Pathophysiology of bone metastases

Normal bone remodeling maintains an appropriate balance between the action of osteoclasts (bone-resorbing cells) and osteoblasts (bone-forming cells). Skeletal malignancies, including bone metastases, disrupt the OPG-RANKL-RANK signal transduction pathway and promote enhanced osteoclast formation, thereby accelerating bone resorption and inducing bone loss. This osteolysis in turn leads to the release of bone-derived growth factors, contributing to a "vicious cycle" in which interactions between tumor cells and osteoclasts not only lead to increased osteoclastogenesis and osteolytic activity, but also aggressive growth and behavior of the tumor cells. The osteolytic complications associated with bone metastases are caused by tumor-induced alterations of the OPG-RANKL-RANK system, which are accompanied by enhanced bone resorption and disassociated from counterbalancing bone formation by osteoblasts.     

Osteoprotegerin diminishes advanced bone cancer pain

Bone cancer pain most commonly occurs when tumors originating in breast, prostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 400,000 new cancer cases per year in the United States alone, and >70% of patients with advanced breast or prostate cancer have skeletal metastases. Whereas pain resulting from bone cancer can dramatically impact an individual's quality of life, very little is known about the mechanisms that generate and maintain this pain. To begin to define the mechanisms that give rise to advanced bone cancer pain, osteolytic 2472 sarcoma cells or media were injected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using dental amalgam, confining the tumor cells to the bone. Twelve days after injection of 2472 tumor cells, animals showed advanced tumor-induced bone destruction of the injected femur, bone cancer pain, and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. Administration of osteoprotegerin, a naturally secreted decoy receptor that inhibits osteoclast maturation and activity and induces osteoclast apoptosis, or vehicle was begun at 12 days, when significant bone destruction had already occurred, and administration was continued daily until day 21. Ongoing pain behaviors, movement-evoked pain behaviors, and bone destruction were assessed on days 10, 12, 14, 17, and 21. The neurochemistry of the spinal cord was evaluated at days 12 and 21. Results indicated that osteoprotegerin treatment halted further bone destruction, reduced ongoing and movement-evoked pain, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of bone cancer, ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction.     

Pathophysiology of multiple myeloma bone disease

Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. The multiple myeloma-induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions. Recently the biologic mechanism involved in the imbalance between osteoclast activation and osteoblast inhibition induced by multiple myeloma cells has begun to be clarified. In this article, the pathophysiology underlying the imbalanced bone remodeling and potential new strategies for the treatment of bone disease in multiple myeloma are reviewed.     

Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment

Metastasis to bone is a common feature in advanced prostate cancer patients. Current treatments, while effective in suppressing tumour growth and relieving tumour associated bone pain, do not provide long term remission or 'cure' for the disease. A greater understanding of prostate cancer metastasis is required if new treatment strategies are to be developed. Growth of tumour foci in skeletal sites is a major cause of morbidity in advanced prostate cancer and has required the development of specialised approaches to treatment, including the use of bisphosphonates. These drugs inhibit tumour induced osteoclastic bone resorption, thereby preventing skeletal related events and treatment induced bone loss. Zoledronic acid is currently the only bisphosphonate with proven benefit in prostate cancer. Bisphosphonates may also modify the bone microenvironment so that it becomes less favourable for the growth and survival of metastases. The most recent developments in our understanding of the advantages for growth and survival gained by metastatic prostate cancer cells in the skeleton are reviewed, along with the clinical evidence supporting the use of bisphosphonates in advanced prostate cancer.     

中医药治疗骨转移癌痛的进展

疼痛是肿瘤骨转移患者难以忍受的症状之一,具有顽固性、持续性、进行性加重等特点,发病机理尚不明确。西医治疗方案以三阶梯止痛药为主,联合放化疗等个性化治疗;中医治疗包括中药口服、中药外敷、针灸、穴位贴敷、中药注射、埋线等多种方式,起到活血化瘀止痛等功效。且中医治疗价廉惠民、无成瘾性、操作便捷、毒副反应少,因此成为骨转移癌痛治疗的研究热点。中西医联合用药可增强止痛效果,实现优势互补,且作用持久,明显提升患者生活质量。本文综述了骨转移癌痛的中医治疗进展,为后续研究提供参考。     

Radioisotopic treatment of bone pain from metastatic prostate cancer

Hormone-refractory prostate cancer patients with painful bony metastatic lesions are potential candidates for boneseeking radiopharmaceutical therapies. After careful assessment of symptoms and localization of pain, a bone scan is the single most useful imaging modality for the clinician to assess patients for the presence and distribution of osteoblastic lesions. Increased uptake (compatible with bony metastases) on a conventional bone scan is currently a prerequisite for treating patients with a bone-targeted therapeutic isotope. Determining whether metastatic bony involvement is focal or diffuse is also important in the clinical decision-making process. Patients with multifocal metastatic disease are excellent candidates for systemic therapies, whereas patients with unifocal metastatic disease may be more appropriate candidates for focal therapies such as external-beam radiation. Patients who are poorly tolerant of narcotics should be actively considered for alternative treatments such as systemic radiopharmaceuticals. Contraindications to administration of current boneseeking radioisotopes include substantial degrees of renal insufficiency or bone marrow suppression.     

