Abstract
Background: The neurological condition called ‘numb chin syndrome’, is a mental nerve neuropathy that is frequently associated with an underlying malignancy or infections. Bisphosphonate (BP) uptake has been recently identified as a new etiology for the syndrome. The mechanism that lies behind this neuropathy and the involvement of BPs have not been elucidated, yet. BPs can cause inhibition of endothelial cell proliferation, migration and adhesion, as well as impairment of capillary tubes formation. In humans, BPs result in reduction of vascularization in bone metabolic diseases, like Paget’s disease. We hypothesize that BPs, taken per os, are capable of producing degenerative changes to the inferior alveolar nerve that may cause a mental nerve neuropathy. Methods: In order to support our hypothesis we conducted an animal study, with Wistar rats, that was approved by the Bioethics Committee of our Institution. The animals were randomly allocated into two groups: Group A, the experimental group that consisted of 3 animals that were given Alendronate per os and Group B, the control group that also consisted of 3 animals, which were given normal saline. The duration was 13 weeks. The samples were observed under a Transmission Electron Microscope. Results: Degenerative changes were defined as: vacuolization of the myelin sheath, detachment of the axon, local thickening and/or disruption of the myelin sheath. Local myelin thickening and detachment of the axon was found in both groups. Myelin sheath disruption was only seen in the control group whereas vacuolization of the myelin sheath was more profound in the experimental group. Interestingly, myelin sheath thickness was reduced in the experimental group. Conclusions: Possible pathophysiological mechanisms causatively related to the histological alterations are: 1. alterations to the blood vessels of the nerve, 2. toxicity effects on Schwann and neuronal cells, or 3. changes to the innate or acquired immunity. The last may, probably, result from the presence of microbial films that cause cytokine production. The hypothesis provides scientific evidence for the presence of degenerative changes after BPs administration and helps in understanding of possible pathophysiological mechanisms.
Highlights
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a category within the broader term of medication-related osteonecrosis of the jaws (MRONJ), a term that has been used in the report of the American Association of Oral and Maxillofacial Surgery (AAOMS) in 2014 [1]
Detachment of the axon was present in both the experimental Group (A) (Figure 1, red arrow)and the control Group (B) (Figure 2, red arrow), whereas disruption of the myelin sheath, by means of vacuolization inside the myelin was more profound in the experimental Group (A) (Figure 1, black arrows), compared to the control Group (Figure 2, black arrow)
BPs administration to the experimental group resulted into a statistical significant reduction of the thickness of the myelin sheath (p
Summary
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a category within the broader term of medication-related osteonecrosis of the jaws (MRONJ), a term that has been used in the report of the American Association of Oral and Maxillofacial Surgery (AAOMS) in 2014 [1]. It is defined by [2]: 1. Bisphosphonates: classification of BRONJ, general issues BPs are drugs mainly implicated in the treatment of osteoporosis, metastatic disease with osteolytic bone metastases like in prostate or breast cancer, hypercalcemia and of hyperparathyroidism cases prior to parathyroidectomy [14,15]. This difference influences their ability to inhibit bone resorption, because nitrogen-containing BPs inhibit bone resorption by 100- to 10,000-fold more than non-nitrogen containing ones [16]
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