Prevention of glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. The role of the Wnt signaling pathway in bone formation and the ratio of receptor activator for NF-κB ligand versus osteoprotegerin in bone resorption are exciting new insights. The absolute fracture risk helps both clinicians and patients to interpret the results of bone density measurement, which may have a positive influence on adherence to therapy. The bisphosphonates alendronate and risedronate are the first-line treatment in the prevention of glucocorticoid-induced osteoporosis, because both increase the bone mineral density of the spine and hips and reduce the vertebral fracture rate. Treatment with the anabolic agent parathyroid hormone (1 – 34) strongly stimulates bone turnover, and seems to be superior to treatment with alendronate. It might be attractive for glucocorticoid-treated patients with new vertebral fractures during treatment with bisphosphonates, and/or with severe fracture risk.     

Treatment needs and current options for postmenopausal osteoporosis

Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased risk of fractures, affecting up to 50% of postmenopausal women worldwide. Over the past 2 decades there have been consistent developments in the pharmacotherapy of osteoporosis with the availability of potent inhibitors of bone resorption (bisphosphonates, and denosumab) or stimulators of bone formation (PTH analogs) with substantial improvements over calcitonin or estrogen replacement.

Areas covered: In this review we summarize the effects of existing treatment options for postmenopausal osteoporosis along with the unmet clinical needs and we discuss about the potential benefits of new compounds under development.

Expert opinion: Despite the recent progresses, there are still limitations and unmeet needs with all the available drugs, mainly concerning treatment adherence, efficacy on the prevention of nonvertebral fractures and the long-term adverse events of antiresorptive regimens. Moreover, PTH analogs are the only available compounds able to stimulate bone formation, but with a restricted anabolic window of no more than 2 years. Of interest, the more recent advances in bone biology identified new targets for the development of drugs with a more potent and selective activity on either osteoclasts or osteoblasts, thus making possible to uncouple bone formation from bone resorption.     

Combination and sequential treatment in women with postmenopausal osteoporosis

ABSTRACT

Introduction: Since postmenopausal osteoporosis is a chronic, potentially disabling condition requiring long-term treatment, the physician is expected to decide the optimal treatment strategy, e.g. how to use the available osteoanabolic and antiresorptive agents, sequentially or in combination, in the most effective and safe way, based on personalized patient care.

Areas covered: Herein, the authors outline clinical data regarding the efficacy and safety of various sequential treatment strategies. More specifically, they compare the efficacy of osteoanabolic agents when they precede or follow antiresorptive treatment, as well as the efficacy of antiresorptives following other antiresorptives. Finally, the authors quote and discuss available evidence regarding the efficacy and safety of the co-administration of osteoanabolics and antiresorptives in comparison with monotherapies.

Expert opinion: Initiation with an osteoanabolic agent followed by an antiresorptive seems to be the optimal treatment sequence, at least in patients with severe osteoporosis. Osteoanabolic treatment following antiresorptives seems to lead in more modest responses in bone mineral density (BMD) and bone turnover markers. Combination therapy with teriparatide and denosumab or zoledronate has achieved higher BMD gains compared to each agent alone; however, due to the high cost, combination therapy is rarely compensated. On the contrary, the combination of teriparatide with alendronate results in smaller BMD increases than TPTD monotherapy.     

New and developing pharmacotherapy for osteoporosis in men

Introduction: Osteoporosis represents a major health and societal burden in men, as well as in women. However, only a minority of men are screened and treated for osteoporosis and fracture prevention, even after first fracture.

Areas covered: This article provides a comprehensive summary of the currently available drugs for osteoporosis in men as well as insights into new and developing pharmacotherapy.

Expert opinion: To date, therapeutic approaches to osteoporosis in men remain not as well defined as in women, since antifracture efficacy data are lacking for most approved pharmaceuticals. Based on the currently available evidence, bisphosphonates are generally recommended as first line pharmacotherapy in men. Conceptually, osteoanabolic agents, such as teriparatide could be more appropriate for men with primary osteoporosis and low bone turnover. However, osteoanabolic agents display a limited anabolic window during which their stimulatory effects on bone formation prevail over the increase in bone resorption and their use, for theoretical safety reasons, is limited to a cumulative duration of two years. Due to the recent advances in bone biology, future drugs for osteoporosis in men might include more selective antiresorptive compounds which do not markedly inhibit bone formation as well as newer osteoanabolic agents that appear to more selectively stimulate bone formation.     

