Summarized mechanisms of bone senescence.
\r\n\tGlobalization does not represent a pure and generous process for humanity or other species, but rather it implies social exclusion and also provokes situations of vulnerability in groups of people, forced exclusion, and apartheid: poor job opportunities, lack of access to education, worse socio-sanitary conditions. Specifically, it can be said that social segregation entails the apartheid of social groups of different ages, genders, and ethnicities; these groups live a reality manifested through the deepening of poverty, in terms of increased vulnerability of the poor and groups with little economic, social, cultural, labor and health stability.
\r\n\r\n\tThis book aims to talk about some topics that are neglected in the discourses of academic communities and political elites. The inequality process is deeply rooted among humans and is part of many people's lives in the form of modern apartheid, gender segregation, lack of health access, and cultural gap. All those structural inequality processes are the product of the biopower perpetuated and produced in the macrosystem, exosystem, mesosystem, and microsystem. For many people from the academy, the information-consuming public, and the society in general, it is a problem to talk about these processes, since they have either lost interest or have normalized the structural and social inequity. For this reason, we see it as transcendental to explain how this situation occurs from the most internal fibers to the most evident processes, intending to make it more visible and thus expose the situation for possible solutions.
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Tsvetkov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"79828",title:"Cellular Senescence in Bone",doi:"10.5772/intechopen.101803",slug:"cellular-senescence-in-bone",body:'Aging is an inevitable physiological condition that comes with organ and tissue function impairment. It is the most significant risk factor for developing chronic diseases, including cancer, cardiovascular disease, metabolic dysfunction, osteoarthritis, and osteoporosis. Osteoporosis originated from the Greek word for porous bones, is one of the most common metabolic diseases. Associated with advancing chronological age, it affects more than 200 million patients worldwide and increases morbidity, mortality, and creates a significant burden of economic expenditures [1, 2]. Given that the population segment with the most rapid growth is the elderly in many countries, osteoporosis could present a global challenge impacting affected individuals’ health quality and life span. Characteristics of aging bone are low bone mineral density and deterioration of bone architecture, producing weakened bone prone to fractures. Thus, osteoporosis presents severe global health concerns, disposing to over 9 million fractures every year [3]. Senescent cells play a crucial role in aging bone; therefore, it is essential to understand the cellular and molecular mechanisms to develop treatments to prevent age-related diseases and maximize a healthy life span. This chapter provides a comprehensive treatise of senescence in bone and emerging therapeutic approaches to treatment.
The skeletal system is one of the most complex structures in mammals and is essential for storing and maintaining the homeostasis of the body’s minerals. Composed of various bones, cartilages, ligaments, tendons, and other tissues, it provides the framework for the body, supports locomotion, and protects vital organs such as the brain and bone marrow. It is commonly thought that the metabolic functions are carried out primarily by trabecular bone and the mechanical functions mainly by cortical bone. Bone, specifically, is a complex tissue that exhibits four types of cells: osteoclasts, bone lining cells, osteocytes, and osteoblasts. In addition, it houses bone marrow and serves as the main reservoir for the body’s calcium and phosphate.
Bone is a highly dynamic tissue that adapts to change and is constantly shifting throughout life. The most rapid rate of bone modeling occurs during childhood and adolescence, where bones are architecturally modified to support skeletal functions. Moreover, human skeletal tissue is in a constant state of remodeling throughout life [4]. A retained net bone mass is needed for homeostasis.
Discovered more than five decades ago by Hayflick and Moorhead [5], cellular senescence has played a significant role in our understanding and advancement in science. By definition, cellular senescence is a permanent state of cell cycle arrest characterized by specific phenotypic changes [6]. Characteristics include distinct cellular morphological alterations, gene expression, chromatin structure, cell signaling, and the senescence-associated secretory phenotype (SASP). Cellular senescence is found in bone and promotes age-related diseases such as osteoporosis [7]. In addition, senescent cells damage bone remodeling by impairing bone formation and osteoblast progenitor cell function, thus promoting osteoclastogenesis [8]. This is triggered by various stressors, including oxidative stress, genomic instability, and telomere shortening (replicative senescence). Telomeres protect chromatins and help maintain replication and genome stability.
The various physiological and pathological processes such as remodeling, aging, and injury can cause cells to become senescent. With aging, more cells become senescent and accumulate in tissues, including bones. A prominent characteristic of cell senescence is the SASPs, which are proinflammatory proteins that are primary contributors to their disease-inducing properties. Cyclin-dependent kinase inhibitors (CDKis) such as p16, p21, p27, the release of cytokines, chemokines, and soluble factors, causes this impaired microenvironment known as SASP. The SASP increases proinflammatory factors and upregulates NF-κB, contributing to aging bone disease [9].
As a hallmark of aging, it is essential to understand cellular senescence to effectively identify novel drugs to treat osteoporosis. Moreover, targeting cellular senescence has emerged as a therapeutic target for preventing or treating age-related diseases. Clearing these cells in mouse models has delayed tissue and organ dysfunctions [10]. In addition, senescence has been shown to have antiproliferative effects, a fundamental key to identifying novel drugs to treat osteoporosis.
