特立帕肽治疗原发性骨质疏松症的短期疗效观察

目的：观察特立帕肽（ Teriparatide ）治疗原发性骨质疏松症的短期疗效和安全性。方法采用自身前后对照临床研究,纳入2011年12月-2012年12月在解放军第309医院骨内科住院的原发性骨质疏松症患者共10名,所有患者在每天口服补充元素钙600 mg和活性维生素D 0.25μg的同时,分别接受特立帕肽治疗,疗程6个月,具体用法为每日皮下注射特立帕肽20μg。所有患者均于用药前、用药后3、6个月采用双能X线吸收法（DEXA）测定腰椎（L2-4）、股骨颈、Ward’s区和大粗隆骨密度（BMD）,用酶联免疫吸附法（ELISA）测定血清骨钙素（sOC）、骨碱性磷酸酶（sBAP）和Ⅰ型胶原交联C端肽（sCTX）水平。观察患者治疗前后骨密度和骨标志物的变化并进行对比分析,记录患者的不良事件。结果10名患者均完成全疗程治疗。治疗3个月时,腰椎（L2-4）、股骨颈、Ward’s区和大粗隆骨密度改善不明显（P＞0.05）,血清骨钙素（sOC）和骨碱性磷酸酶（sBAP）较治疗前明显升高（P＜0.05）。治疗6个月时,腰椎（L2-4）骨密度较治疗前明显增高（P＜0.05）,而股骨颈、Ward’s区和大粗隆骨密度改善不明显（P＞0.05）。血清骨钙素（sOC）和骨碱性磷酸酶（sBAP）呈持续升高趋势（P＜0.05）,Ⅰ型胶原交联C端肽（sCTX）较治疗前略升高,但差异无统计学意义（P＞0.05）。治疗期间不良事件的发生情况：头晕发生2例,恶心发生1例,上述情况均较轻微,没有给予特殊处理即自行缓解。结论特立帕肽能在3个月内改善患者的骨代谢状况（促进骨形成）,6个月内有效增加原发性骨质疏松症患者的腰椎骨密度,适用于绝经后及老年性骨质疏松症患者的治疗。     

Reduced risk of back pain following teriparatide treatment: a meta-analysis

Vertebral fractures are the most common osteoporotic fracture and may result in back pain with functional limitations and diminished quality of life. Teriparatide [rhPTH (1–34)] has been shown to increase bone mass and reduce the risk of vertebral and other osteoporotic fractures. The aim of this study was to evaluate the effects of teriparatide on the risk of back pain in patients with osteoporosis. A systematic review of the literature was performed, and five trials were identified and included in our analyses. All trials were randomized, double-blinded, and parallel with either new vertebral fracture ( n =1) or bone mineral density as the primary endpoint ( n =4). Four studies were in postmenopausal women with osteoporosis, and one was in men with idiopathic or hypogonadal osteoporosis. Two trials were placebo controlled, two trials were alendronate controlled, and one trial involved teriparatide plus hormone replacement therapy versus hormone replacement therapy alone. Reports of back pain, defined as new or worsened back pain after initiating the study drug, were obtained from adverse event databases, and the risk of back pain was analyzed using a multivariate Cox proportional hazards model. Results were not statistically heterogeneous ( P =0.60) across trials, and there were no differences between groups administered teriparatide 20 or 40 mcg/day doses ( P =0.64). The rates of back pain, moderate or severe back pain, and severe back pain per 100 patient-years were numerically lower in the teriparatide versus comparator groups in each study. Compared with the pooled comparator, patients in the pooled teriparatide group had reduced risk for any back pain [relative risk, 0.66 (95% CI, 0.55–0.80)], moderate or severe back pain [relative risk, 0.60 (95% CI, 0.48–0.75)] and severe back pain [relative risk, 0.44 (95% CI, 0.28–0.68)]. Separate meta-analyses comparing teriparatide versus placebo or antiresorptive drugs gave similar results. In conclusion, patients randomized to teriparatide had a reduced risk of new or worsening back pain compared to patients randomized to placebo, hormone replacement therapy or alendronate.     

