Original Full Length ArticleEarly injury to cortical and cancellous bone from induction chemotherapy for adolescents and young adults treated for acute lymphoblastic leukemia☆
Introduction
Chemotherapy for pediatric acute lymphoblastic leukemia (ALL) is known to adversely impact bone density and is associated with skeletal fractures [1], [2], [3], [4]. Recent reports have described the onset of osteotoxicity earlier than previously thought with bone changes now understood to primarily occur during active therapy [5], [6] with potential improvement for some in the years following therapy [7], [8]. While the etiology for the adverse influence of ALL therapy on bone is likely multi-factorial, a significant contributor is prolonged and repetitive high-dose glucocorticoid steroids given throughout the two to three years of ALL treatment [9]. Prior studies of osteotoxicity have therefore principally focused on the cumulative effects of ALL treatment on bone density after months or even years of ALL therapy [10], [11], [12], [13], [14]. Yet, ALL therapy commonly begins with a treatment phase (Induction) that relies on an established backbone of glucocorticoid steroids to obtain the crucial initial remission. Recently, the large Canadian “STeroid-associated Osteoporosis in the Pediatric Population (STOPP)” clinical trial revealed that occult fractures and vertebral compression are already frequent occurrences even during this first treatment phase. However, many studies that have examined bone during this early time period, including the STOPP trial [15] and others [13], [16], have grouped much, or all, of Induction chemotherapy into a single cross-sectional time-point, thereby precluding examination of changes to bone during Induction itself from the days or weeks of osteotoxic chemotherapy [16].
In the present study, we sought to address this knowledge gap through focusing specifically on changes to bone during the Induction phase and to gain greater insight into potential changes due to leukemia infiltration of the marrow even prior to therapy. Use of the advanced imaging modality of quantitative computerized tomography (QCT) provided the opportunity to gain detailed information on bone properties, such as three-dimensional volumetric BMD (vBMD), bone geometry, and other contributors to bone strength. As much of the existing bone density literature in ALL uses the well-validated, and more commonly available, dual-energy x-ray absorptiometry (DXA) to assess areal BMD (aBMD) [12], [17], [18], we concurrently assessed whole body aBMD in our cohort with DXA as well. To our knowledge, this is the first study to use QCT to determine detailed bone structure and density at the time of diagnosis and to focus on early changes from Induction therapy for childhood ALL.
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Study population
Pre-adolescents, adolescents and young adults (AYA) at least ten and less than 21 years of age newly diagnosed with National Cancer Institute/Rome High-Risk B-Precursor (HR BP-ALL) or T-cell ALL were enrolled in a prospective study of osteotoxicity within 24 h from the initiation of Induction chemotherapy. An AYA population was selected for study as an at-risk target population with greater rates of chemotherapy-induced osteotoxicity [19], [20]. All patients were treated following Children's
Effect of leukemia on bone at diagnosis
Of the 51 subjects enrolled on study, 38 were able to complete imaging at diagnosis and were included in the analysis for comparison to healthy controls. The majority of subjects in the ALL cohort were male (58%, n = 22/38), Hispanic (84%, n = 32/38), with an average age of 14.6 years (range 9.9–19.6). Eighteen of these 38 subjects had imaging at the tibia site. As shown in Table 1, Table 2, the subjects in the age- and sex-matched groups did not differ significantly in height, weight, or body
Discussion
We present here the first detailed study using QCT to examine bone density and structure at diagnosis and during early therapy for newly diagnosed pediatric ALL. We documented a dramatic decline in cancellous vBMD during the first month of treatment, along with evidence of early thinning of cortical bone, as measured by QCT. We did not detect declines in moments of inertia derived from imaging technology of the bone during Induction. This suggests that bone strength in the diaphysis may be
Acknowledgements
We would like to thank the Leukemia and Lymphoma Society, the Southern California Clinical and Translational Science Institute (under the National Center for Advancing Translational Sciences), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development for their generous support of this research. We would also like to thank the patients and families who participated and Swati Gulati and Devin Murphy, the study coordinators, for their enthusiasm and dedication to the
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These results have not been previously presented
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Research reported in this publication was supported by:
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A Translational Research Program grant (LLS-6249-11) from the Leukemia and Lymphoma Society
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The Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH (5R01HD059826).
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The National Center for Advancing Translational Sciences/NIH (UL1TR000130) via the Southern California Clinical and Translational Science Institute at the Children's Hospital Los Angeles.
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The content contained herein is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Clinical Trial Registration # NCT01317940
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Disclosure statement: The authors have nothing to disclose
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Present address: Agensys, Inc., 1800 Steward St, Santa Monica, CA 90404, USA.