Vitamin D Prophylaxis and the Lowered Incidence of Fractures in Anticonvulsant Rickets and Osteomalacia HENRYH. SHERK,M.D.,* MIGUELCRUZ,M.D.**
JOHN STAMBAUGH, M.D.?
The incidence of skeletal demineralization has varied with the duration of anticonvulsant therapy, patient activity, sunlight exposure and vitamin D and types of anticonvulsants taken.4-6.9910 Anticonvulsant rickets and osteomalacia have appeared for the most part in isolated reports and the true incidence in a large institutionalized population is uncertain but has been suggested to be as high as 30%.'0 Despite the increasing number of reports of rickets in patients receiving chronic anticonvulsant therapy, high-dose vitamin D or calciferol therapy has not been instituted in some high-risk groups and pathologic fractures remain the single most costly medical problem in some institutionalized patient populations.1° About 3,000 I.U. of vitamin D per week and exposure to sunshine have been shown to prevent significant bone disease in patients treated with anticonvulsantss but reports on the effect of vitamin D therapy on the incidence of fractures in this patient group have not appeared. A review, therefore, of the incidence of skeletal demineralization and fractures in an institutionalized population was made both before and after vitamin D prophylaxis. Two case reports are presented to exemplify the severity of the rickets and osteomalacia observed, and a proposal is made that is hoped
Calciferol must be metabolically changed to 25-hydroxycholecalciferol in the liver in order to become biologically active. Further hydroxylation to the more active metabolite 1, 25-dihydroxycholecalciferol subsequently occurs in the kidney. In patients receiving long-term anticonvulsant therapy with dephenylhydantion, mysoline and phenobarbital, reduced serum levels of 25-hydroxycholecalciferol have been reported.' The exact mechanism for this decreased level of 25-OH calciferol is uncertain but an interference in hepatic metabolism of vitamin D and 25-OH calciferol or their conversion to more polar, less active metabolites has been suggested as a plausible mechanism.2 Regardless of the abnormal chemistries noted in patients receiving long-term anticonvulsants and the severity of the bone changes, the rickets rapidly heal with increased doses of vitamin D above 6,000 I.U./day or with treatment of 5 0 U of 25-hydroxy cholecalciferol given orally.3
* 2647
AND
Westfield Ave., Camden, New Jersey
08105.
** Vineland State School, Vineland, New Jersey. ?Jefferson Medical College, Philadelphia, Pennsylvania. Received: January 4, 1977. 25 I
252
Sherk,
Clinical Orthopaedici and Related Research
Cruz and Stambaugh
FIG. 1A. Roentgenogram of a patient o n admission to the Vineland State School. T h e skeletal tissues appeared normally mineralized and the epiphyseal plates are not cupped or widened. T h e junction of the metaphyses and epiphyseal plates are clearly defined and not frayed or stippled in appearance.
would be mandatory as a simple procedurc to lower the incidence of demineralization and pathologic fractures in these patients. METHODS In December 1973 the patient population at Vineland State School in Vineland, New Jersey was surveyed for those patients who had taken anticonvulsant therapy consisting of Dilantin or Mysoline with or without Phenobarbital. Patients were not listed who had not taken the anticonvulsant therapy for more than 6 months. Forty-one such patients had died in the pl.eceding 5 years (1968-1973) and their charts and X-rays were reviewed. The surviving patients were cross-indexed with all patients who had sustained fractures between 1971 and 1973 and calcium, phosphorous and alkaline phosphatase levels were determined in both groups. In January 1974 all patients at the Vineland State School began routine daily multivitamins
FIG. B. Roentgenogram of the same patient’s tibia showing profound skeletal demineralization and deformity resulting from anticonvulsant rickets, eight years later.
which contained 400 units of vitamin D. Prior to that time patients had not been given vitamins routinely. According to institutional policy all patients had been taken out-of-doors into the sunlight in good weather and this policy was continued. The patients did not drink milk which was fortified with vitamin D. In December 1975 we listed all patients who had sustained frclctures after one year of treatment with 400 units of vitamin D daily. W e also noted whether the patient was admitted to the hospital or treated on an out-patient basis. W e compared these findings in 1975 to similar data gathered in 1973, the last full year before treatment with vitamin D.
