The search for human osteoporosis genes

Osteoporosis is the most prevalent metabolic bone disease and a major clinical and public health problem. Heredity plays an important and well-established role in determining the lifetime risk of this disease. Major efforts are currently underway to identify the specific genes and their allelic variations that contribute to the heritable component to osteoporosis. A number of laboratories are using quantitative trait locus (QTL) methods of genome scanning in families and animal models to identify candidate genomic regions and, ultimately, the genes and genetic variations that lead to osteoporosis. Several chromosomal regions of the human genome have now been linked to osteoporosis-related phenotypes. Although the specific genes contributing to the majority of these linkage signals have not been identified, two positional candidate genes have now been identified: low density lipoprotein receptor-related protein 5 (LRP5) and bone morphogenetic protein 2 (BMP2). A number of QTL has also been identified by cross-breeding strains of mice with variable bone density and several of these QTL have been fine mapped, providing a rich new base for understanding osteoporosis. Genetic association analyses have also provided evidence for a modest relationship between allelic variants in several biological candidate genes and bone mass and the risk of fracture. These ongoing animal and human studies will provide a continuing source of new insight into the genetic regulation of bone and mineral metabolism and the molecular etiology of osteoporosis. The new insight that will emerge from this ongoing research should lead to new ways of diagnosing, preventing and treating the growing clinical and public health problem of osteoporosis.     

Molecular and genetic mechanisms of osteoporosis: implication for treatment

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture risk. Osteoporosis is a complex multifactorial disease, determined by genetic and environmental factors as well as their interactions. A large number of molecular, genetic and environmental factors underlying osteoporosis have been identified in past decades. In this article, we review 1) the molecular mechanisms of several principal systemic and local factors regulating bone metabolism; and 2) the current status of genetic studies searching for genes underlying osteoporosis. Further, we attempt to integrate knowledge from those two fields, and their potential implications for osteoporosis treatment.     

Diagnosis of periarticular osteoporosis in rheumatoid arthritis using digital X-ray radiogrammetry

Osteoporosis can manifest in two ways in rheumatoid arthritis: generalized bone loss, which may result from immobility, the inflammatory process per se and/or treatments such as steroids; and periarticular demineralization, which is probably due to local release of inflammatory agents. Digital X-ray radiogrammetry (DXR) is an effective and sensitive modality for monitoring periarticular osteoporosis, which is among the earliest features of rheumatoid arthritis, preceding bone erosions. DXR is a promising technique, which can provide quantitative data that allow early diagnosis. During the course of rheumatoid arthritis it can be deployed in combination with established X-ray scoring methods to inform decisions regarding the optimal therapy to prevent joint destruction.     

Osteoporosis,inflammation and ageing

Osteoporosis is a condition characterized by low bone mass and increased bone fragility, putting patients at risk of fractures, which are major causes of morbidity substantially in older people. Osteoporosis is currently attributed to various endocrine, metabolic and mechanical factors. However, emerging clinical and molecular evidence suggests that inflammation also exerts significant influence on bone turnover, inducing osteoporosis. Numerous proinflammatory cytokines have been implicated in the regulation of osteoblasts and osteoclasts, and a shift towards an activated immune profile has been hypothesized as important risk factor. Chronic inflammation and the immune system remodelling characteristic of ageing, as well as of other pathological conditions commonly associated with osteoporosis, may be determinant pathogenetic factors. The present article will review the current perspectives on the interaction between bone and immune system in the elderly, providing an interpretation of osteoporosis in the light of inflamm-ageing.     

Hormonal prevention and treatment of osteoporosis--state of the art 1990

Osteoporosis is a growing disease, and attention should be directed to possible means of preventing and treating this disease. Osteoporosis may be caused by a number of diseases (secondary osteoporosis), but it most often occurs in otherwise healthy persons. The major risk factors are a low bone mass at skeletal maturity, and a rapid bone loss. Postmenopausal bone loss may be prevented by hormone replacement therapy. All types of oestrogens and all administration forms are effective, as long as a sufficient serum concentration is obtained. The greatest benefit of hormone replacement therapy is obtained if instituted right after the menopause, when the bone loss is most rapid. But oestrogen will also arrest the bone loss when instituted much later in life.     

Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis

Osteoporosis is a systemic metabolic bone disease with characteristics of bone loss and microstructural degeneration. The personal and societal costs of osteoporosis are increasing year by year as the ageing of population, posing challenges to public health care. Homing disorders, impaired capability of osteogenic differentiation, senescence of mesenchymal stem cells (MSCs), an imbalanced microenvironment, and disordered immunoregulation play important roles during the pathogenesis of osteoporosis. The MSC transplantation promises to increase osteoblast differentiation and block osteoclast activation, and to rebalance bone formation and resorption. Preclinical investigations on MSC transplantation in the osteoporosis treatment provide evidences of enhancing osteogenic differentiation, increasing bone mineral density, and halting the deterioration of osteoporosis. Meanwhile, the latest techniques, such as gene modification, targeted modification and co‐transplantation, are promising approaches to enhance the therapeutic effect and efficacy of MSCs. In addition, clinical trials of MSC therapy to treat osteoporosis are underway, which will fill the gap of clinical data. Although MSCs tend to be effective to treat osteoporosis, the urgent issues of safety, transplant efficiency and standardization of the manufacturing process have to be settled. Moreover, a comprehensive evaluation of clinical trials, including safety and efficacy, is still needed as an important basis for clinical translation.     

