Giant cell tumour of bone in the denosumab era

Giant cell tumour of bone (GCTB) is an intermediate locally aggressive primary bone tumour, occurring mostly at the meta-epiphysis of long bones. Overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated osteoclast-like giant cells, causing lacunar bone resorption. Preferential treatment is curettage with local adjuvants such as phenol, alcohol or liquid nitrogen. The remaining cavity may be filled with bone graft or polymethylmethacrylate (PMMA) bone cement; benefits of the latter are a lower risk of recurrence, possibility of direct weight bearing and early radiographic detection of recurrences. Reported recurrence rates are comparable for the different local adjuvants (27–31%). Factors increasing the local recurrence risk include soft tissue extension and anatomically difficult localisations such as the sacrum. When joint salvage is impossible, en-bloc resection and endoprosthetic joint replacement may be performed. Local tumour control on the one hand and maintenance of a functional native joint and quality of life on the other hand are the main pillars of surgical treatment for this disease. Current knowledge and development in the fields of imaging, functional biology and systemic therapy are forcing us into a paradigm shift from a purely surgical approach towards a multidisciplinary approach. Systemic therapy with denosumab (RANKL inhibitor) or zoledronic acid (bisphosphonates) blocks, respectively inhibits, bone resorption by osteoclast-like giant cells. After use of zoledronic acid, stabilisation of local and metastatic disease has been reported, although the level of evidence is low. Denosumab is more extensively studied in two prospective trials, and appears effective for the optimisation of surgical treatment. Denosumab should be considered in the standard multidisciplinary treatment of advanced GCTB (e.g. cortical destruction, soft tissue extension, joint involvement or sacral localisation) to facilitate surgery at a later stage, and thereby aiming at immediate local control. Even though several questions concerning optimal treatment dose, duration and interval and drug safety remain unanswered, denosumab is among the most effective drug therapies in oncology.     

Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial

BackgroundGiant cell tumor of bone (GCTB) is a rare primary bone tumor, characterized by osteoclast-like giant cells that express receptor activator of nuclear factor-kappa B (RANK), and stromal cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. A RANKL-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with GCTB.Patients and methodsSeventeen patients with GCTB were enrolled. Patients were treated with denosumab at 120 mg every 4 weeks, with a loading dose of 120 mg on days 8 and 15. To evaluate efficacy, objective tumor response was evaluated prospectively by an independent imaging facility on the basis of prespecified criteria.ResultsThe proportion of patients with an objective tumor response was 88% based on best response using any tumor response criteria. The proportion of patients with an objective tumor response using individual response criteria was 35% based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 82% based on the modified European Organization for Research and Treatment of Cancer (EORTC) criteria, and 71% based on inverse Choi criteria. The median time of study treatment was 13.1 months.ConclusionThe findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.     

Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?

BackgroundGiant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly ‘GCTB-schedule’ (120 mg per 12/year, 1440 mg total dose/year) are lacking.MethodsPatients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated.ResultsNinety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6–45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13–76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9–115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7–15 months).Adverse eventsOverall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84–100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%).ConclusionsProlonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.     

Bisphosphonate treatment of aggressive primary,recurrent and metastatic Giant Cell Tumour of Bone

Background  

Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts.     

The Clinical Approach Toward Giant Cell Tumor of Bone

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta‐epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%–27%) or cryosurgery and PMMA (0%–20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra‐articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB‐derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate‐dose radiotherapy (40–55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.     

