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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1215-1221 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.199 Skeletal Morbidity in Childhood Acute Lymphoblastic LeukemiaFrom the Research Institute, Hospital for Sick Children; Department of Pediatrics, University of Toronto, Toronto; and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada Address reprint requests to Paul Pencharz, MB, ChB, PhD, Division of Gastroenterology/Nutrition, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8 Canada; e-mail: paul.pencharz{at}sickkids.ca
PURPOSE: Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL. METHODS: Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group. RESULTS: When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group. CONCLUSION: It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40,000 mg/m2 or a total corticosteroid dose of greater than 9,000 mg/m2 may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.
The treatment of pediatric cancer has become increasingly successful, with the majority of patients now being cured of their disease. Currently, one in 1,000 young adults is a cancer survivor.1 As the length of time from treatment increases, the long-term morbidity associated with treatment will become better identified. Given the large number of pediatric cancer survivors, these late sequelae represent an important public health issue. Acute lymphoblastic leukemia (ALL), the most common malignancy in children, has an overall long-term survival of at least 75%.1-3 All ALL treatment protocols use corticosteroids and methotrexate (MTX), both of which are known to affect bone metabolism.4-6 Protocols vary in the amounts and routes of administration of these drugs and in the use of cranial radiation, which may affect hypothalamic or pituitary function. Decreased physical activity and nutritional deficiencies during therapy also affect bone health.7,8 Halton et al9 previously demonstrated abnormalities in mineral homeostasis in children with ALL at diagnosis. A prospective study done on their patients, who were treated with the Dana-Farber Cancer Institute (Boston, MA) protocol 87-01, reported that 65% of the children had a decrease in bone mass during therapy,10 and 39% sustained fractures, many of which were not clinically suspected. Biochemical abnormalities of bone turnover indicating increased bone resorption were noted, including an elevated urinary cross-linked N-telopeptide.10 Other effects included low vitamin D status and hypomagnesemia.7 Similar results have been reported by other authors.11-13 Most children are diagnosed with ALL in early childhood and complete therapy 2 to 3 years later, in most instances, before the start of puberty. As a proportion of body composition, bone minerals remain constant during childhood and increase almost three-fold during puberty14 to achieve the peak bone mass in early adulthood.15-17 Unless cancer or cancer therapy causes permanent damage to the neurohormonal mechanisms of children with ALL, there is reasonable hope that some, if not a majority, will improve their bone mineralization toward normal after successful completion of therapy. A number of studies have documented the loss of bone mineral mass in ALL.13,18-32 However, most are small, single-center studies, and the results may not be generalizable to all patients with ALL and all treatment protocols. Some report only short-term follow-up25,30 or consist of a mix of patient groups.19-21,23 Often the control group has not been standardized.13,18,29,31 We chose to conduct a large, long-term follow-up study of patients who were treated for ALL as children to determine if they are at risk for decreased bone mineral density (BMD) and the concomitant health risks, such as fractures, and to examine which components of treatment are responsible.
Study Design A unique situation exists in the province of Ontario, where all of the pediatric cancer patients are registered with a single agency, the Pediatric Oncology Group of Ontario (POGO), which has been active since 1985. Approximately 1,600 children have been treated for ALL in that time period. This provides access to a large cohort of patients to study. Approximately 65% of patients in the province have been treated at the Hospital for Sick Children (HSC) in Toronto; the other 35% are divided between the other four centers in Ontario. Thus, it was decided to recruit patients from only the biggest institution (HSC). Patients with ALL at HSC had been treated with the same in-house protocols from 1983 until 1998. Protocols were originally classified as low risk (protocol A), intermediate risk (protocol B), and high risk (protocol C). Criteria for protocol C included any of the following: age at diagnosis (AAD) older than 10 years, L2 blast morphology, significant adenopathy or hepatosplenomegaly, or WMC greater than 20 x 109/L. Protocols A and B were combined into one protocol in 1991. Protocols C and B included cranial radiation for children older than 5 years of age. Children younger than 5 years at diagnosis received high-dose MTX instead of radiation. Protocol A (and after 1991, protocol AB) consisted of intrathecal MTX alone as CNS prophylaxis. Only protocol C contained anthracyclines. Protocol C involved a higher total dose of corticosteroids than protocol A, B, or AB. (Table 1).
