New understanding and treatments for osteoporosis

To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.     

Hip fracture protection by alendronate treatment in postmenopausal women with osteoporosis: a review of the literature

Osteoporosis most commonly affects postmenopausal women, placing them at a significant risk of fractures. In particular, hip fractures are an important cause of mortality and morbidity among postmenopausal women. Anti-resorptive therapies that produce greater decreases in bone turnover markers together with greater increases in bone mineral density (BMD) are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Thus, treatment with potent anti-resorptive drugs like alendronate is a strategy for preventing hip fractures in postmenopausal women with osteoporosis. The purpose of this paper is to discuss the efficacy of alendronate against hip fractures and the mechanism for this anti-fracture efficacy in postmenopausal women with osteoporosis. A meta-analysis of randomized controlled trials has shown that alendronate reduces the risk of hip fractures by 55% in postmenopausal women with osteoporosis. According to the analyses of the Fracture Intervention Trial, each 1 standard deviation reduction in a 1-year change in bone-specific alkaline phosphatase (BSAP) is associated with 39% fewer hip fractures in alendronate-treated postmenopausal women, and those with at least 30% reduction in BSAP have a 74% lower risk of hip fractures relative to those with less than 30%. Alendronate is effective in reducing the risk of hip fractures across a spectrum of ages. The mechanism for this anti-fracture efficacy has been clarified; alendronate strongly suppresses bone turnover and subsequently increases hip BMD, decreases cortical porosity, improves parameters of hip structure geometry (cortical thickness, cross-sectional area, section modulus, and buckling ratio), and produces more uniform mineralization (increases the mean degree of mineralization of bone) in cortical bone. A once-weekly regimen of alendronate administration provides better patient compliance and persistence with the treatment than the once-daily dosing regimen, leading to greater efficacy against hip fractures. Thus, the efficacy of alendronate against hip fractures has been confirmed in postmenopausal women with osteoporosis, especially with a once-weekly dosing regimen.     

Regulation of bone mineralization by parathyroid hormone

In randomized clinical trials, parathyroid hormone (PTH) showed potent anabolic effects on the lumbar spine and decreased the risk of incident vertebral fractures dramatically. Although the anabolic effect of PTH on cortical bone in the femoral neck is still unclear, it should be demonstrated in further clinical studies. Concurrent or sequential therapies of PTH and anti-resorptive agents will be one of the major issues of treatment for osteoporosis in the future.     

The use of combination therapy in the treatment of postmenopausal osteoporosis

In recent years, there has been growing interest in the potential use of combination therapy in the management of osteoporosis in postmenopausal women. Possible regimens include sequential or combined use of anti-resorptive drugs or combinations of anabolic and anti-resorptive agents, given concurrently or in sequence. Combined therapy with anti-resorptive drugs usually produces greater increases in bone mineral density (BMD) than monotherapy but there is no evidence that this results in greater anti-fracture efficacy. The use of bisphosphonates before strontium ranelate or PTH peptides blunts the BMD response. Combined PTH and anti-resorptive therapy results in more rapid gains in spine BMD and a greater increase in hip BMD than PTH monotherapy in the first year of treatment but greater gains in both spine and hip BMD are seen with PTH monotherapy than combined therapy after 2 years of treatment. Anti-resorptive therapy after PTH therapy maintains or increases the gains in BMD. Further research is required to establish the cost-effectiveness and safety of combined and sequential regimens.     

A rational approach to evidence gaps in the management of osteoporosis

Major advancements in the treatment of osteoporosis have occurred over the last decade. Therapies including the anti-resorptive drugs such as alendronate and risedronate have been shown in randomized placebo-controlled trials to increase bone mineral density and reduce fracture risk. Anabolic therapy in the form of parathyroid hormone has been introduced as the first treatment to build bone mass. However, gaps in our knowledge about specific management issues that arise frequently among primary care providers persist. In this paper, three common clinical scenarios are discussed: a postmenopausal woman with only slightly reduced bone mineral density; an osteoporotic woman on anti-resorptive therapy for more than 5 years; and a woman who continues to fracture despite treatment. Evidence gaps in each treatment scenario are presented, and rational approaches to management are suggested.     

