title: The skeletal effects of the tyrosine kinase inhibitor nilotinib.
abstract: Nilotinib is a tyrosine kinase inhibitor (TKI) developed to manage imatinib-resistance in patients with chronic myeloid leukemia (CML). It inhibits similar molecular targets to imatinib, but is a significantly more potent inhibitor of Bcr-Abl. Nilotinib exhibits off-target effects in other tissues, and of relevance to bone metabolism, hypophosphataemia has been reported in up to 30% of patients receiving nilotinib. We have assessed the effects of nilotinib on bone cells in vitro and on bone metabolism in patients receiving nilotinib for treatment of CML. We firstly investigated the effects of nilotinib on proliferating and differentiating osteoblastic cells, and on osteoclastogenesis in murine bone marrow cultures and RAW264.7 cells. Nilotinib potently inhibited osteoblast proliferation (0.01-1uM), through inhibition of the platelet-derived growth factor (PDGFR). There was a biphasic effect on osteoblast differentiation such that it was reduced by lower concentrations of nilotinib (0.1-0.5uM), with no effect at higher concentrations (1uM). Nilotinib also potently inhibited osteoclastogenesis, predominantly by stromal-cell dependent mechanisms. Thus, nilotinib decreased osteoclast development in murine bone marrow cultures, but did not affect osteoclastogenesis in RAW264.7 cells. Nilotinib treatment of osteoblastic cells increased expression and secretion of OPG and decreased expression of RANKL. In 10 patients receiving nilotinib, levels of bone turnover markers were in the low-normal range, despite secondary hyperparathyroidism, findings that are similar to those in patients treated with imatinib. Bone density tended to be higher than age and gender-matched normal values. These data suggest that nilotinib may have important effects on bone metabolism. Prospective studies should be conducted to determine the long-term effects of nilotinib on bone density and calcium metabolism.
authors.affiliation: Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. s.osullivan@auckland.ac.nz
authors.forename: Susannah
authors.initials: S
authors.lastname: O'Sullivan
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Lin
authors.forename: Maureen
authors.initials: M
authors.lastname: Watson
authors.forename: Karen
authors.initials: K
authors.lastname: Callon
authors.forename: Pak Cheung
authors.initials: PC
authors.lastname: Tong
authors.forename: Dorit
authors.initials: D
authors.lastname: Naot
authors.forename: Anne
authors.initials: A
authors.lastname: Horne
authors.forename: Opetaia
authors.initials: O
authors.lastname: Aati
authors.forename: Fran
authors.initials: F
authors.lastname: Porteous
authors.forename: Greg
authors.initials: G
authors.lastname: Gamble
authors.forename: Jillian
authors.initials: J
authors.lastname: Cornish
authors.forename: Peter
authors.initials: P
authors.lastname: Browett
authors.forename: Andrew
authors.initials: A
authors.lastname: Grey
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases