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Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet ^1,2,3,4

¹ From the Divisions of Neurology (AGCB), and Gastroenterology, Hepatology, and Nutrition (JIS, VAS, and BSZ), The Children's Hospital of Philadelphia, Department of Pediatrics and Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH.

³ Supported by NIH (K-23 RR16074, UL1-RR-024134 NCRR), the Clinical Translational Science Award (Children's Hospital of Philadelphia and University of Pennsylvania), the Pediatric Regional Epilepsy Program, the Catherine Brown Foundation, and the Nutrition Center.

⁴ Reprints not available. Address correspondence to AGC Bergqvist, M.D., Division of Neurology, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, CHOP North, Room 1591, Philadelphia, PA 19104. Email: bergqvist{at}email.chop.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: The ketogenic diet (KD) is a high-fat, low-carbohydrate, and protein diet that effectively treats intractable epilepsy (IE).

Objective: The purpose of this study was to measure the change in bone mineral content (BMC) in children with IE treated with the KD for 15 mo.

Design: Prepubertal children 5 y of age with IE were eligible. A 4:1 ketogenic diet was maintained for 15 mo, and whole-body and spine BMCs were measured with dual-energy X-ray absorptiometry. Z scores were generated by comparing the children with IE with a cohort of 847 healthy children. Other measurements included demographics, anthropometry, serum 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone, electrolytes, and dietary intake. All measurements were performed at baseline and at 3, 6, 12, and 15 mo. Longitudinal mixed effects models were used to analyze change in BMC over time.

Results: Twenty-five children (9 girls, 16 boys) with IE [age ( ± SD): 7.3 ± 1.9 y] participated. Growth and bone health status were suboptimal as were serum 25-OHD concentrations and dietary intake of calcium and vitamin D. Whole-body and spine BMC-for-age both declined by 0.6 z score/y and whole-body and spine BMC-for-height declined 0.7 z score/y and 0.4 z score/y, respectively. Height declined 0.5 z score/y. Body mass index (BMI; in kg/m²) z score, age, and ambulation were positive predictors of BMC, which declined sharply over 15 mo of KD treatment.

Conclusion: Bone health in children with IE was poor, particularly for younger nonambulatory children with low BMI status. The KD resulted in progressive loss of BMC. The mechanism is unclear. Further studies are needed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Epilepsy and osteoporosis are national health problems. Intractable epilepsy (IE) occurs in 20–30% of all patients with epilepsy, and this population is recognized as being at high risk of side effects from both seizures and treatments. Older antiepileptic drugs (AEDs) can adversely affect bone health by directly affecting the cells of bone formation and absorption or by secondary effects on calcium and vitamin D metabolism (1). In general, the newer AEDs developed since 1990 have better side effect profiles; however, their effects on bone health in growing children have not been well established.

The ketogenic diet (KD), a high-fat, low-carbohydrate, and protein diet, continues to show excellent efficacy in the IE population. On the KD, 50–75% of patients attain >50% seizure reduction and 15–20% become seizure free (2, 3). Responders to the KD previously treated with many AEDs have a high chance of reducing the number of AEDs needed while on the KD treatment. Half are able to discontinue all AEDs and continue treatment with the KD alone. Serum vitamin D concentrations improve while on the KD, as a result of supplementation (4). Despite bone-sparing effects of improved vitamin D status, some data indicate that use of the KD treatment may lead to growth failure, alteration in body composition, and osteopenia in some patients (5-8). The purpose of this pilot study was to evaluate the pattern of change in bone health in children with IE during 15 mo of exposure to the KD compared with healthy children.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Prepubertal children 1–14 y of age with 1 seizures per 28 d and who failed 3 AEDs were eligible for this 2-phase, 15-mo longitudinal study of growth and nutritional effects of the KD. Prescribed steroid medication was discontinued 3 mo before enrollment. Children with metabolic disorders, genetic disorders known to affect growth, or known or suspected degenerative neurologic disorders were excluded. All subjects were recruited from the Pediatric Regional Epilepsy Program at the Children's Hospital of Philadelphia (CHOP).

