Browsing by Subject "osteoporosis"

Now showing 1 - 10 of 23
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    Alterations in Canine Vertebral Bone Turnover, Microdamage Accumulation, and Biomechanical Properties following 1-year Treatment with Clinical Treatment Doses of Risedronate or Alendronate
    (2006-10) Allen, Matthew R.; Iwata, Ken; Phipps, Roger; Burr, David B.
    One year of treatment with bisphosphonates at 5x the dose used for post-menopausal osteoporosis significantly increases failure load and microdamage, and decreases toughness at multiple skeletal sites in intact female beagles. The goal of this study was to determine if similar changes occur with doses equivalent to those used for post-menopausal osteoporosis treatment. Skeletally-mature female beagles were treated daily for 1 year with vehicle (VEH) or one of three doses of risedronate (RIS; 0.05, 0.10, 0.50 mg/kg/day) or alendronate (ALN; 0.10, 0.20, 1.00 mg/kg/day). Doses of ALN corresponded to treatment dose for PMO, 1/2 that dose, and 5x that dose on a mg/kg basis; RIS was given at a dose-equivalent to ALN. Vertebral density, geometry, percent ash, static/dynamic histology, microdamage, and biomechanical parameters were quantified. Trabecular bone activation frequency (Ac.f) was dose-dependently lower in RIS-treated groups (-40%, -66%, -84%, P < 0.05 vs. VEH) while the three ALN groups were all similarly lower compared to VEH (-65%, -71%, -76%; P <0.05). Crack surface density (Cr.S.Dn) was significantly higher than VEH for all doses of RIS and ALN (+2.9 to 5.4-fold vs. VEH). Stiffness was significantly increased with both agents while there were no significant changes in any other structural or estimated material properties. Cr.S.Dn and Ac.f exhibited a significant non-linear correlation (r(2) = 0.21; P < 0.001) while there was no relationship between Cr.S.Dn and any mechanical properties. These results document that 1 year of bisphosphonate treatment at clinical doses allows significant accumulation of microdamage in the vertebra but this is offset by increases in bone volume and mineralization such that there is no significant impairment of mechanical properties.
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    Application of quantitative analysis in treatment of osteoporosis and osteoarthritis
    (2013-11-08) Chen, Andy Bowei; Yokota, Hiroki, 1955-; Na, Sungsoo; Schild, John H.
    As our population ages, treating bone and joint ailments is becoming increasingly important. Both osteoporosis, a bone disease characterized by a decreased density of mineral in bone, and osteoarthritis, a joint disease characterized by the degeneration of cartilage on the ends of bones, are major causes of decreased movement ability and increased pain. To combat these diseases, many treatments are offered, including drugs and exercise, and much biomedical research is being conducted. However, how can we get the most out of the research we perform and the treatment we do have? One approach is through computational analysis and mathematical modeling. In this thesis, quantitative methods of analysis are applied in different ways to two systems: osteoporosis and osteoarthritis. A mouse model simulating osteoporosis is treated with salubrinal and knee loading. The bone and cell data is used to formulate a system of differential equations to model the response of bone to each treatment. Using Particle Swarm Optimization, optimal treatment regimens are found, including a consideration of budgetary constraints. Additionally, an in vitro model of osteoarthritis in chondrocytes receives RNA silencing of Lrp5. Microarray analysis of gene expression is used to further elucidate the mode of regulation of ADAMTS5, an aggrecanase associated with cartilage degradation, by Lrp5, including the development of a mathematical model. The math model of osteoporosis reveals a quick response to salubrinal and a delayed but substantial response to knee loading. Consideration of cost effectiveness showed that as budgetary constraints increased, treatment did not start until later. The quantitative analysis of ADAMTS5 regulation suggested the involvement of IL1B and p38 MAPK. This research demonstrates the application of quantitative methods to further the usefulness of biomedical and biomolecular research into treatment and signaling pathways. Further work using these techniques can help uncover a bigger picture of osteoarthritis's mode of action and ideal treatment regimens for osteoporosis.
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    Bone material properties and mineral matrix contributions to fracture risk or age in women and men
    (2002) Burr, David B.
