New and Emerging Therapies for Bone Metastases in Genitourinary Cancers

Context

Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality.

Objective

The objective of this review is to discuss the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies.

Evidence acquisition

We reviewed the relevant medical literature, with a particular emphasis on prospective randomized controlled trials. Much of the relevant clinical trial data focus on prostate cancer (PCa). We provide a nonsystematic review and our perspective on the available data.

Evidence synthesis

Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for skeletal metastases often features a combination of disease-specific therapy and bone-targeted therapy. Some agents, such as the radiopharmaceutical radium-223, blur the line between those categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases. Zoledronic acid, a bisphosphonate, is approved for the prevention of skeletal events caused by solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that inactivates receptor activator of nuclear factor-κB ligand and is approved for the same indication. Beta-emitting radiopharmaceuticals can be effective for the palliation of pain caused by bone metastases, but their use is often limited by marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in select men with castration-resistant PCa metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET).

Conclusions

Bone metastases cause considerable morbidity and mortality among patients with genitourinary malignancies. Optimal management requires consideration of bone-targeted therapy as well as disease-specific therapy. Further research is needed to optimize the use of existing agents and to define the therapeutic potential of novel targets.     

Vertebral compression fractures in patients under treatment with denosumab: a contraindication for percutaneous vertebroplasty?

Background contextDenosumab (XGeva) is a receptor activator of nuclear factor-κB ligand (RANKL)–antibody that was approved by the Food and Drug Administration (FDA) in 2010 for the prevention of skeletal fractures in patients with bone metastases from solid tumors. Although there is a widespread use of such drug in patients under risk of pathological fractures, the compatibility of denosumab therapy with percutaneous vertebroplasty (an interventional procedure commonly used for pain control in such population) has not yet been established.PurposeTo present the serial imaging findings and technical report of an attempted percutaneous vertebroplasty in a patient with refractory pain and a lytic pathological vertebral fracture related to small cell lung cancer spinal metastasis and who was actively under medical treatment with denosumab.Study designRetrospective review and case report.MethodsThe authors present the imaging findings and technical report of an attempted percutaneous vertebroplasty in the only patient found to be actively under treatment with denosumab after a retrospective review of the databank of patients with pathological fractures referred to the Department of Radiology of the Ohio State University for percutaneous vertebroplasty (a total sample of 20 patients) since the FDA approval of denosumab (November 2010) until June 2013 (a 30-month period).ResultsAlthough the computed tomography scan of the thoracic spine, performed 6 weeks after the initiation of the treatment with denosumab, presented a remarkable remodeling of the previously lytic vertebral lesion (which became markedly sclerotic in appearance), the clinical response in terms of pain improvement was not satisfactory. At the time of the percutaneous vertebroplasty (which was indicated for pain control), after advancing the 11-gauge needle through the pedicle with extreme difficulty, the needle repeatedly deviated laterally and, despite several attempts, it was not possible to penetrate the vertebral body and perform the cement injection.ConclusionsThis is the first report of the technical peculiarities of percutaneous vertebroplasty in patients under medical treatment with denosumab. According to our experience, because of its RANKL-mediated effects on osteoclasts activity, denosumab has been shown to induce a fast and marked sclerotic response on vertebral bodies that may not be accompanied by a satisfactory improvement in pain control (especially in patients with mechanical type of pain) and which may actually prevent the successful performance of percutaneous vertebroplasty. Therefore, it is of paramount importance that future studies evaluating patients with vertebral fractures under treatment with denosumab include long-term pain outcome measures. Additionally, further investigation is warranted to determine the optimal order of treatment and the best timeframe for combining percutaneous vertebroplasty and denosumab therapy in patients presenting with acute vertebral compression fractures and refractory axial pain.     

