Basic nutritional investigationCan 2-oxoglutarate prevent changes in bone evoked by omeprazole?
Introduction
Proton-pump inhibitors (PPIs) are one of the most widely used classes of drugs and are taken by millions of patients for the prevention and treatment of gastroesophageal diseases; however, this treatment has been associated with hypergastrinemia [1], [2], [3]. Many patients take PPIs for extended periods; thus, the potential long-term adverse effects of these PPIs are receiving increasing attention [3], [4]. An association between acid suppressants and increased hip, spine, and any-site fractures risk has been found in previous studies [2], [5], [6], [7], [8]. Moreover, long-term exposure to PPIs has been found to be associated with osteoporosis-related fractures and the highest risk has been in those patients receiving high-dose PPI therapy [4], [5]. Some studies have shown a relation between PPI use and increased fracture risk, indicating possible additional risk factors such as age, calcium deficiency, dose dependency, specific fracture point, or risk of osteoporosis [2], [9], [10], [11]. However, potential mechanisms for the increased risk of fracture observed are still unexplained [2], [12].
Omeprazole is one of the most frequently prescribed acid-suppressive medications and its administration is one of the standard protocols for the treatment of acid-related disorders such as gastroesophageal reflux disease, laryngopharyngeal reflux, peptic ulcer disease, Zollinger–Ellison syndrome, and idiopathic hypersecretion. This drug also has been successfully administered for the eradication of Helicobacter pylori infection and the treatment of upper gastrointestinal bleeding [1], [2], [13], [14]. Omeprazole treatment has also been associated with an increased risk of vertebral fracture in postmenopausal women and in patients with hypergastrinemia [1], [2], [15].
There is preliminary evidence to show that the dietary supplementation of 2-oxoglutarate (2-Ox) counteracts the bone loss observed in ovariectomized or gastrectomized rats and in postmenopausal women [16], [17], [18]. 2-Ox is a precursor of glutamine that serves as an oxidative fuel for rapidly dividing cells such as lymphocytes and fibroblasts [19], [20], [21]. Glutamine plays an important role in the interorgan flow of nitrogen (in ammonia genesis) and carbon between carbohydrates and proteins [20]. Furthermore, the main components of collagen, such as hydroxyproline and proline, are synthesized in the gastrointestinal tract from 2-Ox [22].
The lack of knowledge concerning the effect of 2-Ox on osteoporosis evoked by omeprazole-induced hypergastrinemia was considered in undertaking this study. There is a need to investigate the problem of the widespread use of PPIs and its consequences for health and its side effects on the skeletal system.
Considering previous studies, it was hypothesized that the oral administration of 2-Ox would induce positive effects on bone metabolism, which has been observed previously in rats and pigs [16], [17], [23]. Because of the basal physiology and similarities in bone formation and remodeling between rats and humans, rats are an appropriate model for the research on bone diseases [24]. For these reasons, it was speculated that the oral supplementation of 2-Ox might also prevent the bone loss that follows omeprazole-induced hypergastrinemia, and this research was carried out to test this hypothesis.
Section snippets
Experimental design and laboratory animals
Eighteen 7-wk-old male Sprague-Dawley rats (120–150 g) were used in the study. The rats were clinically healthy and housed in Macrolon cages (one rat per cage) (Bioscape, Emmendingen, Germany) under standard laboratory conditions (controlled temperature, humidity, and 12-h photoperiod), with free access to water and solid food. The rats were fed a diet of standard feed pellets (Lactamin, Vadstena, Sweden). The feed composition was based on the nutrient requirements of laboratory animals [25].
Bone and selected organ weight and bone length
Omeprazole significantly decrease the relative weights of the two analyzed bones in the O group (femur 2.94 ± 0.16 g/kg BW, P = 0.030; tibia 2.12 ± 0.12 g/kg BW, P = 0.049) and the OA group (femur 2.80 ± 0.17 g/kg BW, P = 0.030; tibia 1.95 ± 0.13 g/kg BW, P = 0.017) compared with the C group (femur 3.42 ± 0.20 g/kg BW, tibia 2.50 ± 0.17 g/kg BW). The livers of animals in the O group (38.23 ± 1.87 g/kg BW) were heavier (P = 0.034) than those in the OA group (34.58 ± 2.68 g/kg BW). The relative
Discussion
The present study examined the influence of omeprazole, one of the most popular acid-suppressive medications, on the mechanical, geometric, and morphologic properties of long bones in a rat model. According to recent data on PPI use and the related risk of bone loss and fracture, we investigated the effects of omeprazole on bone architecture. Some previous studies have observed an increased fracture risk associated with PPI use, whereas other, more recent studies have not detected a clear
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