双膦酸盐在髋部骨折治疗中的若干问题

髋部骨折每年在全球范围内都有很高的发生比例,与之相伴随的严重并发症的发生是临床中亟待解决的问题。而发生髋部骨折的最主要原因是骨质疏松的存在,并在骨折的整个发生发展过程中起着重要的影响作用。双膦酸盐类药物具有抑制破骨细胞活性和增高骨密度的特点,能够有效降低骨质疏松患者发生骨折的风险,同时又具备较好的用药安全性,是临床上应用最广泛的抗骨质疏松类药物。但是,近几年有研究指出长期服用双膦酸盐可抑制骨组织自然更新,导致骨折延迟愈合和再骨折的发生。本文就双膦酸盐类药物在骨质疏松性髋部骨折治疗过程中应该注意的几点问题进行综述。     

双膦酸盐抗血管形成机制研究进展

双膦酸盐具有直接抗肿瘤和抗血管形成作用,具体机制仍未肯定.现有研究认为双膦酸盐通过干扰甲羟戊酸信号通路的关键激酶,使小G蛋白异戊酸化受阻等机制抑制内皮祖细胞分化和小管样形成,阻止血管发生;抑制血管内皮细胞的增殖、黏附和迁移能力,干扰血管形成;调节肿瘤血管形成细胞因子分泌,抑制血管形成相关基因等功能发挥其抗血管形成作用.     

Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer

Goals of work Patients with prostate cancer metastasized to bone frequently experience skeletal morbidities as a result of their disease. We sought to quantify the longitudinal effects on patient-reported outcomes of skeletal-related events (SREs) and to ascertain the declines in health-related quality of life (HRQOL) and pain experienced by patients who experienced SREs. Materials and methods Data are from a clinical trial for the treatment of SREs associated with advanced prostate cancer metastatic to bone. Outcome measures included the Functional Assessment of Cancer Therapy-General (FACT-G) and the Brief Pain Inventory. Among patients who survived 6 months after randomization, patients with no SREs in the initial 6 months after randomization were matched via propensity scores with those experiencing one or more SREs. Similarly, patients with one SRE were matched with a subset of patients with two or more SREs. Main results Patients with SREs in the initial period had significantly worse survival and HRQOL than those with no SREs. Significant differences were found between the pain differences, FACT-G total scores, and FACT-G physical, emotional, and functional subscales. Comparisons of patients with single vs multiple SREs showed similar patterns. Conclusions The presence of SREs is significantly associated with worse survival and poorer HRQOL in this patient population. Increasing SRE intensity shows a pattern of increasingly decreased survival and poorer HRQOL. Ms DePuy is now with INC Research, Raleigh, NC, USA.     

氟与羟乙膦酸钠联合用药对去卵巢大鼠骨计量学和生物力学性质的影响

目的评价抗骨吸收药物与促进骨形成药物联合应用对去卵巢大鼠骨质疏松的潜在治疗作用。方法观察单独用羟乙膦酸钠（１ｍｇ·ｋｇ－１·ｄ－１）和氟钙剂（０４５ｎｇＦ－＋１３５６ｍｇＣａ２＋）·ｋｇ－１·ｄ－１与两者联合用药对去卵巢大鼠胫骨近端次级松质骨骨计量学指标和股骨中段骨生物力学性质的影响。结果与去卵巢不处理组比较，去卵巢氟钙剂处理组、去卵巢羟乙膦酸钠处理组及两者联合用药组小梁骨面积百分比分别高出４２％、１０９％、１１０％；小梁骨的数量分别多２４％、９４％、９０％；小梁骨分离度分别低３５％、１４８％、１３８％；吸收侵蚀表面分别少４５％、５０％、６３％；刺激频率在后两组分别低６１％、５７％。与假手术组比较，上述三种处理使矿化延迟时间分别延长１６％、４２％、２９％；联合用药组股骨干力学强度明显增加。上述诸参数的改变差异均有显著性（Ｐ＜００５）。结论羟乙膦酸钠能显著抑制骨吸收，降低骨转换，其保护小梁骨显微结构作用优于单用氟钙剂处理，与氟钙剂合用明显增加股骨的力学强度。但三种处理均有潜在的抑制矿化作用     

Effects of zoledronic acid on the expression of HIF-1α and VEGF in the osteosarcoma cell line LM8 under hypoxic condition

Objective To investigate the effects of zoledronic acid on the expression of HIF-1α and VEGF in osteosarcoma LM8 cell line under hypoxic condition. Methods The hypoxic culture model was established. After LM8 cells were treated with zoledronic acid, semi-quantitative PCR was used to assess the expression of HIF-1α and VEGF mRNA. The expression of HIF-lct and VEGF protein was de-tected by immunohistochemical staining and ELISA respectively. Results Compared with cells in normoxic conditions, cells in the hypoxic environment and cells treated with zoledronic acid in the hypoxic condition did not show a significant change in the mRNA level of HIF-1α(P >0. 05). However, the protein expression of HIF-1α was markedly decreased in the cells treated with zoledronic acid in the hypoxic envi-ronment. In contrast, both mRNA and protein expression levels of VEGF were down-regulated in the zoledronic acid treatment hypoxic group (P <0.05). Conclusion Under hypoxic conditions in vitro, zoledronic acid inhibited the expression of HIF-1α protein, which decreased VEGF mRNA level and protein expression in osteosarcorna LM8 cell line.     

