PEDIATRICS Vol. 111 No. 5 May 2003, pp. 1030-1036
Height and Weight Development During Four Years of Therapy With Cyclical Intravenous Pamidronate in Children and Adolescents With Osteogenesis Imperfecta Types I, III, and IV
From the Genetics Unit, Shriners Hospital for Children and McGill University, Montréal, Québec, Canada
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Objectives. Treatment with pamidronate improves the clinical course in children with osteogenesis imperfecta (OI), but theoretically might affect longitudinal growth. In this study we analyzed growth during cyclical intravenous pamidronate treatment in children and adolescents (age .04–15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV.
Methods. The effect of 1 year of pamidronate treatment on height and weight was analyzed in 116 patients (OI-I, N = 29; OI-III, N = 42; OI-IV, N = 45). The results of 4 years of therapy were evaluated in 41 children (OI-I, N = 12; OI-III, N = 14; OI-IV, N = 15).
Results. Baseline height was low for age in all OI types. After 1 year of pamidronate therapy, height z scores had increased significantly in OI-III (by 0.3 ± 0.8, mean ± standard deviation; P = .04) and did not change in OI-I and OI-IV. Weight z scores increased significantly in OI-I (by 0.2 ± 0.4, P = .01). After 4 years of pamidronate therapy, mean height z scores increased significantly in OI-IV (by 0.41 ± 0.71, P = .04), whereas nonsignificant trends to increase were found for OI-I and OI-III. When height was expressed as a percentage of the result expected for untreated patients with the same OI type, long-term pamidronate therapy was associated with a significant height gain in all 3 OI types (P < .001). Eight patients who reached final height after 3.0 ± 1.0 years of treatment were taller on average than expected for untreated patients (P = .04).
Conclusions. Four years of cyclical intravenous pamidronate treatment led to a significant height gain in moderately to severely affected OI patients.
Key Words: bisphosphonates • child and adolescent • growth • osteogenesis imperfecta • pamidronate
Abbreviations: OI, osteogenesis imperfecta • aBMD, areal bone mineral density
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and low bone mass. It has been classified by Sillence et al1 into 4 major types according to clinical severity. Type I OI (OI-I) comprises patients without major bone deformities. Type II is lethal in the perinatal period. OI type III (OI-III) is the most severe form in children surviving the neonatal age. These patients have extremely short stature and limb and spine deformities secondary to multiple fractures. Patients with variable bone deformities and short stature are classified as OI type IV (OI-IV).
We and others have shown that cyclical intravenous treatment with the bisphosphonate compound pamidronate significantly improves the clinical course in children and adolescents with OI.2–7 Bisphosphonates are a class of drugs which are thought to exert their skeletal effect by inhibiting bone resorption.8 In most cases, chronic bone pain disappears after the first infusion cycle, bone density increases rapidly, fracture incidence decreases, and mobility improves.4,5,7
Although pamidronate therapy has brought obvious improvements to the lives of young OI patients, safety issues are a concern when bisphosphonates are administered to children and adolescents. Among these, the effect on longitudinal bone growth is high on the list.9 It can be plausibly hypothesized that bisphosphonates could have a deleterious effect on bone growth, because bone resorption is an essential part of the normal endochondral ossification process.10 Indeed, several animal studies appear to support this hypothesis.11–14 However, it is not clear whether these results are applicable to the treatment of children with OI.
The available pediatric data from small patient series do not provide evidence that bisphosphonates at therapeutic doses inhibit growth in OI patients.2–7,15 In 10 of our patients with severe OI who remained prepubertal throughout the observation period, growth rate was at least as high during as before pamidronate treatment.4 In 9 patients with OI-III and OI-IV who started pamidronate therapy under 2 years of age, height z scores increased significantly during the first treatment year.5
These preliminary data are encouraging, but the number of patients in these reports is too small to reach definite conclusions. Therefore, in the present study we evaluated short-term and long-term growth in a large group of children and adolescents with OI. In our clinical experience some patients have a rapid weight increase after the beginning of treatment with pamidronate. The present evaluation offered the opportunity to put this observation on an objective basis. Therefore, we also assessed the effect of pamidronate therapy on weight.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Patients
The study population comprised children and adolescents who received cyclic intravenous pamidronate therapy at the Shriners Hospital for Children in Montréal, Canada. Between October 1992 and October 2001, 125 patients with a diagnosis of OI-I (N = 31), OI-III (N = 47), or OI-IV (N = 47) had received at least 1 pamidronate infusion. Height and weight data at the time of the first pamidronate infusion were used to derive regression curves that reflect the expected height in untreated OI patients (see below). The clinical characteristics of this cohort are presented in Table 1.