地诺单抗治疗骨巨细胞瘤的研究进展

骨巨细胞瘤是一种以溶骨性破坏为特征的侵袭性肿瘤,手术治疗后复发率高,少数会出现肉瘤样恶变及转移。近年来,针对特异性靶向核因子κB受体活化因子配体(receptor activator of nuclear factor kappa B ligand,RANKL)的地诺单抗治疗高级别、不可切除和转移性骨巨细胞瘤疗效显著,能够降低外科分期,增加手术切除几率,减少术后功能丧失,控制肿瘤进展;同时,用药后影像及病理学出现特征性改变,对临床诊断及手术治疗提出新的问题。最后,地诺单抗在用药时间、安全性方面尚有部分争议,有待进一步临床试验证实。      

Giant cell tumour of the distal radius/ulna: response to pre-operative treatment with short-term denosumab

Background

Treatment of giant cell tumour of bone (GCTB) of the distal radius/ulna poses a surgical challenge, as complex reconstructive surgery may be required. This study evaluates the clinical, radiological and pathological findings in five cases of GCTB of the distal forearm where a 3 month course of denosumab was given prior to surgery.

Methods

Patients with biopsy proven distal forearm GCTB, treated for 3 months with denosumab, followed by salvage surgery (curettage and cementation) were included. Wrist pain and function were assessed using the modified Mayo Wrist Score (MMWS). Plain radiographs, MRI and PET/CT were performed pre-treatment and 2 months after initiation of denosumab therapy. Histological comparison was made between the original biopsy and surgical curettage specimens.

Results

Five patients with an average age of 25 years were included in the study. Improvement in wrist pain and function was seen in all patients with the average MMWS increasing from 30 pre-treatment to 85 at 3 months. Plain radiographs demonstrated marginal sclerosis in all cases with reconstitution of cortical and subarticular bone by 2 months; internal matrix sclerosis and osseous consolidation was more variable. Increased tumour heterogeneity and low signal were observed on T2-weighted MR images. PET/CT revealed a decrease in average SUV from 14.8 pre-treatment to 4.7 at 2 months. Histology showed disappearance of osteoclasts and increased fibro-osseous tissue. Denosumab treatment has the potential to facilitate salvage surgery, thus avoiding bone resection and graft reconstruction. A good outcome was achieved apart from local recurrence in one case. Follow up ranged from 17 to 54 months.

Conclusion

Distal forearm GCTB responds clinically, radiologically and histologically to a short course of pre-operative denosumab therapy, which has the potential to facilitate salvage surgery.

     

The role of RANK/RANKL/osteoprotegerin (OPG) triad in cancer-induced bone diseases: physiopathology and clinical implications

Bone homeostasis is maintained by the remodelling of bone which depends on a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Malignant bone lesions are very common in patients with cancer; whether they result from a tumor in bone (giant cell tumour of bone, osteosarcoma, multiple myeloma...) or they are bony metastases from advanced cancers of which the most osteotropic are breast and prostate cancer. Malignant cells within the bone disrupt the normal bone remodelling process, leading to increased bone destruction and occurence of pathological fractures. Receptor activator of NF-kB (RANK) and its ligand (RANKL) play a pivotal role in the regulation of bone remodelling; by binding to RANK, RANKL stimulates osteoclastogenesis and bone resorption, whereas its cognate decoy receptor osteoprotegerin (OPG) blocks this process by interacting with RANKL. Tumour cells produce different factors that manipulate the RANK/RANKL/OPG pathway in order to stimulate bone destruction. Furthermore, pending on the tumour type, RANKL plays a role in the migration, invasion and proliferation of malignant cells within the bone, while OPG increases survival of tumour cells. Inhibition of RANK/RANKL system may therefore offer new therapeutic perspectives for the treatment of primitive and secondary bone cancers.     

脊柱骨巨细胞瘤的诊断与治疗进展

脊柱骨巨细胞瘤（giant cell tumor of bone,GCTB）较为少见,诊断依靠临床、影像和病理三结合原则。脊柱GCTB的治疗难度较大,目前还没有基于循证医学的治疗流程和共识,因而具有很强的挑战性。手术仍然是脊柱GCTB治疗的首选方法,术前选择性动脉栓塞、完整切除肿瘤及术后辅助使用地诺单抗（denosumab）是目前推荐的综合治疗方法。整块切除是脊柱GCTB的理想治疗方式,但手术方法的选择需要遵循个体化原则,根据不同的部位制定不同的手术方案。地诺赛麦对于手术无法完全切除、复发及转移性GCTB的治疗具有一定的优势,术前使用能够有效降低GCTB外科分期,并为整块切除手术创造条件,具有广泛的应用前景。     

