Elsevier

Bone

Volume 47, Issue 1, July 2010, Pages 5-11
Bone

Rapid Communication
Telmisartan alleviates rosiglitazone-induced bone loss in ovariectomized spontaneous hypertensive rats

https://doi.org/10.1016/j.bone.2010.03.016Get rights and content

Abstract

In the present study, we systematically examined telmisartan, an angiotensin AT1 receptor antagonist, on rosiglitazone-induced bone loss in ovariectomized spontaneously hypertensive rats. Telmisartan (5 mg/kg/d, 90 days) was found to be able to significantly alleviate rosiglitazone (10 mg/kg/d, 90 days)-induced decrease in BMD of femur and lumbar vertebrae. The BMD changes were associated with positive biomechanical changes of lumbar vertebrae, improvements in microarchitecture of tibial metaphysic and normalized serum osteocalcin (OC) levels and urinary deoxypyridinoline/creatinine (DPD/Cr) ratio. MicroCT analysis of the tibial metaphysis showed that telmisartan significantly prevented the decreases in bone volume/tissue volume (BV/TV), connect density (Conn. D.), trabecular number (Tb. N.) and trabecular thickness (Tb. Th.), and increase in trabecular separation (Tb. Sp.) induced by rosiglitazone. Histomorphometric analysis also showed that telmisartan had protective effects on rosiglitazone-reduced bone formation indices such as histomorphometric bone volume fraction (BV/TV-Histo), mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS). Our study clearly showed that telmisartan alleviated rosiglitazone-induced bone loss in ovariectomized spontaneous hypertensive rats. The relief of bone loss provides a possible therapeutic application of telmisartan with rosiglitazone for the treatment of elderly women patients afflicted with metabolic syndrome.

Introduction

Glucose intolerance, hyperlipidemia, insulin resistance (Type II diabetes), hypertension and other closely related cardiovascular risk factors are common features of the metabolic syndrome, a condition with rising prevalence in western countries [1], [2], [3]. Rosiglitazone (ROS), a thiazolidinedione (TZD) compound, is often used in clinic for its powerful insulin-sensitizing effects. However, evidence is mounting to link significant bone loss or factures with its use [4], [5], [6], [7], [8], especially in postmenopausal women [9]. Angiotensin AT1 receptor antagonists (sartans), drugs commonly used for the control of hypertension, are often co-administrated with TZDs to treat metabolic syndrome. Furthermore, recent advances on the role of angiotensin II in bone metabolism have revealed blockage of Ang II might be a novel therapeutic approach to prevent bone loss in hypertensive patients [10]. And this raises the intriguing possibility that sartans, when prescribed together with rosiglitazone in patients with metabolic syndrome, might prevent or attenuate rosiglitazone-induced bone loss.

Spontaneously hypertensive rats (SHR), the most widely used model for human essential hypertension, which also expresses the insulin resistance phenotypes [11], had been used as an experimental model to understand the pathological conditions of metabolic syndrome [11], [12], [13]. Ovariectomized spontaneously hypertensive rats were used in our study to mimic human metabolic syndrome with estrogen withdrawal.

Among angiotensin AT1 receptor antagonists (sartans), telmisartan was noted for its unique favorable effects on carbohydrate and lipid metabolism [14], [15], [16], [17]. Hydralazine is a vasodilator used to treat hypertension, congestive heart failure, myocardial infarction, and preeclampsia [18]. To rule out blood pressure as a cofounding factor in our experiment this drug was used as a reference drug. In the present study, we systematically examined telmisartan and hydralazine, on rosiglitazone-induced bone loss in ovariectomized spontaneously hypertensive rats. And indeed, in this model, although equally effective in reducing blood pressure, telmisartan (5 mg/kg/d, 90 days) but not hydralazine (10 mg/kg, 90 days) was able to significantly alleviate ROS (10 mg/kg/d, 90 days)-induced decrease in BMD of femur and lumbar vertebrae. The BMD changes were associated with positive biomechanical changes of lumbar vertebrae, improvements in microarchitecture of tibial metaphysic and normalized serum osteocalcin (OC) levels and urinary DPD/Cr ratio.

Section snippets

Animal experiment

Thirty-two 10-week-old female SHRs weighting 160–190 g were obtained from Vital River (Beijing, China). Rats were housed in standard cages (4 rats per cage) and they were maintained at 25 ± 1 °C and constant humidity (60%) with a 12 h light:12 h dark cycle. The animals were allowed free access to water and standard pellet diet. Animal care and treatment were conducted in accordance with the institutional guidelines.

Animals were allowed to acclimate for at least 8 days before the experiment and then

Body weight, heart rate and systolic blood pressure

Fig. 1A shows body weights of the rats in each group. As expected, the rats given ROS alone significantly increased their body weights by 19.6% (P < 0.01 vs. vehicle control) at the end of the study. However,the excess weight gain induced by ROS was significantly attenuated by TEL (−14.7%, P < 0.05 vs. ROS alone group). The systolic blood pressure measured by the tail-cuff method is shown in Fig. 1B. ROS lowered the systolic blood pressure of rats by 11.3% (P < 0.05 vs. vehicle control) but did not

Discussion

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type II diabetes since 1997. Currently, pioglitazone and rosiglitazone are the only compounds licensed for patients with insulin resistance or type II diabetes. TZDs can be used as monotherapy for blood glucose control or in combination with other agents for the treatment metabolic syndrome. Despite their powerful insulin-sensitizing effects and additional beneficial effects on cardiovascular risk factor, a number

Acknowledgments

This work was supported in part by the China National Science Foundation (Project NO. 30801424/c180112).

References (34)

  • C.E. Quinn et al.

    Thiazolidinediones: effects on insulin resistance and the cardiovascular system

    Br J Pharmacol

    (2008)
  • S.O. Rzonca et al.

    Bone is a target for the antidiabetic compound rosiglitazone

    Endocrinology

    (2004)
  • S. Yaturu et al.

    Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men

    Diab Care

    (2007)
  • A.V. Schwartz et al.

    Thiazolidinedione therapy gets complicated: is bone loss the price of improved insulin resistance?

    Diab Care

    (2007)
  • H. Shimizu et al.

    Angiotensin II accelerates osteoporosis by activating osteoclasts

    FASEB J

    (2008)
  • T. Gotoda et al.

    Absence of Cd36 mutation in the original spontaneously hypertensive rats with insulin resistance

    Nat Genet

    (1999)
  • G.M. Reaven et al.

    Resistance to insulin-stimulated glucose uptake in adipocytes isolated from spontaneously hypertensive rats

    Diabetes

    (1989)
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