依替膦酸二钠治疗老年性骨质疏松症的体会

骨质疏松症是一种以低骨量和骨组织微结构破坏为特征、导致骨脆性增加易发生骨折的全身性疾病。多发生于老年人和绝经后妇女,其发展常在无声无息中进行,早期发现及时治疗,可控制或减缓病程的发展,降低骨折的发生率。依替膦酸二钠(依膦)能有效抑制破骨过程,与钙剂及其他综合疗法合用治疗老年性骨质疏松症,有良好的效果。一、材料和方法1一般资料本组52例老年女性职工,年龄62～70岁,平均64岁。患者均以骨痛就诊,经中国测试技术研究院生产的单光子骨密度测定仪检测,确诊为骨质疏松症。随机分为两组,治疗组26例,对照组26例。检查部位;右桡骨远端…     

依替二膦酸锶对大鼠腰椎及股骨骨密度的影响

目的观察新合成的抗骨质疏松化合物依替二膦酸锶对骨代谢的影响。方法以去势SD大鼠为基础,对依替二膦酸锶、依替二膦酸二钠和二氯化锶以及不同剂量依替二膦酸锶对大鼠股骨及腰椎的骨密度的影响进行动态观察和比较。结果依替二膦酸锶与相同摩尔剂量的依替二膦酸二钠和二氯化锶相比,对去势大鼠腰椎和股骨骨密度的影响更为明显。其干预后去势大鼠骨密度增加的出现更早,且其升高的幅度也较高。50 mg/(kg·d)、100 mg/(kg·d)和150 mg/(kg·d)3种不同剂量的依替二膦酸锶均能有效地增加去势大鼠椎体和股骨的骨密度,且其增加骨密度的能力无明显差异。结论新化合物中的骨吸收抑制物依替二膦酸和骨形成促进物锶进入大鼠体内后,两者的生物学效应可能存在互补性。     

依替二膦酸锶对大鼠腰椎及股骨生物力学的性质的影响

目的 观察新合成的抗骨质疏松化合物依替二膦酸锶对骨组织生物力学的影响。方法 以去势SD大鼠为基础,对依替二膦酸锶、依替二膦酸二钠和二氯化锶以及不同剂量依替二膦酸锶对大鼠股骨及腰椎生物力学性质的影响进行动态观察和比较。结果 依替二膦酸二钠治疗12 w后其股骨的最大负荷升高9.5%(P =0.028),并且其差异表现出统计学意义;依替二膦酸锶治疗组8 w、12 w后,其股骨的最大负荷分别升高21. 9%和22. 3%(P = 0. 020,P =0.047),且均表现出统计学差异。3种不同药物治疗下,股骨于最大负荷下的变形没有明显变化。所有治疗组大鼠椎体的最大负荷均高于去势对照组。依替二膦酸锶治疗12 w后,其椎体的最大负荷明显升高（P =0.016),并表现出统计学差异。观察到100 mg/ ( kg? d)和 150 mg/(kg? d)治疗组干预8 w后,其股骨最大负荷升高(P =0. 035,P = 0. 042),并表现出统计学意义;椎体最大负荷于也明显升高(P =0.018),并表现出统计学意义。大鼠股骨他椎体于最大负荷时的椎体变形并未表现出统计学意义。实验发现依替二膦酸锶与依替二膦酸二钠相比,对去势大鼠腰椎和股骨生物力学性质的影响更为明显。其干预后去势大鼠骨组织生物力学性质的出现更早,且其升高的幅度也较高。50 mg/(kg? d)、100 mg/(kg?d)和150 mg/( kg? d)3种不同剂量的依替二膦酸锶均能有效地改善去势大鼠椎体和股骨的生物力学性质,且其改善生物力学性质的能力无明显差异。结论 新化合物中的骨吸收抑制物依替二膦酸和骨形成促进物锶进人大鼠体内后,两者的生物学效应可能存在互补性。     

依替二膦酸锶对去势大鼠骨代谢的影响

目的观察新合成的抗骨质疏松化合物--依替二膦酸锶对骨代谢的影响。方法本研究以去势SD大鼠为基础,对依替二膦酸锶、依替二膦酸二钠和二氯化锶以及不同剂量依替二膦酸锶对大鼠血清骨钙素(BGP)和血清抗酒石酸酸性磷酸酶5b(TRAP-5b)的影响进行动态观察和比较。结果药物干预治疗后,依替二膦酸锶治疗组其血清TRAP-5b均逐渐下降,与去势对照组的相比表现出明显统计学差异;依替二膦酸锶150mg/kg·d治疗组,其血清BGP有缓慢上升的趋势,于12w末与去势对照组相比差异表现出显著的统计学意义。结论依替二膦酸锶50mg/kg·d、100mg/kg·d和150mg/kg·d治疗剂量均能有效抑制破骨细胞分泌TRAP-5b的能力。依替二膦酸锶150mg/kg·d治疗剂量可能有助于增强绝经期后骨质疏松大鼠成骨细胞分泌BGP的能力。     

依替膦酸二钠抑制绝经后骨质疏松症患者骨吸收的临床研究

目的　评价依替膦酸二钠对绝经后骨质疏松症患者骨吸收的抑制作用。方法　绝经后骨质疏松症患者 32例 ,测定其腰椎、股骨颈骨密度和尿中脱氧吡啶啉的浓度。口服依替膦酸二钠2 0 0mg ,2次 d ,2周后改服钙尔奇D片 (钙 6 0 0mg及维生素D 12 5IU d) 11周 ,共 13周为一疗程 ,治疗两个疗程后复查骨密度和尿脱氧吡啶啉的浓度。结果　治疗两个疗程后 ,患者腰椎骨密度显著增高 (治疗前为 0 6 94± 0 12 4g cm2 ,治疗后为 0 72 1± 0 10 8g cm2 ,P <0 0 5 ) ,股骨颈骨密度无显著变化 (治疗前为 0 5 91± 0 117g cm2 ,治疗后为 0 6 0 2± 0 0 98g cm2 ,P >0 0 5 ) ;尿脱氧吡啶啉浓度显著降低 (治疗前为 6 6 7± 2 0 4nmol mmolCr,治疗后为 4 2 2± 1 6 3nmol mmolCr,P <0 0 1)。结论　依替膦酸二钠能有效抑制绝经后骨质疏松症患者的骨吸收。     

国产羟乙膦酸二钠治疗骨质疏松症180例临床验证报告

对国产的羟乙膦酸二钠（康骨片）进行治疗骨质疏松症的临床验证，考察其疗效和安全性。方法三家医院共观察骨质疏松患者１８０例，将病例接随机双盲法分组，其中羟乙膦酸二钠治疗组１０１例，安慰剂对照组７９例。通过治疗前后腰椎和髋部骨密度值变化和临床症状缓解情况判断疗效。数据经配对ｔ检验和Ｘ２检验处理。结果经两个疗程共６个月的治疗，骨质疏松患者治疗前后的比较，治疗组２～４、股骨颈、大转子和Ｗａｒｄｓ三角区等部位治疗后骨密度增加显著，对照组均无显著变化。两组间比较，Ｌ２～４、大转子和Ｗａｒｄｓ三角区骨密度指标差异有显著性。羟乙膦酸二钠还可缓解因骨质疏松引起的腰背痛等症状，增加关节活动度。治疗期间未见明显的副作用。治疗组晨尿ＨＯＰ／Ｃｒ下降显著，表明羟乙膦酸二钠能抑制骨吸收。结论以上结果表明，羟乙膦酸二钠（康骨片）是骨质疏松症安全有效的治疗药物。     

