Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study.

OBJECTIVE. To assess the optimal dosage of oral tiludronate in Paget's disease of bone. METHODS. We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo-controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale and a global pain index. RESULTS. Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose-dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 +/- 4.2% reduction at 90 days and 49.2 +/- 4.5% at 180 days, mean +/- SEM) and at 800 mg (53.4 +/- 5% at 90 days and 59.3 +/- 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated. CONCLUSION. Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800-mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.     

Comparative prospective,double-blind,multicenter study of the efficacy of tiludronate and etidronate in the treatment of paget's disease of bone

Objective. To compare the efficacy and safety of tiludronate and etidronate at the same dosage (400 mg/day) for the treatment of active Paget's disease of bone. Methods. We studied 234 patients with radiologic lesions characteristic of Paget's disease of bone and serum alkaline phosphatase (AP) concentrations at least twice the upper limit of normal, in a prospective, randomized, double-blind, multicenter clinical trial lasting 6 months. Patients were randomly allocated into 1 of 3 treatment groups: tiludronate for 3 months followed by placebo for 3 months, tiludronate for 6 months, or etidronate for 6 months. Serum AP levels and urinary hydroxyproline excretion were measured at baseline and after 3 months and 6 months. Patients with a reduction of at least 50% in the serum AP concentration were considered to be responders. Results. After 3 months, the proportion of responders was higher in the tiludronate group (57.4%) than in the etidronate group (13.9%) (P < 0.0001). In the etidronate group, this percentage was lower among patients who had received previous treatment with a bisphosphonate (2.3%) than among those who had not (28.6%) (P < 0.01). Previous bisphosphonate treatment was not associated with response in the tiludronate group. After 6 months, the proportion of responders did not differ between the 2 tiludronate groups (60.3% and 70.1%), but was lower in the etidronate group (25.3%) (P < 0.0001). There was a higher proportion of patients with treatment-resistant disease ( < 25% reduction of serum AP) in the etidronate group (51.9%) than in the tiludronate 3-month group (17.9%) or the tiludronate 6-month group (19.5%) (P < 0.0001). Gastrointestinal disturbances were more common, and occurred earlier, with tiludronate, but they were mostly mild, requiring no treatment. Conclusion. Tiludronate at 400 mg/day for 3 months or 6 months is more effective than the same dosage of etidronate for 6 months in the treatment of Paget's disease.     

Skeletal metabolism in paget's disease of bone

Paget's disease of bone is characterized by focal resorption of existing bone followed by the deposition of woven and lamellar bone in a characteristic pattern. Although bone turnover may be markedly increased, the coupling between formation and resorption is maintained. Metabolically there is increased efflux and influx of mineral ions in the involved areas. In addition, there is a parallel increase in resorption of matrix components, particularly collagen, with increased excretion of degradation products containing 4-hydroxyproline, hydroxylysine, and its glycosides. A portion of the urinary 4-hydroxyproline and hydroxylysine is in the form of peptides of approximately 5,000 daltons which appear to be related to collagen synthesis. Circulating levels of other organic matrix components are also increased such as procollagen fragments and the γ-carboxyglutamic acid-bone protein. The increased levels of most of these metabolites return toward normal with specific therapy. The pattern of change suggests that bone resorption is decreased initially with therapy followed by a coupled decrease information.     

Orthopedic aspects of paget's disease of bone

The special features of fractures, usually in the femur or the tibia, and their treatment in Paget's disease of bone are discussed. Osteotomy of the femur or tibia for marked deformity, and joint replacement of the hip or knee for painful arthritis can be carried out quite successfully. The high incidence of sarcomas arising in the humerus, the development of multiple sites of malignant change, and some features of tumors on the skull are noted.     

Paget''s disease of bone treated with a five day course of oral tiludronate.

Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have only been seen at doses much higher than those required to decrease osteoclastic activity, it could be given at high doses over a short period of time. Eighteen patients with Paget's disease of bone were randomly allocated to three therapeutic groups receiving respectively 600, 800, and 1200 mg/day tiludronate for five days. Serum alkaline phosphatase activity and the urinary hydroxyproline/creatinine ratio were quickly and drastically reduced in all three groups. A significant reduction of serum alkaline phosphatases and the hydroxyproline/creatinine ratio was still present six months after the five day therapeutic course, reflecting a sustained activity of tiludronate even after stopping treatment. Dose dependent short and long term reductions of bone turnover rate were observed. Biochemical assessment of haematological, renal, or hepatic tolerance did not show any toxicity of tiludronate. Fifty per cent of patients treated by a dose of 1200 mg/day reported gastrointestinal disturbances, however, making this dosage unsuitable for clinical practice.     