RESULTS Of the 41 seizure patients who had died between 1968 and 1973, 16 manifested profound demineralization. We defined profound demineralization as skeletal change resulting in bowing, multiple pathologic fractures, multiple Umbauzonen (Looser’s lines), thinned,
TABLE 1. January 1971-January
149 fractures 1 14 in non-seizure patients
35 in seizure patients 23.5% of fractures occurred in seizure patients
1973
1830 patients in V.S.S. 415 patients on anti-convulsant medication 22.6% of total population are seizure patients
Number 129 November-December. 1977
Vitamin D Prophylaxis
atrophic cortices which were hazy in appearance on roentgenographic examination. This group of patients averaged 30 years in age at the time of death. Their average I.Q. was 17 and 13 were non-ambulatory for at least 2 years before death. All had taken combined anticonvulsant therapy (phenobarbital with either dilantin or mysoline) all their lives and none had been on a consistent program of vitamin therapy. All patients received a standard diet without special supplementation. An example of this severe skeletal depletion is shown in Figure 1. Since the routine administration of 400 units of vitamin daily this degree of profound demineralization has not been observed. In the 2X-year period from January 1971 to January 1973, 149 fractures were recognized and reported. Thirty-five of these occurred in patients with seizures who had taken anticonvulsant medication for over 6 months. Thus 23.5% of the fractures were occurring in seizure patients taking anticonvulsant therapy. There were 415 seizure patients taking anticonvulsant therapy in a total population of approximately 1,830 patients at the Vineland State School. Thus 22.6% of the population was on anticonvulsant
253
FIG. 2. Case 1 , Anteroposterior roentgenogram of pelvis and femur in 1962 prior to institution of combined anticonvulsant therapy. The bones are normally mineralized, the epiphyses appear normal and the pelvic contour is normal.
therapy. The percentage of fracture patients taking these drugs appeared similar to the percentage of patients taking these medications in the population as a whole i.e. 23.5% compared to 22.6% (Table 1). The comparison of fractures which occurred in 1975 after a full year of treatment with vitamin D with those that occurred before treatment are shown in Table 2. Before 1973, 25.2% of the fracture patients were taking anticonvulsant drugs whereas in 1975 only 11.5% of fracture patients were taking these drugs. It should be noted that many fractures in both the seizure and non-
TABLE 2. 1973 Before Prophylaxis with Vitamin D
1975 After Prophylaxis with Vitamin D
75 fractures 19 in seizure patients 25.2% of fractures in
107 fractures 12 in seizure patients 1 1.1 % of fractures in seizure patients
seizure patients 33 fracture patients admitted 5 seizure patients admitted for total of 463 days in hospital
38 fracture patients admitted 3 seizure patients admitted for total of 214 days in hospital
':' This table was based on all but skull and facial fractures. This variability and the range in patient age from eight years to ninety-one years precluded statistical evaluation.
254
Sherk, Cruz and Stambaugh
FIG. 3. Case 1, Anteroposterior roentgenogram of pelvis and femur after six years of combined anticonvulsant therapy without protection with vitamin D. The severe demineralization has been accompanied by multiple pathologic fractures and deformity of the pelvis.
seizure patients were not severe injuries and were treated on an out-patient basis returning the patients to their cottages and out buildings. Casts, splints or other forms of immobilization were checked daily or weekly in the regular out-patient clinics without adding significantly to cost and inconvenience. Recognizing that the treatment of a fracture on an in-patient basis at the Vineland State School Hospital indicated a much more serious injury than one treated on an ambu-
FIG. 4. Case 1, Lateral roentgenogram of left lower extremity in March 1971 showing multiple ribbon-like zones of rarefaction in the tibia and fibula. In the upper tibia an area of densified spongiosa is noted. The cortices are markedly atrophic with a ground glass appearance suggesting profound osteomalacia.
