RANK Ligand: A Key Role in Cancer-Induced Bone Destruction?

ContextProstate cancer (PCa) is associated with a high risk of bone metastases; androgen-deprivation therapy is associated with significant bone loss. Bone metastases and bone loss are both linked to an increased risk of skeletal-related events, which in turn can reduce quality of life and life expectancy. Understanding of the pathophysiology underlying bone disease in patients with cancer is therefore important for the development of new treatments that can prevent or reverse it as well as for the improvement of patient outcomes.ObjectiveTo provide an overview of bone metabolism in the normal state and to describe recent developments in our understanding of the pathophysiology underlying bone disease induced by cancer as well as cancer treatment–induced bone loss (CTIBL).Evidence acquisitionThis article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisSkeletal integrity is maintained by a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The proteins osteoprotegerin and RANK Ligand play key roles in preserving this balance by preventing and promoting osteoclast activity, respectively. In bone disease associated with cancer, however, the balance shifts in favour of RANK Ligand, resulting in a vicious cycle of osteoclast activation and tumour growth; the same may be true in CTIBL. Denosumab, a fully human monoclonal antibody that binds to and inhibits RANK Ligand, has been shown to block osteoclast-mediated bone resorption and is currently under development as a potential treatment for bone abnormalities associated with cancer and its treatment.ConclusionsInhibition of the RANK Ligand pathway by the human monoclonal antibody denosumab may provide a novel treatment option for bone disease in PCa. Further studies are underway.     

SGLT2 Inhibition: A Novel Prospective Strategy in Treatment of Diabetes Mellitus

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.     

Novel Aspects on RANK Ligand and Osteoprotegerin in Osteoporosis and Vascular Disease

The clinical coincidence of osteoporosis and vascular disease has long indicated that common mediators may adversely affect bone metabolism and vascular integrity alike. Receptor activator of NF-kappaB ligand (RANKL) is an important cytokine for bone resorption that acts through its osteoclastic receptor, receptor activator of NF-kappaB (RANK), while osteoprotegerin serves as a decoy receptor that binds RANKL and prevents activation of RANK. Skeletal and vascular cells are sources and targets of RANKL and OPG both in vitro and in vivo. Modulation of the RANKL/RANK/OPG system in animals results in a skeletal and vascular phenotype, and administration of OPG may prevent osteoporosis and vascular calcification. Recent studies on OPG serum levels and gene polymorphisms also suggest an important role of this cytokine system in skeletal and vascular diseases. In summary, there is increasing evidence that RANKL and OPG may link the skeletal with the vascular system.     

Novel Aspects on RANK Ligand and Osteoprotegerin in Osteoporosis and Vascular Disease

The clinical coincidence of osteoporosis and vascular disease has long indicated that common mediators may adversely affect bone metabolism and vascular integrity alike. Receptor activator of NF-B ligand (RANKL) is an important cytokine for bone resorption that acts through its osteoclastic receptor, receptor activator of NF-B (RANK), while osteoprotegerin serves as a decoy receptor that binds RANKL and prevents activation of RANK. Skeletal and vascular cells are sources and targets of RANKL and OPG both in vitro and in vivo. Modulation of the RANKL/RANK/OPG system in animals results in a skeletal and vascular phenotype, and administration of OPG may prevent osteoporosis and vascular calcification. Recent studies on OPG serum levels and gene polymorphisms also suggest an important role of this cytokine system in skeletal and vascular diseases. In summary, there is increasing evidence that RANKL and OPG may link the skeletal with the vascular system.     

