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· This retrospective study assessed intravenous pamidronate therapy's efficacy and safety in nonambulatory pediatric patients with low bone density. Increasing the average dose in subsequent cycles significantly enhanced its effectiveness, emphasizing the crucial role of optimizing dosage.
Introduction
Osteoporosis is a bone disorder characterized by reduced bone mass and disrupted bone structure, resulting in pathological fractures [1]. In adults, osteoporosis is commonly defined as a bone density of 2.5 standard deviations (SDs) below the mean on dual-emission x-ray absorptiometry (DXA). However, pediatric osteoporosis is diagnosed based on low bone mineral density (BMD) and the occurrence of a clinically significant fracture; pediatric assessments of osteoporosis using DXA alone are associated with overdiagnosis of pediatric osteoporosis. Low pediatric BMD is defined as a BMD z-score ≤-2.0, and clinically significant fracture is defined as a compression fracture of the spine or as 2 or more long bone fractures by 10 years of age and 3 or more long bone fractures prior to 19 years of age [2]. Osteoporosis can lead to a vicious cycle of disability, worsening osteoporosis, and recurrent fractures [1,3,4]. Once a pathological fracture occurs, daily activity is severely restricted. Insufficient weight-bearing exercise and reduced vitamin D levels due to restricted outside activities decrease bone density and cause osteopenia/osteoporosis [5,6]. Additionally, pre-existing cofactors, such as malnutrition and medications for chronic diseases, can cause osteoporosis [6]. This leads to fracture recurrence that sets off a chain of circumstances that support osteoporosis development. Nonambulatory pediatric patients are at a high risk of osteoporosis and fractures because of insufficient physical movement.
Peak bone mass (PBM) in the lumbar spine was reported to occur approximately at the ages of 33–40 years in women and 19–33 years in men. In the hip, PBM occurs at the ages of 16–19 years in women and 19–21 years in men [7]. Approximately 40%– 60% of adult bone mass accumulates in adolescence; of this amount, 25% of PBM is acquired during the 2-year period, with peak velocity of height increase [8]. The peak rate of bone mineral accretion occurs on average at 12.5 years for girls and 14.0 years for boys, and approximately 90% of PBM is accumulated by 18 years in both genders [8]. Thus, considering PBM, proper management of bone health during childhood and adolescence is important as it significantly impacts bone health throughout the lifetime [9].
Bisphosphonates are widely used in adults, and guidelines for bisphosphonate use in adults are based on abundant data that show a favorable cost-benefit ratio of the treatment [10,11]. Various bisphosphonate molecules have been developed, including pamidronate, zoledronate, and risedronate; their therapeutic effects and safety have been confirmed in adults [11]. However, relatively fewer cases of treatment in children with each of the bisphosphonate drugs have been reported. Therefore, their efficacy and safety in children are much less established than in adults. Since bisphosphonates were first suggested as a treatment for primary osteoporosis in children with osteogenesis imperfecta in 1998, these therapies have been widely used as standard therapy for children with osteoporosis and pathologic fractures [10]. Previous studies have shown that bisphosphonates increase BMD [12-16] and decrease the risk of fractures in children with low BMD [17]. Many children with pathologic fractures have experienced improved disease conditions and quality of life after bisphosphonate treatment. Thus, there is a growing consensus on the efficacy of bisphosphonate treatment for pediatric osteoporosis. However, guidelines for treating pediatric osteoporosis using bisphosphonates are limited. Additionally, more research studies into the efficacy and safety of bisphosphonate for treatment of secondary osteoporosis are required. Available data on the appropriate duration and dosage of bisphosphonate therapy in children with skeletal fragility are especially limited [18].
Therefore, we aimed to confirm the effectiveness and safety of pamidronate treatment for nonambulatory children with low BMD and to investigate the contributing factors that may affect the effectiveness of pamidronate treatment to optimize its management.
