Combined treatment with a beta-blocker and intermittent PTH improves bone mass and microarchitecture in ovariectomized mice.
Intermittent administration of parathyroid hormone (PTH) induces bone remodeling and renewed bone modeling, resulting in net bone gain. beta-blockers improve trabecular bone architecture in young ovariectomized mice by preventing the inhibition of bone formation and stimulation of bone resorption induced by the adrenergic system. To test the hypothesis that PTH and beta-blockers may exert synergistic effects on the skeleton, 15-week-old ovariectomized mice were either given oral propranolol (PRO) or left untreated for 8 weeks, adding daily hPTH(1-34) (80 microg/kg/day) or vehicle (VEH) during the last 4 weeks. The skeletal response was evaluated using pDXA, microCT, histomorphometry and biochemical markers. PRO significantly attenuated loss of bone mineral density (BMD) at whole body (WB) (-0.1% in PRO vs. -2.4% in VEH, P < 0.05), but not at spine or femur 4 weeks after OVX. Thereafter, PTH increased BMD at all sites in both PRO- and VEH-treated mice (+6.7% to +14%, P < 0.05 to P < 0.0001 vs. VEH). Over 8 weeks, sequential-combined treatment of PRO and PTH significantly improved BMD over PTH alone at WB (+9.1% vs. +4.4% over baseline, respectively, P < 0.005) and spine (+9% vs. -1.7%, respectively, P < 0.05). These effects were paralleled by a decrease in TRACP5b with PRO (P < 0.05 vs. VEH) and an increase in osteocalcin with PTH, irrespective of PRO (P < 0.0001 vs. VEH). Trabecular bone microarchitecture, such as BV/TV, trabecular number and ConnD, was significantly improved by sequential-combined treatment of PRO and PTH compared to PTH alone. At midshaft femur, both PRO and PTH significantly increased cross-sectional area (CSA), but the effects of the two drugs on CSA and cortical thickness were not additive. Dynamic histomorphometry indicated that bone formation was increased by PTH at both cortical and trabecular surfaces, whereas PRO increased osteoblast number and surface on trabecular surfaces. The combined treatment further improved the extent of mineralization and BFR over PTH alone (P < 0.05) at endocortical surfaces and recapitulated the effects of PTH and PRO alone on trabecular surfaces. These results indicate that beta-adrenergic blockade may partially improve the bone remodeling balance induced by estrogen deficiency. In turn, PRO exerted synergistic effects with intermittent PTH on bone mass and cancellous bone architecture. As such, combined therapy of beta-blockers and PTH may be of interest in the treatment of postmenopausal osteoporosis.
Service of Bone Diseases, WHO Collaborating Center for Osteoporosis Prevention, Department of Rehabilitation and Geriatrics, Geneva University Hospital, HUGs, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland.
Dominique D
DD
Pierroz
Mary L
ML
Bouxsein
René
R
Rizzoli
Serge L
SL
Ferrari
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005269:Femur / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology*; D011897:Random Allocation; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; C470125:PTH protein, human; D010281:Parathyroid Hormone; D011433:Propranolol