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      Fracture healing physiology and the quest for therapies for delayed healing and nonunion

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          ABSTRACT

          Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/β‐catenin signaling, and recombinant FGF‐2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:213–223, 2017.

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          WNT signaling in bone homeostasis and disease: from human mutations to treatments.

          Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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            A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.

            Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Systematic review. Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Romosozumab in postmenopausal women with low bone mineral density.

              Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.
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                Author and article information

                Contributors
                paulkost@umich.edu
                Journal
                J Orthop Res
                J. Orthop. Res
                10.1002/(ISSN)1554-527X
                JOR
                Journal of Orthopaedic Research
                John Wiley and Sons Inc. (Hoboken )
                0736-0266
                1554-527X
                19 December 2016
                February 2017
                : 35
                : 2 ( doiID: 10.1002/jor.v35.2 )
                : 213-223
                Affiliations
                [ 1 ] School of Dentistry University of Michigan Phylon Pharma Services Newbury Park California
                [ 2 ] OrthoSynthesis Inc. San Jose California
                Author notes
                [*] [* ] Correspondence to: Paul Kostenuik (T: 805‐410‐0480; E‐mail: paulkost@ 123456umich.edu )

                Article
                JOR23460
                10.1002/jor.23460
                6120140
                27743449
                6ad4d24e-0c40-4722-ba61-139daa574611
                © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 8028
                Product
                Funding
                Funded by: Radius Health
                Categories
                Perspectives
                Perspectives
                Custom metadata
                2.0
                jor23460
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:03.09.2018

                Orthopedics

                fracture healing, osteogenesis, chondrogenesis, delayed union, nonunion fracture

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