Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women

Postmenopausal osteoporosis is a common clinical entity; its complications represent a significant burden to society. In recent years the choice of therapies available for the treatment of postmenopausal osteoporosis has increased dramatically. There are a number of antiresorptive agents currently available including hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), bisphosphonates, and dual action bone agents. It is difficult to truly compare these therapies given the lack of direct head-to head studies. The efficacy of antiresorptive therapies can be assessed in a number of ways including measurement of bone mineral density (BMD), assessment of bone turnover markers, and fracture reduction. Other important factors include ease of administration and consequent patient compliance. This article reviews the currently available antiresorptive agents and their effects on the above outcome measures.     

Antiresorptive therapies for osteoporosis: a clinical overview

Antiresorptive therapies are used to increase bone strength in individuals with osteoporosis and include five principal classes of agents: bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin and monoclonal antibodies such as denosumab. However, no head-to-head studies have compared different antiresorptive agents using fracture as an end point. Bisphosphonates, which have proven antifracture efficacy and a good safety profile, are the most widely used first-line antiresorptive therapy and are recommended for patients with osteoporosis, a prior fragility fracture or osteopenia, as well as individuals with a high risk of fracture. Denosumab, which also has good antifracture efficacy, is another possible first-line therapy, although long-term safety data are lacking. However, no single antiresorptive therapy is currently appropriate for all patients or clearly superior to other therapies. Antiresorptive agents such as estrogens, SERMs (in postmenopausal women) and calcitonin are considered to be second-line agents that are appropriate in special circumstances. Clinicians should determine the most appropriate pharmacological therapy after a careful assessment of the risk:benefit profiles of these drugs in each patient. In addition, patients should receive a detailed explanation of the treatment goals, so that the therapeutic benefit can be maximized through good compliance and persistence.     

Effects of anticatabolic and anabolic therapies at the tissue level

The recent decade has seen the emergence of a wide variety of new effective therapies for osteoporosis. Although hormone replacement therapy and calcium supplementation were the only available therapies 20 yr ago, we now have a wide variety of anticatabolic (antiresorptive) therapies (bisphosphonates, calcitonin, selective estrogen receptor modulators [SERMs]) and anabolic therapies in the form of recombinant parathyroid hormone [PTH(1–34) and PTH(1–84)] approved and commercially available. Our initial perceptions around these therapies were quite primitive, being mainly based on bone mineral density measurements. However, recent progress in imaging technology and structural and histological evaluation of bone has yielded important new insights into the mechanism of action of the various treatments. This article summarizes current knowledge about both anticatabolic and the more recent anabolic therapies, with special emphasis on the results obtained from histological and structural analyses of bone biopsies. The evidence currently available indicates that anticatabolic therapies exert their significant antifracture efficacy through a pronounced reduction of bone turnover. This reduction in remodeling activity causes preservation of trabecular structure and a decrease in cortical porosity, both effects that will preserve bone biomechanical strength. Although anticatabolic drugs preserve bone architecture, bone-forming (anabolic) therapies, in this context exemplified by PTH, are able to reverse the deterioration of cancellous and cortical bone architecture seen during age-dependent bone loss and osteoporosis. Recent analyses using techniques enabling analysis of bone matrix constituents suggest that both anticatabolic and anabolic therapies also alter the properties of bone tissue components like mineralization and collagen crosslinking.     

Integrating novel systemic therapies for the treatment of mycosis fungoides and Sézary syndrome

Novel systemic therapies are generally prescribed to patients with advanced-stage disease or those with early-stage disease refractory to skin-directed therapies. In general, systemic chemotherapy should be reserved for patients who fail to respond to biological agents. Such biological agents include interferon alfa, bexarotene, histone deacetylase inhibitors (vorinostat, romidepsin), brentuximab vedotin and mogamulizumab. Extracorporeal photopheresis is particularly effective for patients with Sézary Syndrome. Allogeneic transplantation is becoming increasing used for younger patients. Novel agents in advanced development include the monoclonal antibody IPH4102,duvelisib,and the new modified formulation of denileukin diftitox. The choice of agents for patients is typically a balance of patient factors (age, co-morbidities, geographic location), relative efficacy and toxicity.     

Emerging therapies for osteoporosis

This article reviews the conceptual framework for agents that are antiresorptive or anabolic, including pathways that affect bone formation and resorption, and the steps in those pathways that are targets for new therapeutic agents. This article discusses novel antiresorptive and anabolic agents in development. Recent developments that link bone remodeling with serotonin in the gastrointestinal system and the central nervous system via the sympathetic nervous system may change the paradigm for skeletal remodeling. Novel anabolic agents in development include antibodies that target molecules involved in Wnt signaling.     

