Impact of bisphosphonate treatment on bone mineral density after kidney transplant

BACKGROUND Mineral bone disease is associated with chronic kidney disease and persists after kidney transplantation.Immunosuppressive treatment contributes to the patho-genesis of this disease.Bisphosphonate treatments have shown positive but inde-finite results.AIM To evaluate the effectiveness and safety of bisphosphonate treatment on post kidney transplantation bone mineral density(BMD).METHODS We included kidney transplant recipients(KTRs)whose BMD was measured after the operation but before the initiation of treatment and their BMD was measured at least one year later.We also evaluated the BMD of KTRs using two valid mea-surements after transplantation who received no treatment(control group).RESULTS Out of 254 KTRs,62(39 men)were included in the study.Bisphosphonates were initiated in 35 KTRs in total(20 men),1.1±2.4 years after operation and for a period of 3.9±2.3 years while 27(19 men)received no treatment.BMD improved significantly in KTRs who received bisphosphonate treatments(from-2.29±1.07 to-1.66±1.09,P<0.0001).The control group showed a non-significant decrease in BMD after 4.2±1.4 years of follow-up after surgery.Kidney function was not affected by bisphosphonate treatment.In KTRs with established osteoporosis,active treatment had a similar and significant effect on those with osteopenia or normal bone mass.CONCLUSION In this retrospective study of KTRs receiving bisphosphonate treatment,we showed that active treatment is effective in preventing bone loss irrespective of baseline BMD.

Role of bisphosphonates in the management of acute Charcot foot

Diabetes mellitus is the most common cause of Charcot neuropathy affecting foot and ankle. Acute Charcot foot(CF) presents with a red and swollen foot in co-ntrast to the painless deformed one of chronic CF. En-hanced osteoclastogenesis plays a central role in the pathogenesis of acute CF. Many studies have shown elevated levels of bone turnover markers in patients with acute CF confirming it. These findings have led cl-inicians to use anti-resorptive agents [bisphosphonates(BP), calcitonin, and denosumab] along with immobi-lization and offloading in acute CF patients. The ma-ximum evidence among all anti-resorptive agents is available for BPs, although its quality is low. Pamidronate has been shown to reduce the markers of activity of CF like raised skin temperature, pain, edema, and bone turnover markers in the majority of studies. Intravenous BPs are known to cause acute phase reactions leading to flu-like illness following their first infusion, which can be ameliorated by oral acetaminophen. Alendronate is the only oral BP used in these patients. It needs to be taken on an empty stomach with a full glass of water to avoid esophagitis. The side-effects and contraindications to BPs should be kept in mind while treating acute CF patients with them.

Bisphosphonates as potential adjuvants for patients withcancers of the digestive system

Best known for their anti-resorptive activity in bone, bisphosphonates(BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor(HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

Clinical Analysis of Bisphosphonates Treatment on Bone Metastases and Hypercalcemia of Malignancy in Advanced Solid Tumor

Objective： To evaluate the efficacy and toleration of bisphosphonates therapy in patients with bone metastases and hypercalcemia of malignancy in advanced solid tumor. Methods： Patients with histologically or cytologically confirmed cancer and hypercalcemia with bone metastases were designed to open treatment with either 4mg zoledronic acid or 90mg pamidronate. The primary efficacy parameters were pain scores（NRS）, Corrected serum calcium（CSC） and CSC effective rate The vital signs, biochemical and hematological parameters were determined. Results： Twenty patients were enrolled in this study, twelve patients in zoledronic acid group and eight in pamidronate group. Zoledronic acid and pamidronate significantly palliated pain. Pain scores were significantly lower at end-point after Zoledronic acid or pamidronate infusion（5.92 vs 3.25, P〈0.01; 6.13 vs 4.38, P〈0.01, respectively）. The mean CSC level decreased significantly after Zoledronic acid or pamidronate infusion from 12.86 to 10.28mg/dl and 13.19 to 10.36mg/dl respectively. The CSC effective rate was about 90% at 14 days after infusion in two groups. There was no statistical significance for all primary efficacy parameters in zoledronic acid group compared with pamidronate group. An adverse reaction was mild fever after pamidronate infusion and then completely reversible. Conclusion： Zoledronic acid and pamidronate disodium were well tolerated and effective for bone metastases and hypercalcemia of malignancy in advanced solid tumor.

