Effects of large doses of olpadronate (Dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs

Ferretti, J.L.; Mondelo, N; Capozza, Ricardo Francisco; Cointry, Gustavo Roberto; Zanchetta, José R.; Montuori, E

doi:10.1016/s8756-3282(95)80145-6

Cited by 16 publications

(10 citation statements)

References 39 publications

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“…This treatment improved slightly the diaphyseal design and yield stiffness and strength correlatively, in agreement with a previous report from our group [35]. Surprisingly, despite the absence of any effect on bone mineralization and E, a large improvement in postyield bone strength was observed in this case, further enhancing ultimate strength correlatively.…”

Section: Opd Effectssupporting

confidence: 92%

“…This is the first description of such effects of a bisphosphonate in normal animals. The strikingly larger effects on male than female animals in this study, previously reported by us [35], may be related to size/weight effects with some biomechanical impact on the skeleton [8][9][10] and/or a larger bioavailability of bisphosphonates in male compared to female rats.…”

Section: Opd Effectssupporting

confidence: 65%

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Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

et al. 2005

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In this article, we summarize the results of six different tomographic/biomechanical rat studies involving hypophysectomy (Hx), ovariectomy, treatment with rhGH, olpadronate, alendronate, and toxic doses of aluminum and the development of a genetic diabetes in the eSS strain. All these conditions induced some interesting and rarely reported effects on postyield bone strength. These effects were generally related neither to the degree of mineralization or the elastic modulus of the bone tissue nor to the preyield behavior of the bones. In two particular cases (Hx, eSS), the elastic modulus of bone tissue varied independently of its degree of mineralization. These results suggest the involvement of some microstructural factor(s) of bone tissue resistance to crack progression (a postyield feature of bone behavior), rather than to crack initiation (the yield-determining factor) in the corresponding mechanism. Changes in collagen or crystal structure may play that role. These changes are relevant to the mechanism of fracture production during plastic deformation, a feature of bone strength that might be independent from mineralization. Therefore, these changes might help to explain some effects of novel treatments on bone strength unrelated to bone mineralization. This questions the belief that the remaining bone mass in metabolic osteopenias is biologically and mechanically normal.

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Section: Opd Effectssupporting

confidence: 92%

Section: Opd Effectssupporting

confidence: 65%

Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

et al. 2005

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“…Furthermore, Guy et al (1993) described that a 2-year treatment with alendronate did not deteriorate bone strength in normal rats. A similar positive effect of olpadronate was also reported (Ferretti et al 1995). The mechanism by which bisphosphonates, such as alendronate and YM 175, did not impair bone mineralization in normal and osteopenic animals deserves further studies.…”

Section: Discussionsupporting

confidence: 72%

Increase of Bone Mass and Mechanical Strength in Rats after Treatment with a Novel Bisphosphonate, YM175, for Two Years

Motoie¹,

Okazaki²,

Kanoh³

et al. 1997

Pharmacology & Toxicology

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Alxtruct:We have evaluated the relationship between bone mass and mechanical properties of bone from male and female rats treated with YM 175, a novel bisphosphonate, for 104 weeks. YM I75 [disodium (cycloheptylamino) methylenediphosphonate monohydrate] was given via the drinking water at a concentration of 0, 0.005, 0.015, 0.05, or 0.15"/0. Since the mortality in the male 0.15% group exceeded the exclusion criteria (75%) at week 88, this group was omitted from the study. Mean daily intake of YM175 was 2.2-22.1 mgikg for males and 3.6-104 mg/kg for females. After the treatment, mechanical properties and ash weight of the humerus were determined. In males, 0.015 and 0.05% of YM175 (6.6-22.1 mg/kg) significantly increased failure load of the midshaft. In females, failure load and stiffness of the midshaft tended to be increased by YM175 (up to 104 mg/kg). Furthermore, ultimate compressive load at the humeral metaphysis treated with the highest dose of YM175 was 2-or 3.5-fold greater than that of untreated male or female control. Ash weight of the humerus was increased dose-dependently and was positively correlated with failure load of the midshaft. These findings indicate that treatment for 2 years with YM I75 increased bone mass and mechanical strength without blocking bone mineralization.

