Increased Cortical Bone Mineralization in Imatinib Treated Patients with Chronic Myelogenous Leukemia.
Authors: Jonsson Sofia , Wei Yuan , Olsson Bob , Ohlsson Claes , Lorentzon Mattias , Mellstrom Dan , Wadenvik Hans 
Published: October 2019

Background: Imatinib mesylate (Gleevec™) is the drug of choice for most patients with chronic phase CML. It was recently suggested that hypophosphatemia develops in imatinib treated patients as a consequence of suppression of bone turnover and renal phosphate wasting.

Aim: To study the mineral metabolism, and areal and volumetric bone mineral density in chronic phase CML patients treated with imatinib.

Material and methods: Seventeen imatinib treated CML patients (11 males/6 females; mean age 60±11 (SD) years) and 17 healthy volunteers (11 males/6 females; mean age 59±11 (SD) years) were included. All CML patients were treated in first chronic phase, targeting an imatinib dose of 400 mg q.d. At time of study, all patients were in complete cytogenetic remission and the mean imatinib treatment duration was 50±19 (SD) months. Serum levels of total and ionized calcium, phosphate, magnesium, parathyroid hormone (PTH), and markers of bone formation (osteocalcin and bone specific alkaline phosphatase) and bone resorption (carboxyterminal cross-linked telopeptide of type I collagen) were analyzed. Twenty-four hours urine collections, for determination of calcium and phosphate excretion, were also obtained from all patients and controls. Areal and volumetric bone mineral density (aBMD and vBMD) were evaluated by dual energy x-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT), respectively.

Results: Imatinib treated patients had significantly lower serum levels of ionized calcium, phosphate, magnesium, osteocalcin and bone specific alkaline phosphatase. Serum PTH was higher in the patients compared the controls (p=0.06). The patients also excreted less calcium in the urine. aBMD were increased in hip and lumbar spine compared to controls.

The results of the DXA measurements. T-score is the difference of BMD from young adult (20–40 years; same sex) mean value normalised to the population SD. Z-score is the difference of BMD from age-matched (same sex) mean value normalised to the population SD.

vBMD was increased in cortical but not trabecular bone of tibia and radius.

The results of pQCT-measurements. vBMD and cross sectional area were measured at *4% and **25% bone length in the proximal direction.

Conclusion: Our data show that imatinib increases cortical bone mineral density and clearly rules out the previous concern of “imatinib induced osteomalacia”. It can be speculated that tyrosine kinase inhibitors could be novel antiosteolytic agents in skeletal disorders such as osteoporosis, myelomatosis and bone marrow metastatic diseases. Indeed, previous animal studies have shown that imatinib decreases osteoclastogenesis and osteoclast activity.

DXA CML (n=17) Controls (n=17) P-value Hip bone (total) aBMD (g/cm2) 1.08±0.2 0.95±0.1 0.025 T-score 0.07±1.42 −0.82±0.83 Z-score 0.46±1.37 −0.26±0.85 Lumbar spine aBMD (g/cm2) 1.27±0.22 1.12±0.15 0.029 T-score 0.38±1.77 −0.82±1.23 Z-score 0.57±1.72 −0.36±1.29 pQCT CML (=17) Controls (n=17) P-value Radius Trabecular vBMD* (mg/cm3) 190.9±34.2 193.9±28.8 ns Cortical vBMD** (mg/cm3) 1211.3±23.8 1181.1±38.7 0.01 Cortical area** (mm2) 95.1±16.3 88.6±18.7 ns Tibia Trabecular vBMD* (mg/cm3) 240.2±47.3 226.2±23.9 ns Cortical vBMD* (mg/cm3) 1185.6±23.5 1159.4±36.2 0.017 Cortical area** (mm2) 262.6±50.7 261.3±44.4 ns