ORIGINAL ARTICLE

The Progression of Bone Mineral Density Abnormalities After Chemotherapy for Childhood Acute Lymphoblastic Leukemia Nicholas A. Vitanza, MD,* Laura E. Hogan, MD,* Guangxiang Zhang, PhD,w and Robert I. Parker, MD*

Summary: Although reduced bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL) is well documented, the degree of demineralization and relation to age are not well described. This is a retrospective chart analysis of 58 patients consecutively treated for ALL without relapse, cranial irradiation, or transplantation. Bone mineral densities were measured by dualenergy x-ray absorptiometry and patients were divided by sex and age (r5, 6 to 10, and >10 y) at diagnosis. Serial scans for 6 years after therapy were analyzed as Z-scores. Over 6 years after therapy, 93.1% of patients exhibited a decreased Z-score in at least 1 anatomic site. The difference in Z-score among the age cohorts was significant at both the lumbar spine and femoral neck. Patients older than 10 years at diagnosis had the lowest Z-scores: 2.78 and 2.87 for boys and 2.39 and 2.91 for girls at the lumbar spine and femoral neck, respectively. Children after ALL therapy exhibit a significant bone mineral deficit shortly after completion of therapy that persists for at least 6 years. The degree of bone demineralization can be followed up by a dual-energy x-ray absorptiometry scan and is most severe in patients older than 10 years at the initiation of therapy. Key Words: childhood ALL, osteoporosis, late effects, bone, demineralization, leukemia

(J Pediatr Hematol Oncol 2015;37:356–361)

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s the relapse-free survival for children with acute lymphoblastic leukemia (ALL) has neared 90%, the number of childhood leukemia survivors has dramatically increased.1 These survivors are at risk for many treatmentrelated long-term complications including impaired physical growth, neurocognitive dysfunction, emotional and occupational difficulties, cardiac abnormalities, Received for publication June 10, 2014; accepted August 12, 2014. From the *Department of Pediatrics, Division of Pediatric Hematology/Oncology, Stony Brook Long Island Children’s Hospital; and wDepartment of Preventative Medicine, Stony Brook University, Stony Brook, NY. Present address: Nicholas A. Vitanza, MD, Pediatric Neuro-Oncology, Department of Neurology, Stanford University, Lucile Packard Children’s Hospital, Palo Alto, CA. N.A.V. is generously supported by the American Society of Hematology. Author contribution: N.A.V. and L.E.H. designed research, collected data, analyzed and interpreted data, performed statistical analysis, and wrote the manuscript. G.Z. analyzed data, performed statistical analysis, and wrote the manuscript. R.I.P. designed and directed the research, analyzed and interpreted data, and wrote the manuscript. The authors declare no conflict of interest. Reprints: Robert I. Parker, MD, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Stony Brook University, HSC T-11, Room 029, 101 Nichols Road, Stony Brook, NY 11794-8111 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.

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hypertension, secondary neoplasms, and decreased bone mineral density (BMD).2 Children who complete therapy for ALL have been reported to have changes in BMD and an increased incidence of fractures while on therapy.3,4 Additional studies have confirmed these findings and identify multiple factors that may contribute to the bone demineralization in these patients including bone infiltration of leukemic cells, decreased activity, poor nutrition, cranial irradiation, methotrexate, corticosteroids, and genetic predispositions.4–7 However, even with the reduced role of cranial irradiation in current treatment protocols for ALL, the prevalence of BMD abnormalities among survivors of childhood ALL, reported to be as high as 85%, remains a common treatment-related complication.7 Despite some studies describing loss of BMD during therapy for ALL, there remain conflicting reports about the clinical significance and long-term effects on bone growth and development. Some studies have reported normal BMD in long-term survivors,8–10 whereas others describe a prolonged period of abnormal BMD.3,8,11,12 That analysis found age greater than 10 years to be extremely significant (P = 0.00001), and recently the Children’s Oncology Group independently concluded that boys constitute a high-yield screen group for low BMD after completion of treatment for ALL.13 In this study, our aim was to systematically investigate the degree of bone demineralization at specific timepoints immediately after therapy to evaluate differences in BMD on the basis of the age at diagnosis of ALL and initiation of chemotherapy. To increase the yield of any treatment and long-term screening for low BMD, we designed this study to identify which subsets of patients are at greatest risk for bone demineralization and to use dualenergy x-ray absorptiometry (DXA) scans to gain more information about the progression and natural history of this process.

