Low dose beta‐blocker prevents ovariectomy‐induced bone loss in rats without affecting heart functions

Abstract

Findings from animal studies have suggested that bone remodeling is under beta-adrenergic control. However, the level of adrenergic inhibition required to achieve the most favorable effects on the skeleton remains unknown. To address this question, we compared the effects of low (0.1 mg/Kg/day), medium (5 mg/Kg/day) or high (20 mg/Kg/day) doses of propranolol given 5 days per week for 10 weeks in ovariectomized (OVX) rats. Characteristics of bone microarchitecture, biomechanical properties and bone turnover were investigated, whilst heart functions were assessed by echocardiography and catheterization of the left ventricle. We first confirmed the expression of Adrbeta2R and the absence of Adrbeta1R on osteoblasts by PCR and confocal microscopy. We then showed that low dose propranolol prevented OVX induced bone loss by increasing bone formation (+30% of MAR vs. placebo, P = 0.01) and decreasing bone resorption (-52% of osteoclast surface on bone surface vs. placebo, P = 0.01). Consequently, rats receiving 0.1 mg/kg/day propranolol displayed higher stress (+27%), intrinsic energy (+28.7%) and Young's Modulus in compression versus placebo (all, P < 0.05). No significant effects on heart hemodynamic parameters were found in rats receiving this dose. In contrast, medium and high doses of propranolol had a negative effect on heart functions but no significant protective effects on bone mass in ovariectomized rats. These results, consistent with the dominant nature of the high bone mass phenotype and normal heart function of Adrbeta2R-deficient mice, suggest that low doses of beta-blockers may have a therapeutic utility in the treatment of osteoporosis with high selectivity for bone tissues.

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

“…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). The effect of the lowest dose was consistent with the early observation of Minkowitz et al [24] and subsequent studies of Bonnet et al [3,4]. There was an attenuated antiosteoporotic effect of propranolol at 10 mg/kg/day po compared to 0.1 and 1 mg/kg/day po in spontaneously hypertensive rats; however, no deleterious effect of propranolol at 50 and 100 mg/kg/day po on the trabecular microarchitecture of bones was reported [31].…”

Double disruption of α2A- and α2C -adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype

“…1C, D). Since there is evidence that the growth hormone (GH)/IGF-1 axis may mediate the adrenergic signaling in bone and could account for the longer bones, (13,36) we measured serum levels of IGF-1. However, there were no differences between KO and WT mice (Fig.…”

Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

“…61 Treatment with the low-dose agonist isoprenaline, a nonspecific beta-AR agonist, induced bone loss mainly via enhanced bone resorption in mice, 64 whereas lowdose propanolol, a non-selective BB, increased bone formation in a rat model. 65 In humans, the potential role of BB in osteoporosis has largely been based on retrospective database analysis. A large, registry-based, case-control study from the UK, which included 30,601 case subjects (defined as such with any incident fracture) and 120,819 appropriately matched controls, provided evidence that use of BB is associated with a reduced risk of fractures, either alone (OR: 0.77, CI 0.72-0.83) or in combination with thiazide diuretics.…”