Do topical applications of bisphosphonates improve bone formation 
in oral implantology? A systematic review

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Abstract

Background

The aim of this systematic literature review was to evaluate the feasibility of topical bisphosphonate application for preserving/enhancing alveolar bone in oral implantology.

Material and Methods

An electronic search was conducted in the PubMed/Medline, EMBASE, Scopus, Web of knowledge, and Google-Scholar databases for articles dated from January 2000 to December 2016. Two reviewers assessed the quality of the studies independently.

Results

A total of 154 abstracts were identified, of which 18 potentially relevant articles were selected; a final total of nine papers were included for analysis. Comparison of the findings of the selected studies was made difficult by the heterogeneity of the articles, all of them animal research papers that showed heterogeneity in the methodologies used and a high or moderate risk of bias.

Conclusions

The topical application of bisphosphonate solution would appear to favor new bone formation in alveolar defects, and boosts the regenerative capacities of biomaterials resulting in increased bone density.

Key words:Alveolar bone, bone regeneration, topical application, biomaterial, bisphosphonates.

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Most cited references 31

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Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.

T. Rosenberg, Bhoomi Mehrotra, L. Ruggiero … (2004)

Bisphosphonates are widely used in the management of metastatic disease to the bone and in the treatment of osteoporosis. We were struck in the past 3 years with a cluster of patients with necrotic lesions in the jaw who shared 1 common clinical feature, that they had all received chronic bisphosphonate therapy. The necrosis that was detected was otherwise typical of osteoradionecrosis, an entity that we rarely encountered at our center, with less than 2 patients presenting with a similar manifestation per year. We performed a retrospective chart review of patients who presented to our Oral Surgery service between February 2001 and November 2003 with the diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy. Sixty-three patients have been identified with such a diagnosis. Fifty-six patients had received intravenous bisphosphonates for at least 1 year and 7 patients were on chronic oral bisphosphonate therapy. The typical presenting lesions were either a nonhealing extraction socket or an exposed jawbone; both were refractory to conservative debridement and antibiotic therapy. Biopsy of these lesions showed no evidence of metastatic disease. The majority of these patients required surgical procedures to remove the involved bone. In view of the current trend of increasing and widespread use of chronic bisphosphonate therapy, our observation of an associated risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized potential complication. An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone.

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Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo.

Alexandre A. Sasaki, Michael D. Hughes, G D Mundy … (1995)

Bisphosphonates inhibit bone resorption and are therapeutically effective in diseases of increased bone turnover, such as Paget's disease and hypercalcemia of malignancy. The mechanisms by which they act remain unclear. Proposed mechanisms include inhibition of osteoclast formation from precursors and inhibitory or toxic effect on mature osteoclasts. We have developed a new in vitro model to study osteoclast survival and in this paper present in vitro and in vivo evidence that may explain both the observed reduction in osteoclast numbers and in bone resorption by mature osteoclasts, namely that bisphosphonates induce programmed cell death (apoptosis). Three bisphosphonates (risedronate, pamidronate, and clodronate) caused a 4- to 24-fold increase in the proportion of osteoclasts showing the characteristic morphology of apoptosis in vitro. This observation was confirmed in vivo in normal mice, in mice with increased bone resorption, and in nude mice with osteolytic cancer metastases, with similar-fold increases to those observed in vitro. Of the three compounds, risedronate, the most potent inhibitor of bone resorption in vivo, was the strongest inducer of osteoclast apoptosis in vitro. Osteoclast apoptosis may therefore be a major mechanism whereby bisphosphonates reduce osteoclast numbers and activity, and induction of apoptosis could be a therapeutic goal for new antiosteoclast drugs.

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New insights into the molecular mechanisms of action of bisphosphonates.

Peter J. Rogers (2002)

Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.

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Author and article information

Journal

Journal ID (nlm-ta): Med Oral Patol Oral Cir Bucal

Journal ID (iso-abbrev): Med Oral Patol Oral Cir Bucal

Journal ID (publisher-id): Medicina Oral S.L.

Title: Medicina Oral, Patología Oral y Cirugía Bucal

Publisher: Medicina Oral S.L.

ISSN (Print): 1698-4447

ISSN (Electronic): 1698-6946

Publication date (Print): July 2017

Publication date (Electronic): 18 June 2017

Volume: 22

Issue: 4

Pages: e512-e519

Affiliations

[1 ]Clinical Instructor of the International Master in Oral Surgery (IMOS). International University of Catalonia (UIC), Barcelona, Spain

[2 ]Assistant Professor of the International Master in Oral Surgery (IMOS). International University of Catalonia (UIC), Barcelona, Spain

[3 ]Professor and Chairman of the Department of Oral and Maxillofacial Surgery. International University of Catalonia (UIC), Barcelona, Spain

[4 ]Professor and Director of Biotechnology Cathedra of the University Catholica San Antonio de Murcia (UCAM) Murcia, Spain

[5 ]Director and Associate Professor of the International Master in Oral Surgery (IMOS). International University of Catalonia (UIC), Barcelona, Spain

[6 ]Full Professor and Director of International Dentistry Research Cathedra. Faculty of Medicine & Dentistry, San Antonio Catholic University of Murcia (UCAM), Murcia, Spain

Author notes

Faculty of Medicine and Dentistry Universitat Internacional de Catalunya Carrer de Josep Trueta s/n 08195 Sant Cugat del Vallés Barcelona, Spain , E-mail: oscarsalomo@ 123456uic.es

Conflict of interest statement:The authors declare that they have no conﬂict of interest.

Article

Publisher ID: 21887

DOI: 10.4317/medoral.21887

PMC ID: 5549526

PubMed ID: 28624840

SO-VID: a7403e8b-9ab9-4552-8e5d-5314de70b331

License:

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

Do topical applications of bisphosphonates improve bone formation in oral implantology? A systematic review

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Abstract

Background

Material and Methods

Results

Conclusions

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Most cited references 31

Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.

Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo.

New insights into the molecular mechanisms of action of bisphosphonates.

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