METHODS Patients The medical records of 78 consecutively treated patients with ALL at our institution were screened for BMD by DXA scan, as well as clinical and therapeutic features including age at diagnosis, sex, presence or absence of cranial irradiation, relapse and hematopoietic stem cell transplantation. Given the known risk for bone mineral deficit in ALL survivors, it has been our practice to measure BMD at completion of therapy and to monitor BMD serially for a period of time during follow-up surveillance. Of the 78 charts reviewed, 58 patients met our inclusion criteria. We excluded patients who had other pathology or non–ALL-related predisposing factors for bone J Pediatr Hematol Oncol



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demineralization including Down syndrome (n = 4), relapse, hematopoietic stem cell transplantation, and/or cranial irradiation (n = 14).8,14,15 Also, to better assess changes immediately after therapy, patients with initial DXA scans not completed in the first 4 years after therapy (n = 2) were excluded from this analysis. The 58 patients who met our criteria were then subdivided according to sex and age. Patients were divided into 3 age groups (r5, 6 to 10, and >10 y of age) on the basis of the age at the initiation of treatment. The study population included 13 boys aged 5 years or younger, 10 boys 6 to 10 years of age, 5 boys greater than 10 years of age, 14 girls 5 years of age or younger, 9 girls 6 to 10 years of age, and 7 girls greater than 10 years of age. The Institutional Review Board at Stony Brook University approved waiver of consent and the reporting of these data before initiation of the project.

DXA Scans A total of 160 DXA scans were obtained, with a mean of 2.76 DXA scans per patient in their first 6 years after therapy (range: 1 to 6). Time intervals were measured, with the date of completion of therapy representing “time zero.” Subsequent DXA scans were placed into 2-year time cohorts (1 to 2, 3 to 4, and 5 to 6 y) measured from completion of therapy. If a patient had >1 DXA scan in any 2-year period, the mean of the results was used. Eighteen patients were lost to follow-up and consequently had only 1 DXA scan during the 6 years posttherapy follow-up interval. DXA results included BMD measured at the lumbar spine, femoral neck, femoral trochanter, and femoral intertrochanteric region, but as fracture risk is associated with demineralization at the lumbar spine and femoral neck, our analysis focuses on BMD values and changes in these 2 sites.16 The BMDs were measured in g/cm2 and converted to Z-scores, which represent deviation from agematched and sex-matched normative BMDs. From these data, BMD Z-score, DBMD/y, and DZ-score/y, wherein a negative represents worsening compared with normal peers and a positive score represents an improvement, were calculated. Mean values and SD were then calculated for each patient cohort. Following the definition adopted by the International Society for Clinical Densitometry (ISCD), we defined osteoporosis as a BMDr2 SD below the mean (ie, Zr 2).17 Also, following the ISCD guidelines, we did not use the term “osteopenia,” so BMDs that are abnormal but not >2 SD below the mean (ie, 2 > Zr0) were simply described as such.17

Statistical Analysis Statistical analysis was performed to evaluate the significance of the differences in BMD results (Z-scores) between age groups using nonparametric 1-way analysis of variance. The Bonferroni procedure was used to adjust for multiple pairwise comparisons between the 3 age groups. The analysis was first performed for all patients and then for each sex separately. For each sex, box-plots were created for 3 age groups along with the corresponding original Z-scores. The illustration of Z-scores used a Jitter plot technique, which allows multiple observations with the same or close plotted values to be observable on the plot by adding a small amount of random noises to the values in the horizontal direction. Statistical analyses were performed using SAS software version 9.1 (SAS Institute Inc., Cary, NC). Pr0.05 is regarded as statistically significant. Copyright

