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      Bisphosphonate Associated Osteonecrosis of the Jaw: An Update on Pathophysiology, Risk Factors, and Treatment

      review-article
      1 , * , 2
      International Journal of Dentistry
      Hindawi Publishing Corporation

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          Abstract

          Osteonecrosis of the jaw in patients treated with bisphosphonates is a relatively rare but well known complication at maxillofacial units around the world. It has been speculated that the medication, especially long-term i.v. bisphosphonate treatment, could cause sterile necrosis of the jaws. The aim of this narrative review of the literature was to elaborate on the pathological mechanisms behind the condition and also to gather an update on incidence, risk factors, and treatment of bisphosphonate associated osteonecrosis of the jaw. In total, ninety-one articles were reviewed. All were published in internationally recognized journals with referee systems. We can conclude that necrotic lesions in the jaw seem to be following upon exposure of bone, for example, after tooth extractions, while other interventions like implant placement do not increase the risk of osteonecrosis. Since exposure to the bacterial environment in the oral cavity seems essential for the development of necrotic lesions, we believe that the condition is in fact chronic osteomyelitis and should be treated accordingly.

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          Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.

          Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.
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            Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite.

            Bisphosphonates are now the most widely used drugs for diseases associated with increased bone resorption, such as osteoporosis. Although bisphosphonates act directly on osteoclasts, and interfere with specific biochemical processes such as protein prenylation, their ability to adsorb to bone mineral also contributes to their potency and duration of action. The aim of the present study was to compare the binding affinities for hydroxyapatite (HAP) of 6 bisphosphonates currently used clinically and to determine the effects of these bisphosphonates on other mineral surface properties including zeta potential and interfacial tension. Affinity constants (K(L)) for the adsorption of bisphosphonates were calculated from kinetic studies on HAP crystal growth using a constant composition method at 37 degrees C and at physiological ionic strength (0.15 M). Under conditions likely to simulate bisphosphonate binding onto bone, there were significant differences in K(L) among the bisphosphonates for HAP growth (pH 7.4) with a rank order of zoledronate > alendronate > ibandronate > risedronate > etidronate > clodronate. The measurements of zeta potential show that the crystal surface is modified by the adsorption of bisphosphonates in a manner best explained by molecular charges related to the protonation of their side-chain moieties, with risedronate showing substantial differences from alendronate, ibandronate, and zoledronate. The studies of the solid/liquid interfacial properties show additional differences among the bisphosphonates that may influence their mechanisms for binding and inhibiting crystal growth and dissolution. The observed differences in kinetic binding affinities, HAP zeta potentials, and interfacial tension are likely to contribute to the biological properties of the various bisphosphonates. In particular, these binding properties may contribute to differences in uptake and persistence in bone and the reversibility of effects. These properties, therefore, have potential clinical implications that may be important in understanding differences among potent bisphosphonates, such as the apparently more prolonged duration of action of alendronate and zoledronate compared with the more readily reversible effects of etidronate and risedronate.
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              Bisphosphonates: mechanisms of action.

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                Author and article information

                Journal
                Int J Dent
                Int J Dent
                IJD
                International Journal of Dentistry
                Hindawi Publishing Corporation
                1687-8728
                1687-8736
                2014
                1 September 2014
                : 2014
                : 471035
                Affiliations
                1Department Oral and Maxillofacial Surgery, The Sahlgrenska Academy, University of Gothenburg, P.O. Box 450, 405 30 Gothenburg, Sweden
                2Maxillofacial Unit, Linköping University Hospital, 581 85 Linköping, Sweden
                Author notes

                Academic Editor: Giuliano Ascani

                Author information
                http://orcid.org/0000-0002-3922-7865
                Article
                10.1155/2014/471035
                4164242
                25254048
                906a3fcf-62e2-4de8-9bcd-2e3de5686615
                Copyright © 2014 L. Rasmusson and J. Abtahi.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 May 2014
                : 18 July 2014
                Categories
                Review Article

                Dentistry
                Dentistry

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