Combined treatment with a β-blocker and intermittent PTH improves bone mass and microarchitecture in ovariectomized mice
Combined treatment with a β-blocker and intermittent PTH improves bone mass and microarchitecture in ovariectomized mice
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DOI：
10.1016/j.bone.2006.01.145
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发表时间：
2006-08-01
期刊：
影响因子：
4.1
通讯作者：
Ferrari, Serge L.
中科院分区：
文献类型：
--
作者：
Pierroz, Dominique D.;Bouxsein, Mary L.;Ferrari, Serge L.
甲状旁腺激素（PTH）间歇性给药可诱导骨重建和新的骨塑形，从而使骨量净增加。β - 受体阻滞剂通过防止肾上腺素能系统对骨形成的抑制和对骨吸收的刺激，改善年轻卵巢切除小鼠的骨小梁结构。为了验证PTH和β - 受体阻滞剂可能对骨骼产生协同作用这一假设，15周龄的卵巢切除小鼠要么口服普萘洛尔（PRO），要么不进行处理，持续8周，并在最后4周每天添加人PTH（1 - 34）（80μg/kg/天）或赋形剂（VEH）。使用外周双能X线吸收法（pDXA）、微计算机断层扫描（μCT）、组织形态计量学和生化标志物评估骨骼反应。卵巢切除术后4周，普萘洛尔显著减轻了全身（WB）骨矿物质密度（BMD）的损失（PRO组为 - 0.1%，VEH组为 - 2.4%，P < 0.05），但在脊柱或股骨处没有。此后，PTH使PRO组和VEH组小鼠所有部位的BMD均增加（与VEH组相比，增加6.7%至14%，P < 0.05至P < 0.0001）。在8周内，普萘洛尔和PTH序贯联合治疗使全身（与基线相比分别为 + 9.1%和 + 4.4%，P < 0.005）和脊柱（分别为 + 9%和 - 1.7%，P < 0.05）的BMD显著高于单独使用PTH。这些效应伴随着普萘洛尔使抗酒石酸酸性磷酸酶5b（TRACP5b）降低（与VEH组相比，P < 0.05）以及PTH使骨钙素增加，与普萘洛尔无关（与VEH组相比，P < 0.0001）。与单独使用PTH相比，普萘洛尔和PTH序贯联合治疗显著改善了骨小梁微观结构，如骨体积分数（BV/TV）、骨小梁数量和连接密度（ConnD）。在股骨中段，普萘洛尔和PTH均显著增加了横截面积（CSA），但两种药物对CSA和皮质厚度的影响没有叠加性。动态组织形态计量学表明，PTH增加了皮质和骨小梁表面的骨形成，而普萘洛尔增加了骨小梁表面的成骨细胞数量和面积。联合治疗进一步提高了内皮质表面的矿化程度和骨形成率（与单独使用PTH相比，P < 0.05），并重现了单独使用PTH和普萘洛尔对骨小梁表面的影响。这些结果表明，β - 肾上腺素能阻断可能部分改善雌激素缺乏引起的骨重建平衡。反过来，普萘洛尔与间歇性PTH对骨量和松质骨结构产生协同作用。因此，β - 受体阻滞剂和PTH的联合治疗可能对绝经后骨质疏松症的治疗有意义。（c）2006爱思唯尔公司。保留所有权利。
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 mu g/kg/day) or vehicle (VEH) during the last 4 weeks. The skeletal response was evaluated using pDXA, mu CT, 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. (c) 2006 Elsevier Inc. All rights reserved.