Metabolic bone disease and bone quality

On the progress of study concerned with pathology of metabolic bone disease such as osteoporosis, it has been known that most of bone strength can be explained by bone volume. As bone volume can be determine by bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), it has been widely used for diagnosis of osteoporosis or efficacy of treatment. However, with the advance of bone morphometry, decrease of bone strength or existence of insufficiency fracture is influenced by not only loss of BMD but also deterioration of bone quality especially bone microstructure. In this chapter, we will give an outline of change of bone quality in metabolic bone disease.     

Metabolic bone markers and bone cell biology

Various metabolic bone markers have been developed in order to analyze each process of bone resorption and bone formation. By evaluating the two processes using bone markers, an imbalance between bone resorption and formation can be estimated. Metabolic bone markers have already been in clinical use for the early diagnosis and the assessment of treatment efficacy in osteoporotic patients and for the diagnosis of cancer-induced bone diseases. Further elucidation of the mechanisms of formation and secretion, metabolic clearance, diurnal rhythm as well as their changes in various disorders should enable us to evaluate bone turnover at a real-time scale and to utilize for the diagnosis of a variety of metabolic bone diseases.     

Measurements of bone mass and bone density

X-ray-based procedures are available to measure bone mineral density in vitro at almost any skeletal site. These bone density measurements are not useful in the diagnosis of the cause of bone loss but at present are the only tests available for assessing bone mass prior to the occurrence of irreversible changes such as fractures or vertebral compression, which are easily recognizable on x-rays. When fractures are present, the severity of the bone loss and the risk for future fractures can be assessed. Repeated measurements permit estimation of the rate of bone loss, which gives useful information for monitoring treatment effect or course of the disease. Measurement of total body calcium is of less clinical importance because of the predominantly trabecular bone loss that generally occurs in metabolic bone disease. Dual-energy x-ray absorptiometry (DEXA) and quantitative computed tomography (QCT) of the spine are of about equal clinical value in the first approach to the patient with metabolic bone disease, although DEXA allows greater variety in sampling sites. For repeated measurements, DEXA provides better precision at significantly lower radiation burden. For bone mineral measurements, the lumbar spine appears to be the most sensitive skeletal site.     

Alcohol-induced bone loss and deficient bone repair

BACKGROUND: Chronic consumption of excessive alcohol eventually results in an osteopenic skeleton and increased risk for osteoporosis. Alcoholics experience not only increased incidence of fractures from falls, but also delays in fracture healing compared with non-alcoholics. In this review the term "alcohol-induced bone disease" is used to refer to these skeletal abnormalities. Alcohol-induced osteopenia is distinct from osteoporoses such as postmenopausal osteoporosis and disuse osteoporosis. Gonadal insufficiency increases the rate of bone remodeling, whereas alcohol decreases this rate. Thus, histomorphometric studies show different characteristics for the bone loss that occurs in these two disease states. In particular, alcohol-induced osteopenia results mainly from decreased bone formation rather than increased bone resorption. Human, animal and cell culture studies of the effects of alcohol on bone strongly suggest alcohol has a dose-dependent toxic effect on osteoblast activity. The capacity of bone marrow stromal cells to differentiate into osteoblasts has a critical role in the cellular processes involved in the maintenance of the adult human skeleton by bone remodeling. Chronic alcohol consumption suppresses osteoblastic differentiation of bone marrow cells and promotes adipogenesis. In fracture healing, the effect of alcohol is to suppress synthesis of an ossifiable matrix, possibly due to inhibition of cell proliferation and maldifferentiation of mesenchymal cells in the repair tissue. This results in the deficient bone repair observed in animal studies, characterized by repair tissue of lower stiffness, strength and mineral content. Current knowledge of cellular effects and molecular mechanisms involved in alcohol-induced bone disease is insufficient to develop interventional strategies for its prevention and treatment. OBJECTIVES: The objectives of this review are 1) to identify the characteristics of alcohol-induced bone loss and deficient bone repair as revealed in human and animal studies, 2) to determine the current understanding of the cellular effects underlying both skeletal abnormalities, and 3) to suggest directions for future studies to resolve current ambiguities regarding the cellular basis of alcohol-induced bone disease.     

Androgens and bone

Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs.Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERalpha. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERalpha pathways are involved in androgen action on radial bone growth. ERbeta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males.In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERalpha.     

Hyperprolactinemia and bone

Pituitary - Prolactin (PRL) has direct and indirect effects on bone metabolism. Experimental studies showed that in the presence of high PRL levels bone resorption was increased as well as bone...     

Sex differences in cancellous and cortical bone strength, bone mineral content and bone density.

The purpose of this study was to examine sex differences in cancellous and cortical bone strength, bone mineral content (BMC) and bone density of excised cadaver vertebral and phalangeal bones. The samples were age-matched. Bone strength was measured as the mechanical force required to crush or break the bones. Two parameters of bone strength were used on the vertebrae; the force at the first deviation from linearity and the mean force during the consolidation before final failure. The force at first deviation from linearity was not significantly different between the sexes, but there was a significant difference in the consolidation force. The mean men's phalangeal strength was twice that of the women's. BMC and BMC/BW of both types of bone were statistically different between the sexes. Radiographic photodensity measures on the vertebrae showed no sex differences. Cortical diameters of the finger bones were significantly greater in males.     

