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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1098-1104.
Prepublished online as a Blood First Edition Paper on May 9, 2007; DOI 10.1182/blood-2007-03-067710.
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Submitted March 2, 2007
Accepted May 7, 2007
Myeloma bone disease and proteasome inhibition therapies
Evangelos Terpos*, Orhan Sezer, Peter Croucher, and Meletios-Athanassios Dimopoulos
Department of Hematology & Medical Research, 251 General Airforce Hospital, Athens, Greece
Department of Hematology and Oncology, Charite - Universitaetsmedizin Berlin, Berlin, Germany
Academic Unit of Bone Biology, Section of Musculoskeletal Science, University of Sheffield Medical School, Sheffield, United Kingdom
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
* Corresponding author; email: e.terpos{at}imperial.ac.uk.
Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulates osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor- B ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct, and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical endpoints.
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