 |
|
Antiepileptic Drug–Induced Bone Loss in Young Male Patients Who Have Seizures
Dennis L. Andress, MD;
Judy Ozuna, RN, MS;
David Tirschwell, MD;
Lucinda Grande, BS;
Meshell Johnson, MD;
Arnold F. Jacobson, MD, PhD;
William Spain, MD
Arch Neurol. 2002;59:781-786.
ABSTRACT
| |
Background Long-term antiepileptic drug (AED) therapy is a known risk factor for
bone loss and fractures. Vitamin D deficiency is frequently cited as a cause
for bone loss in patients who have seizures.
Objective To determine whether men who have seizures, but who are otherwise healthy,
suffer substantial bone loss in the hip while taking AEDs.
Patients and Methods We prospectively examined femoral neck bone mineral density (BMD) by
dual-energy x-ray absorptiometry in 81 consecutive men, aged between 25 and
54 years old (mean age, 45 years), who were attending an outpatient seizure
clinic. Low BMD values were analyzed for known risk factors for bone loss.
Dual-energy x-ray absorptiometry scans were repeated in 54 patients, 12 to
29 months later (mean, 19 months), to assess the rate of change in BMD over
time.
Results Multivariate linear regression analysis revealed that age (P<.001) and time receiving AEDs (P<.003)
were the 2 important risk factors associated with low femoral neck BMD. Neither
vitamin D deficiency, hypogonadism, cigarette smoking, nor excess alcohol
intake were associated with low BMD after correcting for age and time on AEDs.
Longitudinal analysis of femoral neck BMD revealed that only those in the
youngest age group (25-44 years) showed significant declines in femoral neck
BMD (1.8% annualized loss; 95% confidence interval, -3.1 to -0.9; P<.003) while receiving AED therapy. There was no evidence
that a specific type of AED was more causally related to bone loss in this
group although most patients were taking phenytoin sodium or carbamazepine
during the longitudinal assessment.
Conclusions Long-term AED therapy in young male patients who have seizures causes
significant bone loss at the hip in the absence of vitamin D deficiency. Dual-energy
x-ray absorptiometry scanning of the hip is useful in identifying patients
who are particularly susceptible to rapid bone loss while taking AEDs.
INTRODUCTION
THE LONG-TERM use of antiepileptic drugs (AEDs) in patients who have
seizures has been associated with alterations in the levels of circulating
calcium and calcitropic hormones.1-3
These findings have led to the belief that susceptible patients who develop
bone disease have osteomalacia as the predominant histologic lesion.1, 4-7
In particular, children and institutionalized patients8-9
seem to be at an increased risk for developing hypocalcemia in association
with low vitamin D levels, and bone biopsy evidence of osteomalacia has corroborated
the deleterious effects of inadequate vitamin D replacement therapy in these
patients.10
Recent studies, however, have shown that vitamin D deficiency and osteomalacia
are not as prevalent as once thought, especially in the ambulatory, noninstitutionalized
population who experience seizures.11-12
Biopsy evidence of normal bone mineralization or increased bone turnover12 is more characteristic of ambulatory patients of
both sexes who have seizures and is consistent with bone serum markers demonstrating
increased bone turnover.13
Despite the indirect evidence that AEDs may directly affect bone remodeling,
there is little known about the sustained effects of AEDs on bone mineral
density (BMD). Specifically, BMD has only been examined in small groups of
patients who have seizures5, 11, 13
and longitudinal assessments in adults have not been reported. This study
prospectively examined the relationship between femoral neck BMD and AED therapy
in ambulatory, male patients who have seizures and determined potential risk
factors in patients demonstrating ongoing bone loss.
PATIENTS AND METHODS
PATIENTS
There were 103 consecutive male veteran patients who were asked to participate
in the study. All were active outpatients enrolled in the Seizure Clinic at
the Seattle Veterans Affairs Puget Sound Health Care System, Seattle, Wash.
Only male patients were recruited because of the small number of female veterans
in this clinic population and only patients younger than 55 years were included
to minimize the influence of age-related effects on bone loss. Twenty-two
patients either declined or were unable to undergo serologic testing or to
obtain a x-ray film. Eighty-one men, aged 25 to 54 years (mean age, 45 years),
participated in the study after giving informed written consent. Each patient
completed a questionnaire detailing his fracture history, habits (cigarette
smoking and alcohol intake), comorbid conditions, medications, and dietary
intake of calcium and vitamin D. Data regarding the duration of AED therapy
were derived from these questionnaires and from pharmacy and clinic records.
The study was approved by the Human Subjects Division of the University of
Washington, Seattle.
MEASUREMENTS
Bone mineral density of the femoral neck was measured by dual-energy
x-ray absorptiometry (DEXA) using a densitometer (Hologic QDR-4500A; Hologic
Inc, Waltham, Mass). At this measurement site, the precision (coefficient
of variation) is 1.2% according to the manufacturer. Measurements of the levels
of serum total calcium, phosphate, alkaline phosphatase,  -glutamyl-transpeptidase,
and aspartate transaminase were performed by an autoanalyzer; their normal
ranges, respectively, are 8.4 to 10.2 mg/dL (2.1-2.6 mmol/L), 3.5 to 4.5 mg/dL,
50 to 110 U/L, 15 to 40 U/L, and 16 to 45 U/L. Serum 25-hydroxyvitamin D and
1,25-dihydroxyvitamin D levels were determined by saturation analysis (SmithKline
Laboratories, Philadelphia, Pa); their normal ranges, respectively, are 10
to 45 ng/mL and 15 to 60 pg/mL. Serum intact parathyroid hormone (SmithKline)
and free testosterone (Diagnostics Product Corp, Los Angeles, Calif) levels
were determined by radioimmunoassay; the luteinizing hormone level was measured
by an enzyme-linked immunosorbent assay (Bayer Diagnostics, Tarrytown, NY);
their normal ranges, respectively, are 15 to 54 pg/mL, 9 to 45 ng/mL, and
3 to 11 mIU/mL. A serum sample was lacking for measurement of the following
levels: 1,25-dihydroxyvitamin D, 7 patients; parathyroid hormone, 4; testosterone,
3; 25-hydroxyvitamin D, 1; and phosphate, 1.
STATISTICAL ANALYSIS
Univariate analysis of associations between femoral neck BMD and the
predefined risk factors was performed using nonparametric methods. The Wilcoxon
rank sum test was applied with dichotomous risk factors and the Spearman rank
correlation test was used with continuous risk factors. Controlling for the
influence of age, the effect of years of receiving AED therapy on femoral
neck BMD was analyzed using multivariate linear regression. All of the potential
risk factors were entered into a linear regression model and all associations
with P>.10 were then removed in a backward stepwise
fashion. A separate interaction term was included in the regression models
to account for the possibility that the effect of AEDs on femoral neck BMD
may be modified by the age at the time of BMD determination. Age at the time
of DEXA scanning, number of years receiving AEDs, and their interaction term
were all modeled as continuous linear variables. Regression diagnostics were
performed to identify outliers for closer inspection. To ensure that the observed
associations were not being driven by a few extreme values, the linear regression
was performed a second time excluding the outliers.
A second analysis was performed on patients who had 2 DEXA scans (separated
by at least 12 months) for femoral neck BMD after excluding those for whom
treatment for bone loss had been started. Nonparametric analyses were used
to assess associations with age at the time of the DEXA scans and the annual
change and annual percentage of change in femoral neck BMD were the outcome
measures.
Statistical significance was defined as P<.05.
All analyses were performed using STATA, Version 6.0 (Stata Corp, College
Station, Tex). All data are given as mean (SD).
RESULTS
The mean age of the study population was 45 (7) years and the mean duration
of AED therapy was 18 (10) years (Table
1). The mean femoral neck BMD for the group was 0.80 (0.13) g/cm2. Thirty-eight patients (47%) had osteopenia of the femoral neck as
defined by a T score greater than 1.0 SD below that of young healthy control
subjects. The average calcium and vitamin D intakes for the group were 1162
mg/d and 285 U/d, respectively. At the time of the study the patients were
taking the following medications: phenytoin sodium, 46 patients; carbamazepine,
31; valproic acid, 19; lamotragine, 9; gabapentin, 12; and phenobarbital,
7. Forty-eight patients were taking AEDs as monotherapy (phenytoin in 58%)
and 33 patients (41%) were taking more than 1 AED (polytherapy).
|
|
|
|
Table 1. Characteristics of the Patient Population*
|
|
|
Serologic studies revealed that no patient was frankly hypocalcemic,
although 9 patients (11%) were vitamin D deficient (25-hydroxyvitamin D level,
<10 ng/mL) and 32 (40%) had elevated parathyroid hormone levels. Twenty
patients (25%) had hypogonadism as defined by having either an elevated luteinizing
hormone level (9 patients) or only a low free testosterone level (11 patients).
There were 42 patients (52%) who were current cigarette smokers and 26 (32%)
who had a history of heavy alcohol intake ( 6 drinks/d for >1 year); none
were heavy users of alcohol at the time of the study.
Few comorbid conditions were identified that may have affected BMD.
Four patients had type 2 diabetes mellitus, 1 had rheumatoid arthritis, 1
had liver disease, 1 had sarcoidosis, and 1 had panhypopituitarism. Only 7
patients were taking medications known to influence calcium metabolism—glucocorticoids,
3; furosemide, 1; and thiazide diuretics, 3; and only 5 patients were taking
hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) for hypercholesterolemia
during the study.
Nineteen patients (23%) had suffered 25 fractures since being treated
with AEDs. The sites of fracture were arms (8 patients), ribs (3 patients),
hands (2 patients), legs (5 patients), feet (6 patients), and hip (1 patient).
Seven fractures (28%) were related to a seizure and 7 resulted from high energy
impacts (motor vehicle collision, falling from roof or ladder). The crude
fracture rate was 1.9 fractures per 100 patient-years of observation and the
non–seizure-related fracture rate was 1.4 fractures per 100 patient-years.
Univariate analyses of femoral neck BMD (Table 2) revealed a significant association with cigarette use,
and the associations with age, the number of years receiving AED therapy,
hypogonadism, and alcohol use approached but did not reach statistical significance.
All of the characteristics in Table 2
were then entered into a linear regression model and characteristics with P>.1 were then removed in a stepwise fashion. As summarized
in Table 3, the final model retained
only age, number of years receiving AED therapy, and the interaction term.
To interpret the model with the interaction term, the sample was divided into
3 similar-sized groups based on age (25-44 years, 28 patients; 45-49 years,
30 patients; and 50-54 years, 23 patients) and the femoral neck BMD was plotted
against the number of years receiving AED therapy for each age group. As shown
in Figure 1, the relationship between
femoral neck BMD and time receiving AED therapy was apparent only in the youngest
age group after the regression lines were adjusted for residual confounding
by age (group 1).
|
|
|
|
Table 2. Univariate Associations With Femoral Neck BMD in 81 Male Patients
Who Have Seizures*
|
|
|
|
|
|
|
Table 3. Multivariate Linear Regression Analysis*
|
|
|
|
|
|
|
Relationship between femoral neck bone mineral density (BMD) and
the number of years receiving antiepileptic drug therapy in 81 men who have
seizures. A, Group 1 includes patients from the ages of 25 to 44 years; B,
group 2, patients from the ages of 45 to 49 years; and C, group 3, patients
from the ages of 50 to 54 years. Two outliers in group 1 (A), identified by
regression diagnostics, are indicated by solid circles.
|
|
|
Regression diagnostics identified 2 patients who might be considered
outliers. The first was 25 years old at the time of DEXA scanning, had been
receiving AEDs for 2 years, and had had a femoral neck BMD of 1.240 g/cm2. The other was 39 years old at the time of DEXA, had been receiving
AEDs for 33 years, and had had a femoral neck BMD of 0.760 g/cm2
(see solid circles in Figure 1).
