狄诺塞麦(Denosumab)治疗绝经后骨质疏松症的研究进展

(osteoporosis,OP)是一种多病因的全身性骨骼疾病,它是指以骨量降低、骨组织微细结构退变导致骨强度下降、骨脆性增加及骨折危险性增大为特征的代谢性疾病。随着人类寿命的延长和社会老龄化的发展,骨质疏松所导致的骨折在大大增加老年人病残率和病死率的同时,明显加重了社会公共卫生的经济负担,成为更加严重的世界性公共健康问题。狄诺塞麦(Denosumab)是目前用于治疗绝经期骨质疏松的第一种单克隆抗体药物。它能与细胞核因子-κB受体活化因子配体(RANKL)结合,通过抑制破骨细胞的产生、功能和存活,减少骨吸收达到治疗作用。狄诺塞麦有希望成为治疗骨质疏松的新选择。本文就狄诺塞麦的药理学特性、生物学作用机制及临床相关研究等方面进行综述。     

Denosumab与破骨细胞RANKL/RANK通路

Denosumab(狄诺塞麦)是一种人工合成、完全人源化、可与RNAKL结合的单克隆抗体(IgG2抗体),对人源RANKL具有很高的亲和力和特异性~([1]),具有较好的骨吸收抑制作用,是以破骨细胞RANKL/RANK信号调控通路为靶点的骨质疏松靶向治疗药物,并可降低恶性肿瘤骨转移患者骨骼相关事件(SRE)的发生、延缓骨痛的进展。本文综述了狄诺塞麦抑制骨吸收的生理作用机制,狄诺塞麦治疗骨质疏松和恶性肿瘤骨转移的研究进展,为狄诺塞麦在临床的应用提供更好的循证医学证据。     

双膦酸盐与狄诺塞麦治疗PMOP的“药物假期”EMAS立场声明要点解读

目的为了使骨质疏松领域相关医生能够进一步了解和掌握双膦酸盐与狄诺塞麦的药物假期规律,提高临床治疗水平,本文就欧洲女性与男性更年期协会(EMAS)对双膦酸盐与狄诺塞麦治疗绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)"药物假期"的立场声明进行要点解读,供同仁参考。方法 EMAS系统性回顾分析了双膦酸盐和狄诺塞麦中止使用后在骨折风险方面的影响,同时,评估降低不良事件风险的可能性,形成立场声明。结果 (1)考虑双膦酸盐的长期疗效、安全性及骨折风险,建议采取个性化的药物假期方案;(2)药物假期时机:阿仑膦酸钠治疗超过5年,利塞膦酸钠、唑来膦酸治疗超过3年的患者,应该考虑药物假期;(3)鉴于伊班膦酸钠证据有限,狄诺塞麦停药后可能引起骨折的"反弹效应",所以,不强烈推荐伊班膦酸钠和狄诺塞麦进行药物假期;(4)药物假期时长:一般情况下,双膦酸盐药物假期为1~3年;(5)重启治疗评估内容:双膦酸盐药物假期中,每年应评估病人的特征,包括患者的年龄、跌倒史、是否有新的骨折、可能危险因素、骨密度和骨代谢生化标志物;(6)重启治疗药物:双膦酸盐、狄诺塞麦,特立帕肽,雌激素受体调节剂(selective estrogen receptor modulators,SERMs),性激素补充(menopausal hormone replacement therapy,MHT)和雷奈酸锶等,是药物假期后重启治疗的选择药物。结论双磷酸盐药物假期遵循个体化原则,不推荐狄诺塞麦药物假期。     

双膦酸盐在骨科相关疾病治疗中的地位及再认识

 双膦酸盐是目前临床上治疗骨质疏松症的首选药物, 它能够靶向性地沉积在骨骼中,紧密吸附在骨的羟基磷灰石表面,与之结合并选择性聚积在破骨细胞周围;同时能够有效抑制破骨细胞活性及对骨质的吸收,通过预防骨丢失、提高骨质量以降低骨折风险。迄今为止,双膦酸盐类药物已经研究发展到第三代。第一代双膦酸盐为不含氮的双膦酸盐, 代表药物为羟乙膦酸钠,其分子结构中侧链是直链烃,药物活性和结合力相对较弱,有抑制骨钙化,干扰骨形成,导致骨 软化或诱发骨折的可能,且胃肠道不良反应大。第二代双膦 酸盐药物结构中的侧链引入了氨基称为氨基双膦酸盐,代表药物为帕米膦酸钠和阿仑膦酸钠,其药物活性和结合力比羟乙膦酸钠增加10～100倍,对骨的钙化作用干扰小,选择性强。而第三代双膦酸盐为具有杂环结构的含氮双膦酸盐,如利塞膦酸钠、唑来膦酸等,鉴于其强效、低剂量、使用方便等特点,被认为是具有更强的临床疗效且适应证更加广泛的抗骨吸收药物。目前,双膦酸盐已经广泛用于原发性骨质疏松症、继发性骨质疏松症(如糖皮质激素引起的骨质疏松)以及骨质疏松性骨折的预防及治疗。随着临床应用的深入推广, 越来越多的临床医生和研究人员发现,双膦酸盐除适用于上述疾病外,在关节置换术、脊柱融合术、骨坏死、骨关节炎、软骨损伤的治疗,以及乳腺癌、食管癌、结肠及直肠癌等重大疾病的预防中,扮演着十分重要的角色。为此,本文就双膦酸 盐在骨科相关疾病治疗中的重要作用及新进展做一阐述。     