Bone loss is a part of the natural aging process in both men and women [11]. Developmental, genetic, and lifestyle factors (lack of physical activity, injuries, medication use, smoking, poor diet) contribute to bone fragility in older people. The skeletal system goes through progressive bone loss, where changes in bone quality and quantity will occur. An accumulation of weakened skeletal bone may result in osteoporosis. Advancing chronological age is one of the significant risk factors for osteoporosis [12]. Characteristics of aging bone include low bone mineral density and weakened bone architecture, significantly increasing the risk of fractures for affected individuals (Figure 1).
Pathogenesis of osteoporosis. Aging and various environmental exposures can induce DNA damage and instability, oxidative stress, telomere attrition, dysfunction at the molecular level, and cell cycle arrest and senescence at the cellular level. These will break the remodeling process of bone formation and resorption, decrease bone mineral density, and progress to osteoporosis.
Throughout life, old bone is replaced by new bone, a process termed bone remodeling. This continuous cycle is necessary for fracture healing and adaptation to mechanical strains such as exercise. Bone regeneration occurs within bone cavities to target and replaces bone with accumulated microfracture fatigue.
On a cellular level, the well-balanced actions of three main specialized cell types, osteoclasts, osteoblasts, and osteocytes, regulate bone homeostasis [4]. Osteoclasts resorb damaged bone, and osteoblasts subsequently refill the resorbed area with an equal amount of new bone matrix. Osteocytes are mechanosensory cells that act as the central coordinators of this balanced process in transmitting signals needed to sustain mechanical loads [13, 14]. Disruption among the actions of this repertoire can turn to bone pathological conditions such as osteoporosis and rheumatoid arthritis. On a subcellular level, the bone matrix is changed by rearrangement of trabecular struts, changes in calcium deposition, subperiosteal expansion, and enlargement of the medullary cavity. Unrepaired micro-damaged bone reduces bone health, resulting in the mechanical failure of the tissue (fracture). The remodeling process is the same in cortical and trabecular bone.
Under normal physiological conditions, the amount of bone resorbed and replaced is equal, maintaining the bone mass. This process relies on having an adequate supply of osteoblasts, which comes from the generation of stimulatory signals for osteoblast formation produced by osteoclasts and osteocytes released during resorption [15]. Osteocytes regulate this fundamental bone regeneration process by sending signals to osteoclasts and osteoblasts to control their actions [16]. Furthermore, there is an association between lower osteocyte density in human central cancellous bone and increased surface remodeling [17], an independent contributor to bone fragility [18]. Therefore, a primary strategy in finding therapeutic targets to treat osteoporosis involves targeting osteoclasts [19].
Several molecular mechanisms concur to regulate osteoblast/osteoclast/osteocyte activity. The main one involves the receptor activator of nuclear factor-kappa-Β ligand (RANKL) of tumor necrosis factor (TNF) superfamily ligand 11 (TNFSF11) [20]. This cytokine is expressed on the surface of osteoblasts and osteocytes. On the membrane of osteoclast precursors and mature osteoclasts, RANKL binds to its receptor RANK, a ligand-receptor binding process termed the critical paracrine system, regulating osteoclast function. This process can be inhibited by osteoprotegerin (OPG), a decoy of RANKL produced by osteoblasts and osteocytes.
Moreover, osteocytes regulate bone formation by secreting modulators of the wingless-type mouse mammary tumor virus [MMTV] integration site members (Wnt) signaling pathways. These include activators nitric oxide and ATP, inhibitors sclerostin SOST, as well as dickkopf-related protein 1 (DKK1)). Wnts modulate cell proliferation, differentiation, and stem cell remodeling [21]. Previous studies have found that the activation of Wnts impacts osteoblasts and osteoblast lineages by increasing quantities and enhancing the functionality of osteoblasts [22]. Recently, studies were done in vivo to test whether the Fzd-Lrp receptor with Wnt mimetics can activate Wnt/β-catenin signaling and promote rapid bone growth [23]. It was found that within 2 weeks after treatment with selected Wnt mimetics, bone mineral density and vertebral cortical and trabecular bone growth increased significantly [23]. This could provide a therapeutic therapy used to target bone diseases such as osteoporosis.
However, with aging, the bone remodeling process is affected. Osteoporosis occurs when bone metabolism is perturbed. In addition, chronic diseases such as estrogen deficiency, malignant disease, and chronic inflammation also cause the uncoupling of osteoclasts and osteoblasts [24, 25]. As a result, less new bone is formed relative to the resorption of old bone, ending in a net bone loss. The cortical and trabecular thinning thereby leads to an overall bone loss and fragility. Thus, bone remodeling causes a drastic loss of bone mass and strength over prolonged periods, eventually osteoporosis.
