Endocrine Abstracts (2008) 17 OC9

Possible mechanisms for osteonecrosis during treatment for childhood acute lymphoblastic leukaemia: effects of chemotherapy and lipopolysaccharide on osteocytes

A Abdussalam, C Elford, MEM Jenny, JW Gregory & BAJ Evans

Cardiff University, Cardiff, UK.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Given dramatic improvements in survival rate (>80%), long term quality of life is of rising concern. Skeletal complications including osteonecrosis (ON) are being reported more frequently, affecting up to 38% of children treated for ALL though the pathogenesis is unclear.

The purpose of this study is to examine possible mechanisms causing ON. We hypothesize that polychemotherapy and/or the vulnerability of treated children to infection may predispose to osteocyte apoptosis or effect osteoclastogenesis thus contributing to the development of ON. We have therefore evaluated the effect of several chemotherapeutic agents (dexamethasone, vincristine, methotrexate and L-asparaginase) and the endotoxin lipopolysaccaride (LPS) on culture numbers of cells of established murine cell lines representative of early osteocytes (MLO-Y4) and late osteoblast/early osteocytes (MLO-A5) and on osteoclastogenesis.

All chemotherapeutic agents variably decreased numbers of osteocytes/osteoblasts. There was no adverse effect of LPS +/− dexamethasone on the proliferation of either osteocyte cell line. However, LPS alone decreased human osteoclastogenesis.

Table Lowest concentrations of chemotherapy reducing osteocyte cell numbers in culture.
Dexamethasone10−7 M*10−8 M*
Vincristine10−10 M10−8†
L-asparaginase0.25 IU0.125 IU
P-value *<0.01, <0.001.

In conclusion, chemotherapy may predispose to ON by adverse effects on osteocytes with those more similar to established osteocytes (MLO-Y4) demonstrating greater resistance to this effect. By contrast infection may contribute to ON through effects on osteoclasts. Ongoing work is studying the effects of chemotherapy and LPS on apoptosis and the osteocyte secretion of markers of angiogenesis which have also been implicated in ON.

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