Mechanisms Underlying the Bone Modeling Effects of Combined Anabolic/Antiresorptive Administration

三分之一的女性和五分之一的男性会在一生中经历骨质疏松性骨折。目前 现有的药物可以降低骨折风险，但无法完全恢复骨骼的完整性。因此，仍有遗迹 迫切需要快速有效地恢复骨骼力量的骨质疏松症治疗方法。与大多数不同 在慢性疾病中，骨质疏松症历来一次只能用一种药物治疗。试图 将合成代谢药物与最常用的抗吸收药物(双膦酸类)联合使用并不能证明 很有效。相反，我们最近报道，Teriparatide和受体激活剂的组合 核因子-κB配体(RANKL)抑制剂Denosumab增加骨密度并改善骨骼 微结构和估计强度超过任何一种药物单独使用，也超过任何可用的治疗方法。 我们假设，这种联合的疗效依赖于地诺舒单抗充分发挥作用的能力 阻断雷帕替丁对骨吸收的刺激，同时允许雷帕替丁对骨的刺激 形成(基于建模的骨形成)。在这项建议中，我们将直接评估特雷帕坦的能力 当骨吸收被地诺单抗阻断时，刺激基于模型的骨形成。此外，我们 将确定这种结合达到其疗效的细胞和分子机制。至 为了实现这些目标，我们将进行一项短期临床试验，在该试验中，绝经后骨质疏松症妇女 随机接受为期三个月的Teriparatide、denosumab或两种药物的治疗。髂骨 活检样本将在四重标记后从所有受试者身上取样，这是一项创新的技术， 能够评估短期干预对骨吸收和形成的影响，而不需要 对同一受试者进行“配对”活组织检查。有了这项技术，我们也能够评估治疗诱导 不同骨膜中静态和动态骨代谢指标的变化(松质骨， 皮质内、皮质内和骨膜)，从而计算重塑与建模的比例- 在每个骨骼间隔的基础上骨形成。活组织检查样本也将用于 成骨细胞、破骨细胞、骨髓脂肪细胞及其信号通路的免疫组织化学评价 调节成骨。将额外获得3.5毫米的核心，用于骨骼和骨髓的RNA分析 微环境。此外，将从骨髓抽吸物中分离细胞以评估成骨作用。 潜能(CFU-OB)、谱系标记和信号通路激活。这项研究的圆满完成 将使我们能够更好地定义特定组合无与伦比的功效的基础机制 RANKL抑制和PTH受体刺激。这一新的理解反过来将提供框架 用于设计有可能从根本上推进骨质疏松症治疗的研究。

One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Currently available medications reduce fracture risk but are unable to fully restore skeletal integrity. Thus, there remains an urgent need for osteoporosis treatments that rapidly and effectively restore bone strength. Unlike most chronic conditions, osteoporosis has historically been treated with only one drug at a time. Attempts to combine anabolic agents with the most commonly used antiresorptive agents (bisphosphonates) did not prove efficacious. In contrast, we recently reported that the combination of teriparatide and the receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, denosumab, increases bone density and improves bone microarchitecture and estimated strength more than either drug alone and more than any available therapy. We have hypothesized that the efficacy of this combination is dependent on denosumab’s capacity to fully block teriparatide’s stimulation of bone resorption while allowing for teriparatide-induced stimulation of bone formation (modeling-based bone formation). In this proposal, we will directly assess the ability of teriparatide to stimulate modeling-based bone formation when bone resorption is blocked by denosumab. Furthermore, we will define the cellular and molecular mechanisms by which this combination achieves its efficacy. To accomplish these aims, we will perform a short-term clinical trial in which postmenopausal osteoporotic women are randomized to receive three-months of teriparatide, denosumab or both medications. Iliac crest bone biopsy specimens will then be sampled from all subjects after quadruple-labeling, an innovative technique that is able to assess the effects of short-term interventions on bone resorption and formation without requiring “paired” biopsies in a single subject. With this technique, we are also able to evaluate treatment-induced changes in both static and dynamic indices of bone metabolism in each bone envelope separately (cancellous, endocortical, intra-cortical, and periosteal) and thus calculate the proportion of remodeling versus modeling- based bone formation in each skeletal compartment. Biopsy specimens will also be used for immunohistochemical evaluation of osteoblasts, osteoclasts, marrow adipocytes and signaling pathways that regulate osteogenesis. An additional 3.5-mm core will be obtained for RNA analyses of bone and the marrow microenvironment. Furthermore, cells will be isolated from marrow aspirates to evaluate for osteogenic potential (CFU-OB), lineage markers and signaling pathway activation. The successful completion of this study will allow us to better define the mechanisms that underlie the unparalleled efficacy of the specific combination of RANKL inhibition and PTH-receptor stimulation. This new understanding, in turn, will provide the framework for the design of studies with the potential to fundamentally advance osteoporosis treatment.