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Original Studies |
Departments of Pediatrics and Surgery (H.K.), Kuopio University Hospital, FIN-70211 Kuopio; and the Department of Pediatrics, Tampere University Hospital (M.K.), FIN-33101 Tampere, Finland
Address all correspondence and requests for reprints to: Pekka Arikoski, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland. E-mail: arikoski{at}messi.uku.fi
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Abstract |
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A significant decrease in femoral bone mineral density and apparent volumetric density was observed during the year after diagnosis [(mean (SD), -10.1% (8.8%) and -11.3% (8.1%) respectively; P < 0.01], whereas age- and sex-matched controls showed annual increments of +5.4% (7.7%; P < 0.01) and +0.7% (5.7%; P = NS) respectively. The markers of bone formation (PICP and OC) were significantly decreased at diagnosis. By the end of the follow-up, PICP and OC were normalized, whereas the marker of bone resorption (type I collagen carboxyl-terminal telopeptide) was significantly increased. Reduced levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and IGF-binding protein-3 were observed during the study.
To conclude, increased bone resorption and impaired development of femoral bone density were observed in children with cancer during chemotherapy. Deficient accumulation of bone mass may lead to impaired development of peak bone mass and predispose children with cancer to increased risk of osteoporosis and diminished skeletal resistance to fractures later in life.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The causes of these skeletal changes are most probably multifactorial. The disease processes and some forms of antineoplastic treatments, such as corticosteroids, methotrexate, and radiotherapy, have been described to be harmful to the normal accumulation of bone mass and density (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15). Treatment-induced hypogonadism, GH deficiency, changes in insulin-like growth factors (IGF) and their binding proteins (IGFBPs), and alterations in vitamin D metabolism are factors that might also influence bone mineral density in children with malignancy (2, 7, 12, 13, 16, 17). Insufficient accumulation of skeletal mass during childhood and adolescence may lead to impaired development of peak bone mass, predisposing children with cancer to increased risk of osteoporosis and diminished skeletal resistance to fractures later in life.
The purpose of the present study was to evaluate longitudinal changes in BMD and bone turnover in newly diagnosed children with cancer. Serum levels of 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25-(OH)2D], IGF-I, IGFBP-3, and intact PTH (PTHint) were evaluated to determine possible abnormalities in bone hormonal metabolism during treatment of childhood cancer.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study series comprised 28 (11 males and 17 females) (58%)
of the 48 Caucasian patients who were diagnosed with childhood ALL
(n = 10) or with a solid tumor (n = 18) at Kuopio University
Hospital between January 1995 and December 1997 and treated with
chemotherapy (Table 1
). The patients were
studied at diagnosis and observed for 1 yr after the diagnosis. None of
the patients had a condition known or suspected to affect bone
metabolism before diagnosis (a growth-affecting chronic disease, bone
disease, systemic corticosteroid treatment during the preceding 6
months, history of malignancy or radiotherapy, mental retardation, or
physical disability). No patient had been diagnosed to have GH
deficiency or was being treated with GH. None of the patients developed
a fracture, and no relapses occurred during the study. Twenty (42%) of
the 48 patients were not included in the study: 17 (4 ALL and 13 solid
tumors) due to inadequate study compliance, among whom 13 patients were
3 yr of age or younger, 2 ALL patients due to Down’s syndrome, and 1
patient with a solid tumor due to refusal. The study protocol was
approved by the research ethics committee of Kuopio University
Hospital, and written informed consent was obtained from every parent
and age-appropriate patient.
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). Ten patients
with solid tumor completed their chemotherapy at a median of 10.5
(range, 9.0–12.0) months from diagnosis and had the last follow-up
measurement performed at that stage. All other patients continued their
chemotherapy beyond the 1-yr follow-up point. Table 2 presents data on the cumulative doses
of those antineoplastic agents that were used in both ALL and solid
tumor patients. The duration of hospitalization during the study period
was determined as an estimate of immobilization (Table 2).
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Areal bone mineral densities (BMDareal; grams per
cm2) of the lumbar spine (L2–L4) and left femoral neck
were measured by dual energy x-ray absorptiometry (DXA; DPX,
Lunar Corp., Madison, WI) at diagnosis and at a median of
1 yr from the diagnosis. DPX pediatric software (Lunar Corp.) was used in children younger than 7 yr of age. Due to
device-based soft tissue requirements, femoral BMD was measured only in
children older than 6 yr of age. Due to a measurement artifact, 2
patients did not have data on their lumbar BMD available at diagnosis.
