Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies.
Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.
Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Weill Cornell Medical College, New York, New York 10065, USA.
José O
JO
Alemán
Azeez
A
Farooki
Monica
M
Girotra
D001862:Bone Resorption / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
bone; calcium; metastasis; parathyroid hormone; tyrosine kinase inhibitor