Bisphosphonate-related Osteonecrosis of the Jaws: An Update on Clinical, Pathological and Management Aspects

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is mainly observed in patients with multiple myeloma and bone metastasis from solid tumors receiving iv bisphosphonate therapy. The reported incidence of BRONJ is significantly higher with the iv preparations zoledronic acid and pamidronate while the risk appears to be minimal for patients receiving oral bisphosphonates. Currently available published incidence data for BRONJ are based on retrospective studies and estimates of cumulative incidence range from 0.8 to 12%. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60–70% of cases are preceded by a dental surgical procedure. The signs and symptoms that may occur before the appearance of clinical evident osteonecrosis include changes in the health of periodontal tissues, non-healing mucosal ulcers, loose teeth and unexplained soft-tissue infection. Although the definitive role of bisphosphonates remains to be elucidated, the inhibition of physiologic bone remodeling and angiogenesis by these potent drugs impairs the regenerative capacity of the bone causing the development of BRONJ. Tooth extraction as a precipitating event is a common observation. The significant benefits that bisphosphonates offer to patients clearly surpass the risk of potential side effects; however, any patient for whom prolonged bisphosphonate therapy is indicated, should be provided with preventive dental care in order to minimize the risk of developing this severe condition. This article provides an update review of current knowledge about clinical, pathological and management aspects of BRONJ.     

A review of Paget's disease of bone with a focus on the efficacy and safety of zoledronic acid 5 mg

ABSTRACT

Background: Paget's disease of bone, the second most common metabolic bone disease in the United States, is characterized by localized areas of excessive bone resorption coupled with accelerated bone formation, resulting in new bone that is less structurally organized and is weaker than normal bone. Complications of Paget's disease can include bone pain, osteoarthritis, skeletal deformity, hearing loss, and fractures. The objective of this review is to provide a comprehensive overview of current standards of treatment in Paget's disease.

Scope: A review of literature from 1974 to 2007 was performed on topics such as epidemiology, etiology, treatment of Paget's disease of bone, and bisphos­phonates.

Findings: Paget's disease affects an estimated 2–7% of persons of age 55 years or older in North America and western Europe. Antiresorptive treatment with bisphos­phonates is the standard treatment, but there may be limitations to oral therapy. Intravenous pamidronate is efficacious and has long been available, but its use is hindered by an impractical recommended dosing regimen of 30?mg IV over 4?h for three consecutive days. In two identical, double-blind, 6-month trials, 96% of patients treated with a one-time intravenous treatment of zoledronic acid 5?mg achieved therapeutic response, compared with 74% treated with 60 days of daily oral treatment with risedronate 30?mg (?p < 0.001). One limitation of this review is that historical data are not reviewed in the same level of detail as newer treatments, because recent advances in pharmacotherapy of Paget's disease have reduced the clinical utility of the older drugs.

Conclusion: The etiology of Paget's disease is unclear, but some evidence suggests genetic and viral com­ponents. Bisphosphonates restore normal bone turnover and relieve bone pain, but oral formulations may be limited by complicated dosing regimens and poor gastro­intestinal absorption. The bisphosphonate, zoledronic acid is administered as a single intravenous infusion and offers antiresorptive efficacy and longer-lasting remission.     

