Decreased Bone Turnover Despite Persistent Secondary Hyperparathyroidism during Prolonged Treatment with Imatinib

Abstract

Long-term treatment with imatinib leads to persistent mild secondary hyperparathyroidism. Despite this, bone turnover is decreased, and bone density is stable or increased. Evaluation of the skeletal actions and safety of imatinib during longer-term therapy is warranted.

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

“…(17) Additionally, two subsequent studies showed that CML patients undergoing imatinib therapy exhibited small increases in regional BMD. (40,41) In support of these findings, several groups have shown that CML and gastrointestinal stromal tumor (GIST) patients undergoing imatinib treatment display altered serum biochemistry that is suggestive of changes in bone remodeling. In particular, a number of studies show that decreased levels of serum phosphate occur as early as 3 months following initiation of imatinib treatment in CML and GIST patients.…”

“…(42,45,46) Decreased serum phosphate levels in imatinib-treated patients are associated with increased serum parathyroid hormone levels, decreased levels of the bone resorption marker CTX-1, and in at least some cases, a decrease in serum calcium levels. (17,40,41,(43)(44)(45) To our knowledge, there have been no published reports suggesting that changes in bone remodeling occur in patients receiving dasatinib. However, grade 3 or 4 hypophosphatemia has been reported in 11% of dasatinib-treated patients.…”

Second-generation TKI dasatinib inhibits proliferation of mesenchymal stem cells and osteoblast differentiation in vitro

“…The oncogenic fusion protein MOZ-TIF2 is one of several fusion products resulting from reciprocal chromosomal rearrangements in the MOZ/MYST3/KAT6A gene in acute myeloid leukemia. 1 Previous studies have shown that MOZ-TIF2 transforms haematopoietic progenitors 2,3 and induces acute myeloid leukemia in a murine bone marrow transplant model. 2,4 MOZ-TIF2 induces widespread changes in histone acetylation, 3,5 subverting the development of haematopoietic progenitors towards leukaemia.…”

“…[1][2][3] Considering that dasatinib and imatinib partly inhibit the same tyrosine kinases, similar effects on bone metabolism might be seen with the second-generation TKI dasatinib.…”

“…The increased BMD observed in imatinib-treated patients [1][2][3] can thus be due to diminished bone degradation or increased bone formation. Imatinib inhibits differentiation and activity of osteoclasts in vitro and in animals through the inhibition of colony-stimulating factor 1 receptor (CSF1R), and dasatinib seems to have similar effects on osteoclasts.…”