Bisphosphonates Induce Senescence in Normal Human Oral Keratinocytes

Kim, R.H.; Lee, R.S.; Williams, D.; Bae, Sangmee; Woo, Jeongmin; Lieberman, Mark B.; Oh, Joo Hyun; Dong, Qi; Shin, Kihyuk; Kang, Mo K.; Park, N.-H.

doi:10.1177/0022034511402995

Cited by 70 publications

(87 citation statements)

References 28 publications

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“…Donetti et al [14] detected nuclear damage in the upper granular layer without signs of apoptosis, which is in accordance with in vitro data obtained from oral keratinocytes [17]. It is postulated that the toxic side effects on the oral mucosa were partly caused by interference with the mevalonate pathway.…”

Section: Discussionsupporting

confidence: 72%

Bisphosphonate-Mediated Oral Ulcers: A Rare Differential Diagnosis of Erosive Oral Lesions

et al. 2015

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Oral bisphosphonates are widely used drugs for the treatment of various indications such as postmenopausal osteoporosis. Ulcerations of the upper gastrointestinal tract, predominantly reported for alendronate, are common side effects. The occurrence of ulcerations within the oral cavity is less well known and probably underreported. Especially in cases of incorrect mode of intake, oral bisphosphonates are prone to induce oral ulcerations by as yet incompletely delineated mechanisms. We herein report on 2 elderly female patients suffering from oral ulcerations, which could be attributed to inadequate ingestion of alendronate. Possible ways to cause damage to the oral mucosa include non-specific toxic and pro-apoptotic effects, partly via bisphosphonate-mediated interference with intracellular signalling such as the mevalonate downstream pathway. Adequate patient advice in terms of correct use of oral bisphosphonates is crucial in order to prevent mucosal damage. Otherwise, prompt treatment cessation or a switch to an intravenously administered bisphosphonate is likely to achieve complete healing.

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Section: Discussionsupporting

confidence: 72%

Bisphosphonate-Mediated Oral Ulcers: A Rare Differential Diagnosis of Erosive Oral Lesions

et al. 2015

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“…The long-term use of intravenous third-generation aminobisphosphonates (risedronate and zoledronic acid [ZOL]), the most powerful antiresorptive agents, is considered a critical risk factor related to the development of BONJ (Wessel, Dodson, and Zavras 2008;Basso et al 2013). The pathogenesis of BONJ remains unknown and several hypothesis have been proposed; nevertheless, the suppression of bone remodeling induced by bisphosphonates seems to be the most consistent with their intrinsic mechanism of action (Mawardi et al 2011; R. H. Kim et al 2011;Allen and Burr 2009). …”

Section: Introductionmentioning

confidence: 99%

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Córdova

Guilbaud

Amiaud

et al. 2016

Journal of Cranio-Maxillofacial Surgery

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Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ. Material and methods: Thirty-two mice were treated twice a week with either 100 mu g/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT. Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment. Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells shown in this study could contribute to the pathogenesis of BONJ

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“…Several in vitro and in vivo studies suggest that BP results in higher levels of apoptosis and premature senescence of oral mucosal cells, supporting the idea that BP treatment affects the oral mucosa [9,10]. Soft tissue wound healing might be partly responsible for the development of BRONJ in individuals taking BPs.…”

Section: Introductionmentioning

confidence: 83%

Sinus Mucosal Thickening in Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study

Gallego

Junquera²,

Pelaz³

et al. 2014

ORL

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Osteonecrosis of the jaws is a clinically significant complication of bisphosphonate (BP) medications. Otherwise, the effects of BPs on oral soft tissue or cells remain unknown. The main objective of the present study was to determine whether the presence of sinus mucosal thickening was significantly related to BP-related osteonecrosis of the jaw (BRONJ). A case-control study was conducted on 32 patients who underwent treatment of BRONJ with conventional radiological investigations (panoramic radiographs) and computed tomography. The results indicated that patients with BRONJ had a 5.57-fold greater probability of presenting sinus mucosal thickening than controls. Although the existence of this thickening was more common in patients with advanced-stage disease or low levels of C-telopeptide-cross-linked type I collagen, no significant difference was observed between cases and controls. While considering the limitations inherent in the design and number of cases analyzed in our study, patients with osteonecrosis of the jaw were found to have a 5.57-fold greater probability of presenting sinus mucosal thickening (>3 mm) than healthy subjects.

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Bisphosphonates Induce Senescence in Normal Human Oral Keratinocytes

Cited by 70 publications

References 28 publications

Bisphosphonate-Mediated Oral Ulcers: A Rare Differential Diagnosis of Erosive Oral Lesions

Bisphosphonate-Mediated Oral Ulcers: A Rare Differential Diagnosis of Erosive Oral Lesions

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Sinus Mucosal Thickening in Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study

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