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Pamidronate in Children and Adolescents with Osteogenesis Imperfecta: Effect of Treatment Discontinuation

Genetics Unit, Shriners Hospital for Children and McGill University, Montréal, Québec, Canada

Address all correspondence and requests for reprints to: Dr. Frank Rauch, Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal, Québec, Canada H3G 1A6. E-mail: frauch{at}shriners.mcgill.ca.

	Abstract

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Context: Cyclical iv pamidronate is a widely used symptomatic therapy of osteogenesis imperfecta (OI). What happens after treatment discontinuation is unknown.

Objective: The objective of this study was to assess the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV.

Design: This was an open-label controlled and observational study in patients who had received pamidronate for more than 3 yr.

Setting: This study was performed at a pediatric metabolic bone research unit.

Patients: In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 yr).

Intervention: The intervention was discontinuation of pamidronate treatment for 2 yr.

Main Outcome Measures: The main outcome measures were lumbar spine bone mineral content and areal bone mineral density (aBMD), biochemical markers of bone metabolism, fracture incidence, and clinical evaluation.

Results: In the controlled study, bone resorption activity was higher after treatment discontinuation. Bone mineral content continued to increase in both groups. aBMD z-scores decreased in the untreated group, but increased in the continuation cohort. Fracture rates and functional status were similar between groups. In the observational study, bone resorption activity increased after treatment discontinuation, but remained significantly lower than in untreated OI patients. Bone mineral content and aBMD continued to increase, whereas aBMD z-scores decreased. Changes were faster in patients who continued growing.

Conclusions: Bone metabolism is still suppressed 2 yr after pamidronate discontinuation. Bone mass gains continue after treatment is stopped, but lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent.

	Introduction

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OSTEOGENESIS IMPERFECTA (OI) is a genetic disorder producing increased bone fragility and low bone mass. The most commonly used classification distinguishes four clinical types (1). OI type I comprises patients with absence of bone deformities. Type II is lethal during the perinatal period. OI type III is the most severe form in children surviving the neonatal period. Patients with mild to moderate bone deformities and variable short stature are classified as OI type IV. In the majority of patients with OI, the disease can be linked to mutations in one of the two genes coding for collagen type I -chains (COL1A1 and COL1A2) (1). Recently, three disease entities (named OI types V, VI, and VII) have been identified, which have a similar phenotype as the other types of OI, but are not associated with collagen type I mutations (1).

Cyclical iv treatment with the bisphosphonate pamidronate has a beneficial effect in children and adolescents with severe OI (1). It has been reported that this treatment increases lumbar spine areal bone mineral density (aBMD) and metacarpal cortical width, decreases fracture rates, and improves mobility (1). Pamidronate is now used worldwide to treat children and adolescents with moderate to severe forms of OI.

Nevertheless, it is unclear how long pamidronate treatment should be continued. One might argue that because OI is a life-long disorder, the symptomatic treatment with pamidronate should never be stopped. In contrast, there is lingering concern about the long-term consequences of the treatment. Bisphosphonates are buried in the skeleton, where they have a half-life of many years (2). Any adverse effects that might arise from the presence of the drug in the bones may therefore manifest late and persist for a long time. The available evidence, mostly from women with postmenopausal osteoporosis, does not suggest that long-term bisphosphonate use would have any effect on bone other than a beneficial one (3). Nevertheless, concerns about potential long-term risks may weigh more heavily in a patient who is 10 yr old than in one who is 70 yr of age.

Given the fact that the long-term consequences of this treatment during the growing years are unknown, it appears desirable to limit the exposure of young OI patients to pamidronate. Also, the treatment effect appears to become less evident with increasing duration of therapy. For example, the age-specific z-score for lumbar spine aBMD increased by 2.0 during the first 2 yr of treatment, but only by 0.6 between 2 and 4 yr of treatment (4). Histomorphometric studies have shown that the cortical width of iliac bone almost doubles during the first 2–3 yr of pamidronate treatment, but changes little when therapy is continued for another 3 yr thereafter (5, 6). Finally, healing of osteotomy sites after intramedullary rodding surgery is delayed in many OI patients receiving pamidronate (7).

Starting in 2001, these considerations led us to discontinue pamidronate treatment in patients who had received at least 4 yr of therapy. In the present report we evaluate the effects of treatment discontinuation in young OI patients who had received pamidronate treatment for several years.

