慢性阻塞性肺疾病与心血管疾病相关性研究进展

众所周知,慢性阻塞性肺疾病是一种常伴随有显著肺外表现的慢性炎症性疾病,心血管疾病风险增加即此类肺外表现之一。慢性阻塞性肺疾病与心血管疾病之间相关机制复杂,吸烟、衰老、缺氧、全身性炎症、氧化应激及用药等多种因素均可能参与其中。现就其潜在关联机制的研究现状予以综述。     

Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease

We hypothesized that in patients with chronic obstructive pulmonary disease, loss of fat-free mass (FFM) and loss of bone mineral density (BMD) were related to (1) each other and may be clinically inapparent, (2) urinary markers of cellular and bone collagen protein breakdown, and (3) severity of lung disease. Eight-one patients and 38 healthy subjects underwent dual-energy X-ray absorptiometry to determine body composition and BMD. Urinary protein breakdown markers, inflammatory mediators, and their soluble receptors were determined. Thirty-three patients had a low fat-free mass index (kg/m(2)), 17 of whom had a normal body mass index. Thirty-two percent of patients (13% of healthy subjects) had osteoporosis at the hip or lumbar spine. The marker of cellular protein breakdown was elevated in patients and related to lung disease severity and body composition. The marker of bone collagen breakdown was greater in patients with osteoporosis. Inflammatory mediators were elevated in patients. Loss of FFM and loss of BMD were related, occurred commonly, and could be subclinical in patients with chronic obstructive pulmonary disease. Loss of both was greatest with severe lung disease. Increased excretion of cellular and bone collagen protein breakdown products in those with low FFM and BMD indicates a protein catabolic state in these patients.     

炎症性肠病与骨质疏松研究进展

骨质疏松是炎症性肠病(IBD)患者常见但易被忽视的并发症之一.炎症性肠病患者骨质疏松的发病机制尚未完全明了,皮质类固醇激素的应用、炎性细胞因子的增加、维生素D的缺乏及遗传等众多因素均可能参与骨质疏松的发生.对于炎症性肠病患者并发骨质疏松者应及早诊断及治疗,早期干预可减轻IBD患者骨质疏松的发生与发展.     

Skeletal morbidity in inflammatory bowel disease

Patients with Crohn's disease are at increased risk of developing disturbances in bone and mineral metabolism because of several factors, including the cytokine-mediated nature of the inflammatory bowel disease, the intestinal malabsorption resulting from disease activity or from extensive intestinal resection and the use of glucucorticoids to control disease activity. Inability to achieve peak bone mass when the disease starts in childhood, malnutrition, immobilization, low BMI, smoking and hypogonadism may also play a contributing role in the pathogenesis of bone loss. The relationship between long-term use of glucocorticoids for any disease indication and increased risk for osteoporosis and fractures is well established. However, the relationship between Crohn's disease and ulcerative colitis and bone loss remains controversial. Depending on the population studied the prevalence of osteoporosis has thus been variably reported to range from 12 to 42% in patients with inflammatory bowel disease (IBD). In IBD most studies demonstrate a negative correlation between bone mineral density (BMD) and glucocorticoid use, but not all authors agree on the relationship between long-term glucocorticoid use and continuing bone loss. Whereas prospective studies do suggest sustained bone loss at both trabecular and cortical sites in long-term glucocorticoid users with inflammatory bowel disease, a decrease in bone mass is also observed in patients with active Crohn's disease not using glucocorticoids, and bone loss is not universally observed in patients with Crohn's disease using orally or rectally administered glucocorticoids. Data on vertebral fractures are scarce and there is no agreement about the risk of non-vertebral fractures in patients with Crohn's disease, although it has been suggested that non-vertebral fracture risk may be increased by up to 60% in patients with IBD. A recent publication reports an increased risk of hip fractures in Crohn's disease related to current and cumulative corticosteroid use and use of opiates, although these fractures could not be related to the severity of osteoporosis. The issue of the magnitude of the problem of osteoporosis has become particularly relevant in Crohn's disease, since the ability of therapeutic interventions to beneficially influence skeletal morbidity has been clearly established in patients with osteoporosis, whether post-menopausal women, men or glucocorticoid users. The main question that arises is whether all patients with Crohn's disease should be treated with bone protective agents on the assumption that they all have the potential to develop osteoporosis or whether the use of these agents should be restricted to patients clearly at risk of osteoporosis and fractures, providing these can be identified. We recommend, based on the available literature and our own experience, that all patients with Crohn's disease should be screened for osteoporosis by means of a bone mineral density measurement in addition to full correction of any potential calcium and vitamin D deficiency, to allow timely therapeutic intervention of the patient at risk while sparing the vast majority unnecessary medical treatment.     

