The short- and long-term effects of methotrexate on the rat skeleton

Wheeler, Donna L.; Griend, Robert A. Vander; Wronski, Thomas J.; Miller, Gary J.; Keith, E.E.; Graves, J. E.

doi:10.1016/8756-3282(94)00032-u

Cited by 111 publications

(66 citation statements)

References 8 publications

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“…21 A significant aBMD or aBMC reduction was not seen with MTX at other sites, however. A reduction was observed in femoral length in the MTX treated groups (2.9%) and was consistent with the 5% loss found by Van Leeuwen using a more extensive MTX treatment of nine weekly doses in growing rats.…”

Section: Discussionmentioning

confidence: 95%

“…5,7,8,11,12 MTX was administered following a regimen previously used to model high-dose chemotherapy in an adult Sprague-Dawley rat. 21 Briefly, over the first 19 days of the study CTL and MTX groups received intraperitoneal injections of saline or 0.75 mg/kg/day MTX (Ben Venue Laboratories, Bedford, OH), respectively, in a 5 days on/9 days off/5 days on regimen. Thereafter, the two groups received weekly saline subcutaneous injections.…”

Section: Methodsmentioning

confidence: 99%

“…High-dose methotrexate (MTX), for example, has been associated with resultant osteopenia in adult animals. [19][20][21] The effect of high-dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this specific setting. Van Leeuwen and colleagues found that long bone length and strength was reduced in growing rats by MTX, largely due to treatment-induced malnutrition.…”

Section: Introductionmentioning

confidence: 99%

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Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge

Spadaro¹,

Damron²,

Horton³

et al. 2006

Journal Orthopaedic Research

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Alendronate (ALN) and other bisphosphonates have been used successfully in pediatric patients with osteopenia secondary to connective tissue diseases. Loss of growth in height has not been reported, but concerns remain regarding the effect of these potent antiresorptive agents when used in children and adolescents. High-dose methotrexate (MTX) and other chemotherapy drugs have been implicated in osteoporosis and a high fracture incidence in survivors of childhood cancers and are also associated with osteopenia in adult animals. The effect of high dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this setting. We examined the effects of ALN and MTX administration, alone and in combination, on bone density, morphology, mechanical strength, and longitudinal growth in normal growing rats. Sprague-Dawley rats were given ALN once weekly (0.3 mg/kg) from 5 to 11 weeks of age, with and without a course of methotrexate (MTX) given daily in weeks 1 and 3 (0.75 mg/kg/day). Twenty-four animals were randomly divided into four groups: Control (vehicle), ALN alone, ALN þ MTX, and MTX alone. After 6 weeks, the femora, tibiae, and lumbar spine were studied by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, mechanical strength testing, microradiography, light microscopy, and by determination of ash weights and bone lengths. ALN treatment increased bone mineral density (BMD) by 23% to 68%. The largest increases in the femur occurred in the distal third where endochondral bone growth was greatest and included large increases in trabecular bone and total cross-sectional area. ALN þ MTX produced similar effects to ALN alone. MTX only reduced BMD by 8% in the vertebrae, but not significantly at other sites. MTX also led to femoral length reductions of 2.9%. The small reductions in BMD due to MTX were overwhelmed by the increases due to ALN, whereas the length loss was unaffected. Transverse density banding corresponding to weekly ALN administrations were clearly evident radiographically throughout the growing skeleton, likely due to decreased resorption and possibly increased mineralization in the bands. ALN or ALN þ MTX treatment also led to increases in mechanical strength in the femora. Although MTX administration during growth leads to some BMD reduction, ALN given with MTX eliminates this reduction and in fact bone density and strength increase above control levels. ß

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge

Spadaro¹,

Damron²,

Horton³

et al. 2006

Journal Orthopaedic Research

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“…This has been demonstrated particularly in the growing skeleton [20][21], but there appears to be little data on the mechanisms of the direct toxic effects of chemotherapy agents on bone especially for the newer regimens [22]. There are limited data in experimental animals, eg a demonstration in rats that methotrexate had both shortterm (30 days) and long-term (170 days) significant adverse effects on cancellous bone compared to a control group [23], but this study was phenomenological rather than mechanistic.…”

Section: Discussionmentioning

confidence: 99%

Bone mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: is it dependent on oestrogen deficiency?