Clinical Orthopaadicr and Related Roraarch
latory basis and that such in-patient treatment greatly added to cost and inconvenience, we compared the number of patients admitted both before and after vitamin D prophylaxis. Thirty-three patients were admitted in 1973, the last full year before vitamin D prophylaxis, for treatment of fractures. Of these, 5 were seizure patients taking anticonvulsant therapy. These patients, i.e. the seizure patients who sustained fractures, required 463 days of hospitalization in 1973. There were 38 patients admitted for treatment of fractures in 1975 and of these, 3 were seizure patients taking anticonvulsant therapy. These 3 patients required 214 days of in-patient treatment. CASE REPORT Case 1 . D.B. was admitted to the Vineland State School on September 19, 1951 at the age of 5 with the diagnosis of severe spastic quadriplegia, profound mental deficiency and grand nial epilepsy. Her seizures were mild and infrequent and controlled with intermittent barbiturates and occasionally Dilantin until 1966 (Fig. 2). In that year the seizures began to occur more often and became more severe. Onehundred and fifty milligrams of Dilantin and 90 mg of phenobarbital twice daily were required to control seizures subsequent to 1966 and the patient has been maintained on this medication since. The patient sustained a fracture of the left femur while being turned in bed in January 1970 and in the ensuing 3 years had fractured almost every long bone with no known trauma (Fig. 3). H e r X-rays revealed marked skeletal demineralization with nietaphyseal rarefaction, multiple pathologic fractures, severe deformities and a non-union of the right tibia (Fig. 4 ) . Blood studies at that time revealed no anemia, normal blood sugars, normal creatinine and normal blood urea nitrogen levels. A Sudan 11 fat stool stain was normal. She had a repeatedly low normal serum calcium and serum phosphorus levels and her serum alkaline phosphatase was markedly elevated on repeated determinations. Treatment was begun with 10,000 units of vitamin D every other day intramuscularly in November 1973. T h e non-union of the right tibia healed in approximately 6 weeks and her
Number November-December, 129 I977
skeleton gradually remineralized over the ensuing year. Her calcium and phosphorus levels returned to normal. Her serum alkaline phosphatase level remains slightly elevated although this is probably on a hepatic basis reflecting the direct effect of phenobarbital in the hepatic cytochrome P-450 enzyme system (Fig. 5). Case 2. M.C. is a 40-year-old Caucasian female who was admitted to the Vineland State School in January 1950 with the diagnosis of grand ma1 epilepsy, spastic quadriplegia and severe mental retardation. She has required 1 0 0 m g of Dilantin and 6 0 m g of phenobarbital 3 times daily for the past 5 years for control of her seizures. While being turned in bed in July of 1975 she sustained a supracondylar fracture of the right femur. This was treated with a long leg cast. Twelve weeks later she sustained a fracture of the right femur at the upper limit of the cast again while being turned in bed. These fractures healed slowly in traction over the ensuing 4 months. A fracture of the right tibia occurred with no known injury in December 1975. During this entire time she was being treated with multiple vitamins receiving approximately 3,000 units of vitamin D weekly. Blood chemistries revealed normal liver and kidney function and low normal serum calcium and phosphorous levels. Her alkaline phosphatase levels were consistently elevated. In December 1975 a 24-hour urine calcium was found to be 3 0 m g and the patient had a 75% tubular reabsorption of phosphate. A n iliac crest biopsy was done and osteoid, calcified bone and osteoid surface were measured by point-counting and lins-intersection techniques on several sections of methacrylate imbedded, undecalcified bone stained with Masson’s trichrome. The specimen contained only cancellous bone and the trabecular pattern appeared normal. Calcified bone occupied 20.5% and osteoid 4.7% of the cross section area. Seventy-two per cent of the surfaces were covered with osteoid seams of at least 4 mirons in thickness. These findings were compatible with the diagnosis of severe osteomalacia (Fig. 6). Treatment with 50,000 units of commercially available vitamin D (Ergosterol ) was begun twice weekly after the biopsy had been performed. Within 6 weeks 24 hour urine calcium levels had returned to normal. Four months after the institution of this treatment an iliac crest biopsy was repeated. Osteoid surfaces as
Vitamin D Prophylaxis
255
Fig. 5. Case 1, Lateral roentgenogram of left lower extremity showing healing of the anticonvulsant osteomalacia. The patient has sustained no new fractures since December 1973 when treatment with 10,000 units of ergosterol every other day was begun. measured by point counting and line intersection techniques had decreased to 3% representing an apparent improvement in the severity of the osteomalacia. She has been maintained on 50,000 units of vitamin D weekly since the second biopsy. The fractures of the tibia and femur have been healed and she has developed no new skeletal injuries. Her alkaline phosphatase has remained slightly elevated.
