Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys

Yamagami, Yoshiki; Mashiba, Tasuku; Iwata, Ken; Tanaka, Makoto; Nozaki, Kazutoshi; Yamamoto, Toshiyuki

doi:10.1016/j.bone.2013.01.016

Cited by 33 publications

(18 citation statements)

References 42 publications

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“…Similar results were shown with doses of bisphosphonates recommended in the treatment of osteoporosis (Allen et al 2006). In monkeys treated with different bisphosphonates, microcrack density in vertebral bodies was higher compared to untreated controls, but there was no statistically significant difference in crack morphology or density in the femoral cortex (Yamagami et al 2013). …”

Section: Microcrack Accumulationmentioning

confidence: 91%

“…Also, bone composition seems to vary across anatomic sites (Donnelly et al 2011) and there is evidence that femoral cortical bone behaves differently both in the respect of microdamage accumulation, and changes in bone mineral and matrix properties compared to sites with predominantly trabecular bone (Yamagami et al 2013). Thus the information on bisphosphonate induced changes in biomechanical properties seems insufficient to draw any final conclusions on the pathogenesis of atypical fractures.…”

Section: Mechanical Properties Of Bonementioning

confidence: 99%

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Epidemiology, radiology and histology of atypical femoral fractures

Schilcher¹

2013

Acta Orthopaedica

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Section: Microcrack Accumulationmentioning

confidence: 91%

Section: Mechanical Properties Of Bonementioning

confidence: 99%

Epidemiology, radiology and histology of atypical femoral fractures

Schilcher¹

2013

Acta Orthopaedica

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“…However, these differences in vBMD are so small, that it cannot be reliably concluded that mineralization is lower on the periosteal surface than the endosteal surface. Arrest of natural remodelling in the bone can lead to an accumulation of unrepaired microdamage in the matrix, leading to fatigue fractures (13,14). We observed penetration of basic fuchsin into the matrix, which is a tell-tale sign of diffuse damage.…”

Section: Discussionmentioning

confidence: 79%

Histological and micro Computed Tomography analysis of a femoral stress fracture associated with prolonged bisphosphonate use

Somford

Kloen

et al. 2017

ccmbm

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SummaryBackground. The origin of atypical femoral fractures (AFF) associated with bisphosphonate therapy remains to be elucidated. In this study, a biopsy of an AFF site is analyzed to determine whether microdamage and/or morphological changes are present in the area of the AFF. Material and methods. Cortical bone from an AFF region was obtained during a preventive stabilization in a patient with a symptomatic AFF. This bone was scanned using microCT (resolution=0.01 mm), stained with basic fuchsin and analyzed histologically. Results. The diameter of the Haversian canals was higher in the vicinity of the AFF compared to the bone further away from the AFF. The bone mineral density within the cortex ranged from 1020 to 1080 mg HA/cm 3 . We observed penetration of basic fuchsin into the matrix, which is a tell-tale sign of diffuse damage. Discussion. The higher diameter of haversian canals is likely to result in higher local stresses and consequently increased microdamage. The diffuse microdamage in the biopsy may furthermore be directly related to bisphosphonate use, preventing repair of microdamage, and consequently the development of the AFF. Conclusion. Increased porosity of the cortex and accumulation of microdamage might have lead to a stress fracture and ultimately a complete AFF.

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“…It is well established that 1–3 years treatment with oral ALN [4] or other BPs [5] is associated with a reduction in cancellous bone toughness, a material measure of energy to failure, even at clinical doses [6–8]. Similar reductions in tissue toughness can be inferred from recent data in ovariectomized nonhuman primates [9]. In that study, energy absorption in the lumbar vertebrae of ALN treated primates was similar to that in OVX animals, but BV/TV was higher [Mashiba, pers.…”

Section: Introductionmentioning

confidence: 78%

“…Pre-clinical data using incadronate in dogs did not use a clinically-relevant dose [14]. Pre-clinical studies using other large animal models typically have not measured changes in cortical bone toughness [9,20] and so would not have been able to detect this negative trend on bone’s energy absorption capacity. Our own studies on dog femoral beams did not show an effect of ALN treatment on toughness [15].…”

Section: Discussionmentioning

confidence: 99%

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

Burr

Liu

Allen

2015

Bone

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Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than bone’s material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1 ml/kg/day) or alendronate (ALN) at a clinical dose (0.2 mg/kg/day). Treatment duration ranged from 3 months to 3 years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of femoral cortical bone in humans.

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Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys

Cited by 33 publications

References 42 publications

Epidemiology, radiology and histology of atypical femoral fractures

Epidemiology, radiology and histology of atypical femoral fractures

Histological and micro Computed Tomography analysis of a femoral stress fracture associated with prolonged bisphosphonate use

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

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