骨巨细胞瘤治疗新突破——狄诺塞麦

骨巨细胞瘤（GCTB）是一种富含巨细胞的侵袭性、溶骨性病变,特征为大量多核破骨细胞样巨细胞聚集、表达细胞核因子JCB受体活化因子配体（RANKL）,目前还没有一种方法可彻底有效治愈,尤其是对无法手术的GCTB。近年文献报道在进行性或无法手术的GCTB患者中使用狄诺塞麦（denosumab）,可观察到肿瘤成分明显改变、骨破坏减少及临床有效性。狄诺塞麦是一种人RANKL单克隆抗体,与核因子wB受体活化因子（RANK）结合具有很高的亲和性和特异性。以往很多大规模Ⅲ期试验研究已表明,狄诺塞麦在降低各种肿瘤引起的骨破坏方面明显优于二磷酸盐,还可延缓骨转移出现。该文对相关文献进行回顾,并就狄诺塞麦在GCTB治疗中存在的问题进行探讨。     

骨质疏松治疗的新靶点研究现状与展望

骨质疏松症是一种普遍存在于老年人群体中的疾病, 其发病率随着年龄的增加而逐渐升高。骨质疏松症导致骨组织密度降低和骨质结构异常, 使得骨骼易于受到骨折和损伤。因此, 骨质疏松症对患者的生活质量和健康状况造成了很大影响。目前可用于治疗骨质疏松的药物主要包括骨形成促进药物、骨吸收抑制药物和骨矿化促进药物, 然而这些药物存在很多不良反应和局限性, 因此, 仍需更多的基础研究成果向临床转化。本文对骨质疏松治疗的新靶点进行述评。     

Wnt/β-catenin信号通路调控成骨细胞、破骨细胞在骨质疏松中的作用探讨

骨质疏松症是一种导致骨骼疏松、强度降低、易发生骨骼疼痛和脆性骨折的常见慢性病，影响了全球大部分中老年人健康。目前应用钙剂、维生素D补充剂、双膦酸盐类和雌激素等药物治疗，其主要侧重于预防、延缓骨吸收。针对骨质疏松症需要精准于细胞动力学和分化的靶向治疗药物。通过不断的探索和研究骨质疏松中涉及的信号通路，发现Wnt/β-catenin在骨正常生长和代谢中极为重要，β-catenin是介导成骨细胞存活和分化的关键分子。罗莫珠单抗、狄诺塞麦等新研发药物通过调节Wnt/β-catenin信号通路，进而影响骨髓间充质干细胞的成骨作用、成骨细胞的增殖和分化以及破骨细胞的生成等，参与骨质疏松的调节。本文就β-catenin在成骨细胞、破骨细胞功能调控和骨质疏松中的具体作用进行总结，进一步探讨Wnt蛋白和β-catenin的研究进展，以发掘更多创新的靶点来解决骨质疏松症的治疗问题。     

中医非药物治疗原发性骨质疏松症的临床研究概况

骨质疏松症是以全身骨痛、脊柱变形及易于并发骨折为临床特点的全身代谢性骨病,严重影响着老年患者的生活质量及生活水平。随着近年我国老龄化不断加重,骨质疏松症的发病率也呈现出增长趋势。目前对骨质疏松症的治疗以内服药物为主,但均存在着一定的副作用,不利于临床长期使用及推广。近年来临床报道,中医非药物治疗骨质疏松症具有良好的临床效果及无可比拟的优势。本文基于针灸,埋线,穴位注射,艾灸,推拿及传统健身功法等中医非药物治疗手段,综述近年来中医非药物治疗骨质疏松的临床报道及文献研究,为原发性骨质疏松症的治疗提供新的思路及更加合理的治疗方案,为中医非药物治疗骨质疏松的临床推广提供参考及借鉴。     

