Emerging and potential therapies for osteoporosis

Osteoporotic fractures are an important public health problem, contributing substantially to morbidity and mortality in an ageing world population and consuming considerable health resources. Currently available pharmacological therapies for prevention of fragility fractures are limited in scope, efficacy and acceptability to patients. Considerable efforts are being made to develop new, more effective treatments for osteoporosis and to refine/optimise existing therapies. These novel treatments include an expanding array of drugs that primarily inhibit osteoclastic bone resorption; oestrogenic compounds, bisphosphonates, inhibitors of receptor activator of nuclear factor-kappaB ligand signalling, cathepsin K inhibitors, c-src kinase inhibitors, integrin inhibitors and chloride channel inhibitors. The advent of intermittent para-thyroid hormone (PTH) therapy has provided proof-of-principle that osteo-blast-targeted (anabolic) agents can effectively prevent osteoporotic fractures, and is likely to be followed by the introduction of other therapies based upon PTH, such as orally active PTH analogues, antagonists of the calcium sensing receptor, PTH-related peptide analogues, and/or agents that induce osteoblast anabolism via pathways involving key, recently identified, molecular targets (wnt low-density lipoprotein receptor-related protein-5 signalling, sclerostin and matrix extracellular phosphoglycoprotein).     

Novel therapies for osteoporosis

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason research continues in search of more effective and more tolerable agents. Anabolic agents offer a unique mechanism of action. The anabolic agents parathyroid hormone and strontium will be discussed. The investigational bisphosphonates ibandronate, minodronate and zoledronic acid may offer the advantage of less frequent dosing. Arzoxifene, bazedoxifene, lasofoxifene, MDL-103,323 and ospemifene are investigational selective oestrogen receptor modulators shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. While studies of the effect of isoflavones on bone mineral density have been encouraging, a large, multi-centre study in Europe showed no effect of isoflavones on fractures. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Other agents with unique mechanisms of action in early development include cathepsin K inhibitors, integrin receptor inhibitors, nitrosylated non-steroidal anti-inflammatory agents and Src inhibitors. The efficacy of statins in bone continues to be debated with no prospective, randomised studies yet to confirm the suggestion of benefit seen in epidemiological studies.     

Novel therapies for osteoporosis

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason research continues in search of more effective and more tolerable agents. Anabolic agents offer a unique mechanism of action. The anabolic agents parathyroid hormone and strontium will be discussed. The investigational bisphosphonates ibandronate, minodronate and zoledronic acid may offer the advantage of less frequent dosing. Arzoxifene, bazedoxifene, lasofoxifene, MDL-103,323 and ospemifene are investigational selective oestrogen receptor modulators shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. While studies of the effect of isoflavones on bone mineral density have been encouraging, a large, multi-centre study in Europe showed no effect of isoflavones on fractures. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Other agents with unique mechanisms of action in early development include cathepsin K inhibitors, integrin receptor inhibitors, nitrosylated non-steroidal anti-inflammatory agents and Src inhibitors. The efficacy of statins in bone continues to be debated with no prospective, randomised studies yet to confirm the suggestion of benefit seen in epidemiological studies.     

Emerging drugs for osteoporosis

Introduction: Osteoporotic fracture is a cause of pain, loss of autonomy and excess mortality. Current drugs however, do not allow for a satisfactory non vertebral fracture risk reduction and the compliance is suboptimal.

Areas covered: Current treatments consist of mainly bisphosphonates, denosumabs, selective estrogen receptor modulators and teriparatides. All drugs currently in development will target some aspect of bone remodeling by using the recent advances in our knowledge of bone biology: cathepsin-K inhibitors (odanacatib) are antiresorptive, antisclerostin monoclonal antibodies (romosozumab and blosozumab) are anabolic agents and PTHrp 1-34 (abaloparatide) is an anabolic agent.

Expert opinion: New drugs with better tolerance and ideally with intermittent administration may improve their compliance. New drugs will have to provide higher efficiency levels with regards to reducing the risk of fractures. They may be second-line options, targeted at patients who are poor responders, or those who display contraindications to the older drugs, as a result of cost issues. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after an initial severe fracture such as a hip fracture or a clinical vertebral fracture.     

Emerging therapies for neuropathic pain

Neuropathic pain develops as a result of damage to either the peripheral or central nervous system. It is characterised by spontaneous burning pain and/or ongoing pain with accompanying hyperalgesia and allodynia. Neuropathic pain is difficult to treat as it is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief. At present, there are four major medication categories that are considered first-line treatment for neuropathic pain: antidepressants, anticonvulsants, local anaesthetic/topical agents and opioids. The efficacy of these treatments in neuropathic pain, excepting opioids, has been discovered serendipitously. However, responder rates and overall efficacy is poor with these agents and tolerability or side effects are often limiting. This update will review existing treatment options for neuropathic pain, and highlight more recent advances in the development of novel analgesics to treat this chronic disorder.     