New anabolic therapies in osteoporosis

While antiresorptive drugs have been the cornerstone of osteoporosis therapy, anabolic drugs are an important new advance in the treatment of osteoporosis. By directly stimulating bone formation, anabolic agents might have greater potential than the antiresorptives to increase bone mass and to decrease fractures. It is also possible that the combination of an antiresorptive agent with an anabolic agent could be more potent than either agent alone. Potential anabolic therapies for osteoporosis, including fluoride, growth hormone, insulin-like growth factor-I, strontium, and parathyroid hormone, are reviewed here. Of these, parathyroid hormone has clearly emerged as the most promising treatment at this time.     

Emerging therapies in osteoporosis

The approval of alendronate in 1994 marked a watershed in the treatment of osteoporosis. Before that time there was no therapy for which unequivocal proof of efficacy existed. Since then several more agents, all from the anti-resorptive class, have also been approved for use in the treatment of this disease and the range of indications for alendronate has been extended to include the prevention of osteoporosis in women with lesser degrees of bone loss, the treatment of glucocorticoid-induced osteoporosis and, most recently, the treatment of male osteoporosis. Despite this there are still several areas of unmet medical need in this disease, including the availability of well tolerated and convenient therapies and treatments that will go beyond the levels of efficacy offered by current therapies. An intense effort is now being directed towards meeting these unmet needs with the improvement of existing therapies and the development of novel agents that will provide superior long term benefit. Important and exciting drug targets are yielding novel compounds with anti-resorptive activity or anabolic effects to complement current anti-resorptives. Despite this effort considerable obstacles to the successful development of these compounds remain, not least the stringent safety requirements needed to provide an acceptable risk-to-benefit profile and the increasing difficulties of conducting placebo controlled studies in patients at high risk of fracture.     

New anabolic therapies in osteoporosis.

Anabolic agents represent an important new advance in the therapy of osteoporosis. Their potential might be substantially greater than the anti-resorptives. Because the anti-resorptives and anabolic agents work by completely distinct mechanisms of action, it is possible that the combination of agents could be significantly more potent than either agent alone. Recent evidence suggests that a plateau in BMD might occur after prolonged exposure to PTH. Anti-resorptive therapy during or after anabolic therapy might prevent this skeletal adaptation. Protocols to consider anabolic agents as intermittent recycling therapy would be of interest. Of all the anabolics, PTH is the most promising. However, there are unanswered questions about PTH. More studies are needed to document an anabolic effect on cortical bone. More large-scale studies are needed to further determine the reduction in nonvertebral fractures with PTH, especially at the hip. In the future, PTH is likely to be modified for easier and more targeted delivery. Oral or transdermal delivery systems may become available. Recently, Gowen et al have described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH. This approach could represent a novel endogenous delivery system for intermittent PTH administration. Rising expectations that anabolic therapies for osteoporosis will soon play a major role in treating this disease are likely to fuel further studies and the development of even more novel approaches to therapy.     

Proposed therapies in primary biliary cholangitis

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.     

Targeted therapies in myelodysplastic syndrome

Therapeutic alternatives for patients with myelodysplastic syndrome (MDS) have expanded in recent years but remain limited. While agents approved by the US Food and Drug Administration (FDA), including azacitidine, decitabine, and lenalidomide, have yielded hematologic and cytogenetic responses in a substantial portion of patients, these therapies are not curative. Active investigation of novel targets with biological relevance in myelopoiesis has stimulated the pharmacologic development of a multitude of agents that show promise in the treatment of MDS. Many of these drugs have entered or completed early phase clinical testing in MDS and include immunomodulatory agents, immunosuppressive therapies, survival signal inhibitors, thrombopoiesis-stimulating agents, pharmacologic differentiators, and anti-angiogenic and apoptotic agents. As we continue to collect clinical experience with these agents, the repertoire of available therapeutics for the treatment of MDS will expand and provide a foundation for novel therapeutic combinations.     

Peripherally acting therapies for the treatment of irritable bowel syndrome

Gut-acting therapies are common therapies for irritable bowel syndrome (IBS). Most of these peripheral acting agents are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in treating symptoms of IBS. The clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 antagonist alosetron in the treatment of women with severe IBS with diarrhea refractory to traditional therapy.     

Evolving medical therapies for ulcerative colitis

Patients with ulcerative colitis have traditionally relied on sulfasalazine, mesalamine, and corticosteroids as the mainstay of medical therapy. Steroid-refractory, -dependent, or -intolerant patients have resorted to agents such as cyclosporine for short-term efficacy and 6-mercaptopurine or azathioprine for long-term efficacy. The next generation of evolving therapies includes many novel agents that target various aspects of the human immune response. Therapies that block the production or action of tumor necrosis factor have received much interest in inflammatory bowel disease. Treatments currently under study include interleukins, interferons, T-cell selective antibodies, molecules involved in cellular trafficking and signaling, mucosal healing or growth factors, and novel steroid agents. Other “less traditional” therapies, including probiotics, heparins, and anti–gastric ulcer remedies, challenge our understanding of the pathogenesis of ulcerative colitis and may provide further insights into future therapies.     