RANK Ligand-targeted Therapy: A Novel Approach to Prevent Bone Loss and Fractures in Men with Prostate Cancer

ContextThe importance of bone loss associated with both prostate cancer (PCa) and its treatment is being increasingly recognised, and new options to manage this complication are in development.ObjectiveTo assess the impact of androgen-deprivation therapy (ADT) on bone and to outline recently reported and ongoing phase 3 studies of agents designed to prevent bone loss and fractures in men with PCa.Evidence acquisitionThis article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisADT for PCa is associated with bone loss and an increased fracture risk. Several bisphosphonates have been shown to improve bone mineral density (BMD) during ADT, but their effects on treatment-related fractures are unknown. Denosumab, a fully human monoclonal antibody to RANK Ligand, is being investigated for the management of bone loss associated with PCa. The results of a phase 3 randomised, placebo-controlled trial of denosumab to prevent bone loss and fractures during ADT in men with PCa have recently been reported. Compared with placebo, denosumab (60 mg subcutaneously every 6 mo) significantly reduced the incidence of new vertebral fractures by 62% after 3 yr. Denosumab also increased BMD significantly at various skeletal sites, including the spine, hip, and wrist.ConclusionsADT decreases BMD and increases fracture risk in men with PCa. A recent phase 3 study has demonstrated that denosumab increases BMD and significantly reduces the risk of new vertebral fractures in men with PCa. Two ongoing phase 3 studies are evaluating denosumab for the prevention and treatment of bone metastases in men with castration-resistant prostate cancer.     

~(89)Sr治疗前列腺癌骨转移疗效分析

目的:评价89Sr治疗前列腺癌骨转移的临床疗效。方法:对确认前列腺癌骨转移伴骨痛的116例患者,行双侧睾丸切除术+内分泌药物+89Sr治疗。89Sr治疗静脉给药,剂量1.48～2.22MBq(40～60μCi)/kg。随访分析临床疗效。结果:①33.6%的患者食欲明显改善,56.0%的患者睡眠明显改善,61.2%的患者止痛药用量显著减少;②骨转移性疼痛缓解总有效率为83.6%,24.1%的患者完全缓解;③骨痛缓解开始出现时间3～21d,平均10.2d;④骨痛缓解维持时间3～12个月,平均5.3个月;⑤31.9%的患者出现"闪烁"痛;⑥生活质量(KPS评分)平均升高20.0%;⑦治疗后18.1%的患者血液白细胞由正常水平下降至3.0～3.9×106/L(Ⅰ度血液毒性反应);⑧随访53例骨显像,治疗后73.6%(39例)骨转移灶数目较治疗前明显减少,18.9%(10例)稳定,7.5%(4例)恶化。结论:89Sr治疗能有效抑制骨转移,缓解骨痛,改善生存质量,不良反应轻,是前列腺癌骨转移性疼痛较理想的治疗方法。     

Novel RANK Antagonists for the Treatment of Bone‐Resorptive Disease: Theoretical Predictions and Experimental Validation

Receptor activator of nuclear factor‐κB (RANK) and RANK ligand (RANKL) play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody‐based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure‐ and knowledge‐based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone disease. © 2014 American Society for Bone and Mineral Research.     

前列腺癌骨转移性疼痛的综合治疗

目的 :探讨晚期前列腺癌骨转移性疼痛的综合治疗方法。　方法 :16例确诊为前列腺癌且有多个部位骨转移病灶伴有疼痛的患者 ,采用口服抗雄激素药物治疗的同时 ,辅以核素89Sr静脉内注射治疗和部分病灶放射治疗。　结果 :治疗后 ,疼痛缓解率 3个月为 75 .6 % ,6个月为 80 .5 % ,9个月为 6 3.4 % ;骨转移病灶数量明显减少。结论 :经过综合治疗后 ,本组晚期前列腺癌伴骨转移性疼痛的患者疼痛获得较为满意的缓解、甚至消失 ,从而改善了患者的生活质量。     

Treatment of Bone Metastases in Patients with Advanced Breast Cancer

Bone metastases are usually associated with a variety of skeletal related events (SREs), a term covering both complications (pathological fractures, spinal cord compression) and the need for therapeutic intervention (radiotherapy, surgery to bone) for painful bone lesions and/or lesions carrying a high risk of fracture by which the patient's quality of life, functioning, and independence may be compromised. In view of the availability of improved therapeutic approaches for oncological diseases and the resulting improvements of median overall survival, the aim of preventing and delaying the occurrence of SREs becomes more important. To avoid, wherever possible, therapies requiring hospitalization, is another relevant goal. In recent years, bisphosphonates, along with available tumor-specific medication (chemotherapy, hormone therapy), constituted the standard of care for preventing skeletal complications in treating patients with bone metastases. Recently, a therapeutical alternative with potentially superior efficacy has been found in denosumab, a fully human monoclonal antibody that binds to the receptor activator of nuclear factor-κB ligand (RANKL), thus preventing osteoclast-mediated bone resorption and specifically interfering with bone metabolism.     

