Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats

Schenk, Robert K.; Merz, Walter A.; Mühlbauer, R. C.; Russell, R. G. G.; Fleisch, H.

doi:10.1007/bf02547219

Cited by 476 publications

(182 citation statements)

References 19 publications

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“…This phenomenon has been reported after periodic administration of ALN and other bisphosphonates in young animals 12,24 and in children. 3,52 This banding can be attributed to intermittent reductions in osteoclastic resorption and remodeling in the primary and secondary spongiosa 24 and does not seem to be evident after daily ALN administration, probably because the interval is too short to resolve changes in bone remodeling. Along with trabecular changes, a retardation of periosteal and endosteal remodeling in the metaphysis leads to reduced tubulation of the cortex and a larger cortical diameter.…”

Section: Discussionsupporting

confidence: 59%

“…Along with trabecular changes, a retardation of periosteal and endosteal remodeling in the metaphysis leads to reduced tubulation of the cortex and a larger cortical diameter. 24,52 A contribution of hypermineralization to the banding cannot be ruled out.…”

Section: Discussionmentioning

confidence: 97%

“…The subcutaneous route was chosen to avoid the variability and difficulty of oral dosing and because this method has been used successfully by others. 6,7,24,25 The dose was within the range of that found to be safe and effective for increasing bone density in mice (0.125-0.35 mg/kg/ week), whether given weekly or divided into daily portions. 5,7,8,11,12 MTX was administered following a regimen previously used to model high-dose chemotherapy in an adult Sprague-Dawley rat.…”

Section: Methodsmentioning

confidence: 94%

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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: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 94%

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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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“…Indeed, bisphosphonates have been shown to block the removal of both bone and cartilage in growing rats, thus retarding the modeling of the metaphysis, which becomes club-shaped and radiologically denser than normal (19). This effect is also observed in children treated with high doses of bisphosphonates (20).…”

mentioning

confidence: 99%

Effect of alendronate on the mandible and long bones: an experimental study in vivo

2015

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Background:Bisphosphonates are anticatabolic agents that inhibit bone resorption and are widely used to treat osteoporosis and bone metastases in adults. They are also used in young patients with diseases like osteogenesis imperfecta or juvenile osteoporosis. Bone modeling/remodeling is elevated in growing subjects, and inhibition of osteoclastic activity has been shown to interfere with growth. Thus, our objective was to evaluate the effect of alendronate (ALN) on growing animals. Methods: Healthy male Wistar rats, aged 1 mo, received ALN or vehicle for 8 wk. Serum levels (calcemia, phosphatemia, and total alkaline phosphatase) were determined. Morphometric (rat: femur and tibia weight and length and hemimandible growth) and histomorphometric parameters (thickness of tibial epiphyseal cartilage and each cartilage zone, interradicular bone volume in the first lower molar, trabeculae volume, percentage of bone and cartilage, and osteoclast number in mandibular condyles) were assessed. results: ALN caused a significant decrease in femur and tibia length, tibial cartilage thickness, and longitudinal growth of hemimandibles. It increased interradicular bone volume and mandibular condyle trabeculae volume, increasing the percentage of cartilage and osteoclast number. conclusion: These findings indicate that administration of ALN to growing animals alters the endochondral ossification process, and thus alters growth.

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“…The diameter of the calcified cartilage core is ϳ20 m at its smallest width (as measured from images in Ref. 37). Therefore, a developing trabeculum has been modeled as a cylinder beginning with an initial diameter of 20 m and progressing to 200 m as additional Dimensions of the capillary radius (Rcap), radius of the osteon perimeter (ROP), inner radius of capillary layer (Rcap␤), thickness of osteoblast layer (ROB␣ Ϫ ROB␤), and the thickness of osteocyte layer (ROC␣ Ϫ ROC␤) are shown.…”

Section: System Parametersmentioning

confidence: 99%

Numerical modeling of oxygen distributions in cortical and cancellous bone: oxygen availability governs osteonal and trabecular dimensions

Zahm

Bucaro

Ayyaswamy

et al. 2010

American Journal of Physiology-Cell Physiology

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has demonstrated the role of oxygen tension in the regulation of skeletal cell function and viability, the microenvironmental oxemic status of bone cells remains unknown. In this study, we have employed the Krogh cylinder model of oxygen diffusion to predict the oxygen distribution profiles in cortical and cancellous bone. Under the assumption of saturation-type Michaelis-Menten kinetics, our numerical modeling has indicated that, under steady-state conditions, there would be oxygen gradients across mature osteons and trabeculae. In Haversian bone, the calculated oxygen tension decrement ranges from 15 to 60%. For trabecular bone, a much shallower gradient is predicted. We note that, in Haversian bone, the gradient is largely dependent on osteocyte oxygen utilization and tissue oxygen diffusivity; in trabecular bone, the gradient is dependent on oxygen utilization by cells lining the bone surface. The Krogh model also predicts dramatic differences in oxygen availability during bone development. Thus, during osteon formation, the modeling equations predict a steep oxygen gradient at the initial stage of development, with the gradient becoming lesser as osteonal layers are added. In contrast, during trabeculum formation, the oxygen gradient is steepest when the diameter of the trabeculum is maximal. Based on these results, it is concluded that significant oxygen gradients exist within cortical and cancellous bone and that the oxygen tension may regulate the physical dimensions of both osteons and bone trabeculae. osteon; bone trabeculum; kinetics; Krogh; H; aversian OXYGEN DELIVERY governs the form and function of both soft and hard tissues (25). In the bone, a decrease in the rate of oxygen transport can severely impact skeletal health causing delays in bone healing, a change in the rate of bone turnover, and a raised incidence of vertebral and cranial malformations (7,26,31,33,40). Most commonly, oxemic stress is thought to be caused by a decrease in fluid flow during biomechanical unloading (8,13,22,34); when this occurs, there is a reduction in the oxygen transport rate in the lacunocanalicular system and impaired osteocyte function (29). While it is clear that the local oxygen tension (PO 2 ) is a potent regulator of skeletal cell metabolism and viability (1, 38, 41, 43), the oxygen distribution profile in the bone is currently unknown.The viability and function of cells in complex tissues is dependent on the delivery of oxygen and nutrients. Several numerical studies have attempted to model nutrient exchange by stress-induced fluid flow and diffusion within the lacunocanalicular system of the bone (22,29,34,45). While these studies have provided values for low-molecular-weight solutes, oxygen transport in the bone has not been addressed. In an earlier investigation, we have employed the Krogh cylinder assumption to model the oxygen supply to avian femoral growth cartilage (16); this same model has been used to predict the oxygen tension in skeletal muscle (24), brain (21), and bone marrow (3, 4).The Krogh cy...

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Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats

Cited by 476 publications

References 19 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

Effect of alendronate on the mandible and long bones: an experimental study in vivo

Numerical modeling of oxygen distributions in cortical and cancellous bone: oxygen availability governs osteonal and trabecular dimensions

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