Denosumab Use as a Predictor Variable for External Cervical Resorption: A Case-Control Study

IntroductionThe objective of this case-control study was to investigate the association between denosumab use and the risk of developing external cervical resorption (ECR).MethodsThirty-three patients ≥45 years old who were diagnosed with ECR were selected. Controls were matched to the cases based on sex and age (±5 years) in a 1:1 ratio. Confounders were classified into systemic factors, including a history of systemic sclerosis, hepatitis B, denosumab use, and bisphosphonate use, or local factors, including a history of traumatic occlusion, periodontal procedures (scaling and root planing and periodontal surgeries), and tooth extraction (excluding third molar extraction). Additionally, the number of remaining teeth in each subject was recorded using panoramic radiographs. The baseline characteristics of the 2 groups, including age, sex, and the number of remaining teeth, were compared using the chi-square and Mann-Whitney U tests. Binary logistic regression was used to determine the possible association between denosumab use and the risk of developing ECR (α < 0.05).ResultsNo significant differences in baseline characteristics were observed between the case and control groups (P > .05). After adjusting for systemic and local cofounders, denosumab use was significantly associated with the occurrence of ECR (odds ratio = 7.317; 95% confidence interval, 1.410–37.966; P < .05).ConclusionsBased on the binary logistic regression model, denosumab use could significantly predict the risk of developing ECR.     

The inhibition of RANK-ligand in the management of postmenopausal osteoporosis and related fractures: the role of denosumab

There is great interest in new treatments of osteoporosis owing to general ageing of population and increased risk for fragility fractures in the elderly. Current therapies show a good efficacy in improving bone quality and bone density, but, in spite of a certain reduction in fracture rate, according to each treatment, the problem of osteoporotic fractures is yet far from to be solved. Moreover, some treatments may produce different side effects. Denosumab (Dmab), a receptor activator of nuclear factor kappa-B ligand (RANKL)-inhibitor, is an agent recently introduced in clinical practice for treatment of osteoporosis of postmenopausal women. Dmab has improved bone mineral density and prevented new vertebral and non-vertebral fractures with a similar efficacy in comparison with alendronate. Many clinical studies showed Dmab produces also significant improvement versus placebo in bone quality as indicated by decreasing markers of bone turnover. Patients using Dmab reported less risk of AFF (Atypical Femoral Fractures) and ONJ (Osteonecrosis of the Jaw) with an increased number of cellulitis. Here, we review articles using Dmab for female post-menopausal osteoporosis.     

骨松康合剂联合地诺单抗治疗绝经后骨质疏松症的临床研究

目的探讨骨松康合剂联合地诺单抗治疗绝经后骨质疏松症的临床疗效。方法选取2017年3月—2020年3月在陕西省中医医院治疗的86例绝经后骨质疏松症患者,根据用药的差别分为对照组和治疗组,每组各43例。对照组腹部皮下注射地舒单抗注射液,120 mg/次,1次/4周;治疗组在对照组基础上口服骨松康合剂,30 mL/次,3次/d。两组患者均治疗12个月。观察两组患者临床疗效,比较治疗前后两组患者ADL、Lysholm、VAS评分及骨代谢和骨密度指标。结果经治疗,对照组和治疗组总有效率分别为81.40%、97.67%(P0.05)。经治疗,两组ADL评分和Lysholm评分明显升高,而VAS评分明显下降(P0.05),且治疗组评分项目明显好于对照组(P0.05)。经治疗,两组血清骨碱性磷酸酶(BALP)、前脂肪细胞因子1(Pref-1)、骨钙素(BGP)、I型前胶原氨基端原肽(PINP)、组织蛋白酶K(Cathe K)和抗酒石酸酸性磷酸酶(TRACP-5b)水平显著降低(P0.05),且治疗组比对照组更低(P0.05)。经治疗,两组患者腰椎L2～4、股骨颈、Ward’s三角区骨密度水平明显升高(P0.05),且治疗组升高更明显(P0.05)。结论骨松康合剂联合地诺单抗治疗绝经后骨质疏松症可有效改善患者骨痛,改善骨代谢指标及骨密度,提高患者日常活动能力,改善膝关节功能。     

