Denosumab治疗绝经后骨质疏松症的临床研究进展

狄诺塞单抗(Denosumab)是首个上市的抗核因子κB受体活化因子配体(RANKL)治疗性单克隆抗体产品,主要用于治疗骨质疏松症和其他骨骼疾病.本文主要综述其近年国外治疗绝经后骨质疏松症的临床研究进展.     

Denosumab: a review of its use in the treatment of postmenopausal osteoporosis

Denosumab (Prolia?) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

Enfuvirtide: first fusion inhibitor for treatment of HIV infection.

PURPOSE: The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and availability of enfuvirtide are discussed. SUMMARY: To date, 20 antiretrovirals have been approved by FDA for the treatment of HIV infection. The recent approval of enfuvirtide offers a new and fourth class of antiretroviral agents called fusion inhibitors. Enfuvirtide is indicated for use in treatment-experienced patients who have evidence of viral replication despite receiving current therapy. The drug is a 36-amino-acid synthetic peptide that prevents completion of the HIV fusion sequence. Absolute bioavailability after subcutaneous injection is 84%. Clinical trials indicate that adding enfuvirtide to a salvage regimen in heavily treated patients may lead to an improved virologic response. Up to a 1.48 log decrease in the viral load was seen at 48 weeks when enfuvirtide was combined with an optimized background regimen. Patients who have at least two or more active drugs in the regimen, a CD4+ cell count of >100 cells/mm3, and previous exposure to two or more antiretrovirals prior to starting enfuvirtide appear to respond best. The most common adverse effect, occurring in 98% of all enfuvirtide recipients, is an injection-site reaction that generally can be managed nonpharmacologically. A much less common but more significant concern is an increased risk of bacterial pneumonia. Enfuvirtide is available through the Fuzeon Progressive Distribution Program. The annual cost of therapy is about 24,000 dollars. CONCLUSION: Enfuvirtide is the first fusion inhibitor available for the treatment of HIV infection. The drug is indicated for use with other antiretroviral agents in treatment-experienced patients who have evidence of HIV replication despite ongoing antiretroviral treatment.     

绝经后骨质疏松的治疗

骨质疏松症(Osteoporosis,OP)是一种以骨量减少,骨微结构退化及骨脆性增加为主要特征的全身性骨代谢障碍疾病,易发生骨折[1]。骨质疏松症的发生可能由多种原因引起,绝经后骨质疏松症是最为常见的一种原发性骨质疏松症,是妇女绝经后最常见的一种骨     

Aliskiren: the first renin inhibitor for clinical treatment

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.     

治疗骨质疏松药物的应用现状分析

目的　通过对浙江省 2 8家医院 1 998～ 2 0 0 1年治疗骨质疏松症药物的销售分析 ,了解骨质疏松症治疗药物的应用现状。方法　根据《全国医药经济信息网》和浙江省 6家医药公司销售数据进行统计。结果　 4年来 ,治疗骨质疏松症药物基本呈逐年上升趋势 ,2 0 0 1年较 1 998年增长了 1 0 0 % ,尤其是双膦酸盐类药物增长了 41 5 .84% ,平均年增长率为 82 .0 9%。结论　随着老龄化人口的递增和预防意识的增强 ,治疗骨质疏松症药物的市场需求会不断上升     

Safety considerations with bisphosphonates for the treatment of osteoporosis.

