MONTREAL — Children with epilepsy who are treated with a ketogenic diet (KD) accrue bone mass at a slower rate than their age-matched peers, Australian researchers reported here.
"The findings from this study will inform development of guidelines for bone surveillance in this high-risk group of children to minimize potential negative long-term health consequences of the ketogenic diet," senior investigator Mark Mackay, MD, a pediatric neurologist from Royal Children's Hospital in Melbourne, Australia, told Medscape Medical News.
He presented the findings at the 30th International Epilepsy Congress (IEC).
"In 5 years, this is only the second longitudinal study of the effects of the KD on bone health in growing children, and is therefore an important confirmatory study," said Christina Bergqvist, MD, when asked to comment on the findings.
Dr. Bergqvist, associate professor of neurology and pediatrics at the Children's Hospital of Philadelphia, was not involved in the Australian study but was lead author of the first study on the subject, which found progressive loss of bone mineral content (BMC) of both spine and whole body associated with the KD ( Am J Clin Nutr 2008;88:1678-84).
Dr. Mackay's new prospective, longitudinal study included 29 children (52% female; median age, 6.4 years) who followed a KD for the treatment of epilepsy.
The mean duration of the diet was 2.1 years, ranging from 6 months to 6.5 years, and all children were routinely supplemented with elemental calcium and vitamin D3.
Lumbar spine dual-energy X-ray absorptiometry (DEXA) was performed at baseline and then every 6 months, and areal bone mineral density (BMD g/cm2) Z scores, corrected for bone age, were determined using normative data, he reported.
Biochemical parameters assessed at baseline and every 3 months included the following: serum calcium, phosphate, 25-hydroxy vitamin D, and parathyroid hormone; bone turnover markers, including alkaline phosphatase (ALP) and osteocalcin; and urine calcium/creatinine ratio.
At baseline, median bone mineral density (BMD) Z score was -0.99 for the group, but, as expected, baseline mobility was associated with baseline BMD.
Patients with normal baseline mobility (n = 11) had a median BMD Z of -0.125, whereas for those with limited mobility (n=18), it was -1.820, he reported.
"Children with refractory epilepsy referred for consideration of the ketogenic diet are usually on multiple AEDs [antiepileptic drugs], and there is increasing evidence in adults that AEDs are associated with increased fracture risk," he told Medscape Medical News. Additionally, he said "many of the children we treat have comorbid physical disability which also places them at risk of poor bone health, due to factors including decreased weight bearing, physical activity, and sunlight exposure, which is important for vitamin D production."
At the end of the study, participants demonstrated an average BMD decrease of 0.1756 Z units per year, with no correlation between change in BMD and ambulatory status. In fully mobile patients, BMD declined at a rate of 0.28 standard deviations (SD) per year compared with 0.04 SD per year in patients with limited mobility.
Biochemical markers showed that mean ALP levels were in the normal range, whereas mean serum osteocalcin levels were elevated (26.5 nmol/L). Additionally, mean urine calcium/creatine levels were elevated (0.77), but only 1 patient developed renal calculi, and 1 child suffered a long bone fracture.
"The ketogenic diet induces a state of ketoacidosis through metabolism of fat," explained Dr. Mackay. The high fat, low carbohydrate and protein diet is "extremely restrictive," with a very limited intake of dairy products, "and the body's natural mechanism to maintain neutral pH is to mobilize calcium from bones to buffer excess acid."
"Childhood and adolescence are critical periods for the normal accrual of bone mass. The bone that is laid down needs to last that person for the rest of their life. Therefore, any intervention that affects accrual of bone can have long-lasting health consequences for the child," added Dr. Mackay.
Commenting on the study, Dr. Bergqvist said that the KD is an effective treatment for epilepsy and has been used increasingly over the past 20 years.
"There are many positive effects of the KD, including reduced seizures, with up to 20% of patients becoming seizure free in short-term efficacy studies," she noted. Additionally, antiepileptic drug use can often be reduced by about half, she said. "Because of these positive effects, the duration of KD treatment now often exceeds the initially recommended 3 years. We therefore need to be aware of the side effects associated with the KD and try to prevent them when possible."
She said the Australian study is the first to report markers of bone turnover with the KD. "Osteocalcin measurements were elevated, indicating increased turnover/metabolic rate of the bone as one of the proposed mechanisms for KD-induced osteopenia."
Dr. Bergqvist recently reported that some other side effects of the KD include hyperlipidemia, nephrolithiasis, gastrointestinal dysfunction, and growth failure ( Epilepsy Res 2012;100:261-6).
She said Dr. Mackay's finding of no correlation between ambulatory status and rate of bone loss is surprisingly different from her own.
"In our study, we found ambulatory status, body mass index, and age to be strong positive predictors of BMC — that is, it was protective of bone health."
She agreed with Dr. Mackay that bone health should not be ignored in children with intractable epilepsy. "Neurologists need to be aware and screen their patients for this problem, which may be exacerbated by not only antiepileptic drugs but also by dietary treatments. Screening with DEXA in any child on multiple AEDs with intractable epilepsy is reasonable. At our center, we follow the KD children with abnormal results yearly, and biyearly if normal. Vitamin D and calcium supplementation also need to be maximized, along with weight bearing for optimal effect on the growing skeleton."
Partial funding support for Dr. Mackay's study was provided by a Pfizer Australia Neurosciences Research Grant.
30th International Epilepsy Congress (IEC). Abstract 005. Presented June 24, 2013.
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