Physicians' knowledge and attitude regarding bisphosphonates-related adverse events:An observational study

AIM To assess the knowledge and attitude of Lebanese physicians regarding bisphosphonates(BPs)-related complications.METHODS An observational cross-sectional study was conducted at a major tertiary teaching hospital in Beirut city,and its affiliated primary health care center.Data were collected through a new self-administered questionnaire distributed via a delegated secretary to physicians expected to regularly prescribe BPs(n = 215).It assessed participants' knowledge,fear and experience regarding BPsreported complications.RESULTS One hundred and fifty-seven physicians fulfilled the questionnaire(response rate: 73.0%): 77.7% and 75.2% considered that gastrointestinal intolerance and osteonecrosis of the jaw are linked to BPs,respectively.Conversely,the least recognised complications are ocular inflammation(7.6%) and severe musculoskeletal pain(37.6%).The association of BPs with oesophageal cancer,atrial fibrillation and hepatotoxicity was reported by 11.5%,13.4% and 24.8% of respondents,respectively.The multivariate analysis showed a significant association between level of knowledge and physicians' department affiliation(P-value = 0.043),their gender(P-value = 0.044),whether or not they prescribe a BP(P-value = 0.012),and the number of BP prescriptions delivered monthly(P-value = 0.012).Physicians are mainly concerned about osteonecrosis of the jaw and nephrotoxicity when prescribing a BP.Yet,the complications commonly met in their practice are gastrointestinal intolerance(44.6%) and acute phase reactions(26.7%).CONCLUSION This study revealed the presence of a deficient knowledge regarding BPs-related adverse events among our physicians.Professional training proposals are needed to increase their knowledge and improve their practices.Pharmaceutical industries should reconsider the instructions they provide to physicians regarding the complications of medications they promote.Moreover,they must actively collaborate with education providers and institutions in educational interventions.

Bisphosphonates Zoledronate and Alendronate for the Management of Postmenopausal Osteoporosis

Bisphosphonates are among the most frequently used antiresorptive drugs for the management of postmenopausal osteoporosis. We review here two of the commonly used bisphosphonates zoledronate and alendronate.

Recurrent Transient Osteoporosis during Pregnancy and Treatment with Oral Bisphosphonates: A Case Report

Transient osteoporosis of the hip (TOH), also known as “Bone marrow edema Syndrome”, is a rare disorder mainly affecting pregnant women in their third trimester, as well as middle-aged, overweight men. A 30-year-old Caucasian female G2P2, with history of transient osteoporosis of both ankles and C-Section during the last pregnancy in 2011, presented progressively severe bilateral hip pain with onset already in the 12th gestational week. Imaging of the pelvis and bilateral hips with MRI obtained 6 days after the C-Section demonstrated bilateral bone-marrow edema of the hips. The patient was treated with a monthly single dose of 150 mg ibandronate acid per os, for 3 months and physiotherapy. Repeated MRI performed 5 months postpartum revealed a complete remission of the disease. In contrast to the first onset of transient osteoporosis during the first pregnancy, which was only treated conservatively without bisphosphonates, the remission of the disease and patient’s recovery with oral ibandronate therapy showed to be 4 months shorter. This case is unique in literature for both describing the onset of this rare disease twice in the same patient as well as its oral therapeutic approach.

