Skeletal response to alcohol

This review briefly assesses the well-established effects of alcohol consumption on bone and mineral metabolism and addresses areas of controversy that need additional research. Alcohol consumption is a risk factor for osteoporosis based on the frequent finding of a low bone mass, decreased bone formation rate, and increased fracture incidence in alcoholics. Alcohol also has been shown to reduce bone formation in healthy humans and animals and to decrease proliferation of cultured osteoblastic cells. On the other hand, it has been difficult to demonstrate alcohol-induced bone loss and increased fracture rate in population-based studies. Indeed, most population-based studies have shown a positive association between alcohol and bone mass and no change or a decrease in fracture risk. Overall, the evidence generally supports a detrimental effect of chronic alcohol abuse on the skeleton of men and a neutral or generally beneficial effect of light to moderate alcohol consumption, especially in older women. This latter putative beneficial effect may be due to a reduction in the age-related increase in bone remodeling associated with postmenopausal bone loss. Specific areas of research are recommended to clarify the dose and sex effects of alcohol consumption and to determine cellular and molecular mechanisms of action. The goals of this proposed research emphasis are to determine the degree of risk for the range of alcohol consumption, to set guidelines of consumption compatible with maintaining bone health, and to develop appropriate countermeasures to prevent or reverse the detrimental skeletal effects of alcohol abuse.     

Clinical utility of bone mass measurements in adults:Consensus of an international panel

Low bone mass predicts future fracture risk as well as high cholesterol or high blood pressure can predict the risk of heart disease or stroke. Prevention of the first fracture should be a clinical goal. In patients without fractures, osteopenia and osteoporosis can be diagnosed based on the extent of reduction in bone mass below mean peak bone mass of young healthy individuals. As bone mass decreases, fracture risk increases exponentially. Clinical situations in which an assessment of bone mass and fracture risk affects therapeutic decisions include estrogen deficiency, vertebral abnormalities, radiographic osteopenia, asymptomatic primary hyperparathyroidism, and long-term corticosteroid therapy. Serial measurements can also be used to monitor the effects of osteoporosis treatments. The appropriate technique and skeletal site for bone mass measurements should be chosen based on the patient's circumstances and the precision of measurement. A clinical interpretation can enhance the value of computer generated bone mass measurement reports and improve decision making.     

Alcohol-Induced Bone Disease: Impact of Ethanol on Osteoblast Proliferation

The habitual consumption of even moderate quantities of alcohol (1 to 2 drinks/day) is clearly linked with reduced bone mass (osteopenia). Biochemical and histological evaluation of patients with alcoholic bone disease reveal a marked impairment in bone formation in the face of relatively normal bone resorption. Experiments using well-defined osteoblastic model systems indicate that the observed reductions in bone formation result from a direct, antiproliferative effect of ethanol on the osteoblast itself. As bone remodeling and mineralization are dependent on osteoblasts, it follows that the deleterious effect of alcohol on these cells would result in slowed bone formation, aberrant remodeling of skeletal tissue and, ultimately, osteopenia and fractures. The skeletal consequences of alcohol intake during adolescence, when the rapid skeletal growth ultimately responsible for achieving peak bone mass is occurring, may be especially harmful. The specific subcellular mechanisms whereby ethanol inhibits cell proliferation are, as yet, unknown. During the last few years, attention has shifted from nonspecific membrane perturbation effects to actions on certain signaling proteins. Specifically, there is increasing evidence that ethanol may exert significant effects on transmembrane signal transduction processes that constitute major branches of cellular control mechanisms. At present, abstinence is the only effective therapy for alcohol-induced bone disease. An improved understanding of the pathogenesis of alcohol-induced bone disease may eventually result in alternative therapeutic avenues for those who are unable to abstain.     

