Osteoporosis: A Silent Disease with Complex Genetic Contribution

Osteoporosis is the most common multifactorial metabolic bone disorder worldwide with a strong genetic component. In this review, the evidence for a genetic contribution to osteoporosis and related phenotypes is summarized alongside with methods used to identify osteoporosis susceptibility genes. The key biological pathways involved in the skeleton and bone development are discussed with a particular focus on master genes clustered in these pathways and their mode of action. Furthermore, the most studied single nucleotide polymorphisms(SNPs) analyzed for their importance as genetic markers of the disease are presented. New data generated by nextgeneration sequencing in conjunction with extensive meta-analyses should contribute to a better understanding of the genetic basis of osteoporosis and related phenotype variability. These data could be ultimately used for identifying at-risk patients for disease prevention by both controlling environmental factors and providing possible therapeutic targets.     

Vitamin D receptor gene polymorphism and osteoporosis in the Turkish population

Osteoporosis is one of the most important medical problems facing the aging population. It is defined as a decrease in the bone mass leading to an unacceptably high risk of fractures. Osteoporosis is a multifactorial disease. It is well established that genetic factors are involved in the pathogenesis of osteoporosis. Polymorphism of the vitamin D receptor (VDR) gene has been reported to play a major role in variations for genetic regulation of bone mass. Its role within various ethnic populations is not clear. The purpose of this project was to determine the frequencies of VDR genotypes in Turkey. Three polymorphisms of the VDR gene were analyzed using the polymerase chain reaction-restriction fragment length polymorphism technique. The sample for our study was comprised of postmenopausal women in Turkey, 100 of whom were diagnosed with osteoporosis. They were compared with 146 healthy controls. BsmI genotype frequencies in Turks resemble Caucasians rather than Asians, and Taq genotype frequencies in Turks neither resemble Caucasians nor Asians. The genotype frequencies of VDR were not statistically different between patients with osteoporosis and the control group. Among VDR haplotypes, bbAATT and bbTtAa are more frequent in the osteoporosis group than the control group.     

New Treatment Modalities in Osteoporosis

ObjectiveTo describe recently discovered agents for the management of osteoporosis.MethodsA literature review (PubMed search) was conducted to identify agents at various stages of development for osteoporosis treatment. Agents under study or review for approval were included.ResultsIn menopause, bone remodeling is increased, and agents that suppress bone resorption can stabilize bone mass. In contrast, agents that target the osteoblast can increase bone formation and bone mass. Novel antiresorptive agents can target the formation or the activity of osteoclasts. They include denosumab, an antibody to receptor activated nuclear factor kB; new selective estrogen receptor modulators, such as bazedoxifene; and cathepsin K inhibitors, such as odanacatib. Src kinase inhibitors are in the early phases of development. Parathyroid hormone is the only approved anabolic agent for the treatment of osteoporosis. Novel anabolic therapies for osteoporosis may include the use of factors with anabolic properties for bone or the neutralization of growth factor antagonists. Recent discoveries have demonstrated that the Wnt/β-catenin signaling pathway has a central role in osteoblastic cell differentiation. Antibodies to Wnt antagonists, such as sclerostin, are under development as new therapeutic approaches for osteoporosis. Anabolic therapies have the potential to enhance bone mass, but their long-term safety must be proven.ConclusionsNew developments in the treatment of osteoporosis include novel antiresorptive and anabolic agents. Their success will depend on their long-term effectiveness and safety profile. (Endocr Pract. 2010;16:855-863)     

Genetic and environmental factors in human osteoporosis

Osteoporosis is a common disorder, with prolongation of the average life span it has become a major public health problem. On the formation of osteoporosis genetic factors and environmental influences could play a role then it is considered as multi-factorial. Because a variety of functions to affect susceptibility to the formation of osteoporosis VDR-F, VDR-B, COL1A1, ESR1X, ESR1P and CTR are thought to be candidate genes. In this study, the aim is to investigate the relationship between these genes polymorphism and bone mineral density (BMD) values of lumbar vertebra and femoral neck in 188 Turkish people. Lumbar spine and femoral neck BMD of the individuals included in the study were measured by the dual X-ray absorptiometry method. The genotyped polymorphisms by simultaneous amplification of five regions of the genome, containing six SNPs of interest and detecting the amplified product, using the kit MetaBone Clinical Arrays^?. Statistical analyses indicated that; VDR-B gene polymorphisms major (P?=?0.013), VDR-F polymorphisms have minor (P?=?0.082) effect on femur BMD. None of the other genes has any significant effect on spinal BMD. Patient age, body mass index and diet has significant effect on femoral and spinal BMD. Osteoporosis is a multi-factorial disease and many genetic and non-genetic risk factors contribute to the development of osteoporosis. Early detection of a genetic predisposition to osteoporosis should allow delay and/or limit unfavorable changes in the bone tissue.     