Reproductive toxicity of denosumab in cynomolgus monkeys

Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, an essential mediator of osteoclast formation, function, and survival. Reproductive toxicity of denosumab was assessed in cynomolgus monkeys in an embryofetal development study (dosing GD20–50) and a pre-postnatal toxicity study (dosing GD20–parturition). In the embryofetal toxicity study, denosumab did not elicit maternal toxicity, fetal harm or teratogenicity. In the pre-postnatal toxicity study, there were increased stillbirths, and one maternal death due to dystocia. There was no effect on maternal mammary gland histomorphology, lactation, or fetal growth. In infants exposed in utero, there was increased postnatal mortality, decreased body weight gain, and decreased growth/development. Denosumab-related effects in infants were present in bones and lymph nodes. There was full recovery at 6 months of age from most bone-related changes observed earlier postpartum. The effects observed in mothers and infants were consistent with the pharmacological action of denosumab.     

Regulation of bone destruction in rheumatoid arthritis through RANKL-RANK pathways

Recent studies have demonstrated that osteoclasts, the primary cells responsible for bone resorption, are mainly involved in bone and joint destruction in rheumatoid arthritis(RA) patients. Recent progress in bone cell biology has revealed the molecular mechanism of osteoclast differentiation and bone resorption by mature osteoclasts. We highlight here the potential role of the receptor activator of nuclear factor κB ligand(RANKL)-RANK pathways in bone destruction in RA and review recent clinical trials treating RA by targeting RANKL.     

Western Osteoporosis Alliance Clinical Practice Series: Evaluating the Balance of Benefits and Risks of Long-Term Osteoporosis Therapies

Osteoporosis is a chronic disease that requires life-long strategies to reduce fracture risk. Few trials have investigated the balance of benefits and risk with long-term use of osteoporosis therapies, and fewer still have investigated the consequences of treatment discontinuation. The best available evidence suggests that up to 10 years of treatment with an oral bisphosphonate maintains the degree of fracture risk reduction observed in the 3-year registration trials. With denosumab, 10 years of therapy appears to provide fracture risk reduction similar to or better than that observed in the 3-year registration trial. Available data suggest an increasing but low risk of fractures with atypical features with increasing duration of bisphosphonate therapy. Published data linking duration of therapy to osteonecrosis of the jaw are lacking for bisphosphonates and denosumab. Other side effects associated with denosumab or bisphosphonates do not appear to be related to therapy duration. The antifracture benefits of long-term therapy with bisphosphonates and denosumab in appropriately selected patients outweigh the low risk of serious side effects.     

多发性骨髓瘤骨病临床诊疗专家共识（2021）

多发性骨髓瘤骨病(MBD)是多发性骨髓瘤(MM)患者的常见并发症,严重影响其生活质量和生存期,因此强调规范化的诊断和治疗。此次中国临床肿瘤学会(CSCO)指南工作委员会组织专家组,在2014版MBD专家共识的基础上进行了更新补充,推荐对于初治的MM患者,无论是否存在骨病的影像学证据,均应使用双膦酸盐和/或地舒单抗积极预防MBD及骨相关事件。在双膦酸盐使用期间,应该密切监测肾功能及颌骨改变,对于肾功能不全的患者需要减量甚至禁用,同时这类患者宜优先选用地舒单抗。希望本共识作为学术性指导意见,能够提供恰当的临床诊疗参考,以便使患者获得最佳的治疗,具体实施时应该根据患者的个体情况而定。     

骨巨细胞瘤的地舒单抗药物治疗

骨巨细胞瘤 ( giant cell tumor of bone,GCTB ) 是一种交界性的原发骨肿瘤,在临床上,具有局部侵袭性,可出现局部复发和远处转移 [1-2].GCTB 的发病率在不同国家和地区并不相同,在欧美,GCTB 的发病率为每年 1.03～1.17 /百万人 [3],我国的发病率明显高于欧美人群,约为...