Developments in the pharmacotherapeutic management of osteoporosis

During the last two decades, several medications have been granted a marketing authorisation for the management of osteoporosis. Bisphosphonates are the most widely prescribed drugs in this area, worldwide. Alendronate and risedronate are given daily or weekly and have demonstrated their ability to reduce fracture rates at the spine and hip. Ibandronate has demonstrated spine antifracture efficacy with intervals between dosings greater than weekly. New developments in this class include intravenous administration of ibandronate or zoledronate, once every three months or once yearly. Raloxifene, a selective estrogen-receptor modulator, reduces spine fractures and, in post-hoc analyses, non-spine fractures in high-risk subjects. New selective estrogen-receptor modulators, including lasofoxifene, bazedoxifene and arzoxifene, are expected to demonstrate antifracture efficacy at the hip level, whilst retaining the extra-skeletal benefits (such as in the breast) that are obtained with raloxifene. The peptides from the parathyroid hormone family are potent stimulators of bone formation. Teriparatide (1 – 34 amino acid fragment of the parathyroid hormone) reduces spine and non-spine fractures, an effect that is sustained for up to 30 months after the withdrawal of treatment. The intact hormone (1 – 84 amino acids) showed similar results on spine fractures, and more data are requested to evaluate its effect on non-spine or hip fractures. Strontium ranelate is suggested to be the first medication to uncouple bone formation from bone resorption. It has shown antifracture efficacy at all sites in a large number of postmenopausal women. New developments include: denosumab, an antibody against receptor activator of NF-κB ligand (RANKL); a cytokine that is responsible for osteoclastogenesis; and inhibitors of cathepsin K, a cysteine protease that is involved in the cleavage of collagen.     

Efficacy and safety of abaloparatide for the treatment of post-menopausal osteoporosis

Introduction: Osteoporosis is a skeletal disorder characterized by loss of bone mass and strength affecting up to 30–50% of postmenopausal women worldwide. Current therapeutic options include antiresorptives such as aminobisphosphonates or denosumab and osteoanabolic compounds such as teriparatide.

Areas covered: In this review, the authors summarize the clinical development, safety and efficacy profile of abaloparatide, a new osteoanabolic agent recently marketed in the US for the treatment of postmenopausal osteoporosis in women who are at high risk for fracture or who fail antiresorptive therapy.

Expert opinion: Abaloparatide is a 1-34 PTH related peptide-like molecule that has been modified in order to potentiate the osteoanabolic effect. In its pivotal phase 3 trial in postmenopausal women with osteoporosis, subcutaneous abaloparatide 80 mcg/day reduced the risk of vertebral, nonvertebral, major osteoporotic, and clinical fractures compared with placebo and reduced the risk of major osteoporotic fractures compared with teriparatide. These results, together with a reduced prevalence of hypercalcemia and a lower cost of the marketed compound, point toward improved cost effectiveness with abaloparatide versus teriparatide. However, some concerns have been raised due to a somewhat higher occurrence of adverse effects (particularly with palpitations and increased heart rate) or the resultant discontinuation due to these adverse effects when compared to teriparatide.     

The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women

At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio.     

Treatment of postmenopausal osteoporosis with odanacatib

Introduction: The market of antiosteoporosis drugs has been declining in recent years, possibly in part due to the publicity around adverse events observed with bisphosphonates. Also, the proportion of patients with clinical fracture who receive adequate treatment remains low. So there are still unmet needs in this field. Odanacatib is a cathepsin K inhibitor currently being developed for the treatment of postmenopausal osteoporosis that could be an advance in this context.

Areas covered: Odanacatib is a bone resorption inhibitor, but it preserves some degree of bone formation, which differentiates this new family of drugs from existing therapies. Odanacatib increases bone mineral density at the spine and hip, improves estimated bone strength using finite element analysis at the spine and hip as well as at the distal tibia and radius. The safety profile has been satisfactory so far. A robust antifracture efficacy has been announced when the Phase III pivotal trial was terminated after interim analysis, but we do not yet have access to the complete results.

