Current Pharmaceutical Design - Volume 23, Issue 41, 2017

Bone loss is the result of a negative unbalance between bone formation ad bone resorption. In the last years, the studies on the Wnt canonical pathway have highlighted its crucial role in bone balance through its influence on the activity and maturation of the osteoblast line and in the Receptor Activator of Nuclear Factor Κ B (RANK) - RANK ligand (RANKL)/Osteoprotegerin (OPG) system. These mechanisms are involved not only in the pathological processes inducing not only systemic bone loss (i.e. Postmenopausal osteoporosis, glucocorticoid- induced osteoporosis, etc.), but also at a local level, as happens in Rheumatoid Arthritis (RA). Recently, several new drugs for the treatment of bone loss have been approved, while some others are still under development. The most promising new drugs in the treatment of osteoporosis include the antibody that neutralizes RANKL (denosumab, DMAb), monoclonal antibodies against sclerostin and parathyroid hormone-related protein analogue. Other new strategies for the prevention and treatment of bone loss include calcilytics, cathepsin K inhibitor or the combination or the sequential use of the current drugs. New insights concerning the treatment of the local bone loss in RA and in Complex Regional Pain Syndrome type I are also provided in this review.

Background: Osteoporosis is a systemic bone disease, which is associated with the osteoporotic fracture. Along with prolonged life expectancy, the fracture risk increases dramatically with age. So far, it is usually the first choice to using antiresorptive agents. However, current clinical therapeutic treatments are not enough to inhibit the long-term bone loss and the rising risk of bone fractures. Recently, combination and sequential therapies with anti-osteoporosis drugs have become an inevitable trend. Objective: The purpose of this review is to summarize the present knowledge related to the combination and sequential therapies with anti-osteoporosis drugs. Methods: All articles published in PubMed until 2016 on the combination and sequential therapies with antiosteoporosis drugs were reviewed and the relevant literature was described in this review. Results: As the first-line therapy for osteoporosis, the long-term safety and efficacy on bisphosphonate, teriparatide, and new anti-osteoporosis drugs are ongoing concerns. Combination or sequential therapies of boneforming agents and anti-resorptive agents, or two kinds of anti-resorptive agents, or strontium ranelate and other anti-osteoporosis agents have the advantages on BMD compared with monotherapy. Conclusion: So far, it is still an important public health strategy to therapy on the osteoporosis and related fracture. Alternatively, the combination and sequential therapies with anti-osteoporosis drugs are promising approaches for prevention and treatment of osteoporosis and have far-reaching significance.

Osteoporosis is a condition featured by bone mass loss and bone tissue microarchitectural alterations due to impaired tissue homeostasis favoring excessive bone resorption versus deposition. The trigger of such an impairment and the downstream molecular pathways involved are yet to be clarified. The natural course of osteoporosis is particularly worrisome because, through a “silent” progression, it enhances bone fragility, increases the risk of fractures and is associated with increased risk of disability and mortality. To date, the assessment of bone mineral density by dual-energy X-ray absorptiometry, represents the non-invasive gold standard for the evaluation of bone mineralization and the diagnosis of osteoporosis. Although long known as a condition merely related to the hormonal-driven loss of bone homeostasis, emerging evidence supports the need of reframing osteoporosis in the context of structural and functional changes of the musculoskeletal system as a whole. Several age-related alterations of bone microenvironment and an altered bone-muscle crosstalk have been suggested to be relevant contributors to loss of bone strength and mass characterizing osteoporosis. The present work provides an overview of the current knowledge of the pathophysiology of osteoporosis obtained through advances in epigenetics, cell biology and osteoimmunology. In light of the increasingly recognized importance of bone-muscle interconnection, this review also discusses relevant pathways that may be dissected for identifying new therapeutic targets for age-related musculoskeletal degeneration.

In contemporary society, a large number of adults experience more or less decrease in bone mass or bone density. It is known that bone, in response to mechanical loading, undergoes continuous remodeling throughout life, which helps in the growth and maintenance of the skeleton. Since mechanical loading acts as an important stimulus for bone growth and maintenance, it can be used as a strategy to prevent and treat the conditions of bone loss. This review summarizes the current knowledge about the effects of mechanical loading on bone, in the level of cells and tissue.

