Dose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats

Abstract

Animal studies suggest that bone remodeling is under ␤-adrenergic control via the sympathetic nervous system. The purpose of this study was to examine the preventive effect of different doses of nonspecific ␤-blockers (propranolol) on trabecular and cortical bone envelopes in ovariectomized rats. Six-month-old female Wistar rats were ovariectomized (OVX, n ϭ 60) or shamoperated (n ϭ 15). Then, OVX rats were subcutaneously injected with 0.1 (n ϭ 15), 5 (n ϭ 15), or 20 (n ϭ 15) mg/kg propranolol or vehicle (n ϭ 15) for 10 weeks. Tibial and femoral bone mineral density (BMD) were analyzed longitudinally by dual-energy X-ray absorptiometry. At death, the left tibial metaphysis and L 4 vertebrae were removed, and microcomputed tomography (Skyscan 1072; Skyscan, Aartselaar, Belgium) was performed for trabecular bone structure investigation. Histomorphometry analysis was performed on the right proximal tibia to assess bone cell activities. After 10 weeks, OVX rats had decreased BMD and trabecular parameters and increased bone turnover, as well as cortical porosity compared with the sham group (p Ͻ 0.001). Bone architecture alteration was preserved by 0.1 mg/kg propranolol due to higher trabecular number and thickness (ϩ50.35 and ϩ6.81%, respectively, than OVX; p Ͻ 0.001) and lower cortical pore number (Ϫ52.38% than OVX; p Ͻ 0.001). Animals treated by 0.1 mg/kg propranolol had a lower osteoclast surface and a higher osteoblast activity compared with OVX. Animals treated by 20 mg of propranolol did not significantly differ from OVX rats. Animals treated by 5 mg of propranolol have been partially preserved from the ovariectomy. These results showed a dose effect of ␤-blockers. The lower the dose of propranolol breeding, the better the preventive effect against ovariectomy.

Effects of Propranolol on Bone Metabolism in Spontaneously Hypertensive Rats

“…These results were consistent with the report of Bonnet et al (2006) demonstrating that OVX-induced bone loss was prevented by treatment with PRO at 0.1 and 5 mg/kg s.c. for 10 weeks, but not at 20 mg/kg. OVX rats are a well known high-turnover model for postmenopausal osteoporosis (Wronski et al, 1988).…”

“…In the literature, the antiosteoporotic effect of PRO was demonstrated recently in OVX rats treated with PRO at low doses (0.1-5 mg/kg/day) subcutaneously (Bonnet et al, 2006(Bonnet et al, , 2008, whereas the hypotensive effect of PRO was demonstrated previously in SHR treated orally with high-dose PRO (30 -100 mg/kg/day) (Takeda and Buñ ag, 1980;Antonaccio et al, 1986), suggesting that relatively low doses of PRO were adequate for antiosteoporotic action and high doses were adequate for antihypertensive action in rats. Therefore, we examined in experiment 1 the effects of PRO at a wide range of doses (1, 5, 50, and 100 mg/kg) on blood pressure and bone mass in SHR.…”

“…Epidemiological studies have demonstrated that high blood pressure was associated with increased bone loss at the femoral neck and low bone mineral density, and ␤-blockers are potential candidates of therapeutic drugs for osteoporosis and fracture healing (Cappuccio et al, 1999;Pasco et al, 2004;Schlienger et al, 2004;Graham et al, 2008). In the animal study, a lower dose of propranolol (PRO), a nonselective ␤-blocker with membrane-stabilizing action, has been shown to increase bone mass in ovariectomized (OVX) rats (Bonnet et al, 2006(Bonnet et al, , 2008; however, conflicting evidence about the antiosteoporotic effects of ␤-blockers has been also reported. Rejnmark et al (2004) showed in a small group study no differences in bone mineral density between ␤-blocker users and nonusers, and that the fracture risk was increased in subjects treated with ␤-blockers compared with the nonuser group.…”

Effects of propranolol on the development of glucocorticoid-induced osteoporosis in male rats

“…The reasons for the damaging skeletal effects of the b-adrenergic blockade can only be speculated. Bonnet et al [6] observed that the effect of propranolol on the skeletal system of ovariectomized rats depended on the dose used. The best results in counteracting the development of osteoporosis were demonstrated after administration of a very low dose (0.1 mg/kg, sc); there was a weaker effect with 5 mg/kg, sc and practically no effect with the highest dose (20 mg/kg, sc).…”

“…It was demonstrated that activation of b -adrenergic receptors in osteoblasts and stromal cells leads to the inhibition of bone formation and intensification of bone resorption [36,37]. Propranolol, a nonselective b-receptor antagonist, was reported to be effective in counteracting bone damage in different experimental models of bone disorders [1,6,22,31,34,35,42]. Results of some, but not all, human studies [5, 12, 23, 27-30, 32, 41] confirm the hypothesis that b-blockers may decrease the fracture rate.…”