Dose-Fractionation Schedules for Radiotherapy of Bone Metastases

BACKGROUND: Bone metastases are common in breast cancer patients. Radiotherapy is safe and effective. This review aimes to contribute to the definition of the appropriate radiation regimens for different endpoints. MATERIAL AND METHODS: Information was compiled by searching PubMed and MEDLINE databases including early-release publications. When possible, primary sources were quoted. Full articles were obtained. References were checked for additional material when appropriate. RESULTS: Randomized trials and meta-analyses demonstrated that single-fraction radiotherapy with 1 × 8 Gy is as effective for pain relief as multi-fraction regimens such as 5 × 4 Gy or 10 × 3 Gy. Re-irradiation for recurrent pain is required more often after single-fraction radiotherapy. Re-irradiation with another single fraction is safe and effective. Multi-fraction long-course radiotherapy such as 10 × 3 Gy leads to better re-calcification and better local control of metastatic spinal cord compression (MSCC). Because both re-calcification and MSCC recurrences occur only several months after radiotherapy, long-course radiotherapy is particularly appropriate for patients with a favorable survival prognosis. CONCLUSIONS: For uncomplicated painful bone metastases, single-fraction radiotherapy with 1 × 8 Gy may be considered the standard regimen. If re-calcification is a major goal, longer-course radiotherapy (i.e. 10 × 3 Gy) should be used. For MSCC, 10 × 3 Gy is preferable for patients with a favorable survival prognosis.     

Trends in the Multimodality Treatment of Resectable Colorectal Liver Metastases: an Underutilized Strategy

Objective

Advances in multimodality therapy have led to increased survival for patients with metastatic colorectal cancer, but the impact on patients undergoing resection for colorectal liver metastases is unclear. The purpose of this study was to evaluate patterns of treatment for resectable colorectal liver metastases in the USA over the last two decades.

Methods

Using the Surveillance, Epidemiology, and End Results-Medicare database, 1,926 patients who underwent hepatic resection for colorectal liver metastasis between 1991 and 2007 were included and divided into two cohorts: period 1 (1991–2000) and period 2 (2001–2007). Demographic data, treatment patterns, and outcomes of the two periods were compared by univariate methods. Multivariable regression models were constructed to predict the use of perioperative chemotherapy, postoperative complications, and 90-day mortality following liver resection.

Results

The overall use of perioperative chemotherapy was 33 % and did not differ between periods, but shifted from postoperative to preoperative over time. By multivariable analysis, older age, black race, stage III primary cancer, and metachronous disease were predictive of lesser likelihood of chemotherapy use. The use of preoperative chemotherapy was not associated with any increase in perioperative morbidity or mortality.

Conclusions

Despite increased survival and widespread recommendations for the use of multimodality therapy, the overall resection rate and use of perioperative chemotherapy for resectable colorectal liver metastases remain underutilized and have not increased over time. Efforts to investigate barriers to the widespread use of multimodality therapy for these patients are warranted.     