Pathophysiology of hyperprolactinemia in breast cancer

To characterize the prolactin secretion in human breast cancer, plasma prolactin levels were measured in 514 patients with breast cancer in long term follow-up studies. In hyperprolactinemic patients suppression and stimulation tests were performed and the 24-h secretion profile was recorded. Tissue extracts and sera of hyperprolactinemic breast cancer patients were incubated with cultured pituitary cells in vitro to detect a prolactin releasing activity in these specimens. 44% of breast cancer patients developed hyperprolactinemia in the course of the disease. In 35% of measurements hyperprolactinemia was induced by non tumor related causes, e.g. prolactin-stimulating drugs, surgery, uremia, prolactinoma. Excluding such influences on the prolactin level, hyperprolactinemia over 1,000 mU/l was almost only found in patients with progressive metastatic disease. In these patients hyperprolactinemia was associated with tumor load, but not correlated to BSR, CEA or prognostic factors. Hyperprolactinemia in breast cancer was not of paraneoplastic origin. No prolactin-releasing activity was detected in tumor tissue and sera of hyperprolactinemic breast cancer patients.     

Pathophysiology of seroma in breast cancer

PURPOSE: Seroma is the most common complication of mastectomy. The aim of this systematic review is to clarify the pathophysiology of seroma. MATERIALS AND METHODS: A computer-assisted MEDLINE search was conducted, and additional references were found in the bibliographies of these articles. The reference terms 'breast cancer', 'mastectomy', 'seroma', 'lymphocele' and 'lymphocyst' were used as both keyword and subject terms. The search was limited to studies published in English. RESULTS: The definition of seroma was highly variable across studies, but was most commonly a seroma large enough to be noticed by the patient or medical staff and affecting the patient's satisfaction in the immediate or acute postoperative period. So far, only limited data are available on the severity of seroma. With respect to the pathophysiology of seroma, the data indicated that several anatomical factors, especially dead space, likely contribute to seroma formation. However, it was obscure whether seroma was due to lymph-like fluid or exudate. CONCLUSION: There is considerable variability in the way seroma is defined across studies, and its pathophysiology remains uncertain.     

多发骨转移癌疼痛患者心理调查及相关因素研究

目的：探讨多发骨转移癌疼痛患者的心理状况。方法：采用临床焦虑自评量表（SAS）及抑郁量表（SDS）调查101例多发骨转移癌患者的心理状况。结果：所有多发骨转移患者均不同程度存在焦虑和抑郁。其中单纯疼痛者轻、中、重度分别为SAS：81．20％、89．70％、95．30％,SDS：87．10％、92．30％、97．50％。伴有脊髓损伤感觉异常和行动障碍者SAS：71．00％,SDS：89．70％。结论：多发骨转移癌患者存在明显心理障碍,尤其是存在疼痛、感觉异常和肢体活动障碍者,更应给予心理帮助和指导。     

乳腺癌骨转移疼痛的综合治疗

目的　探讨缓解乳腺癌骨转移疼痛 ,恢复患者活动能力的方法。方法　 31例乳腺癌骨转移患者采用以CMFP或CAFP方案化疗为主 ,辅以放射性同位素或双磷酸盐类药物综合治疗 ,观察治疗后疼痛缓解、活动能力恢复及骨外转移灶的变化情况。结果　全组骨痛缓解率为 87.1 % (2 7/ 31 ) ,功能活动恢复 85 .7% (6/ 7) ,骨外转移灶的有效率为 67.9% (1 9/ 2 8)。结论　以化疗为主的综合治疗 ,不仅能较好地控制骨外转移灶的发展 ,而且能显著地缓解骨痛 ,恢复患者的活动能力     

