Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions.
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.
Bonnet
N
N
INSERM U658, CTI (Caractérisation du tissu osseux par imagerie, techniques et applications), Université d'Orléans, Orleans, France. nicolas.bonnet15@wanadoo.fr
Benhamou
C L
CL
Malaval
L
L
Goncalves
C
C
Vico
L
L
Eder
V
V
Pichon
C
C
Courteix
D
D
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena; D001794:Blood Pressure / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005260:Female; D005269:Femur / Q000187:drug effects / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D018613:Microscopy, Confocal; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D011433:Propranolol / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013131:Spine / Q000187:drug effects / Q000503:physiopathology; D013977:Tibia / Q000187:drug effects / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D011433:Propranolol