When the linear regression was performed a second time without these outliers,
the P values for age at the time of DEXA, the number
of years receiving AEDs, and their interaction all remained statistically
significant with P<.05 (data not shown).
The second set of analyses looked at the change in femoral neck BMD
in the subset of patients who had undergone 2 DEXA scans. Of the 81 patients
in the cohort, 67 had follow-up DEXA scanning. However, 13 of these patients
were excluded from the subsequent analysis because bone antiresorptive therapy
had been started before the second DEXA scan by their referring physicians.
We, therefore, analyzed the remaining 54 patients according to the previously
defined age groups (Table 4).
In only the youngest age group (aged, 25-44 years) was there a significant
change in femoral neck BMD with a mean loss of 1.8% per year (range, 0.1%-4.3%
per year; P<.003). In addition, the correlations
between annual change in femoral neck BMD and age (Spearman R = 0.33, P = .02) and the percentage of annual
change in femoral neck BMD and age (Spearman R =
0.30, P = .03) were both significant. The patients
in the youngest age group had received AEDs for a significantly shorter time
(median duration, 11 vs 17 and 28 years, respectively, in the 2 older age
groups, P<.001, Kruskal-Wallis rank sum test).
|
|
|
|
Table 4. Longitudinal Change in Femoral Neck BMD According to Age*
|
|
|
To determine possible risk factors associated with the loss of BMD in
the youngest age group, we performed univariate and multivariate analyses
of the group who underwent 2 DEXA scans (54 patients) and found that only
age at the time of DEXA scan and the duration of AED therapy were significantly
associated with the decrease in femoral neck BMD. After adjusting for age,
there were no associations between calcium or vitamin D intake, or polytherapy
(>1 AED, 18 of 54 patients) and decline in femoral neck BMD. There was no
evidence that a specific type of AED was more important in causing bone loss
although most patients were taking either phenytoin (30 of 54 patients) and/or
carbamazepine (22 of 54 patients) (Table
4).
COMMENT
To our knowledge, we have shown for the first time that young male patients
who have seizures sustain significant bone loss at the femoral neck while
receiving AED therapy. The finding that 47% had a BMD lower than 1 SD below
normal (osteopenia) at this site indicates that a substantial number are at
an increased risk for hip or other skeletal fractures.14-16
In this regard, one of our study patients had already suffered a fall-related
hip fracture. Moreover, a recent evaluation of noninstitutionalized patients
with epilepsy showed a 4-fold increased risk of femoral neck fractures when
compared with age- and sex-matched healthy controls.17
Since not more than 16% of the healthy US male population in this age group
is expected to be osteopenic,18 our patient
population has more than a 2.5-fold increased prevalence of bone loss at the
hip. Surprisingly, the patients who were continuing to lose bone were those
in the younger age group (mean age, 38 years) who had been receiving AEDs
the shortest length of time (median, 11 years; 95% confidence interval, 7.2-14.7
years). The older patients (mean age, 50 years), in contrast, seemed to have
stabilized their bone loss despite being on comparable amounts and types of
AEDs during the longitudinal assessment period.
Risk factors that have previously been associated with bone loss in
patients who have seizures have included vitamin D deficiency, hypocalcemia,
and secondary hyperparathyroidism.2-3
In our study only 11% had low vitamin D levels and these were not associated
with low BMD values after multivariate analysis. This may be attributable
to our patients' relatively high intake of dietary calcium and vitamin D.
While cigarette use and a history of heavy alcohol use were identified as
potential additional risk factors in the initial analysis, the more rigorous
multivariate regression analysis excluded these factors for being as important
as age and time on AEDs.
