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在其一生中会经历过脊椎骨折。目前 现有的药物降低了骨折的风险，但不能完全恢复骨骼的完整性。因此， 迫切需要快速有效地恢复骨强度的骨质疏松症治疗。不像大多数 在慢性疾病中，骨质疏松症在历史上一次仅用一种药物治疗。试图 联合收割机合成代谢药物与最常用的抗骨吸收药物（双膦酸盐）并没有证明 灵验。相反，我们最近报道，特立帕鲁肽和受体激活剂的组合， 核因子-κB配体（RANKL）抑制剂狄诺塞单抗可增加骨密度并改善骨 微结构和估计的强度超过任何单独的药物和任何可用的治疗。 我们假设，这种组合的疗效取决于狄诺塞单抗的能力， 阻断特立帕肽对骨吸收的刺激，同时允许特立帕肽诱导的骨刺激 骨形成（基于建模的骨形成）。在本提案中，我们将直接评估teriparterum的能力， 当骨吸收被地舒单抗阻断时，刺激基于模型的骨形成。而且我们 将定义这种组合实现其功效的细胞和分子机制。到 为了实现这些目标，我们将进行一项短期临床试验， 随机接受三个月的特立帕鲁肽、地舒单抗或两种药物治疗。髂嵴骨 活检标本将在四重标记后从所有受试者中取样，这是一种创新技术， 能够评估短期干预对骨吸收和骨形成的影响，而不需要 在单个受试者中进行“配对”活检。通过这项技术，我们还能够评估治疗诱导的 分别在每个骨包膜中骨代谢的静态和动态指标的变化（松质骨， 皮质内、皮质内和骨膜），从而计算重塑与建模的比例。 基于每个骨骼隔室的骨形成。活检标本也将用于 成骨细胞、破骨细胞、骨髓脂肪细胞和信号通路的免疫组织化学评价， 调节骨生成。将获得额外的3.5 mm核心用于骨和骨髓的RNA分析 微环境此外，将从骨髓抽吸物中分离细胞以评价成骨细胞。 潜能（CFU-OB）、谱系标志物和信号传导途径激活。本研究的成功完成 将使我们能够更好地定义特定组合无与伦比的功效背后的机制， RANKL抑制和PTH受体刺激。这种新的理解反过来将提供一个框架， 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.