    The strength of bone is related to its mass and geometry, but also to the physical properties of the tissue itself. Bone tissue is composed primarily of collagen and mineral, each of which changes with age, and each of which can be affected by pharmaceutical treatments designed to prevent or reverse the loss of bone. With age, there is a decrease in collagen content, which is associated with an increased mean tissue mineralization, but there is no difference in cross-link levels compared to younger adult bone. In osteoporosis, however, there is a decrease in the reducible collagen cross-links without an alteration in collagen concentration; this would tend to increase bone fragility. In older people, the mean tissue age (MTA) increases, causing the tissue to become more highly mineralized. The increased bone turnover following menopause may reduce global MTA, and would reduce overall tissue mineralization. Bone strength and toughness are positively correlated to bone mineral content, but when bone tissue becomes too highly mineralized, it tends to become brittle. This reduces its toughness, and makes it more prone to fracture from repeated loads and accumulated microcracking. Most approved pharmaceutical treatments for osteoporosis suppress bone turnover, increasing MTA and mineralization of the tissue. This might have either or both of two effects. It could increase bone volume from refilling of the remodeling space, reducing the risk for fracture. Alternatively, the increased MTA could increase the propensity to develop microcracks, and reduce the toughness of bone, making it more likely to fracture. There may also be changes in the morphology of the mineral crystals that could affect the homogeneity of the tissue and impact mechanical properties. These changes might have large positive or negative effects on fracture incidence, and could contribute to the paradox that both large and small increases in density have about the same effect on fracture risk. Bone mineral density measured by DXA does not discriminate between density differences caused by volume changes, and those caused by changes in mineralization. As such, it does not entirely reflect material property changes in aging or osteoporotic bone that contribute to bone's risk for fracture.
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    Bone quality: Understanding what matters
    (2004) Burr, David B.
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    Cohousing Male Mice with and without Segmental Bone Defects
    (American Association for Laboratory Animal Science, 2018-04) Rytlewski, Jeffrey D.; Childress, Paul J.; Scofield, David C.; Khan, Faisal; Alvarez, Marta B.; Tucker, Aamir T.; Harris, Jonathan S.; Peveler, Jessica L.; Hickman, Debra L.; Chu, Tien-Min G.; Kacena, Melissa A.; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Spaceflight results in bone loss like that associated with osteoporosis or decreased weight-bearing (for example, high-energy trauma such as explosive injuries and automobile accidents). Thus, the unique spaceflight laboratory on the International Space Station presents the opportunity to test bone healing agents during weightlessness. We are collaborating with NASA and the US Army to study bone healing in spaceflight. Given the unique constraints of spaceflight, study design optimization was required. Male mice were selected primarily because their femur is larger than females’, allowing for more reproducible surgical outcomes. However, concern was raised regarding male mouse aggression. In addition, the original spaceflight study design included cohousing nonoperated control mice with mice that had undergone surgery to create a segmental bone defect. This strategy prompted the concern that nonoperated mice would exhibit aggressive behavior toward vulnerable operated mice. We hypothesized that operated and nonoperated male mice could be cohoused successfully when they were cagemates since birth and underwent identical anesthetic, analgesic, preoperative, and postoperative conditions. Using quantitative behavioral scoring, body weight, and organ weight analyses (Student t test and ANOVA), we found that nonoperated and operated C57BL/6 male mice could successfully be housed together. The male mice did not exhibit aggressive behavior toward cagemates, whether operated or nonoperated, and the mice did not show evidence of stress, as indicated by veterinary assessment, or change in body or proportional organ weights. These findings allowed our mission to proceed (launched February 2017) and may inform future surgical study designs, potentially increasing housing flexibility.
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    Degeneration of the osteocyte network in the C57BL/6 mouse model of aging
    (Impact Journals, 2017-10-26) Tiede-Lewis, LeAnn M.; Xie, Yixia; Hulbert, Molly A.; Campos, Richard; Dallas, Mark R.; Dusevich, Vladimir; Bonewald, Lynda F.; Dallas, Sarah L.; Anatomy and Cell Biology, School of Medicine
    Age-related bone loss and associated fracture risk are major problems in musculoskeletal health. Osteocytes have emerged as key regulators of bone mass and as a therapeutic target for preventing bone loss. As aging is associated with changes in the osteocyte lacunocanalicular system, we focused on the responsible cellular mechanisms in osteocytes. Bone phenotypic analysis was performed in young-(5mo) and aged-(22mo) C57BL/6 mice and changes in bone structure/geometry correlated with alterations in osteocyte parameters determined using novel multiplexed-3D-confocal imaging techniques. Age-related bone changes analogous to those in humans were observed, including increased cortical diameter, decreased cortical thickness, reduced trabecular BV/TV and cortical porosities. This was associated with a dramatic reduction in osteocyte dendrite number and cell density, particularly in females, where osteocyte dendricity decreased linearly from 5, 12, 18 to 22mo and correlated significantly with cortical bone parameters. Reduced dendricity preceded decreased osteocyte number, suggesting dendrite loss may trigger loss of viability. Age-related degeneration of osteocyte networks may impair bone anabolic responses to loading and gender differences in osteocyte cell body and lacunar fluid volumes we observed in aged mice may lead to gender-related differences in mechanosensitivity. Therapies to preserve osteocyte dendricity and viability may be beneficial for bone health in aging.