Emerging targeted therapies for glioma

Introduction: Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted.

Areas covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development. Our knowledge regarding these pathways are most relevant to Grade IV glioma/glioblastoma, but we will also discuss genomic categorization of low grade glioma. Further, drugs targeting single pathways, which have undergone early phase clinical trials will be reviewed, followed by an in depth discussion of emerging treatments on the horizon, which will include inhibitors of Epidermal Growth Factor Receptor (EGFR) and receptor tyrosine kinases, Phosphoinositide-3-Kinase (PI3K), angiogenesis, cell cycle and mutant Isocitrate Dehydrogenase (IDH) mutations.

Expert opinion: Results from single agent targeted therapy trials have been modest. Lack of efficacy may stem from a combination of poor blood brain barrier penetration, the genetically heterogeneous make-up of the tumors and the emergence of resistance mechanisms. These factors can be overcome by rational drug design that capitalizes on ways to target critical pathways and limits upregulation of redundant pathways.     

Emerging therapies for neuropathic pain

Neuropathic pain develops as a result of damage to either the peripheral or central nervous system. It is characterised by spontaneous burning pain and/or ongoing pain with accompanying hyperalgesia and allodynia. Neuropathic pain is difficult to treat as it is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief. At present, there are four major medication categories that are considered first-line treatment for neuropathic pain: antidepressants, anticonvulsants, local anaesthetic/topical agents and opioids. The efficacy of these treatments in neuropathic pain, excepting opioids, has been discovered serendipitously. However, responder rates and overall efficacy is poor with these agents and tolerability or side effects are often limiting. This update will review existing treatment options for neuropathic pain, and highlight more recent advances in the development of novel analgesics to treat this chronic disorder.     

Emerging therapies for colorectal cancer

Colorectal carcinoma is a leading cause of cancer mortality worldwide. Survival for patients with metastatic disease is approximately 2 years on average and there is an ongoing need for the identification of new therapeutic agents. As the cancer research community has appreciated, newly discovered pathways governing cancer cell growth, survival, apoptosis, invasion and angiogenesis--all a host of potential therapeutic targets--have come into view. Basic research, preclinical data and observations arising from early stage trials have pointed towards possible roles for many of these agents in the future treatment of colorectal cancer. In this review, the authors summarize agents in development, modulating several of the most promising molecules and pathways that are thought to be relevant to colorectal cancer.     

Emerging therapies for heart failure

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.     

Emerging therapies for colorectal cancer

Colorectal carcinoma is a leading cause of cancer mortality worldwide. Survival for patients with metastatic disease is ～ 2 years on average and there is an ongoing need for the identification of new therapeutic agents. As the cancer research community has appreciated, newly discovered pathways governing cancer cell growth, survival, apoptosis, invasion and angiogenesis – all a host of potential therapeutic targets – have come into view. Basic research, preclinical data and observations arising from early stage trials have pointed towards possible roles for many of these agents in the future treatment of colorectal cancer. In this review, the authors summarize agents in development, modulating several of the most promising molecules and pathways that are thought to be relevant to colorectal cancer.     

Investigational anabolic therapies for osteoporosis

Importance of the field: Anabolic therapy, or stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis.

Areas covered in this review: We reviewed bone anabolic agents currently under active investigation. The bone anabolic potential of IGF-I and parathyroid hormone-related protein is discussed in the light of animal data and human studies. We also discuss the use of antagonists of the calcium-sensing receptor (calcilytics) as orally administered small molecules capable of transiently elevating serum parathyroid hormone (PTH). Further, we reviewed novel anabolic agents targeting members of the wingless tail (Wnt) signaling family that regulate bone formation including DKK-1, sclerostin, Thp1, and glycogen synthase kinase 3β. We have also followed up on the promise shown by β-blockers in modulating the activity of sympathetic nervous system, thus affecting bone anabolism. We give critical consideration to neutralizing the activity of activin A, a negative regulator of bone mass by soluble activin receptor IIA, as a strategy to promote bone formation.

What the reader will gain: Update on various strategies to promote osteoblast function currently under evaluation.

Take home message: In spite of favorable results in experimental models, none of these strategies has yet achieved the ultimate goal of providing an alternative to injectable PTH, the sole anabolic therapy in clinical use.     

Emerging therapies for multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM.     