Accrual of Patients All surviving patients of childhood ALL who had completed treatment more than 2 years before, were diagnosed no earlier than 1983, and were registered with POGO were considered eligible. All patients were in first continuous complete remission. Patients were deemed ineligible if they had Down syndrome, had received a bone marrow transplant, or were not treated according to an institutional protocol. Patients were also ineligible if they originally or currently were not living in the province. Potential participants were contacted by letter. Participation was voluntary, with informed consent obtained from the patient or parent for those younger than 16 years of age. Ethics approval for this study was granted by the Research Ethics Board of the HSC.
Parameters Measured The DXA measurements for the spine in both children and adults are reported as a standard deviation (SD) score (z score) compared with the mean for age- and sex-matched normal controls using United States Federal Drug Agency-approved pediatric normal data derived by Lunar. Currently, there is no standard measure to identify low bone mass or fracture risk for children. The WHO provides definitions for diagnosing decreased BMD for postmenopausal Caucasian women.33 Low bone mass or osteopenia is defined as a value for BMD more than 1 SD below the mean for sex-matched normal values for young adults. Osteoporosis is defined as a value for BMD that is equal to or greater than 2.5 SDs below the young adult mean.33 In individuals younger than the age of skeletal maturity, the WHO report states that osteopenia might be defined as a z score of -1 or less; that is, 1 or more SD below the age- and sex-matched reference range.33 In adults the definitions of osteopenia and osteoporosis for the femur are the same as those for the spine.33 There were not enough pediatric data to generate SDs for the control data at the time of this study. The results are expressed as a percent of age- and sex-matched means but interpreted as fracture risk, for which less than 90% is a mild risk, less than 80% is a moderate risk, and less than 70% represents a marked increase in fracture risk.
Data Analysis
The major outcome variable was BMD. Calculations of sample size were for a difference of 0.5 SD ( Statistical analysis. First, the group as a whole was compared with controls; then, using descriptive statistics and analysis of variance, comparisons were made based on AAD, years since diagnosis (YSD), sex, and HOR or LOR groups. For the patients found to have osteopenia or osteoporosis, additional analysis was done to compare them with the rest of the study population using linear regression with respect to treatment parameters including cranial radiation, MTX dose, and corticosteroid dose. The statistical analysis was performed using the SAS (Version 8.2; SAS Institute, Cary, NC) and Minitab (Version 13; State College, PA) software packages. Documentation was poor on actual corticosteroid dose received because corticosteroids were taken on an outpatient basis. Instead, the protocol used was a proxy for the corticosteroid dose because there were two dosage groups, depending on the protocol. Protocol C contained one phase with dexamethasone; prednisone was used in the remainder of the protocols. The approximate total corticosteroid dose received was 7,920 mg/m2 (prednisone equivalent) for protocols A, B, and AB, and 9,080 mg/m2 (prednisone equivalent) for protocol C. Thus, the corticosteroid dose was compared as a high-dose corticosteroid protocol (protocol C) versus low-dose protocols (A, B, and AB) by binary logistic regression.