Expert opinion: Odanacatib may have an important role in future guidelines if it provides a substantial advantage compared to the effective and inexpensive current generic drugs, in terms of antifracture efficacy or safety.     

Glucocorticoids and the risk of osteoporosis

Background: Glucocorticoid-induced osteoporosis (GIO) refers to a clinical condition in which a class of corticosteroids increases the susceptibility of bones to fracture. Numerous recent studies have improved our understanding of the underlying biology of this condition, whereas data from randomized controlled trials have provided clinicians with more options for prevention of GIO. Objective: To review the pathophysiology and epidemiology of GIO, as well as current pharmacologic treatment and prevention modalities available. To review the state of healthcare provider concordance with GIO prevention guidelines. Methods: Representative examples of various cellular and molecular processes underlying GIO were included, with an emphasis towards more recent discoveries. The data used to describe the epidemiology of GIO were derived from both randomized controlled studies and observational studies, framed through a discussion of known osteoporosis risk factors. Results/conclusion: Progress has been made in clarifying the pathophysiologic mechanisms that result in GIO. Although the options for preventions and treatment of GIO continue to expand, provider compliance with preventive measures remains suboptimal.     

双膦酸盐类药物治疗糖皮质激素性骨质疏松的Meta-分析

目的 系统评价双膦酸盐类药物用于治疗糖皮质激素性骨质疏松的疗效及安全性。方法 计算机检索自建库至2018年12月中国学术期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）、维普中文期刊全文数据库（VIP）和万方数据库、Pubmed、Embase、Medline、Web of Science、Cochrane Library等中英文数据库,筛选符合纳入排除标准的随机对照试验（RCT）。提取资料,评价质量,采用RevMan 5.0版和Stata 12.0统计软件进行分析。结果 共纳入25项RCTs,包括2857例患者。结果显示,两组患者腰椎骨密度［SMD=1.01,95% CI（0.83,1.20）,P=0.000］、髋骨骨密度［SMD=0.87,95% CI（0.57,1.17）,P=0.000］等指标比较具有统计学意义。两组患者椎骨骨折发生率［OR=0.63,95% CI（0.34,1.15）,P=0.131］、不良反应发生率［OR=1.04,95% CI（0.82,1.33）,P=0.725］等比较无统计学意义。结论 双磷酸盐可有效改善糖皮质激素性骨质疏松患者的骨质流失,具有降低骨折发生率的趋势,并且与对照组相比具有较好的安全性。     

特立帕肽在行腰椎融合术骨质疏松患者中的应用

近年来行腰椎融合术的老年患者不断增加,老年患者常合并有骨质疏松,是椎体融合的不利因素,会增加骨科术后并发症的发生风险.特立帕肽即重组人甲状旁腺激素1-34,可促进骨形成,临床用于治疗有骨折高风险的重度骨质疏松患者.有研究表明,特立帕肽可提高行腰椎融合术骨质疏松患者的腰椎植骨融合率、缩短融合时间,并可增加内植物稳定性,且...     

地舒单抗与阿仑膦酸盐治疗骨质疏松症的药物经济学对比评价文献研究

目的 对比评价地舒单抗与阿仑膦酸盐用于骨质疏松症治疗的药物经济学研究结果,为骨质疏松的临床用药治疗决策提供参考。方法 ：以“骨质疏松”“地舒单抗”“阿仑膦酸盐”“成本效果”“成本效益”“成本效用”“经济性分析”“药物经济学”为中文检索词,以“osteoporosis”“denosumab”“alendronate”“cost-effectiveness”“cost-utility”“cost-benefit”“economic-analysis”“pharmacoeconomics”为英文检索词,在中国知网、万方数据、维普网、PubMed、Web of Science、EMBASE等数据库中检索2000年1月1日－2022年10月20日公开发表的地舒单抗的药物经济学评价文献,按照纳入与排除标准筛选文献后,提取相关信息,使用卫生经济学评价报告标准共识量表对纳入文献进行质量评价,从文献基本信息、文献质量、模型结构及要素、健康状态及效用值、成本项目和来源、健康产出、经济学评价、敏感性分析等对地舒单抗治疗骨质疏松的药物经济学评价方法和结果进行描述性统计分析。结果 共纳入6篇文献,文献总符合率均在80.00%以上。地舒单抗对比阿仑膦酸盐治疗骨质疏松的药物经济学评价研究主要采用马尔可夫模型,模型结构较为成熟;成本确认的范围应与所选的角度一致,包括直接成本、间接成本、隐形成本;效果值多源于已有文献的随机对照试验系统评价或荟萃分析;敏感性分析采用确定性敏感性分析和概率敏感性分析,主要影响因素为成本。结论 地舒单抗在我国上市不久,本研究可为临床骨质疏松的治疗提供新的思路,更规范地开展相关药物经济学评价研究。     

Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) confirms that abaloparatide is a valuable addition to the armamentarium against osteoporosis

The recently published Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) assessed the efficacy and safety of abaloparatide (80 µg daily subcutaneous) (ABL) vs placebo during 18 months, in postmenopausal osteoporosis. Teriparatide (20 µg daily subcutaneous) (TPD) was used as an open label active comparator. The results of the study suggest that ABL increases bone mineral density more than TPD and reduces major osteoporotic fractures to a greater extent than TPD with a more rapid onset of action. These outcomes combined with a positive safety profile make ABL an interesting addition to the armamentarium against postmenopausal osteoporosis.     

Emerging drugs for postmenopausal osteoporosis

Postmenopausal osteoporosis (PMO) is a common skeletal disease with serious consequences due to fractures, including increased risk of disability and death. The risk of fractures can be reduced with medications that are currently available; however, these drugs are frequently not prescribed due to failure to recognize that a patient is at high risk for fracture; fear of adverse drug effects; or, sometimes, high cost. When these drugs are prescribed, long-term adherence to therapy is poor. Efforts to improve the clinical effectiveness of pharmacological therapies have included lengthening the interval between doses, simplifying drug administration, and manipulating the molecular structure of drugs in existing therapeutic classes. Recent improvement in understanding the pathophysiology of PMO at the molecular level has fostered the development of new therapeutic agents with novel mechanisms of action. This is a review of the data on the efficacy and safety of emerging drugs for the treatment of PMO, including agents with novel mechanisms of action (denosumab, odanacatib, antibody to sclerostin), new estrogen agonists/antagonists (lasofoxifene, bazedoxifene, arzoxifene), new delivery systems for existing drugs (salmon calcitonin, teriparatide), and drug combinations given concurrently, sequentially, or cyclically. These new therapeutic agents, new delivery systems, and new methods of combining drugs may ultimately reduce the great personal and economic burden of osteoporotic fractures.     

依扑拉芬对糖皮质激素所致大鼠骨质疏松的作用

对氢化可的松所致大鼠骨质疏松模型，依扑拉芬能剂量依赖性地逆转糖皮质激素所致血钙降低和尿钙增加，且能升高血清碱性磷酸酶活性，增加股骨干骺端密度。骨干髓质密度及皮质厚度指数。对股骨干重、灰重及骨钙含量亦能明显增加。提示依扑拉芬对糖皮质激素诱发的骨质疏松具有良好的防治作用。     

伊班膦酸钠治疗糖皮质激素诱导的家兔骨质疏松症

目的:应用骨生物力学和组织形态学,研究伊班膦酸钠在糖皮质激素诱导的骨质疏松症家兔模型中的治疗作用。方法:50只家兔随机分为:对照组1和2(注射生理盐水)、模型组1(注射地塞米松,连续6周)、模型组2(注射地塞米松,连续12周)和治疗组(注射地塞米松6周后,注射1次伊班膦酸钠)。6周后将对照组1和模型组1家兔处死;12周后将其他组家兔处死。结果:组织形态学和骨生物力学结果显示骨质疏松症家兔模型成功建立。12周时,治疗组家兔腰椎压缩和股骨3点弯曲最大负荷及肱骨抗扭转最大扭矩比模型组2分别提高了54.36%,21.38%和105.75%(P<0.05),骨质疏松症形态学改变得到明显改善,骨小梁排列较密集,连接增多,成骨活跃,医学图像分析腰椎和股骨颈面密度增加(P<0.05)。结论:伊班膦酸钠可有效治疗糖皮质激素引起的骨质疏松症,提高模型家兔的骨生物力学特性,改善骨小梁的组织结构。     

