Research Progress on the Bone Metastasis Mechanism of Prostate Cancer and Bone-Targeted Drugs

Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.

Non-steroidal anti-inflammatory drugs in postoperative hand fracture management:Do they positively or negatively impact recovery?

This editorial explores the impact of non-steroidal anti-inflammatory drugs(NSAIDs)on postoperative recovery in hand fracture patients,amidst shifting pain management strategies away from opioids due to their adverse effects.With hand fractures being significantly common and postoperative pain management crucial for recovery,the potential of NSAIDs offers a non-addictive pain control alternative.However,the controversy over NSAIDs'effects on bone healing—stemming from their Cyclooxygenase-2 inhibition and associated risks of fracture non-union or delayed union—necessitates further investigation.Despite a comprehensive literature search,the study finds a lack of specific research on NSAIDs in postoperative hand fracture management,highlighting an urgent need for future studies to balance their benefits against possible risks.

Drug Release Characteristics of Hydroxyapatite Bone Cement

To discuss the feasibility of bydroxyapatite bone cement （HAC） used as a drug delivery carrier and observe the bacteriostatic activity of HAC/ Norvancomycin（ HAC/ NVCM ） composite in vitro and its release characteristics in vivo. Bacteriostatic zone and cycle of composite containing 1.5wt% of NVCM were measured in vitro studies. In vivo stndies , the composite was implanted into the top of rabbit＇ s tibia as the local medication group, HAC without NVCM being composed was also implanted and NVCM was injected into auricular vein as the systemic medication group. Cnncentrations of NVCM in blood and local bone were measured in both groups at different time points. The experimental results showed that HAC did not influence the bacteriostatic activity of NVCM otviously, and NVCM exist in the porosities of HAC in the pattern of amorphism. The blood coueemrations of NVCM in local medication group were always lower than those in systemic medication group at any time point, while the bone concentrations of NVCM in local medication group were much higher than those of systemic medication group,which remained to be 3.96μg/mg/mL after 2 weeks. And HAC has good release characteristics as a drug delivery earricr.

Effect of non-steroidal anti-inflammatory drugs on fracture healing in children:A systematic review

BACKGROUND Non-steroidal anti-inflammatory drugs(NSAIDs)are among the most commonly prescribed medications in the United States.Although they are safe and effective means of analgesia for children with broken bones,there is considerable variation in their clinical use due to persistent concerns about their potentially adverse effect on fracture healing.AIM To assess whether NSAID exposure is a risk factor for fracture nonunion in children.METHODS We systematically reviewed the literature reporting the effect of NSAIDs on bone healing.We included all clinical studies that reported on adverse bone healing complications in children with respect to NSAID exposure.The outcomes of interest were delayed union or nonunion.Study quality was assessed using the Newcastle-Ottawa scale for non-randomized studies.A final table was constructed summarizing the available evidence.RESULTS A total of 120 articles were identified and screened,of which 6 articles were included for final review.Nonunion in children is extremely rare;among the studies included,there were 2011 nonunions among 238822 fractures(0.84%).None of the included studies documented an increased risk of nonunion or delayed bone healing in those children who are treated with NSAIDs in the immediate post-injury or peri-operative time period.Additionally,children are likely to take these medications for only a few days after injury or surgery,further decreasing their risk of adverse side-effects.CONCLUSION This systematic review suggests that NSAIDS can be safely prescribed to pediatric orthopaedic patients absent other contraindications without concern for increased risk of fracture non-union or delayed bone healing.Additional prospective studies are needed focusing on higher risk fractures and elective orthopaedic procedures such as osteotomies and spinal fusion.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics

Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-pressed osteoblast(OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells(MSCs) play a critical role in multiple myeloma patho-physiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease(MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients(pMSCs) and their healthy counterparts(dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibi-tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and ac-tivity at various levels(i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncou-pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents(at preclinical or clinical stage) targeting those signaling pathways is commented.