The process of senescence in bone begins after peak bone mass is reached. This is generally during the third decade of life but varies between sexes. Estrogens and androgens are hormones that play crucial roles in skeletal homeostasis during growth and adulthood.
Estrogen is the primary hormonal regulator of bone metabolism, inhibiting osteoblast and osteocyte apoptosis [26, 27]. Therefore, a decrease in androgen and estrogen levels negatively affects bone remodeling by causing the uncoupling of osteoclasts and osteoblasts [28]. Hormonal withdrawal also contributes to mineral disturbances with calcium absorption [29].
The association between a decline of estrogen levels in postmenopausal women and the onset of osteoporosis was first noted by Fuller Albright in 1940. Since then, estrogen deficiency has become the primary cause of bone loss in older women [11]. An accelerated decrease occurs in the perimenopausal period when there is rapid bone remodeling. As a result, women experience the loss of whole trabecular components and combined with a negative remodeling balance, the bone loses mass and strength. In addition, estrogen levels affect T cells by increasing tumor necrosis factor secretion, promoting RANKL-induced osteoclastogenesis [30]. In men, a loss of both estrogens and androgens is associated with a loss of bone mass and the development of osteoporosis [31]. Small increases in estrogen levels can improve bone health without some of the adverse effects of conventional-dose estrogen therapy [32]. Sex steroids can regulate osteoclastogenesis and the survival of osteoclasts [33].
Cellular senescence has been identified as a response to multiple stressors. Common denominators of aging include telomere attrition, genotoxic agents, oxidative stress, chromosome instability, and oncogene activation. Skeletal involution results from the accumulation of poor nutrition, immobility, and the effects of treatments, all of which often come with old age. Mediated with bone remodeling, the progressive and cumulative pathologies of these factors contribute to the pathogenesis of osteoporosis.
Bone homeostasis is a balanced equilibrium between osteoblast and osteoclast activities. In senescent cell microenvironments, osteocytes control myeloid lineage cells [34]. Therefore, the SASP can be the cause of some of the severe effects of senescent cells. With aging, more osteocytes become senescent that acquire a new phenotype. As a result, they secrete various factors, including proinflammatory cytokines, growth modulators, which collectively comprise the SASP. Regulated at epigenetic, transcriptional, and posttranscriptional levels, SASP plays a critical role in contributing to various outputs of senescence [35]. For example, SASP factors mediate developmental senescence, wound healing, and tissue plasticity. In addition, the SASPs secrete signals that are communicated and amplified by neighboring myeloid lineage cells (such as B cells, osteoblasts, and T cells), resulting in the overproduction of proinflammatory cytokines. As a result, it contributes to chronic inflammation and creates a toxic local microenvironment that contributes to age-related bone loss.
DNA damage is considered to be the root of aging-associated multimorbidity [36]. It is caused by exposure to harmful exogenous factors (such as chemical compounds in the environment, chemotherapy, and UV radiation from the sun) and endogenous factors (such as reactive oxygen species and metabolic by-products). Consequences of accumulated DNA damage happen on the cellular and molecular levels. With aging, there are impaired cell and organ functions, inflammation, and cancer [36]. On the cellular level, DNA damage induces permanent cell-cycle arrest. It molecularly triggers genome instability with chromosome aberrations and mutations. Irreparable DNA damage accumulation in tissues and organs leads to cellular senescence, one of the main driving forces of aging [37].
Telomere dysfunction is induced in response to DNA damage. About half of the DNA damage foci in senescent cells localize to telomeres. Accumulated and progressive telomere shortening is a senescence biomarker and drives the aging process, a concept first discovered in the late 1980s [38]. Telomeres are short DNA sequences found at the ends of eukaryotic chromosomes that determine cellular life span [39]. Telomeric TTAGGG repeats and compound proteins make up the ends of chromosomes or the cap. The cap protects the telomere ends from appearing as double-break strands and prevents chromosome fusion and genome degradation.
During each cell replication, DNA polymerase cannot fully replicate chromosome ends, resulting in a loss of DNA. Accumulation of DNA damage at telomeres causes uncapping. With each cell division, telomeres shorten in length, and cell proliferation is restricted [40], a phenomenon termed replicative senescence [41]. To counteract telomere shortening, a specialized ribonucleoprotein enzyme called telomerase synthesizes new telomeric DNA [42].
The result of telomere shortening is telomeric DNA loop destabilization and telomere uncapping, which produces telomere dysfunction-induced foci (TIFs). This further activates the DNA damage repair (DDR), which recognizes double-strand breaks and activates the p53/p21 and p16 pathways [43]. These factors result in the pre-senescent cells withdrawing from the cell cycle and becoming senescent, which increases with age [44]. Furthermore, through inflammatory cytokines and impaired growth signaling, DDR results in replicative senescence [43].
