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      Current and emerging therapies for the treatment of osteoporosis

      Journal of Experimental Pharmacology

      Dove Medical Press

      bone formation, bone resorption, antiresorptive agent, anabolic agent

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          Abstract

          Osteoporosis represents a weakening of bone tissue due to an imbalance in the dynamic processes of bone formation and bone resorption that are continually ongoing within bone tissue. Most currently available osteoporosis therapies are antiresorptive agents. Over the past decade, bisphosphonates, notably alendronate and risedronate, have become the dominant agents with newer bisphosphonates such as ibandronate and zoledronic acid following a trend of less frequent dosing regimens. Synthetic estrogen receptor modulators (SERMs) continue to be developed as drugs that maintain the bone-protective effects of estrogen while avoiding its associated adverse side effects. Currently available agents of this class include raloxifene, the only SERM available in the United States (US), and lasofoxifene and bazedoxifene, available in Europe. Calcitonin, usually administered as a nasal spray, completes the list of currently approved antiresorptive agents, while parathyroid hormone analogs represent the only anabolic agents currently approved in both the US and Europe. Strontium ranelate is an additional agent available in Europe but not the US that has both anabolic and antiresorptive activity. New agents expected to further expand therapeutic options include denosumab, a monoclonal antibody inhibitor of the resorptive enzyme cathepsin K, which is in the final stages of Food and Drug Administration approval. Other agents in preclinical development include those targeting specific molecules of the Wnt/β-catenin pathway involved in stimulating bone formation by osteoblast cells. This review discusses the use of currently available agents as well as highlighting emerging agents expected to bring significant changes to the approach to osteoporosis therapy in the near future.

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          Most cited references 76

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          Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group.

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            Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

            ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.
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              Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

              Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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                Author and article information

                Journal
                J Exp Pharmacol
                J Exp Pharmacol
                Journal of Experimental Pharmacology
                Journal of Experimental Pharmacology
                Dove Medical Press
                1179-1454
                2010
                27 August 2010
                : 2
                : 121-134
                Affiliations
                Department of Molecular and Experimental Medicine, The Scripps Research Institute, CA, USA
                Author notes
                Correspondence: Jill Waalen, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Tel +1 858 784 8042, Fax +1 858 784 2083, Email jwaalen@ 123456scripps.edu
                Article
                jep-2-121
                10.2147/JEP.S7823
                4863293
                27186098
                © 2010 Waalen, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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