Bisphosphonates Induce Apoptosis of Stromal Tumor Cells in Giant Cell Tumor of Bone

Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 M) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 M, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.Both authors (Y.Y. Cheng and L. Huang) contributed equally to this work.     

Lip Ulceration Associated with Intravenous Administration of Zoledronic Acid: Report of a Case

Although osteonecrosis of the jaw is a well-known adverse reaction of bisphosphonates (BPs), random cases of oral mucosal ulceration after per os administration of BP-aledronate have been attributed to prolonged mucosal irritation. This report, for the first time, describes the mucosal ulceration related to intravenous use of zoledronic acid (ZA). A 52-year-old female patient presented with painful ulcers on both cutaneous/mucosal surfaces of the lower lip and a 2-month history of osteonecrosis of the mandible beside the right lower canine. Her medical record included intravenous administration of ZA for 10 months for primary breast cancer metastatic to bone. Examination of the peripheral blood showed severe anemia and a slightly increased white blood cell count, due to urinary tract infection by E. coli, but no evidence of a viral infection. The treatment of anemia and E. coli infection did not improve the labial ulcers. Biopsy from the mucosal lesion revealed a non-specific ulceration with moderate inflammatory infiltration. There was no evidence of infection or malignancy. ZA administration was discontinued and within 3 months the lesions were resolved after treatment with systemic antibiotics (amoxicillin), vitamins A and E, chlorexidine and H₂O₂ (hydrogen peroxide) solutions and local pantothenic acid/vitamin A creams. Recurrence was detected a month after ZA re-administration. Nevertheless, after new treatment, the patient was free of oral/skin lesions 18 months later. This case, which is the first report of ulceration associated with intravenous administration of bisphosphonates, suggests that systemic mechanisms may be implicated in BP-induced oral mucosal ulceration. Furthermore, ZA appears to cause the same oral mucosal manifestations as alendronate. This emphasizes the need for oral examination in all cases of BP therapy, whether per os or intravenously administrated.     

唑来膦酸治疗老年原发性骨质疏松症的临床安全性观察

目的探讨临床应用唑来膦酸静脉滴注治疗老年原发性骨质疏松症的安全性和依从性。方法 观察首次静脉滴注唑来膦酸治疗50例原发性骨质疏松症患者的一般情况和副反应,询问患者是否 愿意接受第二次治疗。结果所有患者在滴注过程中均无严重不良反应发生,但24%_患者在输注后 3凿内出现了急性一过性不良反应,包括发热、关节痛、肌痛、流感样症状、头痛等,绝大多数患者同意 继续使用。结论唑来膦酸治疗原发性骨质疏松症安全性较高,依从性好,是一种较理想的治疗新选 择,其疗效有待于长期随访     

骨巨细胞瘤增殖细胞核抗原与bc1-2基因表达及凋亡的检测研究

探讨骨巨细胞瘤（ＧＣＴ）的细胞学性质、肿瘤发生以及生物学行为。方法用免疫组化（标记的链霉卵白素生物素──ＬＳＡＢ）法检测５１例ＧＣＴ中ＰＣＮＡ和ｂｃ１－２蛋白表达,并用ＴＵＮＥＬ法检测其凋亡细胞。结果全部标本ＰＣＮＡ阳性表达,随病理分级增加,ＰＣＮＡ表达有增高趋势。ｂｃ１－２在Ⅰ与Ⅲ级及Ⅰ与Ⅱ＋Ⅲ级间表达差异有显著性意义。ＧＣＴ中多为单核基质细胞凋亡,ＧＣＴ的凋亡率（ＡＩ）为０．８６％,各级间及ＰＣＮＡ标记指数间ＡＩ的差异无显著性意义,ＧＣＴ的ＡＩ与ｂｃ１－２表达呈显著负相关,ｂｃ１－２表达与否的ＡＩ差异有显著性。结论ＧＣＴ是以增殖为特征的肿瘤;ｂｃｌ－２在ＧＣＴ发生发展中可能起一定的作用。     