The future of nanomedicine in optimising the treatment of inflammatory bowel disease

There have been major advancements in the treatment of inflammatory bowel disease (IBD) over the past three decades. However despite significant progress, the best available treatments continue to demonstrate variable efficacy in patients and are associated with adverse effects. Therefore there remains an unmet clinical need for ongoing therapeutic advances for IBD. In recent years nanomedicines have emerged as promising diagnostic and therapeutic tools. Nanoparticles in particular show promise to facilitate targeted oral drug delivery in IBD. Here we discuss the pitfalls of current therapies and explore the potential for nanoparticles to improve the treatment of IBD. This review examines the range of conventional and novel therapies which have benefited from nanoparticle-mediated delivery and highlights the proven therapeutic efficacy of this approach in preclinical models. These strategies under development represent a novel and innovative treatment for IBD.     

Challenges in sexual medicine

The sexual medicine field has been in mode of revolution until recently. Like all other fields of biomedical research, the economic situation around the world has had a negative impact on the field's momentum-research funding bodies, regulatory bodies and pharmaceutical companies seem to have placed sexual medicine in their low-priority list. But this is not the only challenge the field is facing. The successful development of phosphodiesterase type 5 (PDE5) inhibitors for treatment of erectile dysfunction (ED) means that research in this area seems to have slowed. However, there remain several unmet medical needs within sexual medicine such as premature ejaculation, severe ED and hypoactive sexual desire disorder, which await novel therapeutic approaches. Despite these challenges, research into finding and developing such therapies is likely to continue in the sexual medicine field, in an effort to improve the lives of our patients, who wait for effective therapies.     

Management of primary osteoporosis

Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other "selective estrogen receptor modulators" (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are already in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.     

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics

Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimize currently licensed therapies. Here, we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined, and the potential role of current therapies in the employment of pipeline agents is discussed.     

Current and novel therapies in acute GVHD

Despite improvements in our understanding of transplant immunology and clinical and supportive care, acute graft-versus-host disease (GVHD) remains a clinical challenge and a major cause of morbidity and mortality for patients after allogeneic hematopoietic stem-cell transplantation. While systemic corticosteroid is standard primary therapy for acute GVHD, there is no established standard treatment in the steroid-refractory setting. New generations of monoclonal antibodies, biologics, and chemotherapeutics with immunomodulatory effects have been developed over the past decade, and are being tested as novel therapies in this disease. Many of these agents - including, among others, mycophenolate mofetil, anti-tumor necrosis factor-alpha antibodies, denileukin diftitox, and anti-interleukin-2Ralpha-chain antibodies - have demonstrated promising activity in steroid-refractory acute GVHD. Despite the high response rates, however, long-term survival remains poor due to a high incidence of infections. The key to improving acute GVHD outcomes may, in fact, rest upon successful initial therapy, and timely taper of corticosteroids to promote healthier immune reconstitution. Clinical trials combining these newer agents with systemic corticosteroids as initial treatment are under way, and will determine whether fortifying initial therapy will indeed reduce the development of steroid-refractory GVHD and improve long-term outcomes. In this article, we review current and novel agents available for acute GVHD, and discuss newer investigational approaches - such as phototherapy and cellular therapies - in the management of this common transplant complication.     

Humanizing thrombi in mice

Antiplatelet therapies form the cornerstone of atherothrombosis prevention, reducing the morbidity and mortality associated with cardiovascular disease. Despite these benefits, there is still an unmet need for more effective and safer pharmacological agents. To expedite this process, biological platforms that better reflect the intravascular environment in humans will be required in order to shorten drug development time, enable better determination of dosing regimes, and aid in the design of clinical studies. This article focuses on a unique genetically modified animal model that predicts the in vivo response of antiplatelet agents in humans more accurately than is currently possible using conventional murine models of thrombosis.     

