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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2495-2496. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mathew, P. Search for Related Content PubMed Articles by Mathew, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  CLINICAL OBSERVATIONS Comment on Fitter et al, page 2538 Imatinib and the neoplastic bone microenvironment Paul Mathew M. D. ANDERSON CANCER CENTER The effects of aging, medical comorbidity, and systemic therapeutics interplay with the varied and distinctive capacities of neoplasms to usurp the physiological machinery regulating bone structure and function, thus determining skeletal morbidity and related mortality. In this issue of Blood, Fitter and colleagues report frequent increases in trabecular bone volume—a 2-fold increase over baseline in nearly half of patients with chronic myeloid leukemia (CML)—treated with the multi–tyrosine kinase receptor inhibitor, imatinib mesylate. Although the clinical significance of this anabolic and/or anticatabolic effect remains to be determined, these mechanistic studies offer a plausible explanation for the outcome. Functional studies presented in this issue of Blood, and previously by the same group1 and others,2 suggest that imatinib inhibits osteoclast maturation and function (via c-fms inhibition and decreased RANK expression) and promotes osteoblast maturation (via platelet-derived growth factor [PDGF] receptor inhibition) from mesenchymal osteoprogenitors—effectively tilting the balance in favor of bone formation. Since PDGF is mitogenic for mesenchymal osteoprogenitors, a reduction in the available pool of osteoblast precursors with imatinib therapy may diminish bone-mass formation even if differentiation is potentiated; however, preliminary findings from Fitter and colleagues suggest that this is not the case. Prospective studies to better characterize the cellular mechanisms and resultant effects of imatinib on the dynamic balance between osteoclast and osteoblast function will require detailed bone histomorphometry from undecalcified bone specimens aligned with results from body imaging, such as bone densitometry and microcomputed tomography of the spine and pelvis. View larger version (78K): [in this window] [in a new window]   Proposed mechanism for increased bone mass with imatinib.   Fitter and colleagues suggest that emerging long-term safety data justify the study of imatinib for disorders associated with bone loss if bone-mass data are confirmed. Concerns raised with respect to the potential cardiotoxicity of imatinib via c-abl inhibition in cardiomyocytes3 will have to be sufficiently dispelled to justify its long-term use in treating nonneoplastic conditions. Engineered variants of imatinib that retain beneficial activity without cardiac effects4 present an interesting alternative. Further studies of imatinib or its variants alone, in combination with, or in sequence with anticatabolic agents such as raloxifene, bisphosphonates, and denusomab, or anabolic agents such as the parathormone fragment teriparetide, may then follow. Might imatinib favorably influence neoplastic bone microenvironments that generate significant skeletal morbidity, unlike CML? There are few observations to this effect in the literature; however, in advanced castration-resistant prostate cancer with osteoblastic bone metastases, potent reduction in a marker of bone resorption (urine N-telopeptide) with a stable or increased marker of bone formation (bone-specific alkaline phosphatase) was seen when imatinib was combined with docetaxel.5 These data are in concordance with the inferences from Fitter and colleagues, although no clinical benefit to patients was identified. Tumor resistance may arise from an imatinib-driven tilt in the balance of neoplastic allegiance to osteoblast-generated growth factors rather than from osteoclasts. Studies in pure or dominant-lytic phenotypes of metastatic bone disease may thus be worth exploring; designs that incorporate pharmacodynamic monitoring, bone turnover markers, and skeleton-related endpoints may assist in defining biological subsets that benefit from the addition of imatinib to existing standard therapeutics. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Dewar AL, Farrugia AN, Condina MR, et al. Imatinib as potential antiresorptive therapy for bone disease. Blood 2006; 107:4334–4337.[Abstract/Free Full Text] O'Sullivan S, Naot D, Callon K, et al. Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms. J Bone Miner Res 2007; 22:1679–1689.[CrossRef][Medline] [Order article via Infotrieve] Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908–916.[CrossRef][Medline] [Order article via Infotrieve] Fernandez A, Sanguino A, Peng Z, et al. An anticancer c-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 2007; 117:4044–4054.[CrossRef][Medline] [Order article via Infotrieve] Mathew P, Thall PF, Bucana CD, et al. Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res 2007; 13:5816–5824.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Long-term imatinib therapy promotes bone formation in CML patients Stephen Fitter, Andrea L. Dewar, Panagiota Kostakis, L. Bik To, Timothy P. Hughes, Marion M. Roberts, Kevin Lynch, Barrie Vernon-Roberts, and Andrew C. W. Zannettino Blood 2008 111: 2538-2547. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mathew, P. Search for Related Content PubMed Articles by Mathew, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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