注射用唑来膦酸对恶性肿瘤骨转移疼痛的临床疗效和安全性分析

目的:评价注射用唑来膦酸治疗肿瘤骨转移引起疼痛的有效性及安全性。方法:50例癌症骨转移中度以上疼痛患者随机、双盲和双模拟分为两组,每组25例。研究组为唑来膦酸4 mg加入生理盐水注射液100 mL中静脉滴入15 min;对照组为帕米膦酸二钠60 mg加入5%葡萄糖或生理盐水注射液500 mL中静脉滴入至少4 h。对治疗前、治疗后第7天和第14天的NRS、QOL、KPS、缓解率和加用止痛剂情况进行比较;同时,对药物的不良事件、血尿常规和生化等指标进行评估。结果:治疗前研究组和对照组具有可比性。治疗后两组的NRS较治疗前明显降低(治疗前、治疗后第7天和第14天:研究组6.36vs4.08vs3.28,P<0.01;对照组5.92vs4.20vs3.36,P<0.01),具有明显缓解疼痛的作用;治疗后两组的QOL较治疗前明显提高(治疗前、治疗后第7天和第14天:研究组18.92vs23.40vs24.20,P<0.01;对照组19.56vs23.12vs23.88,P<0.01),明显改善了生活质量,治疗后两组的KPS较治疗前也明显改善(治疗前和治疗后第14天:研究组67.60vs78.00,P<0.01;对照组60.80vs70.80,P<0.01),但治疗后两组间差异均无统计学意义。疼痛总缓解率研究组稍高于对照组,但差异无统计学意义(第7天60%vs48%,P=0.395;第14天80%vs72%,P=0.742);加服即释吗啡人数研究组和对照组各1例。对照组中有1例在输注帕米膦酸后出现轻度全身疼痛,约12 h后自行消失。结论:唑来膦酸对癌症骨转移的疼痛有良好的疗效,且具有给药时间短、给药剂量小和作用时间长的临床特点。不良反应轻微,患者耐受良好。     

Secondary prevention of fractures in older people: evaluation of a protocol for the investigation and treatment of osteoporosis

It has been found previously that the investigation and treatment of osteoporosis following a fracture is poor, with only 9% of older people after a fracture being on effective osteoporosis treatment. To improve this aspect of post-fracture care in older people, a protocol has been instituted on an orthogeriatric rehabilitation ward in Christchurch, New Zealand. An audit was performed to assess the efficacy of this protocol in improving the investigation and treatment of osteoporosis (n = 193). Compliance with the investigation protocol was assessed and the pharmacological therapy initiated was requested from the general practitioner. All recommended blood-test investigations were requested in 62.8% of cases. Compared to a pre-protocol population, there was a marked increase in the measurement of bone mineral density (BMD; 93 vs 11%, P < 0.01) and vitamin D (95 vs 12%, P < 0.01). Vitamin D levels were low/-borderline in 95.6% of cases. BMD was performed in 77.7% of cases and showed osteoporosis and osteopenia to be present in 78.6 and 14.0%, respectively. For the 60 patients with BMD-confirmed osteoporosis whose therapy was obtained, 13.3% had no pharmacological therapy prescribed. Calcium, vitamin D or both were prescribed in 85.0%, bisphosphonates in 50.0% and hormone replacement therapy in 1.7% of patients. Vitamin D deficiency and osteoporosis on the basis of the BMD result are very common. The institution of a protocol has shown a significant improvement in the management of osteoporosis following a fracture. Some of the multifactorial barriers to full implementation of the guidelines are described.     