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Bone Demineralization in Childhood ALL

RESULTS Sixteen of the 30 girls (53.3%) and 11 of the 28 boys (39.3%) had a DXA scan indicating osteoporosis (Zr 2) at the lumbar spine or the femoral neck. Of the total study population, 93.1% (54/58) had evidence of bone demineralization, with 46.6% having BMD loss >1 SD from the mean and 46.6% having osteoporosis documented for at least 1 site. Overall, 96.7% of girls (29/30) and 89.3% of boys (25/28) exhibited bone densities that were below agematched and sex-matched means.

Cohort 1: Age r5 Years at Diagnosis All patients (n = 27) in this age group exhibited an increasing BMD over the 6 years of observation (Figs. 1A, B). However, despite the observed increase in BMD over time, the Z-score generally did not improve. Four of the 14 girls (28.6%) had Z-scores in the osteoporotic range and 1 of the 11 boys (9.1%) had a Z-score in the osteoporotic range. At final evaluation the average Z-score in boys was still abnormal at 1.48 with a DZ-score/y of 0.09 at the lumbar spine (Figs. 1C, E). At the femoral neck, the Z-score was 2.12 with less change in Z-score/y ( 0.04; Figs. 1D, F). Girls in this age group averaged a slightly better Z-score ( 1.13 and 0.96 at the lumbar spine and femoral neck, respectively), with the DZ-score/y measuring 0.02 at the lumbar spine and 0.03 at the femoral neck (Figs. 1E, F). Boys in this age group exhibited a degree of “catch-up” bone mineralization at the lumbar spine between their first and second DXA scans (ie, between 2 and 4 y after therapy), but this enhanced bone mineralization was not sustained at the 6-year timepoint.

Cohort 2: Age 6 to 10 Years at Diagnosis Patients in this cohort displayed the greatest degree of variability in Z-scores after 6 years. Female patient Zscores ranged from 0.24 to 4.65 and male Z-scores ranged from 0.25 to 3.72. Of note, the 2 patients with nearly normal Z-scores were from patients who had just turned 6 when diagnosed. Ninety-five percent of patients in the 6 to 10 years of age cohort displayed abnormally low BMD at some point. At final evaluation, boys had a mean Z-score of 2.68 at the lumbar spine and 2.39 at the femoral neck (Figs. 1C, D). They also exhibited one of the most dramatic changes between 2 and 4 years after therapy at the lumbar spine (DZ-score/y = 0.36, Figs. 1E, F). Although the change in the Z-score was less profound at the femoral neck, a DZ-score/ y of 0.04 shows these patients still moved further behind their age-matched and sex-matched peers over the 3 years after therapy. Girls in this age group exhibited nearly identical changes in their Z-scores at both sites, with DZ-score/y of 0.25 and 0.3 at the lumbar spine and femoral neck, respectively (Figs. 1E, F). This improvement in Z-score represented the most positive change in bone mineralization progression of any cohort.

Cohort 3: Age >10 Years at Diagnosis Patients greater than 10 years old at diagnosis demonstrated the highest absolute BMD, but the lowest Zscores for both sexes (Figs. 1A, B). At the lumbar spine, boys had mean Z-scores of 1.96, 2.36, and 2.78 at 2, 4, and 6 years after therapy, respectively. At the femoral neck, mean Z-scores were 1.5, 3.06, and 2.87 (Figs. 1C, D). Commensurate with the oldest boys having

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FIGURE 1. Decreased bone mineral density in children after treatment for acute lymphoblastic leukemia. A, Bone mineral density (g/ cm2) at the lumbar spine and (B) the femoral neck. C, Z-scores at the lumbar spine measured over time at the lumbar spine and (D) femoral neck. E, DZ-score/y at the lumbar spine and (F) femoral neck. The y axis is time measured in 2-year intervals. F indicates female; M, male.