Therefore, 2 consecutive lumbar BMD measurements were performed in 26
(9 males and 17 females, 9 with ALL and 17 with solid tumor; median
age, 8.0 yr; range, 2.9–16.0 yr) patients, of whom 15 (6 males and 9
females, 3 with ALL and 12 with solid tumor) patients also had femoral
BMD measured. Eleven (3 males and 8 females, 6 with ALL and 5 with
solid tumor) patients were not evaluated for femoral BMD due to young
age (<7 yr). The BMD measurements were performed between February 1995
and December 1998. The short term reproducibility in children,
expressed as the coefficient of variation is 0.8% for the spine and
2.3% for the femoral neck (24). The long term reproducibility of our
DXA instrument based on repeated phantom measurements during the study
was 0.5%. To minimize the effect of bone size on BMD values, bone
apparent volumetric mineral density (BMDvol; grams per
cm3) was calculated from the areal BMD values: lumbar
BMDvol = BMDareal (g/cm2)
x [4/(
x width of measurement area in lumbar spine)];
femoral BMDvol = BMDareal
(g/cm2) x (4/) x (height of measurement
area/measurement area of femoral neck) (24). The BMD results were
compared with those of 26 healthy Finnish age- and sex-matched controls
(9 males and 17 females; median age, 8.4 yr; range, 3.3–16.0) who had
their BMD measured at baseline and after a 1-yr period. To minimize the
effect of age on BMD analyses, two subgroups were formed for BMD
comparisons between patients and their controls: subgroup A, those
patients who had both lumbar and femoral BMD measured (n = 15);
and subgroup B, those patients who did not have their femoral BMD
measured due to young age (n = 11). Patients in subgroup A were
significantly older than those in subgroup B [median, 12.8 (range,
7.3–16.0) vs. 5.7 (range, 2.9–6.8) yr; P
< 0.0001]. Bone age was assessed in 16 (57%) patients at diagnosis
and after the 1-yr follow-up by one of the authors (J.K.) using the
Tanner-Whitehouse (RUS) method (25).
Bone biochemical and hormonal status
Bone biochemical and hormonal parameters were determined at diagnosis and at medians of 1 month, 3 months, 6 months, and 1 yr from the diagnosis. To evaluate bone formation, serum human intact osteocalcin and type I collagen carboxyl-terminal propeptide (PICP) were measured by RIAs [Brahms Diagnostica (Berlin, Germany) and Orion Diagnostica (Espoo, Finland), respectively]. The sensitivity of the intact osteocalcin assay was 0.5 µg/L; the intra- and interassay coefficients of variation were less than 7.0% and 11.6%, respectively. The sensitivity of the PICP assay was 0.2 µg/L; the intra- and interassay coefficients of variation were less than 5.0% and 7.6%, respectively. To evaluate bone resorption, serum type I collagen carboxyl-terminal telopeptide (ICTP) was measured by RIA (Orion Diagnostica). The sensitivity of the ICTP assay was 0.5 µg/L; the intra- and interassay coefficients of variation were less than 7.0% and 10.0%, respectively. A two-site immunoradiometric assay was used for the evaluation of intact PTH (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum levels of calcium, phosphate, magnesium, alkaline phosphatase, albumin, alanine aminotransferase, and creatinine were determined by standard methods, and laboratory-specific age- and sex-matched reference data were used (Kuopio University Hospital, Kuopio, Finland).
The following parameters were determined at baseline and after a median follow-up time of 1 yr. To evaluate vitamin D metabolism, serum concentrations of 25OHD and 1,25-(OH)2D were measured using a modification of the method described by Parviainen et al. (26). The intraassay variations for 25OHD and 1,25-(OH)2D were less than 8% and 14%, respectively. To evaluate the GH axis, serum IGF-I was determined by a double antibody disequilibrium assay (INCSTAR Corp., Stillwater, MN), and serum IGFBP-3 was analyzed by RIA (Diagnostics Systems Laboratories, Inc., Webster, TX) in the Research Laboratory, Department of Pediatrics, University of Oulu (Oulu, Finland). Standard methods were used for evaluation of the following parameters: free T4 and TSH to exclude hypothyroidism, LH, and testosterone in males and estradiol in females to exclude hypogonadism in patients aged 10 yr or more (n = 12; five males and seven females).