The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review

Background: The role of denosumab in patients with resectable giant cell tumour of bone remains unclear. We asked the following research question: for patients (aged ≥ 12 years) with resectable giant cell tumour of bone, what are the benefits and harms of denosumab compared with no denosumab in terms of (1) facilitation of surgery (operative time, blood loss), (2) disease recurrence, (3) pain control, (4) disease stability, and (5) adverse effects (e.g., malignant transformation, osteonecrosis of jaw, atypical femur fracture)? One previous systematic review addressed only one outcome—disease recurrence. Therefore, we undertook this new systematic review to address the above five outcomes. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases were searched on June 30, 2020. Results: This systematic review included one previous systematic review and five comparative studies. Due to poor quality, non-randomized studies fraught with selection bias, it is difficult to determine if a significant difference exists in the outcomes for surgical giant cell tumour of bone with perioperative denosumab. There were no reported cases of adverse effects from denosumab. Conclusion: To date, there is insufficient evidence to understand the value of denosumab in the perioperative setting in patients with giant cell tumour of bone.     

Denosumab treatment of inoperable or locally advanced giant cell tumor of bone – Multicenter analysis outside clinical trial

Background

Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive, rarely metastazing bone tumor. This is a retrospective study evaluating a large series of GCTB patients treated with denosumab in routine practice in 6 European reference centers.

Significance of Histone H3.3 (G34W)-Mutant Protein in Pathological Diagnosis of Giant Cell Tumor of Bone

Objective: This study aimed to examine the expression of Histone H3.3 glycine 34 to tryptophan (G34W) mutant protein in Giant Cell Tumor of Bone (GCTB). Methods: This analytic observation research used a cross-sectional study design on 71 bone tumors. The cases involved 54 tissue samples diagnosed as GCBT. It was divided into GCTB primer (n=37), recurrent GCTB (n=5), GCTB with metastasis (n=9), and malignant GCTB (n=3). There were 17 samples mimics of GCTB also tested, including chondroblastoma (n=1), giant cell reparative granuloma (n=2), giant cell of tendon sheath (n=7), chondromyxoid fibroma (n=2), aneurysmal bone cyst (n=2), and giant cell-rich osteosarcoma (n=3). The Immunohistochemistry was used to evaluate the expression of G34W-mutated protein in these bone tumors. Result: The representation H3.3 (G34W) was expressed in the nuclei of mononuclear stromal cells but not stained on osteoclast-like giant cells. This study was analyzed by the Chi-square test, Fisher’s test, specificity test, and sensitivity test. We obtained p = 0.001 for Histone H3.3 (G34W) mutant expression in GCTB vs Non-GCTB. Statistically, there was no significant difference in the expression level of Histone H3.3 (G34W) in the GCTB and its variants p-value = 0.183. We also obtained that the specificity of Histone H3.3 expression on GCTB was 100% and the sensitivity of Histone H3.3 on GCTB was 77.8%. Conclusion: Histon H3.3 mutant as a mutated driver gene in an Indonesian GCTB can assist to diagnose GCTB and compare it from other bone tumors.     

OPG‐Fc inhibits ovariectomy‐induced growth of disseminated breast cancer cells in bone

Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The majority of these patients will remain asymptomatic, however, ～15% will go on to develop overt bone metastases and this condition is currently incurable. The reason why these dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains to be elucidated. We have recently shown that in an in vivo model, increasing bone turnover by ovariectomy stimulated proliferation of disseminated tumour cells, resulting in formation of bone metastasis. We now show for the first time that osteoclast mediated mechanisms induce growth of tumours from dormant MDA‐MB‐231 cells disseminated in the bone. We also show that disruption of RANK–RANKL interactions following administration of OPG‐Fc inhibits growth of these dormant tumour cells in vivo. Our data support early intervention with anti‐resorptive therapy in a low‐oestrogen environment to prevent development of bone metastases.     