唑来膦酸、雷奈酸锶对去势大鼠股骨干骺端缺损修复的效果对比研究

目的研究不同抗骨质疏松药物唑来膦酸、雷奈酸锶对去势大鼠股骨干骺端缺损修复的影响。方法选用SPF级40只健康雌性SD大鼠行手术建立去卵巢模型(OVX组,n=35)和假手术模型(Sham组,n=5)。手术后3个月处死随机选取的5只OVX组大鼠与5只Sham组大鼠,测量其骨密度(BMD)来证实骨质疏松模型建立成功。随后所有的OVX组大鼠在双侧股骨干骺端建立直径为3mm的骨缺损模型后随机分为3组,唑来膦酸治疗组10只(ZA组,1.5μg/w),雷奈酸锶治疗组10只(SR组,625mg/kg,每周5次),空白对照组10只(Control组,等体积的生理盐水)。术后6、12w进行Micro-CT观察、组织病理学观察。结果 6、12w时成骨效果:ZA组和SR组在缺损区HE染色观察均可见大量骨小梁和较多成熟的骨细胞,但12w时Micro-CT显示骨微观结构修复效果ZA组明显好于SR组,新生骨密度也高于SR组。空白对组HE染色观察可见骨组织生成较少,骨小梁排列稀疏紊乱,Micro-CT显示骨微观结构修复效果不佳,新生骨密度也不够理想。结论唑来膦酸较雷奈酸锶能够更好地修复骨质疏松骨缺损。     

帕米膦酸二钠对人骨髓间充质干细胞增殖和成骨分化的影响

目的观察帕米膦酸二钠对人骨髓间充质干细胞(Mesenchymal stem cells,MSC)生物学特性的影响,以探索双磷酸盐导致骨组织损伤的机制。方法人骨髓MSC培养体系中加入不同浓度的帕米膦酸二钠,培养72 h后,MTT法测定490 nm光密度值,观察细胞增殖情况;培养1周后,流式细胞技术检测细胞表面分子表达。体外诱导MSC成骨分化,体系中加入1μg/mL帕米膦酸二钠,1周后PCR法测定细胞Runx-2表达水平,2周后组织化学法测定细胞内碱性磷酸酶活性,以细胞总蛋白量为参照,观察MSC成骨分化的差异。结果 MTT结果显示,在0.1~10μg/mL浓度范围内,帕米膦酸二钠抑制人骨髓MSC增殖,作用呈浓度依赖性,最低作用浓度为1μg/mL,72 h OD490显著低于对照组(P<0.01)。流式细胞检测显示,帕米膦酸二钠处理后,细胞仍均一表达CD44和CD73,不表达CD31和CD45。PCR及细胞化学结果显示,帕米膦酸二钠无促进MSC成骨分化作用,也未提高成骨诱导体系促分化效果。结论帕米膦酸二钠可抑制MSC增殖,不促进其体外成骨能力,可能是长期使用双磷酸盐导致骨损伤的机制之一。     

唑来膦酸对女性骨质疏松症的疗效及其对骨标志物的影响

目的探讨唑来膦酸注射液(密固达)对女性不同原因所致骨质疏松的临床疗效及其对骨代谢标志物的影响。方法回顾性分析2012年4月至2016年7月在长海医院风湿免疫科接受唑来膦酸治疗的119例女性骨质疏松症患者,根据病情分为原发性骨质疏松组和继发性骨质疏松组,其中原发性骨质疏松组66例,年龄52~87岁,平均69.8±9.6岁;继发性骨质疏松组53例,年龄51~82岁,平均66.1±8.4岁;原发性骨质疏松组患者发病年龄高于继发性骨质疏松组患者(P0.05),两组患者在陈旧性骨折史、血钙、血磷、BUN、Cr、骨代谢标志物、骨密度等方面差异均无统计学意义。所有患者均接受每年1次5mg唑来膦酸,联合骨化三醇0.25μg/日和600 mg碳酸钙D3片/日治疗1年。比较两组患者治疗前和治疗1年后腰椎和髋部骨密度及骨代谢相关指标,观察患者药物不良反应和新发骨折情况。结果与治疗前比较,原发性骨质疏松组患者治疗1年后腰椎和髋部骨密度值均明显增加(P0.05或0.01);骨代谢标志物P1NP、β-CTX、N-MID水平均明显下降(P0.01),25羟基维生素D水平明显升高(P0.01)。继发性骨质疏松组患者治疗1年后腰椎(L_2、L_3、L_4、L_(1-4))、髋部大粗隆和髋部平均骨密度值均明显增加(P0.05或0.01),骨代谢标志物P1NP、β-CTX、N-MID水平均明显下降(P0.01)。治疗1年后,继发性骨质疏松组患者N-MID明显低于原发性骨质疏松组(P0.01),两组间腰椎、髋部骨密度值及骨代谢标志物P1NP、β-CTX、25羟基维生素D、PTH水平无明显差异。两组患者治疗前后的血钙、血磷、BUN、Cr水平均无明显变化。治疗期间两组均无新发骨折。原发性骨质疏松组患者出现2例发热,继发性骨质疏松组3例发热,两组患者不良反应发生率无差异。结论唑来膦酸治疗不同原因导致的女性骨质疏松患者能够有效改善骨代谢标志物水平,降低骨吸收,显著提高腰椎、髋部的骨密度,降低骨折风险,不良反应少。     

