Leukemia, Lymphoblastic, Acute, Osteoporosis
Conditions
Keywords
Bone Density
Brief summary
Research studies have shown that children who are long-term survivors of childhood leukemia may be at greater risk for early bone loss called osteoporosis. This bone loss may lead to a greater risk of broken bones and other spine and bone problems. However, researchers still do not know much about how frequently this long-term side effect may occur and how severe the problem is. St. Jude Children's Research Hospital researchers want to determine the frequency and severity of this side effect. They are also studying whether taking calcium and Vitamin D supplements can help children at risk for osteoporosis and if certain factors can be identified -- such as age at diagnosis, cancer treatments, or family history -- that may increase the chances of having osteoporosis. Researchers will take an x-ray study called quantitative computed tomography (QCT) to measure bone mineral density (BMD). The BMD is a measure of bone strength. If a subject's BMD falls below the average, he/she will be assigned to one of two groups. Subjects will be randomly assigned (like tossing a coin) to receive calcium and vitamin D pills. The other half will receive placebo pills that look like the calcium and vitamin D pills.
Detailed description
The main objectives of the study are: * To estimate, using quantitative computed tomography (QCT), the prevalence of diminished bone mineral density (BMD) in patients treated with contemporary, protocol-based multiagent chemotherapy (+cranial irradiation) for childhood acute lymphoblastic leukemia (ALL). * To investigate possible risk factors for the development of diminished BMD in patients treated with contemporary protocol-based therapy for childhood ALL. Factors to be examined include patient characteristics (age at the time of treatment, gender, race, body mass index, physical activity and nutritional status, menarchal status, oral contraceptive use, growth hormone therapy, smoking and alcohol intake, birth weight, fracture history); treatment effects (intensity of treatment with antimetabolites and glucocorticoids; history of cranial irradiation); and genetic predisposition (i.e., vitamin D and CYP3A4 receptor polymorphism and family history of osteoporosis). * To evaluate, in a prospective placebo-controlled double-blinded randomized trial, the effects of vitamin D and calcium supplementation in addition to nutritional counseling on BMD in patients with BMD scores below the mean for age- and gender-matched controls, compared to an educational program of nutritional counseling alone. Secondary Aim * To evaluate, in a prospective randomized trial, the correlation between BMD as determined by QCT and BMD as determined by dual energy x-ray absorptiometry (DEXA) in patients with BMD more than one standard deviation (SD) below the mean for age- and gender-matched controls.
Interventions
DRUGCalcium carbonate (Tums), vitamin D
Calcium carbonate 100mg/day (Tums), vitamin D 800 units/day
OTHERPlacebo
Placebo
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patient is a survivor of acute lymphoblastic leukemia. * Patient was treated on St. Jude Children's Research Hospital's Total XI, XII, or XIII treatment protocol. * Patient is at least five years out from completion of therapy and is in first remission
Exclusion criteria
* Active disease * Pregnant or lactating females * Inability to chew and swallow pills * Currently taking more than 800 mg supplemental calcium or 800 IU vitamin D * Anemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | Baseline, 12 months, 24 months, and at 36 months or study end | The effect of taking calcium and vitamin D supplements was measured using Quantitative Computed Tomography (QCT) to calculate a QTC Z score. A standardized Z-score was calculated to indicate the difference between the patient's Bone Mineral Density (BMD) and the mean value for age and gender-appropriate controls. Z-scores from 0 to +2 are considered normal, above +2 are considered to be elevated, from 0 to -1 are considered to represent a mild BMD deficit, between -1 and -2 are considered to represent moderate deficits, and below -2 are considered to represent severe deficits. |
| Bone Mineral Density in Male and Female ALL Survivors | Baseline | Using bone mineral density Z-score, assess relationship between predisposing factors (gender) and bone mineral density; a negative value indicates a deficit in bone mineral density. |
| Bone Mineral Density by Race of ALL Survivors | Baseline | Using bone mineral density Z-score, assess relationship between predisposing factors (race) and bone mineral density; a negative value indicates a deficit in bone mineral density. |
| Bone Mineral Density by Age Group of ALL Survivors | Baseline | Using bone mineral density Z-score, assess relationship between predisposing factors (age groups) and bone mineral density; a negative value indicates a deficit in bone mineral density. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype | At enrollment | The Apa1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood |
| Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype | At enrollment | The Bsm1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood |
| Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | Baseline | To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 121 patients at baseline were assessed by both method the QCT and DXA methods to assess Bone Mineral Density. |
Countries
United States
Participant flow
Recruitment details
429 patients were recruited at St. Jude Children's Research Hospital between August 7, 2000 and July 27, 2006. 4 patients were found to be ineligible and 1 patient was taken off study per the PI's request. 424 patients were available at baseline.