胆汁中CEA浓度测定在大肠癌肝转移诊断中的意义

We investigated the clinical features of soft-tissue recurrence in giant cell tumor of bone (GCTB). Among 106 cases with GCTB in our hospital, there were 2 cases occurring soft-tissue recurrence which histories were reported. These two soft-tissue recurrences occurred with the interval of 6.9 years and 2.5 years respectively from primary diagnosis. The clinical presentation was nonspecific masses in soft tissue. Radiographic ossification was not found at periphery or within the masses. Through pathological examination peripheral ossification was found in 1 case and malignant transformation occurred in the other case. Through retrieving and reviewing literatures in PubMed, 19 cases of soft-tissue recurrence with detailed materials were collected and analyzed. Soft-tissue recurrence of GCTB is a rare episode which reflects its locally aggressive nature, the reasons of which are tumor cells implantation and tumor residual. Ossification at periphery or in the masses can be considered as a pathognomonic character of this episode in radiographic and pathohistological examination. The prevention lies in determining tumor extension preoperatively, proper non-tumor manipulations, removing the tumor and irrigating operative wound as completely as possible.     

Clinical Outcome of Sacral Chordoma Patients Treated with Pencil Beam Scanning Proton Therapy

AimsSacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy.Methods and materialsSixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan–Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.ResultsThe median follow-up was 48 months (range 4–186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3–7 years after proton therapy.ConclusionsOur data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume <130 ml and tumour restricted to the bone are favourable prognostic factors for local tumour control.     

地诺单抗用于骨转移癌治疗的研究

癌症转移是致死的主要原因,骨是排第三的好发转移部位。OPG／RANKL—RANK骨调节轴是影响破骨细胞发育及功能的唯一途径。地诺单抗（denosumab）是全人源化结合RANKL的中和抗体,由FDA于2010年11月批准用于实体瘤骨转移的治疗。本文就地诺单抗用于骨转移癌治疗的机制及临床实验研究作一综述,为临床医生更合理的选择骨改构药物用于骨转移癌的治疗做指导。     

Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma

BackgroundCurrent standard therapy for high-grade osteosarcoma is neoadjuvant chemotherapy and complete resection of the primary tumour. Irradiation can improve local control if complete tumour resection is not possible or refused, but data on long-term outcome are not available.Patients and methodsWe report on long-term results for overall survival, occurrence of local recurrence and metastasis, joint function and side-effects in 13 patients with high-grade osteosarcoma having been treated with a combination of local irradiation and polychemotherapy (median follow-up of 13.5 years).ResultsTen of the 13 patients were alive 4–23 years after diagnosis. Three patients suffered local recurrence, in 2 of them tumour control and long-term survival could be achieved by secondary salvage surgery and polychemotherapy. In 5 patients pathological fractures of the irradiated bones occurred, none of them was associated with local recurrence. In 7 of the 10 long-term survivors good or fair joint function was achieved.ConclusionsWe conclude that combination of chemotherapy and intensive local irradiation can achieve long-term local control and even cure in high-grade osteosarcoma. Thus radiation therapy may represent an alternative to definite surgery in selected patients, in particular in those with good response to chemotherapy, when surgery is not feasible or refused.     

Denosumab and giant cell tumour of bone—a review and future management considerations

Giant cell tumour of bone (gctb) is one type of giant-cell-rich bone lesion characterized by the presence of numerous multinucleated osteoclast-type giant cells. Giant cells are known to express rankl (receptor activator of nuclear factor κB ligand) and are responsible for the aggressive osteolytic nature of the tumour. No available treatment option is definitively effective in curing this disease, especially in surgically unsalvageable cases. In recent years, several studies of denosumab in patients with advanced or unresectable gctb have shown objective changes in tumour composition, reduced bony destruction, and clinical benefit.Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and specificity to rankl. Several large phase iii studies have shown that denosumab is more effective than bisphosphonates in reducing skeletal morbidity arising from a wide range of tumours and that it can delay bone metastasis. The relevant articles are reviewed here. The controversies related to the future use of denosumab in the treatment of gctb are discussed.     