唑来膦酸对合并骨关节炎的绝经后骨质疏松症患者的影响

目的 探讨唑来膦酸对合并骨关节炎的绝经后骨质疏松症（Postmenopuasal osteoporosis,PMOP)患者的影响。方法 选取我院2010年2月至2014年5月收治的98例合并骨关节炎的绝经后骨质疏松症患者为研究对象,采用随机数字表法分为观察组和对照组各49例,对照组予以钙剂(碳酸钙D3片600 mg qd)、活性维生素D(阿法骨化醇软胶囊0. 25μg qd)基础补充治疗,同时予以玻璃酸钠25 mg qw关节腔内注射治疗;观察组在上述药物治疗基础上联合唑来膦酸5 mg 一年一次静脉滴注治疗。研究比较两组治疗前后膝关节功能lysholm评分、疼痛VAS评分、生活质量评分（SF-36)以及腰椎及股骨的骨密度变化。结果 Lysholm与VAS评分:治疗6、12个月后,观察组膝关节功能lysholm评分显著高于对照组,VAS评分显著低于对照组(P <0. 05);骨密度：治疗6、12个月后,观察组L1-L4、Ward’ s三角、股骨颈、股骨Troch等部位骨密度显著高于对照组（P < 0.05);生活质量:观察组PF、RP、BP、GH、VT、SF、RE、MH、Total评分均显著高于对照组（P <0.05)。结论唑来膦酸有助于缓解合并骨关节炎的绝经后骨质疏松症患者疼痛程度,增加骨密度,改善膝关节功能,提高生活质量。     

Effect of etidronate disodium on bone turnover following surgical menopause

Summary A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover. Twenty healthy, premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively. Sequential measurements of serum calcium (Ca), alkaline phosphatase (AP), bone Gla protein (BGP), and urinary calcium and hydroxyproline excretion, expressed as a ratio of urinary creatinine (UCa/Cr and UOHp/Cr, respectively) were obtained. Twenty-four-hour whole body retention of diphosphonate (WBR) and radial bone density were also measured. When a postoperative increase in bone turnover was observed, patients were randomized to receive either 400 mg etidronate disodium daily or placebo for 3 months. Oophorectomy was associated with a significant increase in WBR, Ca, AP, and BGP and an insignificant rise in UCa/Cr. A variable pattern of UOHp/Cr was seen. Patients on placebo maintained these elevated levels of Ca, BGP, and UCa/Cr. WBR and AP continued to rise. Etidronate disodium therapy resulted in a fall towards premenopausal levels in WBR, Ca, and UCa/Cr. AP and BGP were unchanged. Three months after stopping etidronate, BGP fell significantly and the decrease in Ca was maintained; however, WBR and UCa/Cr had returned towards pretreatment values. Bone density measurements did not change significantly. An increase in several of the indices of bone turnover was seen following oophorectomy. Etidronate disodium suppressed this increase, affecting indices of both resorption and formation. This effect on formation may be an unavoidable consequence of normal resorption-formation coupling. The ability of etidronate alone to maintain postmenopausal bone mass has yet to be established. However, the suppressive effect of this diphosphonate on the accelerated bone turnover found after oophorectomy suggests that etidronate may have a potentially useful role as an inhibitor of resorption in a pulsed regimen.     

Influence of disodium etidronate on Paget's disease of bone

The use of agents that decrease bone resorption, notably the calcitonins, diphosphonates and mithramycin, has been shown to result in symptomatic and/or biochemical improvement in patients with Paget's disease of bone (osteitis deformans). The effects of short-term (6 months), low-dose (5 mg/kg body mass/d) etidronate disodium, a diphosphonate compound at present subject to registration in this country, on the clinical and laboratory manifestations of this disorder were examined. Marked symptomatic improvement was noted in 70% of patients, while biochemical parameters of bone turnover, namely serum alkaline phosphatase level (44%) and urine hydroxyproline excretion (56%), decreased significantly (P less than 0.001). A technetium-99m bone scan revealed an impressive reduction in uptake of isotope in 50% of patients. The drug was well tolerated and no adverse reactions (clinical, biochemical or haematological) were evident. It is concluded that short-term low-dose etidronate disodium affords a convenient and effective therapeutic alternative in patients with symptomatic Paget's disease.     

