what-when-how
In Depth Tutorials and Information
able to swallow pills and who can take the precautions
that are required with oral bisphosphonates (such as
drinking a large glass of water with the pill, staying in
an upright position for at least 30 minutes thereafter).
55
However, oral therapy also has a number of draw-
backs, such as uncertain compliance, low and variable
bioavailability, as well as the possibility of gastrointes-
tinal side effects.
56
Oral treatment exposes the skeleton
to frequent small doses of medication, whereas intra-
venous treatment acts with lower frequency but at
higher doses. In growing children this difference leads
to specific radiographic features: intravenous treatment
leads to discrete metaphyseal lines that correspond to
horizontal trabecula, whereas oral treatment may lead
to a blurry zone of denser looking bone adjacent to the
growth plate.
In a number of observational case series beneficial
effects of oral alendronate treatment on bone density
and fracture rates were reported.
57-59
One small study
also found that oral alendronate was as effective as
intravenous bisphosphonate in increasing bone den-
sity.
60
A randomized study on 20 patients also found
that quality of life improved during alendronate treat-
ment.
61
Similar observations were made with oral
olpadronate.
62
A double-blind placebo-controlled trial in 139 chil-
dren and adolescents found that 2 years of oral alendro-
nate significantly decreased bone turnover, increased
spine bone mineral density and was generally well
tolerated.
63
However, no significant effect on the inci-
dence of fractures, bone pain or functional status was
evident. Sakkers et al. tested oral olpadronate at a
daily dose of 10 mg per m
2
body surface area in a ran-
domized placebo-controlled study that comprised 34
children and adolescents with OI.
64
After a treatment
period of 2 years, the group receiving active therapy
had a higher lumbar spine areal bone mineral density
and a lower incidence of long-bone fractures. No differ-
ence in functional outcome such as mobility and muscle
force was detected. In a study on children and adoles-
cents with mild OI who were treated with risedronate,
a difference in lumbar spine areal bone mineral den-
sity was observed, but not in fracture rate.
65
Another
study reported that fracture rates were lower during
risedronate treatment than before the institution of this
treatment.
66
In a study on children and adolescents with mild
OI, oral risedronate treatment resulted in an increase
in lumbar spine areal bone mineral density, but skele-
tal effects were weaker than those commonly observed
with intravenous pamidronate treatment.
65
Thus,
it appears that oral bisphosphonates are less effec-
tive in the treatment of pediatric OI than intravenous
bisphosphonates.
COMPLICATIONS OF BISPHOSPHONATE
TREATMENT
Despite the many reports on positive bisphospho-
nate treatment effects, there still remain concerns about
the effects of long-term treatment in growing children.
The documented side effects associated with bisphos-
phonate treatment can be classified into acute and long-
term adverse events.
There is ample documentation of the acute phase
reaction in children receiving the initial intravenous
dose of bisphosphonate; this has been shown with
pamidronate and zoledronic acid.
51
This can be con-
trolled with simple analgesics and does not recur on
subsequent infusions; however, it may be of more con-
cern in small infants who have concurrent respiratory
compromise.
67
Intravenous infusions can also cause a
transient drop in serum calcium with compensatory rise
in PTH and 1,25 vitamin D.
11
The potent anti-resorptive properties of bisphos-
phonates inhibit the normal remodeling activity that
acts to renew and repair bone. On the bone histologi-
cal level, bisphosphonate treatment may lead to the
appearance of unusually large osteoclasts.
68
However,
the presence of large osteoclasts in bone biopsy sam-
ples was not associated with any skeletal adverse
events.
68
Concerns linger about the potential buildup
of microcracks and calcified cartilage which could
potentially lead to poor bone healing and increased
fragility. It is unknown if the alteration of modeling of
the shape of bones may also lead to some detrimental
consequences.
69
Bisphosphonate treatment during early childhood
may delay tooth eruption.
70
A dental issue that has
received far more attention is osteonecrosis of the jaw,
a complication of poor soft tissue and bone healing.
This complication has mainly been reported in elderly
patients with cancer who have been given very high
doses of bisphosphonates.
71
Subsequent concerns have
been raised about whether this complication could arise
with the long-term use of bisphosphonates in children.
However, in 338 pediatric patients who were treated
with pamidronate at the Montreal Shriners Hospital
there was no evidence for delayed healing, exposed
bone or osteonecrosis of the jaw in any patient, even
though 242 teeth were extracted from 65 patients.
72
No
osteonecrosis of the jaw was reported also in 64 chil-
dren treated with pamidronate,
73
42 patients on pami-
dronate and zoledronate,
74
and 102 patients treated
with neridronate.
75
Although there is no evidence of delay in fracture
healing, there is significant delay in the healing of oste-
otomy sites after surgery for intramedullary rod inser-
tion and correction of deformities.
76,77
Treatment is