Oxidative stress is a potential cause of results from various diseases and an important mechanism in bone degradation. Aging causes an increase in reactive oxygen species (ROS), which results in an imbalance of ROS and antioxidant defenses. Increased reactive oxygen species influence numerous cellular processes, including the timing of death by apoptosis, and have been linked to aging and the development of age-related diseases. It can damage DNA and contribute to aging. It has been found that oxidative stress increases with age in the bone of female or male C57BL/6 mice [33]. Oxidative stress alters the bone remodeling process by disrupting osteoclast and osteoblast activity. This can result in low bone mineral density, the characteristics of osteoporosis.
DNA damage is also responsible for oncogene-induced senescence (OIS). Oncogenic stress is commonly known as a critical mechanism of cancer. Oncogene activation is genetic stress and phenotypic changes that induce senescence. With activated oncogenes, there are high levels of replication. Pathways such as the ataxia telangiectasia and Rad3-related (ATR), ataxia–telangiectasia mutated (ATM), and p53 converge with the cyclin-dependent kinase inhibitors p16, p21, and p27 and hyperphosphorylation of the retinoblastoma protein, thereby triggering withdrawal from the cell cycle [45].
Glucocorticoids are drugs used to suppress allergic, autoimmune, and inflammatory diseases. However, prolonged use of glucocorticoids can result in complications such as glucocorticoid-induced osteoporosis (GIO). Glucocorticoids cause senescence in various cell lines and have been found to stimulate the p21 gene expression. During the initial treatment, this drug increases bone resorption with an enhancement of osteoclast maturation and differentiation. However, long-term use inhibits osteoclastogenesis by promoting apoptosis of osteoblasts and osteocytes [46, 47]. Dexamethasone, a type of glucocorticoid, was found to promote cell senescence and activate parts of SASP through inhibition of osteoblast function [48]. This resulted in decreased bone formation and increased bone resorption. Other effects include suppressing insulin-like growth factor 1, which promotes bone formation and further causes collagen degradation and osteoblast apoptosis [48].
Chronic inflammatory diseases are associated with bone loss, which increases bone resorption and decreases bone formation, resulting in a bone deficit [24, 49].
The summary of the pathological factors that induce cellular senescence is provided in Table 1.
Pathological factors | Causes | Mechanisms |
---|---|---|
SASP | Aging | Chronic inflammation |
DNA damage | Aging, environmental factors | Cellular senescence |
Telomere dysfunction | DNA damage | Telomere uncapping, activates the p53/p21 and p16 pathways |
Oxidative stress / ROS | Aging | imbalance of ROS and antioxidant defenses |
Oncogene stress | DNA damage (i.e. cancer) | oncogene-induced senescence. Inhibits, osteoclastogenesis |
Glucocorticoid | Glucocorticoid drugs | stimulate the p21 gene expression, Osteoblast apoptosis |
Chronic-inflammation | Chronic-inflammatory diseases (i.e. arthritis | Increase osteoclast function, decrease osteoblast function |
Summarized mechanisms of bone senescence.
Both nonpharmacological (lifestyle factors, supplements) and pharmacological (antiresorptive and anabolic) treatments exist. The chapter also highlights the ongoing advancements of senescence research on aging-bone diseases (Figure 2).
Treatments of osteoporosis. Antiresorptive and anabolic and senolytic treatments of osteoporosis. These treatments target different pathways. Anabolic treatment options include teriparatide (A), strontium ranelate (B), and romosozumab (C). The antiresorptive treatment includes bisphosphonates (D), calcitonin (E), denosumab (F), cathepsin K inhibitors (G), and SERMs (H). With particular regard, senolytic drugs treatment includes Fisetin, Dasatinib, quercetin, and D + Q.
Optimizing lifestyle factors by diet and physical exercise is beneficial to bone health. Physical exercise and an active lifestyle have a significant impact on bone health. During the muscular activity, the mechanical forces produced are sensed by osteocytes and promote bone growth. In response to exercise, skeletal muscle also secretes myokines, which are molecules that directly affect bone metabolisms, such as irisin, myostatin, and insulin-like growth factor-1 [50]. Exercise also restores body coordination and balance, decreasing the risk of falls, especially among older people. On the other hand, limited physical movement and muscle atrophy with old age result in osteoporosis [51].
In addition, an increase in nutrient intake, specifically vitamin D, protein, calcium, and vitamin K2, will slow osteoporotic regression. Vitamin D has a critical role in regulating calcium homeostasis and bone metabolism. In addition, calcium and vitamin D can suppress serum levels of parathyroid hormones and stimulate bone growth, making them have an antiresorptive effect. The daily calcium intake recommendation is between 800 and 1200 mg, and vitamin D intake is 800 IU per day for men and women over 50 [52].
Vitamin D insufficiency and low serum calcium levels are widespread in elderly people, contributing to lower BMD and increased bone fragility [53]. Dietary sources are the preferred option, but supplementation is beneficial, especially in elderly people. With daily calcium and vitamin D supplements, fracture risk drops significantly, making them essential in aging-bone disease treatments [54]. In most clinical studies testing the efficacy of antiresorptive and anabolic therapies, calcium and vitamin D have been used. When given together, they have been found to have been effective in preventing fractures [53, 55]. However, in most clinical cases, calcium supplementation is subsidiary to bisphosphonates or anti-RANKL drugs [56].