New evidence of the interactions between the immune system and bone has accumulated in bone diseases, including osteoporosis, periodontitis and rheumatoid arthritis. A marked imbalance between bone resorption and formation is central to the onset of pathological bone loss. Osteoimmunology has revealed that the immune system, including T cells, B cells and inflammatory cytokines, is a key regulator of both osteoclasts and osteoblasts. Th1 cells, which differentiate from CD4+T cells, are thought to play a major function during bone loss. Moreover, the correlated expression of Th1 cytokines (interleukin-12 (IL-12), interferon-γ (IFN-γ)) and bone-resorbing cytokines (tumor necrosis factor-α (TNF-α), IL-1) also plays a key role during inflammatory induced bone resorption. Furthermore, a relatively new member of the CD4+T cell family Th17 displays the ability to promote osteoclast activity. The effect of IFN-γ and IL-17 released by Th 17 cells on pre-osteoclast proliferation, differentiation and apoptosis provides the preliminary basis for the immune mechanism of pathological bone loss. The role of B cells in osteoimmunological interactions has long been suspected based on findings of B cells as active regulators of the RANK/RANKL/OPG axis. Pathological bone loss, including osteoporosis and human immunodeficiency virus-associated bone loss, are related to the altered RANKL/OPG through modified production by B cells, supporting this assumption. All of the above evidence may provide new theoretical explanations for the relationship between bone metabolism and the immune system as well as offer perspectives for the prevention and treatment of pathological bone loss.

The abnormal loss of bone tissue is defined as osteoporosis. Increased risk of fractures, low bone mineral density (BMD) and loss of the structural and biomechanical properties of the bone tissue characterize this pathological condition. Physiologically bone undergoes a continuous remodeling process involving balance between the activity of osteoblast and osteoclast. Disruption in this balanced condition increases the risk of osteoporosis. Both sexes are affected, but with higher prevalence in women after menopause. This review aims to enlighten the established and emerging trends in prevention and treatment of bone loss. Herbal supplementation and physical exercises are suggested as addition to the well-established therapy in prevention and management of osteoporosis. Treatment strategies of osteoporosis include non- pharmacological treatment - diet rich of calcium and vitamin D, healthy lifestyle, proper exercise plan, and pharmacological therapy. Preventive and treatment strategies have to consider combination of non-pharmacological and pharmacological approaches for minimization of the fracture risk in osteoporosis.

Hematopoietic bone marrow stem cell transplantation has been regularly used in clinical practice for over 40 years. Further research indicates that bone marrow stromal cells are also stem cells that are capable of self-renewal, proliferation and differentiation. With appropriate induction, the bone marrow stromal cells can differentiate into bone, cartilage, tendon, adipose tissue and fibrous tissue, which would potentially be applied for treating bone loss diseases. This review outlines research in understanding role of bone marrow stem cells and stem cells from other origins in bone repair, and highlight the current and potential stem cell based treatment for bone loss diseases in the future.

Bone loss is common in clinical practice, such as health assessment of postmenopausal women, treatment of tumor metastasis, side-effects of glucocorticoids, and skeletal manifestations of inflammatory diseases. The imbalance of remodeling between bone resorption and bone formation, the pathophysiological basis of bone loss, increases bone fragility. The treatment of bone loss is mainly carried out from the treatment of osteoporosis. There are various pharmacological therapies for bone loss, which will be introduced in 3 aspects, including antiresorptive agents, anabolic agents and new medications. Each kind of medication has its advantages, shortcomings and side-effects. Antiresorptive agents are widely applied in the treatment of bone loss, but can lead to overall decrease of bone turnover rate. Anabolic agents, mainly PTH, are usually combined with other anti-resorptive drugs, and PTHrP might be a promising pure anabolic agent for osteoporosis. In recent years, some novel therapies have been raised and tested in clinical trials which can be promising choices available for osteoporosis treatment. Future drug targets will mainly come from RANK-RANKL-OPG system and Wnt/β-catenin signaling pathway., and the pre-existing drugs could be explored in new patterns.