二膦酸盐对骨巨细胞瘤细胞的生长抑制和诱导凋亡作用

目的观察二膦酸盐对骨巨细胞瘤细胞生长的影响。方法取10例手术切除的骨巨细胞瘤新鲜组织进行原代培养，待瘤细胞贴壁生长后分别给予5、25、50、100、200μmol／L阿仑膦酸钠、帕米膦酸二钠。作用一定时间后，用倒置相差显微镜观察细胞形态，MTT法检测细胞活性，末端酶标记法凋亡染色观察细胞凋亡情况，流式细胞术检测凋亡率和caspase-3表达。结果（1）二膦酸盐作用后，细胞正常形态消失，甚至发生崩解。（2）药物作用24h后，阿仑膦酸钠可以抑制细胞活性的2．79％±0．92％-31．17％±8．05％，帕米膦酸二钠为5．87％±1．94％-39．68％±9．26％；48h后，阿仑膦酸钠可以抑制细胞活性的8．68％±2．87％—46．88％±11．24％，帕米膦酸二钠为10．49％±3．26％～60．43％±13．64％；72h后，阿仑膦酸钠可以抑制细胞活性的11．13％±3．60％-49．94％±11．67％，帕米膦酸二钠为15．57％±5．86％～63．97％±16．42％。（3）药物作用48h后，阿仑膦酸钠和帕米膦酸二钠5μmol／L组的细胞凋亡率分别为16．25％±5．62％、20．48％±6．02％；50μmol／L组分别为37．20％±12．01％、42．39％＋12．41％；200μmol／L组分别为47．53％＋13．92％、54．67％＋15．38％。（4）帕米膦酸二钠作用48h后，5、50、200μmol／L组瘤细胞的caspase-3活性分别为14．93％±5．04％、25．13％±7．60％、26．07％＋7．49％，引起的细胞凋亡表现为时间和浓度依赖性。结论二膦酸盐可能成为治疗和预防骨巨细胞瘤复发的一个治疗方法。     

促凋亡基因bax在骨巨细胞瘤中的表达及分化调控意义

目的：研究促凋亡基因ｂａｘ在骨巨细胞瘤中的表达及其与Ｊａｆｅ分级和预后的关系。方法：采用兔抗人Ｂａｘ多克隆抗体及免疫组织化学ＳＡＢＣ法。结果：７３例骨巨细胞瘤中,Ｂａｘ阳性４７例（６４４％）;其中Ｊａｆｅ病理分级中Ⅰ级２７例中,阳性２２例（８１５％）,Ⅱ级３８例中阳性２３例（６０５％）,Ⅲ级８例中,２例阳性（２５０％）,Ｐ＜００５。在不同预后分组中Ｂａｘ阳性率间无显著差异（Ｐ＞００５）。结论：促凋亡基因在骨巨细胞瘤中不同程度的表达可能参与骨巨细胞瘤凋亡的调节,并与肿瘤分化程度有关。单一Ｂａｘ表达不能反应预后。     

The role of bisphosphonates in hormone-refractory prostate cancer

Men with advanced prostate cancer are at high risk for developing bone metastases, which result in clinically significant skeletal morbidity. Treatments that prevent skeletal complications in these patients could considerably improve their quality of life. Therefore, this paper reviews the role of bisphosphonates in the treatment of hormone-refractory prostate cancer (HRPC). Published studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from scientific meetings. Metastatic bone disease in men with HRPC results in skeletal complications such as pathologic fractures, spinal cord compression, and debilitating bone pain. First- and second-generation bisphosphonates, clodronate and pamidronate, had transient palliative effects that were not durable and did not prevent skeletal events in these patients. A small open-label study of ibandronate demonstrated significant reductions in pain, but these results have not been confirmed in a larger, randomized, controlled trial. To date, zoledronic acid is the only bisphosphonate that has demonstrated a statistically significant reduction in skeletal morbidity in this patient population. In a large, multicenter, randomized, placebo-controlled trial, treatment of men with HRPC and bone metastases with zoledronic acid significantly reduced skeletal-related events and provided a durable reduction of bone pain over 24 months compared with placebo. Zoledronic acid is the only bisphosphonate that has demonstrated efficacy for preventing skeletal complications in patients with HRPC and bone metastases. Therefore, initiation of zoledronic acid therapy should be considered to prevent skeletal morbidity and improve the quality of life of these patients.     