DISCUSSION Prior t o the administration of routine vitamin D prophylaxis of 3,000 I.U. weekly we observed severe anticonvulsant osteomalacia i n many patients w h o h a d been institutionalized f o r long periods of time. T h e osteomalacia was particularly severe i n nonambulatory patients. A f t e r one year of routine vitamin D prophylaxis in these patients we have not observed this profound degree of skeletal demineralization.
256
Sherk, Cruz and Stambaugh
Clinical Orthopaedlcr and Rolatod Roroarch
FIG.6. Case 2, Photomicrography of iliac crest biopsy. The decalcified bone was imbedded in methacrylate and stained with Masson’s trichrome. Calcified bone and osteoid were measured by point counting and line intersection techniques. Osteoid occupied 4.7% of the cross sectional area. (Normal value 0.4% ).
In addition after vitamin D prophylaxis the percentage of fractures in seizure patients has fallen relative to the number of fractures in the institution at large. The questions arise as to whether the fractures in the epileptic group were directly related to seizures and if there was any correlation between the number of seizures and the likelihood of fractures. On reviewing the charts of these patients these questions appear almost impossible to answer since the patients were usually found with the fracture and its cause or mechanism was not observed or reported. Nevertheless, the sharp drop in the percentage of seizure patients in the fracture groups and the decrease in the number of hospital days required for their care suggest that vitamin D prophylaxis has diminished the effect of anticonvulsant osteomalacia. The necessary dosage level of vitamin D may vary, however, and the 2 cases reported herein show that 3,000 1.U. weekly may be inadequate in some instances. Fifty thousand I.U.weekly or more is well-tolerated and has a significant effect on the levels of serum calcium, phosphorous and alkaline phosphatase.7 In these 2 cases this level of vita-
min D appeared to be necessary to prevent fractures and correct the osteomalacia. SUMMARY Small doses of vitamin D can probably prevent catastrophic skeletal demineralization in patients taking antiseizure medication. Moderate doses of vitamin D can reverse this degree of demineralization once it has occurred. Prophylactic vitamin D therapy was associated with a lowered incidence of seizure patients in the overall fracture census and a decrease in the number of in-hospital days for treatment of seizure patients with fractures. Vitamin D therapy should probably be used as a routine dietary supplement in all seizure patients at dosage levels of approximately 400 units daily. Much larger doses (50,000 units once or twice weekly) should be used as necessary when these patients sustain fractures or other injuries. REFERENCES 1. Borgstedt, A. D. Bryson, M.F., Young, L. W.. and Forbes, G. B.: Long term administration of antiepileptic drugs and the development of rickets, J Pediatr. 81:9, 1972. 2. Dent, C. E., Richens, A., Rowe. D. J. E.
Number 129 November-December, 1977
and Stamp, T. C. B.: Disturbance of calcium metabolism by anticonvulsant therapy, Br. Med. J. 4:69, 1970. 3. Hahn, T. J., Hendin, B. A., Scharp. C. P.. Borsseau, V. C. and Haddad, J. C.: Serum 25-OHC and bonc mass in children given anticonvulsants, N. Engl. J. Med. 292:550, 1975. 4. Lifshitz, F. and Maclaren, N. K.: Vitamin
D-dependent rickets in institutionalized mentally retarded children receiving long-term anticonvukant therapy: I. A survey of twohundred and eighty-eight patients, Pediatrics, 83:612, 1973. 5. Richens, A. and Rowe, D. J. E.: Disturbance of calcium metabolism by anticonvulsant drugs, Br. Med. J. 4:73, 1970. 6. Sherk, H. H., Lane, L. A., Berman, P. H.and Crosley. C. J.: Anticonvulsant Rickets: Pro-
Vitamin D Prophylaxis
257
ceedings. American Academy of Orthopedic Surgeons. New Orleans, 1976. 7. Sherk; H. H. and Snape, W.T.: Osteomalacia: prophylaxis with vitamin D in institutionalized adult patients. J. Med. Soc. N. J. 74:26, 1977.
8. Silver, J., Davies. T. J., Kupersmitt, E., Orme, M., Petrie, A. and Vajda, F.: Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs, Arch. Dis. Child. 49: 344, 1974. 9. Teotia, M. and Teotia,
S. P. S.: Rickets precipitated by anticonvulsant drugs. Am. J. Disabled child. 125:850, 1973. 10. Tolman, K. G.. Juhiz, W., Sanella, J. J., Madsen, J. A., Belsey, R. E., Goldsmith, R. S. and Treston, S. W.: Osteomalacia associated with anticonvulsant drug therapy, Pediatrics, 56:45, 1975.
