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Bone Mass After Treatment for Acute Lymphoblastic Leukemia in Childhood

The Juliane Marie CentreRigshospitaletCopenhagen, Denmark
The Royal Veterinary and Agricultural UniversityFrederiksberg, Denmark

To the Editor:We previously¹ reported reduced whole-body bone mass in 95 survivors of childhood acute lymphoblastic leukemia (ALL) who were in first remission a median of 11 years (range, 3 to 23 years) after diagnosis and had never been irradiated outside a cranial field. Recently, we extended our number of young adult control subjects from 53 to 120 and reanalyzed the data. This changed some of the conclusions that we previously presented.

Bone mineral measurements derived from whole-body scans, as well as heights, were compared with local reference values for children and adolescents (n = 343, age 6 to 19 years²) or young adults (n = 120 [40 male], age 20 to 38 years; C. Mølgaard, unpublished data). The latter group consisted of healthy staff members or university students and follow-up of 41 adolescents examined by us previously² (mean height, 182.7 cm [SD = 5.9] in men and 169.1 cm [SD = 6.9] in women; weight, 77.2 kg [SD = 9.1] in men and 63.9 kg [SD = 7.2] in women; body-mass index, 23.1 kg/m² [SD = 2.3] in men and 22.4 kg/m² [SD = 2.7] in women). Results were analyzed as age- and sex-specific z scores. Whole-body bone mineral measurements were also analyzed in a three-step approach suggested by us recently² based on sex-specific z scores for height for age, bone area for height, and bone mineral content (BMC) for bone area. All z scores were based on smoothed modelling of the control data with the LMS method of Cole and Green,³ which summarizes the data in terms of three smooth age-specific curves called L (lambda), M (mu), and S (sigma). The M and S curves correspond to the median and coefficient of variation of the dependent variable (for example, BMC) at each age, whereas the L curve allows for the age-dependent skewness in the distribution of the dependent vairable. Bone area for height and BMC for bone area z scores were furthermore adjusted to account for the covariation of these z scores with weight (bone area for height) and age below or above 20 years (bone area for height and BMC for bone area) among the healthy controls. Z scores for age for the two men who were aged 30 years or older were based on predicted values for age 30 years because only three control men were older than 30 years. Potential predictors of height and bone mass were tested in stepwise multiple linear regression analysis based on sex, age at diagnosis, cranial irradiation, cumulative dose of corticosteroids, cumulative dose of peroral methotrexate, number of intermediate- or high-dose methotrexate infusions, length of follow-up after diagnosis, age 20 years or older at follow-up, tobacco smoking, and sufficient calcium intake at follow-up.

Adjusted for sex and age, the mean whole-body BMC and bone mineral areal density (BMD_A) were both significantly reduced (z = -0.33; 95% confidence interval (CI), -0.57 to -0.09, and z = -0.32; 95% CI, -0.54 to -0.09, respectively). In the lumbar spine, BMC and BMD_A from whole-body scans and BMD_A from dedicated lumbar spine scans were all significantly reduced (z = -0.34, 95% CI, -0.55 to -0.13; z = -0.40, 95% CI, -0.60 to -0.21; and z = -0.55, 95% CI, -0.75 to -0.35, respectively). In a three-step approach previously suggested by us,² the reduced whole-body BMC was due to a significantly reduced height (z = -0.56; 95% CI, -0.80 to -0.32) combined with a significantly raised bone area for height (z = 0.38; 95% CI, 0.20 to 0.56). BMC for bone area did not differ significantly from predicted (z = -0.11; 95% CI, -0.35 to 0.12).