Reference data for bone mineral content
Healthy children 5–21 y of age enrolled in the Reference Project on Skeletal Mineralization at CHOP served as the reference group for bone mineral content (BMC). Data from this study were used to create reference percentiles to generate sex- and race-specific z scores for BMC for the children on the KD. Children who had chronic medical conditions or were taking medications known to affect growth, sexual development, nutritional status, or dietary intake were excluded.

Both protocols were approved by the CHOP Institutional Review Board. Informed consent was obtained from a parent or guardian, and assent was given by children cognitively able to complete the process.

Protocol
The first phase of the study (baseline to 3 mo) tested 2 KD initiation protocols [a traditional fasting initiation (FAST-KD) compared with a gradual initiation without fasting (GRAD-KD) protocol], and the results were published (9). At 3 mo children who responded to the KD, defined as a 50% reduction in their target seizure frequency, were eligible to continue into the second phase study (3–15 mo) to evaluate 2 approaches to managing caloric intake and growth on the KD. They were randomly assigned to a EUCAL-KD (designed to support weight gain at a normal velocity according to the 3-mo KD weight-z score) and a HYPOCAL-KD (restrict caloric intake to maintain the 3-mo weight for the next 12 mo). The goal of the second phase was to test the effect of 2 approaches to maintenance KD on bone health, growth, nutritional status, and seizures. The bone health and growth variables are presented.

Children in the study were prescribed a 4:1 (by weight fat:carbohydrate and protein) KD. Lower ratios were occasionally used to meet protein needs (10). In general, the KD was provided as 3 meals, with 1 snack for children < 4 y. All children were supplemented with one multivitamin with minerals (at a vitamin D concentration approximately recommended for age) (11) and additional calcium and phosphorous at recommended intake for age (11). Acidosis was treated with an oral alkalinizing agent (Bicitra; Ortho McNeil, Raritan, NJ), and, when severe or nonresponsive to oral treatment, medications such as topiramate and zonisamide that may worsen acidosis were discontinued. In general, AEDs were maintained for the first 3 mo of the study (phase 1) after which time weaning of AEDs was considered. The AEDs were weaned over 1–2 mo as tolerated. All protocol measurements were completed at baseline and at 3, 6, 12, and 15 mo of the KD treatment.

Dietary intake assessment
Dietary intake before initiation of the KD (baseline) and then at 3, 6, 12, and 15 mo while on KD therapy was assessed with the use of 3-d weighed food records. Families were provided a calibrated food scale (CS-200; OHaus Corporation, Pinebrook, NJ) accurate to 0.1 g and instructions for weighing and recording everything the child consumed. Dietary intake data were analyzed with the use of the NUTRITION DATA SYSTEM FOR RESEARCH (software version 2005; Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN). With the use of dietary reference intakes (11-13) adequate intake (AI) of vitamin D and calcium and recommended dietary allowances for the intakes of vitamin C, magnesium, phosphorus, and zinc were calculated.

Serum vitamin D, parathyroid hormone, and electrolytes
At baseline, a fasting blood sample was drawn between 0730 and 1000 for serum 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, calcium, phosphorus, magnesium, and intact parathyroid hormone (PTH). Vitamin D concentrations were determined with the use of a radioiodinated tracer technique (14), and PTH concentrations were determined with the use of the radioiodinated tracer (Diasorin, Stillwater, MN). Serum electrolytes, calcium, magnesium, phosphorus, and bicarbonate were obtained simultaneously and measured in the CHOP clinical laboratory with the use of standard techniques and laboratory reference values.

Growth and maturation assessments
For all children, height was assessed to 0.1 cm with the use of a digital stadiometer (Holtain, Crymych, United Kingdom), and weight was assessed to 0.1 kg with the use of a digital electronic scale (Scaltronix, White Plains, NY) as described by Lohman et al (15), and body mass index (BMI; in kg/m²) was calculated. All measurements were obtained in triplicate, and the mean was used in the analysis. Height, weight, and BMI were compared with the Centers for Disease Control and Prevention 2000 reference standards (16), and age- and sex-specific z scores were calculated. Children with IE were determined to be prepubertal based on physician examination (17), and bone age was determined at baseline (18) with relative bone age in years calculated as bone age minus chronologic age.

