The children were treated for various lengths of time, and therefore the magnitude of the effect of treatment
on most outcome measures was extrapolated to an annualized percent change from base line for each child.
In general, the longer-term data were negatively skewed in distribution, and therefore the data were log-transformed
to obtain a near-normal distribution. Analyses were performed with two-sided paired t-tests or the Mann–Whitney
rank-sum test, as appropriate. All the analyses were performed with DataDesk software (version 5.0.1;
Data Description, Ithaca, N.Y.).
Before treatment, all 30 children had normal serum concentrations of calcium and phosphate. After each infusion
cycle, there was a transient (two-to-four-week) decrease in serum calcium (mean decrease, 12±7 percent)
and serum phosphate (23±18 percent). Over a three-to-four-month period, there were more sustained decreases
in the serum concentration of alkaline phosphatase (14±18 percent), the urinary excretion of calcium (66±49
percent), and the urinary excretion of the N-telopeptide of type I collagen (43±31 percent). Throughout
the treatment period, there were steady decreases in serum levels of alkaline phosphatase (13±8 percent
per year, P<0.001) and urinary excretion of N-telopeptide of type I collagen (26±17 percent
per year, P<0.001).
Changes in Bone Density
All the children had low bone mineral density in the lumbar spine, with z scores ranging from –3.3 to
–7.8. During treatment, the mean bone mineral density increased markedly, by 41.9±29.0 percent
per year, and the mean z score improved from –5.3±1.2 to –3.4±1.5 (P<0.001); the z scores
of three patients reached the normal range. There were no significant differences between boys and girls or between
prepubertal children and children undergoing puberty (Table 2). The changes in bone mineral density over time for the nine children treated for two or more years
are shown in Figure 1. Concurrently with the change in bone mineral density, the mean coronal area of the first through fourth
lumbar vertebrae increased markedly, from 21.8±7.8 to 29.2±8.8 cm2 (Table 2).
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|Figure 1. Changes in the Bone Mineral Density of the First through Fourth Lumbar Vertebrae
in Nine Children with Osteogenesis Imperfecta Who Were Treated with Cyclic Administration of Intravenous Pamidronate for Two
or More Years.
The shaded area represents the normal range (mean ±2 SD) for age-matched healthy children (data from Hologic). The arrows
indicate the initiation of treatment. Each symbol represents one measurement.
On successive radiologic examinations of the thoracic and lumbar regions of the spine, no new vertebral crush
fractures were seen. Instead, an increase in vertebral height was noted over time (Figure 2), corroborating the increase in vertebral coronal area (Table 2). Characteristic dense lines appeared under the growth plates, particularly in the bones around the knees and
in the distal forearms, as well as in the vertebrae and along the iliac crests (Figure 3). The regular spaces between these lines corresponded to the intervals between treatment cycles, demonstrating
the continued growth of bone during therapy. Systematic surveys of the epiphyses showed no evidence of widening
or rachitis. In all the children, the bone ages corresponded to the chronologic age.
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|Figure 2. Lateral Radiographs of the Lumbar Spine of a Six-Year-Old Boy with Osteogenesis
Imperfecta before (Left-Hand Panel) and after (Right-Hand Panel) 18 Months of Treatment with Pamidronate.
Increases in the heights of individual vertebrae are evident. The bone mineral density before treatment was 0.205 g per
square centimeter, and after 18 months it was 0.371 g per square centimeter.
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|Figure 3. Anteroposterior Radiograph Showing Sclerotic Bands in the Metaphysis of the Distal
Femur in an Eight-Year-Old Boy with Osteogenesis Imperfecta.
This child received seven cycles of treatment. The seven evenly spaced bands demonstrate that growth continued steadily
An increase in the thickness of the cortex was often
the diaphyses of the long bones. In 26 of the 29 patients for
whom previous x-ray films were
available, the metacarpal cortical
width increased by an average of 27.0±20.2 percent per
year (Table 2
). This compares well with the gain of 8 to 9 percent
per year in healthy children from 3 to 16 years of age.17
Effects on Growth
Before treatment, 10 prepubertal children grew an average of 4.4±2.7 cm per year. During treatment, their growth
rate was maintained, at 5.7±2.2 cm per year (P=0.16). In 11 children undergoing puberty, the pretreatment
growth rate was 2.2±1.7 cm per year and increased slightly, to 4.9±3.4 cm per year, during treatment
(P=0.11). In healthy children the prepubertal growth rate averages 6 cm per year and increases to 9
to 10 cm per year during puberty.18
Clinical Outcome and Side Effects
The earliest response to treatment was a marked reduction in chronic bone pain one to six weeks after the initiation
of therapy, with only an occasional recurrence of pain in the days preceding a treatment cycle. Ambulation
was assessed according to the children's degree of independence and mobility.16 Before therapy, 5 children were fully functional (grade 4), whereas 16 were confined to a bed or a
wheelchair (grade 0 or 1). Ambulation scores improved in 16 children: 6 gained one grade, 5 gained two,
and 1 gained three, and 4 children progressed from being wheelchair-bound (grade 0 or 1) to walking independently
(grade 4). In the other 14 children, no change in grade was noticed.
The incidence of fractures decreased from 2.3±2.2 per year before treatment to 0.6±0.5 per year during treatment.
