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.
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
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
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),
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
of fractures causes severe deformities and short stature, whereas
in type IV, deformities
and dwarfism are present but are less
In most children with type III and many with type IV
osteogenesis imperfecta, the disorder is progressive, with
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)
been used in attempts to increase bone mass and to reduce
the risk of fracture, but none have resulted in sustained
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
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
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
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.
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,
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