Determination of bisphosphonates anti-resorptive properties based on three forms of ceramic materials: Sorption and release process evaluation

There is a strong need to search for more effective compounds with bone anti-resorptive properties,which will cause fewer complications than commonly used bisphosphonates. To achieve this goal, it is necessary to search for new techniques to characterize the interactions between bone and drug. By studying their interaction with hydroxyapatite(HA), this study used three forms of ceramic materials,two of which are bone-stimulating materials, to assess the suitability of new active substances with antiresorptive properties. In this study, three methods based on HA in loose form, polycaprolactone/HA(a polymer-ceramic materials containing HA), and polymer-ceramic monolithic in-needle extraction(MINE) device(a polymer inert skeleton), respectively, were used. The affinity of risedronate(a standard compound) and sixteen aminomethylenebisphosphonates(new compounds with potential antiresorptive properties) to HA was defined according to the above-mentioned methods. Ten monolithic materials based on 2-hydroxyethyl methacrylate/ethylene dimethacrylate are prepared and studied, of which one was selected for more-detailed further research. Simulated body fluids containing bisphosphonates were passed through the MINE device. In this way, sorptionedesorption of bisphosphonates was evaluated using this MINE device. The paper presents the advantages and disadvantages of each technique and its suitability for assessing new active substances. All three methods allow for the selection of several compounds with potentially higher anti-resorptive properties than risedronate, in hope that it reflects their higher bone affinity and release ability.

An Efficient Synthesis of Aromatic 1-Hydroxymethylene-1, 1-bisphosphonates from Aldehydes

A simple and efficient procedure for synthesis of 1-hydroxymethylene-1,1-bisphos- phoates from aldehydes is described. This method was applied to the synthesis of novel catechol substituted bisphosphonates as the anti-osteoporosis agents.

How Long to Treat with Bisphosphonates?

Bisphosphonate class of drugs, the most commonly prescribed for the treatment of osteoporosis, is effective in preventing and treating bone loss and fractures. However, the treatment duration and the applicability of “drug holidays” for bisphosphonates need optimization in order to minimize long-term exposure. Drug holidays may prevent potential adverse events while still maintaining some degree of antifracture efficacy via residual antiresorptive activity by retained bisphosphonates. Patients receiving bisphosphonates, who are at low-moderate risk of fracture, are potential candidates for a drug holiday. However, for high-risk patients or patients with previous history of fragility fractures, the benefits of continuing bisphosphonate therapy considerably out-weigh their potential harm. Evidence-based guidelines regarding starting and stopping a drug holiday are not available;therefore, it is appropriate to monitor patients on a drug holiday to assess a declining antiresorptive effect. In case of a significant rise in bone turnover markers or significant decrease in bone mineral density, it may be time to restart therapy.

Oral bisphosphonates improve the bone mineral density in men with diabetes with or without thiazolidinediones

Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures and decreased bone mineral density (BMD). To our knowledge, no data are available to evaluate bisphosphonate therapy in thiazolidinedione-treated patients. The aim of this study was to investigate the benefit of bisphosphonates to improve changes in BMD in subjects with DM associated with TZDs. Methods: In a cross-sectional observational study using a retrospective review of electronic medical records, the changes in BMD in subjects with type 2 DM. The study subjects were divided into four groups. First group with DM receiving both TZDs and BPs;second group neither;third group receiving only TZDs and the fourth only BPs. The comparison of annual percent changes in BMD between the groups were carried out. Results: Decreased BMD noted in subjects with DM on TZDs. Bisphosphonates improved BMD in subjects with DM on TZDs. BMD improved in subjects with DM in those not receiving TZDs also. Conclusion: We conclude that concomitant treatment with bisphosphonates improves BMD in subjects with diabetes and on TZDs.

使用双膦酸盐药物患者种植体早期失败率及术后药物相关性颌骨坏死的单组率Meta分析

目的系统评价使用双膦酸盐药物(bisphosphonates,BPs)患者种植体早期失败率及种植术后药物相关性颌骨坏死(medication-related osteonecrosis of the jaw,MRONJ)发生率,为临床评估相关风险提供依据。方法计算机检索Cochrane Library、Wiley Online Library、PubMed、中国知网、万方数据知识服务平台,收集纳入各数据库建库至2022年5月发表的关于使用BPs患者种植体早期失败或种植术后发生MRONJ的临床研究。采用Stata 15.0软件对种植体早期失败率进行单组率Meta分析。结果共纳入13篇文献,其中口服BPs患者植入1182颗种植体,静脉注射BPs患者植入79颗,共计1261颗种植体。口服BPs患者合并种植体早期失败率为1.7%(95%CI:0.3%~3.9%),MRONJ发生率为0。静脉注射BPs患者种植体早期失败率为0,MRONJ发生率为5.6%。结论口服BPs患者种植体早期失败率及术后MRONJ发生率低,与健康人群基本相当。静脉使用BPs患者种植术后发生MRONJ风险较高,临床适应证选择应慎重。