Nine children had no fractures during treatment, as compared with three children in the two years before
treatment. Fracture healing was not obviously delayed and there was no instance of fracture nonunion
In 26 children, body temperature increased on the second day of the first infusion cycle, a change accompanied
by back and limb pain in some. This "acute-phase reaction"19 was controlled with standard doses of acetaminophen and did not recur during subsequent treatment cycles.
Despite the small decreases in the serum calcium concentration that occurred soon after each infusion
cycle, none of the children had symptomatic hypocalcemia. Renal function did not change with treatment.
Osteopenia and bone fragility, the hallmarks of severe osteogenesis imperfecta, probably result from structural
abnormalities in bone tissue1 and a reduced rate of osteogenesis.11 Histomorphometric and biochemical studies have indicated that increased resorption of bone also contributes
to the disorder.11,20,21 Our initial goal in undertaking this study was to reduce bone resorption and to increase bone mass
in children with this disease. Cyclic administration of intravenous pamidronate resulted in a rapid increase
in the mineral density of the lumbar vertebrae, resulting from an improvement in the balance between bone formation
and bone resorption. The decrease in urinary excretion of the N-telopeptide of type I collagen,
a measure of bone resorption, was rapid and progressive. Serum concentrations of alkaline phosphatase, a
measure of bone formation, also fell, but to a lesser degree. Taken together, these results indicate that the rate
of bone turnover declined during therapy as a result of changes in the balance between formation and
resorption that favored an increase in bone mass. However, the decrease in resorption did not compromise bone
growth or fracture healing.
The bone mineral density of the lumbar spine, as measured by x-ray absorptiometry, is an area-related measurement
that is affected by both true bone mineral density and the volume of the vertebral body. In growing
children, the area-related bone mineral density increases by 3 to 6 percent per year before puberty
and by 14 to 16 percent per year during puberty.22,23 In our patients, annualized gains in bone mineral density during pamidronate therapy (41.9±29 percent)
substantially exceeded these values. The z scores for bone mineral density take into account the changes
in volume caused by growth.24 In all the children in our study, the z scores improved during therapy, suggesting that pamidronate
has a positive effect on bone mineral density. These changes were not caused by any crush-fracture–related
decreases in vertebral-body size, which would artifactually increase bone mineral density, since the vertebral
area increased in all the children (Table 2) and radiographs showed evidence of new bone formation (Figure 2).
These positive effects were accompanied by a significant increase in the width of the metacarpal cortices (Table 2). Thicker cortices were also seen on x-ray films of the long bones. These changes may have resulted
in part from the improvement in mobility in many children as the mechanical strain of walking stimulated new
bone formation.25 The biologic importance of these effects is underscored by the decrease in the rate of fractures, even though
the risk of fractures may have increased with the children's improved mobility and greater activity. In addition,
all the children reported relief of chronic pain. Pain relief from bisphosphonates has been noted previously
in adults with fibrous dysplasia of bone26 and in a child with vertebral collapse at the onset of acute lymphoblastic leukemia.27
In children with severe osteogenesis imperfecta, the growth rate is greatly reduced before the age of six or
seven years, and growth almost stops thereafter.28 In the children in our study, growth was reduced but not arrested before treatment, and during treatment,
linear growth proceeded at a slightly (but not significantly) increased rate. At least part of this gain
was probably due to increases in the size of the vertebral bodies. The sclerotic lines that appeared in the metaphyses
during treatment have no known functional importance and have been noted previously.7,9 Impairment of mineralization and widening of the growth plates have been reported in a 13-year-old boy who
received pamidronate at a dose similar to those we used in the present study.26 We found no evidence of such changes in any of the 30 children in our study.
In this observational study, both the patients and their physicians and other care givers had full knowledge
of the treatment being administered. We cannot exclude the possibility that there was a placebo effect,
particularly with respect to the relief of bone pain and the improvement in ambulation, or that the changes
reflect the passage of time rather than the effects of the treatment. However, the consistency of the clinical,
biochemical, and radiologic findings suggests that the changes resulted from the administration of pamidronate.
This medical therapy does not stand alone: it should be considered part of a coordinated, multidisciplinary
approach to the treatment of children with osteogenesis imperfecta, including timely corrective surgery,
physiotherapy, and occupational therapy. Continued follow-up will help delineate the response to therapy
over time and the limits of the gains that can be achieved.
Supported by the Shriners of North America. Dr. Bishop is the recipient of a European Society
for Paediatric Endocrinology Research Fellowship, sponsored by Novo Nordisk.
We are indebted to Denyse Lavallée for secretarial help; to Mark Lepik for artwork; to Mireille Dussault and
Anna Lis for technical help; to Nancy Mallinak (of Ostex) for the Osteomark kits; and to Kathleen Montpetit
and Nathalie Gervais (occupational therapy), Joanne Gibis (physiotherapy), Rose-Marie Chiasson (social
work), Jeffrey Hohenkerk (radiology), and the nursing staff of Shriners Hospital for their untiring assistance
in the examination and treatment of our patients.
From the Genetics Unit, Shriners Hospital for Children (F.H.G., N.J.B., H.P., G.C., G.L., R.T.), and the
Departments of Surgery and Pediatrics (F.H.G., N.J.B.), McGill University, Montreal.
Address reprint requests to Dr. Glorieux at the Genetics Unit, Shriners Hospital for Children, 1529 Cedar
Ave., Montreal, QC H3G 1A6, Canada.
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- Glorieux FH, Bishop NJ, Travers R, et al. Type V osteogenesis imperfecta. J Bone Miner Res 1997;12:Suppl 1:S389-S389.abstract
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