甲状旁腺激素和25羟维生素D对2型糖尿病患者并发骨质疏松症的影响

目的 探讨甲状旁腺激素(PTH)和25羟维生素D(25OHD)对2型糖尿病患者并发骨质疏松症的影响。 方法 选择海南医学院第二附属医院内分泌科2014年6月至2016年6月收治的350例2型糖尿病患者,按照《中国骨质疏松性骨折诊疗指南》中的定义,将入组的患者分成骨量正常组,骨量减少组和骨质疏松症组,对三个组别患者的25OHD,PTH,Ⅰ型前胶原氨基端延长肽(PINP),β胶原特殊序列(β-CTX)和糖化血红蛋白(HbA1c)等水平进行测定,并进行数据分析。 结果 三个组别患者的年龄,性别和体质量指数(BMI)三项指标数据结果差异无统计学意义(F=2.035,χ²=0.157,F=1.985,P>0.05)。PTH对比中,骨量正常组[(33.62±9.85)ng·L-1]<骨量减少组[(42.61±11.57)ng·L-1]<骨质疏松症组[(58.64±12.27)ng·L-1],三组差异有统计学意义(F=15.687,P=0.001);25OHD对比,骨量正常组[(22.48±7.95)μg·L-1]>骨量减少组[(17.32±6.58)μg·L-1]>骨质疏松症组[(13.57±5.24)μg·L-1],三组差异有统计学意义(F=12.542,P=0.002)。在PTH比较方面,四个季节来医院就诊的DM患者的数据结果差异无统计学意义(F=1.368,P>0.05),在25OHD,四个季节来医院就诊的DM患者的数据结果差异有统计学意义(F=10.268,P<0.05),经过q检验,夏、秋季患者的25OHD水平明显高于冬季和春季患者(P<0.05)。通过对患者的性别,年龄,就诊季节,BMI和HbA1c调整之后,PTH与PINP呈正相关(r=0.249,P=0.013),PTH与β-CTX呈正相关(r=0.378,P=0.022),25OHD与PTH呈负相关(r=-0.374,P=0.002),25OHD与PINP呈负相关(r=-0.142,P=0.011),25OHD与β-CTX呈负相关(r=-0.131,P=0.003),通过ROC曲线计算得出,PTH, 25OHD, PINP和β-CTX对于骨质疏松症的诊断阈值依次分别为47.61 ng·L-1,15.24 μg·L-1,37.54 μg·L-1,382.64 pmol·L-1。 结论 PTH水平增高的患者更容易患骨量减少或骨质疏松症,25OHD的水平增高是骨量减少或骨质疏松症的保护因素,在不同的季节患者体内的25OHD水平不同,在缺乏日照季节,患者应注意25OHD的适当补充。     

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1–34 for the treatment of osteoporosis

Osteoporosis treatment with PTH 1–34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1–34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1–34 nasal spray formulation bioactivity. The chemically synthesised PTH 1–34 had an EC₅₀ of 0.76 nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol^® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1–34 within an in vitro cell culture model (p > 0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol^® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1–34 into the blood via intranasal delivery produced a Cmax of 2.1 ± 0.5 ng/ml compared to 13.7 ± 1.6 ng/ml with Solutol^® HS15 enhancer (p = 0.016) and a Cmax14.8 ± 8 ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol^® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol^® HS15 formulation therefore demonstrated potential as a PTH 1–34 nasal spray formulation for the treatment of osteoporosis.     

Duration of treatment in postmenopausal osteoporosis: how long to treat and what are the consequences of cessation of treatment?

Although a variety of medications are effective for the treatment of postmenopausal osteoporosis, there is concern that long-term use may incur side effects. Consequently, some have proposed discontinuing or temporarily suspending treatment after a defined period of time. As the benefits of fracture risk reduction may recede during this "drug holiday", the clinician may be faced with deciding when to resume therapy (and with which agent) while avoiding the possible cumulative risk of side effects. This article summarizes data regarding length of treatment and the effects of cessation of treatment on bone density, bone turnover markers, and fracture risk.     