A review of teriparatide and its clinical efficacy in the treatment of osteoporosis

Until recently, antiresorptive medications such as bisphosphonates and raloxifene represented the main pharmacological treatment options for patients with osteoporosis. With the introduction of teriparatide (rhPTH_(1–34)), a recombinant formulation of parathyroid hormone (PTH) consisting of the first 34 amino acids of the N-terminal region, bone-forming therapy has now become possible. Preclinical, as well as human studies, have shown increases in trabecular as well as cortical bone mass with subsequent improvements in bone microstructure and cortical thickness. The subcutaneous daily dose of teriparatide 20 μg has been shown to decrease the occurrence of new vertebral fractures in caucasian women (70 years of age) by 65%, in a large randomised, double-blind placebo-controlled trial. Moderate-to-severe fractures or multiple vertebral fractures could be reduced by 90 and 77%, respectively. There was also a significant beneficial effect on new nonvertebral fractures (-35%) by the end of the 21-month treatment period. The reduction in nonvertebral fractures became evident after ～ 8 – 12 months of treatment. Smaller studies in men with low bone mass showed similar effects on bone mineral density and changes in bone turnover markers when compared to the results obtained in postmenopausal women. Recent data suggest that teriparatide is best given as monotherapy and not in combination with a bisphosphonate. Previous bisphosphonate treatment is also likely to diminish the bone anabolic potential of teriparatide. In order to preserve bone mass gained during the recommended 18- to 24-month treatment period, antiresorptive medication should be prescribed following teriparatide treatment. Studies so far have not shown serious PTH-related side effects. Hypercalcaemia is usually mild and transient and the osteosarcoma risk reported in rat toxicology studies is very unlikely to be predictive of a similar risk in humans. As teriparatide is expensive, its use at the moment should be limited to patients with more severe forms of osteoporosis, usually with the presence or history of one or more fractures because of those patients’ high risk for subsequent fractures.     

激素替代疗法联合阿仑膦酸钠治疗绝经后骨质疏松的临床研究

目的观察激素替代疗法(HRT)联合阿仑膦酸钠治疗绝经后骨质疏松患者的疗效。方法采用随机、对照研究。69例绝经后骨质疏松症患者,随机分为联合用药组(联合组)、雌激素替代治疗组(雌激素组)和阿仑膦酸钠治疗组(阿仑膦酸钠组),每组23例。联合组每2周服尼尔雌醇片1mg,每3个月末10d加服安宫黄体酮6mg/d,同时给予阿仑膦酸钠70mg,每周1次口服。雌激素组为安慰剂+尼尔雌醇片和安宫黄体酮,阿仑膦酸钠组为安慰剂+阿仑膦酸钠。所有受试者均加服钙尔奇D600mg/d(每片含元素钙600mg和VitD125IU)。观察各组治疗后患者腰椎骨密度、血钙、血磷等骨代谢指标的变化及疼痛症状改善情况。结果通过1年治疗,3组患者的L1～4骨密度均有显著上升,其中联合组骨密度的上升更为明显(P<0.01),骨痛症状明显缓解,总有效率为100%,联合组的显效率高于其他两组。结论HRT联合阿仑膦酸钠治疗绝经后骨质疏松症,较单独用药更能有效地改善骨痛,提高骨密度值。     

山楂酸对糖皮质激素诱发骨质疏松大鼠的干预作用研究

目的：研究山楂酸对糖皮质激素造成大鼠骨质疏松的干预作用及其作用机制。方法60只SD大鼠分为6组,正常组、模型组、对照组（灌胃给予碳酸钙375 mg? kg－1? d－1及维生素D 350 U? kg－1? d－1）及3个剂量实验组（灌胃给予山楂酸100,50,25 mg? kg－1? d－1）,共给药12周。生化试剂盒测定血清中的钙、磷的含量、骨钙素含量和抗酒石酸酸性磷酸酶活性,双能X线骨密度测定仪测定骨密度。结果与正常组相比,泼尼松可导致骨无机质钙盐和有机质羟脯胺酸下降,骨密度下降。山楂酸能对抗由泼尼松引起的上述异常,在增加骨密度方面优于对照组。结论山楂酸能有效预防糖皮质激素造成的大鼠骨质疏松。