Materials and methods
1. Study population
This was a retrospective study among pediatric nonambulatory patients with low bone density who presented to the pediatric endocrinology division of Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea. Participants were recruited from January 2020 to January 2022. Eligible participants were nonambulatory patients under the age of 18 years who were rated as Gross Motor Function Classification System grade V with low bone density (BMD z-score ≤-2.0). These patients had to have received bisphosphonate therapy for at least 1 year. Of 207 pediatric patients with osteoporosis treated with pamidronate screened for participation, 175 were excluded due to incompatibility with inclusion criteria. Also, 11 failed to maintain regular BMD follow-ups and were excluded. The remaining 21 patients were enrolled sequentially during the study period. The patient data encompassed demographic data, such as height, weight, body mass index (BMI), body surface area, height standard deviation score (SDS), weight SDS, and medical history. The underlying disease responsible for immobilization and osteoporosis was obtained as was the history of fracture before and after treatment.
2. Study design
Our basic treatment protocol included pamidronate every 4 months at a 3.0 mg/kg dose. On the first day of the first treatment cycle, pamidronate administration was usually initiated at a dose of 0.5 mg/kg/day. The treatment protocol was tailored to the general conditions of the patients and the severity of their underlying diseases. In patients tolerant to 0.5 mg/kg/day of pamidronate, the dose was increased to 1 mg/kg/day. If adverse reactions such as general weakness, high fever, seizures, and hypocalcemia occurred after receiving 1 mg/kg/day, the dose or total number of treatment days per cycle was reduced. We also adjusted the interval between cycles to 3 or 4 months, depending on the patient's condition. Thus, for the participants of this study, the total dose by cycle varied from a minimum of 0.5 mg/kg/day to a maximum of 1 mg/kg/day for 3 days (3 mg/kg/cycle). The total dose in 1 year varied from a minimum of 3 mg/kg/yr to a maximum of 12 mg/kg/yr. Data on changes in BMD, occurrence of fracture, biochemical data, and adverse events after 1 year of treatment with pamidronate were collected for outcome assessment.
3. Data collection
Height was measured by a stadiometer (Harpenden Ltd., Crymych, UK) to the nearest 0.1 cm. Weight was measured using a digital scale with a precision of 0.1 kg (SECA, model 707, Vogel & Halke GmbH & Co., Hamburg, Germany). BMI was calculated as weight (kg) divided by height (m) squared. The height, weight, and BMI were presented as SDS based on the 2017 Korean National Growth Charts [19].
Biochemical tests were conducted at each hospitalization before and after pamidronate administration. Serum calcium, phosphate, and alkaline phosphatase (ALP) were measured using a Hitachi chemistry autoanalyzer 7600-110 (Hitachi Ltd., Tokyo, Japan) at the central laboratory of Severance Hospital. Serum 25-hydroxyvitamin D (25-(OH)D) levels were determined using a radioimmunoassay (DiaSorin, Inc., Stillwater, MN, USA; intraassay coefficient of variation [CV] < 4.1%, interassay CV <7.0%). The serum parathyroid hormone (PTH) concentration was measured at our hospital using a second-generation PTH assay (Elecsys PTH; Roche Diagnostics, Mannheim, Germany) using the Cobas e801 immunoassay analyzer (Roche Diagnostics). Vitamin D sufficiency (>20 ng/mL), vitamin D insufficiency (12–20 ng/mL), and vitamin D deficiency (<12 ng/mL) were defined by serum 25-(OH) D levels, according to the recent guidelines of the Endocrine Society [20]. All patients included in this study received oral supplementary calcium and vitamin D therapy according to age and weight at least 4 weeks before starting pamidronate treatment.
BMD was assessed at baseline and every year after pamidronate treatment using a DXA scanner (Hologic, Inc., Bedford, MA, USA). Posterior anterior lumbar spine (L1–4) scans were acquired in fast array mode. All scans were analyzed using Hologic software (ver. 12.3) to generate areal BMD (g/cm3) and bone mineral content (BMC) (g). Areal BMD was calculated by dividing the BMC by the bone area. The BMD z-score was obtained using the Korean reference data for children. We also calculated the height-for-age z-score (HAZ)-adjusted BMD z-score (BMDhazZ) [21].
