: Altered calcium metabolism in epileptic children on anticonvulsants, Brit. Med. J. 4:202-204 (1971)
5. Sotaniemi, E.A., Hakkarainen, H.K., Puranen, J.K., Lahti, R.O.: Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy, Ann. Intern. Med. 77:389394 (1972) 6. Linde, J., MOlholm-Hansen, J., Siersbaek-Nielsen, K., Fuglsang-Fredriksen, V.: Bone density in patients receiving long-term anticonvulsant therapy, Acta Neurol. scand. 47:650-651 ( 1971) 7. Christiansen. C., Kristensen. M., Rodbro, P.: Latent osteomalacia in epileptic patients on anticonvulsants, Brit. Med. J. 3:738-739 (1972) 8. Lidgren, L., Wall6e, A.: Incidence of IYactures in epileptics. Acta Orthop, Scand. 48:356-361 (1977) 9. Dymling, J.F., Lidgren, L., Wall6e, A: Biochemical variables related to calcium metabolism in epileptics, Acta reed. scand, in press (1978) 10. Westlin, N.E.: An apparatus for gamma absorptiometry of bone-normative data, Opuscula Medico-Technica Lundensia XII:I 1 (1974) 11. Nilsson, B.E. Personal Communication, (1977) 12. Naucldr. L.O.W., Nilsson, B.E.. Westlin, N.E.: An apparatus for gamma absorptiometry of bone--technical data, Opuscula Medico-Technica Lundensia XII: 1:3-1:11 (1974) 13. Christiansen, C., Rodbro, P., Lund, M.: Incidence of anticonvulsant osteomalacia and effect of vitamin D: Controlled Therapeutic Trial, Brit. Med. J. 4:695-701 (1973). 14. Rodbro, P., Christiansen, C., Lund, M.: Development of anticonvulsant osteomalacia in epileptic patients on phenytoin treatment, Acta Neurol. scand. 50:527-532 (1974) 15. Hahn, T.J., Hendin, B.A., Scharp. C.R., Boisseau, V.C., Haddad, J.G.: Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy, N. Engl. J. Med. 292:550-554 (1975) 16. Nilsson. B.E., Westlin. N.E.: Bone mineral content and fragility fractures. Clin. Orthop. 125:196-199 (1977) 17. DeLuca, K., Masotti, R.E., Partington, M.W.: Altered calcium metabolism due to anticonvulsant drugs, Dev. reed. Child. Neurol. 14:318-321 (1972) 18. Kraft, D., yon Herrath, D., Schaefer, K.: Antikonvulsiva und vitamin-D-stoffwechsel, Mfinch. reed. Wschr. 116:15791583 (1974) 19. Schaefer, K.: Aktuelle klinische probleme der vitamin-Dforschung, M/inch. Med. Wschr. 116:1565-1567(1974) 20. Peacock, M., Heyburn, P.J.: Effect of Vitamin D metabolites on proximal muscle weakness, Calc. Tiss. Res. Suppl. 24:20 (1977) Received January 2, 1978 / Revised October 23, 1978 / Accepted Februao' 14. 1978