Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function

Elsayed, Ranya; Abraham, Pheba; Awad, Mohamed E.; Kurago, Zoya B.; Baladhandayutham, Balasudha; Whitford, Gary M.; Pashley, David H.; McKenna, Charles E.; Elsalanty, Mohammed

doi:10.1016/j.bone.2018.01.030

Cited by 25 publications

(22 citation statements)

References 43 publications

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“…Oral swabs showed an increase in bacterial 16s rRNA expression (P = .0023; Figure 1A). Consistent with our previous studies, 5,23 Zol-treated animals showed exposed necrotic bone, persistent for 8 weeks after extraction, compared with complete healing and mucosal coverage in control animals ( Figure 1B). To study the effect of Zol on DC activity, isolation of cervical lymph nodes was performed at 2 weeks, and harvest of mandibles and gingival tissues at 8 weeks following extraction.…”

Section: Impaired DC Activity and Increased Oral Bacterial Load In supporting

confidence: 92%

“…Zol is known to have the highest affinity to the bone matrix, where it accumulates for years . We previously showed that matrix‐bound Zol molecules play an important role in making the alveolar bone susceptible to osteonecrosis . However, the question remained as to why other bone sites that have similarly high levels of matrix‐bound Zol, such as the proximal end of the tibia, are not comparably vulnerable.…”

Section: Discussionmentioning

confidence: 99%

“…1 We previously showed that matrix-bound Zol molecules play an important role in making the alveolar bone susceptible to osteonecrosis. 23 However, the question remained as to why other bone sites that have similarly high levels of matrix-bound Zol, such as the proximal end of the tibia, are not comparably vulnerable. Our studies showed that even with significant trauma to the proximal tibia in Zol-treated animals, osteonecrosis could not be induced there (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Role of dendritic cell‐mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw

et al. 2020

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Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood.Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol in impairment of differentiation and function of migratory and tissue-resident DCs, promoting disruption of T-cell activation in vitro. Results demonstrated a Zol induced impairment in DC functions and an increased bacterial load in the oral cavity. DC-deficient mice were predisposed to osteonecrosis following dental extraction. Zol treatment of DCs in vitro caused an impairment in immune functions including differentiation, maturation, migration, antigen presentation, and T-cell activation. We conclude that the mechanism of Zolinduced osteonecrosis of the jaw involves disruption of DC immune functions required to clear bacterial infection and activate T cell effector response. K E Y W O R D S alveolar bone healing, dendritic cells, osteonecrosis 2596 | ELSAYED Et AL.

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Section: Impaired DC Activity and Increased Oral Bacterial Load In supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Role of dendritic cell‐mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw

et al. 2020

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“…Previous reports have observed that TRAP-positive cells decrease in the MRONJ model [41]. In contrast, TRAP-positive cells increased in our study.…”

Section: Discussioncontrasting

confidence: 84%

Effects of metformin on the prevention of bisphosphonate-related osteonecrosis of the jaw-like lesions in rats

et al. 2021

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In this study, we aimed to investigate the effect of glucose metabolism on bone healing after tooth extraction in an osteoporosis rat model administered zoledronic acid (ZA) and dexamethasone (DX). Methods: In total, 24 male Wistar rats (4 weeks old) were randomly assigned to four groups: Control (subcutaneous physiological saline), ZD (subcutaneous ZA and DX twice a week), Ins+ZD (subcutaneous insulin followed by ZD treatment), and Met+ZD (oral metformin followed by ZD treatment). Blood was collected every two weeks. Two weeks after treatment initiation, the first molar tooth on the right maxilla was extracted from all rats. Four weeks later, the rats were sacrificed, and bone healing was assessed. Maxillae samples were fixed and scanned using micro-computed tomography for quantifying areas of bone defects. Hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate bone apoptosis and osteoclast number. Results: In all experimental groups, body weight was statistically lower than that in the Control group, with no changes observed in uncarboxylated osteocalcin concentrations. The radiological analysis revealed that insulin or metformin administration improved healing in the tooth extraction socket (p < 0.01). Histological examination revealed that the osteonecrosis area was reduced in the Ins+ZD and Met+ZD groups (p < 0.01). TRAP staining presented increased osteoclast numbers in the ZD group when compared with that observed in the Control. Conclusions: Tooth extraction with long-term ZA and DX administration inhibited bone remodeling and induced bisphosphonate-related osteonecrosis of the jaw-like lesions. Metformin exerted protective effects against osteonecrosis of the jaw.

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“…An increasing body of evidence suggests that ZA inhibits the differentiation of osteoclasts in vitro through various pathways, including inhibition of receptor activator of nuclear factor κB ligand (RANKL)/receptor activator of nuclear factor κB (RANK) pathway, non-canonical Wnt/Ca 2+ /calmodulin dependent protein kinase II (CaMKII) pathway, and prevention of macrophage differentiation into osteoclasts [ 19 , 25 , 26 ].…”

Section: Inhibition Of Differentiation Of Osteoclasts By Zamentioning

confidence: 99%

Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

Wang

Fang

et al. 2020

BMC Cancer

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Zoledronic acid (ZA) is one of the most important and effective class of anti-resorptive drug available among bisphosphonate (BP), which could effectively reduce the risk of skeletal-related events, and lead to a treatment paradigm for patients with skeletal involvement from advanced cancers. However, the exact molecular mechanisms of its anticancer effects have only recently been identified. In this review, we elaborate the detail mechanisms of ZA through inhibiting osteoclasts and cancer cells, which include the inhibition of differentiation of osteoclasts via suppressing receptor activator of nuclear factor κB ligand (RANKL)/receptor activator of nuclear factor κB (RANK) pathway, non-canonical Wnt/Ca2+/calmodulin dependent protein kinase II (CaMKII) pathway, and preventing of macrophage differentiation into osteoclasts, in addition, induction of apoptosis of osteoclasts through inhibiting farnesyl pyrophosphate synthase (FPPS)-mediated mevalonate pathway, and activation of reactive oxygen species (ROS)-induced pathway. Furthermore, ZA also inhibits cancer cells proliferation, viability, motility, invasion and angiogenesis; induces cancer cell apoptosis; reverts chemoresistance and stimulates immune response; and acts in synergy with other anti-cancer drugs. In addition, some new ways for delivering ZA against cancer is introduced. We hope this review will provide more information in support of future studies of ZA in the treatment of cancers and bone cancer metastasis.

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Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function

Cited by 25 publications

References 43 publications

Role of dendritic cell‐mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw

Role of dendritic cell‐mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw

Effects of metformin on the prevention of bisphosphonate-related osteonecrosis of the jaw-like lesions in rats

Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

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