Investigational drugs for bladder pain syndrome (BPS) / interstitial cystitis (IC)

Introduction: Bladder pain syndrome (BPS)/interstitial cystitis (IC) is associated with sensory lower urinary tract symptoms. Unfortunately, many of the existing oral treatments are ineffective in most patients of BPS/IC, which is the motivation for developing new drugs and therapeutic approaches. This review covers the latest drugs that have been investigated in BPS/IC patients. Intravesical treatments offer the opportunity to directly target the painful bladder with less systemic side effects.

Areas Covered: In this review, the authors analyze the existing literature supporting the treatment of BPS/IC with conventional drugs including heparin, hyaluronic acid, chondroitin sulfate, and dimethylsulfoxide (DMSO). Furthermore, investigational drugs such as tanezumab and adalimumab, capable of sequestering nerve growth factor (NGF), and Tumor necrosis factor-α (TNF- α) are discussed. Investigational treatments such as liposomes, botulinum toxin (BTX), liposomal BTX, PD-0299685 (a Ca²⁺ channel ɑ2δ ligand), continuous intravesical lidocaine, and AQX-1125 (a novel SHIP1 activating compound) are also covered.

Expert opinion: New investigational drugs offer promising improvements in clinical outcomes for BPS/IC patients; however, BPS/IC is a chronic pain disorder that is very vulnerable to a strong placebo effect. In addition, BPS/IC is a heterogeneous disorder that can be classified into several phenotypes. Since different phenotypes of BPS/IC respond differently to systemic and intravesical treatments, the authors believe that new drugs developed for BPS/IC are more likely to meet their predetermined clinical endpoints if the inclusion/exclusion criterion is tailored to specific phenotype of BPS/IC patients.     

An evaluation of the pharmacotherapy for interstitial cystitis

Introduction: Interstitial cystitis (IC) and bladder pain syndrome (BPS) are chronic conditions that can be debilitating for patients. There is no consensus as to their etiology, and there are many proposed treatment algorithms. Oftentimes multimodal therapy, such as combining behavioral modification and physical therapy alongside pharmacotherapies, will be utilized. With the various treatment options available to patients and providers, there is an ever-growing need to implement evidence-based therapies.

Areas covered: The authors explore the different pharmacotherapies as commonly recommended in the American Urological Association (AUA) and European Association of Urology (EAU) multitiered guidelines for IC/BPS treatment as well as other investigational therapies. Pharmacotherapies targeting bladder, pelvic, and/or systemic factors in the overall treatment of IC/BPS are discussed with a particular focus on evidence-based guideline therapies. This article also looks at emerging therapies of interest.

Expert opinion: IC/BPS is a syndrome that requires a multimodal approach, including clinical phenotyping and directed therapy based on the patient’s symptoms. The AUA and EAU provide guidelines for practitioners to follow, but adequate treatment requires the therapy to be targeted toward the patient’s phenotypic domain.     

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems—such as bladder pain and urinary tract infection—make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the treatment less or non-invasive. Laboratory evidence revealed that liposome can carry BoNT-A across the uroepithelium and act on sub-urothelial nerve endings. A randomized placebo controlled study revealed that intravesical administration of liposome-encapsulated BoNT-A and TC-3 hydrogel embedded BoNT-A can improve urinary frequency, urgency, and reduce incontinence in patients with overactive bladders. A single-arm prospective study also revealed that intravesical administration of TC-3 hydrogel embedded BoNT-A can relieve bladder pain in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We recently administered suprapubic energy shock wave (ESW) after BoNT-A intravesical administration in six patients with IC/BPS. Although pain reduction and symptom improvement were not significant, immunochemical staining showed cleaved synaptosome-associated protein 25 in the bladder after the procedure. This suggests that ESW can promote passage of BoNT-A across the uroepithelium. In conclusion, using vehicles to intra-vesically deliver BoNT-A for functional bladder disorders is promising. Further studies are necessary to confirm the efficacy and explore novel applications.     

