Browsing by Subject "remodeling suppression"

Now showing 1 - 5 of 5
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    Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following three years of daily treatment
    (2008-05) Allen, Matthew R.; Reinwald, Susan; Burr, David B.
    Reduced bone toughness, the energy absorption capacity of the tissue, has been consistently documented in vertebrae of animals treated with a wide range of bisphosphonate doses. Data regarding toughness changes in the rib are conflicting, with one report showing no effect and another showing a significant reduction following treatment of beagle dogs with high doses of bisphosphonates. The goal of this study was to evaluate changes in bone toughness and various other tissue-level properties of the rib following 3 years of bisphosphonate treatment with doses at and above those used to treat osteoporosis. Skeletally mature intact beagle dogs were treated daily for 3 years with vehicle (VEH), alendronate 0.2 mg/kg (ALN0.2), or alendronate 1.0 mg/kg (ALN1.0). The lower ALN dose approximates, on a milligram per kilogram basis, that used for treatment of postmenopausal osteoporosis, with the higher dose being five times higher. Ribs were assessed for biomechanical properties, bone turnover rate, microdamage, density, and geometry. Toughness was significantly lower with ALN1.0 (−33%) but not ALN0.2 (−19%) compared to VEH, while neither ultimate stress nor modulus differed among the groups. Bone density, geometry, and structural biomechanical properties were similar among the three groups. There was no significant difference in overall microdamage accumulation among the groups. Intracortical bone formation rate was significantly lower than VEH in both ALN groups (−69% to −90%). These data show that while rib cortical bone experiences significant reductions in turnover following bisphosphonate treatment, it is only in animals treated with doses above those used to treat osteoporosis that toughness is significantly compromised.
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    Mandible matrix necrosis in beagle dogs After 3-years of daily oral bisphosphonate treatment
    (2008-05) Allen, Matthew R.; Burr, David B.
    Purpose An increasing number of reports have implicated bisphosphonates as contributing to osteonecrosis of the jaw. The goal of this study was to evaluate mandible necrosis in beagle dogs treated for 3 years with oral alendronate (ALN). Materials and Methods Skeletally mature female beagles were treated daily for 3 years with oral doses of vehicle (VEH) or ALN (0.20 or 1.0 mg/kg/day). These doses approximate, on a mg/kg basis, those used for postmenopausal osteoporosis and Paget's disease, respectively. At necropsy, the second molar region of the mandible was excised, stained en bloc with basic fuchsin, and assessed for matrix necrosis and intracortical bone turnover rate using histology. Matrix necrosis was defined as a region greater than 500 μm2 that was void of basic fuchsin stain, assessed using both bright-field and confocal microscopy. Results No animals developed exposed bone lesions in the oral cavity during the 3-year study. Matrix necrosis was observed in 25% of ALN0.2 animals, 33% of ALN1.0 animals, and was noticeably absent from all vehicle animals (P < .05 pooled ALN doses vs VEH). These necrotic regions occurred predominately in the alveolar bone and were clearly void of patent canaliculi. Intracortical bone turnover rate of the alveolar mandible bone region was significantly lower (−75%, P < .05) in ALN-treated animals compared with VEH. Conclusions Three years of daily oral bisphosphonate treatment reduces bone turnover significantly and increases the incidence of matrix necrosis within the mandible of dogs.
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    Recent Advances in Understanding Bisphosphonate Effects on Bone Mechanical Properties
    (Springer, 2018-04) Allen, Matthew R.; Anatomy and Cell Biology, School of Medicine
    Purpose of the Review Bisphosphonates have well-established effects on suppressing bone resorption and slowing bone loss, yet the effects on bone mechanical properties are less clear. We review recent data from pre-clinical and clinical experiments that assessed mechanical properties of bisphosphonate-treated specimens. Recent Findings Pre-clinical work has utilized new techniques to show reduced fatigue life and transfer of stress from the mineral to collagen. Several notable studies have examined mechanical properties of tissue from patients treated with bisphosphonates with mixed results. Pre-clinical data suggest effects on mechanics may be independent of remodeling suppression. Summary The direct effect of bisphosphonates on bone mechanics remains unclear but recent work has set a solid foundation for the coming years.
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    Short-courses of dexamethasone abolish bisphosphonate-induced reductions in bone toughness.
    (doi: 10.1016/j.bone.2013.06.004 Final article can be found at: http://www.sciencedirect.com/science/article/pii/S8756328213002226, 2013) Luo, Tianyi D.; Allen, Matthew R.
    Atypical femoral fractures, which display characteristics of brittle material failure, have been associated with potent remodeling suppression drugs. Given the millions of individuals treated with this class of drugs it is likely that other factors play a role in these fractures. Some evidence suggests concomitant use of corticosteroids may contribute to the pathogenesis although data in this area is lacking. The goal of this study was to assess the combined role of bisphosphonates and examethasone on bone mechanical properties. Skeletally mature beagle dogs were either untreated controls, or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL + DEX. Zoledronic acid (0.06 mg/kg) was given monthly via IV infusion for 9 months. DEX (5 mg) was administered daily for one week during each of the last three months of the 9 month experiment. Ribs were harvested and assessed for bone geometry, mechanical properties, and remodeling rate (n=3-6 specimens per group). DEX significantly suppressed intracortical remodeling compared to vehicle controls while both ZOL and the combination of DEX+ZOL nearly abolished intracortical remodeling. ZOL treatment resulted in significantly lower bone toughness, determined from 3-point bending tests, compared to all other treatment groups while the toughness in ZOL+DEX animals was identical to those of untreated controls. These findings suggest not only that short-courses of dexamethasone do not adversely affect toughness in the setting of bisphosphonates, they actually reverse the adverse effects of its treatment. Understanding the mechanism for this tissue-level effect could lead to novels approaches for reducing the risk of atypical femoral fractures.
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    Skeletal accumulation of bisphosphonates: implications for osteoporosis treatment
    (2008-11) Allen, Matthew R.
    BACKGROUND: Bisphosphonates (BPs), the gold-standard pharmacological treatment for osteoporosis, are unique in that they become physically bound to the bone matrix and therefore accumulate over time. This skeletal accumulation has important physiological implications that are not completely understood. OBJECTIVE: To review concepts related to the biological effects of BP accumulation in the skeleton. METHODS: Articles concerning skeletal accumulation of BP treatment were identified. RESULTS/CONCLUSIONS: Skeletal accumulation of BP, dictated by both chemical and biological factors, is dose-dependent, differs among skeletal sites and likely differs among the various BPs. Bisphosphonate embedded within the skeletal matrix has lasting biological effects, the results of which have both positive and negative implications for bone remodeling. As alternative anti-remodeling agents gain approval for treatment of osteoporosis, the property of skeletal accumulation will likely be unique to BPs and therefore may be the property that determines the future use of this drug class.