复方苦参注射液联合双膦酸盐类药物治疗恶性肿瘤骨转移所致癌性疼痛患者的疗效和安全性Meta分析

目的:系统评价复方苦参注射液(CKI)联合双膦酸盐(BPs)类药物治疗恶性肿瘤骨转移所致癌性疼痛(以下简称癌痛)患者的有效性和安全性。方法:计算机检索中国知网(CNKI)、万方数据库(Wanfang)、维普中文科技期刊数据库(VIP)、PubMed、CochraneLibrary,检索时间均为建库至2024年1月22日,收集CKI联合BPs类药物治疗恶性肿瘤骨转移所致癌痛患者的随机对照试验(RCT)研究文献。通过Cochrane风险评估工具进行文献质量评价,并采用RevMan5.4软件进行Meta分析。结果:共检索出245篇文献,最终纳入27篇文献,共计2255例患者,其中对照组(单用BPs类药物)1108例,联合组(CKI联合BPs类药物)1147例。Meta分析结果显示,在疼痛缓解率、生活质量评分[卡诺夫斯凯计分(KPS)]、血清碱性磷酸酶(ALP)和不良反应发生率方面,CKI联合BPs类药物的治疗效果均优于单用BPs类药物(P<0.01)。结论:CKI联合BPs类药物治疗可有效提高恶性肿瘤骨转移所致癌痛患者的疼痛缓解率、KPS评分,改善血清ALP水平,降低不良事件的发生风险。

老年原发性骨质疏松症患者接受双膦酸盐治疗的临床效果分析

目的:探讨双膦酸盐治疗老年原发性骨质疏松症的效果。方法:选取2020年10月—2023年12月中山市中医院收治的老年原发性骨质疏松症患者200例为研究对象,随机分为对照组与观察组,各100例。对照组应用唑来膦酸治疗,观察组应用双膦酸盐(阿伦膦酸钠)治疗。比较两组患者不良反应、生活质量、治疗效果。结果:治疗3、7 d后,观察组不良反应发生率低于对照组,差异有统计学意义(P<0.05);治疗后,两组心理、躯体、认知及社会功能评分均高于治疗前,观察组高于对照组,差异有统计学意义(P<0.05);观察组总有效率高于对照组,差异有统计学意义(P=0.018)。结论:双膦酸盐(阿伦膦酸钠)治疗老年原发性骨质疏松症的效果理想,可有效提高患者生活质量,减少不良反应发生。