In multiple regression analysis, survivors treated with cranial irradiation had significantly less whole-body BMC and BMD_A (estimated differences: z = 0.72, 95% CI, 0.27 to 1.17; and z = 0.53, 95% CI, 0.09 to 0.96, respectively), less lumbar spine BMC and BMD_A derived from whole-body scans (z = 0.57, 95% CI, 0.16 to 0.98; and z = 0.44, 95% CI, 0.05 to 0.83, respectively), and lower height (z = 0.77, 95% CI, 0.32 to 1.23). In addition, those who were aged 20 years or older at follow-up had significantly less whole-body BMC and BMD_A (estimated differences: z = 0.81, 95% CI, 0.32 to 1.31; and z = 0.65, 95% CI, 0.18 to 1.13, respectively). None of the other variables tested were significant in the multiple regression analysis.

The main new conclusion that appeared when we compared our data with improved local reference values was that the size-adjusted whole-body bone mass (BMC for bone area) was neither reduced nor related to any of the predictive variables tested. Since we wrote our previous article,¹ five other groups have reported on the bone mass of childhood ALL survivors. Compared with local reference values, 29 survivors mostly treated with cranial irradiation⁴ had reduced BMD_A but normal size-adjusted bone mass in the lumbar spine, and 23 unirradiated survivors⁵ had normal whole-body and lumbar spine BMD_A and normal size-adjusted lumbar spine bone mass. The size-adjusted bone mass was normal in the whole body but reduced in the lumbar spine in 35 survivors treated with cranial irradiation.⁶ Compared with nonlocal reference values, the volumetric bone mass measured by quantitative computed tomography and the lumbar spine BMD_A were both reduced in 31 adult survivors treated with cranial irradiation,⁷ and the lumbar spine BMD_A was reduced in 24 irradiated survivors.⁸ It seems that at least part of the reported discrepancies might be attributed to the quality of the reference values used. A number of the studies^4-6 support our finding that the main reason for reduced bone mass in survivors of childhood ALL is reduced height, although this varies with the site measured in some⁶ but not other⁴ studies. Because reduced BMD_A increases the risk of hip fracture⁹ whereas reduced height reduces the risk,^10,11 it is as yet unknown whether the pattern of reduced bone mass of childhood ALL survivors will lead to an increased risk of osteoporotic fractures later in life.

REFERENCES

1. Nysom K, Holm K, Michaelsen KF, et al: Bone mass after treatment for acute lymphoblastic leukemia in childhood. J Clin Oncol 16: 3752-3760, 1998[Abstract/Free Full Text]

2. Mølgaard C, Thomsen BL, Prentice A, et al: Whole body bone mineral content in healthy children and adolescents. Arch Dis Child 76: 9-15, 1997[Abstract/Free Full Text]

3. Cole TJ, Green PJ: Smoothing reference centile curves: The LMS method and penalized likelihood. Stat Med 11: 1305-1319, 1992[Medline]

4. Arikoski P, Komulainen J, Voutilainen R, et al: Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 20: 234-240, 1998[Medline]

5. van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, et al: Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood. Med Pediatr Oncol 35: 415-420, 2000[Medline]

6. Warner JT, Evans WD, Webb DK, et al: Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45: 544-551, 1999[Medline]

7. Brennan BMD, Rahim A, Adams JA, et al: Reduced bone mineral density in young adults following cure of acute lymphoblastic leukaemia in childhood. Br J Cancer 79: 1859-1863, 1999[Medline]

8. Hoorweg-Nijman JJG, Kardos G, Roos JC, et al: Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol (Oxf) 50: 237-244, 1999[Medline]

9. Schott AM, Cormier C, Hans D, et al: How hip and whole-body bone mineral density predict hip fracture in elderly women: The EPIDOS Prospective Study. Osteoporos Int 8: 247-254, 1998[Medline]

10. Meyer HE, Tverdal A, Falch JA: Risk factors for hip fracture in middle-aged Norwegian women and men. Am J Epidemiol 137: 1203-1211, 1993[Abstract/Free Full Text]

11. Joakimsen RM, FønnebøV, Magnus JH, et al: The Tromso Study: Body height, body mass index and fractures. Osteoporos Int 8: 436-442, 1998[Medline]

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