Response to: Zoledronate Increases Bone Mineral Density in Nonambulant Children With Cerebral Palsy: A Randomized, Controlled Trial

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We read with great interest the article by Granild-Jensen et al (1), which examines bone health in children with cerebral palsy (CP). CP is the most common cause of motor impairment in childhood and is associated with low bone mass and high fracture risk. Factors that lead to poor bone quality include immobility, suboptimal nutrition, and vitamin D deficiency, anticonvulsant use, delayed puberty, and growth hormone deficiency (2). Fractures can occur with minimal trauma: the distal femur is a common site of fracture in those who require physical assistance or powered mobility in most or all settings, corresponding to a Gross Motor Function Classification Scale of IV or V. There have been no previous randomized control trials assessing the use of zoledronate (ZOL) in children with CP, but 2 randomized trials of bisphosphonates have been published in this group. Henderson et al (3) randomized 14 children to receive pamidronate every 3 months for 1 year or placebo. Significant improvements in areal bone mineral density (aBMD) at the lumbar spine and lateral distal femur at 18 months was demonstrated in children who received pamidronate treatment. In the second study, Iwasaki et al compared the use of alfacalcidol monotherapy with alfacalcidol and risedronate polytherapy in 20 children: children treated with combined alfacalcidol and risedronate had a significant increase in BMD compared with those who received alfacalcidol alone (4). The lateral distal femur or the total body is the site of choice for bone density measurement using DXA in this population. Measurement of aBMD at the lateral distal femur) has been devised to circumvent difficulties with positioning, metallic hardware, hip dislocation, etc., in children with cerebral palsy. There are established reference ranges in children (5), and correlation between Z-scores at the distal femur and fracture history in a mixed cohort of children with CP or muscular dystrophy (6) has been established. ZOL is a potent third-generation bisphosphonate that is usually given twice a year at a dose of 0.05 mg/kg in children. Given its long half-life, it is an attractive therapeutic option for children with CP necessitating less hospital visits. The study by Granild-Jensen et al randomized 24 nonambulant children with CP 1:1 to 2 doses of ZOL or placebo 6 months apart. It is commendable that Granild-Jensen et al undertook this study in this population. There are significant challenges conducting randomized control trials in CP, including recruitment, regular study visits, and difficulties with positioning for dual-energy x-ray absorptiometry. Although the study sample is small, its results provides important data and insights in this underserved population. ZOL was shown to increase BMD at both the lumbar spine and the lateral distal femur. Increases in Z-score were between 0.3 and 1.6 SD whereas Z scores remained stable or declined in the placebo group. Bone turnover markers were suppressed following ZOL as expected, with small increases in serum creatinine and reductions in serum calcium and phosphate, which all returned to baseline. The high rates of acute phase reaction in the ZOL group with the first dose in this study is consistent with previous reports (7) and should be discussed with patients and their caregivers prior to ZOL infusions. Higher rates of acute-phase reactions have been associated with low vitamin D levels, and routine measurement of calcium and vitamin D with appropriate replacement should be instituted prior to the infusion. We have also observed this phenomenon of severe acute-phase reaction in young adults with CP, and would recommend the use of an oral corticosteroid given prior to the first infusion. Oral corticosteroid has been demonstrated to be effective in reducing acute phase reaction symptoms of headache, nausea, muscle and joint pain, and feverishness in a general adult population receiving their first dose of ZOL (8). This study provides much needed evidence on the use of ZOL in children with CP and can be extrapolated to children with other neuromuscular disabilities. What is to be determined now is when to commence treatment and the duration of treatment. Fracture outcomes are also lacking in studies of children and adults with CP treated with bisphosphonates and are likely to be difficult to attain given the small numbers of participants in studies in this field. The authors have nothing to disclose. bone mineral density cerebral palsy zoledronate

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