Osteonecrosis of the Jaw: Effect of Bisphosphonate Type, Local Concentration, and Acidic Milieu on the Pathomechanism

Otto, Sven; Pautke, Christoph; Opelz, Christine; Westphal, Ines; Drosse, Inga; Schwager, Joanna; Bauss, Frieder; Ehrenfeld, Michael; Schieker, Matthias

doi:10.1016/j.joms.2010.07.017

Cited by 121 publications

(70 citation statements)

References 49 publications

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“…Recent studies have shown that the etiopathogenesis of this condition is more frequent in patients under nitrogen-containing bisphosphonate, which present a higher potency, due to the increased capacity of adhesion to mineral tissues [11,12]. Therefore, the authors selected ZA for this study, considering that ZA is the most potent of all nitrogen-containing bisphosphonates and has been highly related to osteonecrosis development.…”

Section: Discussionmentioning

confidence: 99%

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Zoledronic Acid Inhibits Human Osteoblast Activities

et al. 2013

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Background: Bisphosphonates are potent inhibitors of bone resorption. These kinds of drugs, which are used for the treatment of osteolytic diseases, have been associated with the occurrence of oral osteonecrosis, especially in patients over 60 years old. Current studies have demonstrated that the cytotoxic effects of bisphosphonates on osteoblasts play an important role in oral osteonecrosis development. Objective: The aim of this study was to evaluate the effect of long-term application of a highly potent bisphosphonate - zoledronic acid (ZA) - on human osteoblasts in vitro. Methods: Human osteoblasts (MG63 cell line) were seeded for 72 h in wells of 24-well plates. The Dulbecco's modified Eagle's medium (DMEM) was then replaced by culture medium without fetal bovine serum (FBS), and the cells were incubated for an additional 24 h, after which ZA was added to the DMEM without FBS and incubated in contact with osteoblasts for 7, 14 or 21 days. Cell viability (CV), total protein production (TPP), alkaline phosphatase (ALP) activity, mineral nodule formation (MNF), and gene expression of ALP and osteocalcin (OCN), as well as cell morphology by scanning electronic microscopy, were evaluated. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests, with a significance level of 5%. Results: The cytotoxic effects of ZA on osteoblasts were characterized by reduction of CV, TPP, ALP and MNF production. In addition, ZA MNF caused a decrease in gene expression of ALP and OCN, as well as intense cell morphology alterations. All these negative effects of ZA were concentration and period dependent. Conclusion: Both concentrations of ZA (1 and 5 μM) caused cytotoxic effects to osteoblasts which reduced the production and expression of proteins that play an important role in bone matrix synthesis and mineralization.

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Section: Discussionmentioning

confidence: 99%

“…This is mainly observed with zoledronic acid (ZA), a highly potent bisphosphonate with a high capacity for bone adhesion [11,12]. In this situation, osteonecrosis may be caused by the intense toxic effects of this kind of drug attached to bone tissue on the surrounding osteoblasts.…”

Section: Introductionmentioning

confidence: 99%

Zoledronic Acid Inhibits Human Osteoblast Activities

et al. 2013

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“…This process is exerted by inhibition of the mevalonate and cholesterol biosynthetic pathways, thereby reducing the production of lipids essential for protein prenylation or posttranslational modification of the guanine triphosphates (GTP) signaling which modulates the cellular apoptosis. When GTP is uncontrolled, the osteoclast can be disrupted by an irregular cytoskeletal rearrangement, membrane ruffling, and intracellular vesicle transport [31][32][33]. In this way, the long-term use of nitrogen-containing BPs leads to the development of abnormal osteoclasts which degenerate into necrotic bone tissue.…”

Section: Discussionmentioning

confidence: 99%

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures

et al. 2012

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Summary There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized. Introduction The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ. Methods An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case-control study within a cohort of individuals aged 55+years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ. Results Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3-5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed. Conclusions Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

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“…This is due to a variety of cytokines producedbymetastaticcancercellsthatcaninfluencebothosteoclast and osteoblast function [1]. A remedy to alleviate the effectsofexcessiveboneresorptionistreatmentwithbisphosphonates.Bisphosphonatesaresyntheticpyrophosphateanalogs that generate cytotoxic effects on different cells, and in particularonosteoclastsbecausetheyaccumulateinthiscell type, interfere with various pathways and subsequently reduce osteoclast activity, adhesion and migration ability and induce apoptosis and/or necrosis [2][3][4][5]. According to their chemical structure, bisphosphonates are subdivided into 4groups:bisphosphonateswithoutnitrogensubstitution(e.g.…”

Section: Patient Characteristicsmentioning

confidence: 99%

Incidence and Risk Factors of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma Patients Having Undergone Autologous Stem Cell Transplantation

et al. 2012

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Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy. Due to their long survival and subsequently high cumulative doses of bisphosphonates, multiple myeloma patients have the highest risk of developing BRONJ of all patients treated with bisphosphonates. The purpose of the present study was to evaluate the incidence and risk factors for BRONJ in multiple myeloma patients after high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients and Methods: We retrospectively analyzed the data of 120 multiple myeloma patients after high-dose chemotherapy and ASCT treated with bisphosphonates and assessed the incidence and risk factors of BRONJ. Results: Of the 120 patients, 23 (19%) developed BRONJ. 6 patients suffered several BRONJ events, resulting in a total incidence of 23%. The risk for BRONJ was significantly higher for patients with rheumatism and recent dental manipulations. Furthermore, the number of previous bisphosphonate rotations, the duration of bisphosphonate therapy, and the type and cumulative dose of bisphosphonate used were associated with the incidence of BRONJ. Conclusion: Our study is the first to determine the risk of BRONJ in a homogeneous group of multiple myeloma patients treated with high-dose chemotherapy and ASCT.

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Osteonecrosis of the Jaw: Effect of Bisphosphonate Type, Local Concentration, and Acidic Milieu on the Pathomechanism

Cited by 121 publications

References 49 publications

Zoledronic Acid Inhibits Human Osteoblast Activities

Zoledronic Acid Inhibits Human Osteoblast Activities

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures

Incidence and Risk Factors of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma Patients Having Undergone Autologous Stem Cell Transplantation

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