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the mean) with normal GH testing and without a known
etiology of the short stature. ISS responds modestly to
rGH therapy utilizing doses higher than for the other
indications, with results from trials ranging from 4 to
9 cm of increased linear growth. 118-120 There have been
several studies examining the effects of rGH in children
with cystic fibrosis, although not yet FDA approved.
Overall, the controlled trials have shown improvements
in pulmonary function, weight, growth velocity and
bone mineralization. 121,122 There was also a decrease in
the rate of hospitalizations. Critically ill patients, how-
ever, should not be treated with rGH, as there is a sig-
nificantly increased mortality rate noted in patients
in intensive care units for heart or abdominal surgery,
trauma and acute respiratory failure. 123,124
no definitive correlation was found, and the meaning of
these data is still unclear. 135
In December 2010, the United States Food and Drug
Administration released information concerning the
safety of rGH treatment that was prompted by the
SAGhE study in France ( S afey and A ppropriateness of
G rowth H ormone treatments in E urope) which suggested
a small increased rate of death among patients treated
with rGH between 1985 and 1996 compared to individu-
als in the general population of France (1.3% instead of
the 1.0% expected mortality). The study was published
in 2012 136 but, at this time, the interpretation and further
review of the data are ongoing. Another study published
in 2012 from the Netherlands, Belgium and Sweden
revealed no increase in mortality. 137 Until long-term stud-
ies are appropriately carried out, these findings remain
difficult to interpret. 126-128 The FDA has not changed any
treatment recommendations based on these studies.
SIDE EFFECTS AND RISKS OF GROWTH
HORMONE TREATMENT
GROWTH EFFECTS OF
BISPH OSPHONATE TREATMENT IN OI
The side effects of rGH are well known (for review
see 125 ). The most common side effects of treatment include
pain, discomfort and bruising with injections. Fluid reten-
tion, carpal tunnel syndrome, joint aches and muscle
aches can occur, although are more common in adults
and usually resolve within 1-2 months of treatment. Some
patients develop low thyroid hormone levels and elevated
glucose levels. Benign intracranial hypertension is a rare
side effect that resolves when growth hormone is discon-
tinued or the dose is decreased. Of particular interest for
the treatment of OI patients is that scoliosis may occur if
the growth rate is very rapid, and slipped capital femoral
epiphysis may occur rarely. Other rare side effects include
pancreatitis and adrenal insufficiency. Growth hormone
should not be used in patients with an acute malignancy,
benign intracranial hypertension, preproliferative/prolif-
erative diabetic retinopathy or pregnancy.
Growth hormone is considered overall a safe therapy,
although long-term risks are still being investigated
(for review see 125-128 ). Leukemia has occurred in a small
number of growth hormone deficient children treated
with growth hormone 129 but not at a higher frequency
than in the general population. However, because of the
initial report in 1988, the possibility of an increased can-
cer risk has been followed. There are studies that reveal
a correlation with increased IGF-1 levels with certain
cancers, 130-132 and therefore most pediatric endocrinolo-
gists follow IGF-1 levels while treating with rGH. Large
international databases of patients treated with recombi-
nant growth hormone did not show any association with
malignancy and growth hormone treatment (KIGS dat-
base 133 and NCGS database 134 ). A study in 2002 revealed
a possible increased incidence and mortality from colon
cancer and increase in mortality for Hodgkin's disease in
patients who had received the cadaveric hGH; however,
Although the primary reason for intravenous bisphos-
phonate treatment in patients with moderate to severe
OI has been to improve bone mineral density and
reduce pain with the overall aim of decreasing frac-
tures, bisphosphonates have been found to have sig-
nificant effects on improving height Z-scores in OI type
IV, specifically pamidronate. To date, there are no pub-
lished properly controlled studies of the use of bisphos-
phonates in OI to improve linear growth definitively.
Investigations of intravenous bisphosphonate therapy
on bone fragility led to observations that height Z-score
improved in OI patients who were treated before 3 years
of age 138 and led to further studies on the impact of lin-
ear growth with long-term bisphosphonate treatment
with resultant height Z-score improvements in moderate
OI but without significant trends in mild or severe OI. 3
When the heights were examined as a percentage
of that expected for untreated patients with the same
type of OI, there was still a significant increase in height
in OI type I and type III. 3,4,6 The final height data were
obtained for eight patients while on pamidronate and,
when expressed as percentage of the expected height in
untreated patients, were significantly greater than base-
line height. 3 Bone ages assessed during the course of
treatment matched chronologic age. The initial hypoth-
esis for the potential benefit of pamidronate use 139 was
based on diminishing the ability of osteoclasts to coun-
terbalance the weakness of the osteoblast. Interestingly,
there had been concern that the use of bisphosphonates
in OI could inhibit linear growth in children given that
they could have a negative effect on bone growth by
interfering with osteoclast function 140 or osteoclast
 
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