Cerebral palsy (CP) is defined as a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to no progressive disturbances that occurred in the developing fetal or infant brain, with a prevalence rate of 2.11 per 1,000 people^1,2). The severity of CP patients can be classified by the gross motor function classification system (GMFCS), and the higher the stage is, the lower the bone density of patients³⁾. Although a study claims that the single factor of GMFCS has no correlation with fracture⁴⁾, a low bone density is the most direct indicator of bone metabolism inhibition, and can be the main target of intravenous bisphosphonate treatment⁵⁾.

In addition, CP patients have an epilepsy incidence of 15%–55%, which is much higher than that of general population⁶⁾. Among antiepileptic drugs (AEDs), the cytochrome P450 enzyme-inducing AEDs and valproate, which is one of the enzyme-inhibiting AEDs cause hypocalcemia, elevate parathyroid hormone (PTH), and increase bone turnover, eventually leading to secondary osteoporosis. They act as a high risk factor for fracture^7,8,9). Moreover, CP patients have risk factors for osteopenia, such as less sunlight exposure, immobility and spasticity¹⁰⁾.

Bisphosphonate, pyrophosphate analogue, directly reduces bone resorption by decreasing the activity of osteoclasts, inhibiting recruitment of cells, increasing apoptosis, and it indirectly suppresses osteoclasts by increasing the activity of osteoblasts¹¹⁾. Pamidronate, which is an intravenous bisphosphonate, is an effective and safe treatment that increases the bone mineral density (BMD) in osteopenia of pediatric CP patients⁵⁾. However, no clear treatment guidelines are available on the optimal dosage or the duration of use of pamidronate in quadriplegic children with CP.

In this study, we aimed to evaluate the efficacy of low-dose of cyclic IV pamidronate treatment on pediatric osteoporosis with CP GMFCS level V.

This study was conducted between January 2005 and June 2017 on children with osteoporosis who had quadriplegic CP of GMFCS level V and AEDs treatment in one tertiary hospital. Osteoporosis was defined as less than BMD z score -2¹²⁾.

Pamidronate disodium (Panorin, Hanlim Pharm Co., Seoul, Korea) was diluted in 250 mL of isotonic saline and administered intravenously in cycles of 2 days at a dose of 0.5–1.0 mg/kg per infusion cycle given 3–4 months. Initial doses started at 0.5 mg/kg in patients with poor underlying diseases such as intractable epilepsy and chronic lung diseases. Some patients could start at 0.75 mg/kg considering their general condition. The duration of treatment was 6–15 months. All patients received a daily supplementation of calcium and vitamin D at least 4 weeks before initiation of pamidronate therapy and maintained oral supplemental medication. Dosages of calcium and vitamin D were given appropriately for age and weight.

Serum calcium, phosphate, alkaline phosphatase (ALP), creatinine, serum 25-hydroxyvitamin D (25(OH)D), PTH, and osteocalcin levels were measured at baseline and before each infusion cycle. The urinary excretion of calcium and of N-telopeptide collagen cross-links (NTx) were measured on a urine sample and calcium/creatinine ratio was determined at each cycle. NTx was measured by enzyme linked immunosorbent assay. Renal ultrasound and plain x-ray of the KUB (kidneys, ureters, and bladder) were performed at baseline.

BMDs of the lumbar spine (LS) and femur neck were measured at 6–12 month intervals using dual-energy x-ray bone densitometry (General Electric Medical Systems Lunar, Madison, WI, USA). The femoral neck BMD was measured only 4 patients because of deformation of femur related to severe muscle contracture. Simple x-ray films of spine (anteroposterior and lateral views) were obtained at 6-month intervals. All available radiographs during treatment were assessed for evidence of fractures.

This study was based on the retrospective medical records review. This study was approved by the Institutional Review Board of Inha University Hospital (IUH-IRB 2017-03-016-002).

Descriptive statistics are indicated as the mean±standard deviation. The Wilcoxon signed-rank test was used to compare the changes in all indicators before and after the pamidronate treatment. IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA) was used for statistical analysis.

The total number of patients was 10 subjects and mean age was 10.9±5.76 years (range, 2–18 years). The most common underlying disease was perinatal brain injuries (40%, 4 of 10), others were Lennox-Gastaut syndrome, Menkes disease, and Dandy-Walker syndrome. The dosage of the pamidronate was adjusted depending on the patient's general health condition and the change of BMD. Overall, the children received a mean dosage of 4.49±2.22 mg/kg/yr (Table 1).

