Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Berman, Ellin; Nicolaides, Maria; Maki, Robert G.; Fleisher, Martin; Chanel, Suzanne; Scheu, K.; Wilson, Bri-Anne; Heller, Glenn; Sauter, Nicholas

doi:10.1056/nejmoa051140

Cited by 287 publications

(225 citation statements)

References 24 publications

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“…(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. (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.…”

Section: Discussionmentioning

confidence: 99%

“…(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.…”

Section: Discussionmentioning

confidence: 99%

“…This may be indicative of decreased release of bone phosphate stores through inhibition of osteoclastogenesis, as has been suggested for patients undergoing imatinib therapy. (17,45) There is some concern that an inhibition of bone turnover may result in an increase in bone fragility through the accumulation of microfracture damage. (48)(49)(50) In healthy bone, the accumulation of microfractures over time is controlled by targeted bone remodeling.…”

Section: Discussionmentioning

confidence: 99%

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

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 mg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib-or ZOL-treated animals relative to controls. However, micro-computed tomographic (mCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. ß

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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“…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.…”

mentioning

confidence: 99%

Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis

et al. 2008

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“…In adults, hypophosphataemia in association with decreased levels of calcium, 25-OH-vitamin D, and 1,25-OH-vitamin D has been described. [33][34][35][36] These side effects may be of major concern in still growing patients.…”

Section: Adverse Effects Of Imamentioning

confidence: 99%

Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT

Suttorp

2008

Bone Marrow Transplant

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Allogeneic haematopoietic SCT (HSCT) induces CRs in most patients with CML. With the excellent short-term treatment results induced by imatinib (IMA), attitudes have changed and only a minority of children are now transplanted upfront. This review addresses the role of IMA in children with CML, focusing on the starting dose of IMA, possible adverse effects, timing of HSCT in children, duration of IMA treatment and monitoring of treatment efficacy to unravel failure of early treatment of IMA as well as treatment of CML relapse after HSCT. As the paediatric experience with IMA is still very limited, many answers and algorithms are adapted from CML in adults. Basically, HSCT should be postponed to achieve an optimal tumour cell reduction by IMA treatment. Children with a low-risk EBMT score should undergo HSCT within 2 years after diagnosis to avoid prolonged exposure and unknown late effects of IMA. Without a perfectly HLA-matched donor, HSCT may be postponed until CML becomes refractory to IMA. As realized in the presently activated international trial CML-paed II, this approach represents a risk-adapted therapy with the benefit of being tailored to the needs and profile of an individual patient.

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Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Cited by 287 publications

References 24 publications

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

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

Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis

Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT

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