Osteoporosis in inflammatory bowel disease

Half of all patients with inflammatory bowel disease show a significant reduction of their bone mass during the course of their chronic inflammatory disease. In contrast to women with postmenopausal osteoporosis these patients are much younger and a significant subgroup develops vertebral fractures which are mostly asymptomatic.The activity of the chronic inflammatory disease and the steroid treatment leads to bone loss predominantly through the TNFα-driven osteoprotegerin system. Clinical useful genetic markers to identify patients at risk for fractures have not been developed so far. Long-term clinical remission leads in most patients to normalisation of the bone density. Patients with reduced bone density should be substituted with calcium and vitamin D. Patients with vertebral fractures should receive bisphosphonates.     

Periarticular and generalized osteoporosis in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) develop both periarticular and generalized osteoporosis. Periarticular osteopenia in appendicular bones occurs early in the course of RA and is one of the earliest radiological signs of RA. Periarticular osteoporosis might be mediated through an increased productions of inflammatory cytokines and prostaglandins by synovium and bone marrow. Generalized osteoporosis is also common in RA and leads to increased risk of fractures. Generalized osteoporosis considered to be multifactorial. Corticosteroids and menopausal state are important risk factors for lumbar osteoporosis. Rheumatoid activity and reduced physical activity are also important determinants.     

Glucocorticoid-induced osteoporosis in men

Osteoporosis and fractures are a common consequence of glucocorticoid therapy for inflammatory disorders. Men fracture approximately 10 yr later in life than women and receive less attention as regards osteoporosis risk, including in glucocorticoid-induced osteoporosis (GIOP). In addition, while men are less likely to have certain rheumatologic disorders often treated with glucocorticoids, men are more likely to have chronic obstructive pulmonary disease, inflammatory bowel disease, and organ transplantation as reasons for use of oral glucocorticoids. Attempts to improve recognition of GIOP in general have not been successful, and since men are considered less at risk for osteoporosis in general, attention to men with GIOP is even less. Evaluation of GIOP is similar in men and women, and most modern treatment studies of GIOP have included men. Thus, alendronate, risedronate, and zoledronic acid are Food and Drug Administration (FDA)-approved bisphosphonates for GIOP in men. Teriparatide is also FDA-approved for GIOP. In one 36-month trial of teriparatide vs alendronate for GIOP in men and women, the anabolic agent led to a greater increase in bone density and was associated with a lower incidence of morphologic vertebral fractures. Thus, while good management is available for GIOP, recognition of men at risk is the most important step in improving outcomes.     

Idiopathic osteoporosis: a heterogeneous entity

DEFINITION: Idiopathic osteoporosis refers to the development of osteopenia and fractures with minimal or no trauma in otherwise young, healthy individuals who are not postmenopausal or have other, identifiable secondary causes of osteoporosis. EPIDEMIOLOGY: It is a relatively rare disorder, with an incidence of 0.4 cases per 100,000 person-years. It appears to affect both sexes equally and results primarily in the development of trabecular bone fractures such as vertebral compression fractures and Colles' fractures, although hip fractures are also seen. PATHOPHYSIOLOGY: The disease may be temporally related to pregnancy and/or lactation in some patients, although it is unclear whether pregnancy plays a pathophysiological role or, more likely, simply leads to the clinical presentation of the disease in individuals who are already affected. Various pathophysiological abnormalities have been described in these patients, including hypercalciuria, abnormalities in vitamin D metabolism, and in the production of insulin-like growth factor I and interleukin 1. Findings on bone biopsy have been variable, with some patients having evidence of a defect in osteoblast function, whereas others having evidence for increased bone resorption. TREATMENT: No specific therapy has been proven to be effective in these patients. However, an individualized approach based on an assessment of bone turnover may be reasonable and may decrease the bone loss and subsequent fracture risk.     