the lowest BMD 6 years after therapy, the change in Zscore/y was only + 0.06 and + 0.01 at the lumbar spine and femoral neck 6 years after therapy, essentially showing no “catch-up” bone mineralization. Girls in the greater than 10 years of age cohort had similar mean Z-scores of 2.63, 2.5, and 2.39 at the lumbar spine at 2, 4, and 6 years after therapy, respectively (Fig. 1C). At the femoral neck, mean Z-scores at those same timepoints were 2.97, 2.78, and 2.91 (Fig. 1D). Girls in this age group also failed to show a trajectory toward improved BMDs at both the lumbar spine and femoral neck (DZ-score/y = + 0.05 and 0.107, respectively; Figs. 1E, F). Within this cohort, 3 patients suffered fractures (metatarsal 2, distal radius  1), but all were secondary to trauma.

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Comparison of r5, 6 to 10, and >10 Year Patient Cohorts At the lumbar spine, the overall difference in Z-scores 6 years after therapy among 3 age groups is highly significant (P = 0.0003). The most significant difference lies between the r5 year group and the >10 year group (P = 0.0002). Even after stratifying by sex, the difference between r5 year and >10 year groups still holds significant, wherein no overlapping Z-scores were observed between the 2 age groups for either male or female patients (Fig. 2). The overall difference in Z-scores 6-years after therapy among the 3 age groups at the femoral neck is also highly significant (P = 0.007). Again, the most significant difference lies between the r5 year group and the >10 year

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Female Z-scores Six Years after Chemotherapy L-Spine

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Female Z-scores Six Years after Chemotherapy Femoral Neck -0.5

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FIGURE 2. Bone mineral density abnormalities in children after chemotherapy for acute lymphoblastic leukemia vary according to age and sex. A, Box-plot of Z-scores of girls at the lumbar spine and (B) femoral neck. C, Box-plot of Z-scores of boys at the lumbar spine and (D) femoral neck. Columns from left to right represent girls 5 years old or younger, girls 6 to 10 years old, and girls more than 10 years old. Each point represents an individual patient’s Z-score 6 years after the completion of therapy and the central line of each column represents the mean for that cohort.

group (P = 0.0058). When evaluating by sex, boys (n = 17) display a highly significant difference in Z-scores at the lumbar spine, but not at the femoral neck (P = 0.011 and 0.41, respectively) (Fig. 2C, D). Among girls (n = 21), the overall difference among the 3 age groups is also significant at both the lumbar spine and the femoral neck (P = 0.018 and 0.0019, respectively) (Fig. 2A, B).

DISCUSSION Our study confirms earlier reports of a high incidence of bone demineralization in children who had completed therapy for ALL.18,19 Indeed, almost all of our patients (93.1%) exhibited BMD abnormalities and 46.6% exhibited osteoporosis in at least 1 anatomic site at some time during the first 6 years after chemotherapy. Although our patient group exhibited an increase in BMD over a 6-year interval, their bone mineralization remained deficient when compared with age-matched and sexmatched peers. This failure to improve Z-scores, despite rising BMD, has not previously been reported. Some prior studies suggest that the risk and severity of BMD loss is greater for younger patients, whereas others appear to show that the risk is greater for older patients.18,19 We show that patients under 6 years of age at the time of initiation of therapy appear to have the least long-term effect on their BMD. In fact, in our study girls in this age cohort on average are the only group without mean Z-scores < 1 (mean Z-scores of 0.95 and 0.98 at the Copyright