Statistics
Statistical analyses were carried out with the SPSS for Windows (6.0.1) statistical program (SPSS, Inc., Chicago, IL). The percent change in the absolute BMD values was calculated based on the baseline and follow-up measurements [((BMD follow-up - BMD baseline)/BMD baseline) x 100]. Three BMD comparisons were performed with the Wilcoxon matched pairs test: 1) the absolute BMD values between the patients and their controls at diagnosis, 2) the absolute baseline BMD value with the 1-yr absolute BMD value within the patient and the control group, and 3) the annual percent BMD changes between the patients and their controls. The Mann-Whitney U test was used to compare the percent changes in the absolute BMD values between the two disease groups (ALL and solid tumors), between pubertal and prepubertal children, and between those with and without cerebral radiation, with P < 0.05 considered significant. To facilitate the comparison of data, z-scores were calculated for the follow-up measurements of the biochemical parameters from the mean and SD values of healthy Caucasian children of the same age (26, 27, 28, 29, 30). A log transformation was performed when calculating PICP and ICTP z-scores. Seasonal variation was taken into account when calculating the 25OHD z-scores (30). The Wilcoxon nonparametric test was used to compare the z-scores of the biochemical parameters against a constant for the controls. Similarly, the follow-up measurements of the biochemical parameters were compared to the baseline measurements using the Wilcoxon test. Bonferroni correction was performed for multiple comparisons. Wilcoxon matched pairs test was also used to compare the body mass indexes (BMIs), absolute height and weight values, and relative heights (the absolute height relative to that in the age- and sex-matched healthy population as SD score) (31) between the patients and their controls. Spearman correlation coefficients were calculated for the correlations between the cumulative doses of antineoplastic agents, BMD, and biochemical parameters. Stepwise regression analysis was used to study the effects of gender, disease group, puberty, hospitalization days, and changes in BMI and relative height during the 1-yr follow-up on the percent change in BMD.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Absolute
height (centimeters), relative height (SD score), and BMI
[kilograms per m2; mean (SD)] did not differ
significantly between the patients and their age- and sex-matched
controls at diagnosis [133.6 (24.3) vs. 131.2 (21.7) cm;
0.1 (1.1) vs. -0.1 (1.0) SD score;
16.7 (3.1) vs. 16.7 (2.5) kg/m2;
P = NS, respectively] or after 1 yr of treatment
[135.9 (22.8) vs. 136.5 (20.4) cm; -0.5 (1.1)
vs. -0.1 (0.9) SD score; 18.0 (3.4)
vs. 17.4 (2.6) kg/m2; P =
NS, respectively]. However, growth velocity [mean (SD)]
during the 1-yr follow-up was significantly lower in patients than in
controls [2.5 (2.2) vs. 5.5 (11.2) cm/yr; P
< 0.001]. Primary hypogonadism based on an elevated serum LH level
was observed in one male and one female patient with solid tumor. One
female with a history of cervical radiotherapy had compensated
hypothyroidism.
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and 2 present data on the individual lumbar
and femoral BMDareal and BMDvol values. Lumbar
and femoral BMDvol did not differ significantly from
control values at diagnosis (Table 4).
During the year after diagnosis, femoral BMDareal and
BMDvol decreased significantly in patients, whereas in
controls, there was an increase in femoral BMDareal and no
change in femoral BMDvol (Table 4). In the annual lumbar
BMD percent change, no significant difference was observed between
patients and controls (Table 4). No differences in lumbar and femoral
BMDvol percent changes were seen between patients with ALL
and those with solid tumor, between prepubertal and pubertal children,
or between those with and without cerebral radiation (data not
shown).
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]. A significant increase in PICP and
osteocalcin was observed at 3, 6, and 12 months and in ICTP at 12
months compared to baseline measurements (Table 5). At the end of the follow-up, the mean
z-score of ICTP was significantly increased [1.5 (1.0–2.0);
P < 0.0001] compared to the normal value, whereas the
levels of PICP and osteocalcin did not differ from normal values
[-0.4 (-1.3 to -0.4) and -0.2 (-0.8 to -0.4), respectively;
P = NS; Fig. 3].
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Osteocalcin at diagnosis correlated positively with femoral BMDareal and BMDvol at the end of the follow-up (r = 0.58 and P = 0.01; r = 0.58 and P = 0.01, respectively). PICP at 1 yr correlated positively with lumbar BMDareal and BMDvol by the end of the follow-up (r = 0.66 and P = 0.001; r = 0.49 and P = 0.02, respectively). No correlations were observed between the percent changes in BMD and ICTP at diagnosis or 1 yr. The cumulative dose of iv methotrexate correlated negatively with femoral BMDareal and BMDvol at 1 yr (r = -0.50 and P = 0.03; r = -0.56 and P = 0.02, respectively).