Cameron

Douglas

Brown

et al. 2010

Breast Cancer Res Treat

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mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: is it dependent on oestrogen deficiency?. Breast Cancer Research and Treatment, Springer Verlag, 2010, 123 (3) Pre-menopausal women given adjuvant chemotherapy for breast cancer experience both premature ovarian failure and loss of bone mineral density (BMD), and this study was designed to see if these observations are causally linked. MethodsChemotherapy was administered to 41 pre-menopausal women with early breast cancer enrolled prospectively in a study of ovarian function and BMD in such women given systemic therapy. After giving written informed consent, all patients underwent baseline and regular on-treatment measurements of BMD by dual-energy x-ray absorptiometry (DXA) scan, bone turnover and ovarian function by analysis of serum hormone levels and self-reported menstrual diaries. ResultsBaseline lumbar spine BMD in the 41 women given chemotherapy was higher than the normal population (Z score 0.28±0.14 (mean±sem), p=0.047), and fell significantly over the first six months from a mean of 1.05 to 1.01 g/m 2 , p <0.0001, and similar but smaller changes were demonstrated in hip BMD. This fall was independent of age at diagnosis, type of chemotherapy, development of amenorrhoea or either baseline or on-treatment estradiol concentration. During the six months after completion of adjuvant chemotherapy, BMD fell further only in those women with low estradiol or experiencing amenorrhoea during the first six months, although all groups showed evidence of increased bone turnover. ConclusionsThis study demonstrates loss of both spine and hip BMD in pre-menopausal women during six months' adjuvant systemic chemotherapy to be independent of changes in ovarian function. Ovarian function was however related to BMD changes after chemotherapy ceased.3

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“…These effects occurred independent of circulating IGF-1 and IGFBP-3, which were restored to normal values during treatment. 4,5,7,43,44,46 However, it has been seen in a small …”

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confidence: 99%

Improvement in Bone Mineral Density and Body Composition in Survivors of Childhood Acute Lymphoblastic Leukemia: A 1-Year Prospective Study

Marinovic

Dorgeret²,

Lescoeur³

et al. 2005

Pediatrics

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ABSTRACT. Objectives. Abnormalities in bone mineral density (BMD), body composition, and bone metabolism have been reported in children who were treated for acute lymphoblastic leukemia (ALL) during and after completion of therapy. However, these studies are crosssectional, and no longitudinal data are available in a large group of patients after completion of therapy. In the present study, 1-year longitudinal changes in BMD, body composition, and bone metabolism were evaluated in children with ALL during the first 3 years after completion of therapy without cranial irradiation.Methods. BMD of total body (TB; g/cm 2 ), areal and apparent volumetric lumbar spine (L2-L4), lean body mass, and percentage of body fat were measured by dual-energy x-ray absorptiometry in 37 children (median age: 7.9 years; range: 4.7-20.6 years) who were treated for ALL at a median age of 3.3 years (range: 1.1-16.6 years), after a median time of 2.2 years after the completion of treatment, and after a 1-year follow-up period. Two control subjects (n ‫؍‬ 74) who were matched for gender, age, and pubertal stage were also longitudinally investigated for body composition for 1 year. Usual serum biochemical markers of calcium metabolism and bone turnover were measured in patients during the study period.Results. A slight decrease in TB BMD was found after a median time of 2.2 years after the completion of therapy for ALL in childhood. Patients showed a significantly lower median TB BMD when evaluated <1.5 years as compared with those at >1.5 years since completion of therapy. At the time of first evaluation, the percentage of body fat mass was significantly higher and patients were physically less active than their matched control subjects. Although, as expected, during the 1 year of follow-up both groups showed an annual increment in their BMD measurements, a significantly higher increase in TB BMD was observed in patients in comparison with control subjects. During this same period, the increase in the percentage of body fat mass was slightly lower in ALL patients as compared with control subjects. At the end of the follow-up year, BMD, body-composition parameters, and physical activity of ALL patients were similar to those observed in matched control subjects. Serum biochemical markers of bone turnover were normal at both evaluations.Conclusions. A significant increase in TB BMD and a tendency to a lesser increase in percentage of body fat mass were observed during the study period in ALL patients as compared with chronological age-, gender-, and pubertal stage-matched control subjects. These findings suggest a positive effect of long-term completion therapy and increase in physical activity on BMD, body composition, and bone metabolism in patients who have been treated for ALL. A cute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and 80% of children with standard-risk disease can now expect to be cured. 1,2 Children with ALL have reduced bone formation 3-10 and bone mineral density (BMD) 3,9,10 at diagnosis. Seve...

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The short- and long-term effects of methotrexate on the rat skeleton

Cited by 111 publications

References 8 publications

Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge

Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge

Bone mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: is it dependent on oestrogen deficiency?

Improvement in Bone Mineral Density and Body Composition in Survivors of Childhood Acute Lymphoblastic Leukemia: A 1-Year Prospective Study

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