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For the analysis of the short-term (1-year) effects of pamidronate therapy, 9 patients had to be excluded. Three of these patients had not yet completed 1 year of treatment at the time of analysis, the other 6 had reached final height before the start of therapy. The effects of 1 year of pamidronate therapy on growth were evaluated in the remaining 116 patients (Table 1).
To study growth under long-term therapy, we analyzed patients who had been maintained on cyclical pamidronate treatment for at least 4 years. Forty-seven patients fulfilled this criterion. Six of these patients were excluded from this group and analyzed separately, because they had achieved final height between the first and fourth year of therapy. Thus, 41 patients (OI-I, N = 12; OI-III, N = 14; OI-IV, N = 15) were included in the 4-year height analysis (Table 1). Most of these patients continued pamidronate therapy beyond this time point. At the time when this analysis was performed, the mean duration of pamidronate treatment in this group was 5.0 years (range 4.0–5.9 years).
The effect of pamidronate treatment on final height was analyzed in those 8 patients (OI-III, N = 4; OI-IV, N = 4) who had stopped growing after at least 1 year of therapy. Final height was defined as absence of height gain during at least 1 year in patients older than 15 years.
The classification of OI types followed the criteria established by Sillence.1 However, the OI-IV category did not include patients who fulfilled the Sillence criteria for this diagnosis, but who could be classified as having OI type V, VI, or VII on the basis of our expanded classification.16–18
Height was measured with a Harpenden stadiometer. Infants and children unable to stand were measured in the supine position. Others were measured standing. Gentle traction was applied on lying patients. In cases of leg length discrepancy or contractures, the longest leg was used in all measurements. Weight was measured using digital electronic scales for infants and mechanic scales for children and adolescents with the patients clothed in underwear. Height measurements in children with bone deformities are difficult to perform. Therefore, all measurements were performed by personnel experienced in dealing with subjects with deforming bone disorders.
Pamidronate Treatment
According to our treatment protocol, patients with a diagnosis of OI were eligible for pamidronate treatment if they had long bone deformities or had suffered >3 fractures (including vertebrae) per year during the previous 2 years.4,5 This applies to all patients with OI-III or OI-IV, and generally to the more severe cases of OI-I.
The medication was administered intravenously in cycles of 3 consecutive days, as described before.4,5 In younger children the clinical effect of a pamidronate infusion (suppression of bone pain, sense of well-being) is more short-lived.5 Therefore, younger children received pamidronate infusions more frequently, but at a lower dose per infusion. Children below 2 years of age received 0.25 mg/kg on the first day of the first cycle, 0.5 mg/kg/d on days 2 and 3 of the first cycle, and 0.5 mg/kg/d on all 3 days in subsequent cycles. Cycles were repeated every 2 months. Children from 2 to 3 years of age received 0.38 mg/kg on the first day of the first cycle, 0.75 mg/kg/d on days 2 and 3 of the first cycle, and 0.75 mg/kg/d on all 3 days in subsequent cycles. Cycles were repeated every 3 months. Above 3 years of age, the first 3-day cycle consisted of a dose of 0.5 mg/kg on the first day and 1 mg/kg/d on days 2 and 3. In subsequent cycles, the dose was 1 mg/kg/d for 3 days. Cycles were repeated every 4 months. Thus, the yearly dose of the drug was 9 mg/kg at all ages. Doses and cycle intervals were based on clinical response, as discussed in our previous publications.4,5
Radiologic Measurements
Bone age was determined on posteroanterior radiograph of the left hand according to the method of Greulich and Pyle.19 Areal bone mineral density (aBMD) in the anteroposterior direction was determined at the lumbar spine (L1-L4) using a Hologic QDR 2000W or 4500A device (Hologic, Inc, Waltham, MA). Results were transformed to age-specific z scores using data provided by the manufacturer.
Statistical Analyses
Results for height and weight were transformed into age-matched z scores, using National Center of Health Statistics data.20 Expected height for age and weight for height in untreated OI patients were calculated by simple regression analysis. These analyses were done separately for the 3 OI types. Linear, exponential, logarithmic, and hyperbolic simple regression models were tested. The model with the maximum coefficient of determination (r2) was chosen. In all instances, an exponential model provided the best fit.
The points on these regression lines correspond to the expected height and weight results in untreated OI patients. The measured height and weight data of each patient under treatment at each time point were converted to the percentage of the expected result. Significant male-to-female differences in height-for-age regression curves were observed only in OI-I. However, the untreated group and the cohort that had completed 4 years of treatment had a similar percentage of boys (58% in both groups). Therefore, this analysis was performed by combining both genders also in OI-I.
Longitudinal differences between 2 time points were tested for significance using paired t tests. Throughout the study, a P < .05 was considered significant. These calculations were performed using the SPSS software, version 9.0 for Windows (SPSS, Inc, Chicago, IL).
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RESULTS |
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Effect of Rodding Surgery on Height
Insertion of metal rods into femoral and/or tibial bones is a routine orthopedic procedure in OI to treat and prevent deformities of long bones.21 To evaluate the effect of this procedure on height, we analyzed the height z scores of 39 patients at the closest to the surgery anniversaries of pamidronate treatment. Interval between 2 measurements was 1 year. The time between the surgery and measurements varied within this interval from 0.1 to 0.9 years. Height z scores were not significantly different between these 2 time points (-4.1 ± 2.7 before vs -4.0 ± 2.7 after rodding, P = .12). Therefore, rodding procedures were not taken into account during the subsequent analyses.
Short-Term Effects of Pamidronate on Height and Weight
At baseline, patients of all OI types were short for age (Table 2). After 1 year of pamidronate therapy, height z scores had increased significantly in OI-III, but had not changed in a statistically significant manner in OI-I and OI-IV. Baseline weight was also low for age. One year later weight z scores had increased significantly in OI-I.
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Long-Term Effects of Pamidronate on Height
After 4 years of pamidronate therapy, mean height z scores of all 3 OI types tended to increase as compared with baseline. However, the change in height z scores was significant only for OI-IV (+0.41 ± 0.71; P = .04), but not for OI-I (+0.23 ± 0.55; P = .17) and OI-III (+0.42 ± 1.45; P = .31).
Height and weight z scores as calculated above compare OI patients to age- and gender-matched healthy children. However, children with severe forms of OI who do not receive medical therapy are known to grow slowly.22 To assess the effect of pamidronate on growth, it may be more appropriate to compare the height of treated and untreated patients. To do this, we first evaluated the age-dependency of height in OI patients who had not received pamidronate before (Fig 1). The curves fitted to these data represent the mean height that is expected for each age in untreated patients with OI-I, OI-III, and OI-IV, respectively.
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The individual height changes in patients who had received pamidronate for at least 4 years are shown in Fig 2. Two markers of disease severity, baseline height and aBMD z scores, were similar in the 4-year group and in the control group (P > .4; Table 1). This shows that at baseline the 4-year treatment group was representative of the entire group of patients who contributed to construct the regression lines shown in Fig 1. Therefore, each height measurement of a patient can be expressed as a percentage of the mean value expected for untreated OI patients. During 4 years of pamidronate therapy, height significantly increased above the values expected for untreated patients (Fig 2, Table 3). Fig 2 also includes height results after 5 years of treatment when available.
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aBMD z score increased from -5.0 ± 1.2 at baseline to -2.4 ± 1.0 after 4 years of therapy (P < .001). There was no relationship between the changes in aBMD z score and in height, either expressed as z score or as a percentage of the expected mean value (P > .05).
It can be hypothesized that the height gain during pamidronate treatment might not be an effect of the drug, but could rather result from the prevention of gradual aggravation of leg deformities by rodding surgery. To examine this possibility, we separately analyzed the 15 nonrodded patients who had completed at least 3 years of treatment (OI-I, N = 11; OI-III, N = 2; OI-IV, N = 2). After this treatment period, height expressed as a percentage of the expected value for untreated patients increased by 7.0 ± 6.2% (P = .001). Thus, also children who had not undergone rodding surgery of the lower extremities had faster growth during pamidronate therapy than untreated patients.
Effect of Pamidronate on Final Height
For the expected final height, the height values on the regression curves (Fig 1) corresponding to the age of 16 years were taken. Eight patients attained final height while receiving pamidronate treatment. Final height, expressed as a percentage of the expected height in untreated patients, was significantly higher than baseline height (Table 4).
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Effect of Pamidronate on Bone Age
Bone age data were available for 36 patients of the 4-year treatment group. The mean length of treatment before the assessment of bone age was 1.9 ± 0.9 years. In all instances, bone age was similar to chronological age (P = .7).