In a stepwise regression analysis, an increase in BMI was independently associated with an increase in lumbar BMDareal (r2 = 0.26; P = 0.04). No other independent associations were observed with BMD in the regression analyses.
Serum 25OHD was significantly decreased at diagnosis compared to normal
values (Table 6). Similarly, after the
1-yr follow-up, 25OHD and 1,25-(OH)2D were both
significantly reduced. Serum IGF-I was significantly increased, whereas
IGFBP-3 was significantly decreased at diagnosis and 1 yr compared to
normal values (Table 6). Serum concentrations of 25OHD,
1,25-(OH)2D, IGF-I, and IGFBP-3 at 1 yr did not correlate
with any of the cumulative doses of the antineoplastic agents.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In our study, no decrease in volumetric BMD was observed at the time of diagnosis compared with controls. After 1 yr from diagnosis, a significant reduction in both femoral areal and volumetric BMDs was observed compared to the annual BMD increment seen in the healthy controls. The decline in apparent volumetric BMD was evidence that this represented a real deficit in femoral bone density.
No difference in the lumbar BMD percent change was observed between patients and controls after the follow-up. However, the finding that lumbar volumetric BMD tended to decrease in the older patients (subgroup A) whereas in the younger ones (subgroup B) it tended to increase necessitates a study with a larger number of patients to further assess the effects of cancer therapy on lumbar BMD. The tendency to reduced lumbar BMD in subgroup A suggests that the effects of cancer and its treatment on BMD could be more detrimental at an older age. As the maximum increment in the rate of bone density has been observed to occur during pubertal development (24, 32), cancer therapies during that period could be expected to be more harmful to the development of BMD than those at an earlier age. However, even though we found no difference in the annual BMD change between pubertal and prepubertal children, alterations in BMD during pubertal development could not be assessed accurately enough in the present study due to the small number of pubertal patients. Similarly, the changes in femoral BMD in children younger than 7 yr of age could not be studied due to the device-based soft tissue requirements in DXA.
Previous studies have reported that the spine, which is predominantly trabecular bone, is more sensitive to various therapeutic modalities, including methotrexate and corticosteroids, than the femoral neck, which contains more cortical bone (33, 34, 35). Accordingly, we would have expected the development of lumbar BMD to be more affected than that of femoral BMD in our patients who were commonly treated with high doses of both methotrexate and corticosteroids. Therefore, our finding of significantly reduced femoral BMD indicates that there are other factors that specifically impair the development of femoral bone density in children during cancer treatment.
Prolonged periods of disease and treatment related hospitalization are common in childhood malignancies. In the present study, the patients were hospitalized for considerable periods of time, leading to decreased physical activity. The loss of bone during immobilization has been found to be greater in weight-bearing bones and to be more pronounced in younger patients (36). In cortical bone, immobilization induced bone loss has been shown to become conspicuous after 3–6 months of inactivation (36). Pathological fractures, predominantly in the femur, and osteoporosis after immobilization have been observed in children with cerebral palsy (37). The bone loss caused by immobilization could thus partly explain our finding of a reduction in femoral BMD in children with cancer. However, as most of the patients continued their chemotherapy beyond the 1-yr study period, a follow-up of both lumbar and femoral BMD is required to further evaluate the development of BMD in these children during their entire treatment with chemotherapy. In our previous cross-sectional studies, significant reductions in both lumbar and femoral BMDs were observed in children with ALL at completion of chemotherapy and in long term survivors of childhood ALL (9, 10).
Serum osteocalcin has been shown to be a sensitive and specific marker of bone formation (38). Serum PICP is released into the circulation during type I collagen synthesis, reflecting predominantly the rate of bone collagen formation (38). Serum ICTP is a marker of collagen degradation that can be compared directly with the serum markers of bone formation measured from the same sample (27, 39). In adults, serum ICTP has been found to be less sensitive than the urinary markers to monitor the effects of antiresorptive agents, but in children, its sensitivity to therapeutic interventions has been equal to that of the urinary pyridinium cross-links (40).