These results agree with recent smaller studies suggesting that certain
AEDs have a direct effect on bone turnover12-14
and support the notion that AEDs can cause bone loss without inducing vitamin
D deficiency–related osteomalacia. This is the first study, however,
to quantify ongoing bone loss in a large group of ambulatory young male patients
who have seizures. While the study was not designed to determine the mechanism
of AED-induced bone loss, our finding that the younger patients had the highest
rate of bone loss suggests that bone cell activity in the young adult male
skeleton may be more susceptible to the direct effects of AEDs. Few studies
have examined bone biopsy specimens from men in this age range so it is unclear
whether rates of bone formation and osteoblast activity are normal or increased.11-12 However, recent studies that have
evaluated serum bone markers in young men receiving phenytoin and/or carbamazepine
(mean age, 38 years) therapy indicated that the parameters for bone formation
and bone resorption were higher than in age-matched controls,13
suggesting that these AEDs directly stimulate bone turnover. Moreover, recent
in vitro studies have shown that AEDs directly stimulate osteoblast activity.19 Thus, it is possible that the younger male skeleton
with enhanced bone turnover from AED therapy may require a substantially higher
calcium intake to adequately suppress bone resorption and optimize bone mineralization.
Alternatively, the AED effect may involve the same mechanism that causes age-related
bone loss that could accelerate this process in younger patients.
Despite our finding that 25% of the population had either primary (an
elevated luteinizing hormone level) or secondary (low testosterone without
an elevated luteinizing hormone level) hypogonadism, we found no association
between femoral neck bone loss and gonadal status. While this seems somewhat
surprising in light of the known effects of testosterone in stimulating bone
accretion,20-21 we believe that
the mechanisms involved with AED-induced alterations in testosterone metabolism
may include compensatory protective effects on bone remodeling. For example,
it is known that serum levels of sex hormone–binding globulin are often
elevated in patients who are taking AEDs that result in a decreased free testosterone
index or bioactive testosterone level.22-25
However, it was recently shown that serum estradiol levels are elevated in
male patients who have seizures and who are taking phenytoin,26
possibly as a consequence of AED-induced stimulation of aromatase27 that converts testosterone to estradiol. Thus, it
is possible that raised estradiol levels in some patients who have seizures
may function to protect bone against low bioactive testosterone levels. Because
we did not measure the sex hormone–binding globulin or estradiol levels
in our patients, we cannot determine whether their fluctuations were associated
with femoral bone loss. Future studies on bone loss in male patients who have
seizures should include these measurements to help resolve this issue and
to determine whether testosterone treatment with the aromatase inhibitor,
testolactone,27 would be an effective therapy
for AED-induced bone loss.
While the evaluation of fracture risk was not an end point of this study,
the crude fracture rate in our patients was similar to that of a recent study
by Vestergaard et al.17 They demonstrated a
30% increased risk for nonseizure-related fractures in 348 patients when compared
with a large control population.17 For non–seizure-related
fractures their crude fracture rate of 1.6 fractures per 100 patient-years
of observation is similar to our crude fracture rate of 1.4 fractures per
100 patient-years. We attribute their higher fracture rate, in part, to their
inclusion of older patients (up to 80 years of age) and women (50%), some
of whom may have suffered from postmenopausal osteoporosis.17
The locations of the fractures were similar in the 2 studies with fractures
of the arms, lower legs, and feet accounting for more than 50% of the fractures
in both studies.
CONCLUSIONS
Young male patients who have seizures are susceptible to significant
bone loss in the hip during long-term AED therapy. Bone loss in this region
may be related to a direct effect of AEDs in stimulating bone turnover. We
recommend DEXA scanning of the hip to identify susceptible younger patients
who may suffer from accelerated bone loss. Future studies should examine potential
mechanistic roles for testosterone and estradiol in the bone loss of these
patients and determine whether the newer AEDs are also associated with bone
loss in the hip.
AUTHOR INFORMATION
Accepted for publication December 19, 2001.
