Browsing by Subject "Bisphosphonate"
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Item Absence of exposed bone following dental extraction in beagle dogs treated with nine-months of high dose zoledronic acid combined with dexamethasone(Elsevier, 2013) Allen, Matthew R.; Chu, Tien-Min Gabriel; Ruggiero, Salvatore L.; Anatomy, Cell Biology and Physiology, School of MedicinePurpose: Factors contributing to osteonecrosis of the jaw with anti-remodeling drug treatment are unclear. Epidemiologic and experimental studies have suggested the combination of bisphosphonates and dexamethasone results in osteonecrosis of the jaw more often than either agent alone. The goal of this study was to assess the combination of these 2 drugs in a large animal model previously shown to be susceptible to exposed bone in the oral cavity when treated with bisphosphonates. Materials and methods: Skeletally mature beagle dogs were untreated controls or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL plus DEX. ZOL and DEX were given at doses based on those used in humans. All animals underwent single molar extraction at 7 and 8 months after the start of the study. Extraction sites were obtained at month 9 for assessment of osseous healing using micro-computed tomography and histology. Results: No animals were observed to have exposed bone after dental extraction, yet 1 animal treated with ZOL and 1 treated with ZOL plus DEX had severely disrupted extraction sites as viewed by computed tomography and histology. These 2 animals had an intense periosteal reaction that was less obvious but still present in all ZOL-treated animals and absent from untreated animals. There was no significant difference in bone volume within the socket among groups at 4 or 8 weeks after healing, yet the ratio of surface to volume was significantly higher in animals treated with ZOL plus DEX at 8 weeks compared with control animals. Conclusions: These findings suggest a more complex pathophysiology to osteonecrosis of the jaw than is implied by previous epidemiologic studies and those in rodents and raise questions about the potential role of DEX in its etiology.Item Antiremodeling Agents Influence Osteoblast Activity Differently in Modeling and Remodeling Sites of Canine Rib(Calcified Tissue International, 2006-10-10) Allen, Matthew R.; Follet, Helene; Khurana, M.; Sato, M.; Burr, David B.; Department of Anatomy & Cell Biology, IU School of MedicineAntiremodeling agents reduce bone loss in part through direct actions on osteoclasts. Their effects on osteoblasts and bone formation activity are less clear and may differ at sites undergoing modeling vs. remodeling. Skeletally mature intact beagles, 1–2 years old at the start of the study, were treated daily with clinically relevant doses of alendronate (0.10 or 0.20 mg/kg), risedronate (0.05 or 0.10 mg/kg), raloxifene (0.50 mg/kg), or vehicle (1 mL/kg). Dynamic bone formation parameters were histologically assessed on periosteal, endocortical/trabecular, and intracortical bone envelopes of the rib. Raloxifene significantly increased periosteal surface mineral apposition rate (MAR), a measure of osteoblast activity, compared to all other treatments (+108 to +175%, P < 0.02), while having no significant effect on MAR at either the endocortical/trabecular or intracortical envelope. Alendronate (both 0.10 and 0.20 doses) and risedronate (only the 0.10 dose) significantly (P ≤ 0.05) suppressed MAR on the endocortical/trabecular envelope, while none of the bisphosphonate doses significantly altered MAR at either the periosteal or intracortical envelopes compared to vehicle. Based on these results, we conclude that (1) at clinically relevant doses the two classes of antiremodeling agents, bisphosphonates and selective estrogen receptor modulators, exert differential effects on osteoblast activity in the canine rib and (2) this effect depends on whether modeling or remodeling is the predominant mechanism of bone formation.Item Clinically relevant doses of tiludronate do not affect bone remodelling in pasture‐exercised horses(Wiley, 2025) Tippen, Samantha P.; Metzger, Corinne E.; Sacks, Spencer A.; Allen, Matthew R.; Mitchell, Colin F.; McNulty, Margaret A.; Anatomy, Cell Biology and Physiology, School of MedicineBackground: Bisphosphonates are widely used in equine athletes to reduce lameness associated with skeletal disorders. Widespread off-label use has led to concern regarding potential negative effects on bone healing, but little evidence exists to support or refute this. Objectives: To investigate the influence of clinically relevant doses of tiludronate on bone remodelling and bone healing. Study design: Randomised, controlled in vivo experiments. Methods: Each horse had a single tuber coxae biopsied (Day 0), then were divided into a treatment (IV tiludronate) or control (IV saline) group. Treatments were administered 30 and 90 days following initial biopsy. Biopsy of the tuber coxae was repeated on Day 60 to evaluate bone healing following a single treatment. Oxytetracycline was administered on Days 137 and 147 to label bone formation. The contralateral tuber coxae was biopsied on Day 150 to evaluate effects of repeated treatment. Bone biopsies were evaluated with micro-computed tomography and/or dynamic histomorphometry using standard techniques. Results: Nineteen horses completed the study, with no complications following the biopsies and treatments. No significant differences in the trabecular bone parameters or bone formation rate were observed between treatment groups. Main limitations: The use of a first-generation bisphosphonate may mean some effects of these drugs are underrepresented using this model. The results pertain to the tuber coxae and may not reflect injury or the healing response that occurs in long bones in training or racing. Conclusions: In this model, tiludronate did not affect normal bone remodelling in the horse, despite repeat dosages.Item The Effects of Zoledronate and Raloxifene Combination Therapy on Diseased Mouse Bone(2019-05) Powell, Katherine M.; Wallace, Joseph M.; Yokota, Hiroki; Allen, Matthew R.Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissue’s ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the quality-based effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchical levels.Item Osteonecrosis of the Jaw Risk Factors in Bisphosphonate Treated Patients with Metastatic Cancer(Wiley, 2022) Van Poznak, Catherine; Reynolds, Evan L.; Estilo, Cherry L.; Hu, Mimi; Schneider, Bryan Paul; Hertz, Daniel L.; Gersch, Christina; Thibert, Jacklyn; Thomas, Dafydd; Banerjee, Mousumi; Rae, James M.; Hayes, Daniel F.; Medicine, School of MedicineBackground: A case-control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates. Methods: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status. Results: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio = 0.18, 95% Confidence interval: 0.03-0.97, p = .047) and more likely to have been exposed to bevacizumab (OR = 5.15, 95% CI: 1.67-15.95, p = .005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003. Conclusions: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.Item Raloxifene improves bone mechanical properties in mice previously treated with zoledronate(SpringerLink, 2017-07) Meixner, Cory N.; Aref, Mohammad W.; Gupta, Aryaman; McNerny, Erin M.B.; Brown, Drew; Wallace, Joseph M.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineBisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.Item Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial(BMC, 2018-03-20) Richbourg, Heather A.; Mitchell, Colin F.; Gillett, Ashley N.; McNulty, Margaret A.; Anatomy and Cell Biology, School of MedicineBackground Tiludronate and clodronate are FDA-approved bisphosphonate drug therapies for navicular disease in horses. Although clinical studies have determined their ability to reduce lameness associated with skeletal disorders in horses, data regarding the effect on bone structure and remodeling is lacking. Additionally, due to off-label use of these drugs in young performance horses, effects on bone in young horses need to be investigated. Therefore, the purpose of this randomized, experimental pilot study was to determine the effect of tiludronate and clodronate on normal bone cells, structure and remodeling after 60 days in clinically normal, young horses. Additionally, the effect of clodronate on bone healing 60 days after an induced defect was investigated. Results All horses tolerated surgery well, with no post-surgery lameness and all acquired biopsies being adequate for analyses. Overall, tiludronate and clodronate did not significantly alter any bone structure or remodeling parameters, as evaluated by microCT and dynamic histomorphometry. Tiludronate did not extensively impact bone formation or resorption parameters as evaluated by static histomorphometry. Similarly, clodronate did not affect bone formation or resorption after 60 days. Sixty days post-defect, healing was minimally affected by clodronate. Conclusions Tiludronate and clodronate do not appear to significantly impact bone tissue on a structural or cellular level using standard dose and administration schedules.Item Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone(Elsevier, 2019-10-01) Powell, Katherine M.; Skaggs, Cayla; Pulliam, Alexis; Berman, Alycia; Allen, Matthew R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and TechnologyCurrent interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties in a cell-independent manner by binding to collagen and increasing tissue hydration. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality. In this study, wildtype (WT) and heterozygous (OIM+/−) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or both from 8 weeks to 16 weeks of age. Using the OIM model allows for investigation of therapeutic effects on a quality-based bone disease. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, which are direct measures of the tissue's ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/− compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, trabecular bone volume fraction was significantly higher with combination treatment in both genotypes. Combination treatment resulted in higher ultimate stress in both genotypes. RAL and combination treatment in OIM+/− also increased resilience compared to the control. In conclusion, this study demonstrates the beneficial effects of using combination drug treatments to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a potential method to improve bone health and combat skeletal fragility on both the microscopic and macroscopic levels.Item Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes(Springer, 2016-12) Aref, Mohammad W.; McNerny, Erin M.B.; Brown, Drew; Jepsen, Karl J.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineAref, M. W., McNerny, E. M. B., Brown, D., Jepsen, K. J., & Allen, M. R. (2016). Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes. Osteoporosis International : A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 27(12), 3637–3643. https://doi.org/10.1007/s00198-016-3701-9