Patient Characteristics There were 361 surviving patients with ALL registered at HSC from 1985 (the year the POGO database was computerized) through 1993. Addresses were not available for all of the remaining 304 patients; thus, 271 patients were sent letters. Of the letters that were returned, additional efforts to find a correct address were unsuccessful for 15 patients. One hundred forty-five people responded but only 15 declined participation. Five of those 15 respondents were interested, but traveling distance or scheduling difficulties precluded their participation. Because of resource limitations, we studied 113 patients of the 130 interested responders. Although efforts were made to prescreen potential participants from the database, exclusion factors were not always noted. Thus, some ineligible patients received letters. They were studied to assess their personal BMD but were not included in the analysis. Seven participants were ineligible: two had Down’s syndrome, three had bone marrow transplantation, and two did not complete the study. This left 106 assessable patients. There was no significant difference between those studied and those eligible with respect to sex, age, AAD, and YSD. There were 62 females and 44 males who ranged in age from 7.8 to 30.6 years at the time of the study. The mean age was 15.9 years. The average time since diagnosis was 10.1 years (range, 5.5 to 15.4 years) and the average AAD was 5.8 years (range, 1.0 to 17.1 years). The length of treatment was 3 years, thus the time since completion of therapy ranged from 2.5 to 12.4 years. Eighteen patients were treated on protocol A, 15 were treated on protocol B, 10 were treated on protocol AB, and 63 were treated on protocol C. Fifty-three of 106 patients received cranial radiation; all received the same total dose of 18 Gy divided in 10 fractions. MTX doses were broken down into three general groups: 86 patients received standard dose (500 to 8,000 mg/m2), seven patients received high dose (25,000 to 32,000 mg/m2), and 13 patients received very high dose (> 50,000 mg/m2). No patient received doses between these ranges. The group characteristics are listed in Table 2.
There were a total of 81 LOR and 25 HOR participants, with no significant difference in time since diagnosis for the four risk groups. There were differences in treatment features between risk groups but this was due to treatment protocol being, to some degree, age dependent. We were unable to recruit the target number of high-risk males despite a concerted effort. However, post hoc analysis showed that the study had enough power on the basis of the total number of patients and the number of patients in each group.
Study Group Compared With Normal Controls When data were analyzed by AAD, sex, and LOR or HOR (AAD and sex) using analysis of variance, there was no difference between the study group and age-matched normal controls (Table 3).
Bone mineral density of femur. Femur measurements ranged from 68% to 138% of normal values (mean, 100.43%; SD, 12.59% [compared with 10% for normal controls]). These results also are listed in Table 3. There was no statistical difference in femoral BMD for the group overall or when divided by AAD, sex, and LOR or HOR (AAD and sex).
Subanalysis of Patients With Decreased BMD The subgroup with low BMD of either the spine or the femur did not differ from the remainder of the group with respect to age, AAD, or YSD. Bone mineral density of spine. Those who had a spine BMD of more than 1 SD below the mean for age-matched controls were no more likely to have received cranial radiation than those who did not (P = .48). There also was no relationship detected between the MTX dose received and having a decreased spine BMD, nor was there any association of treatment found when both of these factors were analyzed together. Finally, those who received higher-dose corticosteroids were not more likely to have lower BMD in the lumbar spine than those who received lower doses. Bone mineral density of femur. Neither cranial radiation nor MTX dose was noted to have an effect on BMD of the femur. However, there was a trend (P = .083) to an effect of very high-dose MTX. Given that no radiated patients received high-dose or very high-dose MTX, because these higher doses were used as radiation-sparing therapy in patients younger than 5 years of age, the effect of MTX dose was analyzed further using only the unirradiated patients (Table 4). Patients who received very high dose MTX have the greatest proportion of femoral BMD less than 90% of normal (P < .05).
Those patients with reduced femoral BMD were more than twice as likely to have received protocol C or higher-dose corticosteroids (odds ratio, 2.81; P = .049). This effect was preserved even when controlling for age.