Genetic research in osteoporosis: Where are we? Where should we go next?

Fractures resulting from low bone mass and excessive skeletal fragility (osteoporosis) are common worldwide both in males and females, particularly in later years of life. Both fractures, and the most important predictor of fractures, bone mass, are now known to be strongly heritable. This fact, plus the current growth in genetic science, has led to a surge of genetic research in osteoporosis, mostly in the search for genes and their polymorphisms that are responsible for variation in bone mass. Finding the genetic basis underlying variation in bone mass will lead us to deeper understanding of the biology of bone mass accumulation, maintenance and adaptation to load. This, plus finding the genetic basis for overall variation in fracture risk per se, will facilitate the development of interventions, both pharmaceutical and non-pharmaceutical, to prevent and/or treat osteoporosis successfully. This research has produced a rather large number of gene loci that seem to influence bone mass. The challenge now is to refine the statistical genetics and the phenotypes involved so that we can confidently identify those gene loci that truly influence bone mass, and to find ways to study the genetic basis for the most direct disease outcome of interest, fracture.     

Parathyroid hormone and its analogues - molecular mechanisms of action and efficacy of osteoporosis therapy

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.     

Prospect of mesenchymal stem cells in therapy of osteoporosis: A review

Osteoporosis is a systemic skeletal disease associated with reduced bone strong point that results in raised fracture risk, with decreased bone strength, leading to reduced bone mineral density and poor bone quality. It is the most common in older females but some men are also at high risk. Although considered as a predictable result of aging, it is can be avoidable and treatable. The existing treatment of osteoporosis mainly contains antiresorptive and anabolic agents. In spite of these improvements, concerns around unusual side-effects of antiresorptive drugs, and the lack of perfect confirmation in maintenance of their long-standing effectiveness is bring about many patients not receiving these drugs. Over the years, the stem cell-based therapy has attained substantial clinical consideration because of its potential to treat numerous diseases. The stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell-based therapy for osteoporosis has caught substantial attention, no clinical trial has been published on humans. The cell studies based on osteoporosis are primarily focused on osteoclastic activity and bone resorption procedures. Earlier, it was on osteoblastogenesis and in recent times, on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell-based strategy in osteoporosis.     

Parathyroid hormone and its analogues--molecular mechanisms of action and efficacy in osteoporosis therapy

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.     

Recent advances in the genetics of osteoporosis

It has been known for over 20 years that osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable. Other known risk factors for osteoporotic fractures such as reduced bone quality, femoral neck geometry and bone turnover are now also known to be heritable. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect. Different approaches are being used currently to identify the many genes responsible. These include linkage studies in man and experimental animals as well as candidate gene studies and alterations in gene expression. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, with twin studies, have indicated that the effects of these loci are partly site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not yet been isolated. Most studies have used the candidate gene approach. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. Genes may vary in their influence of particular intermediate phenotypes, and we now know that not all genes influencing BMD will be important in fracture. In addition, the study of other diseases such as osteoarthritis and metabolic bone syndromes may prove fruitful in highlighting genes which overlap to osteoporosis as well. As large scale genetic testing becomes more cost-effective, recent findings have illustrated the potential of novel approaches. These include combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.     

Mechanotransduction determines the structure and function of lung and bone: a theoretical model for the pathophysiology of chronic disease

Multicellular organisms have evolved in adaptation to the Earth's gravitational and oxygen environment. This epigenetic process is dependent on the capacity of mesodermal cells to act as mechanosensors that can conform, deform, and reform in adaptation to the organism's physical environment. Mechanical forces, such as hydrostatic pressure and gravity, play important roles in the embryonic development, homeostasis, and repair of lung and bone. We discuss the role of parathyroid hormone-related protein (PTHrP) as a mechanotransducer for stretch in these organs during normal development, particularly as it lends itself to homeostasis; we further demonstrate that "uncoupling" of such mechanisms may play a central role in injury repair, particularly as it relates to chronic diseases of lung and bone. Endothermal PTHrP signaling through its G-protein coupled receptor promotes normal cell-cell signaling that maintains the homeostatic phenotypes of lung and bone. Molecular disruption of the PTHrP/PTHrP receptor pathway from endoderm to mesoderm, because of such factors as volutrauma, hyperoxia, inflammation, and microgravity, alters intracellular signaling, causing maladaptive cellular changes, resulting in myofibroblast proliferation and granulation. Examples of such pathologic changes specifically related to this cellular/molecular mechanism of maladaptation are chronic lung disease and osteoporosis. We suggest a new paradigm that may help in the future creation of diagnostic and therapeutic modalities for a wide range of developmental and chronic diseases ranging from bronchopulmonary dysplasia in newborns to idiopathic pulmonary fibrosis and osteoporosis as a result of aging or microgravity.     