An educational intervention for providers to promote bone health in high-risk older patients

OBJECTIVES: To design, implement, and assess an educational intervention for providers focused on osteoporosis screening and management in older patients with chronic obstructive pulmonary disease or asthma who have been prescribed prolonged courses of oral or high‐dose inhaled corticosteroids or both and are therefore at high risk for bone loss and fractures. DESIGN: One‐group pretest–posttest. SETTING: Academic outpatient pulmonary practice. PARTICIPANTS: Nineteen pulmonary specialists at an academic medical center. INTERVENTION: Educational theory and a needs assessment and attitude survey guided the development of a multicomponent educational intervention. MEASUREMENTS: Change in provider behavior was assessed by auditing the electronic medical records for adherence to osteoporosis management guidelines in high‐risk patients seen by participants at baseline and for 6 months after the educational intervention. Knowledge transfer and changes in attitude were assessed using pre‐ and posttests and surveys. RESULTS: A 19% increase in overall rate of adherence to osteoporosis management guidelines in high‐risk patients was observed: 45% before intervention to 64% after intervention (n=249 patients, P=.003). Postintervention surveys and test scores also showed statistically significant gains from baseline. CONCLUSION: An educational intervention improved adherence to osteoporosis management guidelines of academic pulmonary specialists. The results of this study provide evidence for the positive effect of a multimodal educational program in altering practice behaviors.     

Metabolic bone disease in inflammatory bowel disease

Osteoporosis is associated with a high morbidity rate and is a risk factor for fractures. Patients with inflammatory bowel disease are at increased risk of developing osteopenia and osteoporosis. Corticosteroid use, malnutrition, and proinflammatory cytokines are unique risk factors for bone loss in ulcerative colitis and Crohn disease. Bone mineral density is assessed by dual-energy X-ray absorptiometry and reported as a T score or number of standard deviations away from the mean. A T score < 1 SD below the mean is normal, 1 to 2.5 SD below the mean is consistent with osteopenia, and greater than 2.5 SD below the mean is defined as osteoporosis. Treatment includes a combination of basic preventative measures, for example, weight-bearing exercise, calcium, vitamin D, and pharmacologic agents, (e.g., bisphosphonates).     

Osteoporosis in chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis because of their age, limited physical activity, low body mass index, smoking, hypogonadism, malnutrition, and use of corticosteroids. Systemic inflammation represents an additional pathomechanism contributing to the development of osteoporosis in COPD patients. Males in their mid to late 60s with a smoking history of greater than 60 pack-years have a prevalence rate of vertebral fractures similar to, and possibly greater than, postmenopausal women greater than or equal to 65 years old: in patients with severe COPD, up to 50-70% have osteoporosis or osteopenia, and up to 24-30% have compression vertebral fractures. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Systemic corticosteroids remain the most common cause of drug-related osteoporosis, and a meta-analysis concluded that the use of more than 6.25 mg prednisone daily led to decreased bone mineral density (BMD) and increased fracture risk. In contrast, the effects of the long-term use of inhaled corticosteroids on BMD remain debatable. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only but the recommendations follow the general recommendations for the diagnosis and treatment of osteoporosis. Early recognition of BMD loss is essential, and assumes close interdisciplinary cooperation between respirologists and reumatologists. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted. In the future, novel therapeutical strategies such as monoclonal antibodies against osteoclasts activators may prove their beneficial effects in the treatment of COPD-related osteoporosis.     

Enfermedad pulmonar obstructiva crónica y osteoporosis

Osteoporosis is one of the systemic effects associated with chronic obstructive pulmonary disease (COPD). Risk factors for bone loss include smoking, skeletal muscle weakness, low bone mass index (BMI), vitamin D deficiency, glucocorticoid use, hypogonadism and systemic inflammation. The most important clinical feature is vertebral fracture, due to its significant morbidity and mortality. The treatment of osteoporosis includes calcium and vitamin D, bisphosphonates, anabolic agents and pulmonary rehabilitation. Prospective studies are required to determine the prevalence of osteoporosis in COPD and to identify which patients are at high risk for osteoporotic fracture. The development of new drugs to control systemic inflammation may contribute to specific treatments for osteoporosis in COPD.     

