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ORIGINAL ARTICLE
Year : 2017  |  Volume : 10  |  Issue : 5  |  Page : 412-416  

Phenytoin-induced changes in the bone mineral metabolism in young males


1 Department of Neurology, Dr. D. Y. Patil Medical College, Hospital and Research Center, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
2 Consultant Endocrinologist, Columbia Asia Hospital, Gurugram, Haryana, India

Date of Submission16-Mar-2017
Date of Acceptance19-Jun-2017
Date of Web Publication14-Nov-2017

Correspondence Address:
Shalesh Rohatgi
Department of Neurology, Dr. D. Y. Patil Medical College, Hospital and Research Center, Dr. D. Y. Patil University, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MJDRDYPU.MJDRDYPU_56_17

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  Abstract 


Background: Antiepileptic drugs (AEDs) have an adverse effect on the bone mineral metabolism. Patients and Methods: The objective of the study was to determine the bone loss and change in bone mineral parameters in patients treated with phenytoin sodium. We prospectively studied 36 young males aged 20–30 years, with new-onset epilepsy, and treated with phenytoin. Patients were clinically examined and subjected to determination of the bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at the femur neck, spine, and lower third of radius. We also assessed Vitamin 25-OH-Vitamin D3, parathyroid hormone (PTH), and osteocalcin at the onset and after 1 year of treatment. Results: There were no significant changes noted in the 25-OH-Vitamin D3, (20.7 ± 10 ng/dl before and 18.5 ± 7.3 ng/dl after therapy, P = 0.198), and serum parathyroid levels (8.8 ± 6.8 pg/ml before and 14.2 ± 11.5 pg/ml, P = 0.114) at the end of 1-year therapy. There was declines in BMD at all the three sites; the spine (0.943 ± 0.11 vs. 0.943 ± 0.12 g/cm2, P = 0.15), femur neck (0.912 ± 0.0.12 vs. 0.896 ± 0.124 g/cm2, P = 0.093), and a statistically significant decline lower third of radius (0.659 ± 0.07 vs. 0.644 ± 0.073 g/cm2, P ≤ 0.001). We did not find any significant change in levels of 25-OH-Vitamin D3, PTH, and serum alkaline phosphatase, but found significant elevation in levels of osteocalcin. Conclusions: Phenytoin therapy in young male patients for 1-year causes a bone loss at femur and spine in the absence of Vitamin D deficiency and significant bone loss in the cortical bone radius. DXA should be done in patients during the treatment with AEDs to identify patients who are susceptible to increased risk of fractures.

Keywords: Bone mineral density, phenytoin, Vitamin D3


How to cite this article:
Rohatgi S, Ahluwalia AI. Phenytoin-induced changes in the bone mineral metabolism in young males. Med J DY Patil Univ 2017;10:412-6

How to cite this URL:
Rohatgi S, Ahluwalia AI. Phenytoin-induced changes in the bone mineral metabolism in young males. Med J DY Patil Univ [serial online] 2017 [cited 2017 Nov 23];10:412-6. Available from: http://www.mjdrdypu.org/text.asp?2017/10/5/412/218198




  Introduction Top


AEDs can adversely affect the bone metabolism. The earliest description of the association with bone disease with AEDs was reported in the 1960s on the bone biopsies conducted on institutionalized adults receiving AEDs.[1] These biopsies showed evidence of osteomalacia.[2] Peak bone mass is an important determinant of osteoporosis and risks for fracture.[3] It is the amount of bony tissue present at the end of skeletal maturation and is dependent on volume of bone and density of the mineralized tissue. The fracture rate in patients with epilepsy is 2–6 times higher than observed in the general population.[4],[5]

There are number of mechanisms by which AEDs may be associated with fractures. The abnormalities in calcium metabolism is known with AEDs.[6]

It has been suggested that enzyme-inducing AEDs are associated with Vitamin D deficiency due to increase in catabolism of Vitamin D and undercarboxylation of the bone Gla protein osteocalcin. Other mechanisms may include direct effects of AEDs on bone cells, resistance to parathyroid hormone (PTH), inhibition of calcitonin secretion, and impaired calcium absorption.[7],[8]

Dual-energy X-ray (DXA) is a sensitive technique to quantify the changes in bone mineral status and bone mineral content.[9] It has been documented that the bone mineral density (BMD) is lower in patients receiving AEDs.[10] We undertook the study to determine the change in markers of bone mineral metabolism and BMD after the start of AED in apparently healthy men.


  Patients and Methods Top


This study was carried out at a tertiary care hospital. The period of the study was 1 year.