Oxycodone-induced analgesic effects in a bone cancer pain model in mice

The femur bone cancer pain model was developed by implanting mouse osteolytic tumor cells (NCTC 2472) into the intramedulla of the femur in C3H/HeN mice. In vivo imaging analysis revealed that the implanted tumor cells grew progressively over 14 days. Associated with the tumor growth, guarding behavior, which was an indication of ongoing pain, time-dependently increased. Limb use abnormality and allodynia, which were indications of ambulatory and neuropathic pain, respectively, also appeared. The analgesic effects of oxycodone and other opioids, such as morphine and fentanyl, were evaluated at 14 days when all pain-related behaviors clearly appeared. Oxycodone (2-20 mg/kg, s.c.), morphine (10-50 mg/kg, s.c.) and fentanyl (0.05-0.2 mg/kg, s.c.) significantly reduced guarding behavior. Oxycodone (5-20 mg/kg, s.c.) and fentanyl (0.1 and 0.2 mg/kg, s.c.) significantly reversed limb use abnormality, but morphine (5-50 mg/kg, s.c.) did not. Moreover, oxycodone (5-20 mg/kg, s.c.) dose-dependently reversed allodynia without affecting the sham-treated mice. Morphine (50 mg/kg, s.c.) and fentanyl (0.075-0.2 mg/kg, s.c.) also reversed allodynia, but morphine (50 mg/kg, s.c.) tended to affect and fentanyl (0.1 and 0.2 mg/kg, s.c.) affected the withdrawal threshold in sham-treated mice. These results suggested that oxycodone relieved not only ongoing pain, but also ambulatory and neuropathic pain, and that the analgesic profile of oxycodone could be different from that of either morphine or fentanyl.     

槐定碱对骨癌痛小鼠的影响及其作用机制

目的 探讨槐定碱在骨癌痛小鼠中的影响及其作用机制。方法 将24只C57BL/6小鼠随机分成假手术组（Sham 组）、骨癌痛组（BCP 组）、骨癌痛+生理盐水组（BCP+NS组）、骨癌痛+槐定碱组（BCP+Sophoridine组,25 mg/kg）。分别于癌细胞接种前1 d以及接种后3 d、5 d、7 d、10 d和14 d时检测机械缩足阈值和热痛阈值;Western blot法检测脊髓L4⁃L5段背根神经节和大脑皮层组织中DAP12/Trem2/TLR4轴相关蛋白的表达水平。结果 与Sham组相比,在术后5 d、7 d、10 d、14 d,BCP组机械缩足阈值及热痛阈值均明显降低（均P<0.05）。与BCP组相比,在术后5 d、7 d、10 d、14 d,BCP+Sophoridine组的热痛阈值均明显升高（均P<0.05）;术后10 d、14 d,BCP+Sophoridine组机械缩足阈值均明显升高（均P<0.05）。Western blot实验结果显示,与BCP组相比,BCP+Sophoridine组小鼠背根神经节和大脑皮层组织中的TLR4蛋白表达水平均显著减少（均P<0.05）,DAP12、Trem2蛋白表达水平均显著升高（均P<0.05）。结论 槐定碱可减轻骨癌痛小鼠癌痛行为,其机制可能与调控DAP12/Trem2/TLR4轴有关。     

唑来膦酸治疗骨转移癌疼痛的临床观察

目的观察唑来膦酸治疗恶性肿瘤骨转移导致疼痛的疗效及安全性。方法恶性肿瘤骨转移伴中重度疼痛患者38例,随机双盲分为A组(治疗组)20例唑来膦酸4mg溶于生理盐水50ml,静脉滴注(15min);安慰剂 生理盐水500ml,静脉滴注(4h);B组(对照组)18例安慰剂 生理盐水50ml,静脉滴注(15min);帕米膦酸二钠60mg 生理盐水500ml,静脉滴注(4h)。结果A组显效率85.0%,B组为83.4%,差异无显著性(P>0.05)。起效时间分别为5.2d与5.5d。结论唑来膦酸缓解恶性肿瘤骨转移所致疼痛有效,副作用小,患者可耐受,其有效性和安全性与帕米膦酸二钠相似。     

大鼠骨癌痛模型的建立及组织学研究

目的建立一个有用的癌痛动物模型.方法将MRMT-1大鼠乳腺癌细胞接种到SD大鼠胫骨上段骨髓腔内,造成骨癌痛动物模型.用von Frey细丝刺激足底和后肢负重测量仪分别测量机械性痛觉超敏和痛觉过敏,放射学方法评估骨破坏,同时,组织切片镜下观察肿瘤和骨结构的破坏情况.结果造模动物在14天左右开始出现机械性痛觉超敏和痛觉过敏,胫骨X线摄片显示明显的骨破坏,组织学研究显示骨髓腔内肿瘤生长,向外侵蚀破坏骨皮质,同时伴有新生的编织骨形成.结论从疼痛行为学、放射学、组织学多方面研究的结果,表明大鼠骨癌痛模型已复制成功.该癌痛模型的建立,将为我国癌痛新药的评价,尤其是研究治疗癌痛中药的疗效及作用机制提供一个有用的工具.     

