Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse
Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse
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DOI：
10.1152/japplphysiol.00632.2007
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Bateman, Ted A.
中科院分区：
文献类型：
--
作者：
Lloyd, Shane A. J.;Travis, Neil D.;Bateman, Ted A.
需要安全有效的应对太空飞行引起的骨质疏松症的措施，以减轻任务关键型骨折的可能性，并确保宇航员的长期骨骼健康。研究了两种抗骨吸收药物，双膦酸唑来膦酸（ZOL）和nf - κ B配体蛋白骨保护素（OPG）的抗受体激活剂，以找到最小的、可比较的剂量，从而最大限度地提高骨质量，同时最大限度地减少对骨转换和矿化的有害影响。通过对正常负荷的雌性小鼠（56只/次）进行5次试验，利用显微计算机断层扫描分析小梁体积分数和连连性，结合生物力学测试、定量组织形态学和成分分析，选择45 μ g/kg ZOL和500 μ g/kg OPG作为满足这些标准的剂量。然后通过后肢悬吊（HLS）检查这些剂量减轻短期卸骨后骨质流失的能力。72只小鼠预防性给予ZOL、OPG或PBS，并被分配到负荷对照组或2周HLS组（6组各n = 12）。两种抗吸收剂均能保持HLS小鼠的小梁微结构、股骨弹性和最大力（ZOL/OPG比PBS + 30-40%）。在HLS小鼠中，与PBS相比，抗吸收剂量使股骨皮质内表面的吸收周长减少30%。在负荷对照小鼠中，抗吸收剂对骨形成率没有影响；然而，抗骨吸收治疗加剧了HLS导致的骨形成率降低，提示在废弃期间成骨细胞受到协同抑制。精细的抗吸收剂量将倾向于针对废弃期的对策，从而使宇航员恢复得更快，不利影响更小。
Safe and effective countermeasures to spaceflight-induced osteoporosis are required to mitigate the potential for mission-critical fractures and ensure long-term bone health in astronauts. Two anti-resorptive drugs, the bisphosphonate zoledronic acid (ZOL) and the anti-receptor activator of NF-kappa B ligand protein osteoprotegerin (OPG), were investigated to find the minimum, comparable doses that yield a maximal increase in bone quality, while minimizing deleterious effects on turnover and mineralization. Through a series of five trials in normally loaded female mice (n = 56/trial), analysis of trabecular volume fraction and connectivity using microcomputed tomography, along with biomechanical testing, quantitative histomorphometry, and compositional analysis, was used to select 45 mu g/kg ZOL and 500 mu g/kg OPG as doses that satisfy these criteria. These doses were then examined for their ability to mitigate bone loss following short-term unloading through hindlimb suspension (HLS). Seventy-two mice were prophylactically administered ZOL, OPG, or PBS and assigned to loaded control or 2-wk HLS groups (n = 12 for each of 6 groups). Both anti-resorptives were able to preserve trabecular microarchitecture and femoral elastic and maximum force in HLS mice (+ 30-40% ZOL/OPG vs. PBS). In HLS mice, anti-resorptive dosing reduced resorption perimeter at the femoral endocortical surface by 30% vs. PBS. In loaded control mice, anti-resorptives produced no change in bone formation rate; however, reductions in bone formation rate brought about by HLS were exacerbated by anti-resorptive treatment, suggesting synergistic inhibition of osteoblasts during disuse. Refined anti-resorptive dosing will tend to target countermeasures to the period of disuse, resulting in faster recovery and less adverse effects for astronauts.