Author contributions: Study concept and design (Drs Andress and Spain and Ms Ozuna); acquisition of data (Drs Andress, Tirschwell, Johnson, Jacobson, and Spain and Mss
Ozuna and Grande); analysis and interpretation of data (Drs Andress, Jacobson, and Spain); drafting of the manuscript (Drs Andress, Jacobson, and Spain); critical revision of
the manuscript for important intellectual content (Drs Andress,
Tirschwell, Johnson, Jacobson, and Spain and Ms Ozuna); statistical
expertise (Dr Tirschwell); administrative, technical,
and material support (Drs Andress and Spain and Mss Ozuna
and \ Grande); study supervision (Drs Andress and
Spain).
Corresponding author and reprints: Dennis L. Andress, MD, Veterans
Affairs Puget Sound Health Care System (111A), 1660 S Columbian Way, Seattle,
WA 98108 (e-mail: dandress{at}u.washington.edu).
From the Departments of Medicine (Drs Andress and Johnson) and Neurology
(Mss Ozuna and Grande and Drs Tirschwell and Spain) and the Division of Nuclear
Medicine (Dr Jacobson), Veterans Affairs Puget Sound Health Care System and
the University of Washington School of Medicine, Seattle.
REFERENCES
| |
1. Dent CE, Richens A, Rowe DJ, Stamp TC. Osteomalacia with long-term anticonvulsant therapy in epilepsy. BMJ. 1970;4:69-72.
2. Hahn TJ, Hendin BA, Scharp CR, Haddad JG Jr. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol
levels in adults. N Engl J Med. 1972;287:900-904.
3. Bouillon R, Reynaert J, Claes JH, Lissens W, DeMoor P. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin
D, calcium and parathyroid hormone. J Clin Endocrinol Metab. 1975;41:1130-1135.
ABSTRACT
4. Genuth SM, Klein L, Rabinovich S, King KC. Osteomalacia accompanying chronic anticonvulsant therapy. J Clin Endocrinol Metab. 1972;35:378-386.
PUBMED
5. Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled
therapeutical trial. BMJ. 1973;4:695-701.
6. Rodbro P, Christiansen C, Lund M. Development of anticonvulsant osteomalacia in epileptic patients on
phenytoin treatment. Acta Neurol Scand. 1974;50:527-532.
ISI
| PUBMED
7. Mosekilde L, Melsen F, Christensen MS, Lund B, Sorensen OH. Effect of long-term vitamin D2 treatment on bone morphometry
and biochemical values in anticonvulsant osteomalacia. Acta Med Scand. 1977;201:303-307.
PUBMED
8. Lifshitz F, Maclaren NK. Vitamin D-dependent rickets in institutionalized, mentally retarded
children receiving long-term anticonvulsant therapy, I: a survey of 288 patients. J Pediatr. 1973;83:612-620.
FULL TEXT
|
ISI
| PUBMED
9. Fischer MH, Adkins WN Jr, Liebl BH, VanCalcar SC, Marlett JA. Bone status in nonambulant, epileptic, institutionalized youth: improvement
with vitamin D therapy. Clin Pediatr (Phila). 1988;27:499-505.
10. Rodbro P, Christiansen C. Anticonvulsant osteomalacia treated with different doses of vitamin
D2. In: Norman AW, ed. Vitamin D and Problems Related
to Uremic Bone Disease. Berlin, Germany: Walter de Gruyter GmbH &
Co KG; 1975:749-753.
11. Mosekilde L, Melsen F. Dynamic differences in trabecular bone remodeling between patients
after jejuno-ileal bypass for obesity and epileptic patients receiving anticonvulsant
therapy. Metab Bone Dis Rel Res. 1980;2:77-82.
12. Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels
with anticonvulsant drug treatment. J Clin Endocrinol Metab. 1984;58:1003-1009.
ABSTRACT
13. Valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and
novel markers of bone formation and resorption in patients on antiepileptic
drugs. J Bone Miner Res. 1994;9:631-637.