唑来膦酸钠对高转换患者椎体成形术后椎体再骨折发生率影响因素的相关性分析

目的分析高转换患者椎体成形术后应用唑来膦酸钠降低骨质疏松性椎体再骨折发生状况,并探讨再骨折发生率与骨转换指标、骨密度、疼痛、生活质量四者之间的相关性。方法选取2012年7月至2014年10月于我院行椎体成形术治疗骨质疏松性椎体压缩性骨折的282名女性患者,治疗组于术后3 d开始在口服阿法迪三及钙尔奇D的基础上静脉点滴唑来膦酸钠,(阿法迪三和钙尔奇D用三个月,停半个月),共160名,脱落5名;对照组于术后3 d开始口服阿法迪三及钙尔奇D抗骨质疏松基础治疗,共122名,脱落7名;术前3 d行骨密度测定、抽血检测β-胶原特殊序列(β-CTx)和总Ⅰ型胶原氨基酸延长肽(t-P1NP)、为了避免由于手术时机不同而导致患者临床症状缓解不佳对调查结果的影响,术后1周后进行VAS评分及生活质量SF-36评分;于术后1年、2年回访记录患者唑来膦酸钠使用次数及再发椎体骨折情况,并再次行骨密度测定、血清检验骨转换指标、疼痛VAS、SF-36评估,统计数据并运用统计学SPSS17.0软件分析,椎体成形术后应用唑来膦酸钠对骨质疏松性椎体压缩性骨折患者再骨折、骨代谢、骨密度、疼痛、生活质量的影响,并探讨它们之间的相关性。结果实验中共脱落12名,8名出现骨水泥泄露、4名再次骨折后行椎体成形术;治疗组中连续两年口服阿法迪三和钙尔奇D并使用唑来膦酸钠治疗者64例,为治疗A组;第2年由于静滴唑来膦酸钠出现肌痛,关节不适,费用等原因只口服阿法迪三和钙尔奇D而未继续使用唑来膦酸钠者91例,为治疗B组;再骨折发生率,对照组术后1年内椎体再骨折12例,骨折率10.43%,治疗A组再骨折6例,骨折率降为9.38%,治疗B组再骨折8例,骨折率为8.79%,经卡方试验分析,治疗组间差异无统计学意义,P0.05,而治疗组与对照组间差异有统计学意义,P0.05;第2年内治疗A组发生椎体再骨折4例,骨折率6.25%,治疗B组再骨折9例,骨折率9.89%,两组比较A组可显著降低骨折发生,P0.05;对照组再骨折12例,骨折率10.43%,治疗B组与对照组比较,治疗B组可显著降低骨折;组间自身比较,治疗A组在第2年内降低骨折3.13%,治疗B组增加骨折1.10%。于骨转换指标,t-P1NP在实验各组中均无显著差异,均P0.05;而β-CTx在1、2年后治疗组相较对照组均能显著降低;骨密度1年后治疗A组可提高1.61%,治疗B组可提高1.29%,对照组提高0.32%,两治疗组差异无统计学意义,P0.05,治疗组与对照组比较,差异均有统计学意义,P0.05;2年后,治疗A组骨密度可增加3.53%,治疗B组增加1.61%,对照组提高0.64%,治疗组间比较骨密度的提高差异存在统计学意义,P0.05,治疗B组与对照组比较,差异亦存在统计学意义,P0.05。疼痛VAS评分及生活质量SF-36评分在1、2年后治疗组与对照组比较,差异均有统计学意义,P0.05。结论椎体成形术后应用唑来膦酸钠能降低骨折发生率、提高骨密度、降低骨转换率、缓解疼痛、提高生活质量,连续使用疗效更佳;降低骨折发生率、提高骨密度在观察时间上有相关性,可能是通过降低骨转换率、提高骨密度而降低骨折的发生,从而缓解疼痛、逐步提高生活质量。     

Zoledronic acid – Related osteonecrosis of the jaws. Experimental model with dental extractions in rats

IntroductionBisphosphonate-related osteonecrosis of the jaws (BRONJ) is a pathologic condition of increasing frequency, with a poorly understood pathophysiology and which can be difficult to manage.The aim of this study was to find a reproducible experimental model that directly relates chronic bisphosphonate administration with the development of osteonecrosis with or without tooth extraction, with no other drug involved.Material and methodsTwenty male Wistar rats were divided into 4 groups (n = 5/group). Animals were injected over 9 weeks with zoledronic acid (0.1 mg/kg). In groups 1 and 2 three times a week intraperitoneally, and in group 3 once a week intravenously. A control group (group 4) received intraperitoneal injections of saline solution three times a week. After 8 weeks of treatment, 3 right upper jaw molars were extracted in groups 1, 3 and 4 and all rats were sacrificed 1 week later. The maxillae were histologically analyzed for presence of osteonecrosis foci, number of osteoclasts, vascularity, bone resorption status and presence of abscess. Radiographic examination was performed with a plain radiograph of each hemi-head.ResultsWe found that group 1 (dental extractions and highest cumulative dose of zoledronic acid) had the highest incidence of osteonecrosis (80%), absence of bone resorption (100%) and lowest number of osteoclasts (mean 7.9/field at 40×). Zoledronic acid-treated groups showed variable degrees of osteosclerosis and trabecular disorganization on X-ray study.ConclusionsWe offer a new animal model of BRONJ after zoledronic acid administration and dental extractions, achieving bone changes similar or superior to previous studies, highlighting the dental extraction as an important trigger factor.     