Effect of disodium etidronate (EHDP) on bone ingrowth in a porous material

This study evaluated the effect of disodium etidronate (EHDP) on biomechanical and histologic characteristics of bone ingrowth in a porous material. EHDP was administered parenterally to six adult mongrel dogs at a dose of 2 mg/kg/day for eight weeks. Six additional dogs served as controls and were injected with saline. Porous titanium fiber composites were inserted into the proximal humeri and the left olecranons of all animals after the first four weeks of treatment. Upon completing a total of eight weeks of treatment, all animals were sacrificed and the bone-porous implant interfacial shear strength was determined by a pull-out test to failure. Mean shear strength of fixation for the EHDP-treated group was reduced by 76% compared to the control group (p less than 0.001). Bone ingrowth was mineralized in all of the control specimens. Mineralization of tissue ingrowth was inhibited, however, in all specimens from EHDP-treated animals. These findings suggest that cementless skeletal fixation of porous-coated implants by bone ingrowth may be delayed or prevented by the administration of EHDP.     

Effect of etidronate on bone in orchidectomized and sciatic neurectomized adult rats

The purpose of the present study was to determine whether etidronate treatment could prevent bone loss caused by orchidectomy (ORX) and unilateral sciatic neurectomy (NX) in adult male rats. Seventy-four male Wistar rats, aged 10 months, were randomly divided into eight groups: baseline controls (n = 10); age-matched sham-operated controls (AMC; n = 9); ORX (n = 9); NX (n = 10); ORX + NX (n = 9); ORX + etidronate treatment (ORX + E; n = 7); NX + E (n = 10); and ORX + NX + E (n = 10). Etidronate treatment (10 mg/kg per day subcutaneously) was initiated 2 weeks after surgery and was continued for 2 weeks. Four weeks after surgery, bone mineral density (BMD) of the proximal and middle tibia (PT and MT, respectively), distal and middle femur (DF and MF, respectively), and fourth lumbar vertebral body (LVB) was measured by dual-energy X-ray absorptiometry (Model DCS-600, Aloka, Tokyo, Japan). The mechanical properties of the MF and third LVB were measured by three-point bending and compression tests, respectively. Levels of urinary deoxypyridinoline (Dpd) and serum osteocalcin (Oc) were also measured by enzyme-linked immunosorbent assay. Four weeks of aging had no significant effects on BMD, bone mechanical properties, or bone markers. ORX significantly increased the levels of urinary Dpd and serum Oc, which resulted in significant decreases in BMD of the PT, MT, DF, MF, and fourth LVB, as well as the mechanical strength (maximum load) of the MF and third LVB. NX significantly increased levels of urinary Dpd and decreased levels of serum Oc, resulting in a significant decrease in BMD of the PT, DF, and fourth LVB. The ORX-induced decrease in BMD of the PT was more pronounced when combined with NX. Etidronate treatment for NX, ORX, and ORX + NX rats significantly decreased levels of urinary Dpd and serum Oc, resulting in complete prevention of loss of BMD and/or bone mechanical strength. The present study demonstrates the efficacy of etidronate treatment for prevention of bone loss caused by testosterone deficiency and immobilization in adult male rats.     