Post-operative breast cancer patients diagnosed with skeletal metastasis without bone pain had fewer skeletal-related events and deaths than those with bone pain

Background  

Skeletal metastases are often accompanied by bone pain. To investigate the clinical meaning of bone pain associated with skeletal metastasis in breast cancer patients after surgery, we explored whether the presence of bone pain was due to skeletal-related events (SREs) or survival (cause specific death, CSD), retrospectively.     

大鼠骨癌痛模型中脊髓背角神经元与星型胶质细胞相互联系的研究

目的:研究大鼠骨癌痛模型中脊髓背角神经元与星型胶质细胞相互联系。方法:利用Walker256乳腺癌细胞建立大鼠骨癌痛模型后,分别鞘内注射药物阻断神经元的活化（c-Fos反义寡核苷酸探针,c-Fos ASO）和星形胶质细胞的活化（L-α-aminoadipate,L-α-AA）,然后分别检测大鼠痛行为学改变;利用免疫荧光染色法和Western blot实验检测大鼠脊髓背角神经元活化标记物c-Fos和星形胶质细胞标记物GFAP的表达变化。结果:骨癌痛大鼠出现了显著的痛行为学改变并激活了脊髓背角神经元和星形胶质细胞,表现为早期c-Fos和晚期GFAP的表达增加。鞘内注射c-Fos ASO或L-α-AA均有明显镇痛效果。免疫荧光染色提示c-Fos ASO不仅能显著抑制骨癌痛大鼠神经元的活化,而且对星形胶质细胞的活化也有抑制作用。与此同时,Western blot显示L-α-AA不但抑制了星形胶质细胞的活化,也缩短了神经元的活化时间。结论:神经元和星形胶质细胞相互联系伴随着骨癌痛的发生发展。因此,研究新的镇痛策略,应综合考虑两者的协调关系。     

国产因卡膦酸二钠治疗骨转移癌疼痛的Ⅱ期临床试验

目的 :观察评价国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛的有效性和安全性。方法 :自 2 0 0 1年 1 2月至2 0 0 2年 1 0月 ,收治恶性肿瘤骨转移患者 4 3例 ,随机分配至试验组和对照组 ,分别给予国产因卡膦酸二钠 1 0mg与帕米膦酸二钠 90mg静滴 ,观察其疗效和毒副作用。结果 :试验组 2 3例止痛有效率 5 2 2 % ,生活质量改善有效率为 4 3 5 % ,与对照组 2 0例相比无显著性差异 (P >0 0 5 ) ,但毒副反应少见。结论 :国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛疗效显著 ,安全可靠 ,值得临床上推广使用     

Mechanisms of cancer-induced bone pain

Cancer-induced bone pain (CIBP) is common and challenging to treat. Common therapies, such as opioids, radiotherapy and bisphosphonates, are often only partially effective. CIBP is a different entity to inflammatory or neuropathic pain and needs to be considered as such. This overview examines the mechanisms of CIBP; the imbalance of bone turnover, peripheral and central nervous involvement and key neurochemical mediators. The current understanding of the underlying pathophysiology of CIBP is discussed.     

何首乌有效成分对大鼠骨癌痛的镇痛效果

目的  探讨何首乌有效成分对大鼠骨癌痛的镇痛作用。方法 将36只SPF级雌性SD大鼠随机分成3组：A组为正常空白对照（n=6），B组大鼠注射无菌生理盐水（n=6），C组大鼠左后腿胫骨注射乳腺癌细胞walker256建立骨癌痛模型（n=24）。建立骨癌痛模型的C组SD大鼠按灌胃药物随机分成C1、C2、C3、C4 4组，每组6只。建模成功后14 d、15 d、16 d连续对C1~C4组大鼠分别灌胃生理盐水（2 mL）、二苯乙烯苷（60 mg/mL，2 mL）、大黄素（60 mg/mL，2 mL）和儿茶素（60 mg/mL，2 mL）。每次灌胃前、灌胃后30 min、灌胃后1.0 h测量大鼠左脚掌的机械痛阈值。结果 癌痛模型喂养第5天起，与A、B两组比较，C组大鼠机械痛阈值降低（P<0.05），骨质明显破坏；A、B两组大鼠机械痛阈值无明显差异，骨质结构正常。C2组大鼠各时点的机械性痛阈值均较C1组、C3组、C4组明显增加（P<0.05）。与灌胃前比较，C2组大鼠模型灌胃30 min和灌胃后1 h后机械性痛阈值明显升高（P<0.05），但灌胃30 min和灌胃后1 h后的机械性痛阈值无统计学意义（P>0.05）。结论 何首乌可有效降低大鼠的骨癌痛，其有效单体成分是二苯乙烯苷。