Nutraceuticals are substances including isolated nutrients, dietary supplements, herbal products, and medical foods. For example, higher intakes of antioxidants, phytoestrogens (plant compounds that function like estrogen agonist-antagonists), and other minerals such as phosphorus can be markers for a healthy lifestyle [57, 58]. Phosphorus is another critical factor in preventing aging-bone diseases such as osteoporosis. It is an essential nutrient for bone formation, but too much of it harms bone health [58].
Physical exercise and muscle fitness have a dramatic impact on bone health. Muscle secretes a set of molecules, known as myokines, directly affecting bone metabolisms, such as irisin, myostatin, and insulin-like growth factor-1. During activity that produces mechanical force, osteocytes sense this and convert it into bone deposition. On the contrary, disuse or muscle atrophy results in osteoporosis.
The search for armamentariums targeting metabolic bone diseases is increasing. Currently, various antiresorptive and anabolic therapies are available as treatments for osteoporosis [23]. Antiresorptive therapies are the most common pharmacological tools to prevent osteoporosis progression. These drugs inhibit osteoclast proliferation and the recruitment and differentiation of its precursors [54]. It is suggested for early menopausal women or patients with moderate osteoporosis. Anabolic therapies are another option for treatment that targets osteoblasts to stimulate bone mineralization.
In comparison to antiresorptive medications, anabolic agents reduce fracture risk more efficiently. Thus, these should be considered first-line therapy for patients at very high risk or with a history of vertebral fracture [59]. In addition, pharmaceutical medications seek to improve bone fidelity and architectural foundation for long-term skeletal health. Therefore, the search for armamentariums targeting skeletal diseases is increasing. Currently, various antiresorptive and anabolic therapies are available as treatments for osteoporosis [23].
Bone homeostasis is a balanced equilibrium between osteoblast and osteoclast activities. In senescent cell microenvironments, osteocytes control myeloid lineage cells [34]. With aging, more osteocytes become senescent that produces SASP signals. These signals are communicated and amplified by neighboring myeloid lineage cells (such as B cells, osteoblasts, and T cells), resulting in the overproduction of proinflammatory cytokines. As a result, a toxic local microenvironment is created that contributes to age-related bone loss.
The antioxidant NAC, coupled with estrogens or androgens in male and female mice, prevents a gonadectomy-induced increase in oxidative stress, bone loss, osteoblast, and osteocyte apoptosis. So, sex steroids can regulate osteoclastogenesis and the survival of osteoclasts via antioxidant actions [33].
Antiresorptive therapy is the most common pharmacological tool to prevent osteoporosis progression. These drugs inhibit osteoclasts’ proliferation and the recruitment and differentiation of their precursors [54].
Bisphosphonates (BPs) are the primary therapeutic options used to inhibit osteoclast-mediated bone resorption. These nitrogen-containing drugs have a strong affinity for bone apatite in vitro and in vivo. BPs bind to hydroxyapatite crystals on bone surfaces and inhibit the mevalonate pathway in osteoclasts, increasing apoptosis. This preferentially occurs in sites with accelerated skeletal turnover rates. BPs have been shown to increase bone mineral density (BMD), reduce bone turnover markers, and reduce the risk of osteoporotic fractures. Some drug options include alendronate, risedronate, and zoledronic acid. Currently, they are the most common and effective drugs used for osteoporosis, Paget’s disease, and inflammation-related bone loss [60].
Denosumab, an anti-RANKL antibody, is a fully human monoclonal antibody to the RANKL, which blocks its binding to RANK. The prevention of RANKL and its receptor RANK interaction thereby inhibits osteoclast differentiation [61]. Presently, denosumab is the only FDA-approved monoclonal antibody to treat osteoporosis. These antiresorptive agents have been most influential in decreasing the risk of vertebral fractures by more than 50%, nonvertebral fractures by 20–25%, and hip fractures by 40–50% [62].
Selective Estrogen Receptor Modulators (SERMs) are an alternative for estrogen and are used primarily in postmenopausal women of younger age. SERMs rely on their tissue-selective estrogen receptor agonist or antagonist activity and their interaction with the estrogen receptor. They interact with the RANKL/RANK/OPG system and downmodulate osteoclast function [63]. This process allows for the treatment of vasomotor systems and the prevention of osteoporosis [64]. Various SERMs, including raloxifene, which represents dual agonistic and antagonistic properties in estrogenic pathways, have decreased bone fragility. In postmenopausal women with low BMD, raloxifene has been shown to reduce vertebral fracture risk by 30–50% [63]. In particular, this drug is recommended for patients with a family history of breast cancer, as it has also significantly demonstrated reduced risks of breast cancer in women [29].
