| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Genetics Unit, Shriners Hospital for Children, and Departments of Surgery and Pediatrics, McGill University, Montréal, Québec, Canada H3G 1A6
Address all correspondence and requests for reprints to: F. H. Glorieux, M.D., Ph.D., Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal, Québec, Canada H3G 1A6. E-mail: glorieux{at}shriners.mcgill.ca
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Medical treatment of OI has long been largely ineffective in altering the course of the disease. We recently reported that cyclical iv treatment with pamidronate (3-amino-1- hydroxypropylidene-bisphosphonate) is of benefit to children with severe forms of OI (3). Bone mineral density (BMD) and physical activity increased markedly in these patients, and fracture rate decreased. These children were more than 3 yr of age when treatment was started and already had serious functional disabilities. In an attempt to prevent these functional limitations, we extended the treatment protocol to children less than 3 yr of age. Here we report on the first nine infants with severe OI who completed 12 months of therapy with pamidronate.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
). Eight patients were diagnosed
as having type III OI, and one had type IV OI (1). The clinical course
in these children during the first 12 months of treatment was compared
to corresponding findings in a group of historical controls. The
control group consisted of severe OI patients who were first seen at
our institution before the age of 2 yr, had a follow-up without
pamidronate treatment of at least 12 months, and had a starting BMD
z-score below -3. Six children (3 boys), aged 10.7 ± 4.5 months
(mean ± SD; P = 0.95 compared to
baseline age of treated group), fulfilled these criteria (Table 2). These were first examined at our
institution between 1991 and 1997, before the current study was
started, and received the same multidisciplinary care as the treated
patients, including physiotherapy and occupational therapy assessment
and intervention.
|
|
Pamidronate (Aredia, Novartis, Dozval) was administered iv in
cycles of 3 consecutive days. As no previous experience with this drug
in this age group was available, cycles were initially given every 4
months, as in older children (3), but using a lower dosage (0.5
mg/kg·day). However, it was noted that after 6–8 weeks the patients
started to show signs of discomfort, suggesting that the effects of the
drug were diminishing. The reason for this could be the more rapid
turnover and growth of the skeleton during infancy. The interval
between treatments was therefore shortened to 6–8 weeks. For this
reason, there was variability in the number of infusions and in the
cumulative dose each patient received during the first year of
treatment (Table 1
).
The drug was diluted in normal saline to a final concentration of at most 0.1 mg/mL and was administered over 4 h. Four patients received the drug through a sc Infuse-a-port system (Bard Canada, Missisauga, Ontario, Canada). In the others, a Teflon catheter was inserted in a peripheral vein and left in place for the entire infusion cycle. All patients had a daily intake of vitamin D of at least 400 IU/day, and calcium intake was at least 600 mg/day. All subjects underwent specific physiotherapy and occupational therapy evaluation and intervention, including exercises and provision of special seating devices.
Clinical studies
Fractures were confirmed by radiologists blinded to the treatment status of the subjects. Spine compression fractures were not included in the analysis, because no normative data for vertebral morphometry are available in children; therefore, it is not possible to accurately define vertebral fractures. Due to the spontaneous decrease in fracture rate in OI patients in this age group, the fracture rates before and after treatment were not comparable. Instead, the fracture rates during the 1-yr period of observation for treated patients and controls were compared, considering that age and severity were not significantly different in the two groups. Weight and height measurements were converted to age- and sex-specific z-scores using Canadian reference data (4).
Radiological studies
X-Rays were obtained at baseline and after 6–12 months of treatment. Areal BMD and coronal area in the antero-posterior direction were determined at the lumbar spine (L1–L4) using either a QDR 2000 device (controls) or a 4500A device (patients) (Hologic, Inc., Waltham, MA; entrance radiation dose, <5 mRem). Each subject was studied with the same model of densitometer. All densitometry studies were performed using a pediatric (low density) software. BMD results were transformed to age-specific z-scores combining reference data from Salle et al. (5) and data provided by the densitometer manufacturer.
Laboratory studies
Serum calcium was measured before and after each infusion using a colorimetric method (Monarch, Instrumentation Laboratory, Inc., Lexington, MA). Serum PTH levels were determined by RIA (6) before and after the first infusion cycle and before each of the infusion cycles thereafter.
Statistical analysis
Differences between treatment and control groups were tested for significance using unpaired t tests. Paired t tests were used to analyze changes during treatment. All tests were two-tailed, and a 5% significance level was maintained.
The study was approved by the Shriners Hospital institutional review board, and informed consent was obtained from legal guardians.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Serum PTH levels responded appropriately to the decreased calcium concentration to reach values up to twice the upper limit of the reference range (data not shown). However, levels consistently returned to pretreatment values by the time of the next treatment cycle.
Pretreatment BMD was below the lower limit of the reference range
in all subjects (Fig. 1). In all treated
children BMD had increased by the time of the second infusion cycle.