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. This review provides an overview of the safety issues associated with the nitrogen-containing class of bisphosphonates and discusses the potential effect of these issues on adherence. The review specifically considers upper gastrointestinal (UGI) adverse events (AEs), renal toxicity, influenza-like illness, osteonecrosis of the jaw and evidence on how to treat or prevent these events.In clinical trials, UGI AEs, including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms. However, postmarketing studies have highlighted UGI AEs as a concern. These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs. Some clinical trials with oral bisphosphonates have suggested that a decrease in the frequency of administration may lead to improvement in gastrointestinal tolerability. In the authors' experience, the issue of UGI tolerability can be minimised by explaining to the patient and/or caregiver the importance of following administration instructions.Intravenous (IV) bisphosphonates have been recently approved for use in osteoporosis, offering an alternative regimen for patients with osteoporosis. Earlier generation IV bisphosphonates (e.g. etidronate) have been associated with acute renal failure. Alternatively, late-generation IV bisphosphonates (i.e. ibandronate) have shown a better safety profile in relation to renal toxicity.Influenza-like illness, often referred to as an acute-phase reaction, covers symptoms such as fatigue, fever, chills, myalgia and arthralgia. These symptoms are transitory and self-limiting and usually do not recur after subsequent drug administration. Symptoms of influenza-like illness have been associated with both IV and oral bisphosphonates.Osteonecrosis of the jaw has also been associated with IV bisphosphonate treatment, particularly in patients treated with high doses. A small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this AE. As osteonecrosis of the jaw is difficult to treat and is often associated with dental procedures and poor oral hygiene, preventive measures seem to be the best management option for patients taking bisphosphonates.Overall, the safety and tolerability profile of the nitrogen-containing bisphosphonates is good, and long-term treatment does not appear to carry a risk of serious AEs. By encouraging adherence to administration instructions physicians can minimise certain complications, such as UGI intolerability. By being aware of other potential safety issues, such as renal impairment, influenza-like illness and osteonecrosis of the jaw, physicians can detect these AEs early in the course of treatment.     

Prevention and treatment of nonpostmenopausal osteoporosis.

PURPOSE: The causes, prevention, and treatment of osteoporosis in specific populations are discussed. SUMMARY: Osteoporosis and osteopenia affect 44 million women and men ages 50 years or older. Fractures are the most devastating consequence of this disease and significantly affect quality of life, activities of daily living, survival, and health care costs. Most osteoporosis research has focused on postmenopausal women, but several other populations are at risk for osteoporosis, such as patients taking certain medications that affect bone health and those with various health conditions that cause bone loss, including anorexia nervosa, hyperthyroidism, organ transplantation, chronic obstructive pulmonary disease, and inflammatory bowel disease. Glucocorticoids are the most common secondary cause of osteoporosis. Other medications that have been implicated as secondary causes include anticonvulsants, heparin, warfarin, and methotrexate. Preventing osteoporosis may be even more important in adolescence than after menopause. CONCLUSION: Osteoporosis needs to be recognized, monitored, and appropriately treated in patients taking medications that affect bone health and in patients with conditions that increase the risk of osteoporosis.     

Bazedoxifene for the treatment of osteoporosis

Introduction: Bazedoxifene (BZD) is a third-generation selective estrogen receptor modulator approved for the treatment of postmenopausal osteoporosis with additional favorable effects in lipids, uterine and breast tissue.

Areas covered: In this review, the authors outline clinical data regarding the efficacy, safety, and tolerability of continuous BZD administration up to seven years in randomized, placebo-controlled, phase III clinical trials. Long-term treatment with BZD for postmenopausal osteoporosis is generally safe and well tolerated. BZD achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip. In addition, BZD reduces significantly the risk of vertebral fractures but not of non-vertebral and hip fractures, with the exception of high fracture risk postmenopausal women in whom BZD significantly reduces non-vertebral fractures.

Expert opinion: BZD does not seem to offer significant advantages over the other available antiresorptive agents. However, considering the need for long-term management of osteoporosis, BZD may have a place in the long-term therapeutic planning of the disease.     

Odanacatib for the treatment of osteoporosis

Introduction: Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib, are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue.

Areas covered: The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib.

Expert opinion: Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.     