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“…There are concerns, however, over safety issues involved in treating an infant whose bones are rapidly growing and remodeling with a drug that inhibits bone resorption. In animal studies, high doses of bisphosphonates given to growing rats have been found to decrease growth (17) and femur length (18). Similar studies in an animal model of OI are needed to evaluate the effect of treatment on growth and to look histologically at the effects of bisphosphonates on bone quality.…”

mentioning

confidence: 99%

Alendronate Treatment for Infants with Osteogenesis Imperfecta: Demonstration of Efficacy in a Mouse Model

MCCARTHY

2002

Pediatric Research

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Recent non-placebo-controlled studies of the bisphosphonate pamidronate have shown it to be effective in reducing fractures and improving bone density in infants and children with osteogenesis imperfecta (OI). To evaluate the effects of bisphosphonate treatment in a controlled study, the oim/oim mouse model of OI was studied. Nursing infant mouse pups (~2 wk old) with moderate to severe OI (oim/oim mouse) and age-and background-matched control mice (ϩ/ϩ) were treated either with the third-generation bisphosphonate alendronate (ALN), or with saline. Fracture risk, bone quality, and growth were evaluated over a 12-wk treatment period. ALN at a dose of 0.03 mg/kg/d or saline was administered via s.c. injection to infant oim/oim and wild-type (ϩ/ϩ) mice from 2 to 14 wk of age (n ϭ 20 per subgroup). The average number of fractures sustained by the ALN-treated oim/oim mice was reduced significantly compared with the untreated oim/oim mice (0.7 Ϯ 0.7 fractures/mouse versus 2.0 Ϯ 0.2 fractures/mouse). Bone density increased significantly in the femur and the spine with treatment (2.0 Ϯ 0.5 versus 1.2 Ϯ 0.5 in femur and 2.1 Ϯ 0.5 versus1.6 Ϯ 0.5 in spine). Histologic evaluation revealed the percentage of metaphyseal tibial bone increased significantly with treatment in both ϩ/ϩ and oim/oim mice. Mechanical testing revealed an increase in structural stiffness for both treated ϩ/ϩ and oim/oim mice compared with untreated animals. None of the material properties examined were significantly altered with treatment, nor was spinal curvature affected. Weight gain and long bone growth were comparable in the treated and untreated oim/oim mice. In wild-type mice, femur lengths were significantly shorter in the treated mice compared with untreated counterparts. This animal study demonstrates that treatment of OI in mice as early as 2 wk of age with ALN appears to be effective in reducing fractures and increasing bone properties. Based on the data from this study, ALN therapy in infants with OI should prove to be effective. Abbreviations OI, osteogenesis imperfecta oim/oim, mice homozygous for spontaneous mutation causing the skeletal defects of OI ؉/؉, wild-type mice AP, anteroposterior ML, mediolateral BMD, bone mineral density ALN, alendronate OI, also known as "brittle bone disease," occurs in about 1 in 20,000 births (1). The real incidence is probably higher because a significant number of children are not diagnosed at birth due to mild expression of the disease (2). OI is predominately a collagen defect, caused by heterogeneous genetic mutations that result in an array of clinical manifestations, ranging from blue sclerae and dentinogenesis imperfecta to extremely short stature and progressive limb/spine deformities secondary to multiple fractures. Surgical treatment of the extremities and spine are often indicated to stabilize the long bones and optimize functional ability and walking capacity. According to the Sillence classification (3) there are four forms of OI, although recent data has added additional variants (4). Typ...

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Effects of large doses of olpadronate (Dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs

Cited by 16 publications

References 39 publications

Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

Increase of Bone Mass and Mechanical Strength in Rats after Treatment with a Novel Bisphosphonate, YM175, for Two Years

Alendronate Treatment for Infants with Osteogenesis Imperfecta: Demonstration of Efficacy in a Mouse Model

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