Bone remodelling is a strictly regulated dynamic process between bone resorption and bone formation. Many factors are involved in the process and affect the dynamic balance. Inflammation-mediated bone loss is a major feature of various bone diseases, including periodontitis, rheumatoid arthritis (RA) and spondyloarthritis (SpA). Interleukin-17 (IL-17) plays an important role in inflammatory bone disease and could be an attractive therapeutic target. This review focuses on the osteoclastic effects of IL-17 in different cell types and summarizes the current knowledge of IL-17 signalling pathways. Typical IL-17–mediated bone destruction disorders are examined. The review also provides an overview of possible strategies for therapeutic intervention for inflammatory loss of bone targeting IL-17.

Objective: Nephropathy is among the most common and most devastating complications of diabetes mellitus. Recent data suggest that there is a multifaceted interaction between the kidney and antidiabetic drugs. Thus, the deterioration of renal function may result in important changes in the pharmacokinetic and pharmacodynamic properties of glucose-lowering compounds. Additionally, drugs that exert their antidiabetic properties through the inhibition of proximal glucose reabsorption are now available whereas accumulating evidence suggests that some of these drugs may exert renoprotective properties that are independent of their effect on carbohydrate metabolism. Methods: All articles published until the end of 2016 in PubMed that dealt with the relationship of antidiabetic drugs and the kidney were reviewed and the relevant information is presented here. Results: In this review, we summarize the available evidence on the drugs that act through the inhibition of renal glucose reabsorption, discuss the adjustments in the dose of antidiabetic drugs in patients with various stages of kidney disease and explore the renoprotective potency of the various glucose-lowering compounds. Conclusion: Sodium glucose cotransporter 2 inhibitors represent a very promising option for the treatment of type 2 diabetes, especially in patients with established cardiovascular disease. These drugs, along with pioglitazone and incretin mimetics may also reduce the incidence and the rate of progression of diabetic nephropathy.

Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.

Tissue engineering offers a promising strategy to restore injuries resulting from trauma, infection, tumor resection, or other diseases. In spite of significant progress, the field faces a significant bottleneck; the critical need to understand and exploit the interdependencies of tissue healing, angiogenesis, and inflammation. Inherently, the balance of these interacting processes is affected by a number of injury site conditions that represent a departure from physiological environment, including reduced pH, increased concentration of free radicals, hypoglycemia, and hypoxia. Efforts to harness the potential of immune response as a therapeutic strategy to promote tissue repair have led to identification of natural compounds with significant anti-inflammatory properties. This article provides a concise review of the body's inflammatory response to biomaterials and describes the role of oxygen as a physiological cue in this process. We proceed to highlight the potential of natural compounds to mediate inflammatory response and improve host-graft integration. Herein, we discuss the use of natural compounds to map signaling molecules and checkpoints that regulate the cross-linkage of immune response and skeletal repair.

Background: Colorectal cancer is the third most common form of cancer in both men and women around the world. The chemistry and biological study of heterocyclic compounds have been an interesting area for a long time in pharmaceutical and medicinal chemistry. Methods: A new synthetic compound, 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-3-((2-hydroxyphenyl)amino) acrylaldehyde, abbreviated as DBID, was prepared through the reaction of 2-(diformylmethylidene)-1,1- dimethylbenzo[e]indole with 2-aminophenol. The chemical structure of the synthesized compound was characterized by 1H NMR, 13C NMR and APT-NMR spectroscopy and confirmed by elemental analysis (CHN). The compound was screened for the antiproliferation effect against colorectal cancer cell line, HCT 116 and its possible mechanism of action was elucidated. To determine the IC50 value, the MTT assay was used and its apoptosisinducing effect was investigated. Results: DBID inhibited the proliferation of HCT 116 cells with an IC50 of 9.32 μg/ml and significantly increased the levels of caspase -8, -9 and -3/7 in the treated cells compared to untreated cells. Apoptosis features in HCT 116 cell was detected in treated cells by using the AO/PI staining that confirmed that the cells had undergone remarkable morphological changes in apoptotic bodies. Furthermore, this changes in expression of caspase -8, -9 and -3 were confirmed by gene and protein quantification using RT-PCR and western blot analysis, respectively. Conclusion: The current study showed that the DBID compound has demonstrated chemotherapeutic activity which was evidenced by significant increases in the expression and activation of caspase and exploit the apoptotic signaling pathways to trigger cancer cell death.