唑来膦酸治疗类风湿关节炎继发骨质疏松患者的临床分析

目的 通过对类风湿关节炎继发骨质疏松患者,给予唑来膦酸的治疗,观察及分析治疗后的临床指标,评价唑来膦酸的疗效及安全性。方法 所有患者均静脉输注5mg唑来膦酸注射液,第6、12个月回访,复查DXA、ESR、血清RF、CRP,以及通过FRAX计算未来10年的髋部骨折概率。结果 腰3、Ward区、大转子、股骨颈12个月时BMD与治疗前相比存在统计学差异,其余虽无统计学意义,但存在提高的趋势。未口服激素的RA病人在12个月时髋骨骨折概率与治疗前相比存在统计学差异。合并OP的RA病人在应用唑来膦酸后,随着治疗的进行,炎性指标下降,病情活动评分下降,血沉和C反应蛋白与治疗前对比有统计学意义。结论 唑来膦酸能在短期内有效改善类风湿关节炎继发骨质疏松的骨质量,提高骨密度,减低骨折概率,并对类风湿病情活动有一定的抑制作用。     

The Effect of Zoledronic Acid on the Volume of the Fusion-Mass in Lumbar Spinal Fusion

Background

Few studies have explored the effects of bisphosphonates on bony healing in patients undergoing spinal fusion surgery. Most previous studies used animal models and found that bisphosphonate shows negative effects on spinal fusion consolidation. We intended to evaluate the effect of a single-dose of zoledronic acid on the volume of the fusion-mass in lumbar spinal fusion.

Methods

A retrospective review was carried out on 44 patients with symptomatic degenerative lumbar spinal stenosis who underwent one or two-level posterolateral fusion from January 2008 and January 2011. They were divided into 4 groups: group 1, autograft and zoledronic acid; group 2, allograft and zoledronic acid; group 3, autograft alone; and group 4, allograft alone. Functional radiography and three-dimensional computed tomography scans were used to evaluate and quantify the volume of the fusion-mass. The visual analog scale (VAS), the Oswestry disability index (ODI), and the short form 36 (SF-36) were used to evaluate the clinical outcomes.

Results

The mean volume of the fusion-mass per level was 8,814 mm³, 8,035 mm³, 8,383 mm³, and 7,550 mm³ in groups 1, 2, 3, and 4, respectively, but there were no significant differences between the groups (p = 0.829). There were no significant decreases in the volume of the fusion-mass (p = 0.533) in the zoledronic acid groups (groups 1 and 2). The VAS, the ODI, and the SF-36 at the 6-month follow-up after surgery were not significantly different (p > 0.05) among the 4 groups. The VAS, the ODI, and the SF-36 were not correlated with the volume of the fusion-mass (p = 0.120, 0.609, 0.642).

Conclusions

A single dose of zoledronic acid does not decrease the volume of the fusion-mass in patients undergoing spinal fusion with osteoporosis. Therefore, we recommend that zoledronic acid may be used after spinal fusion in osteoporotic patients.     

仙灵骨葆胶囊联合唑来膦酸治疗骨质疏松性椎体压缩性骨折的临床研究

目的探究仙灵骨葆胶囊联合唑来膦酸治疗骨质疏松性椎体压缩性骨折的疗效。方法选取2014年1月—2016年1月天津中医药大学第一附属医院收治的骨质疏松性椎体压缩性骨折行经皮椎体成形术的112例患者,随机分为对照组和治疗组,每组各56例。两组均行经皮椎体成形术,对照组术后第3天静脉滴注唑来膦酸注射液,5 mg/次,1次/年。治疗组患者在对照组的治疗基础上口服仙灵骨葆胶囊,3粒/次,2次/d,3个月为一个疗程,共服用2个疗程。观察两组的临床疗效,同时比较治疗前,治疗3、6个月时腰椎、股骨前端的骨密度、VAS评分和PINP水平的变化情况,比较两组治疗前后椎体后凸Cobb角及其恢复率。结果治疗后,对照组和治疗组的总有效率分别为82.14%、96.43%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者腰椎、股骨前端骨密度均明显提高,VAS评分和PINP水平均明显降低,同组治疗前后差异有统计学意义(P0.05);治疗后,治疗组患者腰椎、股骨前端骨密度高于对照组,治疗组VAS评分和PINP水平低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组椎体后凸Cobb角均较治疗前显著降低,同组治疗前后差异有统计学意义(P0.05);治疗后治疗组椎体后凸Cobb角低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组椎体后凸Cobb角恢复率明显高于对照组,两组比较差异具有统计学意义(P0.05)。结论仙灵骨葆胶囊联合唑来膦酸治疗骨质疏松性压缩性骨折具有较好的临床疗效,可增加患者骨密度,有效减轻患者疼痛感,促进椎体压缩性骨折的愈合,具有一定的临床推广应用价值。     