From this study, it seems that most survivors of childhood ALL do not sustain significant long-term deficits in BMD of the spine or femur. However, a small subset of patients does demonstrate lower than expected BMD for age, which may be related to certain aspects of their treatment. Children are most vulnerable to interference with skeletal development during the peripubertal and adolescent growth phases, when bone formation exceeds resorption and bone mass increases. Peak bone mass, which represents adult bone mass, is reached early in the third decade of life.36 Equal formation and resorption stabilize bone mass until 35 to 40 years of age, when resorption then begins to exceed formation and the bone mass starts to slowly decrease. This process of bone turnover in the adult is known as remodeling.37 Disruptions to the linkage of formation and resorption are more notable if they are superimposed on the natural imbalances in the childhood growth phase or the later senescent phase. Treatment for ALL uses corticosteroids and MTX, both of which are known to affect bone metabolism. MTX causes an inhibition of formation accompanied by an increase in resorption.38 Inhibition of formation is likely a result of the drug's effects on osteoblast proliferation by its antimetabolite action on primitive mesenchyme precursors and some direct effects on matrix mineralization. The mechanism for increased resorption is unclear.37 Corticosteroids cause a decrease in osteoblastic activity and direct effects on bone matrix resulting in decreased formation. Increased resorption results partly from direct effects on osteoclasts and partly from decreased intestinal absorption and increased urinary excretion of calcium.39 Other drugs such as cyclophosphamide and doxorubicin also have been noted to have skeletal effects.37 In addition, children undergoing cancer therapy may have limited physical activity and even suffer from malnutrition during their illness, further influencing the achievement of potential peak bone mass. The results of the work of Halton et al4,5 and others7-9,40,41 have demonstrated abnormalities of BMD and bone mineral metabolism in children with ALL at diagnosis, as well as during and at the completion of chemotherapy. Forty years ago, Thomas et al42 reported impairment in bone growth in children with active leukemia. Halton's study and another by Rogalsky et al43 report frequent fractures in children at presentation and during therapy. Vertebral compression fractures are commonly reported.44,45 There are at least 15 studies in the literature that have examined BMD in survivors of ALL; only three studied more than 50 patients.25,27,31 The results of our study and two others13,25 do not show the significant decrease in BMD that has been reported in the other studies. Decreased BMD has been associated with cranial radiation, growth hormone deficiency, reduced body size, low calcium intake, gonadal dysfunction, male sex, white race, and higher doses of antimetabolites. Henderson et al13 showed an increase in BMD with increasing time after completion of therapy, whereas Nysom31 demonstrated that older patients at the time of measurement had decreased BMD. This may be due to a higher dose of cranial radiation received in those treated earlier. Most studies have shown no effect of AAD and YSD. As a group, our patients who were treated for ALL as children do not have reduced BMD at an average of 10 years from diagnosis and thus have no increased fracture risk compared with the general population. However, some subsets of patients, specifically those who received very high dose MTX (> 50,000 mg/m2) and those who received higher-dose corticosteroids, did have lower femoral BMD when compared with the remainder of the group and controls. Kaste et al27 demonstrated the effect of MTX as well. Other studies28,31 have shown no association with drug doses received. Our study was limited to patients treated within the modern era of chemotherapy. Good cure rates had been established with protocols in use in the early 1980s and during the next 20 years no major changes have been made, but rather protocols have been refined to reduce morbidity while maintaining high cure rates. Our protocols included the era of very high doses of MTX, which revealed an effect on those who received those doses that would not have been detected in other studies. Cranial radiation has been limited to older children to protect the developing brain and doses have been reduced. This allowed us to study patients who had received similar therapy over a long period of time. All of our patients who received cranial radiation received the same total dose of 18 Gy divided in 10 fractions. There was no effect demonstrated on the BMD of the spine or the femur with this regimen. The same cannot be said for other total doses or dosing regimes. Indeed, the damaging effect of cranial radiation on bone status is the one consistent factor in the aforementioned studies and is most likely due to effects on the hypothalamic-pituitary axis resulting in growth hormone dysfunction.38 It is probable that 18 Gy is below the threshold that damages the pituitary. It is encouraging that overall, the majority of patients treated for ALL in childhood in the modern era recover their bone mass by 10 years after diagnosis. However, those patients who received very high dose MTX (> 50,000 mg/m2) and/or corticosteroid doses greater than 9,080 mg/m2 (prednisone equivalent) over 3 years or greater than 3,000 mg/m2/y for protocols of other lengths, seem to be at risk and should have the BMD of their femoral neck screened. Research into the mechanisms behind the deficiency in those who do not recover is needed. Radiation doses of 18 Gy were not noted to have an effect on either the BMD of spine or the femur, but there is enough evidence in the literature to recommend screening for those who received higher doses. Certainly, where treatment protocols have similar cure rates, those with less toxicity to bone should be chosen.