Breast Cancer: Rank Ligand Inhibition

Breast cancer and bone health are closely linked. Early menopause induced by gonadotropin-releasing hormone analogues or chemotherapy as well as aromatase inhibitors reduce oestrogen levels, thereby causing cancer treatment-induced bone loss (CTIBL). Furthermore, bone metastases are commonly found in advanced disease. Current treatment options for bone lesions comprise systemic anti-tumour therapy, irradiation, surgery and bisphosphonates. The main mechanism of osteolysis, osteoclast activation, is induced by the RANK ligand and suppressed by osteoprotegerin (OPG). A human antibody targeting the RANK ligand, denosumab, had superior activity compared to OPG and was therefore further developed in the clinical setting. This article reviews clinical data on denosumab. Data were obtained by searching the Medline database and abstracts from the ASCO annual meeting, ASCO breast meeting, ECCO, ESMO, and the San Antonio Breast Cancer Symposium. Clinical trials have demonstrated that denosumab reduces markers of bone turnover, and suggest equal efficacy to bisphosphonates in reducing the rate of skeletal-related events. While overall fewer side effects were observed, a numerically increased rate of osteonecrosis of the jaw was reported. Denosumab was well tolerated, and clinical activity was similar to bisphosphonates in metastatic disease. Trials of denosumab in the prevention of CTIBL are ongoing.     

Radionuclide Therapy of Bone Metastases

The skeleton is a potential metastatic target of many malignant tumors. Up to 85% of prostate and breast cancer patients may develop bone metastases causing severe pain syndromes in many of them. In patients suffering from multilocular, mainly osteoblastic lesions and pain syndrome, radionuclide therapy is recommended for pain palliation. Low-energy beta-emitting radionuclides ((153)samarium-ethylenediaminetetrameth-ylenephosphonate (EDTMP) and (89)strontium) deliver high radiation doses to bone metastases and micrometastases in the bone marrow, but only negligible doses to the hematopoietic marrow. The response rate regarding pain syndrome is about 75%; about 25% of the patients may even become pain free. The therapy is repeatable, depending on cell counts. Concomitant treatment with modern bisphosphonates does not interfere with the treatment effects. Clinical trials using a new, not yet approved nuclide ((223)Radium) and/or combinations of chemotherapy and radionuclides are aiming at a more curative approach.     

Cancer Pain Management and Bone Metastases: An Update for the Clinician

Breast cancer patients with bone metastases often suffer from cancer pain. In general, cancer pain treatment is far from being optimal for many patients. To date, morphine remains the gold standard as first-line therapy, but other pure μ agonists such as hydromorphone, fentanyl, or oxycodone can be considered. Transdermal opioids are an important option if the oral route is impossible. Due to its complex pharmacology, methadone should be restricted to patients with difficult pain syndromes. The availability of a fixed combination of oxycodone and naloxone is a promising development for the reduction of opioid induced constipation. Especially bone metastases often result in breakthrough pain episodes. Thus, the provision of an on-demand opioid (e.g., immediate-release morphine or rapid-onset fentanyl) in addition to the baseline (regular) opioid therapy (e.g., sustained-release morphine tablets) is mandatory. Recently, rapid onset fentanyls (buccal or nasal) have been strongly recommended for breakthrough cancer pain due to their fast onset and their shorter duration of action. If available, metamizole is an alternative non-steroid-anti-inflammatory-drug. The indication for bisphosphonates should always be checked early in the disease. In advanced cancer stages, glucocorticoids are an important treatment option. If bone metastases lead to neuropathic pain, coanalgetics (e.g., pregabalin) should be initiated. In localized bone pain, radiotherapy is the gold standard for pain reduction in addition to pharmacologic pain management. In diffuse bone pain radionuclids (such as samarium) can be beneficial. Invasive measures (e.g., neuroaxial blockage) are rarely necessary but are an important option if patients with cancer pain syndromes are refractory to pharmacologic management and radiotherapy as described above. Clinical guidelines agree that cancer pain management in incurable cancer is best provided as part of a multiprofessional palliative care approach and all other domains of suffering (psychosocial, spiritual, and existential) need to be carefully addressed («total pain»).     

