Proteasome inhibition therapies in childhood cancer

We enjoyed the excellent and timely review by Terpos et al.1 in a recent issue of Leukemia on the effects of novel anti-myeloma agents on bone metabolism. In this review, the authors elaborate on the ubiquitin/proteasome system in bone, and the use of proteasome inhibitors (PIs) in myeloma bone disease. The authors emphasize that PIs, including bortezomib, act locally in the bone to stimulate osteoblast differentiation while inhibiting osteoclast formation and making them attractive agents for further investigation, as they may combine anti-myeloma activity with beneficial effects on bone. Indeed, recent in vitro and in vivo observations support the hypothesis that a direct stimulatory effect on the bone formation process could occur during bortezomib treatment.2 Terpos et al. propose prospective studies with specific clinical end points, such as bone mineral density, to be undertaken. However, when designing such studies, we believe that it is important to pay particular attention to the recent observation that systemic administration of PIs specifically impairs the ubiquitin/proteasome system in chondrocytes and growth plate cartilage.3