	Subjects and Methods

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Subjects

This study comprised patients with a diagnosis of OI type I, III, or IV who had received pamidronate at the Shriners Hospital for Children (Montréal, Canada). Patients were eligible for pamidronate treatment if they had long-bone deformities or had suffered three or more fractures per year (including vertebrae) in the 2 yr before starting therapy (8, 9). The present analysis does not include patients who fulfilled the Sillence criteria for OI type IV, but who could be further classified as having OI type V, VI, or VII on the basis of our expanded classification (1). Two different studies were performed to assess the effect of pamidronate discontinuation: an open-label controlled study and an observational study. The study was approved by the Shriners Hospital institutional review board, and informed written consent was obtained from patients and/or legal guardians, as appropriate.

Open-label controlled study

This study included patients who had received at least 4 yr of pamidronate treatment. Twelve pairs of patients with similar disease severity and length of pamidronate treatment were identified. Pamidronate was stopped in one patient of each pair, and treatment was continued in the other patient. Mutations affecting collagen type I were found in all but one of the 24 patients included in this study.

Observational study

The observational study included patients who had received pamidronate for a minimum of 3 yr and had discontinued this treatment before July 2003 (this cutoff date was chosen to allow for sufficient follow-up time). Of the 44 patients who fulfilled these criteria, six did not return for clinic appointments after pamidronate was stopped. Thus, follow-up data were available for 38 patients (15 girls and 23 boys). Collagen type I mutations were found in 34 of these patients. In four patients, no collagen type I mutation was detectable by full-sequence analysis of the collagen type I -chain (COL1A1 and COL1A2) genes, but a diagnosis of OI was made on the basis of typical clinical findings (dentinogenesis imperfecta and blue sclerae).

Treatment

Pamidronate was administered iv on 3 consecutive days in all patients. As described in detail previously (1), the timing and dosage of these 3-d cycles varied with age, but the yearly dose of pamidronate remained at 9 mg/kg throughout the treatment period. Calcium intake was maintained adequately according to the recommended daily allowance. All patients underwent standard physiotherapy and occupational therapy programs and orthopedic care, as required (10).

Follow-up assessments

The observation period of the present evaluation was 2 yr for all patients. Patients who continued receiving pamidronate were assessed every 4 months during their treatment visits. Patients who stopped receiving this treatment were evaluated every 6 months. The workup was identical in the two groups and comprised clinical examination, biochemistry, lumbar spine densitometry, evaluation by occupational therapists and physiotherapists, as well as radiographs and orthopedic consultations as required for clinical management.

Height was measured with a Harpenden stadiometer. Height and weight measurements were converted to age- and sex-specific z-scores on the basis of reference data published by the Centers for Disease Control and Prevention (11). Patients were classified as having achieved final height when their height change over the previous year was less than 2 cm.

Occupational therapists and physiotherapists experienced in the care of children and adolescents with OI assessed the subjects before the start of pamidronate therapy and at each subsequent treatment cycle. The Pediatric Evaluation of Disability Inventory was used to assess gross motor and self-care abilities (12).

Bone densitometry was performed in the antero-posterior direction at the lumbar spine (L1–L4) using a Hologic QDR 2000W (before 1997) or 4500A device (for measurements taken in 1997 and later; Hologic, Inc., Waltham, MA). The 4500A system was used for all measurements that were taken at treatment discontinuation and thereafter. Simultaneous examination using both the QDR 2000W and 4500A systems in 700 subjects, aged 2 months to 52 yr, had shown that aBMD results differed by about 1% between the two devices (our unpublished observation). Because this difference is negligible compared with the changes commonly seen in children, no adjustments were performed to account for device performance. aBMD results were transformed to age-specific z-scores using data provided by the densitometer manufacturer, which are based on the studies by Glastre et al. (13) and Southard et al. (14) that comprised at total of 353 children and adolescents. Densitometry was not performed in the three patients who had had spinal fusion surgery for scoliosis (two patients who continued on pamidronate in the controlled study and one patient in the observational study).

aBMD is a composite measure of three-dimensional mineral density and bone length in the antero-posterior direction (15). A size-independent measure of three-dimensional density was estimated by calculating the ratio between bone mineral content and the extrapolated external volume of the measured bones (volumetric BMD). This was performed as described by Carter et al. (15) using the formula: volumetric BMD = (bone mineral content)/(projection area)^1.5. Serum PTH concentrations (fragment 39–84) were determined by an RIA that has a reference range of 2.6–10.0 pmol/liter (16). 25-Hydroxyvitamin D was measured with a RIA (Incstar Corp., Stillwater, MN). Urinary cross-linked N-telopeptides of type I collagen (NTX) were quantified by ELISA (Osteomark, Ostex, Seattle, WA) using the second void sample of the morning. Results for urinary NTX/creatinine ratios in OI patients were expressed as a percentage of age- and sex-specific mean values using published reference data (17). Serum levels of NTX were quantified by ELISA (Osteomark NTX Serum, Wampole Laboratories, Princeton, NJ). Patients were fasting at the time of blood and urine sampling. In patients receiving pamidronate, samples for biochemical analyses were obtained immediately before starting a new treatment cycle. Biochemical data were measured sequentially as the study progressed.

