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.