4. Statistical analysis
All statistical analyses were performed using SAS 9.4 (SAS Inc., Cary, NC, USA) and R package ver. 3.6.3 (http://www.R-project.org). Statistical significance was confirmed when the P-value was less than 0.05. Continuous variables are presented as mean and SD. We used a paired t-test to compare BMD before and after treatment, and univariate linear regression analysis was used to investigate the factors that affected the efficacy of pamidronate treatment. A generalized estimating equations analysis was used to compare fracture incidence before and after treatment under the assumption that the incidence of fractures of the participants followed a Poisson distribution.
5. Ethical statement
This study was performed in accordance with the Declaration of Helsinki. As this was a retrospective study on data obtained during the general course of medical treatment, the need for informed consent was waived. This study was approved by the Institutional Review Board (IRB) of Yonsei University Health System (IRB No. 4-2021-1570).
Results
1. Clinical characteristics of participants
A total of 21 children, 11 boys and 10 girls, was included in this study (Table 1). The mean age of the participants on the first day of pamidronate treatment was 8.9±4.0 years (range, 3.0–16.0 years). Of the 21 children, 11 (52.4%) had intractable epilepsy, 3 (14.3%) had mitochondrial disease, 3 (14.3%) had hypoxic brain damage, 1 had GM-1 gangliosidosis, 1 had Rett syndrome, 1 had Parry-Romberg syndrome, and 1 had idiopathic cerebral palsy as their underlying diseases. Seventeen patients (81.0%) had a history of bone fracture before pamidronate treatment; 16 patients had long bone fractures and 1 patient had a spine fracture. The baseline height SDS was -1.51±2.00 (range, -5.35 to 0.96), and the baseline weight SDS was -1.72±2.23 (range, -6.04 to 3.36). The baseline lumbar spine BMD z-score (n=20) was -3.4±1.5 (range -6.7 to -0.1). The average duration of pamidronate treatment was 2.0±0.9 years, and the mean cumulative dose of pamidronate according to body weight was 7.7±2.5 (mg/kg/yr).
2. Effectiveness of pamidronate therapy
After pamidronate therapy, the mean L1–4 spine BMC and mean L1–4 spine BMD significantly increased from 14.20±8.58 g and 0.402±0.136 g/cm2 to 19.38±9.89 g and 0.488±0.137 g/cm2, respectively (P<0.001) (Table 2). The improvement in the BMD z-score with age was not statistically significant (from -3.38±1.45 to -2.76±1.30, P=0.1281); however, BMDhazZ showed significant improvement after treatment (pretreatment, -2.7±1.7; posttreatment, -1.6±1.4; P=0.014) (Table 2, Fig. 1). We assessed serum biochemical values, including calcium, phosphate, ALP, PTH, and vitamin D in every treatment cycle; these values showed no significant difference before and after treatment (Table 2).
We showed that pamidronate treatment decreased the risk of fracture (Table 3). Before treatment, 17 patients (81%) had fractures (long bone in 16 patients; spine in 1 patient). After treatment, only 3 patients (14.3%) had fractures. All of these were long bone fractures. The mean annual rate of total fractures before and after treatment was 0.32 and 0.07, respectively. The relative risk was 0.21 with P=0.003, suggesting that pamidronate treatment reduced fracture incidence significantly.
3. Factors affecting the effectiveness of pamidronate treatment
We evaluated several factors that may affect the effectiveness of pamidronate treatment, including the total cumulative dose, duration of treatment, annual cumulative dose, and average dose in each cycle (Table 4). In univariate linear regression analyses, the average dose in each cycle was positively associated with BMDhazZ. When the average dose in each cycle was increased by 1 mg/kg, the BMDhazZ increased by 1.065 (P=0.044).
4. Adverse events caused by pamidronate treatment
Nine patients (42.9%) experienced adverse events during treatment, most of which were fever and flu-like symptoms (n=7, 77.8%). All patients who had fever and flu-like symptoms experienced these during the first treatment cycle. One patient developed hypocalcemia that required calcium replacement therapy. The ninth patient had acute kidney injury and received 8 mg/kg of pamidronate during the first year of treatment; he experienced fever in 3 treatment cycles. However, the patient developed Fanconi syndrome after the second treatment cycle in the second year (a total of 4 mg/kg). The kidney injury improved after 1 month of pediatric intensive care with hemodialysis. The patient is currently on maintenance vitamin D supplementary therapy. Hyperparathyroidism and bone pain did not occur.