Calcitonin receptors are found on osteoclasts and osteoblasts and serve as regulators of osteoclast function and maturation. Calcitonin is a naturally occurring peptide hormone that binds to specific receptors primarily on the surface of osteoclasts to inhibit bone resorption activity strongly. It has been used to treat osteoporosis for many years, especially for patients with acute osteoporotic fractures and postmenopausal women [65].
Cathepsin K (CatK) is one of the most potent proteases in the lysosomal cysteine proteases family. CatK’s primary function is to mediate bone resorption, making it a strategic target for osteoporosis treatments. The only CatK inhibitor candidate, Odanacatib (ODN), was developed by Merck & Co. Phase III clinical trials; it showed high therapeutic efficacy in patients with postmenopausal osteoporosis but was terminated due to the cardio-cerebrovascular adverse effects. As of now, there is no available drug approved by the FDA that targets cathepsin k but is an ongoing direction for osteoporosis treatment [66].
PTHrP is required for normal bone development. Teriparatide is a bioactive form of the parathyroid hormone of recombinant human PTH 1–34 fragment rhPTH(1–34) [67]. It is the first and only available therapeutic agent that activates and stimulates osteoblasts. In contrast with antiresorptive therapy, teriparatide increases bone formation by inhibiting sclerostin production in osteocytes and increases bone resorption by stimulating RANKL production by osteoblasts and osteocytes. In addition, PTH inhibits p16Ink4a and thereby downregulates senescence [68]. Intermittent administration of PTH increases osteoblast amounts and activities, thereby improving skeletal architecture at both trabecular and cortical bone sites [69].
Furthermore, this drug provides some remediation of the architectural defects in the osteoporotic skeleton [70]. Daily injections of teriparatide in patients with severe osteoporosis can reduce hip fractures by 56% [71]. Abaloparatide, a 34 amino acid synthetic analog of parathyroid hormone-related protein analog drug, is an FDA-approved drug to treat postmenopausal osteoporosis.
Wnt signaling pathways modulate cell proliferation, differentiation, and stem cell remodeling [21]. Activation of Wnts impacts bone remodeling by increasing quantities and enhancing the functionality of osteoblasts. The discovery of this pathway has opened the way to new anabolic treatments. For example, sclerostin is a protein secreted primarily by osteocytes and protects against the excessive bone formation. Anti-sclerostin antibodies stimulate osteoprotegerin production, leading to decreased bone resorption and uncoupling of osteoclast and osteoblast activity [4]. In addition, romosozumab, an anti-sclerostin monoclonal antibody that binds sclerostin, has favorable dual effects on bone by increasing bone formation and reducing bone resorption [72]. In studies done with postmenopausal women prone to osteoporosis, a dose of 210 mg romosozumab monthly amounts resulted in significantly increased BMD and was more effective than daily teriparatide or weekly alendronate doses [73]. Thus, it is considered another emerging therapeutic for skeletal aging.
Strontium ranelate is a relatively novel drug currently approved in Europe for the treatment of postmenopausal osteoporosis. It has dual effects of inhibiting bone resorption and promoting bone formation [74, 75]. It can stimulate the differentiation of pre-osteoblasts into osteoblasts and promotes osteoblast release of OPG. This can act as a decoy receptor for RANKL and thereby interfere with osteoclast differentiation. In every gram of bone, strontium is naturally occurring in trace amounts at around 100 μg. In other words, the therapeutic strategy with strontium ranelate is producing more strontium available to incorporate into bone [76]. In other words, the therapeutic approach with strontium ranelate is producing more strontium available to incorporate into bone [76].
Dual acting treatments that can coordinately stimulate osteoblasts and inhibit osteoclasts have significantly improved bone quality compared with monotherapy [77]. For example, a combination of teriparatide and denosumab generated more significant increases in BMD and bone strength than independent use of either drug [77]. In addition, the combination of Wnt mimetics and current clinical treatments has been found to improve bone mass and strength [23]. Thus, compared with monotherapy, sequential therapy can improve bone health and serve as an emerging option for treatment. Compared with monotherapy, dual-acting treatments that can coordinately stimulate osteoblasts and inhibit osteoclasts have significantly improved bone quality [67]. For example, the combination of Wnt mimetics and current clinical treatments has been found to improve bone mass and strength [23]. Thus, in comparison to monotherapy, sequential therapy has the potential to improve bone health significantly.
Interest in targeting senescence to halt or prevent age-related diseases, also known as senotherapy, has grown. Senolytic drugs are SASP modulators that eliminate cell senescence. More cells become senescent with advancing age and accumulate in tissues, suggesting that targeting the senescent cells is a promising treatment. Hence, several studies have explored senescent cells and their role in aging-bone diseases. The first thorough evidence showing senescence in mammalian bone cells was found in 2016 [78]. Osteocytes have the vital role of orchestrating bone remodeling, and osteocytes with senescence attributes contribute to osteoporosis [78]. To build off of this, another study found that genetically eliminating senescent cells and their SASP could prevent age-related osteoporosis [79]. In addition, the elimination of p16Inka-senescent cells improved bone quality. To build on this finding, researchers performed another study and found that genetically eliminating senescent cells and their SASP could prevent age-related osteoporosis [79]. Also, the elimination of p16Inka-senescent cells improved bone quality [10]. In mice, senolytic intervention improved bone mass, strength, and microarchitecture [7]. Novel drugs that use this strategy include Dasatinib (D), Quercetin (Q), D + Q [80], and Fisetin [81]. Senolytic drugs have shown a positive impact on bone metabolism by preventing bone loss and increasing health span.