Proteomic study of in vitro osteogenic differentiation of mesenchymal stem cells in high glucose condition

Molecular Biology Reports - Patients with diabetes have been widely reported to be at an increased risk of secondary osteoporosis. Osteoporosis is caused by an imbalance in bone remodeling due to...     

Ethnic difference in osteoporosis-related phenotypes and its potential underlying genetic determination

Osteoporosis is a serious health problem in both Caucasians and Asians. Caucasians and Asians are two distinct major ethnic groups, which may have differential genetic determination underlying complex genetic diseases such as osteoporosis. However, to date, there has been no systematic review focusing on the aspect of ethnic difference in risk to osteoporosis and its potential underlying genetic determination between Asians and Caucasians. Here, we firstly review diverse aspects of osteoporosis-related differences, including the differences of epidemiology of osteoporotic fractures, peak bone mass, bone loss, bone area, bone geometry and drug treatment response between Asians and Caucasians. Then, we provide some potential genetic evidence on the different heritability and inheritance mode of bone phenotypes, the different osteoporosis candidate genes and the differential results in related molecular studies between them, to explain the above osteoporosis-related phenotypic differences. The results suggest that the osteoporosis-related phenotypic differences between Asians and Caucasians may be partially the result of the different ethnic genetic background. The present review may increase our understanding of potential different mechanisms related to ethnicity in pathogenesis of osteoporosis for effective and potentially customized treatments in different major ethnic groups.     

自噬与骨质疏松症的相关性

骨质疏松症是一种全身性骨骼疾病,其特征为低骨量和骨组织微结构退化。自噬是一个动态的、高度规律的自我消化过程,负责细胞存活和氧化应激反应,可以控制人体老化和骨质疏松症。尽管目前自噬对骨质疏松症的调控机制并没有完全解释清楚,但是随着对自噬研究的不断深入,其与骨质疏松症之间可能的联系和相互影响机制不断被揭示。本文回顾了近年来自噬与骨质疏松症的相关研究文献,探寻自噬与骨质疏松症相关的科学依据,发现对自噬与骨质疏松症共同影响的机制包括衰老、基因调控等。同时,自噬对糖皮质激素诱导的骨质疏松发病及药物治疗均有一定的影响。为进一步利用与自噬相关的调控体系来防治骨质疏松症提供证据。     

OPG/RANK/RANKL系统与骨质疏松研究最新进展

骨质疏松是严重威胁中老年人健康的骨科常见病,OPG/RANK/RANKL是参与调节骨重建的最重要的分子系统之一,与骨疾病相关的骨质疏松有密切联系,并已成为药物设计的新靶点.因此,对该系统的深入研究将为骨生理、病理机制阐明及骨疾病防治带来积极影响.     

Changes in bone mineral density in patients with prostate cancer treated with androgen deprivation therapy

Osteoporosis is a complication of permanent androgen deprivation in men with prostate carcinoma, following either bilateral orchiectomy or treatment with GnRH agonists. The present approach to the problem of osteoporosis includes prevention, adequate follow-up and appropriate treatment as an imperative of contemporary urological and endocrinological management of these patients. Bone densitometry was performed in 18 patients who were on GnRH agonists treatment during 1-3 years. The patients under therapy were followed clinically, PSA (prostate-specific antigen) values were determined and bone scintigraphy was performed. The bone mineral density values in 13 patients indicated osteopenia, whereas in one patient the finding was compatible with osteoporosis. Four patients had normal bone mineral density findings. Bone densitometry should be performed before initiation of treatment with GnRH agonists in order to quantify the therapy-related bone loss. Prevention of development of osteoporosis and its complications depends on the assessment of pharmacological treatment in this group of patients, including e.g. bisphosphonates and possible intermittent androgen deprivation.     

Night shift work and osteoporosis: evidence and hypothesis

Osteoporosis is an important public health problem worldwide. Among the countries with a very high population risk of fractures, there are those with the highest level of economic development. Osteoporotic fractures are the main cause of disability among elderly people, and the resultant disabilities require particularly large financial support associated not only with the direct treatment of the fracture but also with the necessity for long-term rehabilitation and care for the disabled person. Many well-established factors can have impact on bone mass and fracture risk. Recently, it has been hypothesized that working during nighttime which leads to endocrine disorders may have an indirect impact on bone physiology among night shift workers. Therefore, it can be presumed that the night shift work may contribute to the etiology of osteoporosis. The aim of our work was to make a review of the epidemiological evidence on the association between night shift work and bone mineral density or fracture risk as well as to discuss the potential biological mechanisms linking the work under this system with the development of osteoporosis. We have identified only four studies investigating the association between system of work and bone mineral density or fracture risk among workers. The findings of three out of four studies support the hypothesis. None of the studies has investigated a potential relationship between night shift work and bone turnover markers. Given that there have been no epidemiological studies in European countries that would concern working populations and the noticeable difference in the risk of osteoporosis between communities, further studies are warranted to elucidate the problem. It is presumed that further in-depth studies will not only identify the underlying factors of the disease but also contribute to developing guidelines for policy makers and employers for primary prevention of osteoporosis in workplace.     