Emerging pharmacological therapies for fibromyalgia

Fibromyalgia is a chronic pain disorder for which pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness and significant tolerability. To date, no drugs have been officially approved for the indication of fibromyalgia, and randomized, controlled clinical trials with fibromyalgia patients are taking place to identify potential therapeutic approaches. Although emerging therapies, such as the antidepressants duloxetine and milnacipran and the antiepileptic pregabalin, offer certain efficacy, randomized controlled trials are generally difficult due to factors such as a lack of understanding of the pathophysiology and a heterogenous fibromyalgia patient population. For a significant advance in the drug treatment of fibromyalgia, novel clues are still awaited that may offer an effective therapeutic approach.     

Emerging therapies for graft-versus-host disease

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: (i) recipient conditioning, (ii) donor T cell activation, and (iii) effector cells mediating GVHD. Standard agents and agents under development to prevent and treat GVHD are discussed. The various pharmacological agents impact on different phases of the GVHD cascade. Sirolimus is a new immunophilin binding agent that appears to be synergistic with tacrolimus and cyclosporin. It also seems to promote allograft tolerance. Mycophenolate mofetil (MMF) is an antimetabolite that is currently under study for prophylaxis and treatment of acute and chronic GVHD; results are encouraging. Other agents such as the purine analogue pentostatin and the monoclonal antibodies alemtuzumab, daclizumab and infliximab are discussed at length within the GVHD context. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for the treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Emerging therapies for respiratory diseases

This Society for Medicines Research symposium, sponsored by UCB, was held on September 11, 2007, at the Wellcome Trust Conference Centre, Hinxton, Cambridge, United Kingdom. The meeting, organized by Ruth Lock, Steve Collingwood and Andrew Ratcliffe, reviewed current thinking in the area of airway drug delivery and the challenges and progress made in the discovery and development of novel medicines to treat respiratory diseases, such as chronic obstructive pulmonary disease, asthma, allergic rhinitis and cystic fibrosis.     

Emerging drugs for postmenopausal osteoporosis

Postmenopausal osteoporosis (PMO) is a common skeletal disease with serious consequences due to fractures, including increased risk of disability and death. The risk of fractures can be reduced with medications that are currently available; however, these drugs are frequently not prescribed due to failure to recognize that a patient is at high risk for fracture; fear of adverse drug effects; or, sometimes, high cost. When these drugs are prescribed, long-term adherence to therapy is poor. Efforts to improve the clinical effectiveness of pharmacological therapies have included lengthening the interval between doses, simplifying drug administration, and manipulating the molecular structure of drugs in existing therapeutic classes. Recent improvement in understanding the pathophysiology of PMO at the molecular level has fostered the development of new therapeutic agents with novel mechanisms of action. This is a review of the data on the efficacy and safety of emerging drugs for the treatment of PMO, including agents with novel mechanisms of action (denosumab, odanacatib, antibody to sclerostin), new estrogen agonists/antagonists (lasofoxifene, bazedoxifene, arzoxifene), new delivery systems for existing drugs (salmon calcitonin, teriparatide), and drug combinations given concurrently, sequentially, or cyclically. These new therapeutic agents, new delivery systems, and new methods of combining drugs may ultimately reduce the great personal and economic burden of osteoporotic fractures.     

Emerging therapies for pulmonary arterial hypertension

Pulmonary arterial hypertension is characterised by increased pulmonary vascular resistance due to increased vascular tone and structural remodelling of pulmonary vessels. The therapies that are in use so far have been developed to correct endothelial dysfunction and reduce vasomotor tone. These treatments have a limited effect on the remodelling process and, increasingly, the focus is turning to potent strategies for inhibiting vascular proliferation and promoting vascular apoptosis. Multiple novel targets have been uncovered over the last 5 years and several are now in early clinical trials. At present, it is clear that there is no single treatment for the condition. Although this is the case, studies are investigating the role of combining therapies that are already established.     

Emerging therapies for female sexual dysfunction

Epidemiological studies in the US, the UK and Sweden indicate that approximately 40% of women aged 18 - 59 have significant complaints about their sexual lives. The majority of complaints concern low sexual desire. Other common problems include difficulty reaching orgasm, insufficient lubrication and painful coitus. A vacuum erection device which increases blood flow to the clitoris has been approved by the US Food and Drug Administration. There are no pharmacological agents with approval for the treatment of female sexual dysfunction. Phosphodiesterase inhibitors and other drugs which cause genital vasocongestion in women appear to have minimal clinical efficacy. Although many of these agents increase the vasocongestive response to sexual stimulation, there is minimal correlation between subjective and objective measures of sexual arousal in women. Trials with androgens have clearly and convincingly demonstrated that supraphysiological doses of testosterone increase libido in postmenopausal women. The long-term safety of such doses is unclear. To date, no studies have shown lower doses of androgens to be beneficial. There have been minimal studies of drugs targeting the central nervous system to date. Bupropion may have a beneficial effect on orgasm attainment in women with hypoactive sexual desire disorder.