Musculoskeletal manifestations of paget's disease of bone

A review of 290 patients with Paget's disease of bone revealed 83% had one or more rheumatic syndromes. The most common finding was back pain (37%), most often related to an independent osteoarthritic process or Paget's disease precipitating or complicating spinal osteoarthritis. Paget's disease as a sole source of back pain was distinctly uncommon (2%). Osteoarthritis related to Paget's disease was present in the hip (30%) and knee (11%). Paget's disease in spondylitis was present in 4 patients and in ankylosing hyperostosis in 4 patients. The latter group had very active Paget's disease. Rheumatoid arthritis (1%), hyperuricemia (20%), and gout (4%) did not appear increased in this group.     

Quantitative bone scintigraphy in the management of monostotic paget's disease of bone

Objective. To assess the use of quantitative bone scanning (QBS) in the monitoring of patients with intravenous pamidronate–treated symptomatic mono-stotic Paget's disease of bone in whom biochemical markers of bone turnover are relatively normal. Methods. QBS was performed in 9 patients and the results were expressed as a ratio, obtained by comparing isotope uptake at an affected and a control (unaffected) site. Results. Serum alkaline phosphatase levels were normal in 7 of the 9 patients and changed minimally with treatment. The median QBS ratio was 2.72 (range 1.69–24.6) at baseline and 1.49 (range 0.63–4.18) post- treatment (P = 0.008). The median symptom score decreased with treatment, but QBS ratios provided the only objective measure of disease activity by which response to pamidronate therapy could be judged. Conclusion. QBS may be a useful technique for evaluating the effects of treatment in patients with Paget's disease of bone.     

Bone tissue in paget's disease of bone ultrastructure and immunocytology

Ultrastructural observations in Paget's disease of bone clarify aspects of bone cells in bone tissue and demonstrate the presence of specific intranuclear inclusions composed of microcylinders in the osteoclasts. The morphologic analysis of these structures suggests an analogy with virus material of the measles group. Results obtained using indirect immunofluorescence and immunoperoxidase techniques lend further support to the hypothesis of a viral etiology in Paget's disease of bone.     

Use of etidronate (ehdp) in paget's disease of bone

Etidronate used in recommended doses (usually 5 mg/kg/day for 6 months) produces symptomatic improvement in approximately 60% of patients. The serum alkaline phosphatase and urinary hydroxyproline are reduced to about 50% of initial values. A sustained remission occurs in many patients and retreatment is usually effective upon relapse. The abnormally elevated osteoclast count and resorption surfaces are reduced, and at the low dose there is no accumulation of osteoid. The medication is generally well tolerated and at the recommended dosage there is no evidence of increased fracture rate.     

口服国产阿伦膦酸钠治疗绝经后骨质疏松症的疗效评价

目的为评价国产阿伦膦酸钠（ＡＬＮ）治疗绝经后骨质疏松症（ＰＭＯ）的有效性和安全性。方法将确诊的１８９例ＰＭＯ患者的前１２０例随机地分为试验组与对照组，其余６９例作为开放组。试验组与开放组口服ＡＬＮ１０ｍｇ／日，对照组服安慰剂。三组均日服等量的磷酸氢钙（含元素钙５１０ｍｇ），疗程为１年。结果试验组与开放组腰椎骨密度分别增加了６．３％及６．０％，明显高于对照组１．７％，且两组椎体无新发压缩性骨折发生，而对照组新发６例。骨痛缓解率也明显高于对照组。骨吸收与骨形成指标（尿Ｈｙｐ／Ｃｒ、ＡＬＰ、骨特异性ＡＬＰ、骨钙素），于治疗第３、６及１２月下降幅度亦明显大于对照组（Ｐ＜０．０５～０．００１）。部分病例有轻度、一过性胃肠道反应，但不影响治疗。三组血、尿常规及肝、肾功能未见异常改变。结论国产ＡＬＮ１０ｍｇ／日治疗ＰＭＯ有效、安全。     

Long term effectiveness of low dose mithramycin for paget's disease of bone

Nineteen patients with Paget's disease of bone were studied 7 months to 5 years after therapy with mithramycin in a dose averaging 11.5 μg/kg body weight daily for 10 days. Thirteen patients, including 3 with the longest followup intervals, remained free of pain. Objective measures of disease activity (serum alkaline phosphatase level and ^99mtechnetium pyrophosphate bone scan) were less favorable. There was no evidence of long term toxicity.     