Pre-assignment details
424 total patients were enrolled on the study. 149 patients were ineligible for randomization. 275 patients were identified with Bone Mineral Density (BMD) Z-scores \> 0 and thus were eligible for intervention and were randomized to receive either Calcium and Vitamin D supplementation or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Group Nutritional counseling + placebo | 134 |
| Supplement Group Nutritional counseling + supplementation with calcium, 1000mg/day + vitamin D, 800 units/day, for a 2 year period | 141 |
| Patients Ineligible for Randomization 424 patients were enrolled into the study, 149 were ineligible for randomization. | 149 |
| Total | 424 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | ALL relapse or second malignancy | 1 | 2 | 0 |
| Overall Study | Bone Mineral Density > 0 | 0 | 0 | 149 |
| Overall Study | Bone Mineral Density dropped > 5% | 9 | 7 | 0 |
| Overall Study | Limited adherence to study requirements | 20 | 23 | 0 |
| Overall Study | Lost to Follow-up | 6 | 3 | 0 |
| Overall Study | Open label | 3 | 2 | 0 |
| Overall Study | Pregnancy | 6 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 0 |
Baseline characteristics
| Characteristic | Placebo Group | Supplement Group | Patients Ineligible for Randomization | Total |
|---|---|---|---|---|
| Age, Continuous | 17.9 years STANDARD_DEVIATION 5.6 | 17.6 years STANDARD_DEVIATION 6.3 | 19.2 years STANDARD_DEVIATION 6.6 | 17.8 years STANDARD_DEVIATION 5.9 |
| Sex: Female, Male Female | 56 Participants | 63 Participants | 87 Participants | 206 Participants |
| Sex: Female, Male Male | 78 Participants | 78 Participants | 62 Participants | 218 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 134 | 0 / 141 | 0 / 149 |
| serious Total, serious adverse events | 0 / 134 | 0 / 141 | 0 / 149 |
Outcome results
Primary
Bone Mineral Density by Age Group of ALL Survivors
Using bone mineral density Z-score, assess relationship between predisposing factors (age groups) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time frame: Baseline
Population: Assess baseline participants to determine whether age was a contributing factor in bone mineral density.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Bone Mineral Density by Age Group of ALL Survivors | -0.6 Z-score | Standard Error 1.1 |
| Supplement | Bone Mineral Density by Age Group of ALL Survivors | -0.54 Z-score | Standard Error 1.21 |
| 18 to 22 Years | Bone Mineral Density by Age Group of ALL Survivors | -0.59 Z-score | Standard Error 1.2 |
| Above 22 Years | Bone Mineral Density by Age Group of ALL Survivors | -0.25 Z-score | Standard Error 1.29 |
p-value: 0.0092Kruskal-Wallis
Primary
Bone Mineral Density by Race of ALL Survivors
Using bone mineral density Z-score, assess relationship between predisposing factors (race) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time frame: Baseline
Population: Assess baseline participants to determine whether race contributed to bone mineral density.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Bone Mineral Density by Race of ALL Survivors | -0.54 Z-score | Standard Error 1.14 |
| Supplement | Bone Mineral Density by Race of ALL Survivors | 0.15 Z-score | Standard Error 1.56 |
p-value: 0.0023Wilcoxon (Mann-Whitney)
Primary
Bone Mineral Density in Male and Female ALL Survivors
Using bone mineral density Z-score, assess relationship between predisposing factors (gender) and bone mineral density; a negative value indicates a deficit in bone mineral density.