ISI
| PUBMED
14. Chevalley T, Rizzoli R, Nydegger V, et al. Preferential low bone mineral density of the femoral neck in patients
with a recent fracture of the proximal femur. Osteoporos Int. 1991;1:147-154.
FULL TEXT
| PUBMED
15. Karlsson MK, Johnell O, Nilsson BE, Sernbo I, Obrant KJ. Bone mineral mass in hip fracture patients. Bone. 1993;14:161-165.
PUBMED
16. De Laet CE, Van Hout BA, Burger H, Weel AE, Hofman A, Pols HA. Hip fracture prediction in elderly men and women: validation in the
Rotterdam study. J Bone Miner Res. 1998;13:1587-1593.
FULL TEXT
|
ISI
| PUBMED
17. Vestergaard P, Tigaran S, Rejnmark L, Tigaran C, Dam M, Mosekilde L. Fracture risk is increased in epilepsy. Acta Neurol Scand. 1999;99:269-275.
ISI
| PUBMED
18. Looker AC, Wahner HW, Dunn WL, et al. Proximal femur bone mineral levels in US adults. Osteoporos Int. 1995;5:389-409.
FULL TEXT
|
ISI
| PUBMED
19. Lau KHW, Nakade O, Barr B, Taylor AK, Houchin K, Baylink DJ. Phenytoin increases markers of osteogenesis for the human species in
vitro and in vivo. J Clin Endocrinol Metab. 1995;80:2347-2353.
ABSTRACT
20. Finkelstein JS, Klibanski A, Neer RM, et al. Increases in bone density during treatment of men with idiopathic hypogadotropic
hypogonadism. J Clin Endocrinol Metab. 1989;69:776-783.
ABSTRACT
21. Anderson FH, Francis RM, Peaston RT, Wastell HJ. Androgen supplementation in eugonadal men with osteoporosis: effects
of six months' treatment on markers of bone formation and resorption. J Bone Miner Res. 1997;12:472-478.
FULL TEXT
|
ISI
| PUBMED
22. Toone BK, Wheeler M, Fenwick PB. Sex hormone changes in male epileptics. Clin Endocrinol (Oxf). 1980;12:391-395.
PUBMED
23. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal
lobe origin. Arch Neurol. 1986;43:347-350.
ABSTRACT
24. Isojarvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllyla VV. Serum hormones in male epileptic patients receiving anticonvulsant
medication. Arch Neurol. 1990;47:670-676.
ABSTRACT
25. Brunet M, Rodamilans M, Martinez-Osaba MJ, et al. Effects of long-term antiepileptic therapy on the catabolism of testosterone. Pharmacol Toxicol. 1995;76:371-375.
PUBMED
26. Herzog AG, Levesque LA, Drislane FW, Ronthal M, Schomer DL. Phenytoin-induced elevation of serum estradiol and reproductive dysfunction
in men with epilepsy. Epilepsia. 1991;32:550-553.
PUBMED
27. Herzog AG, Klein P, Jacobs AR. Testosterone versus testosterone and testolactone in treating reproductive
and sexual dysfunction in men with epilepsy and hypogonadism. Neurology. 1998;50:782-784.
FREE FULL TEXT
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2002;59(5):878-880.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Progressive bone deficit in epilepsy
Sheth et al.
Neurology 2008;70:170-176.
ABSTRACT
| FULL TEXT
Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone
Mikati et al.
Neurology 2006;67:2005-2014.
ABSTRACT
| FULL TEXT
Advances in epilepsy
Kelso and Cock
Br Med Bull 2005;72:135-148.
ABSTRACT
| FULL TEXT
Metabolic concerns associated with antiepileptic medications
Sheth
Neurology 2004;63:S24-S29.
ABSTRACT
| FULL TEXT
Antiepileptic drug use increases rates of bone loss in older women: A prospective study
Ensrud et al.
Neurology 2004;62:2051-2057.
ABSTRACT
| FULL TEXT
More Evidence Associating AEDs with Bone Disease
JWatch Neurology 2002;2002:6-6.
FULL TEXT
|