JOHN STAMBAUGH, M.D.?
The incidence of skeletal demineralization has varied with the duration of anticonvulsant therapy, patient activity, sunlight exposure and vitamin D and types of anticonvulsants taken.4-6.9910 Anticonvulsant rickets and osteomalacia have appeared for the most part in isolated reports and the true incidence in a large institutionalized population is uncertain but has been suggested to be as high as 30%.'0 Despite the increasing number of reports of rickets in patients receiving chronic anticonvulsant therapy, high-dose vitamin D or calciferol therapy has not been instituted in some high-risk groups and pathologic fractures remain the single most costly medical problem in some institutionalized patient populations.1° About 3,000 I.U. of vitamin D per week and exposure to sunshine have been shown to prevent significant bone disease in patients treated with anticonvulsantss but reports on the effect of vitamin D therapy on the incidence of fractures in this patient group have not appeared. A review, therefore, of the incidence of skeletal demineralization and fractures in an institutionalized population was made both before and after vitamin D prophylaxis. Two case reports are presented to exemplify the severity of the rickets and osteomalacia observed, and a proposal is made that is hoped
Calciferol must be metabolically changed to 25-hydroxycholecalciferol in the liver in order to become biologically active. Further hydroxylation to the more active metabolite 1, 25-dihydroxycholecalciferol subsequently occurs in the kidney. In patients receiving long-term anticonvulsant therapy with dephenylhydantion, mysoline and phenobarbital, reduced serum levels of 25-hydroxycholecalciferol have been reported.' The exact mechanism for this decreased level of 25-OH calciferol is uncertain but an interference in hepatic metabolism of vitamin D and 25-OH calciferol or their conversion to more polar, less active metabolites has been suggested as a plausible mechanism.2 Regardless of the abnormal chemistries noted in patients receiving long-term anticonvulsants and the severity of the bone changes, the rickets rapidly heal with increased doses of vitamin D above 6,000 I.U./day or with treatment of 5 0 U of 25-hydroxy cholecalciferol given orally.3
* 2647
AND
Westfield Ave., Camden, New Jersey
08105.
** Vineland State School, Vineland, New Jersey. ?Jefferson Medical College, Philadelphia, Pennsylvania. Received: January 4, 1977. 25 I
252
Sherk,
Clinical Orthopaedici and Related Research
Cruz and Stambaugh
FIG. 1A. Roentgenogram of a patient o n admission to the Vineland State School. T h e skeletal tissues appeared normally mineralized and the epiphyseal plates are not cupped or widened. T h e junction of the metaphyses and epiphyseal plates are clearly defined and not frayed or stippled in appearance.
would be mandatory as a simple procedurc to lower the incidence of demineralization and pathologic fractures in these patients. METHODS In December 1973 the patient population at Vineland State School in Vineland, New Jersey was surveyed for those patients who had taken anticonvulsant therapy consisting of Dilantin or Mysoline with or without Phenobarbital. Patients were not listed who had not taken the anticonvulsant therapy for more than 6 months. Forty-one such patients had died in the pl.eceding 5 years (1968-1973) and their charts and X-rays were reviewed. The surviving patients were cross-indexed with all patients who had sustained fractures between 1971 and 1973 and calcium, phosphorous and alkaline phosphatase levels were determined in both groups. In January 1974 all patients at the Vineland State School began routine daily multivitamins
FIG. B. Roentgenogram of the same patient’s tibia showing profound skeletal demineralization and deformity resulting from anticonvulsant rickets, eight years later.
which contained 400 units of vitamin D. Prior to that time patients had not been given vitamins routinely. According to institutional policy all patients had been taken out-of-doors into the sunlight in good weather and this policy was continued. The patients did not drink milk which was fortified with vitamin D. In December 1975 we listed all patients who had sustained frclctures after one year of treatment with 400 units of vitamin D daily. W e also noted whether the patient was admitted to the hospital or treated on an out-patient basis. W e compared these findings in 1975 to similar data gathered in 1973, the last full year before treatment with vitamin D.