Fractures reported by patients or parents were radiologically verified. Fracture data given in this report represent radiologically confirmed fractures of long bones (humerus, radius, ulna, femur, tibia, and fibula). In the majority of patients, the pretreatment observation period was insufficient to obtain reliable fracture data before pamidronate treatment was started. Fracture incidence could therefore be determined only during and after the pamidronate treatment interval.

Statistical analyses

Variables were tested for normal distribution using the Kolmogorov-Smirnov test. Normally distributed data were expressed as the mean and SD. Geometric means and geometric SD were calculated for nonnormally distributed variables. These variables were log transformed before performing tests that require normal distribution. Comparisons between two groups were performed using Student’s unpaired t test or Mann-Whitney’s U test, as appropriate. Comparisons between two time points in the same group of subjects were carried out using paired t tests or Wilcoxon tests. Comparisons between more than two time points were performed using ANOVA for repeated measures. Bonferroni’s adjustment was used for post hoc comparisons. In the two participants in the observational study who restarted pamidronate treatment, the last observations before restarting were carried forward to the 2 yr point. All tests were two-tailed, and throughout the study, P < 0.05 was considered significant. These calculations were performed using SPSS software (version 11.5 for Windows, SPSS, Inc., Chicago, IL).

	Results

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Controlled study

Two groups of 12 patients each were compared. Pamidronate was stopped in the first group. The second group of patients continued to receive pamidronate throughout the 2-yr observation period. The two groups had started pamidronate treatment at a similar age and had received therapy for a comparable length of time (Table 1). Clinical characteristics at the outset of the present study were similar between the two groups, apart from weight z-scores, which were higher in the group that had stopped treatment.

Observational study

A group of 38 patients (OI type I, n = 14; OI type III, n = 6; OI type IV, n = 18) was followed for a period of 2 yr after discontinuation of pamidronate treatment. These patients had started pamidronate between 0.2–15.6 yr of age (mean ± SD, 8.4 ± 4.2 yr) and had stopped treatment 3.0–7.1 yr (mean ± SD, 5.4 ± 1.2 yr) later, when their ages ranged from 4.1–21.5 yr (mean ± SD, 13.8 ± 4.5 yr). In two patients (a 5-yr-old boy and a 6-yr-old girl), pamidronate treatment was restarted after 15 and 16 months, respectively, because they began to feel unwell and lacked stamina after treatment discontinuation. These symptoms subsided within 2 wk after restarting therapy. The other 36 patients completed the 24-month observation period without pamidronate treatment.

The discontinuation of pamidronate did not affect height and weight z-scores (Table 3). There were no changes in serum levels of calcium, phosphorus, and PTH, but 25-hydroxyvitamin D levels were significantly higher 1 yr after stopping pamidronate. The serum activity of alkaline phosphatase decreased during the second year. Over the 2-yr observation period, levels of the bone resorption marker NTX increased by 28% in serum and by 27% in urine.

View larger version (186K): [in this window] [in a new window]   FIG. 1. Radiological changes after discontinuation of pamidronate treatment. Left panel, Lateral spine radiograph of a 14.0-yr-old boy with OI type I who had received pamidronate from 8.4–11.7 yr of age. The bone tissue that was deposited after the discontinuation of pamidronate (arrows) can be clearly distinguished from the higher density bone that was present at the time of treatment (arrowheads). Upper right panel, Distal forearm and wrist x-ray of a 17.1-yr-old male with OI type I who had received pamidronate from 8.2–14.6 yr of age. Lower density bone was added at all long bones after pamidronate was discontinued. The thinner lines in the distal radius represent Harris lines (growth arrest lines, indicated by asterisks) that resulted from intercurrent illnesses. Lower right panel, Distal forearm and wrist x-ray of a 20-yr-old male with OI type III who had received pamidronate from 10.1–18.8 yr of age. Growth plate activity had ceased at the time of pamidronate discontinuation. Consequently, no bone with lower density was added after treatment was stopped.