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    Fracture discrimination capability of ulnar flexural rigidity measured via Cortical Bone Mechanics Technology: study protocol for The STRONGER Study
    (Oxford University Press, 2024-01-04) Warden, Stuart J.; Dick, Andrew; Simon, Janet E.; Manini, Todd M.; Russ, David W.; Lyssikatos, Charalampos; Clark, Leatha A.; Clark, Brian C.; Physical Therapy, School of Health and Human Sciences
    Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, which leads to bone fragility (ie, weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is DXA, which quantifies areal BMD, typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating the bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicate that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: Better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).
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    Genomics of Osteoporosis
    (2004-08) Krishnan, Subha; Econs, Michael J.
    Osteoporosis is the most common bone disease in United States and developed countries and a major public health threat for an estimated 44 million Americans. It is characterized by low bone mineral density and micro architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture, especially of hip, spine and wrist. Osteoporosis is multifactorial disease influenced by large number of environmental and genetic factors. Though a number of FDA approved drugs are available for treating this complex disease, a medication, which could specifically and effectively reverse symptoms of it is lackin. As the initial step for approaching disease treatment my current research focuses on locatin candidate genes on linkage regions for BMD on human chromosomes, which potentially can be used for developing novel targets and strategies for therapeutic interventions. We will also define the mouse homologs in the syntenic regions as basis for future studies involving animal models of disturbed BMD. An automated interface which will give information on human - mouse synteny between human marker intervals of interest was developed which will expedite future synteny studies.
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    Kalirin Decreases Bone Mass Through Effects in Both Osteoclasts and Osteoblasts
    (Office of the Vice Chancellor for Research, 2012-04-13) Huang, Su; Eleniste, Pierre; LeBlanc, Paula; Brown, Drew; Allen, Matthew R.; Bruzzaniti, Angela
    Bone homeostasis is maintained by the balance between osteoclasts which degrade bone and osteoblasts, which form new bone. When the activity of either of these cells is dysregulated, bone loss can ensue, leading to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. The activity of osteoclasts and osteoblasts is regulated by local and systemic factors, as well as by key signaling proteins expressed in these cells. Kalirin is a novel GTP-exchange factor protein that plays a role in signaling pathways leading to cytoskeletal remodeling and dendritic spine formation in neurons, but its function in other cells is unknown. Western blotting and real time PCR confirmed that Kalirin is expressed in osteoclasts and osteoblasts, suggesting it may play a role in regulating bone cell function and bone mass. We used micro-CT to examine the bone phenotype of 14 week old female mice lacking Kalirin in all tissues (Kal-KO). Kal-KO mice exhibited a 40% lower trabecular bone volume in the distal femur compared to wild-type (WT) mice (n=9/group, p<0.05). We next quantified osteoclasts in histological sections by counting multinucleated cells expressing tartrate-resistant acid phosphatase (TRAP), a marker of mature osteoclasts. We found 48% higher osteoclast surface/bone surface in trabecular bone of Kal-KO mice, compared to WT mice (n=6/group, p<0.05). Osteoclast differentiation is controlled by osteoblasts, which secrete receptor activator of NF-kB ligand (RANKL), macrophage colony stimulating factor (MCSF) and osteoprotegerin (OPG), a decoy receptor for RANKL. We examined if Kalirin could regulate osteoclast differentiation in vitro. Osteoclasts were generated from the bone marrow of WT or Kal-KO mice by incubation with RANKL and MCSF for 7 days, and TRAP+ multinucleated cells were counted. Consistent with our in vivo studies, osteoclast number was significantly higher in cultures from Kal-KO mice, compared to WT mice. We next examined if Kalirin altered the ratio of secreted RANKL and OPG secreted by osteoblasts. Osteoblasts were generated from the calvaria of 2 day old neonates and the level of secreted RANKL and OPG in conditioned media was quantified by ELISA. Consistent with increased osteoclast differentiation, we found a higher RANKL/OPG ratio in conditioned media from Kal-KO osteoblasts, compared to WT cells. These data confirm a role for Kalirin in the regulation of trabecular bone mass through effects in both osteoclasts and osteoblasts.