Mechanotransduction determines the structure and function of lung and bone

Multicellular organisms have evolved in adaptation to the Earth's gravitational and oxygen environment. This epigenetic process is dependent on the capacity of mesodermal cells to act as mechanosensors that can conform, deform, and reform in adaptation to the organism's physical environment. Mechanical forces, such as hydrostatic pressure and gravity, play important roles in the embryonic development, homeostasis, and repair of lung and bone. We discuss the role of parathyroid hormone-related protein (PTHrP) as a mechanotransducer for stretch in these organs during normal development, particularly as it lends itself to homeostasis; we further demonstrate that “uncoupling” of such mechanisms may play a central role in injury repair, particularly as it relates to chronic diseases of lung and bone. Endothermal PTHrP signaling through its G-protein coupled receptor promotes normal cell-cell signaling that maintains the homeostatic phenotypes of lung and bone. Molecular disruption of the PTHrP/PTHrP receptor pathway from endoderm to mesoderm, because of such factors as volutrauma, hyperoxia, inflammation, and microgravity, alters intracellular signaling, causing maladaptive cellular changes, resulting in myofibroblast proliferation and granulation. Examples of such pathologic changes specifically related to this cellular/molecular mechanism of maladaptation are chronic lung disease and osteoporosis. We suggest a new paradigm that may help in the future creation of diagnostic and therapeutic modalities for a wide range of developmental and chronic diseases ranging from bronchopulmonary dysplasia in newborns to idiopathic pulmonary fibrosis and osteoporosis as a result of aging or microgravity.     

Gene variants for osteoporosis and their pleiotropic effects in aging

The prevalence of osteoporosis is raising worldwide as improving conditions of living and treatment of other common diseases continuously increases life expectancy. Thus, osteoporosis affects most women above 80 years of age and, at the age of 50, the lifetime risk of suffering an osteoporosis-related fracture approaches 50% in women and 20% in men. Numerous genetic, hormonal, nutritional and life-style factors contribute to the acquisition and maintenance of bone mass. Among them, genetic variations explain as much as 70% of the variance for bone mineral density (BMD) in the population. Dozens of quantitative trait loci (QTLs) for BMD have been identified by genome screening and linkage approaches in humans and mice, and more than 100 candidate gene polymorphisms tested for association with BMD and/or fracture. Sequence variants in the vitamin D receptor (VDR), collagen 1 alpha 1 chain (Col1A1), estrogen receptor alpha (ESR1), interleukin-6 (IL-6) and LDL receptor-related protein 5 (LRP5) genes were all found to be significantly associated with differences in BMD and/or fracture risk in multiple replication studies. Moreover, some genes, such as VDR and IL-6, were shown to interact with non-genetic factors, i.e. calcium intake and estrogens, to modulate BMD. Since these gene variants have also been associated with other complex disorders, including cancer and coronary heart disease, they may represent common genetic susceptibility factors exerting pleiotropic effects during the aging process.     

Association of vitamin D receptor polymorphisms with osteoporosis in mexican postmenopausal women

It has been reported that Vitamin D receptor polymorphisms are associated with osteoporosis, particularly those demonstrated by the BsmI and FokI restriction enzymes. Herein we report the results of a case-control study performed in postmenopausal Mexican women. We studied 65 osteoporotic women (< or = -2.5 SD bone mineral density [BMD] of young normal females) and 57 controls (over 90% > or = -1.5 SD BMD of young normal females. Restriction enzymes BsmI and FokI were used to identify polymorphisms. Odds ratios and their 95% confidence intervals were calculated, and analysis was performed controlling for age as a covariate. The BsmI genotypes revealed a higher frequency of the bb genotype in cases than in controls, contradicting much of the literature that suggests this genotype protects females against osteoporosis. Regarding the FokI genotypes, we were unable to confirm that the FF genotype has a protective effect against osteoporosis. The inconsistencies found in the literature and the results obtained in the present work suggest to us that other genetic and nongenetic factors are involved in the occurrence of osteoporosis, confounding the results of the possible association of osteoporosis and VDR polymorphisms.     

Osteocyte biology: its implications for osteoporosis

Osteocyte viability may play a significant role in the maintenance and integrity of bone. Bone loss due to osteoporosis may be due in part to osteocyte cell death. We have identified a factor that will protect both osteoblasts and osteocytes from cell death due to agents known to be responsible for various forms of osteoporosis. Not only does estrogen preserve osteoblast and osteocyte viability, but so does a molecule called CD40Ligand. This molecule is expressed on activated T lymphocytes, human dendritic cells, and human vascular endothelial cells, whereas its receptor CD40 is expressed on normal epithelium, B cells, and dendritic cells. CD40Ligand protects osteoblasts and the MLO-Y4 osteocyte-like cells against apoptosis induced by glucocorticoids, tumor necrosis factor alpha or etoposide. As tumor necrosis factor a has been shown to be responsible for post-menopausal bone loss and glucocorticoids induce dramatic bone loss, this finding has important implications with regards to potential therapy for both post-menopausal and steroid-induced osteoporosis.     