Whole-body and spine bone assessments
Dual-energy X-ray absorptiometry (DEXA) scans (Hologic, Bedford, MA) of the whole body and lumbar spine (L1–L4) were obtained with the use of a fan beam in the array mode (Hologic software version 12.3). Quality control scans with the use of a spine phantom were obtained daily: the in vitro and in vivo CVs were <0.6% and <1%, respectively. For subjects with the vagus nerve stimulator, the measured values for the left rib section of the whole-body scan were excluded, and interpolated values from the right side rib section of the body were used to compute the whole-body BMC (WBBMC) value.

WBBMC (in g) and lumbar spine BMC (LSBMC) were the DEXA outcome of interest. In children, BMC is the preferred outcome measure because bone expansion and the increase in BMC occur at different rates during childhood (19, 20). Consequently, bone mineral density (BMD), calculated as BMC/bone area, is not an appropriate ratio to use in growing children. To combine DEXA results for children of different ages and to account for the growth-related changes in BMC, z scores for BMC-for-age and BMC-for-height were calculated based on the healthy reference sample. Because of known sex and racial differences (black compared with non-black) in bone measures (21-24), z scores were sex and race specific.

Statistical analysis
Race- and sex-specific z scores for WBBMC-for-age, LSBMC-for-age, WBBMC-for-height, and LSBMC-for-height were based on the sex- and race-specific (black compared with non-black) distributions of BMC in the healthy reference sample (n = 847) with the use of the LMS statistical method (25). Children with IE of the appropriate age [(5 y) + height (103 cm)] had z scores calculated. The LMS method characterizes the distribution of BMC values and estimates 3 measures as a function of age (or height), the power (L) based on a Box-Cox transformation, the median (M), and the SD (S), needed to calculate z scores. Z scores were calculated as z = [(BMC/M)^L –1]/LS, where BMC was the measured spine or WBBMC, and the values for L, M, and S were determined by the child's sex, race, and age (or height). BMC-for-age and BMC-for-height z scores were calculated for the baseline and 3-, 6-, 12-, and 15-mo measurements.

Multiple regression analysis was used to determine significant predictors of WBBMC- and LSBMC-for-age and BMC-for-height z scores at baseline. In all models, independent predictors of BMC status were age, sex, number of AEDs taken at KD initiation, type of seizure (generalized compared with partial), ambulation status, cerebral palsy (CP) comorbidity, dietary intake, and serum concentrations of selected nutrients known to affect bone health.

Longitudinal analyses of BMC status were performed with the use of the longitudinal mixed effects (LME) analysis procedure (XTREG) in STATA (version 9.0; Stata Corp, College Station, TX). The LME model recognizes that multiple observations from the same subject are dependent, so the regression coefficients vary across subjects and are considered to be random. Fixed variables, such as sex or CP, and random variables, such as growth status, can be considered simultaneously. Interaction terms were tested to identify potential factors that might affect the rate of change in BMC z score. For example, a significant sex x time interaction term would indicate that males and females had a different rate of change in BMC z score over time.