We found that the markers of bone formation were significantly decreased at diagnosis, reflecting a negative balance in bone turnover, even though no reduction in volumetric BMD was observed at that stage. The markers of bone metabolism are known to respond relatively rapidly compared to changes in BMD. The secretion of PTH-related peptides, tumor-related cytokines, disturbances in vitamin D metabolism and GH secretion, leukemic infiltration of the bone marrow, and disease-related poor health and physical inactivity are factors that may impair bone metabolism in children with a malignancy at an early stage of the disease (2, 12, 13, 41). In our study, the levels of osteocalcin and PICP were normalized, whereas the level of the marker of bone resorption (ICTP) was significantly increased by the end of the follow-up, which is in accordance with the impaired development of femoral BMD observed in our patients.
Osteocalcin and ICTP are largely cleared by the kidneys (38). The elevated serum ICTP and osteocalcin levels could thus be partly due to impaired renal function. However, we observed no increase in the level of serum creatinine during the study period. Serum PICP is largely cleared via the hepatic endothelial cells, and impaired hepatic function would lead to increased serum PICP levels (38). We found no significant increase in serum alanine aminotransferase during the follow-up. Thus, the increased levels of PICP in our study do not seem to be due to impaired liver function.
Osteopenia in children with cancer has been associated with alterations in vitamin D metabolism. Halton et al. observed that the majority of children with ALL had low 1,25-(OH)2D concentrations at diagnosis, and the levels remained low throughout the therapy, whereas plasma 25OHD levels were normal (1, 2). They speculated that low 1,25-(OH)2D might be due to the receptor-mediated binding of 1,25-(OH)2D to leukemic cells and to the requirement for 1,25-(OH)2D before the cells in the myeloid lineage can differentiate. In the present study, we found low levels of serum 1,25-(OH)2D in both patients with ALL and those with solid tumor at the end of the follow-up, indicating that factors other than those related to leukemic cell lineage could also contribute to alterations in vitamin D metabolism. An accelerated rate of cell turnover due to chemotherapy, leading to increased utilization of 1,25-(OH)2D, and a disordered synthesis of 1,25-(OH)2D due to corticosteroids have been suggested as causes of reduced 1,25-(OH)2D concentrations (2, 3). The majority of our patients were treated with corticosteroids and various antineoplastic agents, which could have contributed to 1,25-(OH)2D depletion.
Additionally, the reduction of 25OHD at diagnosis as well as at the end of the study suggested a primary vitamin D deficiency, possibly as a consequence of malnutrition and diminished sunlight exposure due to poor health and decreased physical activity, which are often observed in children with cancer at an early stage of the disease and during hospitalization. Deficient vitamin D hydroxylation in liver, kidney, and intestine may lead to low levels of 25OHD during therapy. Also, intestinal mucositis due to intensive chemotherapy may result in vitamin D malabsorption.
The low serum total calcium levels in our study could be attributed to hypoalbuminemia, which has been considered to be a metabolic response to fever and infection in children with malignant disease (42). The concentrations of serum ionic and urinary calcium and the intake of calcium were not analyzed in the present study.
GH plays an important role in bone growth as well as in the development of bone mass and density (43). Crofton et al. in their recent study in children with ALL, observed low bone turnover, decreased levels of serum IGFBP-3 and IGF-I, and increased urinary GH excretion at diagnosis indicative of GH resistance due to the disease itself (12). In the present study, serum IGFBP-3 levels were decreased at diagnosis as well as at the end of the follow-up, reflecting disturbed GH function during chemotherapy. This was corroborated by our finding of decreased growth velocity during the first year of cancer treatment. In contrast, serum IGF-I levels were increased in our study. In previous studies, corticosteroids have been shown to increase circulating IGF-I levels, but at the same time they may antagonize the IGF-I activity by direct or indirect inhibitory mechanisms (44, 45). This could explain our finding of a significant increase in serum IGF-I level at the end of the study after corticosteroid treatment, but would not explain increased IGF-I levels at diagnosis, the reasons for which need to be further investigated.
In conclusion, newly diagnosed children with cancer presented with decreased bone formation and normal bone resorption. During chemotherapy, bone formation normalized, but there was evidence of increased bone resorption and impaired development of femoral bone density. The causes of these changes are probably multifactorial. Our findings suggest that an early intervention program on bone turnover should be considered in newly diagnosed children with cancer. Also, in addition to optimal treatment of the possible late endocrinopathies, such as GH deficiency and hypogonadism, which might disturb bone metabolism in survivors of childhood cancer, a follow-up of BMD could facilitate the identification of those patients who may be left with impaired peak bone mass and who would require specific therapeutic interventions to prevent any further decrease in skeletal mass and to preserve BMD.
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Acknowledgments |
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Received February 12, 1999.
Revised May 4, 1999.
Accepted May 24, 1999.
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References |
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