Thapsigargin potentiates TRAIL-induced apoptosis in giant cell tumor of bone

TNF-related apoptosis-inducing ligand (TRAIL) is capable of causing apoptosis in tumor cells but not in normal cells; however, it has been shown that certain types of tumor cells are resistant to TRAIL-induced apoptosis. In this study, we examined the potentiation of TRAIL-induced apoptosis in the stromal-like tumor cells of giant cell tumor of bone (GCT). We show that both mRNA and protein of TRAIL receptors—death receptors (DR4, DR5) and decoy receptors (DcR1, DcR2) are present in GCT stromal tumor cells. However, the expression profiles in all GCT clones tested do not readily correlate with their differential sensitivity to TRAIL. To this end, we selected thapsigargin (TG), an agent known to cause perturbations in intracellular Ca²⁺ homeostasis to enhance the apoptotic action of TRAIL. When added alone, neither TRAIL nor TG induces a therapeutically important magnitude of cell death in GCT tumor cells. Interdependently, scheduled treatment of the cultures with TG followed by subsequent addition of TRAIL resulted in a significant synergistic apoptotic activity, while in contrast, no obvious augmentation was seen when TRAIL was added before TG. This effect was in accord with our observation that TG predominantly up-regulated both mRNA and protein expression of DR5, as well as DR4 mRNA while down-regulating DcR1 protein in GCT stromal-like tumor cells. Taken together, our findings suggest that TG is able to sensitize tumor cells of GCT to TRAIL-induced cell death, perhaps in part through up-regulating the death receptor DR5 and down-regulating the decoy receptor DcR1. These findings provide an additional insight into the design of new treatment modalities for patients suffering from GCT.     

Intravenous bisphosphonate therapy does not delay fracture healing in inter-trochanteric femur fractures – A randomised controlled study

Hip fractures in elderly are commonly associated with osteoporosis and surgical outcome is influenced by its concurrent management. The purpose of our study is to determine the association between timing of bisphosphonate administration in inter-trochanteric (IT) fractures and fracture healing. Patients with IT fractures (aged≥50 years) and T-score ≤ -1.5 [WHO defines osteopenia as T-score between −1 and −2.5, and osteoporosis as T-score ≤ -2.5 on DEXA scan (which was obtained post-operatively in our cohort)], who underwent proximal femoral nailing were included. Patients were divided into three groups: group 1a-intravenous bisphosphonate {ivBP [zoledronic acid (ZA)]} given within one week, group 1b-ZA at six weeks and group 2-control group. Post-operative radiographs were assessed for reduction parameters [neck-shaft angle, tip-apex distance, reduction variance]. Radiological union was determined using RUSH score and functional outcome (at one year) with Modified Harris Hip Scores. 41 (23 males), 40 (15 males) and 42 (15 males) patients were included in groups 1a, 1b and 2, respectively (no statistical difference in sex distribution among the groups; p = 0.12). Mean age in groups 1a, 1b and 2 was 71.8 ± 8.1, 75.9 ± 8.5 and 72.3 ± 10.6 years (p = 0.09). There was no significant difference in the pattern of injuries (AO classification) among the groups (p = 0.72). Mean time to union in groups 1a, 1b and 2 was 13.7,13.7 and 14.2 weeks, respectively (p = 0.69). Mean time to union in AO types A1, A2 and A3 fractures was 13.2 ± 2.1, 13.7 ± 2.8 and 16.1 ± 4.9 weeks (p = 0.01). We did not observe any association between T-scores and fracture union (hip:p = 0.52, spine:p = 0.93).The functional outcome was similar among groups (p = 0.96). Early administration of ZA did not negatively influence fracture healing in patients undergoing fixation of IT fractures. Among the various other factors analyzed, there was a statistically significant association between the fracture type (AO type A3) and longer time to fracture union.     

Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid

Intravenous bisphosphonates—the potent inhibitors of osteoclast-mediated bone resorption are among the most commonly prescribed drugs in the management of multiple myeloma (MM). Zoledronic acid (ZA) is a new generation potent intravenous bisphosphonate that has been approved for the treatment and prevention of bone lesions, and/or hypercalcemia associated with MM. Osteonecrosis of the jaw (ONJ) is an emerging serious side effect of the new generation bisphosphonates with a growing number of reports related to this pathological entity. ONJ usually appears following oral surgical and dental procedures but sometimes occur spontaneously. These cases are mostly seen and treated by dentists and oral surgeons. The aim of this study was to discuss the frequency, characteristics, risk factors, management and histopathological features of ZA induced ONJ based on the literature and illustrated with five own cases. Thirty-two patients with MM who received ZA for a median period of 26.5 ± 18.7 months (min: 5 months, max: 76 months) were evaluated. ONJ was detected in five patients and mean drug duration time was 34 months. The frequency was 15% and the patients were usually symptomatic. There was no significant difference in terms of the duration of ZA in patients with and without ONJ. Management of these established cases were performed with medical treatment, minor debridement, sequestrectomy, and combining bone resection with autologous platelet rich plasma. Our data indicate that ZA therapy has a major role in the development of ONJ a fact that should be considered by physicians treating MM patients.     