Synthesis and biological evaluation of a series of 99mTc‐labeled diphosphonates as novel radiotracers with improved bone imaging

Three radiolabeled diphosphonates, ^99mTc‐labeled 1‐hydroxy‐3‐(2‐propyl‐1H‐imidazol‐1‐yl)propane‐1,1‐diyldiphosphonic acid (PIPrDP), 1‐hydroxy‐4‐(2‐propyl‐1H‐imidazol‐1‐yl)butane‐1,1‐diyldiphosphonic acid (PIBDP), and 1‐hydroxy‐5‐(2‐propyl‐1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid (PIPeDP), have been designed and synthesized with good chemical yields and high radiochemical purity. Their in vitro and in vivo biological properties were investigated and compared. All radiotracers evaluated in mice showed substantial retention in bone (8.42 ± 0.53, 9.08 ± 0.65, and 10.3 ± 0.61 ID%/g, respectively) at 1 h post‐injection and had rapid clearance in blood (1.9484, 1.3666, and 0.7704 ID%/g/min, respectively). ^99mTc‐PIBDP has the highest uptake ratio of bone‐to‐soft tissue at 1 h post‐injection among the three radiotracers. The results indicate that ^99mTc‐PIBDP is the most promising bone imaging agent. Copyright © 2012 John Wiley & Sons, Ltd.     

利塞膦酸钠治疗绝经后骨质疏松症患者血清IL-6、TNF-α的变化

目的探讨白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)在利塞膦酸钠治疗绝经后骨质疏松症中变化的意义。方法根据骨密度(BMD)检查结果,选择46例绝经后骨量减少和骨质疏松妇女,采用放免法测定治疗前后血清IL-6、TNF-α、骨钙素(BGP),ELASA法测I型胶原交联氨基末端肽(NTX)。结果绝经后骨质疏松妇女应用利塞膦酸钠5mg/d治疗1年后,与治疗前相比血清IL-6、TNF-α水平下降,血清BGP水平及尿NTX/尿肌酐(Cr)水平降低,BMP上升。对照组治疗后,上述指标无明显改变。两组治疗后相比,上述指标差异有显著性。结论利塞膦酸钠治疗骨质疏松症可能部分是通过抑制IL-6、TNF-α的产生而发挥作用的。     

双膦酸盐对破骨细胞分化及抗酒石酸酸性磷酸酶的影响

背景：抗酒石酸酸性磷酸酶是破骨细胞分化及骨吸收功能的特异性标志酶,是破骨细胞分化成熟的标志。目的：观察双膦酸盐对破骨细胞分化及骨吸收功能相关因子抗酒石酸酸性磷酸酶的影响。方法：小鼠单核巨噬细胞RAW264.7诱导培养破骨细胞。实验分2组：对照组开始时加入质量浓度100μg/L核因子kB受体活化因子配体进行诱导至收获细胞,双膦酸盐组在对照组的基础上加入10-7 mol/L阿仑膦酸盐处理至收获细胞。培养第7天检测各组破骨细胞生成和骨吸收功能,免疫荧光检测两组抗酒石酸酸性磷酸酶表达的差异,Western blot检测抗酒石酸酸性磷酸酶蛋白表达情况。结果与结论：各组细胞均有抗酒石酸酸性磷酸酶阳性多核破骨细胞生成,并在牙本质磨片上形成吸收陷窝;但对照组抗酒石酸酸性磷酸酶阳性多核细胞数目、吸收陷窝数目及陷窝面积均大于双膦酸盐组（P〈0.01）。免疫荧光检测显示,对照组抗酒石酸酸性磷酸酶表达均强于双膦酸盐组（P〈0.01）。Western blot检测显示,双膦酸盐组抗酒石酸酸性磷酸酶蛋白的表达低于对照组（P〈0.01）。说明双膦酸盐通过抑制抗酒石酸酸性磷酸酶蛋白的表达,阻碍破骨细胞分化生成及骨吸收功能。     

INFLUENCE OF PYROPHOSPHATE AND DIPHOSPHONATES ON RAT LIVER ADENYLATE CYCLASE

SUMMARY 1. Inorganic pyrophosphate (PPi) and diphosphonates inhibit glucagon-stimulated and fluoride-stimulated adenylate cyclase activity of rat liver.
2. Concentrations of diphosphonates required to produce inhibition are lower than those of PPi, and PPi inhibited fluoride-stimulated activity to a greater extent than glucagon-stimulated activity.
3. Diphosphonates have inhibitory activity in the presence and absence of an ATP regenerating system in the adenylate cyclase assay, and do not substantially affect the efficiency of the ATP regenerating system. No evidence was obtained that reversal of adenylate cyclase was responsible for PPi inhibition.
4. Fluoride virtually completely inhibits pyrophosphatase activity in crude membrane preparations from rat liver, whereas glucagon has no detectable effect.     