糖皮质激素与骨

糖皮质激素在临床上应用广泛,但所致的骨质流失、代谢失调等不良反应也限制了其使用.本文对糖皮质激素对骨及其细胞的生理和病理生理作用进行综述,并对其不良反应发生的分子机制进行讨论.     

Ageing and bone

Bone loss by ageing has been investigated from standpoints of systemic abnormality and some deficiency in osteoblastic bone formation. This seminar summarize the involvements of a key molecule of adipocytic differentiation PPAR-gamma, essential IGF-I signaling molecules IRS-1 and IRS-2, and an anti-aging gene klotho in the pathophysiology of age-related osteoporosis.     

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A-mFc) in vivo. mBMPR1A-mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A-mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A-mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.     

Mechanisms of bone resorption and new bone formation in spondyloarthropathies

Spondyloarthropathies (SpA) share clinical features such as sacroiliitis, axial immobility, and peripheral arthropathies. They also share a strong association with human leukocyte antigen-B27, implicating T cells and antigen-presenting cells in the disease process. Inflammation seems to underlie the pathogenesis of SpA, particularly in the axial skeleton and entheses. Pathologic bone loss and formation occur simultaneously in inflamed regions, suggesting an inflammation-induced dysregulation of osteoclast and osteoblast activity. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) appear to be central to the disease, because TNFα blockade has been shown to effectively improve clinical outcome. Other cytokines such as transforming growth factor-beta, interferon-gamma (IFNγ), and interleukin-18 are also likely to be important in SpA. Activated T cells have been shown to produce cytokines such as IFNγ and receptor activator of nuclear-factorkappaB ligand, with direct effects on osteoclastogenesis. The dual role of T cells in immunobiology and skeletal biology provides a possible link between human leukocyte antigen-B27, pro-inflammatory cytokines, and bone cells in SpA.     

Notch信号通路与骨发生和骨重建

Notch信号通路对调节胚胎细胞和成体细胞增生、分化、凋亡以及前体细胞的自我更新具有重要意义。它可通过协调胚胎期生长板内软骨细胞分化和生长,控制骨组织正常发生。骨重建是对病损骨组织的再生和修复,主要由成骨细胞和破骨细胞参与,Notch信号除可对上述2种细胞增生、分化、成熟等进行调控外,也可介导依赖于成骨细胞的破骨细胞生成。本文试以Notch信号对软骨细胞、成骨细胞、破骨细胞等细胞学行为改变为主线,探讨Notch信号对上述2种骨生物学行为调节的作用机制。     

应力负荷与骨骼结构及骨重建的关系

应力负荷是骨质量和骨骼几何形状的主要调节因子.骨细胞信号网络通过感知骨骼力学负荷而发挥作用,是应力负荷的主要传感器.骨细胞死亡后发生骨重建,骨骼力学负荷减小或丧失.骨折后所致长期卧床、局部制动导致骨细胞凋亡和骨吸收,引起严重的骨质疏松.通过分析骨骼适应应力负荷的机制,骨细胞感受机械刺激和骨骼的力学负荷,力学负荷对骨骼的作用和应力负荷与骨重塑过程的分子调控等,可以探讨应力负荷与骨骼结构及与骨重建的关系.     

DHEA and bone metabolism

A strong positive correlation of serum dehydroepiandrosterone sulfate (DHEA-S) and estrone (E1) with bone mineral density (BMD) in postmenopausal women but no correlation between serum estradiol (E2) and BMD in the same group suggest that circulating adrenal androgen may be converted to estrogen in peripheral tissues including osteoblast and may contribute to BMD maintenance. Actually, in cultured human osteoblast cells, DHEA can be converted to androstenedione and then androstenedione to estrone through the apparent aromatase activity. In human bone cells, intracrine mechanism through aromatase activity may contribute to the local production of estrogens, thus leading to protective effect against osteoporosis especially after menopause.     

Kidney transplantation and bone

Osteoporosis, renal osteodystrophy and osteoarthropathy derived from hemodialysis associated amyloidosis are three major bone diseases after the kidney transplantation. Osteoporosis that is induced by steroid administration is an inevitable side effect and develops more frequently in the elderly recipients. After the recovery of renal function due to grafted kidney, secondary hyperparathyroidism usually improves and the serum level of PTH-intact downs to the almost normal range. However, the patients who have tertiary hyperparathyroidism are unable to show the enough lowering of PTH-intact. In these cases, renal osteodystrophy progresses even though kidney grafts have fine renal function. Osteoarthropathy derived from hemodialysis associated amyloidosis reveals distinct clinical courses depending to the types of diseases. Some of them improve and the remained ones become worse. After the kidney transplantation we must keep to concern for the bone condition of grafted patients.     

Bisphosphonates and bone quality

The clinical use of drugs, which modestly increase bone mineral density, but have sufficient effects on the fracture prevention comparable to bisphosphonates, focuses on the research of the quality of the bone. Clinical investigations using micro CT, Fourier transform infrared imaging spectroscopy, quantitative computerized tomography, and/or other new modalities which support bisphosphonate treatment do not show any quality problems of the bone. In the clinical setting, evaluation of bone quality is very limited, even in the evaluation of patients treated with bisphosphonate, except evaluation by the changes of metabolic markers of bone. The new modalities such as low radiation-dose CT, sensitive MRI or ultra sonography are expected for the clinical evaluation of the changes of bone quality.