The Controlled-releasing Drug Implant based on the Three Dimensional Printing Technology: Fabrication and Properties of Drug Releasing in vivo

Three dimensional （3D） printing technology was utilized to fabricate a new type of drug implant with complicated architectures, employing levofloxacin （LVFX） and rifampicine （RFP） as model drugs. The prepared drug implant prototype consists of a doublelayer structure, of which the upper region is a reservoir system containing RFP and the lower region is a matrix one containing LVFX. The release test in vivo revealed that LVFX was released in the early stage; no RFP was detected until 8th day; both of them continuously released more than 6 weeks. Therefore, 3D printing technology provides a precise and feasible method to fabricate a controlled-releasing drug implant with complicated architectures and this drug implant may present a new strategy for the prophylaxis and treatment of bone diseases such as combined bone infections and bone tuberculosis in the near future.

Critical review of bone health,fracture risk and management of bone fragility in diabetes mellitus

The risk of fracture is increased in both type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).However,in contrast to the former,patients with T2DM usually possess higher bone mineral density.Thus,there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes.Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk.Moreover,some antidiabetic medications further enhance the fragility of the bone.On the other hand,antiosteoporosis medications can affect the glucose homeostasis in these patients.It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk.Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature.With the advancement in imaging technology,newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes.The purpose of this review is to explore the patho-physiology behind poor bone health in diabetic patients.Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.

Combination of simvastatin and hydroxyapatite fiber induces bone augmentation

This study evaluated the capability of hydroxyapatite fiber (HAF) as a carrier and the bone formation by blending simvastatin. The mixture of HAF and simvastatin (0.15, 0.45, 0.75 mg) was placed in 1 ml of tris-buffer and the release of simvastatin from HAF was calculated per 24 hours for 10 days. Bilateral 5 mm-diameter and 3 mm-hight Teflon chambers were fixed on calvaria of adult Japanese white rabbits and filled with 40 mg HAF which containing simvastatin (0, 0.15, 0.45, 0.75 mg). The animals were sacrificed at 4 and 8 weeks and calculated radiologically by Micro-CT. After dyeing by toluidine blue the samples were analyzed histologically. In all of the study groups approximately 25% of simvastatin was released until 10 days. The new bone volume ratio measured by Micro-CT of 4 and 8 weeks group was (22.4%, 21.3%, 41.6%, 26.3%) and (20.2%, 11.7%, 42.1%, 31.2%) in different doses respectively. The 0.45 mg group showed significantly higher new bone volume ratio than 0 mg group and 0.15 mg group. The histological measurement and observations also supported these results. In conclusion, the HAF could be used as a carrier for simvastatin. Combinations of HAF and simvastatin have the potentiality to stimulate new bone formation and approximately 0.45 mg simvastatin in 40 mg HAF is the optimal dose in rabbit chamber model.

Study on Oxygen Supply and Protection of Bone Marrow in Acute Radiation injured Mice

After irradiated by & Gy 60Co γ-ray, mice were intraperitoneally injected immediately with 0.2 ml 100 % compound blood-activating soup twice a day for 10 days. The in situ ulnar bone marrow partial pressure of oxygen (PbO2) was determined in vivo before, during and after irradiation respectively. The bone marrow sections in the same part were observed. Our results showed that the normal murine ulnar PbO2 was 12.72±1. 05kpa. During irradiation, the level of PbO2 decreased to 10. 78±1. 17 kpa (P＜0. 001). And 3 days after irradiation, PbO2 decreased to 9. 75±0. 52 kpa, suggesting that the commonly used 'blood-activating and stasis-eliminating' Chinese drugs could promote the rehabilitation and proliferation of bone marrow microvessels in the acute radiation injured mice, expand their areas, increase the oxygen supply of bone marrow microenviroment, thereby leading to PbO2 much higher increase than that of control group. It is also helpful in the proliferation and rehabilitation of hematopoietic cells.