Time frame: Baseline
Population: Baseline participants were assessed to determine whether gender was a pre-disposing factor for bone mineral density.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Bone Mineral Density in Male and Female ALL Survivors | -0.62 Z-score | Standard Error 1.18 |
| Supplement | Bone Mineral Density in Male and Female ALL Survivors | -0.3 Z-score | Standard Error 1.18 |
p-value: 0.0004Wilcoxon (Mann-Whitney)
Primary
Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD)
The effect of taking calcium and vitamin D supplements was measured using Quantitative Computed Tomography (QCT) to calculate a QTC Z score. A standardized Z-score was calculated to indicate the difference between the patient's Bone Mineral Density (BMD) and the mean value for age and gender-appropriate controls. Z-scores from 0 to +2 are considered normal, above +2 are considered to be elevated, from 0 to -1 are considered to represent a mild BMD deficit, between -1 and -2 are considered to represent moderate deficits, and below -2 are considered to represent severe deficits.
Time frame: Baseline, 12 months, 24 months, and at 36 months or study end
Population: Of the 275 pts identified with BMD z-scores \< 0, 134 were randomized to the placebo group and 141 to the supplement group. Bone Mineral Density QCT Z-scores were calculated at baseline, 12 months, 24 months, and at 36 months or study end.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | Baseline | -0.95 Z-Score |
| Placebo | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 12 Months | -0.87 Z-Score |
| Placebo | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 24 Months | -0.72 Z-Score |
| Placebo | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 36 Months (study end) | -0.56 Z-Score |
| Supplement | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 36 Months (study end) | -0.61 Z-Score |
| Supplement | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | Baseline | -0.97 Z-Score |
| Supplement | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 24 Months | -0.76 Z-Score |
| Supplement | Effect of Taking Calcium and Vitamin D Supplements on Bone Mineral Density (BMD) | 12 Months | -1.04 Z-Score |
Comparison: Baseline where N=134p-value: 0.86Wilcoxon Test
Comparison: 12 Month BMD Z-Score Calculation where N=109p-value: 0.99Wilcoxon Test
Comparison: 24 Month BMD Z-Score calculation where N=91p-value: 0.54Wilcoxon Test
Comparison: 36 Month (End of Study) BMD Z-Score calculation where N=84p-value: 0.31Wilcoxon Test
Secondary
Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype
The Apa1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood
Time frame: At enrollment
Population: Of the 424 patients screened, 417 participants consented for genetic testing. Of the 417 patients screened for the Apa 1 vitamin D receptor, only 68 had the AA genotype, 104 had the Aa genotype, and 49 had the aa genotype.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype | -0.56 QCT Z-Score | Standard Deviation 1.27 |
| Supplement | Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype | -0.44 QCT Z-Score | Standard Deviation 1.28 |
| 18 to 22 Years | Mean QCT Z-Score by Apa1 Vitamin D Receptor Genotype | -0.57 QCT Z-Score | Standard Deviation 1.13 |
p-value: 0.4Kruskal Wallis
Secondary
Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype
The Bsm1 Vitamin D Receptor has been associated with bone mineral density and bone turnover markers in various patient cohorts but has not been investigated I survivors of childhood
Time frame: At enrollment
Population: Of the 424 patients screened, 417 participants consented for genetic testing. Of the 417 patients screened for the Bsm 1 vitamin D receptor, only 41 had the BB genotype, 65 had the Bb genotype, and 77 had the bb genotype.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype | -0.5 QCT Z-Score | Standard Deviation 1.2 |
| Supplement | Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype | -0.17 QCT Z-Score | Standard Deviation 1.25 |
| 18 to 22 Years | Mean QCT Z-Score by Bsm 1 Vitamin D Receptor Genotype | -0.17 QCT Z-Score | Standard Deviation 1.24 |
p-value: 0.21Kruskal Wallis
Secondary
Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 188 patients were assessed at 24 months by the QCT method and 90 were evaluated using the DXA methods to assess Bone Mineral Density. 90 patients received both scans.