Pharmacological management of interstitial cystitis /bladder pain syndrome and the role cyclosporine and other immunomodulating drugs play

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a symptomatic disorder characterized by pelvic pain and urinary frequency. Immunological responses are considered as one of the possible etiologies of IC/BPS. In this review, we focused on emerging targets, especially on those modulating immunological mechanisms for the treatments of IC/BPS.

Area covered: This review was based on the literature search of PubMed/MEDLINE, for which key words following bladder pain syndrome, interstitial cystitis, and/or cyclosporine A (CyA) were used. We discussed current treatments and the drugs targeting the immune responses including CyA and other drugs with different mechanisms including NGF antibodies and P2X3 antagonists.

Expert commentary: IC/BPS is often difficult to treat by current treatments. Immunosuppression agents, especially CyA are considered as effective treatments for IC/BPS with Hunner’s lesion because these drugs suppress the inflammatory responses in the bladder underlying urinary symptoms of the disease. Base on the previous literatures, we should use CyA for the refractory IC/BPS, especially that with Hunner’s lesion due to its side effects. New drugs targeting other mechanisms such as urothelial or afferent nerve dysfunction or new delivery systems such as sustained drug releasing devices or gene therapy techniques may be promising for the future treatments of IC/BPS.     

Efficacy of pentosan polysulfate for the treatment of interstitial cystitis/bladder pain syndrome: results of a systematic review of randomized controlled trials

Background: Among the numerous therapeutic approaches used in the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) few have been assessed with a sufficient level of evidence. The safety and efficacy of pentosan polysulfate sodium (PPS) has been shown in several open-label and comparative clinical trials with different populations including two meta-analyses. In the context of the approval procedure of PPS for the treatment of IC/BPS by the European Medicines Agency we updated the findings of the previous analyses by incorporating the results of the latest studies.

Method: Relevant studies based on a systematic review of PubMed/Medline and the Cochrane Library in June 2018 were identified. For completeness control, clinical trial registries were also searched. Only randomized, placebo-controlled clinical trials providing sufficient information to estimate at least one relevant effect size measure to compare the efficacy of PPS versus placebo were included in the analysis.

Results: Of the studies identified in the literature search, six randomized placebo-controlled studies met the pre-defined eligibility criteria. Analyses showed no indication of heterogeneity or publication bias. Treatment with PPS led to a statistically significant improvement in the patient’s overall response assessment (p?<?.001), pain (p?=?.009) and urgency (p?=?.005).

Conclusions: Our meta-analyses confirmed the results of preceding meta-analyses showing that PPS is efficacious compared to placebo in the treatment of bladder pain, urinary urgency and frequency of micturition and thus an evident option for the treatment of IC/BPS symptoms.     

Bridging pharmacotherapy and minimally invasive surgery in interstitial cystitis/bladder pain syndrome treatment

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful and debilitating clinical entity which is challenging to diagnose and even more difficult to treat. Unfortunately, none of the existing oral and intravesical medications have been established as effective and therefore relevant research is ongoing.

Areas covered: In this review, the authors present established and emerging treatment options for IC/BPS in terms of medication and minimal invasive procedures. Both American and European Urological Association Guidelines recommend multimodal behavioral techniques alongside oral (e.g. amitriptyline and pentosan polysulfate sodium) or minimally invasive treatments (e.g. dimethyl sulfoxide, botulinum toxin, chondroitin sulfate, triamcinolone, hyaluronic acid, and lidocaine). Novel treatment modalities include immunomodulating drugs, stem cell therapy, nerve growth factor, and ASP6294.

Expert opinion: IC/BPS is still a pathophysiological enigma with multifactorial etiopathogenesis that may be controlled but not completely cured. Patient-tailored phenotype-directed multimodal therapy is the most promising treatment strategy. Combined phenotypic categorization with specific biomarkers could help toward better treatment.     

Intravesical therapy for bladder cancer

Introduction: Transurethral resection of bladder tumor (TURBT) is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). However, TURBT alone is inadequate for optimal management of NMIBC, as patients will experience recurrence or progression depending on tumor characteristics. Adjuvant intravesical therapy with either immunotherapy or chemotherapy has been shown to reduce recurrence and/or progression in appropriately selected patients through immunostimulation or direct cell ablation.