RESULTS Of the 41 seizure patients who had died between 1968 and 1973, 16 manifested profound demineralization. We defined profound demineralization as skeletal change resulting in bowing, multiple pathologic fractures, multiple Umbauzonen (Looser’s lines), thinned,
TABLE 1. January 1971-January
149 fractures 1 14 in non-seizure patients
35 in seizure patients 23.5% of fractures occurred in seizure patients
1973
1830 patients in V.S.S. 415 patients on anti-convulsant medication 22.6% of total population are seizure patients
Number 129 November-December. 1977
Vitamin D Prophylaxis
atrophic cortices which were hazy in appearance on roentgenographic examination. This group of patients averaged 30 years in age at the time of death. Their average I.Q. was 17 and 13 were non-ambulatory for at least 2 years before death. All had taken combined anticonvulsant therapy (phenobarbital with either dilantin or mysoline) all their lives and none had been on a consistent program of vitamin therapy. All patients received a standard diet without special supplementation. An example of this severe skeletal depletion is shown in Figure 1. Since the routine administration of 400 units of vitamin daily this degree of profound demineralization has not been observed. In the 2X-year period from January 1971 to January 1973, 149 fractures were recognized and reported. Thirty-five of these occurred in patients with seizures who had taken anticonvulsant medication for over 6 months. Thus 23.5% of the fractures were occurring in seizure patients taking anticonvulsant therapy. There were 415 seizure patients taking anticonvulsant therapy in a total population of approximately 1,830 patients at the Vineland State School. Thus 22.6% of the population was on anticonvulsant
253
FIG. 2. Case 1 , Anteroposterior roentgenogram of pelvis and femur in 1962 prior to institution of combined anticonvulsant therapy. The bones are normally mineralized, the epiphyses appear normal and the pelvic contour is normal.
therapy. The percentage of fracture patients taking these drugs appeared similar to the percentage of patients taking these medications in the population as a whole i.e. 23.5% compared to 22.6% (Table 1). The comparison of fractures which occurred in 1975 after a full year of treatment with vitamin D with those that occurred before treatment are shown in Table 2. Before 1973, 25.2% of the fracture patients were taking anticonvulsant drugs whereas in 1975 only 11.5% of fracture patients were taking these drugs. It should be noted that many fractures in both the seizure and non-
TABLE 2. 1973 Before Prophylaxis with Vitamin D
1975 After Prophylaxis with Vitamin D
75 fractures 19 in seizure patients 25.2% of fractures in
107 fractures 12 in seizure patients 1 1.1 % of fractures in seizure patients
seizure patients 33 fracture patients admitted 5 seizure patients admitted for total of 463 days in hospital
38 fracture patients admitted 3 seizure patients admitted for total of 214 days in hospital
':' This table was based on all but skull and facial fractures. This variability and the range in patient age from eight years to ninety-one years precluded statistical evaluation.
254
Sherk, Cruz and Stambaugh
FIG. 3. Case 1, Anteroposterior roentgenogram of pelvis and femur after six years of combined anticonvulsant therapy without protection with vitamin D. The severe demineralization has been accompanied by multiple pathologic fractures and deformity of the pelvis.
seizure patients were not severe injuries and were treated on an out-patient basis returning the patients to their cottages and out buildings. Casts, splints or other forms of immobilization were checked daily or weekly in the regular out-patient clinics without adding significantly to cost and inconvenience. Recognizing that the treatment of a fracture on an in-patient basis at the Vineland State School Hospital indicated a much more serious injury than one treated on an ambu-
FIG. 4. Case 1, Lateral roentgenogram of left lower extremity in March 1971 showing multiple ribbon-like zones of rarefaction in the tibia and fibula. In the upper tibia an area of densified spongiosa is noted. The cortices are markedly atrophic with a ground glass appearance suggesting profound osteomalacia.