Discussion
In this study, we evaluated the effectiveness of bisphosphonate therapy in nonambulatory children with low BMD. The key findings of our study were (1) pamidronate treatment improved bone health and decreased the risk of fracture in these patients; (2) the safety of pamidronate treatment was confirmed because there were no significant adverse events; and (3) the effectiveness of pamidronate increased significantly with increase in the average dose per body weight in each cycle, independent of cumulative dosage and duration of treatment.
Poor bone health is commonly associated with immobilization in children. In a previous study, in pediatric patients with moderate to severe cerebral palsy, osteopenia (BMD <-2 SD) was detected in the femur of 77% of the study population; 97% of these patients were older than 9 years and unable to stand [6].Loss of mechanical stimulation of the bone due to immobilization is a major cause of osteopenia and osteoporosis [22]. In a previous study investigating bone mineral loss after 17 weeks of bed rest, the total body, lumbar spine, and femoral neck demonstrated significant BMD losses of 1.4, 2.9, and 3.6%, respectively [23]. In other clinical studies under various conditions, including spinal cord damage, vegetative conditions, bed rest, and spaceflight, disuse or unloading has been reported to lead to immediate bone loss accompanied by relatively increased bone resorption and decreased bone formation [22]. Once the mechanical stimulus decreases, mechano-sensation mediated by the lacunocanalicular system induces biochemical responses of the bone matrix that result in the suppression of osteoblast activity, osteocyte apoptosis, and increased bone resorption [22,24]. Consequently, cortical deterioration associated with lower osteocyte viability and impaired osteocyte connectivity causes osteoporosis.
Pediatric nonambulatory patients with osteoporosis usually have neurological diseases, and their medications can also contribute to poor bone health [25]. Antiepilepsy drugs (AEDs) may induce the liver cytochrome P450 enzyme system, which leads to increased catabolism of vitamin D. In addition, AEDs may have direct effects on bone cells, including impaired absorption of calcium, increased bone resorption, and inhibition of response to PTH. Vitamin K deficiency, hyperparathyroidism, and calcitonin deficiency have been suggested as possible etiologies for AED-related osteoporosis [25].
Pediatric patients with osteoporosis also have several coexisting vulnerabilities. These patients often have poor nutritional status that is significantly associated with low BMD. This association is more prominent when accompanied by feeding difficulties [6]. In addition, pediatric patients with osteoporosis engage in a limited number of outdoor activities, leading to insufficient sun exposure, which can cause vitamin D deficiency and osteopenia [26].
Several studies of secondary osteoporosis and bisphosphonate treatment have been conducted since 2002 (Supplementary Table 1) [13-17,27]. In each study, patients received bisphosphonate treatments of various durations and dosages. The results of the studies showed that pamidronate could improve the BMD of patients with secondary osteoporosis and various underlying diseases. In a double-blind, placebo-controlled clinical trial published in 2002, 6 patients with severe cerebral palsy received 12 mg/kg of pamidronate for 1 year and showed significant improvement in bone health [13]. In that study, lumbar BMD increased by 89%±21% in the pamidronate group and by only 9%±6% in the control group. The age-adjusted z-score increased from -4.0±0.6 to -1.8±1.0 in the pamidronate group, but no significant change was observed in the control group (-4.2±0.3 to -4.0±0.3) [13]. A recent study reaffirmed the effectiveness of pamidronate treatment for secondary osteoporosis caused by chronic diseases, including idiopathic juvenile osteoporosis, cerebral palsy, inflammatory bowel disease, and chronic enteropathy [16]. The patients received 9 mg/kg of pamidronate for 1 year and showed improvement in BMD z-score by the end of the treatment (lumbar spine, from -3.8±1.4 to -1.6±1.9, P=0.001; femoral neck, from -5.7±2.4 to -3.6±3.0, P=0.029). A study of 25 patients with cerebral palsy demonstrated a significant decrease in fracture incidence after 1 year of pamidronate treatment [17].