Possible benefits of strontium ranelate in complicated long bone fractures

Osteoporosis drugs are prescribed to prevent fragility fractures, which is the principal aim of the management of osteoporosis. However, if fracture does occur, then it is also important to promote a fast and uneventful healing process. Despite this, little is known about the effect of osteoporosis drugs on bone healing in humans. Strontium ranelate is an osteoporosis agent that increases bone formation and reduces bone resorption and may therefore be beneficial in fracture healing. We report four cases of fracture non-union for up to 20 months. Treatment with strontium ranelate (2 g/day) for between 6 weeks and 6 months appeared to contribute to bone consolidation in the four cases. Animal studies support beneficial effects of strontium ranelate on bone healing via improvement of bone material properties and microarchitecture in the vicinity of the fracture. The clinical cases described herein provide new information on these effects, in the absence of randomized controlled studies on the clinical efficacy of pharmacological treatments in osteoporosis in fracture repair. Further studies are necessary. Fracture healing is an important topic in orthopedic research and is also a concern for patients with postmenopausal osteoporosis. Evidence from case reports and animal studies suggests that strontium ranelate improves bone microarchitecture and accelerates fracture healing. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.     

Effects of parathyroid hormone on bone formation in a rat model for chronic alcohol abuse

BACKGROUND: Alcoholism is a risk factor for osteoporosis and it is not clear whether the detrimental effects of alcohol on bone are reversible. Parathyroid hormone (PTH) is a potent stimulator of bone matrix synthesis and is being investigated as a therapeutic agent to reverse bone loss. The present investigation was designed to determine the effects of PTH on bone formation in a rat model for chronic alcohol abuse. METHODS AND RESULTS: Alcohol was administered in the diet of female rats (35% caloric intake) for 2 weeks. Human (1-34) PTH (80 microg/kg/day) was administered subcutaneously during the second week of the study. Alcohol resulted in a transient reduction in steady-state mRNA levels for the bone matrix proteins type 1 collagen, osteocalcin, and osteonectin compared with rats that were fed an alcohol-free (control) diet. As expected, alcohol decreased and PTH increased histologic indices of bone formation. Additionally, two-way ANOVA demonstrated that alcohol antagonized PTH-induced bone formation. Despite antagonism, bone formation and mRNA levels for bone matrix proteins in alcohol-fed rats treated with PTH greatly exceeded the values in rats fed the control diet. CONCLUSIONS: The results of this study contribute to a growing body of evidence that alcohol-induced bone loss is primarily due to reduced bone formation. We conclude that alcohol does not prevent the stimulatory effects of PTH on bone formation. This is evidence that the effects of alcohol on the skeleton are reversible. Additionally, the positive effects on bone formation in rats that consumed high concentrations of alcohol suggested that PTH may be useful as an intervention to treat alcohol-induced osteoporosis.     

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.     

Osteopenia and osteoporosis in children.

The purpose of this paper is to review the normal physiologic processes of skeletal accretion, abnormalities that may occur in children with chronic illnesses, and therapeutic maneuvers that the clinician may be able to employ to prevent or partially correct abnormalities of skeletal growth. Skeletal maturation in children is dependent upon bone formation exceeding resorption, whereas in adults these two fundamental processes of homeostasis are closely balanced. Skeletal growth is effectively completed at the end of the period of adolescent growth acceleration with closure of the epiphyses. An important determinant of future fracture risk and osteoporosis is the peak bone mass achieved during this second decade of life. If the hereditarily determined peak bone mass is not established during that time, the patient will enter young adulthood with osteopenia, an increased fracture risk, and accelerated postmenopausal osteoporosis or involutional osteoporosis. Thus osteopenia and osteoporosis have their origins in childhood and adolescence.     

