title: Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge.
abstract: 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.
authors.affiliation: Department of Orthopedic Surgery, Musculoskeletal Science Research Center, Room 3119, Institute for Human Performance, 505 Irving Avenue, Syracuse, New York 13210, USA. spadaroj@mail.upstate.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Spadaro
authors.forename: T A
authors.initials: TA
authors.lastname: Damron
authors.forename: J A
authors.initials: JA
authors.lastname: Horton
authors.forename: B S
authors.initials: BS
authors.lastname: Margulies
authors.forename: G M
authors.initials: GM
authors.lastname: Murray
authors.forename: D A
authors.initials: DA
authors.lastname: Clemente
authors.forename: J A
authors.initials: JA
authors.lastname: Strauss
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050071:Bone Density Conservation Agents; D019386:Alendronate; D008727:Methotrexate