Original research article
Effect of glimepiride on the skeletal system of ovariectomized and non-ovariectomized rats

https://doi.org/10.1016/j.pharep.2013.12.013Get rights and content

Abstract

Background

Diabetes mellitus type 2 and osteoporosis are major health problem, especially in postmenopausal women. Glimepiride is a third-generation sulfonylurea derivative and is used as a first-line drug in the treatment of type 2 diabetes mellitus. The effect of this drug on bone tissue is unknown. The aim of the present study was to investigate the influence of glimepiride on the skeletal system in ovariectomized and non-ovariectomized rats.

Methods

The experiment was conducted on 3-month-old female Wistar rats, divided into 4 groups (n = 10 per group): I (NOVX)–non-ovariectomized control rats, II (NOVX + G)–non-ovariectomized rats receiving glimepiride (0.8 mg/kg po), III (OVX)–ovariectomized control rats, IV (OVX + G)–ovariectomized rats receiving glimepiride (0.8 mg/kg po). Bilateral ovariectomy was performed 7 days before the start of the experiment, under ketamine-xylazine anesthesia. Glimepiride was administered once daily for 28 days. The effect of glimepiride on the skeletal system was assessed based on macrometric parameters, histomorphometric parameters and mechanical properties of the tibial metaphysis, femoral diaphysis and femoral neck. Bone mass, mineral mass, calcium and phosphorus content, as well as serum estrogen, osteocalcin and RatLaps levels were also studied.

Results

Estrogen deficiency in ovariectomized rats caused increased bone remodeling, with an intensification of bone resorption and formation, and mineralization impairment. Glimepiride in ovariectomized rats inhibited the development of changes in the skeletal system caused by estrogen deficiency, intensifying bone formation. In the presence of estrogens (in non-ovariectomized rats), glimepiride also intensified bone formation, but to a lesser extent.

Conclusions

Glimepiride, in the therapy of type 2 diabetes mellitus in postmenopausal women, may have a beneficial effect on bone remodeling and may reduce the risk of development of osteoporosis.

Introduction

Glimepiride is an oral antidiabetic drug, a third-generation sulfonylurea derivative, used in the treatment of type 2 diabetes mellitus. Hormonal and metabolic disturbances, noted in the course of type 2 diabetes mellitus, result in lesions that have the character of neuropathies, nephropathies, micro- and macroangiopathies, or retinopathies; they also predispose to more frequent occurrence of osteoporotic bone fractures [1], [2], [3], [4], [5]. Diabetes mellitus type 2 develops most often in people who are aged between 40 and 50 years, when, simultaneously, resorption prevails in the bone remodeling processes, which leads to the development of osteoporosis.

It has been demonstrated so far that bone tissue condition in patients suffering from type 2 diabetes mellitus is the result of factors that affect bone condition in a protective manner (body mass increase, hyperinsulinemia), factors that intensify bone resorption (insulin resistance, hyperglycemia, advanced glycation end products), as well as the influence of the pharmacological therapy [1], [6]. It is known that some oral antidiabetic drugs (in particular the derivatives of thiazolidinedione) may cause bone loss, and reduced bone mineral density, which is why they cannot be used safely in the treatment of diabetes, especially in postmenopausal women [7], [8].

The influence of glimepiride on bone tissue is poorly understood. So far, the experiments that have been conducted on cell cultures demonstrate beneficial effect of this drug on proliferation and differentiation of osteoblasts [9], [10].

The aim of this study was to examine the influence of glimepiride on the skeletal system in ovariectomized rats with estrogen deficiency, and in non-ovariectomized rats, with physiological estrogen levels.

Section snippets

Material and methods

The study concerning the influence of glimepiride on bone tissue was conducted, with the approval of Local Ethics Commission in Katowice on 40 sexually mature female Wistar rats, with an initial body weight of 200–250 g. In case of 20 female rats, the procedure of bilateral ovariectomy was conducted under general anesthesia with ketamine (Bioketan, Vetoquinol Biowet) at a dose of 35 mg/kg and xylazine (Rometar, Spofa) at a dose of 5 mg/kg, administered intraperitoneally (ip). Seven days after the

Body mass gain, uterus and thymus mass

In the group of bilaterally ovariectomized (OVX) rats, a statistically significant increase in the body mass, by 246.9%, reduction in the uterus mass, by 74.6%, as well as increase in the thymus mass, by 81.2%, in comparison with the results obtained in the group of non-ovariectomized control animals (NOVX) has been demonstrated (Table 1). Those results indicate the occurrence of estrogen deficiency in ovariectomized rats, and confirm the correct performance of the bilateral ovariectomy

Discussion

Bilateral ovariectomy causes similar changes in the rat skeletal system to those observed in postmenopausal women. Therefore bilateral ovariectomy in female rats has been accepted as an experimental model of postmenopausal osteoporosis, commonly used in pharmacological studies [17], [18], [19].

The results of this study confirmed that bilateral ovariectomy caused estrogen deficiency in the organism of animals, which was manifested by a significant reduction in the mass of the uterus/body mass

Conflict of interest

There is no current, or potential conflict of interest.

Funding

The study was supported by Medical University of Silesia in Katowice – grant KNW-1-044/D/1/0.

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