Protective action of some diphosphonates against injury to lymphocytes by antilymphocytic serum

Rabbit antilymphocytic serum and complement were used in quantities causing death of 50% of human lymphocytes isolated in a Ficoll-Verografin (amidotrizoate) density gradient. The experimental samples (0.2 ml of a lymphocyte suspension containing 2.4×10⁴–6×10⁴ cells) were treated with 10 mM solutions of diphosphonates [disodium salt of hydroxyethylenediphosphonic (HEDP) acid, alkylated HEDP-acid, aminomethyl-HEDP-acid, aminobenzyldiphosphonic and aminoisopropyldiphosphonic acids] in doses of 0.001 to 0.2 ml. A decrease in the number of dead cells was observed after staining with 0.1% trypan blue. The disodium salt of HEDP-acid and alkylated HEDP-acid proved to be most effective and exhibited protective properties in doses as low as 0.01 ml. In a dose of 0.1 ml, all the tested compounds had a marked protective action.Research Institute of Pediatrics and Pediatric Surgery, Ministry of Health of the RSFSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR, P. N. Kosyakov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 9, pp. 339–341, September, 1978.     

Immediately loaded bar-connected implants with an anodized surface inserted in the anterior mandible in a patient treated with diphosphonates for osteoporosis: a case report with a 12-month follow-up

Background: It has been suggested that tooth loss is greater in the osteoporotic patient population. Only a few cases have been reported in the literature about the use of dental implants in patients with osteoporosis. Diphosphonates are stable analogs of pyrophosphate, a physiologic regulator of calcification and bone resorption. Multiple implant failures have been reported in a patient undergoing treatment with diphosphonates. Recently, several clinical and experimental reports have shown that immediate loading of dental implants is possible in selected situations. Purpose: The aim of this case report was to present the clinical outcome of immediate loading of implants in a patient undergoing diphosphonate treatment for osteoporosis. Materials and Methods: In a 65‐year‐old patient undergoing diphosphonate treatment for osteoporosis, four implants were inserted in the anterior mandible. The implants were connected with a bar supporting an overdenture and were then loaded the same day. Results: No problems occurred in the postoperative period. At 1‐year follow‐up, all four of the implants appeared to be clinically osseointegrated, and no mobility was present. Minimal bone resorption was present around all implants. Conclusions: Our case report points to the fact that, contrary to what has been reported in the literature, it is possible to successfully insert and load immediately after surgery dental implants in a patient undergoing diphosphonate treatment for osteoporosis     

Osteonecrosis of the jaw among cancer patients in Denmark: risk and prognosis

Osteonecrosis of the jaw (ONJ) is a serious complication of anti-resorptive therapy used in the treatment of multiple myeloma and cancerous bone metastases. In this study, patients with either multiple myeloma or solid tumours with a simultaneous or subsequent record of anti-resorptive treatment or bone metastases were identified using population-based medical registries. These patients were followed for the outcome of ONJ. Considering death as a competing risk, the cumulative incidence of ONJ was estimated, overall and by cancer site. Patients who developed ONJ were followed for the outcome of death overall and by several risk factors for ONJ. A total of 33,975 cancer patients fulfilling the inclusion criteria were identified; 233 incidents of ONJ and a cumulative incidence of 1.9% (95% confidence interval 1.6–2.3%) over a maximum follow-up time of 7.5 years were observed. The 5-year cumulative incidence was 1.3% (95% confidence interval 1.2–1.6%) and varied by cancer site. There were 126 deaths among cancer patients with ONJ over a maximum follow-up time of 6.4 years, resulting in a 5-year mortality of 91% (95% confidence interval 81–97%). Mortality among patients with ONJ varied by cancer site, osteonecrosis stage, and by history of trauma to the mucosa.