特立帕肽和双膦酸盐治疗绝经后骨质疏松性骨折有效及安全性的Meta分析

目的:通过Meta分析比较特立帕肽和双膦酸盐治疗绝经后骨质疏松性骨折有效性与安全性。方法:通过检索PubMed、Cochrane Library、EMbase、中国知网、万方和维普数据库,根据纳入及排除标准筛选出关于特立帕肽和双膦酸盐治疗绝经后骨质疏松性骨折的随机对照试验文章18篇,使用EndNote X9软件管理文献,使用RevMan 5.3软件对所提取的数据进行Meta分析,主要分析绝经后骨质疏松患者接受特立帕肽和双膦酸盐药物治疗后椎体骨折、非椎体骨折及不良反应发生率。结果:共纳入18项随机对照试验,其中10篇文献属于中高质量文献,8篇文献属于低质量文献。Meta结果显示:①特立帕肽组骨折发生率(RR=0.56,95%CI:0.48-0.66,P<0.00001)低于双膦酸盐组,特立帕肽在预防绝经后骨质疏松症妇女骨折方面优于阿仑膦酸钠(RR=0.50,95%CI:0.35-0.69,P<0.0001)和其他双膦酸盐(RR=0.58,95%CI:0.49-0.70,P<0.00001)。②根据不同随访时间,在超过18个月的研究中,特立帕肽在预防绝经后骨质疏松妇女骨折方面均优于双膦酸盐(RR=0.56,95%CI:0.48-0.69,P<0.00001)。③此外,文章发现特立帕肽预防绝经后骨质疏松妇女椎体骨折(RR=0.48,95%CI:0.37-0.62,P<0.00001)和非椎体骨折(RR=0.63,95%CI:0.51-0.78,P<0.0001)方面均优于双膦酸盐。④特立帕肽在增加腰椎骨密度(OR=4.16,95%CI:2.96-5.36,P<0.0001)和股骨颈骨密度(OR=1.02,95%CI:0.04-2.01,P=0.04)方面优于双膦酸盐。⑤特立帕肽与双膦酸盐之间的不良反应无显著差异(RR=0.95,95%CI:0.85-1.06,P=0.37)。结论:①特立帕肽预防绝经后骨质疏松妇女椎体骨折和非椎体骨折方面均优于双膦酸盐,但安全性及药物不良反应方面特立帕肽和双膦酸盐基本相似。②特立帕肽无论是短期(<18个月)还是长期(≥18个月)使用,在预防骨折发生率、提高腰椎骨密度和股骨颈骨密度方面,均优于双膦酸盐。

唑来膦酸注射液可能致横纹肌溶解综合征一例报告

唑来膦酸注射液是临床上治疗骨质疏松的一线用药,使用唑来膦酸后出现横纹肌溶解综合征的情况罕有发生。本文报道一例老年骨质疏松女性患者,在使用唑来膦酸后出现横纹肌溶解伴肝肾功能损害。基于诺氏(Naranjo's)药物不良反应评估量表判定该患者使用唑来膦酸与横纹肌溶解综合征发生的因果关系为可能。其发病机制可能与唑来膦酸诱发低磷血症,导致组织细胞氧化磷酸化受阻,红细胞存储损伤造成组织器官严重缺氧缺血有关。现报道该罕见病例的病情及治疗经过,探讨该特殊情况的防治策略。

双膦酸盐修饰生长分化因子5促进MC3T3-E1细胞的成骨分化

背景:生长分化因子5作为骨形态发生蛋白的一员在软骨及骨组织修复领域表现出良好的应用潜力,增强生长分化因子5与骨组织的亲和力是提高蛋白使用效率的关键,因而开发具有骨靶向性的生长分化因子5蛋白具有重要意义。目的:利用双膦酸盐修饰生长分化因子5并探讨改性后蛋白对小鼠成骨前体细胞生长分化的影响。方法:采用化学交联法将生长分化因子5与帕米膦酸钠偶联,得到偶联帕米膦酸钠的生长分化因子5,采用傅里叶变换红外光谱、圆二色谱对其基团及结构进行表征,利用ELISA试剂盒测定生长分化因子5与磷酸钙的结合量以及生长分化因子5的体外释放量,用于表征其体外骨靶向性。将生长分化因子5(对照组)、偶联帕米膦酸钠的生长分化因子5(实验组)分别与成骨前体细胞MC3T3-E1共培养,以单独培养的细胞为空白对照,评价复合物对细胞增殖及分化等的影响。结果与结论:①红外光谱及圆二色谱结果表明,实验成功制备了双膦酸盐/生长分化因子5复合物且蛋白二级结构无显著变化;体外磷酸钙吸附结果表明,偶联帕米膦酸钠后,生长分化因子5与磷酸钙的吸附率增加了约1倍;在半胱氨酸存在条件下,偶联帕米膦酸钠的生长分化因子5的蛋白可释放出来;②CCK-8实验结果显示,实验组培养4,7 d的吸光度值高于对照组、空白对照组(P<0.0001);培养7 d后,实验组碱性磷酸酶表达明显高于对照组、空白对照组(P<0.0001);培养13 d后,实验组钙结节含量明显高于对照组、空白对照组(P<0.0001);qRT-PCR结果检测结果显示,培养7 d后,实验组碱性磷酸酶、骨钙素及Runx2的mRNA表达高于对照组、空白对照组(P<0.01,P<0.001,P<0.0001);③结果表明,双膦酸盐修饰有利于增强生长分化因子5与磷酸钙的结合能力,同时有利于增强其生物活性。