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.     

Nutritional factors and bone homeostasis: synergistic effect with zinc and genistein in osteogenesis

Bone homeostasis is regulated through osteoclasts and osteoblasts. Osteoporosis, which is induced with its accompanying decrease in bone mass with increasing age, is widely recognized as a major public health problem. Bone loss may be due to decreased osteoblastic bone formation and increased osteoclastic bone resorption. There is growing evidence that nutritional and food factors may play a part in the prevention of bone loss with aging and have been to be worthy of notice in the prevention of osteoporosis. Zinc, an essential trace element, or genistein, which are contained in soybeans, has been shown to have a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption, thereby increasing bone mass. These factors have an effect on protein synthesis and gene expression, which are related to bone formation in osteoblastic cells and bone resorption in osteoclastic cells. The combination of zinc and genistein is found to reveal the synergistic effect on bone anabolic effect. The oral administration of those factors has been shown to prevent on bone loss in ovariectomized rats, an animal model for osteoporosis, indicating a role in the prevention of osteoporosis. Supplemental intake of ingredient with the combination of zinc and genistein has been shown to have a preventive effect on osteoporosis in human subjects, suggesting a role in the prevention of bone loss.     

Update on nutrients involved in maintaining healthy bone

Osteoporosis is a leading cause of morbidity and mortality in the elderly and influences quality of life, as well as life expectancy. Currently, there is a growing interest among the medical scientists in search of specific nutrients and/or bioactive compounds of natural origin for the prevention of disease and maintenance of bone health. Although calcium and vitamin D have been the primary focus of nutritional prevention of osteoporosis, a recent research has clarified the importance of several additional nutrients and food constituents. Based on this review of the literature, supplementation with vitamins B, C, K, and silicon could be recommended for proper maintenance of bone health, although further clinical studies are needed. The results of studies on long-chain polyunsaturated fatty acids, potassium, magnesium, copper, selenium, and strontium are not conclusive, although studies in vitro and in animal models are interesting and promising.     

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.     

纳米材料应用于骨质疏松治疗研究进展

骨质疏松症是一种以骨密度减低和骨结构改变为特征的代谢性骨病,目前的治疗方法不能有效解决其引起的骨量减低及其增加的骨折风险。纳米材料由于其独特的性能已被广泛应用于骨组织工程中,本文归纳了几种纳米材料研究的新进展以及其在骨质疏松中的应用前景。     

Bone loss induced by ovariectomy in rats is prevented by gene transfer of parathyroid hormone or an Arg-Gly-Asp-containing peptide

Osteoporosis is a major and growing healthcare concern as the population ages. The genes of both a Arg-Gly-Asp (RGD)-containing peptide and parathyroid hormone (PTH) were used to reduce bone loss induced by ovariectomy (OVX) in rats. Plasmids with either RGD or PTH gene were delivered into the quadriceps of OVX rats. The expression of the genes was detected by RT-PCR and radioimmunoassay. Analysis of bone mineral density, bone mechanical testing and bone mineral content indicated an improvement in bone properties in both RGD-transferred and PTH-transferred rats compared to OVX rats. Gene transfer of either RGD or PTH is therefore a possible approach to prevent bone loss in OVX rats thus providing a potential method to prevent osteoporosis in clinical situations.These authors contributed equally to this work     

Osteoporosis in Men

ObjectiveTo review information pertinent to bone health and osteoporosis in men.MethodsA review of pertinent literature was conducted.ResultsOsteoporosis affects approximately 2 million men in the US and accounts for an estimated 600,000 fractures each year. There are significant differences in skeletal size and structure between men and women that account for differences in fracture incidence, location, and outcomes. Bone density testing is appropriate for men age 70 and older and younger men (50-69) who have risk factors for osteoporosis. Lifestyle management, including adequate calcium and vitamin D intake, appropriate physical activity, and avoidance of tobacco and heavy alcohol use, is appropriate for all men. Pharmacologic therapy to reduce fracture risk is advisable for men with a clinical diagnosis of osteoporosis (a spine or hip fracture) or a T-score of −2.5 or below in the spine, femoral neck, total hip or 1/3 radius; however, the majority of men at high risk will only be identified using a fracture risk assessment tool, such as FRAX. Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug Administration (FDA)-approved therapeutic options.ConclusionOsteoporosis in men presents an important public health problem with significant morbidity and mortality. There are recommended strategies for identifying men at high risk of fracture, and effective agents are available for treatment. (Endocr Pract. 2013;19:834-838)