乳腺癌内分泌治疗后骨质疏松的防治体会

目的探讨乳腺癌内分泌辅助治疗后所致骨质疏松的防治措施。方法乳腺癌术后内分泌治疗前后,应用骨密度测定及骨显像检查确诊为骨质疏松患者37例。随机分成两组,均使用钙剂和活性维生素D3,治疗组同时加用唑睐磷酸治疗,观察患者的症状、体征。结果经过治疗两组病情均有缓解,但唑睐磷酸组总有效率明显高于对照组。结论唑睐磷酸能有效改善乳腺癌内分泌治疗后的骨质疏松,治疗不良反应少。     

^99mTc—MDP显像用于乳房肿块良恶性的诊断研究

为评价９９ｍＴｃ羟基亚甲基二膦酸（ＭＤＰ）乳房显像鉴别诊断乳房肿块良恶性的价值，对１２１例体格检查或钼靶摄片高度怀疑乳房癌的病人进行９９ｍＴｃＭＤＰ乳房显像。病人均经穿刺活组织检查或手术切除获得病理结果，其中８４例为乳房癌，３７例为乳房良性肿瘤。在８４例乳房癌病人中，９９ｍＴｃＭＤＰ乳房显像７７例阳性，检出的最小病灶为７ｍｍ；３７例乳房良性肿瘤患者，３例假阳性，诊断灵敏度、特异性和假阳性率分别为９２％、９２％和８１％。９１例钼靶摄片高度疑为乳房癌病人的诊断灵敏度和假阳性率分别为７６％和２４％，诊断的灵敏度与肿瘤大小有关。因此，９９ｍＴｃＭＤＰ乳房显像是一种简单、有效而准确的非损伤性鉴别诊断乳房肿块良恶性的手段，明显优于钼靶摄片，且容易推广。     

Bisphosphonates: A New Treatment for Diabetic Charcot Neuroarthropathy?

Charcot neuroarthropathy is one of the most devastating complications of diabetes causing much discomfort and disability and sometimes leading to amputation. The current therapies are disappointing and fail to address the underlying disease process. In order to try and halt the underlying bone resorption we have studied the action of the bisphosphonate, pamidronate, in six diabetic patients with active Charcot neuroarthropathy. The treatment was associated with improvement in the patients' symptoms and a reduction in Charcot activity as measured by temperature of the affected foot which fell from 3.4 ± 0.7 (SE)°C to 1.0 ± 0.5°C above the intact foot (p = 0.05). There was a significant reduction in bone turnover as judged by alkaline phosphatase activity which fell by 25 ± 3% (p < 0.001). These preliminary data suggest that bisphosphonates may be the first definitive treatment for active Charcot neuroarthropathy and that controlled trials are now indicated.     

Bone loss and bone blood flow in paraplegic rats treated with calcitonin,diphosphonate, and indomethacin

Summary Sham-operated (SO) and paraplegic rats were treated from the day of operation during a period of 4 or 6 weeks with salmon calcitonin 4 IU/kg/day or a diphosphonate (APD) 1mM/kg/day or indomethacin 2.5 mg/kg/day. The consequence of spinal cord section on the femur and tibia is a loss of mineral which affects predominantly trabecular bone (−24 and −13% in calcium content for the tibial metaphysis and the whole bone, respectively, when compared with the SO controls), a twofold increase in bone blood flow as measured by the technique of the microspheres trapping, a moderate decrease of the 72 hour⁴⁵Ca accretion rate in the bone shaft, and an increase in the number of metaphyseal osteoclasts in the tibia. In paraplegics, all three drugs inhibit bone loss to some degree, calcitonin and indomethacin being mostly effective on the cortical bone of the shaft, and APD tremendously increasing the trabecular network of the metaphysis. APD is the only drug to exhibit a significant effect on the calcium content of the bones of the SO controls, but some effect is apparent for calcitonin on X-rays and histological preparations. The increase in bone blood flow in paraplegics is unaffected, this point being discussed in view of the hypothesis of the resorptive action of prostaglandins produced by newly formed vessels.⁴⁵Ca accretion rate increases in the shaft of calcitonintreated paraplegics, whereas it decreases in APD-treated controls and paraplegics. The number of osteoclasts decreases in paraplegics treated with calcitonin and indomethacin, and increases in both controls and paraplegics treated with APD. Thus, APD shows an outstanding effect on the bone loss at the very place where it occurs preferentially in the paraplegics (the trabecular metaphysis), but this and other effects affect the controls as well. Calcitonin and indomethacin act almost selectively on the diseased animals. All three drugs fail to inhibit the bone blood flow increase observed in paraplegics and supposedly associated with bone resorption.     

Effects of two diphosphonates (EHDP and Cl2MDP) on serum uric acid in pagetic patients

Summary The effects on serum uric acid (SUA) of two diphosphonates (EHDP at 5 and 20 mg/kg/day and Cl₂MDP at 400 and 1600 mg/day) were studied in 49 pagetic patients treated for 6 months. Patients were divided into two groups: group I, initially normouricemic (SUA <385μmol/l); group II, initially hyperuricemic (SUA ⩾385μmol/l). SUA was significantly decreased (P<0.01) after 6 months of diphosphonate therapy in all group II patients. However, 3 months after withdrawal of therapy, SUA returned to values not significantly different from those initially recorded in this group. SUA did not change during or after treatment in the group I patients. Groups I and II could not be differentiated on the basis of initial serum alkaline phosphatase or urinary hydroxyproline values. In response to therapy, both groups showed the same reduction in these parameters. These results suggest that diphosphonates have no effect at a single level in uric acid metabolism. They certainly reduce the part of the urate pool coming from the nucleic acids of the increased bone cell population by reducing the number of osteoclasts and osteoblasts, which is extremely high in pagetic bone. They also must act on uric acid metabolism through other mechanisms which need to be investigated in further studies.