Areas covered: This review will discuss risk stratification of patients with NMIBC and role of intravesical therapies in reducing recurrence and progression of disease in these patients. A Medline search was performed to identify the best available evidence available from various systematic reviews, meta-analyses, and clinical trials on various immunotherapy and chemotherapy agents. In addition, the main aspects of drug pharmacology (mechanism of action, dosing and administration) and side effects will be reviewed.

Expert opinion: The selection of the appropriate intravesical agent for NMIBC is complex and is dependent on risk stratification and intravesical agent toxicity. Intravesical induction and maintenance immunotherapy with Bacillus Calmette–Guerin (BCG) is the preferred and most effective agent for patients with high-risk NMIBC (carcinoma in situ and high-grade disease) and reduces both recurrence and progression.     

Investigational therapies for non-muscle invasive bladder cancer

Importance of the field: Bacillus Calmette–Guérin (BCG) is currently the most effective adjuvant intravesical agent at preventing disease recurrence and the only therapy shown to inhibit disease progression in non-muscle invasive bladder cancer (NMIBC). However, recurrence rates as high as 30% and significant local/systemic toxicity have resulted in an increased interest in the use of alternative intravesical agents.

Areas covered in the review: Our aim is to discuss recent clinical trial evidence utilizing novel intravesical agents for treatment of NMIBC. A systematic literature review was performed via the National Center for Biotechnology Information databases to identify pertinent studies from 2000 – 2009.

What the reader will gain: A durable response has been demonstrated with alternative agents in patients refractory to or intolerant of BCG. This review compares the merits and shortcomings of these emerging agents, focusing on clinical trial safety and efficacy results.

Take home message: Despite recent enthusiasm for novel agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy. However, evidence is accumulating that novel agents provide an efficacious alternative in patients refractory or intolerable to BCG or unfit for cystectomy. Further randomized prospective data are required to demonstrate a recurrence- and progression-free benefit compared with BCG.     

Is there an appropriate strategy for treating co-morbid irritable bowel syndrome and bladder pain syndrome?

Introduction: Two of the most frequent components of chronic pelvic pain syndrome (CPPS) are irritable bowel syndrome (IBS) and bladder pain syndrome (BPS), characterized by considerable overlapping symptoms and pathophysiology. Currently, its management is challenging meaning there is high the demand for novel efficient therapeutics to aid patient care and to tackle the socioeconomic burden of IBS and BPS. As there are presently no sufficient treatment strategies, identifying the mechanisms that result in their main symptoms is the opportunity for developing appropriate therapies.

Areas covered: Herein, the authors explore the potential common treatment strategies for co-morbid IBS and BPS and highlight the absolute need for further research of these deliberating clinical entities.

Expert opinion: In the future, the authors summise that the discovery of predictive molecular biomarkers combined with clinical phenotypic categorization will likely allow for more definitive differentiation of patients and thus for better treatment options. Furthermore, it has been suggested that effective IBS treatment strategies would be of great value to co-morbid IBS and BPS therapy.     

Polymeric Growth Factor Delivery Strategies for Tissue Engineering

Purpose. Tissue engineering seeks to replace and regrow damaged or diseased tissues and organs from either cells resident in the surrounding tissue or cells transplanted to the tissue site. The purpose of this review is to present the application of polymeric delivery systems for growth factor delivery in tissue engineering. Methods. Growth factors direct the phenotype of both differentiated and stem cells, and methods used to deliver these molecules include the development of systems to deliver the protein itself, genes encoding the factor, or cells secreting the factor. Results. Results in animal models and clinical trials indicate that these approaches may be successfully used to promote the regeneration of numerous tissue types. Conclusions. Controlling the dose, location, and duration of these factors through polymeric delivery strategies will dictate their utility in tissue regeneration.     

