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

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 + 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 + 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 + 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.

Novel radioprotectant drugs for sparing radiation-induced damage to the physis.

PURPOSE: To determine if pentoxifylline, interleukin 1alpha, selenium and misoprostol can minimize damage to physeal longitudinal growth during single radiation dose exposure in an animal model. MATERIALS AND METHODS: Eighty-seven weanling Sprague-Dawley rats were randomized into 15 drug/dose groups. All groups received a single 17.5-Gy gamma-irradiation exposure to the right knee, the left limb serving as an internal control. Pentoxifylline was injected 30 min before exposure, sodium selenite and interleukin 1alpha 24 h before exposure and misoprostol 2 h before exposure. Positive controls received 17.5 Gy. At 6 weeks, animals were sacrificed, the hind limb lengths were measured and detailed histomorphometric analysis was performed. RESULTS: Statistically significant reductions (p < or = 0.03) in mean limb length discrepancy compared with irradiation alone were seen following administration of pentoxifylline (50 mg kg(-1)), interleukin 1alpha (15 mcg kg(-1)), selenium (5 mg kg(-1)) and misoprostol (20 mg kg(-1)). Histomorphometric endpoints and growth rate remained altered at 6 weeks despite treatment, but length discrepancy reduction was highly correlated with the appearance of regenerative clones. CONCLUSIONS: Each drug reduced the amount of anticipated growth arrest in the animal model and some compared favourably in magnitude with that previously demonstrated for the established radioprotectant drug amifostine. Restoration of growth appears related to appearance of regenerative clones.