Update on bazedoxifene: A novel selective estrogen receptor modulator

In the elderly population, osteoporosis is a significant clinical problem leading to disability and even death. Many patients remain untreated, despite effective therapies, because of patients’ unwillingness to take current therapies or inability to tolerate the therapies. For this reason, ongoing research continues to search for more effective and tolerable osteoporosis agents. Bazedoxifene is a selective estrogen receptor modulator (SERM) currently in development for osteoporosis prevention and treatment. A new drug application (NDA) for postmenopausal osteoporosis prevention was recently submitted to the FDA. Preclinical and clinical studies with bazedoxifene demonstrate more tissue selectivity than other SERMs. In particular, bazedoxifene has minimal if any agonist activity in the uterus and is able to antagonize effects of estrogen on the uterus. Animal studies and early clinical studies suggest effects in the bone similar to other SERMs with prevention of postmenopausal bone loss. Until more data on efficacy and safety are published, however, its role in osteoporosis is unknown.     

How best to use new therapies in multiple myeloma

Advances in the molecular understanding of myeloma have led to the development of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib). When used alone, these agents have significant activity against myeloma and responses increase significantly when they are combined with additional agents including glucocorticosteroids and chemotherapeutic agents such as alkylators. There is a drive to use these novel agents in patients with newly diagnosed myeloma, where they lead to impressive response rates with increasing duration of responses. In addition, novel agents are now the mainstays of therapy for relapsed disease. In the following paper, we summarize the key observations from recent completed and ongoing studies that determined the effect of these novel therapies both in the setting of newly diagnosed myeloma and for relapsed disease. We also discuss our approach to the use of these agents in specific myeloma settings.     

New therapies for systemic lupus erythematosus

New therapies for the treatment of SLE have gained increased attention, as demonstrated by a growing number of new modalities being studied. These modalities include novel biologic agents that target specific immunologic responses and more traditional pharmaceutical agents. This article summarizes these new therapies and briefly discusses their mechanisms of action and the most recent research performed to characterize their safety and efficacy.     

New therapies for immune thrombocytopenic purpura

PURPOSE OF REVIEW: The treatment landscape of immune thrombocytopenic purpura has the potential for dramatic change in the near future as promising new agents and adaptations of older therapies enter clinical study. An update on the status of current research in immune thrombocytopenic purpura and a preview of agents in development are provided here. RECENT FINDINGS: The recent literature shows a multitude of strategies employed in the treatment of immune thrombocytopenic purpura. These therapies under active investigation include the use of the B-cell-depleting monoclonal antibody rituximab, higher doses of dexamethasone and anti-D immunoglobulin, and thrombopoiesis-stimulating agents that are in early clinical development. SUMMARY: Clinical investigation of novel therapies in immune thrombocytopenic purpura is undergoing a revolution that has the potential to change the standard of care. While older therapies are experiencing a rebirth by being given a new spin, newer agents such as thrombopoietins are showing significant promise.     

Promising biological therapies for ulcerative colitis: A review of the literature

Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.     

Monoclonal antibodies and other biologic therapies

The treatment of systemic lupus erythematosus (SLE) presents a significant therapeutic challenge: multi-organ involvement and a variable disease course characterized by clinical exacerbations and remissions make it difficult to predict outcome. Few products have been specifically developed in this clinical indication and most accepted therapies have not been tested in randomized controlled trials in SLE. A variety of biologic agents under investigation as potential treatments for SLE are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. These include therapies to downregulate IL-10 and/or upregulate TGFb production. Agents which interfere with T cell activation and T cell-B cell collaboration, such as CTLA4-Ig and anti-CD40 ligand monoclonal antibodies, may result in long term therapeutic benefit; alone or in combination, even following brief treatment courses. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation may prevent immune complex deposition and amerliorate organ-specific manifestations such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation. As these agents enter clinical trials, efforts to develop international consensus regarding trial methodology and outcome measures will be crucial to their successful development.     

Novel therapies for chronic lymphocytic leukemia

New therapies for chronic lymphocytic leukemia (CLL) are moving away from non-specific cytotoxic to more targeted approaches. The monoclonal antibody alemtuzumab induces responses in 33% to 43% of patients with relapsed or refractory disease, with 2-5% CR. Side effects include infusional reactions as well as immunosuppressive effects. Rituximab has limited activity in relapsed refractory patients, but response rates are comparable to follicular non-Hodgkin's lymphoma in untreated patients. Other antibodies in early phases of development include anti-CD23 [IDEC-152], anti-CD22 [epratuzumab], Hu1D10 [apolizumab], and anti-CD80 [anti-B7, IDEC-114]. Other agents that are being studied include denileukin diftitox fusion protein (Ontak), and bcl-2 antisense [G3139, Genasense]. The mechanism of action of the new drugs and their role in CLL, as well as the emergence of new prognostic markers are discussed.     

Venetoclax-based therapies for acute myeloid leukemia

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.