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      In Vivo Bone Effects of a Novel Bisphosphonate‐EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model

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          ABSTRACT

          Pathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12 weeks, seven groups of rats were treated for 8 weeks via tail‐vein injection. The groups were: C3 conjugate at low and high doses, vehicle‐treated ovariectomy (OVX) and sham, C1 (a similar conjugate, but with active ALN at high dose), inactive ALN alone, and a mixture of unconjugated ALN and EP4a to evaluate the conjugation effects. Bone turnover was determined by dynamic and static histomorphometry; μCT was employed to determine bone microarchitecture; and bone mechanical properties were evaluated via biomechanical testing. Treatment with C3 significantly increased trabecular bone volume and vertebral BMD versus OVX controls. There was also significant improvement in the vertebral load‐bearing abilities and stimulation of bone formation in femurs after C3 treatment. This preclinical research revealed that C3 resulted in significant anabolic effects on trabecular bone, and EP4a and ALN conjugation components are vital to conjugate anabolic efficacy. A combined therapy using an EP4 selective agonist anabolic agent linked to an inactive ALN is presented here that produces significant anabolic effects, allows bone remodeling, and has the potential for treating postmenopausal osteoporosis or other diseases where bone strengthening would be beneficial. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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          Most cited references 58

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          Normal bone anatomy and physiology.

           Bart Clarke (2008)
          This review describes normal bone anatomy and physiology as an introduction to the subsequent articles in this section that discuss clinical applications of iliac crest bone biopsy. The normal anatomy and functions of the skeleton are reviewed first, followed by a general description of the processes of bone modeling and remodeling. The bone remodeling process regulates the gain and loss of bone mineral density in the adult skeleton and directly influences bone strength. Thorough understanding of the bone remodeling process is critical to appreciation of the value of and interpretation of the results of iliac crest bone histomorphometry. Osteoclast recruitment, activation, and bone resorption is discussed in some detail, followed by a review of osteoblast recruitment and the process of new bone formation. Next, the collagenous and noncollagenous protein components and function of bone extracellular matrix are summarized, followed by a description of the process of mineralization of newly formed bone matrix. The actions of biomechanical forces on bone are sensed by the osteocyte syncytium within bone via the canalicular network and intercellular gap junctions. Finally, concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength. This information lays the groundwork for understanding the utility and clinical applications of iliac crest bone biopsy.
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            The ovariectomized rat model of postmenopausal bone loss.

             Dike Kalu (1991)
            An animal model of postmenopausal bone loss can be defined as a living animal in which spontaneous or induced bone loss due to ovarian hormone deficiency can be studied, and in which the characteristics of the bone loss and its sequalae resemble those found in postmenopausal women in one or more respects. Although in comparison to humans, the skeletal mass of rats remains stable for a protracted period during their lifespan, rats can be ovariectomized to make them sex-hormone deficient, and to stimulate the accelerated loss of bone that occurs in women following menopause. Ovariectomy induced bone loss in the rat and postmenopausal bone loss share many similar characteristics. These include: increased rate of bone turnover with resorption exceeding formation; and initial rapid phase of bone loss followed by a much slower phase; greater loss of cancellous than cortical bone; decreased intestinal absorption of calcium; some protection against bone loss by obesity; and similar skeletal response to therapy with estrogen, tamoxifen, bisphosphonates, parathyroid hormone, calcitonin and exercise. These wide-ranging similarities are strong evidence that the ovariectomized rat bone loss model is suitable for studying problems that are relevant to postmenopausal bone loss.
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              Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.

              Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures. Randomized, blinded, placebo-controlled trial. Eleven community-based clinical research centers. Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later). All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial. Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry. Alendronate increased BMD at all sites studied (P 2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects. In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.
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                Author and article information

                Contributors
                grynpas@lunenfeld.ca
                Journal
                JBMR Plus
                JBMR Plus
                10.1002/(ISSN)2473-4039
                JBM4
                JBMR Plus
                John Wiley & Sons, Inc. (Hoboken, USA )
                2473-4039
                09 November 2019
                December 2019
                : 3
                : 12 ( doiID: 10.1002/jbm4.v3.12 )
                Affiliations
                [ 1 ] Lunenfeld‐Tanenbaum Research Institute Mount Sinai Hospital Toronto Ontario Canada
                [ 2 ] Department of Laboratory Medicine and Pathology University of Toronto Toronto Ontario Canada
                [ 3 ] Faculty of Dentistry University of Toronto Toronto Ontario Canada
                [ 4 ] Faculty of Dentistry Dalhousie University Halifax Nova Scotia Canada
                [ 5 ] Department of Chemistry Simon Fraser University Burnaby British Columbia Canada
                [ 6 ] Division of Comparative Medicine University of Toronto Toronto Ontario Canada
                [ 7 ] Department of Physiology University of Toronto Toronto Ontario Canada
                [ 8 ] Department of Dental Oncology and Maxillofacial Prosthetics Princess Margaret Cancer Centre Toronto Ontario Canada
                [ 9 ] Institute of Biomaterials and Biomedical Engineering University of Toronto Toronto Ontario Canada
                Author notes
                [* ]Address correspondence to: Marc D Grynpas, PhD, Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, 60 Murray Street, Box 42, Toronto, Ontario, Canada M5T 3L9. E‐mail: grynpas@ 123456lunenfeld.ca
                Article
                JBM410237
                10.1002/jbm4.10237
                6894726
                © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 2, Pages: 12, Words: 7967
                Product
                Funding
                Funded by: Institute of Musculoskeletal Health and Arthritis , open-funder-registry 10.13039/501100000033;
                Funded by: Canadian Institutes of Health Research , open-funder-registry 10.13039/501100000024;
                Funded by: Natural Sciences and Engineering Research Council of Canada , open-funder-registry 10.13039/501100000038;
                Funded by: Health Research , open-funder-registry 10.13039/100005622;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                December 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

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