Elsevier

Nutrition

Volume 29, Issue 3, March 2013, Pages 556-561
Nutrition

Basic nutritional investigation
Can 2-oxoglutarate prevent changes in bone evoked by omeprazole?

https://doi.org/10.1016/j.nut.2012.07.014Get rights and content

Abstract

Objective

Proton-pump inhibitors, such as omeprazole, are widely used in the prevention and treatment of gastroesophageal diseases. However, an association between proton-pump inhibitors and the increased risk of bone fractures has been observed, especially in patients treated for extended periods. Conversely, 2-oxoglutarate, a precursor of hydroxyproline, the most abundant amino acid in bone collagen, counteracts the bone loss. The aim of the present study was to elucidate the influence of omeprazole on bone and investigate whether dietary 2-oxoglutarate supplementation could prevent the effects of omeprazole.

Methods

Eighteen male Sprague-Dawley rats were used. Rats received omeprazole in the diet and 2-oxoglutarate in the drinking water. Body and organ weights and serum concentrations of cholecystokinin and gastrin were measured. The femurs, tibias, and calvarias were collected. Histomorphometric analysis of bone and cartilage tissues was conducted. Bone densitometric and peripheral quantitative computed tomographic analyses of the femur and tibia were performed.

Results

Omeprazole decreased the femur and tibia weights, the mechanical properties of the femur, the volumetric bone density and content, the trabecular and cortical bone mineral content, the total, trabecular, and cortical bone areas, the mean cortical thickness, and the periosteal circumference of the femur. Omeprazole had a minor effect on the examined bone morphology and exerted negligible effects on the cartilage. 2-Oxoglutarate lowered the gastrin concentration.

Conclusions

Omeprazole treatment exerts its effects mostly on bone mineralization and cancellous bone, adversely affecting bone properties. This adverse effect of omeprazole was not markedly abolished by 2-oxoglutaric acid, which acted as an anti-hypergastrinemic agent.

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

References (47)

  • M.T. Fox et al.

    Effects of Ostertagia ostertagi and omeprazole treatment on feed intake and gastrin-related responses in the calf

    Vet Parasitol

    (2002)
  • C. Roux et al.

    Increase in vertebral fracture risk in postmenopausal women using omeprazole

    Calcif Tissue Int

    (2009)
  • F. De Vries et al.

    Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates

    Osteoporos Int

    (2009)
  • T. Ito et al.

    Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium

    Curr Gastroenterol Rep

    (2010)
  • L.E. Targownik et al.

    Use of proton pump inhibitors and risk of osteoporosis-related fractures

    CMAJ

    (2008)
  • Y.X. Yang et al.

    Long-term proton pump inhibitor therapy and risk of hip fracture

    JAMA

    (2006)
  • P. Vestergaard et al.

    Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture

    Calcif Tissue Int

    (2006)
  • E.W. Yu et al.

    Acid-suppressive medications and risk of bone loss and fracture in older adults

    Calcif Tissue Int

    (2008)
  • S.L. Gray et al.

    Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women

    Arch Intern Med

    (2010)
  • H. Zojaji et al.

    Effect of omeprazole on bone mineral density and frequency of osteopenia and osteoporosis

    Gastroenterol Hepatol

    (2008)
  • G.L. Cui et al.

    Long-term omeprazole treatment suppresses body weight gain and bone mineralization in young male rats

    Scand J Gastroenterol

    (2001)
  • P. Dobrowolski et al.

    Dietary α-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats

    Scand J Gastroenterol

    (2008)
  • R.P. Radzki et al.

    The effect of alpha-ketoglutarate (AKG) on mineralization of femur in ovariectomized rats

    Acta Orthop Scand

    (2002)
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