Current use of monoclonal antibodies in the treatment of multiple myeloma

Multiple myeloma (MM) is the second most common haematological malignancy after non‐Hodgkin lymphoma. Despite the improvement in outcomes over the last decade with the introduction of novel therapies, such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), MM remains an incurable disease. Patients who are both refractory to IMiDs and PIs carry a particularly dismal prognosis. The development of targeted therapy in the form of monoclonal antibodies has shifted the treatment paradigm of this disease, resulting in unprecedented response rates, even among the highest‐risk patients. In this review, we will summarize the mechanism of action and provide an overview of the clinical trials that have led to the US Food and Drug Administration approval of Daratumumab and Elotuzumab, and their current use in the treatment of MM.     

Treating osteoporosis to prevent fractures: current concepts and future developments

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40–70%), nonvertebral (by 25–40%) and hip fractures (by 40–53%) in postmenopausal women with osteoporosis. Due to the risk of rare side‐effects, the use of bisphosphonates has been limited to up to 10 years with oral bisphosphonates and 6 years with intravenous zoledronic acid. Despite their well‐proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk‐based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long‐term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone‐building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long‐term fracture prevention and should be the golden standard of future osteoporosis treatment.     

New cytokine targets in inflammatory rheumatic diseases

With the advent of biological therapies, considerable advances have been achieved in the treatment of inflammatory arthritis. These have arisen primarily from studies elucidating mechanisms of pathophysiology and are best exemplified in the wide use of tumour necrosis factor (TNF) blockade in several rheumatic diseases. The identification of additional pro-inflammatory factors in rheumatic diseases and an understanding of their effector function, now offers major possibilities for the generation of novel therapeutics. To address unmet clinical need, such interventions will ideally fulfil several of the following criteria: (1) control of inflammation, (2) modulation of underlying immune dysfunction - promoting the re-establishment of immune tolerance, (3) protection of targeted tissues such as bone and cartilage - this should encompass promoting healing of previously damaged tissues, (4) preservation of host immune capability - to avoid profound immune suppression and (5) amelioration of co-morbidity associated with underlying inflammatory arthritis. This short review will consider those novel cytokine activities that represent optimal utility as therapeutic targets. Since we wish to reflect the current predominant research effort, we will focus primarily on rheumatoid arthritis (RA) based studies.     

Bisphosphonates

After the development of potent bisphosphonates including alendronate and risedronate, evidence has accumulated that not only vertebral but also non-vertebral fractures can be prevented by these agents. In addition, numbers needed to treat for both vertebral and non-vertebral fractures by alendronate and risedronate are around 30 to 90. Thus, these agents are expected to improve the socio-economical situation of osteoporosis treatment as well as the survival and quality of life of osteoporotic patients. Once-a-week oral bisphosphonates and long-acting intravenous formula that can successfully inhibit bone resorption for 3 months or longer are also under development. Although PTH and alendronate treatment in combination did not show much beneficial effects, there are results showing additive effect of sequential treatment with PTH followed by alendronate. From these studies, we can expect even better prospect for osteoporosis treatment by choosing from or sequentially combining these different modality of therapies.     

Recapitulation of the round-table discussion--assessing the role of anti-tumour necrosis factor therapy in the treatment of rheumatoid arthritis

Clinical trials specifically targeting and neutralizing the cytokine, tumour necrosis factor (TNF), have recently provided evidence of efficacy and a promise of a novel approach for the treatment and management of rheumatoid arthritis (RA). With the evolving emergence of anti-TNF therapeutics, several unresolved issues have come to light, including the assessment of safety and efficacy of current therapies, study design for new agents and cost-benefit issues. During an international meeting of leading rheumatologists and specialists, the majority opinion regarding the use of anti-TNF therapy was that these agents are most appropriate in patients with active disease who have insufficient response to methotrexate, which is presently considered the standard for RA treatment. Anti-TNF therapy was also recommended in patients with active disease unable to tolerate methotrexate therapy, or who have not responded to at least two other disease-modifying anti-rheumatic drugs (DMARDs). In patients with RA who have serious infection or malignancy, the use of anti-TNF therapies was not advised. Time, experience and clinical data from recently completed and currently ongoing studies of infliximab and etanercept, which will be available in the future, will help determine the ultimate role of such targeted therapeutics. Additional data on anti-TNF therapeutics as monotherapy or in various combinations are still needed to achieve maximum disease control safely with currently available DMARDs.     

