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 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

A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

“…Indeed, in our experiments, ZA increased BMD and improved all histomorphometric parameters. These results are consistent with those of Spadaro and colleagues, who found that alendronate prevented bone loss induced by high-doses of MTX treatment in rats [39]. Other bisphosphonates, such as alendronate, have also been shown to be effective in the prevention of systemic bone loss associated with RA during treatment with MTX [40] or corticosteroids [11].…”

Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits

“…The limited number of studies using OVX rabbits makes it difficult to conclude whether the lack of a large decline in bone strength in response to estrogen deficiency applies to this species in general. Strong and positive effects of ALN on bone density, bone strength, and fracture risk in human and other species have been widely acknowledged 26–29. Interestingly, these studies demonstrated that a higher dose of ALN (200 to 600 µg/kg/week s.c.) was needed to protect against OVX‐induced bone loss in the rabbit than in rat and other species 30, 31.…”

Cathepsin K inhibitors increase distal femoral bone mineral density in rapidly growing rabbits

“…A more recent experiment showed increased trabecular bone volume following seven days of subcutaneous (SC) alendronate (ALN) (0.010 mg/kg/d) [18]. Furthermore, a more recent study using weanling rats showed an increase in distal femoral metaphyseal BMD following six weeks of once-weekly treatment with ALN [19]. A higher growth rate of the distal and proximal femur, the proximal tibia, and the proximal and distal radius has been observed in the rapidly growing rabbit than that typically observed with other species or in more mature animals [20,21].…”