Role of the RANK/RANKL pathway in breast cancer

The discovery of the OPG/RANK/RANKL pathway two decades ago has initiated novel insights into regulation of bone formation. More recently this pathway has been found to be also relevant in osteoclastic-independent mechanisms, mainly in mammary physiology and breast cancer. RANKL/RANK function is essential for epithelial cell proliferation and cellular survival as well as lobulo-alveolar development. The endogenous OPG functions as a soluble decoy receptor, binding the cytokine RANKL to prevent RANKL from activating its receptor RANK. The regulatory function of RANKL is one of the key factors in progesterone-induced proliferation of the breast. Progesterone has a direct action of progesterone on progesterone-receptor (PR) expressing cells but PR-negative cells are affected indirectly through RANKL-induced paracrine actions leading to proliferation of mammary epithelial PR-negative cells. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Inhibition of the RANK/RANKL pathway using the monoclonal antibody denosumab can neutralize RANKL and inhibiting its interaction with its receptor RANK. Denosumab is currently used to treat osteoporosis and in prevention of skeletal related events in patients suffering from bone metastases due to solid tumors. As preclinical experiments suggest the RANKL/RANK pathway plays an important role in primary breast cancer development. The interference with the RANK/RANKL system could therefore serve as a potential target for prevention and treatment of breast cancer.     

Prevention of incident fractures in patients with prevalent fragility fractures: Current and future approaches

Fragility fractures are a significant, independent risk factor for new fractures, but treatment uptake in subjects with prevalent fractures is disappointing. We addressed the question of the efficacy of pharmacological interventions in reducing the risk of incident fractures in patients with prevalent fragility fractures. For this, we reviewed randomised controlled trials (RCTs), pre-planned and post-hoc analyses of RCTs of approved agents for the treatment of osteoporosis. Results showed that a number of agents decrease the risk of incident vertebral and nonvertebral fractures in subjects with prevalent vertebral fractures, justifying the recommendation of treating such patients independently of the level of bone mineral density (BMD). By contrast, the evidence of antifracture efficacy of these agents in patients with prevalent nonvertebral fractures is limited. Advances in our understanding of the regulation of bone metabolism at the molecular level have identified targets for the development of new therapeutics for osteoporosis, some of which are currently in phase 3 clinical development.     

Osteonecrosi dei mascellari associata a bisfosfonati,denosumab e farmaci anti-angiogenetici nei pazienti oncologici e osteoporotici: diagnosi e terapia

Objectives

The present work aims at providing clinicians with a useful guide for diagnosis and management of osteonecrosis of the jaws (usually defined ONJ).

Materials and methods

The authors, directly involved with the recent publication of the Raccomandazioni clinico-terapeutiche sull’osteonecrosi delle ossa mascellari associata a bisfosfonati e sua prevenzione, endorsed by Società Italiana di Chirurgia Maxillo-Facciale (SICMF) and Società Italiana di Patologia e Medicina Orale (SIPMO), reviewed the relevant literature on ONJ associated with bisphosphonates, denosumab and anti-angiogenic drugs. They report all known epidemiological data and describe the clinical features of the disease; they also display the local and systemic risk factors associated with ONJ development, and present novel criteria for the diagnosis and staging of ONJ. Finally, they provide recommendations for prevention and dental management of cancer and non-cancer, mainly osteoporotic, patients, and summarize the medical and surgical therapies to be used in case of established ONJ.

Results and conclusions

ONJ, which is usually associated with bisphosphonates and more recently also with denosumab and anti-angiogenic drugs, is one of the most emergent among severe oral diseases, with important implications for the patient's quality of life: in the last decade, thousands of cases have been reported in the literature. The medical and dental communities fear the severity of this condition and solicit for rules, protocols, preventive measures for patients at risk of bisphosphonate related ONJ occurrence, as well as therapies for established ONJ. This effort has been carried out extensively in several countries, including Italy with the support of the Italian SICMF and SIPMO, leading to the publication of expert panel recommendations for prevention and therapy of ONJ, both in cancer and less frequently non-cancer (mainly osteoporotic) patients.     

The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease

BackgroundWe compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma.MethodsPatient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM.ResultsDenosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41–0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29–0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab.ConclusionDenosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.     

骨巨细胞瘤治疗新突破——狄诺塞麦

骨巨细胞瘤（GCTB）是一种富含巨细胞的侵袭性、溶骨性病变,特征为大量多核破骨细胞样巨细胞聚集、表达细胞核因子JCB受体活化因子配体（RANKL）,目前还没有一种方法可彻底有效治愈,尤其是对无法手术的GCTB。近年文献报道在进行性或无法手术的GCTB患者中使用狄诺塞麦（denosumab）,可观察到肿瘤成分明显改变、骨破坏减少及临床有效性。狄诺塞麦是一种人RANKL单克隆抗体,与核因子wB受体活化因子（RANK）结合具有很高的亲和性和特异性。以往很多大规模Ⅲ期试验研究已表明,狄诺塞麦在降低各种肿瘤引起的骨破坏方面明显优于二磷酸盐,还可延缓骨转移出现。该文对相关文献进行回顾,并就狄诺塞麦在GCTB治疗中存在的问题进行探讨。     

Denosumab as a potential treatment alternative for patients suffering from diffuse sclerosing osteomyelitis of the mandible—A rapid communication

Purpose

Diffuse sclerosing osteomyelitis (DSO) is a rare disease of the jaw bone. Its treatment is challenging. Different medical and surgical treatment protocols have been proposed; however, none of these treatment protocols produce reliable results. Recently, ibandronate administration has been attempted as a treatment alternative in acute cases of DSO. Due to the similar antiresorptive effect, we sought to explore the application of the human monoclonal antibody to the receptor activator of nuclear factor kappaB ligand (RANKL), denosumab, in the treatment of DSO.

Biology and management of myeloma-related bone disease

Bone disease is one of the most common complications of multiple myeloma. It is the result of increased osteoclast activity which is not compensated by osteoblast activity and leads to osteolytic lesions characterized by bone pain and increased risk for pathological fracture, spinal cord compression and need for radiotherapy or surgery to the bone. Recent studies have revealed novel pathways and molecules that are involved in the biology of myeloma bone disease including the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the Wnt signaling inhibitors dickkopf-1 and sclerostin, macrophage inflammatory proteins, activin A, and others. A thorough study of these pathways have provided novel agents that may play a critical role in the management of myeloma related bone disease in the near future, such as denosumab (anti-RANKL), sotatercept (activin A antagonist), romosozumab (anti-sclerostin) or BHQ-880 (anti-dickkopf 1). Currently, bisphosphonates are the cornerstone in the treatment of myeloma related bone disease. Zoledronic acid and pamidronate are used in this setting with very good results in reducing skeletal-related events, but they cannot be used in patients with severe renal impairment. Furthermore, they have some rare but serious adverse events including osteonecrosis of the jaw and acute renal insufficiency. This review paper focuses on the latest advances in the pathophysiology of myeloma bone disease and in the current and future treatment options for its management.     

Teriparatide and denosumab treatment for pregnancy and lactation-associated osteoporosis with multiple vertebral fractures: A case study

Objective

Pregnancy and lactation-associated osteoporosis (PLO) is a rare disease, which can lead to vertebral fractures in women of reproductive age. No treatment strategy for PLO has been established. Here we report a case of PLO treated with teriparatide followed by denosumab, in which remarkable improvement in bone mineral density (BMD) was achieved.