Type 2 diabetes and bone fragility- An under-recognized association

Background and aimsDiabetes and osteoporosis are common chronic disorders with growing prevalence in the aging population. Skeletal fragility secondary to diabetes increases the risk of fractures and is underestimated by currently available diagnostic tools like fracture risk assessment (FRAX) and dual-energy X-ray absorptiometry (DXA). In this narrative review we describe the relationship and pathophysiology of skeletal fragility and fractures in Type 2 diabetes (T2DM), effect of glucose lowering medications on bone metabolism and the approach to diagnosing and managing osteoporosis and bone fragility in people with diabetes (PWD).MethodsA literature search was conducted on PubMed for articles in English that focused on T2DM and osteoporosis or bone/skeletal fragility. Articles considered to be of direct clinical relevance to physicians practicing diabetes were included.ResultsT2DM is associated with skeletal fragility secondary to compromised bone remodeling and bone turnover. Long duration, poor glycemic control, presence of chronic complications, impaired muscle function, and anti-diabetic medications like thiazolidinediones (TZD) are risk factors for fractures among PWD. Conventional diagnostic tools like DXA and FRAX tool underestimate fracture risk in diabetes. Presence of diabetes does not alter response to anti-osteoporotic treatment in post-menopausal women.ConclusionEstimation of fragility fracture risk should be included in standard of care for T2DM along with screening for traditional complications. Physicians should proactively screen for and manage osteoporosis in people with diabetes. It is important to consider effects on bone health when selecting glucose lowering agents in people at risk for fragility fractures.     

The role of growth factors in skeletal remodeling

Bone remodeling is a complex process regulated by systemic agents and local factors. During the past several years most or perhaps all the growth factors associated with the bone matrix have been characterized, and important information regarding hematologic factors has become available. Growth factors have significant effects on bone remodeling and likely play a major role in the maintenance of normal bone mass, wound healing, and fracture repair (Tables 3 and 4). Current studies indicate that systemic hormones regulate the synthesis and receptor binding of a number of local factors. By these mechanisms, specific hormones may target their effects to the skeleton. Although our knowledge of local growth factors is still limited, future work should determine their role in skeletal physiologic and pathophysiologic conditions and their potential as therapeutic agents.     

Osteoporosis and periodontal bone loss

Osteoporosis and osteopenia are characterized by reductions in bone mass, and may lead to skeletal fragility and fracture. Until the advent and widespread use of such methodology to measure bone density, such as dual energy X-ray absorption (DXA), the definition of osteoporosis was usually made using the clinical signs of a fracture. In 1994 the World Health Organization defined osteoporosis as a bone mineral density level more than 2.5 standard deviations below the mean of young normal women (WHO, 1994). The potential inter-relationship of the two diseases will be discussed in this paper.     

Bone quality in fracture callus

We reviewed the effect of agent for osteoporosis on fracture healing. Bisphosphonates increased the callus volume, while delaying remodeling of the callus woven bone into lamellar bone, which is structurally and mechanically superior to woven bone. Selective estrogrn receptor modulator mildly suppressed callus remodeling, which had no effect on fracture repair and intrinsic material properties. Intermittent treatment of parathyroid hormone accelerated the healing process as evidenced by earlier replacement of woven bone to lamellar bone, increased new cortical shell formation, and increased the ultimate load.     

Postmenopausal osteoporosis: A heterogeneous disorder as assessed by histomorphometric analysis of iliac crest bone from untreated patients

Twenty-six women with untreated postmenopausal osteoporosis underwent iliac crest biopsy following tetracycline-labeling and mineral metabolism studies. Histomorphometric assessment of their bone remodeling rates, including formation determined by the tetracycline-labeling technique, revealed considerable variation. Eight women had no evidence of active bone formation (inactive remodeling osteoporosis), whereas the others showed a spectrum of bone formation rates (active remodeling osteoporosis). Clinical and biochemical studies failed to predict the histomorphometric findings.Postmenopausal osteoporosis is a histologically heterogeneous disorder with morphologic expression in bone that cannot be predicted by single or combined routine clinical and laboratory parameters. Bone biopsy, necessary to identify the histologic lesion and assess skeletal dynamics, may prove to be important for optimal therapy of osteoporosis, as a variety of agents—with different effects on bone remodeling—are available.     

Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.     

Bone loss in chronic liver diseases: Could healthy liver be a requirement for good bone health?

Given that the liver is involved in many metabolic mechanisms, it is not surprising that chronic liver disease (CLD) could have numerous complications. Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients. Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis. Recent publications indicated that CLD-induced bone fragility depends on the etiology, duration, and stage of liver disease. Therefore, the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention, diagnosis, and treatment measures. The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood, especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals. It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals. Bone mineral density is widely used as the “golden standard” in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk. Therefore, microscale bone alterations (bone microstructure, mechanical properties, and cellular indices) were analyzed in CLD individuals. These studies further support the thesis that bone strength could be compromised in CLD individuals, implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients. However, more well-designed studies are required to solve the bone fragility puzzle in CLD patients.     

Immune system and bone remodeling.

The skeleton undergoes continuous cellular remodeling in a manner similar to that of replacement of a wall, brick by brick. Products of immune cells are likely to modulate all of the cellular events involved in bone remodeling. The local factors that modulate bone cell function and bone remodeling-osteotropic cytokines or growth-regulatory factors-are similar to those involved in other body processes such as wound healing, immune function, oncogenesis, angiogenesis, and embryogenesis.     

Ankylosing spondylitis and bone mineral density—what is the ideal tool for measurement?

Ankylosing spondylitis (AS) is characterised by chronic inflammation and partial ossification, yet vertebral fractures due to osteoporosis, although common, are frequently unrecognised. The aim of this study was to (1) show the frequency of changes in the progress of osteopenia/osteoporosis in AS depending on duration and stage of the disease and (2) assess the ranking of two different methods of bone density measurement in this clinical pattern. We measured bone density in 84 male and female patients with both dual X-ray absorptiometry (DXA) and single energy quantitative computed tomography (SE-QCT). In the initial and advanced stages of the disease, a high decrease in axial bone density could be verified (DXA: osteopenia in 5% and osteoporosis in 9.2%; SE-QCT: osteopenia in 11.8% and osteoporosis in 30.3%). Peripheral bone density decrease as in osteopenia could be proven in 17.6% by DXA measurement. With SE-QCT, a decrease in vertebral trabecular bone density could already be observed in the initial stage and continued steadily during the course of the disease; cortical bone displayed the same trend up to stages of ankylosis. With DXA, valid conclusions are more likely to be expected in less marked ankylosing stages of AS. In stages of advanced ankyloses in the vertebral region (substantial syndesmophytes), priority should be given to SE-QCT, due to the selective measurement of trabecular and cortical bone. The DXA method often yields values that are too high, and the replacement of vertebral trabecular bone by fatty bone marrow is not usually recorded as standard. There may already be an increased risk of bone fracture in AS in osteopenia on DXA along with an osteoporosis already established on SE-QCT.     

Aromatase activity and bone homeostasis in men

It is known that sex steroid hormones play an important role in the maintenance of bone mass in males as well as in females. Even though androgens are the major sex steroids in men, their primacy in regulating male skeletal remodeling has been increasingly questioned as direct and indirect evidence emerged suggesting that estrogens may also play a major role in male skeletal health. Recent data suggested that a threshold level of bioavailable estradiol is needed to prevent bone loss, and that with aging an increasing percentage of elderly men begin to fall below this level. The testes account for, at most, 15% of circulating estrogens in the male; the remaining 85% comes from peripheral aromatization of androgen precursors in different tissues, including bone. Human models of aromatase deficiency were the first to demonstrate the critical importance of the conversion of circulating androgens into estrogen in regulating male skeletal homeostasis. All four cases of aromatase-deficient men reported to date showed an identical skeletal phenotype, characterized by tall stature due to continued longitudinal growth, unfused epiphyses, high bone turnover, and osteopenia. Studies using knockout mice along with experimental observations in rats treated with an aromatase inhibitor provided useful information about the importance of aromatase in the male skeleton. Confirmatory evidence comes from recent interventional studies in adult men using aromatase inhibition, which confirmed that estrogens are critically important to the male skeleton by helping to control rates of bone remodeling. Intriguingly, common polymorphisms at the human aromatase (CYP19) gene have been associated with differences in aromatase activity, bone turnover, and rates of bone loss in elderly men, suggesting that variations in aromatase efficiency may also be relevant for skeletal homeostasis. Several additional mechanisms have been proposed in which aromatase activity could be modulated under certain circumstances in different tissues. Additional studies are needed to identify how these genetic, environmental, pathological, and pharmacological influences might modulate aromatase activity in vivo, increasing or reducing estrogen production in males and thereby affecting skeletal health.     