Time frame: 24 months
Population: 188 patients were assessed at the 24 months interval and received a QCT Scan. 90 patients were also assessed using the DXA Scan. Comparison of the two methods used 90 paired studies to arrive at a correlation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.75 Z-score | Standard Deviation 0.82 |
| Supplement | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.77 Z-score | Standard Deviation 1.31 |
| 18 to 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.84 Z-score | Standard Deviation 0.86 |
| Above 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.60 Z-score | Standard Deviation 1.07 |
Comparison: 188 patients were assessed at baseline and received a QCT Scan. 90 patients were also assessed using the DEXA Scan. Comparison of the two methods used 90 paired studies to arrive at a correlation coefficient.p-value: <0.000195% CI: [0.36, 0.66]Z-test
Secondary
Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 180 patients were assessed at 36 months by the QCT method and 89 were evaluated using the DXA methods to assess Bone Mineral Density. 89 patients received both scans.
Time frame: 36 months
Population: 180 patients were assessed at the 36 months interval and received a QCT Scan. 89 patients were also assessed using the DEXA Scan. Comparison of the two methods produced 89 paired studies to arrive at a correlation.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.54 Z-score | Standard Deviation 0.86 |
| Supplement | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.63 Z-score | Standard Deviation 1.14 |
| 18 to 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.71 Z-score | Standard Deviation 0.98 |
| Above 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.63 Z-score | Standard Deviation 1 |
Comparison: 180 patients were assessed at 36 months and received a QCT Scan. 89 patients were also assessed using the DXA Scan. Comparison of the two methods used 89 paired studies to arrive at a correlation coefficient.p-value: <0.000195% CI: [0.3, 0.63]Z-test
Secondary
Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 218 patients were assessed at 12 months for QCT. 94 were evaluated using DXA. 94 patients received both scans.
Time frame: 12 months
Population: 218 patients were assessed at the 12 months interval and received a QCT Scan. 94 patients were also assessed using the DXA Scan. Comparison of the two methods used 94 paired studies to arrive at a correlation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.02 Z-score | Standard Deviation 0.87 |
| Supplement | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.20 Z-score | Standard Deviation 1.36 |
| 18 to 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.04 Z-score | Standard Deviation 0.89 |
| Above 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -0.79 Z-score | Standard Deviation 0.93 |
Comparison: 218 patients were assessed at 12 months and received a QCT Scan. 94 patients were also assessed using the DEXA Scan. Comparison of the two methods used 94 paired studies to arrive at a correlation coefficient.p-value: <0.000195% CI: [0.38, 0.67]Z-test
Secondary
Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density.
To compare the bone mineral density scores determined by Quantitative Computed Tomography (QCT) with those determined by dual energy x-ray absorptiometry (DXA) scan. 121 patients at baseline were assessed by both method the QCT and DXA methods to assess Bone Mineral Density.
Time frame: Baseline
Population: 275 patients were assessed at baseline and received a QCT Scan. 121 patients were also assessed using the DEXA Scan. Comparison of the two methods used 121 paired studies to arrive at a correlation coefficient.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.06 Z-score | Standard Deviation 0.7 |
| Supplement | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.30 Z-score | Standard Deviation 1.21 |
| 18 to 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.09 Z-score | Standard Deviation 0.74 |
| Above 22 Years | Quantitative Computed Tomography (QCT) and Dual Energy X-ray Absorptiometry (DXA) Scan Scores for Bone Mineral Density. | -1.18 Z-score | Standard Deviation 1.02 |
Comparison: 275 received a QCT and 121 received a DXA scan. 121 paired scans were evaluated.p-value: <0.000195% CI: [0.25, 0.55]Z-test