Our study also confirmed that pamidronate treatment has a significant positive effect on secondary childhood osteoporosis. The patients showed significantly increased BMC and BMD after pamidronate treatment without any significant adverse events. The age-related BMD z-score did not significantly improve after treatment in our study. As physical growth is usually restricted in nonambulatory patients with underlying diseases, the age-based BMD z-score may not accurately reflect the current bone health status. Because the areal BMD is calculated using a 2-dimensional image, this measure incorporates the bone area but not the depth of the bone. In a previous study, an adjustment method (BMDhazZ) based on height-for-age, which was suggested to estimate the effect of short or tall stature on BMD measures, yielded the least biased approach [21]. Analysis using BMDhazZ for patients with severely restricted growth in our study confirmed significant improvement in bone density.
There was no statistically significant association between annual cumulative dose and increase in BMD. According to the consensus guidelines on the use of bisphosphonate therapy in children and adolescents, the administration of pamidronate 9 mg/kg annually is recommended as the initial treatment for pediatric osteoporosis [18]. However, there is controversy regarding the optimal dose of pamidronate that should be administered under various conditions. As no randomized trial has been conducted to compare the efficacy and safety of pamidronate with different dosages, the ideal dose of pamidronate to maximize its effect with an adequate tolerability is yet to be elucidated. In a study of pediatric patients with OI, the average annual vertebral BMD gain after treatment using a high dose of pamidronate (1 mg/kg/day for 3 days every 4 months; 9 mg/kg/year) was 42% [12]. In other studies, the annual vertebral BMD gain in children with cerebral palsy was 33% in a high-dose group (12 mg/kg/yr) [13] and 38% in a low-dose group (4.12 mg/kg/yr) [27]. In univariate regression analysis in our study, we did not find a difference in treatment effect according to the annual cumulative dose. Further randomized controlled studies will be needed to find the optimal dose of pamidronate for the treatment of osteoporosis due to immobilization.
In our study, there was a significant association between the average dose of pamidronate administered in each cycle and improvement in BMDhazZ, independent of the annual cumulative dose. In a previous placebo-controlled study conducted with 60 patients (mean age, 64.9 years) with distal forearm fracture, pamidronate may have caused a dose-related reduction in the biochemical markers of bone resorption [28]. Moreover, in another in vitro study that tested the dose-dependent effects of zoledronic acid, another type of bisphosphonate, on osteoclast suppression, zoledronate was found to inhibit osteoclasts at a minimum concentration of 1×10−6 mol/L. This inhibitory effect was enhanced at the concentration of 1×10-5 mol/L [29]. As the mechanism of action of pamidronate is similar to that of zoledronate, the implication is that there is an appropriate dose for maximizing the therapeutic effects.
This study has some limitations. First, this study was conducted only on consecutive patients who were referred to the pediatric endocrine department of a single institute, suggesting a possibility of selection bias. Second, most of the participants in our study had neurologic disorders; this study did not include enough patients with chronic diseases other than neurological diseases, such as chronic inflammatory bowel diseases. Third, although the patients generally had more frequent long bone fractures than vertebral fractures, we could not obtain sufficient data on femur BMD because measurement could not be performed for patients with hip flexion contractures or a history of hip surgery. Fourth, we partially adjusted the dosage and interval of treatment according to patient condition and disease severity. The medical conditions may have been a source of bias during the treatment, even though we limited the patient population to those with severe cerebral palsy. Fifth, the endpoint of treatment and the number of infusion cycles were not precisely unified. Sixth, due to an insufficient number of participants, we could not adjust for age, sex, etiology of immobilization, and medication history. Also, this study did not report changes in bone turnover markers since laboratory data on these markers were not collected.
In conclusion, this study was meaningful because its results suggest that pamidronate is an appropriate treatment for pediatric patients with low BMD. We confirmed that pamidronate is effective and safe for treating secondary childhood osteoporosis. After treatment with pamidronate, BMD improved and fracture events were reduced without major adverse events. Importantly, a sufficient dose in each cycle needs to be administered for the therapeutic effects of the drug to be observed: the effectiveness of the drug is improved when the average dose per body weight in each cycle is increased. However, there were unadjusted factors that could limit the validity of the results. Further studies with larger sample sizes of patients and longer observation periods are necessary to confirm these findings over the long term.
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