Bisphosphonate-induced gastrointestinal mucosal injury is mediated by mitochondrial superoxide production and lipid peroxidation

Abstract

Bisphosphonates such as alendronate and risedronate are commonly used for the treatment of postmenopausal osteoporosis. They have the gastrointestinal adverse effects such as erosions and ulcers in stomach and small intestine. However, the detailed biological mechanism remains to be elucidated. Since alendronate is suggested to increase the risk of non-steroidal anti-inflammatory drug-related gastropathy, we hypothesized that bisphosphonates and non-steroidal anti-inflammatory drugs have the same pathophysiological mechanisms in gastrointestinal mucosa: Bisphosphonates may induce cellular lipid peroxidation by inducing the production of mitochondrial superoxide. We also hypothesized that geranylgeranylacetone, an antiulcer drug, may prevent lipid peroxidation by reducing superoxide production. We treated gastric RGM1 cells and small intestinal IEC6 cells with alendronate or risedronate, and examined cellular injury, lipid peroxidation and superoxide production with specific fluorescent dyes, and underwent electron paramagnetic resonance spectroscopy to detect the production of superoxide in vitro. The results indicated that bisphosphonates indeed induced cellular injury, cellular lipid peroxidation, and superoxide production. We also demonstrated that the pretreatment of geranylgeranylacetone decreased superoxide production and prevented cellular lipid peroxidation. These results suggested that bisphosphonates, like non-steroidal anti-inflammatory drugs, induce lipid peroxidation by producing mitochondrial superoxide, which was prevented by geranylgeranylacetone.

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

“…Histological findings in our patients, in accordance with the literature, include ulceration, inflammatory lympho-plasmacellular subepithelial band-like or perivascular infiltrate or chronic granulation tissue [8,11]. In vitro studies showed pro-apoptotic effects of bisphosphonates on murine keratinocytes and gastrointestinal mucosa [12,13]. Furthermore, it was shown that alendronate leads to a reduction in the proliferation of gingival fibroblasts and oral keratinocytes [13].…”

Elimination of intravenous alendronate by hemodialysis: A kinetic study

“…In taking alendronate tablets, patients need to follow strict dosing instructions (for example, with a glass of plain water, staying upright, and at least 30 min before food). Furthermore, 16–20% of patients prescribed oral alendronate had gastric distress symptoms due to gastric cellular injury, which is induced by superoxide production . In Japan, intravenous alendronate (900 μg, every 4 weeks) was approved for the treatment of osteoporosis in 2012 and was reported not to be inferior to oral alendronate (35 mg/week) in a 12‐month comparative study .…”

Geranylgeranylacetone Blocks Doxorubicin-Induced Cardiac Toxicity and Reduces Cancer Cell Growth and Invasion through RHO Pathway Inhibition

“…However, because GGA is protective in models of oxidative stress (8)(9)(10)(11)(12)(13)(14), we questioned whether GGA would be cardioprotective in mice with oxidative stress in the heart induced by doxorubicin. To evaluate cardiac function, echocardiography was performed in conscious mice from four treatment groups: saline control, GGA alone, doxorubicin (9 mg/kg) alone, and doxorubicin combined with GGA.…”

“…GGA treatment is known to reduce oxidative stress in various animal models (8)(9)(10)(11)(12)(13)(14), yet GGA has never been used in the setting of doxorubicin toxicity. To evaluate the contribution of ROS generation in doxorubicin-induced cardiac toxicity and whether GGA pretreatment would reduce oxidative stress, lucigenin chemiluminescence assay was performed to measure superoxide in freshly frozen mouse cardiac tissue (41).…”

“…In multiple animal models of ischemia and reperfusion, GGA prevents oxidative stress in liver, heart, brain, kidney, and retina (8)(9)(10)(11)(12)(13)(14). A second mechanism linked to GGA's mechanism of action is its ability to inhibit the activation of the RHO family of GTPases through reduction of protein geranylgeranylation, a posttranslational modification required for RHO family membrane targeting and signaling (15,16).…”