不同给药方案阿仑膦酸钠对骨质疏松大鼠股骨的影响

目的比较阿仑膦酸钠(ALN)两种不同给药方案对维甲酸所致实验性骨质疏松大鼠的防治效果,为临床治疗骨质疏松用药方案的选择提供药理学实验依据。方法维甲酸灌胃诱发大鼠骨质疏松模型,ALN每天给药(用药方案相当于临床用药的10mg,每日用药一次)或每周给药(用药方案相当于临床用药的70mg,每周用药一次)。比较两种给药方案对骨质疏松大鼠股骨湿重、干重、骨密度(BMD)和骨组织形态的影响。结果两种给药方案均可提高骨质疏松大鼠股骨的湿重、干重、BMD,改善骨质疏松大鼠的病理改变。但两种治疗方案的治疗效果无明显差异。结论阿仑膦酸钠两种不同给药方案对骨质疏松均有预防和治疗作用,疗效无明显差异。从临床用药的依从性方面考虑,我们推荐70mg,每周用药一次的给药方案。     

Effect of cyclical therapy with phosphorus and etidronate on axial bone mineral density in postmenopausal osteoporotic women

Forty seven women with postmenopausal osteoporosis and at least one but no more than four vertebral compression fractures received sequential and cyclical therapy with phosphorus and etidronate (p/etid). During the same 2-year period of observation, three other groups of patients received either sodium fluoride (n=12), estrogen replacement therapy (n=12), or vitamin D and calcium (Ca⁺⁺) alone (n=15).Axial bone mineral density (BMD) was measured by means of dual-photon absorptiometry. Lateral thoracic and lumbar spine radiographs were taken to assess fractures. Bone mineral density increased from baseline during p/etid therapy: Mean 15.7±1.6% (SD) (P<0.001). During the same time, the patients in the sodium fluoride group showed a comparable increase in their BMD from baseline: mean 15.7±1.1% (P<0.001). During the first year of therapy, patients in the estrogen replacement group had an increase in their BMD from baseline: mean: 4.6%±1.1% (P<0.05). No change in BMD was seen in the control group that received vitamin D and Ca⁺⁺ alone.No patient who received p/etid, sodium fluoride, or estrogen replacement therapy had any new vertebral compression fractures or height loss, whereas in the control group that received vitamin D and Ca⁺⁺ alone 6 out of 15 had height loss and at least one new vertebral fracture (P<0.01).p/etid therapy increases BMD in women with postmenopausal osteoporosis comparable to sodium fluoride but without side effects or toxicity and stabilizes vertebral compression fractures.     

Estimation of defect volume in segmental defects of the tibia and femur

BACKGROUND: With the advent of modern limb salvage techniques, segmental bone loss in the lower extremity has become more common. METHODS: To aid preoperative planning when dealing with segmental bone loss in the femur and tibia, we performed a cadaveric study to estimate the volume of autogenous or allograft material required to fill defects located in various areas of the bones. RESULTS: The greatest volume was generally required in metaphyseal defects, with an average of 12 cc/cm in the distal femur and proximal tibia, 11 cc/cm in the proximal femur, and 6 cc/cm in the distal tibia. Diaphyseal defects were found to have the least variability with regard to the volume of graft material required for different specimens. Femoral diaphyseal defects required 7 cc/cm and tibial diaphyseal defects required 5 cc/cm. A slightly larger volume of allograft material was needed to fill all defects compared with autograft. CONCLUSION: This method allows one to estimate the amount of graft required for a defect of the femur and the tibia.     

基因修饰的组织工程骨修复节段性骨缺损及相关免疫学研究

目的：观察骨形态发生蛋白-2（BMP-2）基因修饰的组织工程骨修复节段性骨缺损效果及异种骨支架体内应用的安全性。方法：①制备去抗原牛松质骨块（BCB），植入小鼠股四头肌袋内，术后行淋巴细胞转化试验和组织学观察。②在腺病毒载体介导下将BMP-2基因导入兔骨髓间质干细胞后，种植到BCB支架中，构建基因修饰的组织工程骨。于兔双侧桡骨中段造成15mm骨缺损，采用5种方法进行处理：BMP-2基因转染细胞＋B（B（A组）；未转染细胞＋重组BMP-2＋BCB（B组）；对照基因转染细胞＋BCB（C组）；未转染细胞＋B（B（D组）；单纯BCB（E组）。术后4、8、12周行X线、组织学和生物力学检测。结果：①BCB具有较低的抗原性和良好的组织相容性；②A组术后4周诱导生成软骨组织并向编织骨转化，12周骨缺损修复，髓腔再通，新骨强度明显优于其他各组（P〈0．01）。结论：BMP-2基因修饰的组织工程骨是修复节段性骨缺损的好方法。