This study demonstrated that the administration of low-dose pamidronate in severe CP patients was effective in increasing the BMD. Regarding the appropriate dose of pamidronate, many studies have introduced various doses and treatment periods (Table 3), but no definition of “low dose” is available^{5,14,15,16,17)}. On the basis of the studies published so far, Plotkin et al. reported that using the dose of 0.75 mg/kg/day for 2 consecutive days every 16 weeks (4.5 mg/kg/yr), which is smaller than the frequently used typical dose of 1 mg/kg/day for 3 consecutive days every 12–16 weeks (9–12 mg/kg/yr), was effective in increasing the BMD of pediatric CP patients of GMFCS levels IV–V. In addition, the low-dose administration could be advantageous in various aspects by citing a previous study on administrating pamidronate to osteogenesis imperfecta patients^14,18).

The fracture incidence in pediatric CP patients has been reported to be 4% per year, and the probability of refracture in patients with a previous fracture was 7% per year⁴⁾. Although Bachrach et al.¹⁹⁾ reported that fracture incidence in pediatric CP patients certainly decreased after pamidronate treatment for 1 year, refracture occurred after discontinuation of treatment in some cases. The metaphyseal lines that are generated like annual rings in growing bones by the cyclic administration of pamidronate are called zebra lines²⁰⁾ or pamidronate bands. The parts between these bands where the density decreases could act as a stress riser and cause refractures. To prevent this possibility, low-dose treatment was suggested²¹⁾. In this study, the average cumulative dose was 4.49±2.22 mg/kg/yr, which is lower than the general dose (Table 3). In terms of the welfare of patient with chronic illness, the low-dose treatment has a greater significance compared to the general dose treatment because it can decrease adverse reactions and improve quality of life while preventing fracture. The optimal dose of pamidronate can be defined by achieving the effects as increased BMD while minimizing the adverse reactions.

In the patient 6, the LS BMD improved after a 1-year treatment, but the BMD z score of the femur remained at -4.0. After a 1-year additional treatment, z score of the LS BMD increased further to 0.8, but the BMD z score of the femur was -3.8. Although the patient had no fracture before, because the femur is the most frequent site of fracture in CP²²⁾, a closer assessment of the therapeutic effect and the continuous monitoring of the patient are required.

Among the biochemical markers of bone metabolism, ALP decreased significantly. Bone-specific ALP is the important bone turnover marker of bone formation; unfortunately, it was not measured in this study. Urine NTx clearly decreased in 7 of 8 subjects, but patient 10 showed an increase in urine NTx even though her BMD increased. No statistically significant result could be obtained (P=0.069). Moreover, no consistent change patterns were observed in other bone markers, such as calcium, phosphorus, PTH, and osteocalcin (Table 2).

Most patients showed nonspecific systemic symptoms from the first infusion of pamidronate, but their symptoms improved in one to 2 days with antipyretic analgesics (e.g., acetaminophen). All the patients were taking calcium before treatment, and their doses were increased by 1.5–2.0 times during hospitalization to prevent against symptomatic hypocalcemia. A temporary decreasing pattern for calcium immediately after treatment was observed frequently in each cycle, but the symptomatic or continuous hypocalcemia did not appear, and no significant adverse reactions were observed.

Bisphosphonate is known to accumulate in bone and act in the body for a long time²³⁾. In addition, some studies have reported improved bone density in a single cycle of treatment and in most cases BMD could be expected to improve within a year^14,24). Considering the duration of action of the drug in the body, the timing of drug withdrawal can be determined by monitoring BMD within the treatment period of 1 to 2 years.

The study for low-dose therapy on severe CP children has been reported outside Korea, but there were no similar studies in Korea thus far¹⁴⁾. There are 4 limitations in this study; the small sample of patients, the omission of femur BMD measurement, and the fact that the end point of treatment and the number of infusion cycle were not exactly unified. Nevertheless, this study emphasized the efficacy of low-dose pamidronate treatment in severe pediatric CP group, and proposed a direction for practical treatment of pamidronate and contributes to improving the quality of life for severe CP children. Appropriate guidelines for pamidronate treatment for this group should be developed through a large-scale study.