The cellular morphological changes that come with aging dramatically affect bone health and increase the risk of developing age-related bone diseases. The sequelae of osteoporosis include decreased bone mass and increased pronation to fractures, a significant concern for the aging population. Recent literature is addressing utilizing new pharmaceutical targets to reverse or treat the adverse effects of aging. For example, cell senescence in bone paves the way for developing new therapeutic targets. With improved knowledge of the pathophysiology of osteoporosis and new targets, potential new treatments are being investigated. The use of pharmaceuticals and nonpharmaceuticals appears promising in preventing or treating aging bone diseases, including osteoporosis.
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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This is described by the well-known “Seebeck effect”. TE materials can convert also electricity into cooling through the “Peltier effect”. As such, TE materials and thermoelectric generator (TEG) devices can be utilized for potential applications including (i) thermal energy harvesting, (ii) local cooling and (iii) temperature sensing. The direct conversion of heat into electricity has been one of the most attractive solutions to the severe environmental and energy issues the humanity is coming across. This chapter covers the fundamental working principle of TE materials, the synthetic protocols for inorganic and organic thermoelectric materials, techniques and technologies for the fabrication of thermoelectric generators (otherwise defined as thermoelectric module devices) and a number of applications. Finally, future aspects and outlooks for further advancements at the “material” or “device” level for efficient power generation are remarked.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Lazaros Tzounis",authors:[{id:"288931",title:"Dr.",name:"Lazaros",middleName:null,surname:"Tzounis",slug:"lazaros-tzounis",fullName:"Lazaros Tzounis"}]},{id:"11874",doi:"10.5772/10128",title:"Some Chaotic Points in Cuprate Superconductors",slug:"some-chaotic-points-in-cuprate-superconductors",totalDownloads:2122,totalCrossrefCites:2,totalDimensionsCites:3,abstract:null,book:{id:"3573",slug:"superconductor",title:"Superconductor",fullTitle:"Superconductor"},signatures:"Özden Aslan Cataltepe",authors:null}],mostDownloadedChaptersLast30Days:[{id:"67825",title:"Organic Thermoelectrics and Thermoelectric Generators (TEGs)",slug:"organic-thermoelectrics-and-thermoelectric-generators-tegs-",totalDownloads:1259,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Inorganic and organic thermoelectric (TE) materials have received an extensive scientific interest during the last decades, due to their ability to directly convert the thermal energy to electricity. This is described by the well-known “Seebeck effect”. TE materials can convert also electricity into cooling through the “Peltier effect”. As such, TE materials and thermoelectric generator (TEG) devices can be utilized for potential applications including (i) thermal energy harvesting, (ii) local cooling and (iii) temperature sensing. The direct conversion of heat into electricity has been one of the most attractive solutions to the severe environmental and energy issues the humanity is coming across. This chapter covers the fundamental working principle of TE materials, the synthetic protocols for inorganic and organic thermoelectric materials, techniques and technologies for the fabrication of thermoelectric generators (otherwise defined as thermoelectric module devices) and a number of applications. Finally, future aspects and outlooks for further advancements at the “material” or “device” level for efficient power generation are remarked.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Lazaros Tzounis",authors:[{id:"288931",title:"Dr.",name:"Lazaros",middleName:null,surname:"Tzounis",slug:"lazaros-tzounis",fullName:"Lazaros Tzounis"}]},{id:"11871",title:"X-ray Micro-Tomography as a New and Powerful Tool for Characterization of MgB2 Superconductor",slug:"x-ray-micro-tomography-as-a-tool-for-quantitative-characterization-of-mgb2-superconducting-materials",totalDownloads:2815,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"3573",slug:"superconductor",title:"Superconductor",fullTitle:"Superconductor"},signatures:"Gheorghe Aldica, Ion Tiseanu, Petre Badica, Teddy Craciunescu and Mattew Rindfleisch",authors:null},{id:"66134",title:"Heat Recovery and Power Generation Using Thermoelectric Generator",slug:"heat-recovery-and-power-generation-using-thermoelectric-generator",totalDownloads:1271,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"In this chapter, experimental analysis of the direct conversion of thermal energy into electric energy was carried out, in order to encourage the conscious use of energy and to reduce waste. The conversion of thermal energy into electrical energy occurs in a thermoelectric generator through the Seebeck effect. This effect is associated with the appearance of an electric potential difference between two different