von Willebrand's disease and menorrhagia: prevalence, diagnosis, and management

The reported prevalence of von Willebrand's disease (vWD) is increased in women with menorrhagia, with current estimates ranging from 5% to 20%. The consistent results of multiple studies suggest testing should be included in the evaluation of patients with menorrhagia, especially in unexplained cases and prior to surgical intervention. Although a cyclic variation in von Willebrand's factor levels has not been confirmed, several studies suggest lower levels during menses and the early follicular phase. Menorrhagia is one of the most common bleeding manifestations of von Willebrand's disease, reported by 60-95% of women afflicted with this bleeding disorder. Menorrhagia is typically severe, often resulting in anemia and interfering with quality of life. Despite the frequency of menorrhagia, there is no consensus on optimal management. Although oral contraceptives are frequently prescribed, there are no studies confirming their efficacy using objective measures of response. Desmopressin was associated with an 80-92% response rate in several uncontrolled studies relying on patient assessment of efficacy. However, a small, randomized trial found no significant reduction in menstrual blood flow compared with placebo. There are anecdotal reports of the successful use of antifibrinolytic agents alone and in combination with other therapies. There are no studies comparing the relative efficacy and safety of the available medical therapies for von Willebrand's disease associated menorrhagia. Until these studies are completed, treatment should be individualized based on von Willebrand's disease subtype, patient age, contraceptive needs, and personal preference.     

New immunological approaches and cytokine targets in asthma and allergy.

The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.     

Osteoporosis

Osteoporosis is the most common metabolic bone disease (>70 million cases worldwide) and an increasing cause of morbidity and mortality throughout the world. Over the past 10 yr, the understanding of bone physiology and remodeling and the pathophysiology of osteoporosis expanded dramatically. Paralleling these discoveries has been the development of new drugs for the management of osteoporosis with demonstrated efficacy in improving bone mineral density (BMD) and reducing fracture risk. Despite the availability of several Food and Drug Administration-approved agents with demonstrated efficacy and safety, osteoporosis remains a significant clinical problem. Many patients cannot take or tolerate currently available the rapies, and some patients do not adequately respond to treatment. Additionally, no existing therapy can completely eliminate fracture risk. Therefore, research continues to seek more effective and better-tolerated agents. In addition to agents that target unique aspects of bone resorption and bone formation, there are also drugs nearing approaval that that target multiple areas of the bone remodeling cycle and utilize unique dosage forms potentially maximizing efficacy, safety, and adherence. This article reviews bone remodeling, the pathophysiology of osteoporosis, and drug development in osteoporosis. Select agents with novel mechanisms of action or innovative dosing that are in or nearing human clinical trials are discussed, including cathepsin K inhibitors, nitrosylated nonsteroidal anti-inflammatory drugs (NO-NSAIDs), receptor activator of nuclear factor (NF)-KB ligand (RANKL) inhibitor (AMG 162), recombinant complex of insulin-like growth factor-I and insulin-like growth factor binding protein-3 (SomatoKine^®), α_vβ₃-integrin receptor antagonists, and prote in tyrosine kinase Src inhibitors.     

Bringing Attention to Lesser-known Bone Remodeling Pathways

Osteoporosis, a disease of low bone mass, places individuals at enhanced risk for fracture, disability, and death. In the USA, hospitalizations for osteoporotic fractures exceed those for heart attack, stroke, and breast cancer and, by 2025, the number of fractures due to osteoporosis is expected to rise to nearly three million in the USA alone. Pharmacological treatments for osteoporosis are aimed at stabilizing or increasing bone mass. However, there are significant drawbacks to current pharmacological options, particularly for long-term management of this chronic condition. Moreover, the drug development pipeline is relatively bereft of new strategies. Consequently, there is an urgent and unmet need for developing new strategies and targets for treating osteoporosis. Casual observation led us to hypothesize that much of the bone remodeling research literature focused on relatively few molecular pathways. This led us to perform bibliometric analyses to determine the relative popularity of bone remodeling pathways in publications and US National Institutes of Health funding of the last 10 years. In this review article, we discuss these findings and highlight several less-examined signaling pathways that may hold promise for future therapies.