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Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw.

ABSTRACT: The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. This study evaluated the potential of a gelatine-hyaluronic acid hydrogel loaded with the angiogenic growth factor, vascular endothelial growth factor (VEGF), as a local delivery system to aid in maintaining vascularization in a bisphosphonate-treated (Zoledronic Acid) rodent maxillary extraction defect. Healing was assessed four weeks after implantation of the VEGF-hydrogel into extraction sockets. Gross examination and histological assessment showed that total osteonecrosis and inflammatory infiltrate was significantly reduced in the presence of VEGF. Also, total vascularity and specifically neovascularization, was significantly improved in animals that received VEGF hydrogel. Gene expression of vascular, inflammatory and bone specific markers within the defect area were also significantly altered in the presence of VEGF. Furthermore, plasma cytokine levels were assessed to determine the systemic effect of locally delivered VEGF and showed similar outcomes. In conclusion, the use of locally delivered VEGF within healing extraction sockets assists bone healing and prevents MRONJ via a pro-angiogenic and immunomodulatory mechanism.

SUBMITTER: Sharma D

PROVIDER: S-EPMC8642483 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.

Project description:BackgroundAccurate documentation of a patient's prior medication use and awareness of side effects associated with anti-osteoporotic agents can assist dentists to prevent medication-related osteonecrosis of the jaw. I aimed to determine the awareness of Korean dentists regarding medication-related osteonecrosis of the jaw and the duration of drug holidays they prescribe to patients who need to undergo various dental procedures.MethodsAn online, questionnaire-based survey was conducted among 1000 dentists registered in an online community in Korea. The following were determined: general characteristics; type of practice; recordkeeping regarding patients' use of bone-modifying agents; requirement of a doctor's referral letter; advice given regarding drug holidays of bone-modifying agents before dental surgery procedures; and experience with medication-related osteonecrosis of the jaw. Differences between dentists with and without experience in treating patients with medication-related osteonecrosis of the jaw were evaluated using the χ2 test.ResultsAlthough a relatively high proportion (293/1000, 29.3%) of dentists had experienced cases of medication-related osteonecrosis of the jaw, only 650/1000 (65.0%) routinely documented the type of bone-modifying agent used by patients and the duration of its use. Moreover, only 591/1000 (59.1%) dentists routinely requested referral letters from doctors before performing dental surgery on patients. Although the recommended period for a drug holiday differs for each drug, 533/1000 (53.3%) dentists did not make such a distinction. There was a statistically significant difference in the level of detail documented in terms of anti-osteoporotic drug use between dentists who had no experience in medication-related osteonecrosis of the jaw (707/1000) and those who had such experience (P = 0.007). There was a statistically significant difference in the length of drug holidays prescribed between dentists with and without prior experience with the condition (P = 0.001).ConclusionsThese results suggest that dentists do not respond consistently to patients' drug history prior to performing dental procedures. This implies the need for increased cooperation between dentists and physicians, as well as the development of targeted educational interventions for the dental profession, to reduce the risk of medication-related osteonecrosis of the jaw.Trial registrationNot applicable.

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Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw.

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