Long-Term Efficacy and Safety of Repeated Intravescial OnabotulinumtoxinA Injections Plus Hydrodistention in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome

Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks sustainability. Repeated injections have been shown to provide a superior outcome to a single injection, but data on long-term efficacy and safety is limited. In this prospective study, we enrolled patients with refractory IC/BPS, and treated them with 100 U of BoNT-A injection plus hydrodistention followed by repeated injections every six months for up to two years or until the patient wished to discontinue. A “top-up” dose was offered after the fourth injection. Of these 104 participants, 56.7% completed four BoNT-A injections and 34% voluntarily received the fifth injection due to exacerbated IC symptoms. With a follow-up period of up to 79 months, O’Leary-Sant symptom and problem indexes (ICSI, ICPI, OSS), pain visual analogue scale (VAS) functional bladder capacity, frequency episodes, and global response assessment (GRA) all showed significant improvement (p < 0.0001). Those who received repeated injections had a better success rate during the long-term follow-up period. The incidence of adverse events did not rise with the increasing number of BoNT-A injections. A higher pre-treatment ICSI and ICPI score was predictive for successful response to repeated intravesical BoNT-A injections plus hydrodistention.     

Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer

Introduction: Bladder cancer (BC) is a severe health burden: and has high recurrence and progression rates. Standard treatment starts with TURB followed by intravesical chemotherapy with Mitomycin C or immunotherapy with BCG. However, successful management still remains a challenge, because approximately 30% of patients have recurrence or progression within 5 years, and treatment has considerable side effects. Anticipating on the upcoming BCG shortage emphasizes, moreover, the necessity to develop and study novel treatments. This review explores emerging and novel salvage treatments as well as approaches of current treatments with decrease side-effects for non muscle-invasive bladder cancer (NMIBC).

Areas covered: In this review, the authors provide an overview of the novel and emerging therapies for NMIBC. They also provide the currently available data and ongoing trials.

Expert opinion: Key findings in the field of research on emerging intravesical drugs for the treatment of NMIBC are the promising results for device assisted treatments, treatment with intravesical immunotherapy, and treatments to expedite the immunotherapy checkpoint inhibitors. Other novel therapies are still in an experimental stage and have to make the transition towards the clinical setting to determine the benefit in terms of reduced side-effects, recurrence and progression rates.     

O’Leary-Sant Symptom Index Predicts the Treatment Outcome for Onabotulinumtoxin A Injections for Refractory Interstitial Cystitis/Bladder Pain Syndrome

Although intravesical injection of onabotulinumtoxinA (BoNT-A) has been proved promising in treating patients with interstitial cystitis/bladder pain syndrome (IC/BPS), what kind of patients that may benefit from this treatment remains unclear. This study investigated the predictors for a successful treatment outcome. Patients with IC/BPS who failed conventional treatments were enrolled to receive intravesical injection of 100 U of BoNT-A immediately followed by hydrodistention. Variables such as O’Leary-Sant symptom and problem indexes (ICSI and ICPI), pain visual analogue scale (VAS), functional bladder capacity (FBC), voiding diary, and urodynamic parameters were measured at baseline and six months after treatment. A global response assessment (GRA) ≥ 2 at six months was defined as successful. There were101 patients enrolled. Significant improvements were observed in mean ICSI, ICPI, OSS (ICSI + ICPI), pain VAS, FBC, frequency, nocturia and GRA at six months after BoNT-A injections (all p < 0.05). The successful rate at six months was 46/101 (45.54%). Multivariate logistic regression revealed the baseline ICSI (odds ratio = 0.770, 95% confidence interval = 0.601–0.989) was the only predictor for a treatment outcome. ICSI ≥ 12 was the most predictive cutoff value for a treatment failure, with a ROC area of 0.70 (sensitivity = 69.1%, specificity = 60.9%).     

Current advances in BCG-unresponsive non-muscle invasive bladder cancer

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette–Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm.

Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials.

Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients     

Nanotechnology based platforms for survivin targeted drug discovery

Introduction: Development of an effective, safe and targeted drug delivery system to fight cancer and other diseases is a prime focus in the area of drug discovery. The emerging field of nanotechnology has revolutionised the way cancer therapy and diagnosis is achieved primarily due to the recent advances in material engineering and drug availability. Further, the recognition of the crucial role played by anti-apoptotic proteins such as survivin, has initiated the development of therapeutics that can target this protein as an attempt to develop alternative cancer therapies. However, a key challenge faced in drug development is the efficient delivery of survivin-targeted molecules to specific areas in the body.

