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Original Article
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Volume 339:947-952 October 1, 1998 Number 14
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Cyclic Administration of Pamidronate in Children with Severe Osteogenesis Imperfecta
Francis H. Glorieux, M.D., Ph.D., Nicholas J. Bishop, M.D., Horacio Plotkin, M.D., Gilles Chabot, M.D., Ginette Lanoue, R.N., and Rose Travers, R.T.

 

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by Marini, J. C.

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ABSTRACT

Background Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption.

Methods In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [±SD] dose, 6.8±1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment.

Results Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9±29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from –5.3±1.2 to –3.4±1.5. The cortical width of the metacarpals increased by 27.0±20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue.

Conclusions In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.


Osteogenesis imperfecta, often referred to as "brittle-bone disease," is a heritable disorder characterized in most affected persons by either a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes.1 The clinical severity of its expression varies widely. In its milder form (type I), fractures before puberty occur occasionally, deformity is minimal, and stature is normal. In its most severe form (type II), fractures in utero lead to pulmonary insufficiency, causing perinatal death. In type III osteogenesis imperfecta, a high frequency of fractures causes severe deformities and short stature, whereas in type IV, deformities and dwarfism are present but are less severe.2 In most children with type III and many with type IV osteogenesis imperfecta, the disorder is progressive, with increasing deformity of the limbs and spine, dependence on others for help in walking, and chronic pain. A variety of agents (including anabolic steroids, sodium fluoride, magnesium oxide, and calcitonin) have been used in attempts to increase bone mass and to reduce the risk of fracture, but none have resulted in sustained improvement.3,4,5,6

The bisphosphonate compounds are potent inhibitors of bone resorption, and they have been reported to have beneficial effects in children with osteogenesis imperfecta.7,8,9,10 We have reported the results of histomorphometric studies of bone suggesting that this disorder is associated with an increase in osteoclastic activity and a reduction in the formation of new bone.11 Our study was designed to assess the effects of bisphosphonate treatment in children with severe osteogenesis imperfecta.

Methods

Subjects

Between October 1992 and December 1997, we administered pamidronate to 30 children, 3 to 16 years old, who had severe osteogenesis imperfecta (Table 1). All had severe osteopenia, and 27 were small for their age (below the third percentile for height). All but five had moderate-to-severe restrictions in ambulation. The study was approved by the ethics review board of our institution, and parents or legal guardians gave written informed consent.

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Table 1. Characteristics of 30 Children with Osteogenesis Imperfecta before Pamidronate Treatment and Their Treatment Schedules.

 
In nine children the osteogenesis imperfecta was classified as type III, and in nine others as type IV. In 12 children the disorder could not be classified; these children had features similar to those of type IV osteogenesis imperfecta but with various combinations of severe long-bone deformity resulting from fractures after birth, vertebral collapse, and changes in the long-bone metaphyses. Four of these 12 patients had the clinical features of the newly described type V osteogenesis imperfecta.12

Treatment

Pamidronate disodium (Aredia, Ciba–Geigy, Dorval, Que., Canada) was diluted in 250 to 500 ml of isotonic saline and administered by slow intravenous infusion over a four-hour period on each of three successive days. The dose, based on the dose given to adults for the treatment of Paget's disease of bone,13,14 was 1.5 or 3.0 mg per kilogram of body weight per infusion cycle. Half the children received the lower dose during the first year of treatment, after which their regimen was shifted to the higher dose. The other half received only the higher dose. In one child, because of a slow initial response to therapy, the dose was increased after one year to 3.75 mg per kilogram per cycle. Overall, the children received a mean (±SD) of 6.8±1.1 mg per kilogram per year and 4 to 12 cycles of treatment. The mean duration of treatment was 765 days (range, 490 to 1813 [approximately 1.3 to 5.0 years]) (Table 1). Initially, the interval between cycles was six months. However, monthly measurements of the serum alkaline phosphatase concentration and the urinary excretion of calcium revealed an increase in both after four months, and therefore the interval between cycles was shortened to four months. The patients' calcium intake was regularly evaluated and was maintained at 800 to 1000 mg per day through diet and supplementation. Their vitamin D intake was at least 400 IU per day.

Measurements

Clinical evaluation, including assessment of anthropometric variables and pubertal development, occupational-therapy evaluation, and bone densitometric measurements, were performed at each admission for pamidronate infusion. Accurate records for use in evaluating the growth rate before treatment were available for 21 of the 30 children (10 prepubertal and 11 pubertal).

The subjects fasted overnight. Blood and urine (from the second morning voiding) were obtained before each infusion of pamidronate, and blood alone immediately thereafter. Serum and urine concentrations of calcium, phosphate, and creatinine and the serum concentration of alkaline phosphatase were measured by colorimetric methods (Monarch, Instrumentation Laboratory, Lexington, Mass.). The urinary excretion of the cross-linked N-telopeptide of type I collagen, a marker of bone resorption, was measured by enzyme-linked immunosorbent assay (Osteomark, Ostex, Seattle).

X-ray films of the skull, upper and lower limbs, and spine (anteroposterior and lateral views) were obtained at 6-to-12-month intervals. Films were examined on an ongoing basis by pediatric radiologists unaware of the treatment status of the children. Changes in the bone mineral density of the lumbar spine, both in terms of absolute values and in terms of age-corrected values (z scores), were measured by dual-energy x-ray absorptiometry (QDR 2000W, Hologic, Waltham, Mass.). The coronal area of the first four lumbar vertebrae, automatically measured by the software used for absorptiometric analysis, was taken as an index of vertebral-body size. The coefficient of variation for the bone mineral density of the lumbar spine was 1 percent on repeated measures in healthy children. On posteroanterior radiographs of the hand taken at a uniform 40-in. (102-cm) tube-to-film distance, the cortical width of the metacarpals (defined as the distance between the external cortical surfaces minus the width of the medullary cavity) was measured with vernier calipers at the midpoint of the second left metacarpal. These measurements were made immediately before treatment and after one or two years of treatment. On the same radiographs, the bone age was determined according to the method of Greulich and Pyle.15 All available radiographs from the two years before treatment and those obtained during treatment were assessed for evidence of fractures.

Occupational therapists experienced in the care of children with osteogenesis imperfecta evaluated the subjects' mobility and ambulation using a five-point scale, as follows: 0 (bed- or wheelchair-bound), 1 (able to walk with aids, but not functionally mobile), 2 (able to walk in the household, with or without aids), 3 (able to walk short distances, with or without aids), and 4 (able to walk independently).16 Edit Text

 

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