This trend continued thereafter, resulting in a rise between 86–227%
during the study period (P < 0.001). The increase in
absolute BMD values translated into significantly higher BMD z-scores
for all infants (Table 2). The control group tended to have a higher
BMD z-score than the treated group in the baseline evaluation. During
the observation period, a significant decrease in the BMD of controls
was noted. Thus, mean BMD z-score in controls was significantly lower
than that in the treated group at the end of the observation period
(Table 2).
|
). Similarly, vertebral body area
measured as part of the densitometric studies increased significantly
during treatment (Table 2). In contrast, a significant decrease in
vertebral area occurred in all control subjects (P <
0.05; Table 2).
|
). The previously described
parametaphyseal dense lines corresponding to each treatment cycle were
evident in all patients (3, 7, 8).
|
. There was a large interindividual
variation in weight and height, reflecting the heterogeneity of OI.
Compared to measurements obtained at birth, there was a significant
decrease in mean z-scores of both weight (-1.2 ± 1.6 to
-3.9 ± 1.1) and height (-2.4 ± 1.7 to -7.7 ± 2.6)
by the time treatment was started (P > 0.001),
confirming the delay in physical development typically associated with
severe OI (9). All patients were short for age before treatment, and
their height z-scores increased significantly during treatment
(P = 0.004). All children included in this study had a history of multiple fractures, often without recognizable trauma. During the treatment period, the fracture rate was significantly lower in the treated group. Those fractures occurred after moderate trauma. Pamidronate did not compromise fracture healing.
Signs of bone pain, such as crying during handling and autoimmobilization of a limb, were present in all children before therapy was instituted. Within 1 week after the start of treatment signs of bone pain disappeared. All but one patient acquired head control and the ability to maintain a sitting position by the end of the treatment period.
All patients underwent the well known acute phase reaction after the first infusion, with short term fever up to 38.5 C (10). No other side-effects of treatment were noted.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In this group of infants under 3 yr of age, the response to treatment appeared to be faster and more pronounced than what we had observed in older children (3). Signs of bone pain disappeared within days, and an increase in BMD was evident as early as 6 weeks after the start of treatment. Without exception, the gain in BMD was greater than the increase expected in healthy children. In contrast, a decrease in BMD occurred in the untreated controls. This strongly suggests that the observed changes reflect a drug effect rather than the passing of time or the natural evolution of the disease.
Vertebral size increased in all treated children, as expected in growing individuals. In contrast, a decrease in vertebral size was noted in all untreated children, indicating that vertebral collapse had occurred in these patients. Thus, it appears that pamidronate infusions not only increased lumbar spine BMD, but also protected bone integrity. This view is further strengthened by the readily apparent reshaping of both vertebrae and long bones.
Concomitant with these radiological changes, fracture rate decreased significantly. Fracture incidence is a weak efficacy parameter in open therapeutic studies of OI patients, as it can be influenced by external factors (e.g. mode of handling, mobility) and may spontaneously decrease with age (9). Despite the higher risk of injury due to increased mobility, we noted a significant difference from the fracture rate in the age-matched control group, suggesting a direct effect of the therapy.
During each treatment cycle, a drop in serum calcium induced a transitory increase in PTH levels. The design of the study did not allow us to fully document the time course of these variations. We thus cannot evaluate a possible effect of these bursts of PTH secretion on the increase in BMD. Indeed, PTH has been advocated for treatment of osteoporosis in adults (15, 16).
Although cyclical pamidronate infusions were of clear benefit to our patients, the effect of therapy on growth is an issue of concern in young children. In animal studies, long term treatment with bisphosphonates did not affect growth, unless very high doses were administered (17). In our group of patients, as in the older children recently studied (3), pamidronate did not have a detrimental effect on growth. To the contrary, the data show an increase in z-score in all treated children and no significant changes in the control group.
Pamidronate does not alter the genetic defect underlying OI and therefore is a symptomatic, not a curative, treatment. It is unclear at present how long this treatment should be continued. It is also not known which is the optimal treatment schedule and whether other bisphosphonates have a similar or better effect on the clinical course of the disease. These issues should be addressed in further studies.
In conclusion, cyclical pamidronate infusions markedly improve bone density and decrease fracture rate in severely affected OI patients less than 2 yr of age without causing major adverse side-effects. These encouraging results warrant continuation of the evaluation of this therapeutic approach.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Present address: University of Sheffield Division of Child Health,
Sheffield Children’s Hospital, Sheffield, United Kingdom S10
2TH.
Received October 28, 1999.
Revised December 29, 1999.