Combination antiresorptive and osteoanabolic therapy for osteoporosis: We are not there yet

Abstract

Osteoanabolic therapy is theoretically and practically an appealing therapeutic option for men and postmenopausal women with osteoporosis because bone formation is directly stimulated, an action that is not shared by any antiresorptive agent. Parathyroid hormone (PTH), in the form of the full-length molecule (PTH[1-84]) and its fully active but truncated amino-terminal fragment teriparatide (PTH[1-34]), belong to this osteoanabolic class. Both formulations of PTH increase bone mineral density, increase biochemical markers of bone turnover, and reduce fracture incidence. They improve skeletal microstructure. While antiresorptive agents are considered by most to be first line for the treatment of osteoporosis, there are situations when anabolic therapy could be reasonably considered as first line. In most situations, however, treatment with PTH follows a course of antiresorptive therapy. Simultaneous combination therapy with PTH and an antiresorptive drug does not appear to provide any advantages over monotherapy. After the recommended 2-year period of PTH treatment, an antiresorptive should be used to maintain densitometric gains. The drugs are well tolerated. Early safety concerns about osteosarcoma in rats have not been borne out after almost 9 years experience with human subjects.     

The use of parathyroid hormone in the treatment of osteoporosis

Anabolic skeletal agents have recently broadened our therapeutic options for osteoporosis. By directly stimulating bone formation, they reduce fracture incidence by improving bone qualities in addition to increasing bone mass. Teriparatide [recombinant human parathyroid hormone(1–34)], the only anabolic agent currently approved in the United States for osteoporosis, has emerged as a major therapeutic approach to selected patients with osteoporosis. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. With the use of this anabolic agent, bone density and bone turnover increase, microarchitecture improves, and bone size is beneficially altered. The incidence of vertebral and nonvertebral fractures is reduced with teriparatide use. Combination therapy with parathyroid hormone and an antiresorptive does not appear to offer definitive advantages over the use of PTH or an antiresorptive alone, although recent ideas about combining these agents may offer new insights. In order to maintain increases in bone density acquired during PTH therapy, it is important to follow its use with an antiresorptive agent.     

Treatment persistence and changes in fracture risk,back pain,and quality of life amongst patients treated with teriparatide in routine clinical care in France: Results from the European Forsteo Observational Study

ObjectivesThe European Forsteo Observational Study assessed the clinical fracture incidence, back pain, quality of life (QoL), and treatment persistence amongst post-menopausal women, who were prescribed teriparatide in routine care in eight European countries. We present the results for France, with health-insurance reimbursement criteria channel teriparatide to women with severe disease and limit treatment to 18 months.MethodsA representative sample of women initiating teriparatide in France was followed in routine care for 36 months. We described patients’ characteristics at baseline and persistence to teriparatide (Kaplan–Meier analysis), fracture incidence, back pain, and QoL (EQ-5D) at baseline, 18 and 36 months follow-up (last-observation-carried-forward (LOCF) and mixed-models-for-repeated-measures (MMRM).ResultsOne hundred and sixteen rheumatologists included 309 patients, of whom 290 (93.9%) had at least one follow-up visit. Women's mean age (standard deviation) was 74.5 years (7.4) and 296 (95.8%) had greater or equal to two vertebral fractures prior to teriparatide initiation. Clinical fracture incidence, mainly vertebral fractures, decreased around 6 months after teriparatide initiation, and was sustained at 36 months (P = 0.013) when most patients were treated by anti-resorptives. Back pain and EQ-5D measures improved significantly at 18 and 36 months (P < 0.0001) in the LOCF analyses but did not improve in the EQ-5D VAS measure after covariate adjustment in the MMRM model. Median treatment duration was 17.4 months.ConclusionFrench women initiating teriparatide in routine care had severe osteoporosis and showed good treatment persistence, consistent with France's insurance reimbursement criteria. Improvements in fracture risk and back pain began soon after treatment and was maintained at 36 months follow-up.