In Reply

The authors respond to the observations and remarks of Cavanna et al. concerning the clinical guidance paper on giant cell tumor of bone (GCTB) in the era of denosumab and update the paper with respect to the European Medicines Agency’s recent positive opinion recommending denosumab for the treatment of adults and skeletally mature adolescents with GCTB that is unresectable or for which surgical resection is likely to result in severe morbidityWe thank Cavanna et al. for sharing their interesting observations and remarks [1] concerning our clinical guidance paper on giant cell tumor of bone (GCTB) in the era of denosumab [2]. We also would like to take the opportunity to update our paper with respect to the recent positive opinion, dated July 25, 2014, of the European Medicines Agency’s Committee for Medicinal Products for Human Use recommending denosumab for the treatment of adults and skeletally mature adolescents with GCTB that is unresectable or for which surgical resection is likely to result in severe morbidity [3].Regarding the case report of Cavanna et al. [1], the apparently asymptomatic GCTB was detected through a fluorodeoxyglucose F 18 (¹⁸F-FDG) positron emission tomography (PET) scan while staging a melanoma. GCTB is often PET positive, as mentioned in our paper [2]. In this particular case, additional imaging and an open biopsy led to the final diagnosis.What we can learn from their report [1] is that in cases of screening for metastases in a highly malignant tumor, such as melanoma, an ¹⁸F-FDG PET-positive lesion is not always a metastasis. In this rare case, an asymptomatic PET-positive GCTB could mimic a metastasis. Further imaging and histology of the PET-positive lesion is always warranted to confirm or exclude metastatic disease and led to the correct diagnosis. That said, we believe that despite the fact that ¹⁸F-FDG PET is generally positive in GCTB, this should not be routinely recommended in the initial diagnosis of GCTB because conventional imaging plus histology is sufficient for clinical decision making.We also would like to emphasize that an open biopsy, as used in the case report by Cavanna et al. [1], is not our first choice for GCTB. We have shown that the high accuracy of the core needle biopsy, combined with the advantages of this technique over the incisional surgical biopsy, makes it a safe, fast, and adequate technique for obtaining a histologic sample of a bone tumor [4]. The European Society for Medical Oncology guidelines also state that, in many situations, core needle biopsies (preferably taken under imaging control) are an appropriate alternative to open biopsy [5].     

Anti-RANKL antibody for treatment of patients with bone metastasis from breast cancer

Breast cancer is known to be associated with a high incidence of bone metastases. Recent advances in treatment for breast cancer have improved patient prognosis, including those with bone metastasis, highlighting the importance of treating bone metastasis to reduce incidence of skeletal complications and to improve patients' QOL. Currently, bisphosphonates(BP), which are recommended by domestic and international clinical practice guidelines, are commonly used for the treatment of bone metastasis. However, the outcomes of BP therapy leave room for improvement in regard to their efficacy, safety, and convenience. Prior studies have indicated that RANK ligand(RANKL), a cytokine mainly expressed in osteoblasts and bone marrow stromal cells, plays an important role in bone resorption by osteoclasts, which are key mediators in the formation and progression of bone metastasis. Denosumab is a fully human monoclonal anti-RANKL antibody which suppresses differentiation, activation, and survival of osteoclasts by inhibiting the binding of RANKL to its receptor, RANK. In a phase III clinical trial, denosumab significantly decreased the time-to-first and time-to-first-and-subsequent skeletal related events(SRE), compared with zoledronic acid in advanced breast cancer patients with bone metastases. Further more, denosumab was more effective than zoledronic acid in preventing the progression of bone pain and maintaining patients QOL. In the future, treatment of bone metastases for breast cancer patients is expected to evolve further with the introduction of denosumab, which is conveniently administered by subcutaneous injection.