双膦酸盐类药物用于钙化防御治疗的文献分析

目的分析双膦酸盐类药物用于钙化防御患者治疗的有效性和安全性。方法检索PubMed、Embase、中国知网及万方数据库,收集报道双膦酸盐用于钙化防御的病例报告,提取患者相关信息进行统计分析。结果纳入文献共18篇病例报告,患者20例,结果显示13例患者(65.0%)采用帕米膦酸盐治疗,4例患者(20.0%)采用依替膦酸盐,2例患者(10.0%)采用阿仑膦酸盐,1例患者(5.0%)采用唑来膦酸。13例患者(65.0%)完全康复,康复时间为0.5~9个月。大部分患者双膦酸盐类药物的耐受性较好(90.0%),1例不耐受帕米膦酸盐的患者在调整给药频次后康复,1例依替膦酸盐高给药剂量患者在停用后指标恢复正常。结论双膦酸盐类药物作为一种骨吸收的抑制剂,兼具有效性和安全性,有望用于钙化防御患者的治疗。

双膦酸盐抗三种顶复门原虫研究进展

顶复门原虫可引起严重疾病威胁人类健康,如每年导致近100万人死亡的疟原虫,感染全球约1/3人口的弓形虫以及导致新生儿腹泻的隐孢子虫等。这3种顶复门原虫对全球的生物安全和公共卫生构成巨大隐患,且目前在临床上有效治疗药物有限。双膦酸盐临床上广泛用于治疗骨代谢疾病,但其化合物可有效抑制顶复门原虫生长,作用机制为竞争性抑制寄生虫类异戊二烯分子生物合成的2C-甲基-D-赤藓糖醇-4-磷酸途径(MEP途径)中的法尼基焦磷酸合酶,干扰类异戊二烯化合物的合成而发挥作用。本文综述了双膦酸盐化合物在疟原虫、弓形虫和隐孢子虫方面的相关研究,以期为临床治疗相关疾病提供理论基础。

脉冲电磁场联合双膦酸盐对绝经后骨质疏松症患者心理健康和生活质量的影响

目的:观察脉冲电磁场联合双膦酸盐对绝经后骨质疏松症患者心理健康和生活质量的影响。方法:选取2022年10月—2023年5月南昌市洪都中医院收治的90例绝经后骨质疏松症患者为研究对象,采用随机单盲、平行对照的研究方法。将患者随机分为三组,各30例。A组给予低频脉冲电磁场联合伊班膦酸钠治疗,B组采用低频脉冲电磁场治疗,C组采用伊班膦酸钠治疗,三组均连续治疗3个月。比较三组性激素、骨密度、骨代谢指标、心理状态、疼痛程度、生活质量及不良反应发生情况。结果:治疗后三组髋部及腰椎骨密度均提高,且A组高于B组、C组(P<0.05);治疗后三组β-胶原降解产物(β-CTX)、总Ⅰ型前胶原氨基端肽(T-PⅠNP)均降低,A组低于B组、C组,骨钙素(OCN)、25-羟维生素D均升高,A组高于B组、C组(P<0.05);治疗后三组焦虑自评量表(SAS)、抑郁自评量表(SDS)、视觉模拟评分法(VAS)评分均降低,A组低于B组、C组(P<0.05);治疗后,三组健康调查量表36(SF-36)各维度评分均提高,且A组高于B组、C组(P<0.05);三组治疗期间均未见严重不良反应。结论:脉冲电磁场联合双膦酸盐治疗可调节绝经后骨质疏松症患者骨代谢指标,提高骨密度,缓解骨痛,改善心理状况,提升生活质量,且治疗安全性较高。