what-when-how
In Depth Tutorials and Information
survival.
141
In addition, impaired growth was seen in
animal models including the
oim
mouse model.
142,143
In the
oim
mouse there was an overall increase in the
hypertrophic zone implicating failure of vascular inva-
sion-induced apoptosis in the hypertrophic cells and
inhibition of long bone length through alteration of the
growth plate.
143
However, in human studies, pamidro-
nate improved linear growth overall, as detailed above;
in addition, bisphosphonates improved vertebral bone
mineral mass and helped to attain more normally shaped
vertebral bodies
144,145
as well as increase cortical thick-
ness as evidenced in iliac crest bone biopsy samples.
4,145
growth hormone injections increased spine and femur
length in a mouse model of OI when compared with
saline-treated control animals. Femur BMC, cross-sec-
tional area and BMD were increased, with smaller gains
in vertebral BMC and cross-sectional area. Biomechanical
testing showed improvements to structural and material
properties in the femur midshaft.
151
Marini et al., in their initial study, treated OI patients
with either rGH or clonidine (a stimulant of GH secre-
tion) and found an increase in linear growth rate in a
group of children with type I, III and IV OI.
18
In a later
study by these authors,
91
26 children with type III and IV
OI ranging in age from 4.5 to 12 years were treated with
rGH at 0.1-0.2 IU/kg/day for 6 days/week for at least
1 year (0.033-0.067 mg/kg/day). Approximately half of
the children who were treated had a ≥50% increase in
linear growth over their baseline growth rate (referred
by the authors as “responders”). There appeared to be a
group of children with type IV OI specifically who ben-
efited from the rGH treatment in terms of linear growth
velocity and synthesis of bone matrix (10 out of 14 chil-
ren), more than those with other OI types who showed
less of a response. Interestingly, the responders to rGH,
again mostly with type IV OI, were distinguished from
the non-responders by higher baseline carboxy-terminal
propeptide of type 1 procollagen values, suggesting an
intrinsically higher capacity for collagen production.
There was also an apparent decrease in the fracture rate
for the responders during the treatment compared with
the average fractures per year prior to treatment. In this
study GH treatment determined an increase in cancel-
lous bone volume and trabecular number in “respond-
ers,” but cortical bone did not change at all, even in those
responding in terms of growth. This is an important
issue to consider, as cortical bone is critical for the bio-
mechanics of long bones. Furthermore, bone resorption
appeared to be increased in “non-responders.” An exten-
sion of this study is ongoing.
152
The authors currently
propose to treat up to an additional 20 children who
are responsive to growth hormone (0.06 mg/kg/day)
until final adult stature is attained. Children are eligible
for entry into the growth hormone treatment arm of the
protocol until age 8. Under this protocol, all participants
will be treated for 1 year to identify responders. Only
responders will be treated for an additional 2 years. After
the third year of treatment, responders will be defined
as those children who demonstrate a sustained increase
of 30% or greater above baseline. These 3-year respond-
ers will be treated with growth hormone through final
adult height. No study results have been posted on
ClinicalTrials.gov to date. The estimated completion date
for this study is February, 2014.
Antoniazzi et al. found that linear growth veloc-
ity increased after 1 year of rGH treatment in patients
with OI compared to the untreated group and that the
GROWTH HORMONE AND COMBINED
GROWTH HORMONE/BISPHOSPHONATE
TRIALS IN OI
Growth hormone was proposed as a possible treat-
ment in OI as far back as 1975
146
based on the fact that
GH stimulated the expression of IGF-1 and IGFBP-
3, which then stimulated collagen type I. A concern
with GH treatment that has been proposed is that fur-
ther stimulation of bone turnover, which occurs with
GH, may be undesirable in a condition in which there
is already increased bone turnover.
6,147
In addition, a
concern of a possible increase in fracture rate in some
patients was proposed based on a review of all studies
of GH use in OI.
148
A review of 13 children with OI (all
types) who were enrolled in one of the large clinical data-
bases of rGH treatment (National Growth Cooperative
Study) revealed increases in growth velocities through
to the third year of therapy with a leveling off by year
4 (although long-term data were only available in three
patients).
148
To date, there have been no published properly con-
trolled human studies for the use of GH treatment in
patients with OI. The few published studies were uncon-
trolled or controlled versus bisphosphonates (and the
effects of bisphosphonates on growth of patients with
OI had not been tested in properly controlled stud-
ies).
18,87,88,91,149
Similarly, human studies have been short-
term, and no published studies present data on final
height which is the gold standard for treatment effect.
Animal studies have been conducted in a mouse OI
model. In one study, a human growth hormone trans-
gene was bred into mice of the Cola2oim (oim) lineage.
Caudal vertebrae from male and female mice at early
skeletal maturity and at midlife were evaluated for
physical and biomechanical properties.
150
The authors
found that GH transgene expression increased the size
and mineral content of the vertebrae from mutant mice,
and increased biomechanical structural values for maxi-
mum load and energy to failure, although failure stress
was not improved. The same group found that systemic