中医药治疗老年痴呆症的疗效与安全性

目的系统评价中医药干预对老年痴呆症患者认知功能症状的改善与安全。方法全面搜集单纯中医药与中西医结合对比西药治疗老年痴呆症的相关随机对照试验(RCT)文献,采用计算机综合检索维普数据库、万方数据库、中国知网及中国生物医学文献数据库、Cochrane Library、EMbase与Pub Med,相关文献检索时间止于2014年8月1日;同时在大学图书馆以手工方式检索期刊资料库,对纳入研究的试验则依据Cochrane Handbook 5.1评估偏倚性风险及文献质量;采用软件Rev Man5.2.6进行相关数据分析,结合软件GRADE profiler对本研究的证据质量进行标化测评。结果本研究共纳入31个RCT临床干预文献,受试者2 583例;Meta分析提示:在有效率评测层面,中西医结合(中医药结合西药)疗效优于单纯西药治疗〔OR=3.35,95%CI(2.17,5.17)〕,单纯中医药与西药的有效率比较差异无统计学意义〔OR=1.20,95%CI(0.95,1.51)〕;在痊愈率评测层面,中西医结合(中医药结合西药)效应优于单纯西药治疗〔OR=1.86,95%CI(1.31,2.63)〕,单纯中医药和西药的痊愈率(临床控制率)比较差异无统计学意义〔OR=1.17,95%CI(0.94,1.46)〕;在MMSE评分层面对单纯中医药与西药进行亚组分析,即干预4 w〔WMD=0.31,95%CI(-0.38,0.99)〕、6 w〔WMD=0.18,95%CI(-0.52,0.89)〕、8 w〔WMD=0.75,95%CI(-0.32,1.83)〕及12 w〔WMD=0.06,95%CI(-0.76,0.88)〕组间评分皆无统计学差异(P0.05)。中医药(中医药结合西药)治疗老年痴呆患者不良事件的发生率(1.18%)显著低于西药干预(9.61%)。结论中医药作为一种有效的干预措施,相对安全可靠,不良反应较少,与西药干预效应相当。     

Salmon calcitonin therapy for paget's disease of bone the problem of acquired clinical resistance

During the initial months of long-term treatment of Paget's disease of bone with salmon calcitonin, circulating alkaline phosphatase activity and urinary hydroxyproproline excretion usually decrease by about 50%. In 22 of 85 patients these parameters returned to pretreatment levels despite continuous therapy. Nineteen patients who were resistant to salmon calcitonin had salmon calcitonin antibodies in high titer. Human calcitonin has been effective in suppressing disease activity in these patients. The pathogenesis of calcitonin resistance in patients without antibodies is unknown.     

噻托溴铵粉雾剂治疗慢性阻塞性肺病的有效性及安全性

目的观察噻托溴铵粉雾剂治疗慢性阻塞性肺病（COPD）的有效性及安全性。方法采用随机、双盲、双模拟阳性药平行对照、多中心临床研究的方法。对223例COPD稳定期Ⅰ、Ⅱ和Ⅲ级患者,分别吸入噻托溴铵粉雾剂（试验组）和异丙托溴铵定量气雾剂（对照组）,治疗28 d,测定患者用药前后不同时间的肺功能。结果 1.治疗28 d,对照组和试验组的临床改善率分别为47.71%（P〈0.05）和59.46%（P〈0.05）。2.各组给药后30、60、120 m in、28 d,FEV1与基线相比,差别均有统计学意义（P〈0.05）。治疗后28 d,试验组FEV1、FVC与对照组相比,差别有统计学意义（P〈0.01）。结论规律吸入噻托溴铵粉雾剂可显著改善COPD患者的临床症状,无严重药物不良反应。     

Evaluation of the safety and efficacy of amrinone in chronic obstructive lung disease with cor pulmonale

In a pilot study the effect of a bolus dose of amrinone intravenously (IV), 0.5 or 1 mg/kg body weight, in 10 patients with chronic obstructive lung disease and cor pulmonale was evaluated. We found that the higher dose of 1.0 mg/kg IV significantly (P less than 0.05) decreased the mean pulmonary artery pressure and pulmonary wedge pressure without significant changes in cardiac output, in systemic blood pressure or in arterial blood gas values. No adverse effects were recorded in any of the patients.     

