Elsevier

Bone

Volume 85, April 2016, Pages 131-137
Bone

Original Full Length Article
Early injury to cortical and cancellous bone from induction chemotherapy for adolescents and young adults treated for acute lymphoblastic leukemia

https://doi.org/10.1016/j.bone.2016.01.027Get rights and content

Highlights

  • Newly diagnosed ALL does not significantly affect bone density and structure as compared to a healthy cohort of children.

  • Osteotoxic chemotherapy for childhood ALL significantly affects bone health during the initial month of chemotherapy alone.

  • DXA underestimates specific aspects of osteotoxicity as compared to QCT.

  • Further research is necessary to delineate the clinical role of qCT in monitoring changes to bone during ALL chemotherapy.

Abstract

Diminished bone density and skeletal fractures are common morbidities during and following therapy for acute lymphoblastic leukemia (ALL). While cumulative doses of osteotoxic chemotherapy for ALL have been reported to adversely impact bone density, the timing of onset of this effect as well as other changes to bone structure is not well characterized. We therefore conducted a prospective cohort study in pre-adolescent and adolescent patients (10–21 years) newly diagnosed with ALL (n = 38) to explore leukemia-related changes to bone at diagnosis and the subsequent impact of the first phase of chemotherapy (“Induction”). Using quantitative computerized tomography (QCT), we found that pre-chemotherapy bone properties were similar to age- and sex-matched controls. Subsequently over the one month Induction period, however, cancellous volumetric bone mineral density (vBMD) decreased markedly (− 26.8%, p < 0.001) with sparing of cortical vBMD (tibia − 0.0%, p = 0.860, femur − 0.7%, p = 0.290). The tibia underwent significant cortical thinning (average cortical thickness  1.2%, p < 0.001; cortical area  0.4%, p = 0.014), while the femur was less affected. Areal BMD (aBMD) concurrently measured by dual-energy X-ray absorptiometry (DXA) underestimated changes from baseline as compared to vBMD. Biochemical evidence revealed prevalent Vitamin D insufficiency and a net resorptive state at start and end of Induction. Our findings demonstrate for the first time that significant alterations to cancellous and cortical bone develop during the first month of treatment, far earlier during ALL therapy than previously considered. Given that osteotoxic chemotherapy is integral to curative regimens for ALL, these results provide reason to re-evaluate traditional approaches toward chemotherapy-associated bone toxicity and highlight the urgent need for investigation into interventions to mitigate this common adverse effect.

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.

Section snippets

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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  • Cited by (0)

    These results have not been previously presented

    • Research reported in this publication was supported by:

      • o

        A Translational Research Program grant (LLS-6249-11) from the Leukemia and Lymphoma Society

      • o

        The Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH (5R01HD059826).

      • o

        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.

      • o

        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.

    • Clinical Trial Registration # NCT01317940

    • Disclosure statement: The authors have nothing to disclose

    1

    Present address: Agensys, Inc., 1800 Steward St, Santa Monica, CA 90404, USA.

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