骨巨细胞瘤的局部复发与治疗

目的：防止骨巨细胞瘤的局部复发。方法：观察本院１９８１￣１９９８年４０例骨巨细胞瘤患者的术后疗效。结果：２８例骨巨细胞瘤病灶刮除骨水沁填充后,只有１例复发、６例肿瘤病灶刮除自体骨移植后,４例复发。结论：肿瘤病灶刮除后骨水泥填充能减少局部肿瘤复发;对于Ｘ线ＣａｍｐａｎａｃｃｉⅢ级,或者Ｅｎｎｅｃｋｉｎｇ外科分期Ⅰｂ或Ⅱｂ,或者Ｊａｆｆｅ病理分期Ⅲ级患者,应扩大切除肿瘤病灶,近关节处肿瘤可扩大切除术后     

双膦酸盐与狄诺塞麦治疗PMOP的“药物假期”EMAS立场声明要点解读

目的为了使骨质疏松领域相关医生能够进一步了解和掌握双膦酸盐与狄诺塞麦的药物假期规律,提高临床治疗水平,本文就欧洲女性与男性更年期协会(EMAS)对双膦酸盐与狄诺塞麦治疗绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)\"药物假期\"的立场声明进行要点解读,供同仁参考。方法 EMAS系统性回顾分析了双膦酸盐和狄诺塞麦中止使用后在骨折风险方面的影响,同时,评估降低不良事件风险的可能性,形成立场声明。结果 (1)考虑双膦酸盐的长期疗效、安全性及骨折风险,建议采取个性化的药物假期方案;(2)药物假期时机:阿仑膦酸钠治疗超过5年,利塞膦酸钠、唑来膦酸治疗超过3年的患者,应该考虑药物假期;(3)鉴于伊班膦酸钠证据有限,狄诺塞麦停药后可能引起骨折的\"反弹效应\",所以,不强烈推荐伊班膦酸钠和狄诺塞麦进行药物假期;(4)药物假期时长:一般情况下,双膦酸盐药物假期为1~3年;(5)重启治疗评估内容:双膦酸盐药物假期中,每年应评估病人的特征,包括患者的年龄、跌倒史、是否有新的骨折、可能危险因素、骨密度和骨代谢生化标志物;(6)重启治疗药物:双膦酸盐、狄诺塞麦,特立帕肽,雌激素受体调节剂(selective estrogen receptor modulators,SERMs),性激素补充(menopausal hormone replacement therapy,MHT)和雷奈酸锶等,是药物假期后重启治疗的选择药物。结论双磷酸盐药物假期遵循个体化原则,不推荐狄诺塞麦药物假期。     

Modern Interpretation of Giant Cell Tumor of Bone: Predominantly Osteoclastogenic Stromal Tumor

Owing to striking features of numerous multinucleated cells and bone destruction, giant cell tumor (GCT) of bone, often called as osteoclastoma, has drawn major attractions from orthopaedic surgeons, pathologists, and radiologists. The name GCT or osteoclastoma gives a false impression of a tumor comprising of proliferating osteoclasts or osteoclast precursors. The underlying mechanisms for excessive osteoclastogenesis are intriguing and GCT has served as an exciting disease model representing a paradigm of osteoclastogenesis for bone biologists. The modern interpretation of GCT is predominantly osteoclastogenic stromal cell tumors of mesenchymal origin. A diverse array of inflammatory cytokines and chemokines disrupts osteoblastic differentiation and promotes the formation of excessive multi-nucleated osteoclastic cells. Pro-osteoclastogenic cytokines such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin (IL)-6, and tumor necrosis factor (TNF) as well as monocyte-recruiting chemokines such as stromal cell-derived factor-1 (SDF-1) and monocyte chemoattractant protein (MCP)-1 participate in unfavorable osteoclastogenesis and bone destruction. This model represents a self-sufficient osteoclastogenic paracrine loop in a localized area. Consistent with this paradigm, a recombinant RANK-Fc protein and bisphosphonates are currently being tried for GCT treatment in addition to surgical excision and conventional topical adjuvant therapies.     