Osteoporosis: the current status of mesenchymal stem cell-based therapy

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.     

Crosstalk between TNF and glucocorticoid receptor signaling pathways

TNF is a Janus-faced protein. It possesses impressive anti-tumor activities, but it is also one of the strongest known pro-inflammatory cytokines, which hampers its use as a systemic anti-cancer agent. TNF has been shown to play a detrimental role in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Glucocorticoids are strongly anti-inflammatory and exert their therapeutic effects through binding to their receptor, the glucocorticoid receptor. Therefore, glucocorticoids have been used for over half a century for the treatment of inflammatory diseases. However, many patients are or become resistant to the therapeutic effects of glucocorticoids. Inflammatory cytokines have been suggested to play an important role in this steroid insensitivity or glucocorticoid resistance. This review aims to highlight the mechanisms of mutual inhibition between TNF and GR signaling pathways.     

Linkage of interleukin 6 locus to human osteopenia by sibling pair analysis

Osteopenia and osteoporosis are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlations between levels of bone mass and a number of genetic factors. The genes involved could regulate metabolism, formation and resorption of bone, all processes that determine bone mass. We tested 192 sibling pairs of adult Japanese women from 136 families for genetic linkage between osteopenia and allelic variants of four candidate genes (interleukin-6, interleukin-6 receptor, calcium-sensing receptor, and matrix gla protein) using qualitative and quantitative methods, and using as genetic markers dinucleotide-repeat polymorphisms present in or near each of those loci. The interleukin-6 locus showed evidence of linkage to osteopenia analyzed as a qualitative trait, with mean allele sharing of 0.40 (P=0.0001) in discordant pairs and 0.55 (P=0.04) in concordant affected pairs. Variation at this locus was also linked to decreased bone mineral density measured as a quantitative trait (P=0.02). Analyses limited only to the post-menopausal women showed similar or even stronger results. No other locus among those tested showed any evidence of linkage by either method. The results provided strong evidence that genetic variation at the interleukin-6 locus affects regulation of bone mineral metabolism and confers risk for osteopenia and osteoporosis in adult women.     

Wnt signaling: a win for bone

Wnt signaling plays a central role in many processes during embryonic development and in later stages of life. At least three distinct wnt signaling pathways have been described. In 2001, evidence was obtained from genetic studies on some rare hereditary conditions, that the canonical wnt signaling pathway plays an important role in bone formation. Functional studies and experimental analysis of relevant animal models confirmed the anabolic effect of wnt signaling by modulating the differentiation, the proliferation, the activity and finally the apoptosis of (pre)osteoblasts and osteocytes. More recently, also non-canonical wnt signaling was shown to play a role in bone formation. Since there is currently a major lack of anabolic therapeutic agents for the prevention and treatment of osteoporosis this signaling pathway deserves major attention. A big concern, however, is the pleiotropic function of the pathway that needs to be taken into account in order to avoid unwanted side-effects. Preliminary data are already indicating that this might be achieved by targeting sclerostin, a bone-specific extracellular antagonist of canonical wnt signaling.     

Mechanisms of glucocorticoid action in bone cells

Glucocorticoids play an important role in the normal regulation of bore remodeling; however continued exposure of bone to glucocorticoid excess results in osteoporosis. In vivo, glucocorticoids stimulate bone resorption and decreasae bone formation, and in vitro studies have shown that while glucocorticoids stimulateosteoblastic differentiation, they have important inhibitory actions on bone formation. Glucocorticoids have manyeffects on osteoblast gene expression, including down-regulation of type 1 collagen and osteocalcin, and up-regulation of interstitial collagenase. The synthesis and activity of osteoblast growth factors can be modulated by glucocorticoids as well. For example, insulin-like growth factor 1 (IGF-1) is an important stimulator of osteoblast function, and expression of IGF-1 is decreased by glucocorticoids. The activity of IGF 1 can be modified by IGF binding proteins (IGFBPs), and theirsynthesis is also regulated by glucocorticoids. Thus, glucocorticoid action on osteoblasts can be direct, by activating or repressing osteoblast gene expression, or indirect by altering the expression or activity of osteoblast growth factors. Further investigation of the mechanisms by which glucocorticoids mnodulate gene expression in bore cells will contribute to our understanding or steroid hormone biology and will provide a basis for the design of effective treatments for glucocorticoid-induced osteoporosis.