Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins

Abstract

Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly Streptococcus mutans, in the oral microbiome in the context of insufficient acid buffering due to impaired salivary glands maintains the low pH that sustains damage to the mucosa. Significant associations between ONJ and adrenal insufficiency, vitamin C deficiency, and Sjögren's syndrome were found. Glucose 6 phosphate dehydrogenase (G6PD) deficiency can explain much of the pathology. An inability to maintain vitamin C and other antioxidants in the reduced form leads to vascular oxidative damage and impaired adrenal function. Thus, pathogen-induced acidosis, hypoxia, and insufficient antioxidant defenses together induce ONJ. G6PD deficiency and adrenal insufficiency are underlying factors. Impaired supply of adrenal-derived sulfated sterols such as DHEA sulfate may drive the disease process.

Increased risk of bisphosphonate-related osteonecrosis of the jaw in patients with Sjögren’s syndrome: nationwide population-based cohort study

“…Risk factors for BRONJ include DM, cancer and the use of corticosteroids, immunosuppressants and radiotherapy. A significant association between ONJ and SS was observed in a recent study analysing the Food and Drug Administration (FDA’s) Adverse Event Reporting System 16. In this study, we further confirmed that patients with SS were susceptible to BRONJ after tooth extraction.…”

“…In the current study, there were no differences in tooth extraction between patients with and without SS. Low saliva flow combined with acid reflux could lead to a low pH in the oral cavity and overgrowth of acidophilic pathogens, which promote tooth decay and mucosal erosion 16. Even when patients with cancer were excluded, the use of BPs, suppuration and extractions remained associated with ONJ 19.…”

Are medication-induced salivary changes the culprit of osteonecrosis of the jaw? A systematic review

“…It should be noted that patients with SS were more susceptible to bisphosphonate-related osteonecrosis of the jaw, which might be due to the shared risk factors and molecular pathways ( 25 , 27 ). Low salivary flow in combination with acid reflux might result in an oral environment of low pH, which promotes the growth of acidophilic bacteria, in turn, leading to tooth destruction and mucosal degradation ( 40 ). Even in low dosages, these drugs can exert a considerable influence on the expression of genes that play a role in the differentiation and growth of osteoblasts.…”

Bisphosphonate-incorporated coatings for orthopedic implants functionalization

“…4 A). During bone resorption, the proton pump in the OC trap produces an acidic environment, which significantly increases the association of BPs with HA crystal [ 46 ]. OCs take up the released BPs via liquid phase endocytosis [ 47 ].…”