Osteoprotegerin and its Ligand: A New Paradigm for Regulation of Osteoclastogenesis and Bone Resorption

In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hematopoietic osteoclast precursor cells that leads to osteoclastogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastogenesis inhibitory activity, rapid progress was made to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells that binds to RANK, a transmembrane receptor on hematopoietic osteoclast precursor cells. The interaction of RANK and RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active osteoclasts capable of resorbing bone. OPG acts as a decoy receptor, binding to RANKL and blocking its interaction with RANK, inhibiting osteoclast development. Many of the calciotropic hormones and cytokines, including 1,25(OH)₂D₃, PTH, PGE₂ and IL-11, appear to act through a dual capacity to inhibit production of OPG and stimulate production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for diseases such as osteoporosis. The new understanding provided by the RANK/RANKL/OPG paradigm for both differentiation of osteoclasts and their activation has had tremendous impact on the field and opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption.     

Inhibition of osteoclastogenesis by RNA interference targeting RANK

ABSTRACT: BACKGROUND: Osteoclasts and osteoblasts regulate bone resorption and formation to allow bone remodeling and homeostasis. The balance between bone resorption and formation is disturbed by abnormal recruitment of osteoclasts. Osteoclast differentiation is dependent on the receptor activator of nuclear factor NF-kappa B (RANK) ligand (RANKL) as well as the macrophage colony-stimulating factor (M-CSF). The RANKL/RANK system and RANK signaling induce osteoclast formation mediated by various cytokines. The RANK/RANKL pathway has been primarily implicated in metabolic, degenerative and neoplastic bone disorders or osteolysis. The central role of RANK/RANKL interaction in osteoclastogenesis makes RANK an attractive target for potential therapies in treatment of osteolysis. The purpose of this study was to assess the effect of inhibition of RANK expression in mouse bone marrow macrophages on osteoclast differentiation and bone resorption. METHODS: Three pairs of short hairpin RNAs (shRNA) targeting RANK were designed and synthesized. The optimal shRNA was selected among three pairs of shRNAs by RANK expression analyzed by Western blot and Real-time PCR. We investigated suppression of osteoclastogenesis of mouse bone marrow macrophages (BMMs) using the optimal shRNA by targeting RANK. RESULTS: Among the three shRANKs examined, shRANK-3 significantly suppressed [88.3%] the RANK expression (p < 0.01). shRANK-3 also brought about a marked inhibition of osteoclast formation and bone resorption as demonstrated by tartrate--resistant acid phosphatase (TRAP) staining and osteoclast resorption assay. The results of our study show that retrovirus-mediated shRANK-3 suppresses osteoclast differentiation and osteolysis of BMMs. CONCLUSIONS: These findings suggest that retrovirus-mediated shRNA targeting RANK inhibits osteoclast differentiation and osteolysis. It may appear an attractive target for preventing osteolysis in humans with a potential clinical application.     

Risk Factors for the Development of Bone Metastases in Prostate Cancer

ObjectivesBone health of men with prostate cancer is threatened throughout the disease course. The majority of patients with advanced prostate cancer will develop bone metastases that can undermine skeletal integrity and result in skeletal complications including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone. The early identification of patients who are at a high risk for bone metastases may enable earlier identification and treatment of bone lesions, thereby preserving patients’ independence throughout the disease course.MethodsCurrent guidelines for bone health maintenance were reviewed and PubMed key word searches performed to identify risk factors for the development of bone metastases in patients with prostate cancer. Additionally, guidelines and consensus recommendations were reviewed to identify bone health issues and their management in patients with early prostate cancer.ResultsCurrent prostate cancer monitoring guidelines recommend bone scans at initial diagnosis for patients with prostate-specific antigen (PSA) levels >20 ng/ml and in patients with chronic bone pain or fractures. Multiple studies have concluded that high baseline PSA levels, rising PSA despite androgen-deprivation therapy (ADT), and high PSA velocity are risk factors for the development of bone metastasis in patients with prostate cancer. In patients with early prostate cancer, bone loss is an emerging concern, and bisphosphonates have been demonstrated to prevent bone loss from ADT. Use of risk factors such as PSA kinetics may optimize screening and enable earlier identification of bone metastases.ConclusionsMonitoring bone mineral density may allow for better preservation of skeletal health in patients undergoing ADT.