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lumbar spine and femoral neck, respectively). Consequently, one might consider these younger patients to be potentially at a lower risk for fracture than older patients. However, this conclusion must be tempered by a recent report of children without cancer that found an increased risk for fracture during adolescence in children with osteoporosis earlier in childhood even if their BMD had subsequently normalized.20 Our study was not aimed at eliciting the fracture incidence in this population, therefore routine or surveillance x-ray films were not obtained; thus subclinical fractures may have been present. The association of abnormally low BMDs and osteoporosis with subclinical fractures and pathologic fractures would be important to evaluate in future studies. Also, we did not perform quantitative computed tomography or obtain bone biopsies, so, although we can report on changes in BMD, we are limited by not describing changes in bone architecture. Our results are limited by the fact that 18 patients only had 1 DXA scan and, although they were not selected to stop DXA screening, bias could have affected their lack of follow-up. Also, Z-scores were adjusted for age and sex but not height. Although DXA scans may misdiagnosis osteoporosis in 11% to 30% of pediatric patients because of variation in height and weight for age, BMDs by DXA have been shown to predict fracture risk in children.20,21 Our results indicate boys, particularly school-age children (more than 5 y of age at diagnosis) and adolescents (more than 10 y of age at diagnosis), had more

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severe bone demineralization than did their age-matched female counterparts, with the most profound sexdependent discrepancy noted in the school-age children. This reinforces our impression that male sex represents a risk for increased therapy-induced BMD deficit, which is consistent with recent findings identifying male individuals as a subgroup with a higher screening yield for low BMD.13 However, this study is limited by small numbers in each cohort and the lack of additional hormonal and metabolic information. All patients older than 10 years at the time of initiation of therapy had Z-scores in the osteoporotic range at 6 years after therapy. The average Z-score for girls was 2.39 and 2.91 at the lumbar spine and femoral neck, respectively, with the corresponding Z-scores for boys being 2.78 and 2.87 at the same sites. In this age group, the highest (ie, least negative) individual Z-score was 1.91. Not only is BMD deficit profound as late as 6 years after therapy for ALL, analysis of change in Z-score does not reveal any meaningful recovery toward normal despite an increase in absolute BMD. Our study is again limited in that this oldest cohort represents our smallest patient subset with the lowest amount of total DXA scans. Three fractures were noted in 2 adolescent patients during the posttherapy observation period, but none of our patients experienced a pathologic fracture (ie, a fracture disproportionate to the degree of injury felt to be a result of decreased BMD). Of note, no patients received bisphosphonate therapy to improve bone mineralization, because of concern for the potential of bisphosphonate therapy to result in the production of bone with abnormal biomechanical properties when used in growing children.22–24 The recent reports of therapy-related osteonecrosis and a heightened risk for atypical femur fracture secondary to bisphosphonate use (primarily in older women) has further reinforced our concern that bisphosphonate use in these children may not be indicated.25–27 Patients in our study also did not receive routine vitamin D or calcium testing or replacement as there is no current evidence that survivors of childhood ALL benefit from these practices. The association of decreased BMD in survivors of childhood ALL with serum calcium, parathyroid hormone, and vitamin D levels is currently being investigated and will be the topic of a future publication, at which time we aim to provide recommendations on the role of laboratory monitoring and supplementation. In conclusion, the development of therapy-induced bone mineral loss as a consequence of chemotherapy for ALL is severe, frequent, and occurs in the absence of cranial irradiation. We have shown that after completion of chemotherapy absolute BMD increases over time, but still remains well below the normal range for at least 6 years. Older patients of either sex are at a greater risk for significant decrease in BMD after therapy for ALL, with male individuals exhibiting the greatest risk. DXA scans are sensitive and, in comparison with magnetic resonance imaging, may provide a cost-effective means to monitor these changes. Given the high frequency and potential longterm consequences of bone mineral loss in these survivors, further studies are warranted to access the correlation between low BMD on DXA scans with the future incidence of osteoporosis, to clarify treatment and genetic risk factors, and to investigate interventions to counteract patient’s bone demineralization.

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The Progression of Bone Mineral Density Abnormalities After Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

Although reduced bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL) is well documented, the degree of demineralization ...
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