Clinical Orthopaadicr and Related Roraarch
latory basis and that such in-patient treatment greatly added to cost and inconvenience, we compared the number of patients admitted both before and after vitamin D prophylaxis. Thirty-three patients were admitted in 1973, the last full year before vitamin D prophylaxis, for treatment of fractures. Of these, 5 were seizure patients taking anticonvulsant therapy. These patients, i.e. the seizure patients who sustained fractures, required 463 days of hospitalization in 1973. There were 38 patients admitted for treatment of fractures in 1975 and of these, 3 were seizure patients taking anticonvulsant therapy. These 3 patients required 214 days of in-patient treatment. CASE REPORT Case 1 . D.B. was admitted to the Vineland State School on September 19, 1951 at the age of 5 with the diagnosis of severe spastic quadriplegia, profound mental deficiency and grand nial epilepsy. Her seizures were mild and infrequent and controlled with intermittent barbiturates and occasionally Dilantin until 1966 (Fig. 2). In that year the seizures began to occur more often and became more severe. Onehundred and fifty milligrams of Dilantin and 90 mg of phenobarbital twice daily were required to control seizures subsequent to 1966 and the patient has been maintained on this medication since. The patient sustained a fracture of the left femur while being turned in bed in January 1970 and in the ensuing 3 years had fractured almost every long bone with no known trauma (Fig. 3). H e r X-rays revealed marked skeletal demineralization with nietaphyseal rarefaction, multiple pathologic fractures, severe deformities and a non-union of the right tibia (Fig. 4 ) . Blood studies at that time revealed no anemia, normal blood sugars, normal creatinine and normal blood urea nitrogen levels. A Sudan 11 fat stool stain was normal. She had a repeatedly low normal serum calcium and serum phosphorus levels and her serum alkaline phosphatase was markedly elevated on repeated determinations. Treatment was begun with 10,000 units of vitamin D every other day intramuscularly in November 1973. T h e non-union of the right tibia healed in approximately 6 weeks and her
Number November-December, 129 I977
skeleton gradually remineralized over the ensuing year. Her calcium and phosphorus levels returned to normal. Her serum alkaline phosphatase level remains slightly elevated although this is probably on a hepatic basis reflecting the direct effect of phenobarbital in the hepatic cytochrome P-450 enzyme system (Fig. 5). Case 2. M.C. is a 40-year-old Caucasian female who was admitted to the Vineland State School in January 1950 with the diagnosis of grand ma1 epilepsy, spastic quadriplegia and severe mental retardation. She has required 1 0 0 m g of Dilantin and 6 0 m g of phenobarbital 3 times daily for the past 5 years for control of her seizures. While being turned in bed in July of 1975 she sustained a supracondylar fracture of the right femur. This was treated with a long leg cast. Twelve weeks later she sustained a fracture of the right femur at the upper limit of the cast again while being turned in bed. These fractures healed slowly in traction over the ensuing 4 months. A fracture of the right tibia occurred with no known injury in December 1975. During this entire time she was being treated with multiple vitamins receiving approximately 3,000 units of vitamin D weekly. Blood chemistries revealed normal liver and kidney function and low normal serum calcium and phosphorous levels. Her alkaline phosphatase levels were consistently elevated. In December 1975 a 24-hour urine calcium was found to be 3 0 m g and the patient had a 75% tubular reabsorption of phosphate. A n iliac crest biopsy was done and osteoid, calcified bone and osteoid surface were measured by point-counting and lins-intersection techniques on several sections of methacrylate imbedded, undecalcified bone stained with Masson’s trichrome. The specimen contained only cancellous bone and the trabecular pattern appeared normal. Calcified bone occupied 20.5% and osteoid 4.7% of the cross section area. Seventy-two per cent of the surfaces were covered with osteoid seams of at least 4 mirons in thickness. These findings were compatible with the diagnosis of severe osteomalacia (Fig. 6). Treatment with 50,000 units of commercially available vitamin D (Ergosterol ) was begun twice weekly after the biopsy had been performed. Within 6 weeks 24 hour urine calcium levels had returned to normal. Four months after the institution of this treatment an iliac crest biopsy was repeated. Osteoid surfaces as
Vitamin D Prophylaxis
255
Fig. 5. Case 1, Lateral roentgenogram of left lower extremity showing healing of the anticonvulsant osteomalacia. The patient has sustained no new fractures since December 1973 when treatment with 10,000 units of ergosterol every other day was begun. measured by point counting and line intersection techniques had decreased to 3% representing an apparent improvement in the severity of the osteomalacia. She has been maintained on 50,000 units of vitamin D weekly since the second biopsy. The fractures of the tibia and femur have been healed and she has developed no new skeletal injuries. Her alkaline phosphatase has remained slightly elevated.
DISCUSSION Prior t o the administration of routine vitamin D prophylaxis of 3,000 I.U. weekly we observed severe anticonvulsant osteomalacia i n many patients w h o h a d been institutionalized f o r long periods of time. T h e osteomalacia was particularly severe i n nonambulatory patients. A f t e r one year of routine vitamin D prophylaxis in these patients we have not observed this profound degree of skeletal demineralization.