Fracture healing and bone mass in rats fed on liquid diet containing ethanol

BACKGROUND: Studies in animal models for alcohol abuse have suggested that ethanol inhibits bone growth, decreases bone formation, and increases fracture risk. METHODS: Experimental tibia fracture healing in rats fed a liquid diet containing 7.2% ethanol for 8 weeks was investigated with histological and osteodensitometric studies with respect to the control group. After 4 weeks of vitamin A- and sucrose-enriched milk containing 7.2% ethanol feeding, we created closed tibia fractures, which were then fixed with intramedullary nails, in 10 rats. After a follow-up time of 4 weeks, the rats were killed for examination. The same procedure was performed in another 10 rats, which were fed on the same diet (isocaloric modified liquid diet) but without ethanol and used as the control group. A histological scoring system was developed for fracture healing. RESULTS: Histological evaluation of fracture region revealed an average fracture healing score of 1.9 in the ethanol-fed group versus 2.6 in the control group (p = 0.014). In the test group, dual-energy x-ray absorptiometry measurements in the fracture region showed a mean bone mineral density of 0.11 +/- 0.03 g/cm(2), whereas it was 0.130 +/- 0.051 g/cm(2) in the control group (p = 0.000). The mean bone mineral content in the fracture region was 0.103 +/- 0.08 g/cm(3) in the test group versus 0.128 +/- 0.06 g/cm(3) in the control group (p = 0.000). A significant correlation was found among histological scores, bone mineral density (r = 0.64, p = 0.04), and bone mineral content (r = 0.63, p = 0.04). CONCLUSIONS: This study showed that rats fed on a diet mixed with ethanol have a histologically delayed fracture healing associated with decreased bone density and mineral content. Besides the negative effects of ethanol on bone metabolism, it also interferes with the fracture-healing process.     

Deranged bone mineral metabolism in chronic alcoholism

Chronic alcoholic subjects may suffer from osteopenia with either osteomalacia or osteoporosis as the main histologic finding. The reasons may be multifactorial, including nutrition, direct effects of alcohol on bone, and deranged liver function. Seventeen asymptomatic subjects with chronic alcoholism were studied. Serum PTH (carboxyl and midmolecule fragments), 25 hydroxyvitamin D [25(OH)D], 1-25 dihydroxyvitamin D [1-25(OH)2D], and ionized calcium were measured in each subject. In addition to these tests, we employed a sensitive technique of dual photon absorptiometry to measure vertebral bone density and a radioimmunoassay of serum bone gla protein (BGP) to estimate osteoblast function. Our results show that subjects suffering from chronic alcoholism had significantly lower serum 25(OH)D and higher ionized calcium, BGP, PTH (midmolecule) and 1,25(OH)2D while four patients had bone density values below the fracture threshold (0.96 g/cm2). These findings demonstrate that asymptomatic patients with chronic alcoholism have deranged bone mineral metabolism including abnormal BGP and some subjects may even have abnormal dual photon absorptiometry measurements. These particular subjects may be at risk in the future for developing osteopenia and consequent vertebral compression fractures.