Basic models were tested separately for WBBMC- and LSBMC-for-age and BMC-for-height z scores for significant changes in these measures over time. Additional variables were added to the models to determine whether, age, sex, height and BMI z scores, ambulation status, FAST-KD compared with GRAD-KD initiation of the KD, and random assignment to the EUCAL-KD compared with the HYPOCAL-KD protocol at 3 mo were significant predictors of the change in BMC over time. Final models were selected on the basis of statistical significance and maximum R² values. Only final models are shown.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Of the 48 enrolled children with IE, a subsample of 25 (9 girls, 16 boys) with evaluable DEXA results were included in this report. The clinical, nutritional, and biochemical characteristics at baseline are presented in Table 1. Children with IE had failed an average of 8 AEDs and were treated with polytherapy at the time the KD was started. The most commonly used AED at the time the KD was started were lamotrigine (n = 13), topiramate (n = 9), zonisamide (n = 7), valproic acid (n = 6), chlorazepate (n = 5), levetiracetam (n = 4), phenytoin (n = 4), and oxcarbazepine (n = 2). The seizures were frequent with an even split between generalized and partial seizures. Approximately one-third had CP, two-thirds had moderate-to-severe mental retardation, but 84% were able to walk. Growth status was suboptimal (height and weight z scores <0); however, skeletal maturation was not delayed. At baseline no child was receiving dietary supplements. Dietary intakes of calcium and vitamin D were low in the group as a whole, with 63% and 54%, respectively, having intakes <100% AI. Serum vitamin D concentrations were low, with 73% having suboptimal (<32 ng/mL) concentrations at baseline. Intact PTH and serum calcium, magnesium, potassium, and bicarbonate were within the laboratory reference ranges for age.

Table 2

Table 3

Table 4

Results from LME models describing significant predictors of spine and WBBMC are presented in Table 5. Children with IE randomly assigned to the FAST-KD compared with the GRAD-KD initiation or to the EUCAL-KD compared with HYPOCAL-KD maintenance group at 3 mo showed no significant differences in longitudinal BMC trends. Therefore, all groups were combined for this analysis. Included in the prediction models were time (annual change), BMI z score, ambulation status, and the ambulation status x time interaction term. For WBBMC-for age and LSBMC-for age z scores, height z score was added to the models, whereas for WBBMC-for height and LSBMC-for-height z scores, age was added to the models. In all models, BMI z score and ambulation status were significant positive predictors of BMC. For LSBMC-for-age z score, children with better height status had significantly higher BMC, and also the ambulation status x time interaction was significant, indicating that the drop in BMC over time was significantly greater for children who were walking than for those who were nonambulatory. Height status was also significantly positively associated with WBBMC-for-age z score. Height, BMI ambulation status, and time explained 67% and 70% of the variance in WBBMC-for-age and LSBMC-for-age z scores, respectively. In addition to BMI and ambulation status, age was a significant and positive predictor of WBBMC-for-height z score: older children had higher BMC. After controlling for these variables, a steep and significant decline (P < 0.001) was observed in BMC status over time for both LSBMC-for-height z score (–0.86 z score annual change) and WBBMC-for-height z score (–0.75 z score annual change). Time, BMI status, ambulation status, and age accounted for 44% and 49% of the variance in WBBMC-for-height and LSBMC-for-height z scores, respectively. Sex, seizure type and frequency, number of AEDs, having CP as a comorbidity, dietary intake, or serum nutrient concentrations did not significantly contribute to these models. By 15 mo, the AED use had been dramatically reduced to 1.0 ± 0.94 AED and 36% were treated with the KD only. No subjects used valproic acid, and lamotrigine (n = 4) was the only AED used by >2 subjects. Because the AED use was too heterogeneous and limited, we were not able to use the AED as a predictor of BMC in the longitudinal models.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Hahn et al (8) first described KD-associated osteopenia in 1979. Five children treated with the KD and AEDs for an average of 2.5 y had low serum vitamin D, elevated serum PTH, and low BMD (single-photon absorptiometry). They postulated that the KD adversely affected bone health secondary to chronic acidosis, which removes bone mineral for buffering capacity, and that acidosis further interfered with conversion of serum 25-OHD to 1,25-dihydroxyvitamin D. In contrast, Bertoli et al (31) found no significant changes in BMC in their retrospective report of 7 children with 6-mo exposure to KD.

This study describes progressive loss of BMC in both the whole body and spine in children with IE treated with KD. These findings persisted after correction for both age and height. The decline in BMC occurred despite prescribed vitamin D and calcium supplementation and with a reduction in the number of AEDs used.

