Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment

Bernadette Anna Sophia Jaeger, Josephine Tabea Tauer, Anna Ulmer, Eberhard Kuhlisch, Heinz Juergen Roth, Meinolf Suttorp, Bernadette Anna Sophia Jaeger, Josephine Tabea Tauer, Anna Ulmer, Eberhard Kuhlisch, Heinz Juergen Roth, Meinolf Suttorp

Abstract

Background: Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure.

Material/methods: Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type l N propeptide [PINP], and C-terminal cross-linking telopeptide of collagen [CTX-I], osteocalcin [OC]; pyridinoline [PYD], and desoxypyridinoline [DPD]) were determined in 17 patients with CML aged 4-17 years under imatinib treatment in three-month intervals over a 2.5 year period.

Results: Hyperparathyroidism developed in 8/17 patients and low 25-hydroxyvitamin-D3 levels were found in 15/17 patients. Increased OC levels were detected in 58% of all specimen showing a linear significant decline of -0.30 µg OC per l per week (p=0.04). Serum PINP was lowered in 25% and serum CTX-I was above the normal range in 57% of the specimen originating exclusively from prepupertal patients. Urine PYD and Urine DPD levels were above the normal range in 10% and 9%, respectively, of all specimen collected and a statistically significant linear decline of -0.16 nmol DPD/mg creatinine/week was calculated (p=0.01).

Conclusions: Bone remodeling may be dysregulated by imatinib. Data suggest that impaired bone formation exceeds that of decreased bone resorption. Regular evaluation of the skeletal actions during long-term imatinib treatment in childhood CML is warranted.

Trial registration: ClinicalTrials.gov NCT00445822.

Figures

Figure 1
Figure 1
(A) 25-vit-D3 (major circulating vitamin D metabolite) serum levels during imatinib treatment. Compared to months with higher sunlight exposure measurements were significantly lower in the winter time. The probability to exhibit normal measurements was calculated to be 5.86-fold higher in the summertime than in the wintertime (p=0.016). (B) 1,25-vit-D3 serum levels during imatinib treatment. No effect of exposure to sunlight could be detected.
Figure 2
Figure 2
Osteocalcin (marker of bone formation) plasma levels during imatinib treatment. Normal values are age and sex dependent and measurements were classified as above, within, or below the normal range in correlation to Tanner stages as indicated in reference [20]. Thirty-three out of 57 measurements (58%) were above the normal range. A significant decline over time of 0.03 mg osteocalcin per l per week could be calculated.
Figure 3
Figure 3
Desoxypyridinoline (DPD, marker of bone resorption) concentration in second void urine specimen during imatinib treatment. Although 50 out of 57 measurements were found within the normal range a significant linear decline of −0.16 nmol DPD per mg creatinine per week could be demonstrated.

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