Imatinib Mesylate, Increased Bone Formation, and Secondary Hyperparathyroidism

Abstract

T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;23 www.nejm.org december 7, 2006 * Plus-minus values are means ±SD. Statistical analyses were performed with the use of a mixed-models approach to repeated measures (PROC Mixed software, SAS, version 9.1). Significant time effects were investigated post hoc with the use of the Tukey method to preserve an overall level of significance of 0.05. All tests were two-tailed. Reference ranges for osteocalcin, PINP, and β-CTX are for men and premenopausal women. GFR denotes glomerular filtration rate, and ND not done. † P<0.01 for the comparison with the baseline value. ‡ P<0.05 for the comparison with the baseline value. § Testosterone was measured in men only. The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission.

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

“…(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.…”

“…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. (17,(42)(43)(44) This decrease in serum phosphate is maintained for at least 12 months, (44) and in at least 50% of patients, the phosphate levels decrease to below the normal range (hypophosphataemia) at least once during therapy. (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.…”

Dysregulation of bone remodeling by imatinib mesylate

“…14 Similarly, a prospective study of 9 CML patients found that, relative to baseline, phosphate levels were significantly decreased after 3,6, and 18 months of imatinib treatment. 15,16 In a retrospective study of 17 CML patients receiving imatinib therapy over 17 to 69 months, there was a significant decrease in serum phosphate levels, compared with baseline. 17 In the largest study to date, Osorio et al 18 reported that 36 CML patients showed a significant decrease in serum phosphate levels after 3 months of imatinib treatment that was sustained until the final analysis at 12 months.…”

“…These studies strongly suggest that imatinib treatment results in decreased serum phosphate levels, [14][15][16][17][18] resulting in hypophosphatemia in at least 50% of patients. [12][13][14] In addition, these patients exhibit an increase in serum levels of PTH, secondary to decreased calcium levels, and increased serum 1,25 hydroxyvitamin D 3 .…”

Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis

“…To this end, current evidence suggests that patients undergoing treatment with imatinib mesylate exhibit dysregulated bone remodelling, resulting in an overall increase in trabecular bone volume. [11][12][13] This is thought to result from an inhibition of osteoclast activity and a concomitant activation of osteoblast activity by imatinib, through inhibition of c-fms and PDGFR, respectively. 5,11 Although it is unknown whether dasatinib alters the mineralization activity of osteoblasts, it could be predicted to promote osteogenesis as it is a potent inhibitor of PDGFR.…”