View larger version (19K): [in this window] [in a new window]   FIG. 2. Observational study. Urinary NTX/creatinine ratios (presented as a percentage of the results expected in age- and sex-matched healthy subjects) and aBMD z-scores at the start of pamidronate treatment (PAM Start), in the last 2 yr of therapy (indicated as –2y and –1y, respectively), at the time of the last pamidronate cycle (PAM Stop), and 2 yr thereafter (+1y and +2y).

The skeletal effects of stopping pamidronate treatment are different in growing and nongrowing patients (Fig. 1). We therefore analyzed the changes after discontinuation of treatment separately for patients who were still growing (n = 21) and those who had reached final height (n = 17). As shown in Fig. 3, the increase in urinary levels of NTX and the decrease in areal BMD z-scores after discontinuation of treatment were faster in growing patients. These differences reached statistical significance after 2 yr of follow up.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Comparison of urinary NTX/creatinine ratios (presented as a percentage of the results expected in age- and sex-matched healthy subjects) and aBMD z-scores in patients who had reached final height before pamidronate was stopped (n = 17) and patients who were still growing at the start of the observation period (n = 21). *, Significant differences between the two groups (P < 0.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Even though the activity of bone resorption increased after treatment discontinuation, urinary NTX excretion remained well below pretreatment levels, similar to findings in adults (18, 19). This suggests that pamidronate buried in the bone tissue during iv treatment cycles has biological activity for at least 2 yr after the last dose of the drug is given.

Although aBMD z-scores at the lumbar spine decreased after treatment discontinuation, these changes were small and slow compared with the increases seen when pamidronate was started in children and adolescents with OI (4). Consequently, aBMD z-scores remained well above pretreatment levels. It should be noted that a decrease in aBMD z-scores does not mean that these patients experienced bone loss. Quite to the contrary, they continued to gain bone mass (i.e. bone mineral content) even after pamidronate treatment was stopped. However the gain in bone mass was less than what would be expected in healthy subjects who experience a similar increase in bone size (i.e. area). Consequently, aBMD did not increase as quickly as in healthy subjects, leading to a decline in z-scores.

The increase in urinary NTX levels and the decrease in areal BMD z-scores after treatment discontinuation were faster in patients who were still growing than in patients who had achieved final height. Bone tissue added after stopping pamidronate was never exposed to the medication and, therefore, should be similar to the bone tissue of untreated OI patients. If so, the skeletons of patients who are still growing after treatment discontinuation should consist of a mixture of high-density, low-turnover bone tissue (the tissue that was already present at the time of pamidronate infusions) and of low-density, high-turnover bone (the new tissue). This scenario cannot be directly verified on the basis of the present densitometric and bone marker data, because lumbar spine aBMD and urinary NTX levels only provide averaged information on lumbar vertebrae L1–L4 and the entire skeleton, respectively. However, the difference between bone that was exposed to pamidronate and bone that was added after treatment was quite obvious on radiographs of growing patients. The correlation between these radiological observations and bone strength is unclear at present.

In the present analysis, we did not detect any effect of treatment discontinuation on fracture rates and functional status. However, the number of subjects who could be included in this study was not sufficient to detect anything but drastic changes in these outcome measures. It is therefore still possible that stopping pamidronate treatment has an effect on fracture incidence.

In conclusion, the present study shows that discontinuation of pamidronate treatment in young OI patients leads to an incomplete reactivation of bone metabolism. Bone mass gains during therapy are maintained for at least 2 yr after discontinuation, but increases in aBMD lag behind those in healthy subjects. The effects of treatment discontinuation are more pronounced in growing patients than in those who have achieved final height.

	Acknowledgments

 
We are indebted to the nursing staff as well as to the Departments of Occupational Therapy and Physiotherapy at Shriners Hospital for Children for their expert help with data collection.

	Footnotes

 
This work was supported by the Shriners of North America. F.R. is a Chercheur-Boursier Clinicien of the Fonds de la Recherche en Santé du Québec.

The authors have nothing to declare.

First Published Online January 24, 2006

Abbreviations: aBMD, Areal bone mineral density; NTX, cross-linked N-telopeptide of type I collagen; OI, osteogenesis imperfecta.

Received November 4, 2005.

Accepted January 12, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rauch, F. Articles by Glorieux, F. H. Search for Related Content PubMed PubMed Citation Articles by Rauch, F. Articles by Glorieux, F. H. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Genetics Home Reference Medline Plus Health Information Osteogenesis Imperfecta Related Collections Pediatric Endocrinology Calcium and Bone Metabolism