Pharmacology, efficacy and safety of oral phosphate binders

The ideal serum level of phosphate in patients on dialysis, and the benefits of controlling levels of phosphate in serum remain unclear despite observational studies that associate phosphate levels with mortality. In the absence of robust data from trials, current guidelines are necessarily based on opinion. Oral phosphate binders are required by the majority of patients on dialysis, and all of these binders can control serum levels of phosphate to similar degrees. Patient preference and adherence to prescribed therapy is at least as important as the efficacy of the prescribed binder. Avoidance of calcium-containing binders has become accepted practice where the alternatives are affordable, but incontrovertible evidence in favor of this approach is lacking. Use of sevelamer and lanthanum avoids calcium loading, but at considerable financial cost and with no reliable patient outcome data to prove their value. Additional approaches to aid control of serum levels of phosphate include blockade of gastrointestinal phosphate absorption and possibly binding of salivary phosphate. Importantly, the role of phosphate control in determining patient outcomes must be quantified, which is likely to require a large randomized, controlled study of two levels of phosphate control. Without such a study we will continue to rely on observational data with all its uncertainties and potential to mislead.     

Biochemical and clinical responses to dichloromethylene diphosphonate (cl2mdp) in paget's disease of bone

Dichloromethylene diphosphonate (Cl₂MDP, or clodronate disodium) is one of the most potent of the known diphosphonates as an inhibitor of bone resorption and differs from EHDP in that it does not inhibit skeletal mineralization. It is one of the second generation diphosphonates now undergoing clinical evaluation. In the study described here Cl₂MDP was given by mouth (800-1600 mg/day for 6 months) to 35 patients with symptomatic Paget's disease of bone. Cl₂MDP induced a marked fall in serum alkaline phosphatase and urinary hydroxyproline to normal or near normal values in all patients. This was accompanied by clinical improvement in all but 4 patients. Cl₂MDP appears to be another effective oral drug for the treatment of Paget's disease of bone and compares favorably with the calcitonins and EHDP.     

Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy

OBJECTIVE:To compare the effects of tiludronate and risedronate on Paget's disease activity assessed by biochemical markers of bone turnover and quantitative bone scintigraphy. METHODS: An open-labeled non-randomized study was performed in 49 patients with Paget's disease who had completed treatment with tiludronate (400 mg/d) for 3 months (28 patients) or risedronate (30 mg/d) for 2 months (21 patients). Biochemical markers of bone turnover, including serum total alkaline phosphatase (TAP), bone alkaline phosphatase (BAP), procollagen type I N propeptide (PINP) and urinary N-terminal cross-linking telopeptide of type I collagen (NTX) were measured at baseline and at 6 and 12 months after the end of treatment. Quantitative bone scintigraphy at baseline and 6 months after the end of treatment was performed in all patients obtaining a scintigraphic activity index (SAI). RESULTS: At baseline there were no significant differences in disease activity between both groups of patients, since markers of bone turnover as well as SAI were similar in both groups. The effects of tiludronate and risedronate in reducing the biochemical markers of bone turnover were comparable at 6 months (tiludronate vs risedronate: TAP -52% vs -43%; BAP -69% vs -56%; PINP -68% vs -63%; NTX -62% vs -59%) and at 12 months after the end of treatment (tiludronate vs risedronate: TAP -47% vs -36%; BAP -57% vs -46%; PINP -57% vs -52%; NTX -51% vs -52%). The effects of tiludronate and risedronate on SAI were also similar 6 months after the discontinuation of treatment. In addition, the percentage of patients who showed normalized serum TAP levels at 6 months after treatment were similar with both agents (74% with tiludronate and 70% with risedronate). CONCLUSION: Tiludronate and risedronate given at the currently recommended dosages induce similar responses in Paget's disease activity.