Introduction
Bony morbidity is common in children with acute lymphoblastic leukemia
(ALL). Pain is a frequent symptom at diagnosis,1associated with an expanding cell mass in the medullary cavity, and
vertebral fractures at this time are prominent and often unrecognized
clinically.2 Osteopenia, reflecting loss of bone
mineral, is demonstrable before the initiation of
therapy3 and becomes more evident with the onset of
treatment.4 The contributing factors include
glucocorticoid and methotrexate medication, cranial irradiation (now
used much less frequently) and reduced physical
activity.5
Additional bony morbidity is seen in the form of osteonecrosis that
shares an etiology with osteopenia, from exposure to high cumulative
doses of corticosteroids, although the pathogenesis is
different.6 Both osteopenia7 and the
symptoms of osteonecrosis8 may be ameliorated by the
administration of bisphosphonates.
These compounds are structural analogues of natural inorganic
pyrophosphate which explains their very high affinity for bone because
they bind to crystals of hydroxyapatite and impede their breakdown, so
suppressing bone resorption.9 The third generation
bisphosphonates, including alendronate and pamidronate, have side chains
containing nitrogen. These agents bind to and inhibit farnesyl
pyrophosphate synthase, an important enzyme in the mevalonic acid
pathway. In turn this results in dysregulation of osteoclast metabolism
with eventual apoptosis.9 Bone resorption remains
suppressed for the duration of treatment. With oral agents only about
50% of the absorbed dose is retained in the skeleton, the remainder
being excreted in the urine. The amount of bisphosphonate retained
varies considerably among patients and between clinical disorders,
probably reflecting variations in bone turnover.8
In our preliminary experience from 2000, intravenous pamidronate was
effective in redressing the depletion of bone mineral but poorly
tolerated;10 however, oral alendronate, with 5 fold
greater potency,9 was well tolerated and retained
clinical efficacy,11 despite low
bioavailability.12
Nonetheless, concerns have been expressed about the safety and efficacy
of bisphosphonates in children.13 While there have
been no reports in childhood of the uncommon but dramatic problem of
osteonecrosis of the jaw encountered in adults,14 even
in those children undergoing invasive dental procedures while receiving
a bisphosphonate,15 the long-term impact of these
drugs on growing bones is uncertain.16 Likewise,
although bisphosphonates may exert anti-tumor
effects,17,18 minor hematological abnormalities have
been described with the administration of these
agents19 and longer term adverse sequelae on
hematopoiesis should be considered, including relapsed disease.
Consequently, we have undertaken studies of the short and long-term
efficacy and safety of bisphosphonates in children with ALL.