Effects of chitosan on dental bone repair

Objectives: Bone defects following tumor resection and osteolysis due to dental and bone lesions and periodentium tissue disorders are serious challenges. One of these materials used is chitosan, a derivative of crustaceans’ exoskeleton. The aim of this study was to assess effects of chitosan on socket repair after dental extraction. Methods: Twenty four dental sockets of 15-24 years old patients were visited by a maxillofacial surgeon for extracting premolar teeth for orthodontic purposes. The sockets in one side were filled-in by chitosan. In the other side, the sockets were left unfilled. After 10 weeks, periapical radiographs were obtained from the repair sites, were digitalized and then evaluated for densitometry using Adobe Photoshop Software. Each socket was divided into coronal, middle and apical. Dental density of each socket in case and control groups was recorded. The density of regenerated bone was compared against the maximum bone density of each individual. Wilcoxon signed range test and paired t-test were used for data analysis. Results: Bone density in middle and apical sections in case group was significantly more than control group. In apical section in case group regenerated bone reached up to 98.2% of normal bone density. In each patient, the bone density in epical and middle sections was increase 29.3% and 10.8% of normal bone density. Conclusions: Chitosan significantly increased bone density in epical and middle sections. Chitosan can be used for bone repair in cases of bone loss. Various densitometry studies for evaluating chitosan effects in different bone defects are suggested.

Preliminary delivery efficiency prediction of nanotherapeutics into crucial cell populations in bone marrow niche

Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches.Precise regulation of these cell types can remodel niches and develop new therapeutics.Multiple nanocarriers have been developed to transport drugs into the bone marrow selectively.However,the delivery efficiency of these nanotherapeutics into crucial niche cells is still unknown,and there is no method available for predicting delivery efficiency in these cell types.Here,we constructed a three-dimensional bone marrow niche composed of three crucial cell populations:endothelial cells(ECs),mesenchymal stromal cells(MSCs),and osteoblasts(OBs).Mimetic niches were used to detect the cellular uptake of three typical drug nanocarriers into ECs/MSCs/OBs in vitro.Less than 5%of nanocarriers were taken up by three stromal cell types,and most of themwere located in the extracellular matrix.Delivery efficiency in sinusoidal ECs,arteriole ECs,MSCs,and OBs in vivo was analyzed.The correlation analysis showed that the cellular uptake of three nanocarriers in crucial cell types in vitro is positively linear correlated with its delivery efficiency in vivo.The delivery efficiency into MSCs was remarkably higher than that into ECs and OBs,no matterwhat kind of nanocarrier.The overall efficiency into sinusoidal ECswas greatly lower than that into arteriole ECs.All nanocarriers were hard to be delivered into OBs(<1%).Our findings revealed that cell tropisms of nanocarriers with different compositions and ligand attachments in vivo could be predicted via detecting their cellular uptake in bone marrow niches in vitro.This study provided the methodology for niche-directed nanotherapeutics development.

Mechanism of "Epimedium-Cistanche deserticola" in the treatment of breast cancer with bone metastasis

Objective:"Epimedium - Cistanche deserticola" is a kind of kidney tonifying drug commonly used in the treatment of breast cancer bone metastasis, which has good clinical effect, but the pharmacological mechanism has not been fully clarified. Methods: In this study, the network pharmacology and bioinformatics technology were used to explore the mechanism of "Epimedium - Cistanche deserticola" in the treatment of breast cancer bone metastasis. TCMSP, TCM database@Taiwan and TCMID databases were used to screen the main effective components of the drug. Swiss Target Prediction and STITCH databases were used to search the potential target of action of Epimedium and Cistanche deserticola. Genecards, OMIN and Drugbank databases were used to search the cause of bone metastasis of breast cancer. The target of action of the drug and the disease gene were mapped for GO and KEGG signal pathway analysis, A visualized network of "drug - component - target - signaling pathway" was constructed by using the software of Cytoscape 3.6.0, and the core genes were screened out. Results: The study found that there are 30 main effective components of Epimedium and Cistanche deserticola, and 544 genes are involved in the potential therapeutic targets, among which 101 genes are potential targets of Epimedium and Cistanche deserticola in the treatment of breast cancer bone metastasis. Through the analysis of GO and KEGG pathways, we found that the mechanisms involved in antitumor, osteoblast differentiation, osteoclast apoptosis and regulation of bone microenvironment, such as apoptosis, osteoclast differentiation, PI3K-Akt, HIF-1 signaling pathway, T cell receptor signaling pathway, etc. TP53, VEGFA, AKT1, EGFR, SRC, CCND1, MAPK3, ESR1 may be the key genes in the treatment of breast cancer bone metastasis. Conclusion: In this study, the network of "drug - component - target- signaling pathway" was constructed through network pharmacology, and it was found that the mechanism of "Epimedium - Cistanche deserticola" in the treatment of breast cancer bone metastasis involves multiple targets and pathways, which is conducive to guiding clinical medication.