Study design

A prospective study to evaluate the patients with seizures on phenytoin followed as outpatient. Informed consent was obtained from all patients.

Inclusion criteria

Young males age between 20 and 30 years were recruited in the study. They were freshly diagnosed to have epilepsy and all of them were treated with phenytoin sodium for at least 1 year.

Exclusion criteria

Exclusion criteria for the study were mental retardation, immobilization, overt bone deformities, and the presence of conditions known to affect bone metabolism.

Baseline clinical assessment

A complete medical history and physical examination were performed. Any systemic disorders were excluded from this study. A questionnaire assessing the risk factors of osteoporosis such as smoking, alcohol use, calcium and caffeine intake, lack of physical activity, and family history of osteoporosis was recorded for all participants. Average daily dietary intake of calcium and Vitamin D were measured with a food frequency questionnaire. Vitamin D intake was defined as the sum of Vitamin D from supplements and diet, whereas calcium intake included all calcium from supplements and diet. All the patients were consuming at least 2400 Kcal diet comprising at least 1000 mg of calcium.

Biochemical and hormonal assessment

The first sample of the patients was taken before the start of the treatment and after 12 months of continuous therapy.

After an overnight fast, a nontourniquet blood was collected for the measurement of albumin, phosphorus, creatinine, liver function tests, serum calcium, inorganic phosphorous, and serum alkaline phosphatase, intact PTH, 25-OH-D3, and osteocalcin.

  1. Intact PTH was measured in duplicate by immunoradiometric assay (normal range 7–53 pg/ml, intra-assay variability <2.5%).
  2. 25-Hydroxy-Vitamin D3 (25-OH-D3) was measured in duplicate by radioimmunoassay (RIA; DiaSorin, Minnesota, USA) (normal range 9–37 ng/ml, intra-assay variability <2.5%)
  3. Serum osteocalcin was estimated by radioimmunoassay using kits (normal range 0.01–100 ng/ml, coefficient of variation for intraassay was 3.7% and interassay was 2.5%).


Bone mineral density

The BMD (grams/cm 2) was measured by DXA using a general electric (Lunar Prodigy) densitometer. The areas covered were the lumbar spine, proximal femur, and distal radius.

Statistical analysis

The statistical analysis was performed using SPSS 10 (IBM Corporation, Chicago) for Windows. Distribution curves were expressed as means ± standard deviation. Student's paired t-test was used for repetitive measurements. Correlations among two continuous variables were run by the Pearson's test regression and discriminate analysis was used. The significance was set at P < 0.05.

Pearson's bivariate analysis

To investigate the research, the relationship of BMD at 1 year of therapy, Pearson's product-moment r correlation will be conducted to assess the relationship between BMD with other variables. The Pearson's r correlation is a bivariate measure of association (strength) of the relationship between two variables. Given that all variables are continuous (interval/ratio data) and the hypotheses seek to assess the relationships, or how the distribution of the Z-scores vary, Pearson's r correlations are the appropriate bivariate statistic correlation coefficients, r, vary from 0 (no relationship) to 1 (perfect linear relationship) or -1 (perfect negative linear relationship). Positive coefficients indicate a direct relationship, indicating that as one variable increases, the other variable also increases. Negative correlation coefficients indicate an indirect relationship, indicating that as one variable increases, the other variable decreases. Cohen's standard will be used to evaluate the correlation coefficient, where 0.10–0.29 represents a weak association between the two variables, 0.30–0.49 represents a moderate association, and 0.50 or larger represents a strong association.

We used Pearson's analysis of the BMD at the three sites with other parameters which could have an effect on the BMD at 1-year posttreatment.

Paired t-test and analysis of variance

The t-test and analysis of variance (ANOVA) compare group means. The mean of a variable to be compared should be substantively interpretable. The groups which were compared the parameters before the onset of therapy and after 1 year of treatment. We had used the SPSS software which the commands perform the paired t-test and ANOVA. This is inbuilt in the statistical software. While the t-test is limited to comparing means of two groups, one-way ANOVA can compare more than two groups. Therefore, the t-test is considered a special case of one-way ANOVA.


  Observations and Results Top


[Table 1] gives the baseline characteristics of the patients.
Table 1: Baseline characteristics of the patients

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The mean T scores and mean Z-scores are given in [Table 2].
Table 2: Baseline bone mineral and bone density parameters of the patient

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Comparison of bone biochemical parameters before and after start of treatment was as per [Table 3].
Table 3: Comparison of bone biochemical parameters at start and at end of 1 year (n=36)

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There was a reduction in the levels of 25-OH-Vitamin D3, which was not statistically significant (P = 0.76). There was increase in levels of PTH but was not statistically significant (P = 0.114). Similarly, there was no significant change in levels of serum calcium, phosphorus, and alkaline phosphatase (ALP).

