what-when-how
In Depth Tutorials and Information
of screening can detect about 90% of all type I collagen
mutations.
22
The need for these studies is best deter-
mined by a geneticist.
observational study, the authors concluded that cyclic
administration of intravenous pamidronate improved
clinical outcomes, including a reduction in the number of
fractures.
Plotkin and coworkers
28
evaluated the effects of pami-
dronate on early infancy. They administered intravenous
pamidronate to nine severely affected OI patients less
than 3 years of age for a period of 12 months. A control
group consisted of six age-matched, severely affected
OI patients who did not receive pamidronate treat-
ment. After 6 to 8 months, the fracture rate in the treated
group was lower than in control patients (2.6 versus 6.3
fractures/year). The authors noted that these younger
patients appeared to respond to treatment more rapidly
and to a greater degree than did older children.
Bajpai and colleagues
25
prospectively evaluated 20
children with OI treated with intravenous pamidronate
between the ages of 3 months and 8 years. The authors
reported that the rate of fractures decreased significantly
during treatment from approximately three fractures per
year to less than one fracture per year, with eight subjects
(40%) having no fractures during the treatment period.
Other studies have shown similar reduction of fracture
rates using pamidronate,
24,26,29,37
including type VI OI.
38
Recently, intravenous bisphosphonates other than
pamidronate have been found to reduce the rate of frac-
ture. Panigrahi et al.
39
retrospectively reviewed the use
of intravenous zoledronate, a longer-acting bisphos-
phonate, on a group of patients with type III OI. The
authors reported significant improvement in a reduction
in the frequency of fractures in all patients. As well, Gatti
et al.
40
in a randomized controlled study using intrave-
nous neridronate found a lower risk of clinical fractures
in the study group.
In studies using oral bisphosphonates in children, the
effect on fracture rates has been mixed. In a prospective
double-blind crossover study, Seikaly and coworkers
41
evaluated the impact of daily orally administered alen-
dronate on both the quality of life and bone parameters
in 20 children with OI, 18 of whom had type III and IV
OI. After 1 year of alendronate therapy, the authors noted
a reduction in the number of fractures in the treated
group.
Rauch et al.
42
studied the effect of orally administered
risedronate in a single-center randomized double-blind
placebo-controlled trial on 26 children and adolescents
aged 6 to 17 years with type I OI. After 2 years of treat-
ment, while the authors were able to demonstrate some
increase in the spinal bone density and decreased bone
turnover, there were no differences in the number of new
fractures when compared to the controls. More recently,
Ward et al.
43
in a large, multi-center, randomized con-
trolled trial of oral risedronate in children with moder-
ate to severe OI showed similar results demonstrating no
influence on reducing fractures.
ROLE OF MEDICAL MANAGEMENT TO
REDUCE FRACTURES
Bisphosphonate therapy is now commonly used
to treat children with moderate to severe OI. These
agents act as specific inhibitors of osteoclast-mediated
bone resorption. Intravenous pamidronate is the most
widely used bisphosphonate to treat OI in children.
Pamidronate is usually administered in a cycle of three
infusions on three successive days. The interval between
cycles is 2 to 4 months. Although generally not subjected
to randomized, placebo-controlled trials, intravenous
bisphosphonate treatment has been associated with
improvement of bone pain, long bone and vertebral bone
mass, and a reduced fracture rate compared to historical
controls.
24-31
Compared to normal children, the bone in children
with OI has fewer, thinner trabeculae and has decreased
cortical width. Treatment using bisphosphonates
increases the number of trabeculae, although it does
not alter their thickness. As well, these agents allow an
increase in cortical thickness by inhibiting bone resorp-
tion at the endosteal surface, while not interfering with
new bone formation at the periosteal surface.
30,32,33
One
study by Rausch and colleagues
32
compared parameters
of iliac bone histomorphometry from 45 patients before
and after approximately 2 years of pamidronate treat-
ment. The authors observed that cortical width increased
by 88%, and that cancellous bone volume increased by
46%. The latter finding was due to a higher trabecular
number, whereas trabecular thickness remained unal-
tered. The rationale for the use of bisphosphonates is that
these changes may result in improved mechanical bone
strength and make the bone more resistant to fracture.
Determining whether the administration of bisphos-
phonates truly reduces the rate of fracture in children
is complicated by the observation that the frequency of
fractures within an individual patient may vary with
age. As well, the fracture rate in patients with the mild to
moderate phenotype typically falls after puberty.
34-36
Despite these limitations, several studies of bisphos-
phonate treatment in children have described a reduction
of the fracture rate. In 1998, Glorieux and colleagues
30
administered pamidronate intravenously to 30 chil-
dren who were 3 to 16 years old and had severe OI. The
authors reported that the mean incidence of radiologi-
cally confirmed fractures decreased by 1.7 per year and
that treatment with pamidronate did not alter the rate
of fracture healing, the growth rate or the appearance
of the growth plates. Although this was an uncontrolled