materials, placed in contact at different temperatures. This relation between temperature and electrical properties of the material is known as thermoelectricity. This experimental study has as objective the obtaining of operating characteristic curves of the thermoelectric generator TEG1-12611-6.0, for different temperature gradients and under constant pressure between the heater plate and the heat sink. Resistors were used to heat the thermoelectric generator, which simulates the residual heat, and insulation material to minimize the dissipation of heat to the environment. For cooling, a heat exchanger was used in order to maximize the temperature difference between the sides of the thermoelectric generator. In this way, it was possible to perform an experimental analysis of the obtained electric power for different temperature ranges between the faces of the generator and, with this, verify the applicability in real systems.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Luis Vitorio Gulineli Fachini, Pedro Leineker Ochoski Machado, Larissa Krambeck, Romeu Miqueias Szmoski and Thiago Antonini Alves",authors:[{id:"227996",title:"Prof.",name:"Thiago",middleName:null,surname:"Antonini Alves",slug:"thiago-antonini-alves",fullName:"Thiago Antonini Alves"},{id:"229395",title:"MSc.",name:"Larissa",middleName:null,surname:"Krambeck",slug:"larissa-krambeck",fullName:"Larissa Krambeck"},{id:"286032",title:"Mr.",name:"Luis Vitorio",middleName:null,surname:"Gulineli Fachini",slug:"luis-vitorio-gulineli-fachini",fullName:"Luis Vitorio Gulineli Fachini"},{id:"293535",title:"Mr.",name:"Pedro Leineker",middleName:null,surname:"Ochoski Machado",slug:"pedro-leineker-ochoski-machado",fullName:"Pedro Leineker Ochoski Machado"},{id:"293537",title:"Prof.",name:"Romeu",middleName:null,surname:"Miqueias Szmoski",slug:"romeu-miqueias-szmoski",fullName:"Romeu Miqueias Szmoski"}]},{id:"66622",title:"Thermoelectric Generator Using Passive Cooling",slug:"thermoelectric-generator-using-passive-cooling",totalDownloads:899,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter presents an analysis of a point-of-use thermoelectric generator that is patented by one of the authors. The design, implementation and performance of the generator for powering electronic monitoring devices and charging batteries is discussed. This passive generator has no moving parts and relies on ambient air cooling. In one iteration it produces 6.9 W of steady state power using six Laird thermoelectric modules (Laird PB23 Series, HT8, 12) when placed on a 160°C steam pipe with a 30°C ambient environment (\n\nΔ\nT\n\n of 130°C). The generator produced 31.2 volts (V) open circuit and 0.89 amperes (A) short circuit. It successfully powered two microcontroller-based security cameras, one with a wireless Local Area Network (LAN) and another with cellular connectivity. In another scenario, the generator produced approximately 6 W with a steam pipe temperature of 140°C and an ambient of 25°C (\n\nΔ\nT\n\n of 115°C). This second system powered LED lights, a cellular-interfaced video surveillance system, and monitoring robots, while simultaneously trickle charging batteries. A third installation totally powered a stand-alone 3G web security camera system.",book:{id:"7626",slug:"advanced-thermoelectric-materials-for-energy-harvesting-applications",title:"Advanced Thermoelectric Materials for Energy Harvesting Applications",fullTitle:"Advanced Thermoelectric Materials for Energy Harvesting Applications"},signatures:"Robert Dell, Michael Thomas Petralia, Ashish Pokharel and Runar Unnthorsson",authors:[{id:"86966",title:"Dr.",name:"Runar",middleName:null,surname:"Unnthorsson",slug:"runar-unnthorsson",fullName:"Runar Unnthorsson"},{id:"285210",title:"Prof.",name:"Robert",middleName:null,surname:"Dell",slug:"robert-dell",fullName:"Robert Dell"},{id:"294487",title:"MSc.",name:"Michael Thomas",middleName:null,surname:"Petralia",slug:"michael-thomas-petralia",fullName:"Michael Thomas Petralia"},{id:"294497",title:"BSc.",name:"Ashish",middleName:null,surname:"Pokharel",slug:"ashish-pokharel",fullName:"Ashish Pokharel"}]},{id:"67254",title:"Quantum Theory of the Seebeck Coefficient in YBCO",slug:"quantum-theory-of-the-seebeck-coefficient-in-ybco",totalDownloads:737,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The measured in-plane thermoelectric power (Seebeck coefficient) \n\n\nS\nab\n\n\n in YBCO below the superconducting temperature \n\n\nT\nc\n\n\n (\n\n∼\n\n94 K) \n\n\nS\nab\n\n\n is negative and \n\nT\n\n-independent. This is shown to arise from the fact that the “electrons” (minority carriers) having heavier mass contribute more to the thermoelectric power. The measured out-of-plane thermoelectric power \n\n\nS\nc\n\n\n rises linearly with the temperature \n\nT\n\n. This arises from moving bosonic pairons (Cooper pairs), the Bose-Einstein condensation (BEC) of which generates a supercurrent below \n\n\nT\nc\n\n\n. The center of mass of pairons moves as bosons. 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Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. 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