There was a significant increase in the levels of serum osteocalcin (P = 0.006) which is a marker of bone formation.

Change in BMD after treatment is given in [Table 4] and [Figure 1].
Figure 1: Bone mineral density pre- and post-treatment

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Table 4: Comparison of bone mineral density parameters at start and at end of 1 year (n=36)

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There was reduction in BMD at all sites which was statistically significant at the lower end of radius (T-score P = 0.078) [Table 4] and [Figure 2].
Figure 2: The T- and Z-score pre- and post-treatment

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We found that the BMD at spine radius and femoral neck did not correlate significantly with serum calcium, serum Vitamin D3, PTH, or osteocalcin level. Relationship of BMD after 1-year treatment with pretreatment variables is given in [Table 5].
Table 5: Relationship of the bone mineral density at the radius, spine, and femur neck after 1-year posttreatment with phenytoin sodium with pretreatment variables

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  Discussion Top


In normal healthy males before 50 years who are not on any medication, there is no significant change in BMD is expected in 1 year.[11]

Our patients had no initial Vitamin D deficiency. They had serum 25-OH-Vitamin D3 levels >20 ng/ml. We took a normal level of 25-OH-Vitamin D3 as 20 ng/ml at the time when the study was designed.[12] There has been a change in the normal levels which are considered to be 25 ng/ml as per the published report from Mayo Clinic.[13]

Our results were similar to earlier reports of no change in the levels of these hormones despite anticonvulsant use in young patients.[14] Feldkamp et al.[15] and Välimäki et al.[16] observed low levels of 25-OH-D3 in patients taking phenytoin therapy.

Bogliun et al.[17] observed that in 20 female patients treated for 2–37 years with anticonvulsant drugs, there were high levels of PTH as compared to matched controls. Moderate physical activity, adequate sunlight exposure, and good nutrition probably prevented development of hypovitaminosis and secondary hyperparathyroidism in our patients.

Osteocalcin is one of the earliest bone formation markers. The high levels of serum osteocalcin have been reported with AED treatment.[18] We found significant increase in the serum osteocalcin levels after 1 year of phenytoin therapy. This indicates that there is bone remodeling activity taking place at the end of 1 year of therapy. Lau et al.[19] found an increase in osteocalcin, ALP, and procollagen peptide after treatment compared to age-matched controls.

The best surrogate to study the changes in the structure of the bone in the bone mineral content of the bone is the BMD. We observed a decrease in BMD at spine and femoral neck at 1 year although it did not reach statistical significance. However, there was a significant decline in BMD (T-score) at lower one-third radius at the end of 1 year. The loss in cortical bone is more than the loss in the trabecular bones.

However, as expected, there was no significant change in Z-score because the period of study was only 1 year.

Ensrud et al.[20] found the average rate of decline in total hip BMD was -0.70%/year in nonusers. Stephen et al.[21] studied 78 patients on long-term AEDs and found that male patients had significantly lower BMD than controls at the lumbar spine (P< 0.01) and neck of femur (P< 0.05).

Andress et al.[22] also found significant declines in the femoral neck BMDs (1.8% annualized loss) in patients taking phenytoin sodium for 19 months. Feldkamp et al.[15] observed that BMD in the lumbar spine was significantly lower in patients who were taking phenytoin as compared to age- and sex-matched controls.

Kothari et al.[23] also reported that patients taking phenytoin had low femoral neck and spine T-score compared to age-matched controls, however, low BMD had no correlation with other markers of bone metabolism.


  Conclusions Top


We observed changes in BMD at the end of 1 year of treatment with phenytoin sodium. It was statistically significant at lower end of radius. This decrease in the BMD occurs even though there is no significant decline in the levels of 25-OH-Vitamin D3 or PTH levels. We recommend that the patients of epilepsy should have a study of BMD and bone metabolism parameters during the course of disease, especially those who require life-long medication and those patients who have low BMD be treated with agents that stimulate bone formation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: When to test and how to treat. Mayo Clin Proc 2010;85:752-7.  Back to cited text no. 13
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Välimäki MJ, Tiihonen M, Laitinen K, Tähtelä R, Kärkkäinen M, Lamberg-Allardt C, 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;9:631-7.  Back to cited text no. 16
    
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Ensrud KE, Walczak TS, Blackwell T, Ensrud ER, Bowman PJ, Stone KL. Antiepileptic drug use increases rates of bone loss in older women: A prospective study. Neurology 2004;62:2051-7.  Back to cited text no. 20
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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