An Enzymologic Study on Bone Marrow Cells in Patients with Aplastic Anemia Treated by Supplementing the Kidney and Removing Blood Stasis

The content of cytochrome oxidase (CCO), succinate dehydrogenase (SDH) and neutrophil alkaline phosphatase (NAP) in bone marrow cells in 68 cases of aplastic anemia before and after treatment was determined by computerized graphical analysis and compared with that of normal volunteers (control group). The significantly lowered CCO and SDH levels and the markedly increased NAP content before treatment (P<0.01) became approximately normal after that of supplementing the kidney and removing blood stasis (P >0.05).

Chinese expert consensus on the diagnosis and treatment of bone metastasis in lung cancer(2022 edition)

Lung cancer is the leading cause of cancer-related deaths worldwide.Bone is a common metastatic site of lung cancer,about 50%of bone metastatic patients will experience skeletal related events(SREs).SREs not only seriously impact the quality of life of patients,but also shorten their survival time.The treatment of bone metastasis requires multi-disciplinary therapy(MDT)and development of individualized treatment plan.In order to standardize the diagnosis and treatment of bone metastasis in lung cancer,the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.

麝香黄芪复方滴丸含药血清促进骨髓间充质干细胞增殖分化

背景:骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)已被广泛用于治疗神经系统疾病,但由于血脑屏障的限制以及干细胞在受损部位存活率、分化率低,导致治疗效果有限。目的:探讨麝香黄芪复方滴丸含药血清对BMSCs增殖、迁移和向星形胶质细胞分化的影响。方法:SD雄性大鼠连续灌胃麝香黄芪复方滴丸5 d后进行腹主动脉取血,分离血清备用。采用CCK-8法检测体积分数5%,10%,20%含药血清对BMSCs增殖的影响;划痕实验观察体积分数10%含药血清对BMSCs横向迁移的影响;Transwell小室培养BMSCs,用结晶紫染色和DAPI核染色观察体积分数10%含药血清对BMSCs纵向迁移的影响;用含体积分数10%含药血清的诱导液或与星形胶质细胞共培养观察BMSCs向星形胶质细胞分化情况。结果与结论:①体积分数10%和20%含药血清在第2,3天促进细胞增殖更明显,且两种体积分数无统计学差异;②在划痕30,48 h时,10%含药血清组BMSCs迁移量显著高于对照组;③10%含药血清组BMSCs穿过Transwell小室滤过膜的数量高于对照组;④体积分数10%含药血清可能促进BMSCs向星形胶质细胞方向分化,但分化作用较弱,星形胶质细胞能进一步促进含药血清诱导BMSCs向星形胶质细胞方向分化;⑤结果表明,体积分数10%含药血清能促进BMSCs体外增殖、迁移;与星形胶质细胞共培养可能促进BMSCs向星形胶质细胞方向分化。

2型糖尿病与骨质疏松症药物治疗间相关性研究进展

2型糖尿病是目前世界上最为常见的慢性疾病之一,这些患者并发骨质疏松症的概率远高于非糖尿病患者。另外,糖尿病合并骨质疏松症出现的致残率与死亡率极高,严重影响人类生活健康。不少研究发现2型糖尿病与骨质疏松症有许多共同的高危发病因素以及发病机制,但二者药物治疗之间的相关性仍存在较大争议,未能给予临床用药准确的参考价值。因此,笔者通过归纳分析总结近些年最新参考文献,发现两者在药物治疗方面的关联性十分密切,如某些抗2型糖尿病药物不仅可以改善血糖水平而且还能调节骨平衡,某些抗骨质疏松症药物对降低血糖又具有一定的价值,不过两者药物治疗之间的关联性还需要更进一步的研究探索。因此,笔者探讨了2型糖尿病与骨质疏松症两者药物治疗之间的相关性并作一综述,以期能够为临床治疗提供一些参考价值。