Areas covered: This review primarily focuses on the different strategies employing nanotechnology for targeting survivin expressed in human cancers. Different nanomaterials incorporating nucleic molecules or drugs targeted at survivin are discussed and the results obtained from studies are highlighted.

Expert opinion: There are extensive studies reporting different treatment regimens for cancer, however, they still result in systemic toxicity, reduced bioavailability and ineffective delivery. Novel approaches involve the use of biocompatible nanomaterials together with gene or drug molecules to target proteins such as survivin, which is overexpressed in cancerous cells. These nanoformulations allow the benefits of protecting easily degradable molecules, allow controlled release, and enhance targeted delivery and effectiveness. Hence, nanotherapy utilizing survivin targeting can be considered to play a key role in the development of personalized nanomedicine for cancer.     

Biomaterial-based scaffolds – current status and future directions

Introduction: Biomaterial-based scaffold formulations (three-dimensional Porous matrix, nano-fibre mesh, hydrogels and microspheres) are the major components that are used to deliver the bioactive molecules into the body organs through different routes for an effective treatment of various diseases.

Areas covered: Various fabrication techniques such as freeze-drying, polymerisation, spray drying, gas foaming, supercritical fluid technology, etc., are successfully used for fabrication of scaffold formulations. Due to their unique characteristics, these formulations are widely used against various diseases such as tuberculosis, bone defects, cartilage repair, skin diseases, cardiovascular diseases, periodontal diseases, wound dressing, etc.

Expert opinion: The study of biomaterial-based scaffold formulations is exhilarating with novel approaches to drug/cell/gene delivery being developed all the time. At present, there is a huge extent of research being performed worldwide on all aspects of tissue engineering/drug or gene delivery. In the future, the main focus will be on the development of more patient compliant, sustained and controlled delivery systems against various diseases by modification of polymers, manufacturing technologies as well as carrier systems.     

Adverse Events of Intravesical OnabotulinumtoxinA Injection between Patients with Overactive Bladder and Interstitial Cystitis—Different Mechanisms of Action of Botox on Bladder Dysfunction?

Intravesical onabotulinumtoxinA (BoNT-A) injections have been proposed to treat both overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) in patients with refractory conditions. We compared adverse events (AEs) after BoNT-A treatment between IC/BPS and OAB in women. IC/BPS patients who failed conventional treatments were enrolled to receive suburothelial injections of BoNT-A (100 U) followed by hydrodistention. Age matched OAB female patients refractory to antimuscarinic agents underwent BoNT-A (100 U) injections. The bladder capacity, maximum flow rate (Qmax), post-void residual (PVR), and voiding efficiency (VE) at baseline, 3 and 6 months, and the post-treatment AEs were analyzed between groups. Finally, 89 IC/BPS and 72 OAB women were included. In the OAB group, the bladder capacity and PVR increased, and VE decreased significantly at three and six months after BoNT-A treatment. In the IC/BPS group, the Qmax increased significantly at six months. There were significant differences in changes of capacity, Qmax, PVR and VE between the two groups. Moreover, OAB patients suffered more frequently from events of hematuria, UTI, and large PVR (>200 mL), but less frequently from events of straining to void. In conclusion, OAB women had higher PVR volume and lower VE than those in IC/BPS after BoNT-A injections. These results imply that the bladder contractility of OAB patients are more susceptible to BoNT-A, which might reflect the different mechanisms of action of Botox on bladder dysfunction. Further investigations to confirm this hypothesis are warranted.     

Developing models for cachexia and their implications in drug discovery

Introduction: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia.

Areas covered: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia.

Expert opinion: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery.     

QSAR studies in the discovery of novel type-II diabetic therapies

Introduction: Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure–activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity.

Areas covered: This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds.

Expert opinion: Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.