BMC increases with age and body size in growing children, and it also differs by sex and race. With the use of data from a healthy reference group, we have z scores for BMC relative to age and height for boys and girls and for black compared with non-black children. The progressive growth failure of children with IE while on the KD makes it difficult to interpret DEXA measures that are usually presented relative to only age and sex. Children with IE have significantly compromised bone health before initiation of the KD. While on the KD, BMC z scores declined further, even when accounting for linear growth failure. The use of BMC-for-height z scores and BMC-for-age z scores adjusted for height z score in our LME models confirmed the loss of BMC of the spine and whole body relative to both age and body size.

We previously showed that children with IE had poor dietary intake of vitamin D and calcium and low serum 25-OHD concentrations before the KD (32). Serum 25-OHD concentrations were deficient (<11 ng/dL) in 4% and insufficient (<32 ng/dL) in 55% of the children with IE before the KD (4), similar to otherwise healthy children in the same region (33). The KD food supply is deficient in vitamin D and calcium, and the protocol requires supplementation with a multivitamin (200% AI vitamin D and 500 mg elemental calcium) and additional calcium to achieve the AI (34). Vitamin D dietary intake and serum concentrations improved during the first 3 mo of the KD and then remained stable between 3 and 15 mo, suggesting that the KD-related BMC loss is less likely a result of a vitamin D–related mechanism. Total intake of calcium remained stable while on the KD (4), because children were adequately supplemented. In some KD treatment programs calcium intake is restricted, because of concerns about kidney stone formation, which may occur in 5–10% of children on the KD (35, 36). To support the BMC in growing children, higher calcium supplementation may be needed during treatment with the KD.

Acidosis may play a significant role in the mechanism of KD BMC loss (37). The ketone bodies are acidic, yet blood pH in children on the KD is usually normal (38). The serum bicarbonate is often lower than normal, indicating an insufficient production or increased need of the bicarbonate ion associated with the KD. The acidic environment of the KD may be preventing the normal accumulation of BMC. Alkalinizing agents (Bicitra and Polycitra LS; Ortho McNeil) are often needed with the KD, particularly with use of AEDs that have acidic properties (ie, topiramate and zonisamide) (9, 35). Acidosis may also have an effect on linear growth (39), and growth faltering was reported with both AEDs that cause acidosis (40) and with the KD (5-7). In this study, linear growth velocity was particularly affected, which is primarily regulated by growth hormone and insulin-like growth factor I. Insulin-like growth factor I is also instrumental in bone formation (41) and may be suppressed by a KD (42). Thus, the failure to accrue bone mineral on the KD is likely multi-factorial and may include direct or indirect efforts of disruption of the growth hormone axis.

Long-term adverse effects of the KD may be overlooked or understated both because the usual treatment period is short, ie, 2–3 y, and because some adverse effects may be reversible. However, some children remain on the KD much longer. Groesbeck et al (43), in a retrospectively report of 28 children treated with the KD for 6–12 y, found that 21% experienced fractures. The median time to the first fracture occurred after 1.5 y of KD treatment, and 14% had a history of multiple fractures.

In summary, our longitudinal study indicated that at baseline, children with refractory epilepsy had poor bone health and suboptimal growth status. Progressive loss of BMC resulted in osteopenia and osteoporosis that occurred with KD treatment despite improved serum vitamin D concentrations. Most at risk were younger nonambulatory children with low BMI status. Further study is needed to determine the mechanisms of action of the KD on bone health in children. Current practices for supplementation of vitamin D and calcium were not sufficient to prevent BMC loss and should be reassessed. Increased supplementation or interventional studies that use alkalinizing agents or newer treatments such as low-magnitude mechanical stimulator would be of great interest and may effectively prevent or treat the loss of BMC in children treated with the KD (44-46).

	ACKNOWLEDGMENTS

 
We thank all the children, parents, and other care providers for their participation and cooperation in this research study. We also thank the CHOP Ketogenic Diet Team, CTSA/Clinical Translational Research Center, and Nutrition and Growth Lab staff for their dedication and commitment to this demanding project.

The author's responsibilities were as follows—AGCB, VAS, and BSZ: designed the study; AGCB: collected the data; BSZ and JIS: completed the statistical analyses and interpretation. All authors wrote the manuscript. None of the authors had a personal or financial conflict of interest.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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