Effects of the Phosphodiesterase-5 (PDE-5) Inhibitors, Avanafil and Zaprinast, on Bone Remodeling and Oxidative Damage in a Rat Model of Glucocorticoid-Induced Osteoporosis

Abstract

Background: The aim of this study was to evaluate the effects of the phosphodiesterase-5 (PDE-5) inhibitors, zaprinast and avanafil, on NO signalling pathway, bone mineral density (BMD), epiphyseal bone width, bone marrow angiogenesis, and parameters of oxidative stress in a rat model of glucocorticoid-induced osteoporosis (GIOP).

Material/Methods: Twenty-four 8-month-old male rats in four groups were given a single daily treatment during a 30-day period: an (untreated) control group (n=6): a dexamethasone-treated group (120 μ/kg) (n=6); a group treated with dexamethasone (120 μ/kg) and zaprinast (10 mg/kg) (n=6): and a group treated with dexamethasone (120 μ/kg) and avanafil (10 mg/kg) (n=6). Rat whole body bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA), and bone histology was performed. Also, selected oxidative stress parameters by HPLC method and the other biochemical parameters by ELISA method were measured.

Results: The GIOP model rats treated with zaprinast and avanafil showed a significant increase in NO, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) (NO/cGMP/PKG) signaling-pathway components, and in C-terminal telopeptide of type I collagen (CTX-1), bone marrow angiogenesis, BMD, and epiphyseal bone width, compared with the (untreated) control rats (p<0.05). Levels of pyridinoline (PD) and deoxypyridinoline (DPD) were significantly reduced in the dexamethasone + zaprinast, and dexamethasone + avanafil treatment groups (p<0.05). Malondialdehyde (MDA), ubiquinone-10 (CoQ10), ubiquinol CoQ10 (CoQ10H), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were significantly increased in the dexamethasone-treated group, compared with the (untreated) controls (p<0.05).

Conclusions: In the GIOP rat model, markers of oxidative stress and bone atrophy were significantly reduced by treatment with the PDE-5 inhibitors, zaprinast and avanafil.

Keywords: Bone Density; Dexamethasone; Osteoporosis; Phosphodiesterase 5 Inhibitors.

Figure 1

Photomicrographs of new vessel formation (angiogenesis) in the bone marrow of the right femur in the rat model of glucocorticoid-induced osteoporosis (GIOP) treated with dexamethasone or the phosphodiesterase-5 (PDE-5) inhibitors, avanafil and zaprinast. (A) The control (untreated) group. (B) The dexamethasone-treated group. (C) The dexamethasone + zaprinast-treated group. (D) The dexamethasone + avanafil-treated group. The histological tissue sections viewed by light show new vessel formation. Scale bar: 20 μm. Hematoxylin and eosin (H&E).

Figure 2

Images showing the bone mineral density (BMD) of the right femoral head in rats with glucocorticoid-induced osteoporosis (GIOP). (A) The control (untreated) group. (B) The dexamethasone-treated group. (C) The dexamethasone + zaprinast-treated group. (D) The dexamethasone + avanafil-treated group. The channels indicate mineral deposits. Scale bar: 100 μm.

Figure 3

Images showing the right femur epiphyseal bone width in rats with glucocorticoid-induced osteoporosis (GIOP). (A) The control (untreated) group. (B) The dexamethasone-treated group. (C) The dexamethasone + zaprinast-treated group. (D) The dexamethasone + avanafil-treated group. The area or distance between of the two arrows indicates the epiphyseal area (bone growth plate). Scale bar: 50 μm.

Figure 4

Comparison of bone mineral density, pyridinoline (PD), and deoxypyridinoline (DPD) values before and after treatment with dexamethasone and the phosphodiesterase-5 (PDE-5) inhibitors, avanafil and zaprinast. (A) The radiologically measured values of bone mineral density (BMD) (g/cm²). (B) Urine pyridinoline (PD) values (nmol/mL). (C) Urine deoxypyridinoline (DPD) values (nmol/mL). * p<0.05: when compared with the control group after the administration of dexamethasone and the phosphodiesterase-5 (PDE-5) inhibitor. ^# p<0.05: when compared with the other groups after the administration of dexamethasone and the phosphodiesterase-5 (PDE-5) inhibitor. ^@ p<0.05: when compared with the administration of dexamethasone and the phosphodiesterase-5 (PDE-5) inhibitor in the same group. ^a p<0.05: when compared with the other groups before the administration of dexamethasone and the PDE-5 inhibitor in the same group.