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cartilage within trabecular bone tissue.
33,34
Decreased
bone turnover will delay the removal of primary bone
that is synthesized at the growth plate/metaphyseal
bone interface and that contains calcified cartilage cores.
Indeed, iliac bone histology reveals that pamidronate
therapy of growing OI patients is associated with a sig-
nificant increase in the amount of calcified cartilage.
33,34
This observation may explain why the radiographic den-
sity of vertebral bodies increases most at locations that
are close to the growth cartilage (end plates).
29
Although increased bone mass, size and density
cannot be simply equated with increased bone strength,
it can be assumed that these changes contribute to
decreased fracture rates in these patients.
29,31,35
One study followed 38 patients (age 4 to 21 years) for 2
years after the discontinuation of pamidronate treat-
ment.
39
Lumbar spine areal BMD continued to increase
in absolute terms after stopping pamidronate treatment.
However, since healthy subjects of the same age are
expected to increase their areal BMD even faster, areal
BMD z-score declined by 0.3. The effect of stopping pami-
dronate treatment varied between growing and non-
growing patients. The decrease in lumbar spine areal
BMD z-score following the discontinuation of treatment
was faster in growing patients (z-score decrease of −0.45)
than in patients who had reached final height (−0.15).
The long-bone changes on BMD after pamidronate
discontinuation are far more dramatic than those found
at the lumbar spine.
21,40
A study using peripheral quan-
titative computed tomography found that growing
patients receiving pamidronate had high trabecular vol-
umetric BMD at the distal radius.
21
When pamidronate
was stopped in these growing patients, metaphyseal
trabecular volumetric BMD decreased markedly from
significantly elevated values to significantly decreased
values within 2 years. In contrast, in patients who were
no longer growing at the time of their last pamidronate
infusion, trabecular volumetric BMD remained almost
unchanged. This was proof that the effect of pamidronate
discontinuation was much greater during the growing
period. Metaphyseal bone tissue added by longitudinal
growth after treatment discontinuation has a lower den-
sity than tissue created during treatment. It is possible
that this produces zones of localized bone fragility after
pamidronate treatment is stopped in growing children.
Indeed, fractures in the “untreated” metaphyseal bone
have been observed in growing children with OI who
had discontinued pamidronate treatment.
21
Oral Bisphosphonates
The increase on BMD with bisphosphonate treatment
is not limited to intravenous therapy but is also seen
with oral therapy. A multicenter, randomized controlled
trial on children and adolescents with moderate to severe
OI found that 2 years of treatment with oral alendronate
increased lumbar spine areal BMD by 51%, which was
significantly higher than the change observed in the pla-
cebo group (+12%).
36
The mean spine areal BMD z-score
increased significantly from −4.6 to −3.3 with alendro-
nate, while the change in the placebo group (from −4.6
to −4.5) was insignificant.
A smaller effect was found in a pediatric randomized
controlled trial on mild OI that assessed risedronate.
37
Two years of treatment increased lumbar spine areal
BMD z-score by 0.65 whereas patients receiving placebo
experienced a decrease of 0.15. However, risedronate did
not have a detectable effect on the volumetric BMD of
trabecular bone, as measured by peripheral quantitative
computed tomography at the distal radius. This is sur-
prising, as bisphosphonate effects in the growing skel-
eton are usually largest in the newly created metaphyseal
bone close to the growth plates.
21,38
For example, intrave-
nous pamidronate treatment of growing children leads
to radiographically visible lines in metaphyseal bone
and, correspondingly, to very high readings for trabecu-
lar volumetric BMD at this site.
21
In contrast, patients
who received risedronate did not have radiographically
detectable changes in the density of long-bone metaphy-
ses and no change in trabecular volumetric BMD at the
distal radial metaphysis. These observations in metaphy-
seal bone point to a weaker effect of oral risedronate than
intravenous pamidronate.
References
Bisphosphonate Treatment Discontinuation
One of the issues surrounding bisphosphonate ther-
apy in children and adolescents with OI is the question
of what happens when the treatment is discontinued.