中医非药物疗法治疗骨伤术后疼痛临床观察

目的探讨分析中医非药物疗法治疗骨伤术后疼痛的临床效果。方法选择遂川县中医院于2020年1月—2022年1月收治的60例骨伤术后疼痛患者,采取随机数字表法分组,奇数患者纳入观察组(30例),实施中医非药物疗法,偶数患者纳入对照组(30例),实施常规治疗。对比两组临床疗效、焦虑自评量表(SAS)评分、抑郁自评量表(SDS)评分、视觉模拟量表(VAS)评分、生活质量评分以及关节活动度(ROM)等情况。结果观察组临床总有效率为93.33%(28/30),高于对照组的70.00%(21/30)(P<0.05)。治疗后,观察组SAS、SDS、VAS和生活质量评分以及ROM均优于对照组,差异均有统计学意义(P<0.05)。结论应用中医非药物疗法治疗骨伤,可有效缓解患者疼痛以及因疾病产生的焦虑、抑郁等不良情绪,其关节活动度改善明显,生活质量切实提升,值得临床大力推广、应用。

中医药联合医用水凝胶治疗疾病的策略及意义

背景:医用水凝胶是具有三维结构网络的新型功能高分子材料,具有出色的生物相容性,目前已在组织工程领域、药物载体领域有广泛研究,但基于组织工程探究医用水凝胶与中医药结合治疗疾病的研究还处于初期探索阶段。因此,通过对医用水凝胶机制作用的剖析,整合医用水凝胶与中医药在研究中联合应用的文章,进而更好地为科研工作者提供思路,对中医药与医用水凝胶联合应用具有重要意义。目的:基于组织工程研究探讨中医药联合医用水凝胶治疗疾病的策略及意义。方法:利用PubMed和中国知网数据库,检索有关中医药联合医用水凝胶在组织工程中应用的文献,检索时间为2010年1月至2022年11月,英文检索词为“hydrogel,traditional Chinese medicine,drug carrier,tissue engineering”,中文检索词为“医用水凝胶、中医药、药物载体、组织工程”。根据纳入与排除标准对所有文章进行初筛后,最终纳入61篇文章进行综述。结果与结论:①中医药联合医用水凝胶的应用虽然在关节内、组织器官内、软组织伤口和组织工程等方面有所涉及,但除了中医药结合水凝胶敷料在临床应用治疗软组织损伤外,其他方面尚处于基础实验阶段。②中医药联合医用水凝胶的发展有着巨大潜力和发展前景,但对于性能要求较高的凝胶在制造方面存在一定难度,理化性质精确掌握难度较大。③目前综合来看可注射水凝胶凭借着简便易用的特点,其在与中医药联合使用可延伸范围较广,可用于关节、器官和组织工程相关疾病的治疗;智能水凝胶有较高的灵敏度和可逆转化性也可满足特殊环境下的使用;将两者结合的中医药使用过程中还需要明确中药成分的作用机制。④中医药联合医用水凝胶治疗疾病的策略应着手于中医药对器官、组织、细胞的治疗作用联合适当种类的医用水凝胶进行匹配,可弥补传统中医给药方式和频繁给药的不足,在组织工程方面可以用水凝胶负载中药干预后的干细胞,或者同时负载中药和干细胞用于相关疾病的治疗。⑤在中医药联合医用水凝胶应用的未来研究中,还需要考虑:应当确保医用水凝胶生物性能可以量化,以不同材料不同制造工艺把握水凝胶特性,制造出所需要的符合应用条件的医用水凝胶;在中医药方面需要对已知中药单体、中药复方提取物的治疗效果和应用机制全面了解剖析,在更明了的机制下实现中医药与医用水凝胶更多更完美的结合;借助医学科技创新能力的不断提高,医用水凝胶可以创新性地结合中医药其他传统治疗方法比如针灸、推拿和拔罐等方式进行多角度运用。

肺癌骨转移治疗中纳米材料应用的研究进展

根据世界卫生组织国际癌症研究机构(IARC)发布的“2020年全球新发癌症病例”报道,全球肺癌新发病例约220万例,死亡约180万例,肺癌是癌症死亡的主要原因。肺癌骨转移发生率为30%~40%,46%的肺癌骨转移患者并发疼痛、高钙血症、病理性骨折等骨相关事件(SRE)^([1,2])。