Accepted January 14, 2000.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  G. Burnei, C. Vlad, I. Georgescu, T. S. Gavriliu, and D. Dan Osteogenesis Imperfecta: Diagnosis and Treatment J. Am. Acad. Ortho. Surg., June 1, 2008; 16(6): 356 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Senthilnathan, E Walker, and N J Bishop Two doses of pamidronate in infants with osteogenesis imperfecta Arch. Dis. Child., May 1, 2008; 93(5): 398 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Fox, J. Sadowsky, K. P. Pringle, A. Kidd, J. Murdoch, D. E.C. Cole, and E. Wiltshire Neonatal Hyperparathyroidism and Pamidronate Therapy in an Extremely Premature Infant Pediatrics, November 1, 2007; 120(5): e1350 - e1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Al Muderis, T. Azzopardi, and P. Cundy Zebra Lines of Pamidronate Therapy in Children J. Bone Joint Surg. Am., July 1, 2007; 89(7): 1511 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-C. Chang, S.-Y. Lin, and K.-H. Hsu The craniofacial characteristics of osteogenesis imperfecta patients Eur J Orthod, June 1, 2007; 29(3): 232 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Astrom, H. Jorulf, and S. Soderhall Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta Arch. Dis. Child., April 1, 2007; 92(4): 332 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. H. Glorieux Experience With Bisphosphonates in Osteogenesis Imperfecta Pediatrics, March 1, 2007; 119(Supplement_2): S163 - S165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hickey, D. Lemons, P. Waber, and M. G. Seikaly Bisphosphonate Use in Children With Bone Disease J. Am. Acad. Ortho. Surg., November 1, 2006; 14(12): 638 - 644. [Full Text] [PDF]
|
|
|
|
|
|
J Thornton, D M Ashcroft, M Z Mughal, R A Elliott, T W O'Neill, and D Symmons Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis Arch. Dis. Child., September 1, 2006; 91(9): 753 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Rauch, C. Munns, C. Land, and F. H. Glorieux Pamidronate in Children and Adolescents with Osteogenesis Imperfecta: Effect of Treatment Discontinuation J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1268 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rauch, R. Travers, and F. H. Glorieux Pamidronate in Children with Osteogenesis Imperfecta: Histomorphometric Effects of Long-Term Therapy J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 511 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Ward, A. E. Denker, A. Porras, S. Shugarts, W. Kline, R. Travers, C. Mao, F. Rauch, A. Maes, P. Larson, et al. Single-Dose Pharmacokinetics and Tolerability of Alendronate 35- and 70-Milligram Tablets in Children and Adolescents with Osteogenesis Imperfecta Type I J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4051 - 4056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rudge, S. Hailwood, A. Horne, J. Lucas, F. Wu, and T. Cundy Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment Rheumatology, June 1, 2005; 44(6): 813 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N J Shaw and N J Bishop Bisphosphonate treatment of bone disease Arch. Dis. Child., May 1, 2005; 90(5): 494 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Rauch Bisphosphonate Therapy in Children With Osteogenesis Imperfecta IBMS BoneKEy, May 1, 2004; 1(5): 5 - 8. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Plotkin, F. H. Glorieux, F. Rauch, J. R. Shapiro, N. H. Bjarnason, M. P. Whyte, D. Wenkert, W. H. McAlister, and J. C. Marini Bisphosphonates in Children with Bone Diseases N. Engl. J. Med., November 20, 2003; 349(21): 2068 - 2071. [Full Text] [PDF]
|
|
|
|
|
|
L. Zeitlin, F. Rauch, H. Plotkin, and F. H. Glorieux 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 Pediatrics, May 1, 2003; 111(5): 1030 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rauch, H. Plotkin, R. Travers, L. Zeitlin, and F. H. Glorieux Osteogenesis Imperfecta Types I, III, and IV: Effect of Pamidronate Therapy on Bone and Mineral Metabolism J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 986 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Falk, S. Heeger, K. A. Lynch, K. R. DeCaro, D. Bohach, K. S. Gibson, and M. L. Warman Intravenous Bisphosphonate Therapy in Children With Osteogenesis Imperfecta Pediatrics, March 1, 2003; 111(3): 573 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Horwitz, P. L. Gordon, W. K. K. Koo, J. C. Marx, M. D. Neel, R. Y. McNall, L. Muul, and T. Hofmann Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone PNAS, June 25, 2002; 99(13): 8932 - 8937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kalajzic, J. Terzic, Z. Rumboldt, K. Mack, A. Naprta, F. Ledgard, G. Gronowicz, S. H. Clark, and D. W. Rowe Osteoblastic Response to the Defective Matrix in the Osteogenesis Imperfecta Murine (oim) Mouse Endocrinology, May 1, 2002; 143(5): 1594 - 1601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Astrom and S Soderhall Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta Arch. Dis. Child., May 1, 2002; 86(5): 356 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. V. Sekhar, S. Culbert, W. K. Hoots, M. J. Klein, H. Zietz, and R. Vassilopoulou-Sellin Severe Osteopenia in a Young Boy With Kostmann's Congenital Neutropenia Treated With Granulocyte Colony-Stimulating Factor: Suggested Therapeutic Approach Pediatrics, September 1, 2001; 108(3): e54 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Horwitz, D. J. Prockop, P. L. Gordon, W. W. K. Koo, L. A. Fitzpatrick, M. D. Neel, M. E. McCarville, P. J. Orchard, R. E. Pyeritz, and M. K. Brenner Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta Blood, March 1, 2001; 97(5): 1227 - 1231. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