六味地黄丸联合唑来膦酸治疗妇女绝经后骨质疏松的临床研究

目的探讨六味地黄丸联合唑来膦酸治疗妇女绝经后骨质疏松的临床效果。方法选取2015年6月—2017年1月广东医科大学附属医院收治的86例绝经后骨质疏松患者,随机分为对照组和治疗组,每组各43例。对照组静脉滴注唑来膦酸注射液,5 mg/次,1次/年。治疗组在此基础上口服六味地黄丸,8丸/次,3次/d。所有患者均连续治疗12个月。观察两组的临床疗效,比较两组治疗前后视觉模拟(VAS)评分、简明健康状况调查量表(SF-36)评分、腰椎1~4骨质密度(BMD)、全髋关节骨BMD、左侧股骨颈BMD、Ⅰ型原胶原氨基端前肽(PINP)、β-胶原降解产物(β-CTX)、碱性磷酸酶(ALP)、骨钙素(BGP)的变化情况。结果治疗后,对照组和治疗组的总有效率分别为79.07%、95.35%,两组比较差异有统计学意义(P0.05)。治疗后,两组VAS评分、血清PINP、β-CTX、ALP及BGP水平显著降低,SF-36评分、腰椎1~4 BMD值、全髋关节骨BMD值、左侧股骨颈BMD值显著升高,同组治疗前后比较差异有统计学意义(P0.05);治疗后,治疗组VAS评分、血清PINP、β-CTX、ALP及BGP水平低于对照组,SF-36评分、腰椎1~4 BMD值、全髋关节骨BMD值、左侧股骨颈BMD值高于对照组,两组比较差异有统计学意义(P0.05)。结论六味地黄丸联合唑来膦酸治疗妇女绝经后骨质疏松具有较好的临床疗效,可有效缓解患者疼痛症状,增加骨密度,提高生活质量,具有一定的临床推广应用价值。     

唑来膦酸与替勃龙治疗绝经后骨质疏松疗效比较及对骨折的预防作用

目的比较唑来膦酸与替勃龙治疗绝经后骨质疏松的临床疗效及对骨折的预防作用。方法将本院诊治的128例绝经后骨质疏松患者随机分入唑来膦酸组与替勃龙组,两组患者均接受骨化三醇、钙剂治疗,唑来膦酸组患者同时接受唑来膦酸5 mg/年静脉注射,替勃龙组患者接受替勃龙2.5 mg/d,口服。用药后2年比较两组髋部及腰椎骨密度变化、血清Ⅰ型前胶原肽（CTX）、骨碱性磷酸酶（BALP）及不良反应发生情况。结果两组治疗后2年腰椎L1-L4和髋部区、股骨颈、大转子骨密度均显著增加（P〈0.05）,唑来膦酸组L1-L4骨密度增加显著优于替勃龙组（P〈0.05）;治疗后两组CTX及BALP均显著下降,唑来膦酸组CTX显著低于替勃龙组（P〈0.05）;唑来膦酸组与替勃龙组新发骨折发生率分别为4.5%和8.1%,两组比较差异无统计学意义（P〉0.05）;唑来膦酸组不良反应发生率为19.7%,替勃龙组为11.3%,两组均未发生严重不良反应。结论唑来膦酸与替勃龙治疗绝经后骨质疏松均可获得理想的临床疗效,唑来膦酸组腰椎骨质密度增加更为显著,患者治疗依从性好。     

唑来膦酸联合来曲唑治疗对绝经期乳腺癌术后生命质量的改善

探讨唑来膦酸联合来曲唑改善绝经期乳腺癌术后生命质量的治疗效果。方法：49例绝经期乳腺癌术后患者随机分为2组,观察组23例联合应用唑来膦酸和来曲唑,对照组26例单纯口服来曲唑。于术后6,12个月检测两组患者的骨密度（BMD）和血清骨特异性碱性磷酸酶（BALP）、I型胶原c端肽（CTX）,VAS评分镇痛效果,乳腺癌治疗功能评价系统（FACT-B）生命质量评分等指标并作比较。结果：观察组骨密度和FACT—B生命质量评分较对照组改善明显（P〈0．05或0．01）,观察组6,12个月时VAS评分、血清BALP水平、CTX含量等指标均较对照组明显减低（P〈0．05）。病变远处转移发生率两组差异无统计学意义（P〉0．05）。结论：唑来膦酸能有效改善来曲唑引起骨量丢失等不良反应,调高镇痛效果减低骨折风险发生提高患者生命质量。．