Skeletal effects of tyrosine kinase inhibitors

Chronic myeloid leukaemia (CML) is a pluripotent hematopoietic stem cell disorder characterized by a reciprocal translocation between chromosomes 9 and 22 resulting in formation of the Philadelphia chromosome. This chromosomal translocation gives rise to the chimeric BCR-ABL gene. The resulting BCR-ABL fusion protein is a constitutively active, oncogenic tyrosine kinase (TK) that causes cell transformation and CML. Ongoing from the year 2000 targeted therapy with imatinib has been replacing former therapies as frontline treatment for CML, not only in adults but also in children. Imatinib is a TK inhibitor (TK-I) acting by binding to the activation loop of ABL kinase and its derivative BCR-ABL, which traps the kinase in an inactive conformation.

In doing so, imatinib inhibits activity of the kinase and in patients with CML leads to an improvement of the median survival from formerly 5 years up to estimated >15 years. However, resistance to imatinib has become of increasing importance as relapse during imatinib treatment is most often caused by mutations in the kinase domain of BCR-ABL thus interfering with imatinib binding. Therefore “second generation” TK-I such as dasatinib and nilotinib were developed, being more active against BCR-ABL and against most of the imatinib resistant subclones. However, all these TK-I are multitarget TK-I which are not highly selective and also bind to other receptor TKs such as cKit, PDGF-R and c-FMS. For example, c-FMS represents the receptor for M-CSF, which after stimulation induces differentiation of blood monocytes into bone resorbing osteoclasts. Bone forming osteoblasts derive from mesenchymal stem cells which undergo differentiation under the control of signalling pathways including PDGF-R and c-ABL.

Thus, the inhibitory action of TK-I on TK active in downstream signals cascades may influence bone metabolism by inhibiting proliferation and differentiation of osteoblasts and osteoclast as well as their precursor cells. As a net result the balance between bone resorption and bone formation is changed. In line with these nonselective inhibition of non-BCR-ABL TKs clinical observations on adult patients with CML in imatinib describe hypophosphatemia and changes in bone metabolism by bone turnover serum markers, an increase in trabecular bone volume of iliac crest biopsies in one third to one half of the patients under investigation, as well as an increased bone mineral density as assessed by pQCT. In adult rodents imatinib decreases in vivo the number of bone lacunae as a result of reduced osteoclast activity. CML constitutes approximately 2–3% of all childhood leukemias and only a few studies have specifically addressed CML in childhood. Since licensing of imatinib in 2003 for children also pediatric patients with CML are treated increasingly with this drug responding with rates and side effects similar to adults. Probably due to the small number of cases so far -in contrast to adults-no data from larger series of children with CML on the influence of imatinib on the skeleton have been reported.

However, in three single case reports massive longitudinal growth retardation in prepubertal patients with CML under long term imatinib treatment has recently been documented (Mariani S et al. Lancet 2008; 372:111; Kimoto T et al. Int J Hematol; 2009, 89:251; Schmid et al Haematologica 2009;94:1177). Therefore any impact of imatinib on the bone in this not yet outgrown cohort might be of special concern.

  

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