The authors indicated no potential conflicts of interest.
We thank Dr David Gilday for his help in interpreting the DXA scans and Derek Stephens, biostatistician, for performing the statistical analysis.
Supported by a grant from the Pediatric Oncology Group of Ontario. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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2. Pui CH, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339:605-615, 1998 3. Brenner H, Kaatsch P, Burkhardt-Hammer T, et al: Long-term survival of children with leukemia achieved by the end of the second millennium. Cancer 92:1977-1983, 2001[CrossRef][Medline] 4. Adinoff AD, Hollister JR: Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 309:265-268, 1983[Abstract] 5. Halton JM, Wu B, Atkinson SA, et al: Comparative skeletal toxicity of dexamethasone and prednisone in childhood acute lymphoblastic leukemia (ALL). J Pediatr Hematol Oncol 22:369, 2000 (abstr) 6. Schwartz AM, Leonidas JC: Methotrexate osteopathy. Skeletal Radiol 11:13-16, 1984[CrossRef][Medline] 7. Atkinson SA, Halton JM, Bradley C, et al: Bone and mineral abnormalities in childhood lymphoblastic leukemia: Influence of disease, drugs and nutrition. Int J Cancer Suppl 11:35-39, 1998[Medline] 8. Warner JT, Evans WD, Webb DK, et al: Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45:544-551, 1999[Medline] 9. Halton JM, Atkinson SA, Fraher L, et al: Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia. J Pediatr 126:557-564, 1995[CrossRef][Medline] 10. Halton JM, Atkinson SA, Fraher L, et al: Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia. J Bone Miner Res 11:1774-1783, 1996[Medline]
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38. Pfeilschifter J, Diel IJ: Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol 18:1570-1593, 2000 39. Canalis E: Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol 81:3441-3447, 1996[CrossRef][Medline] 40. Van Der Sluis IM, Van Den Heuvel-Eibrink MM, Hahlen K, et al: Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia. J Pediatr 141:204-210, 2002[CrossRef][Medline] 41. Boot AM, van den Heuvel-Eibrink MM, Hahlen K, et al: Bone mineral density in children with acute lymphoblastic leukaemia. Eur J Cancer 35:1693-1697, 1999 42. Thomas LB, Forkner CE Jr, Frei E III, et al: The skeletal lesions of acute leukemia. Cancer 14:608-621, 1961[CrossRef][Medline]
43. Rogalsky RJ, Black GB, Reed MH: Orthopedic Manifestations of Leukemia in Children. J Bone Joint Surg 68:494-501, 1986
44. Newman AJ, Melhorn DK: Vertebral compression in childhood leukemia. Am J Dis Child 125:863-865, 1973
45. Pandya NA, Meller ST, MacVicar D, et al: Vertebral compression fractures in acute lymphoblastic leukemia and remodeling after treatment. Arch Dis Child 85:492-493, 2001 Submitted April 30, 2003; accepted January 20, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
=.05; ß = .20). For the study to detect a difference of 0.5 SD, 12 patients were needed per age group. Given that there were four groups (HOR males, HOR females, LOR males, and LOR females), we required 48 patients. The multiple regression analysis to examine for treatment effects (AAD, sex, protocol used, MTX dose, and cranial radiation) required a minimum of 100 patients. Therefore, we required a minimum of 100 patients, with relatively equal numbers of males and females. 
89%. Twelve patients had both spine BMD of more than 1 SD below the mean for normal controls and femoral BMD 