Long-Term Effects of Pamidronate on Body Weight
In all 3 groups of OI patients, mean height was considerably below the average of healthy children (Table 2). For this reason, expressing their weight data as age- and gender-specific z scores may not be the best way to evaluate changes during therapy. It may be more appropriate to relate body weight to height rather than to age, and to compare treated OI patients to untreated patients rather than to healthy children. Therefore, we first assessed the relationship between weight and height in patients who had not previously received pamidronate (Fig 3). Most patients on long-term pamidronate continued to follow the regression line of untreated patients, but in several children the weight gain was considerably above the expected level (Fig 4). Taken as a group, the mean weight of pamidronate-treated patients increased significantly when expressed as a percentage of the expected weight for-height result (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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This study provides evidence that cyclical pamidronate therapy of children and adolescents with severe OI-I, OI-III, and OI-IV does not have a detrimental effect on longitudinal growth. After 1 year of therapy, age- and gender-specific height z scores remained similar or even increased, showing that growth proceeded at a speed which was similar to that of healthy children. Compared with untreated patients with the same OI types, there even was a significant height gain after 4 years of pamidronate therapy. This height gain above expected levels was largest in the most severely affected patients (11% in OI-III, 12% in OI-IV) and less in OI-I (5%). As can be calculated from the regression curves shown in Fig 1, these percentages translate into an average gain of 7 cm in OI-I, 9 cm in OI-III, and 12 cm in OI-IV at 15 years of age.
Our results for expected height in untreated OI patients are similar to data published by Vetter et al.22 Markedly short stature is a common feature in moderate to severe OI. Severely affected patients may be short because of vertebral compression fractures, scoliosis, lower limb deformities, and disintegration of growth plates ("popcorn epiphysis").23 However, growth can also be slow in the absence of these abnormalities. The etiology of this growth restriction is not entirely clear, but it could be viewed as a self-protective mechanism. A given mechanical load creates smaller stresses in a short bone than in a long bone. Therefore, a short bone will break less easily.
It is not entirely clear how pamidronate treatment might improve growth. Acceleration of skeletal maturation is an unlikely candidate, as bone age was similar to chronological age during therapy. In addition, our preliminary final height data suggest that there is not just a transitory acceleration of growth but a lasting effect of the treatment on height.
Pamidronate might increase growth in moderate to severe forms of OI by preventing long bone deformities and further vertebral collapse. Reshaping of vertebral bodies can also be observed in many patients.5,7 In addition, as pamidronate therapy makes bones stronger, there might be less need to protect bones by keeping growth rates low. The observation that there was a more pronounced height gain in the most severely affected patients is compatible with all of these hypotheses.
It is important to note that the present study was limited to the use of cyclical intravenous pamidronate at the annual dose of 9 mg/kg and to moderately and severely affected patients with OI-I, OI-III, and OI-IV. Our results are not necessarily applicable to other treatment schedules involving bisphosphonates. It is also unclear whether the results can be extrapolated to milder forms of OI or to other pediatric bone fragility disorders. Adequately sized studies are required to resolve these issues.
Body weight changes in pamidronate-treated OI patients have not been reported previously. In most of our patients, weight increased as expected for the changes in height. However, several children experienced a rapid weight gain during therapy. This is a cause of concern because the exaggerated weight puts additional loads on the skeleton and interferes with rehabilitation. Why some patients increase their weight rapidly during pamidronate therapy is unclear. OI is associated with a well-recognized but ill-explained problem in the body’s energy management, as evidenced by excessive sweating.24 Pamidronate appears to have an effect on energy expenditure, as excessive sweating disappears after treatment has started.4,7 It is also possible that the decrease in bone pain and fracture rate increases appetite and thus energy intake.
In conclusion, cyclic intravenous pamidronate treatment does not have a detrimental effect on linear growth in moderately to severely affected children and adolescents with OI-I, O-III, or OI-IV. Long-term pamidronate therapy is associated with a significant height gain as compared with untreated OI patients with the same type of the disease. Some children with OI gain weight excessively during pamidronate treatment. Body weight of children with OI receiving pamidronate should be closely monitored.
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ACKNOWLEDGMENTS |
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This study was supported by the Shriners of North America.
We thank Nancy Cyr and Patricia Roy for secretarial help, the nursing staff of Shriners Hospital for data collection, and Mark Lepik for artwork.
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FOOTNOTES |
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Received for publication Jul 9, 2002; Accepted Oct 22, 2002.
Reprint requests to (F.H.G.) Genetics Unit, Shriners Hospital for Children, 1529 Cedar Ave, Montréal, Québec, Canada H3G 1A6. E-mail: glorieux{at}shriners.mcgill.ca
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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