骨质疏松症的药物治疗进展

骨质疏松症是一种以骨量降低、骨微结构破坏、骨脆性增加、骨强度下降、骨折风险性增大为特征的全身性、代谢性骨骼系统疾病。由于骨质疏松症是一种全身性的疾病,骨质疏松症的原始治疗、骨质疏松性骨折术后及术后再骨折过程中抗骨质疏松药物的治疗非常重要,临床应用的抗骨质疏松药物主要包括两大类：骨吸收抑制类及促进骨形成类。随着骨代谢途径认识的不断加深,不断升级目前已有药物、已有药物的合理配伍使用、研发新型的改变细胞功能和基因表达的药物、继承和发展祖国传统中医药等都是值得探索的方向。随着这些新进展、新方案逐步通过临床试验的检验,将会给骨质疏松症的治疗带来新的希望。     

雷尼酸锶治疗骨质疏松症的研究进展

目的 对雷尼酸锶在骨质疏松症中的临床应用、作用机制进行综述和评价.方法 从人群试验、动物试验、细胞培养和不良反应等方面进行综述.结果 雷尼酸锶具有抗骨吸收和增进骨形成双重作用,其作用可能通过CaSR和增加血清IGF-1、降低高半胱氨酸.结论 雷尼酸锶作为一种新型抗骨质疏松药物,对骨质疏松症具有良好的疗效,代表了骨质疏松症治疗的一个重要发展方向,但应注意其不良反应.     

Denosumab: What��s New?

Denosumab is the first fully human monoclonal antibody that inhibits the formation, function, and survival of osteoclasts by blocking the interaction of receptor activator of nuclear factor-κB (RANK) ligand with its osteoclastic receptor RANK. Clinical studies have shown that the decreased bone resorption and increased bone mineral density resulting from the use of denosumab 60 mg twice yearly entail significant risk reduction of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis, with an acceptable rate of side effects so far. Following its approval by the US Food and Drug Administration and the European Medicines Agency, a number of clinical trials with denosumab are ongoing to demonstrate its value for other indications and to further characterize its effects on immunomodulation. Denosumab offers a new choice for the treatment of postmenopausal osteoporosis in patients at high risk for fracture.     

Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX

Denosumab has been shown to reduce the incidence of vertebral, nonvertebral, and hip fractures. The aim of the current study was to determine whether the antifracture efficacy of denosumab was dependent on baseline fracture probability assessed by FRAX. The primary data of the phase 3 FREEDOM study of the effects of denosumab in women with postmenopausal osteoporosis were used to compute country-specific probabilities using the FRAX tool (version 3.2). The outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. At baseline, the median 10-year probability of a major osteoporotic fracture (with bone mineral density) was approximately 15% and for hip fracture was approximately 5% in both groups. In the simplest model adjusted for age and fracture probability, treatment with denosumab over 3 years was associated with a 32% (95% confidence interval [CI] 20% to 42%) decrease in clinical osteoporotic fractures. Denosumab reduced fracture risk to a greater extent in those at moderate to high risk. For example, at 10% probability, denosumab decreased fracture risk by 11% (p = 0.629), whereas at 30% probability (90th percentile of study population) the reduction was 50% (p = 0.001). The reduction in fracture was independent of prior fracture, parental history of hip fracture, or secondary causes of osteoporosis. A low body mass index (BMI) was associated with greater efficacy. Denosumab significantly decreased the risk of clinical osteoporotic fractures in postmenopausal women. Overall, the efficacy of denosumab was greater in those at moderate to high risk of fracture as assessed by FRAX.     

Osteoporosis: New-Generation Drugs

A new understanding in the pathophysiology of bone led to the development of a fully human monoclonal antibody directed against RANK ligand (RANKL). Denosumab inhibits the interaction of RANKL with its receptor RANK, thereby suppressing osteoclast differentiation, function and survival. In this respect, denosumab mimics osteoprotegerin, the endogenous antagonist of RANKL. Recently, denosumab has been approved by the European Medicines Agency (EMEA) for the treatment of postmenopausal osteoporosis (PMO) and treatment-induced bone loss in breast and prostate cancer patients undergoing hormone ablation. Oncologic indications affecting bone are promising, but still under clinical evaluation. In clinical trials for PMO, denosumab has shown significant increases in bone mineral density (BMD) at various skeletal sites, decreases in bone turnover markers, and reductions in fracture risk. In head-tohead studies, denosumab proved to be superior to alendronate with regard to the increase in BMD. Considering clinical trial data, the risk-benefit profile of denosumab seems to be favorable since the rates of adverse events, serious adverse events, infections, malignancies and deaths were not higher compared to the control arms. In PMO, denosumab is applied subcutaneously as a 60-mg dose twice yearly. This administration scheme and route might have a high acceptance by patients and physicians.     

Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis

Denosumab reduces the risk of new vertebral and nonvertebral fractures. Previous trials suggest that the efficacy of antiresorptives on fractures might differ by patients' characteristics, such as age, bone mineral density (BMD), and fracture history. In the FREEDOM study, 7808 women aged 60 to 90 years with osteoporosis were randomly assigned to receive subcutaneous injections of denosumab (60 mg) or placebo every 6 months for 3 years. New vertebral and nonvertebral fractures were radiologically confirmed. Subgroup analyses described in this article were prospectively planned before study unblinding to evaluate the effect of denosumab on new vertebral and nonvertebral fractures across various subgroups. Compared with placebo, denosumab decreased the risk of new vertebral fractures in the overall study population over 3 years. This effect did not significantly differ for any of the nine subgroups analyzed (p > 0.09 for all potential interactions). Denosumab also reduced all nonvertebral fractures by 20% in the full study cohort over 3 years. This risk reduction was statistically significant in women with a baseline femoral neck BMD T‐score ≤ ?2.5 but not in those with a T‐score > ?2.5; in those with a body mass index (BMI) < 25 kg/m² but not ≥ 25 kg/m²; and in those without but not with a prevalent vertebral fracture. These differential treatment effects were not explained by differences in BMD responses to denosumab. Denosumab 60 mg administered every 6 months for 3 years in women with osteoporosis reduced the risk of new vertebral fractures to a similar degree in all subgroups. The effect of denosumab on nonvertebral fracture risk differed by femoral neck BMD, BMI, and prevalent vertebral fracture at baseline. © 2012 American Society for Bone and Mineral Research     

Osteoporoseprophylaxe unter Androgendeprivationstherapie

Bone loss is a frequent side effect of androgen deprivation therapy, which leads to a significant number of pathologic fractures. Prevention of osteoporosis aims at reducing skeletal-related events. The RANK ligand antibody denosumab and bisphosphonates are used for this indication. Denosumab has been shown to increase bone density and to reduce the incidence of fractures at any location by 72%. Bone density can also be increased by bisphosphonates; however, there is no conclusive evidence so far that the fracture rate can be reduced significantly. Therefore guidelines do not recommend use of these substances for this indication.     

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension

Denosumab is a fully human monoclonal antibody against receptor activator of NF‐κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3‐year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low‐frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3‐year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long‐term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low‐frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.     

Denosumab Rapidly Increases Cortical Bone in Key Locations of the Femur: A 3D Bone Mapping Study in Women With Osteoporosis

Women with osteoporosis treated for 36 months with twice‐yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60 mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One‐third of the increase came from increasing cortical density, and two‐thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab‐treated women at increased risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Vertebral Fractures After Denosumab Discontinuation in Breast Cancer Survivors: A Single Institution Experience

Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer—especially those continuing to take aromatase inhibitors—should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.     

Intervention thresholds for denosumab in the UK using a FRAX®-based cost-effectiveness analysis

Summary

The objective was to undertake a health economic analysis of denosumab for the treatment of osteoporosis in women from the UK, using the FRAX® tool. Denosumab was cost-effective in women with a risk of major osteoporotic fracture meeting or exceeding approximately 20 % who are unable to take, comply with or tolerate generic alendronate.

Introduction

Denosumab is a novel biologic agent developed for the treatment of osteoporosis, which has been shown to reduce the risk of fractures in a phase-III trial. The objective of the present study was to undertake a health economic analysis of denosumab in women from the UK. Ten-year probabilities of a major osteoporotic fracture at which denosumab is a cost-effective alternative to no treatment, generic alendronate, risedronate and strontium ranelate were estimated.

Methods

A previously published Markov model was adapted to incorporate fracture and mortality risk assessments based on absolute fracture probability, as estimated by FRAX®. The model included treatment persistence and residual effect after discontinuation.

Results

At a willingness-to-pay (WTP) of £30,000 per quality-adjusted life year and a 10-year fracture probability equivalent to a woman with a prior fragility fracture, denosumab was cost-effective compared to no treatment from the age of 70 years. At the same WTP, denosumab was—irrespective of age—cost-effective compared to no treatment at a major osteoporotic fracture probability of approximately 20 %. Denosumab was estimated to cost-effectively replace strontium, risedronate and generic alendronate at 10-year probabilities exceeding 11, 19 and 32 %, respectively.

Conclusion

FRAX® facilitates the estimation of cost-effectiveness-based intervention thresholds applicable to patients with different combinations of clinical risk factors, which more closely matches the situation in clinical practice. Denosumab is cost-effective in patients with major osteoporotic fracture probabilities meeting or exceeding approximately 20 % who are unable to take, comply with or tolerate generic alendronate.