256
Sherk, Cruz and Stambaugh
Clinical Orthopaedlcr and Rolatod Roroarch
FIG.6. Case 2, Photomicrography of iliac crest biopsy. The decalcified bone was imbedded in methacrylate and stained with Masson’s trichrome. Calcified bone and osteoid were measured by point counting and line intersection techniques. Osteoid occupied 4.7% of the cross sectional area. (Normal value 0.4% ).
In addition after vitamin D prophylaxis the percentage of fractures in seizure patients has fallen relative to the number of fractures in the institution at large. The questions arise as to whether the fractures in the epileptic group were directly related to seizures and if there was any correlation between the number of seizures and the likelihood of fractures. On reviewing the charts of these patients these questions appear almost impossible to answer since the patients were usually found with the fracture and its cause or mechanism was not observed or reported. Nevertheless, the sharp drop in the percentage of seizure patients in the fracture groups and the decrease in the number of hospital days required for their care suggest that vitamin D prophylaxis has diminished the effect of anticonvulsant osteomalacia. The necessary dosage level of vitamin D may vary, however, and the 2 cases reported herein show that 3,000 1.U. weekly may be inadequate in some instances. Fifty thousand I.U.weekly or more is well-tolerated and has a significant effect on the levels of serum calcium, phosphorous and alkaline phosphatase.7 In these 2 cases this level of vita-
min D appeared to be necessary to prevent fractures and correct the osteomalacia. SUMMARY Small doses of vitamin D can probably prevent catastrophic skeletal demineralization in patients taking antiseizure medication. Moderate doses of vitamin D can reverse this degree of demineralization once it has occurred. Prophylactic vitamin D therapy was associated with a lowered incidence of seizure patients in the overall fracture census and a decrease in the number of in-hospital days for treatment of seizure patients with fractures. Vitamin D therapy should probably be used as a routine dietary supplement in all seizure patients at dosage levels of approximately 400 units daily. Much larger doses (50,000 units once or twice weekly) should be used as necessary when these patients sustain fractures or other injuries. REFERENCES 1. Borgstedt, A. D. Bryson, M.F., Young, L. W.. and Forbes, G. B.: Long term administration of antiepileptic drugs and the development of rickets, J Pediatr. 81:9, 1972. 2. Dent, C. E., Richens, A., Rowe. D. J. E.
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and Stamp, T. C. B.: Disturbance of calcium metabolism by anticonvulsant therapy, Br. Med. J. 4:69, 1970. 3. Hahn, T. J., Hendin, B. A., Scharp. C. P.. Borsseau, V. C. and Haddad, J. C.: Serum 25-OHC and bonc mass in children given anticonvulsants, N. Engl. J. Med. 292:550, 1975. 4. Lifshitz, F. and Maclaren, N. K.: Vitamin
D-dependent rickets in institutionalized mentally retarded children receiving long-term anticonvukant therapy: I. A survey of twohundred and eighty-eight patients, Pediatrics, 83:612, 1973. 5. Richens, A. and Rowe, D. J. E.: Disturbance of calcium metabolism by anticonvulsant drugs, Br. Med. J. 4:73, 1970. 6. Sherk, H. H., Lane, L. A., Berman, P. H.and Crosley. C. J.: Anticonvulsant Rickets: Pro-
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ceedings. American Academy of Orthopedic Surgeons. New Orleans, 1976. 7. Sherk; H. H. and Snape, W.T.: Osteomalacia: prophylaxis with vitamin D in institutionalized adult patients. J. Med. Soc. N. J. 74:26, 1977.
8. Silver, J., Davies. T. J., Kupersmitt, E., Orme, M., Petrie, A. and Vajda, F.: Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs, Arch. Dis. Child. 49: 344, 1974. 9. Teotia, M. and Teotia,
S. P. S.: Rickets precipitated by anticonvulsant drugs. Am. J. Disabled child. 125:850, 1973. 10. Tolman, K. G.. Juhiz, W., Sanella, J. J., Madsen, J. A., Belsey, R. E., Goldsmith, R. S. and Treston, S. W.: Osteomalacia associated with anticonvulsant drug therapy, Pediatrics, 56:45, 1975.
