Melatonin supports alendronate in preserving bone matrix and prevents gastric inflammation in ovariectomized rats

Abstract

The anti-catabolic bisphosphonate alendronate is considered as the first-line medical treatment in post-menopausal osteoporosis; but several side effects, including gastric mucosal injury, are associated with its use. The aim was to elucidate whether combined treatment with melatonin plus alendronate would be more advantageous in the maintenance of bone and the prevention of gastric side effects. Under anaesthesia, female Sprague-Dawley rats underwent bilateral ovariectomy (OVX), while control group had sham surgery. Four weeks after the surgery, OVX rats were treated with saline, melatonin (25 μg/mL/d), alendronate (70 μg/kg/wk), melatonin + alendronate, melatonin + melatonin receptor antagonist (luzindole, 10 μg/kg/d) or alendronate + melatonin + luzindole for 8 weeks. Rats were euthanized at the end of 12th week. Runx2 expression, apoptotic cells, and trabecular thickness were evaluated in tibiae, while gastric tissues were analysed for oxidative injury parameters. In all OVX groups, Runx2 expression was depressed. Saline-treated OVX group presented an extreme decrease in calcified area in opposition to melatonin-or alendronate-treated groups, while the bones in alendronate + melatonin-treated group were similar to those of the sham-operated group. Concomitant with the improvements examined histologically in bone tissues, quantitative TUNEL (+) cells were similarly lower in alendronate-or melatonin-treated groups. Oxidative gastric damage was increased in saline-or alendronate-treated groups, which were depressed in the presence of melatonin. Although melatonin and alendronate exerted similar supportive effects on the maintenance of bone mass, melatonin may have a more advantageous impact by protecting against OVX-induced gastric injury, which was aggravated by alendronate use. Highlights:Our results demonstrate that alendronate and melatonin had similar supportive effects on the maintenance of bone mass, while melatonin prevented the gastric side effects of alendronate, making this combination an advisable therapeutic approach in the treatment of menopausal osteoporosis.

Identification of a novel melatonin‐binding nuclear receptor: Vitamin D receptor

“…Melatonin positively regulates Runx2 in many cells and tissues, such as osteogenic and chondrogenic differentiation of human MSCs, osteoblastic differentiation of MSCs from rats, co‐culture models (transwell or layered) of human MSCs and peripheral blood monocytes, human osteosarcoma‐derived Saos2 cells, human periodontal ligament cells and cementoblasts, osteogenic potential of platelet‐rich plasma in dental stem‐cell cultures, the differentiation of mouse osteoblastic MC3T3‐E1 cells, primary bone marrow MSCs from ovariectomized mice, bovine ovarian granulosa cells, a blind mouse model (MMTV‐Neu transgenic mice), and pinealectomized or ovariectomized rats. Our study further confirmed that there was no direct interaction between melatonin and Runx2 although melatonin directly penetrates cytomembrane and enters the cell nucleus where it could bind to Runx2.…”

Myrtus communisleaf extract protects against cerulein‐induced acute pancreatitis in rats

“…Previous clinical (Gullo et al, 1996;Warshaw & O'Hara, 1978) and experimental animal studies (Ceranowicz et al, 2015;Dembiński et al, 2001;Vollmar & Menger, 2003;Waldner, 1992) pro-inflammatory cytokines (Gress, Arnold, & Adler, 1990;Kusterer, Enghofer, Zendler, Blochle, & Usadel, 1991;Tomkötter et al, 2016;Vollmar & Menger, 2003). The increase in MPO activity shows widespread inflammation in many inflammation models, including AP (Gurler et al, 2019;Ozgul et al, 2019;Sen et al, 2016). It is well-known that leukocyte recruitment within the inflamed pancreas begins in the early phase of AP (Escobar et al, 2009).…”

“…It is well-known that leukocyte recruitment within the inflamed pancreas begins in the early phase of AP (Escobar et al, 2009). The increase in MPO activity shows widespread inflammation in many inflammation models, including AP (Gurler et al, 2019;Ozgul et al, 2019;Sen et al, 2016). This increase in enzyme activity causes the formation of oxidant molecules by neutrophils and initiates oxidant damage.…”

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis

“…New treatment strategies for osteoporosis are therefore needed that are as effective or more so, with the ability to promote bone formation without the side effects of existing medications. Promisingly, the combination of melatonin with the bisphosphonate alendronate in OVX rats was associated with much less severe gastric damage than in OVX rats treated with alendronate alone [37]. Moreover, histological analyses of trabecular bone sections from the melatonin + alendronate group revealed similar bone matrix and architecture to that in the sham-operated controls, while the alendronate-or melatonin-treated rats had similar increases in trabecular thickness and reductions in apoptotic cells [37].…”

“…Promisingly, the combination of melatonin with the bisphosphonate alendronate in OVX rats was associated with much less severe gastric damage than in OVX rats treated with alendronate alone [37]. Moreover, histological analyses of trabecular bone sections from the melatonin + alendronate group revealed similar bone matrix and architecture to that in the sham-operated controls, while the alendronate-or melatonin-treated rats had similar increases in trabecular thickness and reductions in apoptotic cells [37]. Thus, melatonin protected against OVX-induced gastric injury that was worsened by alendronate and melatonin provided similar supportive effects to those of alendronate concerning preservation of bone mass.…”