Eldecalcitol for the treatment of osteoporosis

Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)-vitamin D?] is an analogue of 1α,25-dihydroxyvitamin D? [1,25(OH)?D?], bearing a hydroxypropyloxy residue at the 2β position. Eldecalcitol shows stronger effects than alfacalcidol to increase bone mineral density and reduce bone resorption markers in osteoporotic patients, and oral once-daily 0.75 μg eldecalcitol reduced vertebral fracture incidence by 26% compared to 1.0 μg alfacalcidol in a 3-year randomized, double-blind, active-comparator clinical trial. The effect of eldecalcitol on vertebral fracture incidence was sustained throughout the 3-year study period, and the annual incidence of vertebral fracture during the third year was significantly lower with eldecalcitol rather than with alfacalcidol treatment (3.9% vs 7.0%, respectively). Eldecalcitol also reduced the incidence of wrist fractures by 71% compared to alfacalcidol. Eldecalcitol is well tolerated and is not associated with serious side effects including sustained hypercalcemia. Eldecalcitol was approved for the treatment of osteoporosis in Japan in 2011.     

The cost effectiveness of treatment for alcoholism: a first approximation.

This study undertakes an analysis of cost effectiveness of alcoholism treatment modalities based upon (1) findings from clinical trials, (2) costs for treatment in settings and/or by providers and (3) recommendations from treatment experts about appropriate settings, providers and treatment events. This analysis, which assumes a prototypic patient, suggests that modalities with the most evidence of effectiveness (based on three or more clinical trials) are not the most expensive. Within this study, total cost of care was negatively related to effectiveness. Modalities categorized as having insufficient evidence of effectiveness (i.e., lacking three or more clinical trials) are in the higher cost categories. The results of this first effort to establish initial cost/effectiveness considerations are intended to stimulate researchers to conduct the types of clinical studies where both cost and effectiveness are carefully measured to increase the scientific basis for future cost/effect policy considerations. The authors expect future clinical studies will revise the results of this initial effort.     

The bone-building action of the parathyroid hormone: implications for the treatment of osteoporosis.

As populations age in the world's 7 major pharmaceutical markets, an increasing number of men and women, but especially women during their first postmenopausal decade, are falling victim to a bone disease that can result in hospitalisation, disability and death. This disease is osteoporosis. Indeed, by the year 2007, as many as 153,000,000 people will have experienced at least some significant osteopenia, if not osteoporosis. Although there are many different drugs, such as calcitonin, the bisphosphonates, estrogen and selective estrogen receptor modulators, that can slow or even stop further bone loss, there are currently few that can replace already lost bone by directly stimulating bone growth. However, a family of potent bone-building (or bone-anabolic) peptides is currently undergoing clinical development. These are the first-generation 84-amino acid native parathyroid hormone (PTH) and its 34- to 38-amino acid N terminal fragments, and the potent second-generation mini-PTHs. In this article, we briefly summarise what has so far been learned about how these molecules stimulate the production of new biomechanically strong bone in animals and humans.     

The use of raloxifene in osteoporosis treatment

Management of the menopause is a rapidly growing concern due to the ageing human population. The overall female lifespan has increased over the last century and up to a third of a woman’s life is now spent in menopause. To that end, significant attention has been placed on maximising the quantity and quality of life in the menopausal years. The optimal management strategies are ones that are highly flexible and sensitive to an individual’s expectations and concerns. Thus, while traditional oestrogen replacement therapy has been in place for > 20 years, there is now a greater interest in alternatives to this modality for those women who cannot or will not use it. This article reviews some of the alternative therapies that are being incorporated both in the allopathic and complementary medicine arenas.     