指骨内原发性腱鞘巨细胞瘤四例报告

指骨原发性骨内腱鞘巨细胞瘤较罕见，本院曾收治４例，作一报道。其临床特征是患指指骨增粗，有隐痛感．Ｘ线片显示指骨皮质骨膨胀性变而，极似指骨内生软骨瘤。组织学特征是组织细胞性基质细胞增殖，胞浆里网状空泡样改变，并有散在的多核巨细胞存在。诊断时需与骨巨细胞瘤相鉴别．４例均行病灶刮除加酒精灭活植骨治疗，术后随访平均１３个月．功能恢复良好．未见复发．指骨内原发性腱鞘巨细胞瘤主要诊断依据必须结合病理改变及Ｘ线片表现，才能和其他有关肿瘤相鉴别．     

手部腱鞘巨细胞瘤

本文报告２３例手部腱鞘巨细胞瘤的治疗结果，病变同时存在手腕，手掌及手指者８例、手掌６例、手背侧３例，手指６例。２３例均作病变广泛切除，１９例治愈、４例复发，本组无恶变，无截肢（指）病例。我们提出手术切口的充分显露及病变部位腱鞘、滑膜的彻底切除是减少复发的关键，放射治疗对本病无明显疗效。     

Recurrence of a giant cell tumor of the hand after 42 years: case report

Giant cell tumors of bone in the hand are rare. We present a case of a recurrent giant cell tumor in the metacarpal 42 years after intralesional excision and autogenous bone grafting. The possibility of recurrent disease should be considered in the evaluation of any patient presenting with new onset of pain at the site of a previously addressed giant cell tumor. Management of these recurrent lesions should include wide excision with digit salvaging procedures or ray amputation owing to the high rates of treatment failures seen with marginal excision.     

Multicentric giant cell tumor of the upper extremities: 16 years of ongoing disease

Multicentric giant cell tumor is rare and accounts for less than 1% of all giant cell tumors of bone. We describe a case in which all the lesions occurred in the upper extremities. The 13-year-old boy's first tumor was in the left index metacarpal. Over 16 years, giant cell tumors occurred in 8 sites: right distal radius, left lunate, left middle metacarpal, left distal radius, right ring finger proximal phalanx, right radial head, left distal humerus, and left proximal humerus. Intralesional curettage of the lesions located in the hand and carpals was associated with a high incidence of local recurrence, whereas lesions in the proximal radius and in the humerus have not recurred.     

Recurrent giant cell tumors of the tendon sheath

Seventy patients underwent surgical excision of a giant cell tumor of the tendon sheath. The patients were monitored for an average of 3 years 4 months. Nineteen of the 70 patients (27%) had a surgically and histologically documented recurrence at an average of 2 years 3 months (range, 3 months to 10 years) following the initial procedure. Eight of 19 patients (42%) with recurrence had a prior recurrence. Statistically significant risk factors for recurrence included presence of adjacent degenerative joint disease, location at the distal interphalangeal joint of the finger or interphalangeal joint of the thumb, and radiographic presence of an osseous pressure erosion. Age, gender, size, and location within the digit (volar vs. dorsal) were not risk factors for recurrence. Awareness of these associations should be reflected in the surgeon's approach and preoperative discussion with the patient.     

Giant cell tumor in queer location with lung metastasis!

Giant cell tumor (GCT) of bone accounts for ∼ 5 % of primary bone tumors, however involvement of rib is uncommon. We here discuss a rare case of giant cell tumor of anterior arc of rib mimicking malignant breast mass with associated lung metastasis in a 28 year old woman. CECT and MRI revealed large soft tissue mass with epicenter at 3rd rib and erosion of 3rd rib. CECT also revealed lung metastasis. Histopathology confirmed the diagnosis of giant cell tumor.     

放射治疗在脊柱骨巨细胞瘤治疗中的价值

作者回顾性评价放射治疗在脊柱骨巨细胞瘤（ＧＣＴ）治疗中的价值。本组１０例（男６例，女４例），年龄１８～３４岁（平均２７岁）。发病部位：颈椎６例，胸腰椎２例，腰、骶椎各１例。Ｊａｆｅ分级：Ⅰ级３例，Ⅰ－Ⅱ级２例，Ⅱ级１例，Ⅲ级２例，未分级２例。治疗方法：（１）单纯放疗治疗颈椎ＧＣＴ３例。（２）先放疗后手术治疗胸腰段ＧＣＴ２例。（３）先手术后放疗治疗颈椎ＧＣＴ３例，腰椎ＧＣＴ１例。（４）手术配合术前与术后放疗治疗骶椎ＧＣＴ１例。随访１．５～２９年（平均１４年）均无复发。５例生活自理，４例恢复工作，１例恢复较差。本组无放疗后恶变。作者认为，脊柱解剖复杂，难以将肿瘤彻底切除，所以手术配合术前术后放疗对脊柱ＧＣＴ的治疗有重要意义。