糖皮质激素所致骨质疏松的防治

糖皮质激素长期应用可导致糖皮质激素所致的骨质疏松症(GIOP)。GIOP是临床常见的继发性骨质疏松症,也是最常见的药物导致的骨质疏松。本综述通过复习既往文献,介绍了GIOP的流行病学,发病机制、分析糖皮质激素使用与骨质疏松的关系,并探讨了相应的预防和治疗方案,强调在计划使用糖皮质激素时,需要采取措施对GIOP进行预防。具有循证医学证据的二膦酸盐为首选药物,如唑来瞵酸钠等,还应及时补充钙剂和维生素D。总之,应加强对GIOP的关注,更有效地预防和治疗GIOP。     

A bright future for osteoporosis treatment

Osteoporosis is a serious and common condition with very high associated healthcare costs. However, methods for earlier detection and more effective treatment appear likely to produce significant improvement both in the immediate future and in the longer term. Introduction of biological markers of bone turnover should greatly assist in the conduct and evaluation of clinical trials. In addition, a number of very novel approaches are also under investigation that could lead to the introduction of new agents with a wide range of mechanisms of action. These developments were discussed at the Second Joint Meeting of the European Calcified Tissue Society and the International Bone and Mineral Society, held June 25-29, 2005, in Geneva, Switzerland.     

自制补骨脂汤与密钙息治疗老年性骨质疏松症的临床对比研究

目的 对自制补骨脂汤与密钙息治疗老年性骨质疏松症的临床疗效进行对比研究。方法 将161例临床确诊的老年性骨质疏松症患者随机分为两组：Ⅰ组（n=81）应用自制补骨脂汤治疗；Ⅱ组（n=80）应用密钙息治疗；两组均辅以口服钙剂，连续治疗6个月后复查骨密度（BMD），观察疼痛症状改善情况及血钙（Ca^2＋）、血磷（P^5＋）和碱性磷酸酶（ALP）指标。结果 两组治疗后两个部位的BMD值均明显升高，但组间比较差异无显著意义（P〉0．05）；两组的疼痛缓解总有效率分别为88．89％、90．00％，两组问无显著差异（x^2=0．02，P〉0．05）；治疗前后两组的血Ca^2＋、P^5＋和ALP均元显著变化，且在正常范围内。结论 自制补骨脂汤与密钙息治疗骨质疏松症效果同样显著，但补骨脂汤具有价格低廉、服用方便、副作用小等优势。     

胰高血糖素样肽2与骨质疏松症的治疗

胰高血糖素样肽2（glucagon-like peptide 2,GLP-2）是一种多肽类胃肠道生长因子,具有多种生理效应。作为外源性药物,GLP-2可用于治疗骨质疏松症。临床试验结果显示,GLP-2可降低骨吸收,且具有剂量依赖性,但对骨形成没有作用,完整的胃肠道是其发挥作用的必要条件。本文回顾了近年来关于GLP-2的合成、分泌、代谢、GLP-2受体及其介导的信号转导通路的研究进展,以及其用药的安全性和耐受性等问题。     

Single annual injectable treatment for postmenopausal osteoporosis

BACKGROUND: Several treatments for postmenopausal osteoporosis have become available over the last decade, but adherence to treatment is inadequate and the prevention of non-vertebral fracture by those medications is still modest. METHODS: We have performed a literature search regarding treatment with zoledronic acid in postmenopausal women. RESULTS: In the Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, involving 7765 postmenopausal women with low bone mineral density or with prevalent vertebral fracture, women taking zoledronic acid had a 70% vertebral fracture relative risk reduction and a 41% relative risk reduction for hip fracture, at 3 years, compared to placebo. In the HORIZON Recurrent Fracture Trial, 2127 patients (76% were women) were randomized to receive either zoledronic acid or a placebo after sustaining an initial hip fracture. After a median follow-up of 1.9 years, a relative risk reduction of 35% of clinical fractures was observed. Death from all causes was reduced by 28% in the zoledronic acid group. Zoledronic acid was generally safe in those trials, although a slightly increased rate of severe atrial fibrillations was observed in the HORIZON Prevention Fracture Trial, although not in the HORIZON Recurrent Fracture Trial. The clinical significance of this remains unclear. CONCLUSION: Yearly zoledronic acid presents a new option for the treatment of postmenopausal osteoporosis, with the perspective of improving the long-term persistence of therapy because of its once-a-year regimen.