Osteoporosis in rheumatic diseases

Rheumatic diseases, characterized by chronic inflammation and damage to various organs and systems, include systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis and other connective tissue diseases. Bone is a target in many inflammatory rheumatic diseases. In recent years, the survival of patients with rheumatic diseases has increased markedly and the relationship between rheumatic diseases and osteoporosis (OP) has become more prominent. OP and related fragility fractures increase the morbidity and mortality of rheumatic disease. The cause of OP in rheumatic diseases is complex. The pathogenesis of OP in rheumatic diseases is multifactorial, including disease and treatment-related factors. Osteoimmunology, a crosstalk between inflammatory and bone cells, provides some insight into the pathogenesis of bone loss in systematic inflammatory diseases. The aim of this article is to review different risk factors in rheumatic diseases. Several factors play a role, such as chronic inflammation, immunological factors, traditional factors, metabolism and drug factors. Chronic inflammation is the most important risk factor and drug treatment is complex in patients with OP and rheumatic disease. Attention should be paid to bone loss in rheumatic disease. Optimal treatment of the underlying rheumatic disease is the first step towards prevention of OP and fractures. Apart from that, a healthy lifestyle is important as well as calcium and vitamin D supplementation. Bisphosphonates or denosumab might be necessary for patients with a low T score.     

Assessment of bone mineralization in children and adolescents

Bone mineral accrual during growth results in gender-, race-, and maturation-specific changes in trabecular and cortical density and dimensions. Children with chronic disease have multiple potential risk factors for impaired bone accrual. Risk factors include delayed growth and maturation, decreased weight-bearing activity, malnutrition, vitamin D deficiency, glucocorticoid therapy, impaired sex hormones and growth hormone, and increased bone resorption by inflammatory cytokines. The impact of chronic diseases may be immediate, resulting in childhood fragility fractures, or delayed, owing to suboptimal peak bone mass accrual and increased fracture risk with the inevitable bone loss during aging. Dual energy X-ray absorptiometry is, by far, the most frequent method for the assessment of bone health in children at risk. This assessment is hampered by lack of a agreement on the quantitative definition of osteopenia and osteoporosis in children, inadequate reference data, technical limitations in small children, and varied approaches to the interpretation of results in children with delayed growth and maturation. This review summarizes the expected gains in bone size, mass and strength during childhood and adolescence, the role of the bone—muscle unit, the advantages and disadvantages of the available technologies for the assessment of skeletal health in children, and possible alternative strategies for the assessment of bone healthy in children with delayed growth and maturation.     

Declining bone mass in men with chronic pulmonary disease: contribution of glucocorticoid treatment, body mass index, and gonadal function

BACKGROUND: Men with chronic lung disease (CLD) are at risk for osteoporosis, but the relative contributions of their chronic pulmonary disease, glucocorticoid therapy, and other factors toward loss of bone has not been established. Understanding the relative importance of these factors would assist in selecting patients for bone densitometry screening and in policy decisions regarding Medicare reimbursement. OBJECTIVE: To identify patients with CLD who are most likely to benefit from bone densitometry screening based on clinical and biochemical measures. DESIGN: Cross-sectional medical survey. PATIENTS: Patients with CLD who were treated with either oral, inhaled, or no glucocorticoid therapy. A control group without lung disease was recruited from the same clinic population. MEASUREMENTS: Dual-energy X-ray absorptiometry was obtained for each group, and the association between bone mass and clinical variables, glucocorticoid use, gonadal hormones, and biochemical markers of bone metabolism was determined. RESULTS: Osteoporosis (a T score < -2.5 at the hip or spine) was five times as likely in patients with CLD as in control subjects. Although the prevalence of osteoporosis was higher (ninefold) after chronic glucocorticoid therapy, patients with CLD who had never been treated with glucocorticoids had a substantial (fourfold) risk of osteoporosis. Chronic inhaled glucocorticoid therapy offered no protection from bone loss compared to treatment with oral glucocorticoids. Of the clinical and biochemical measures that were obtained, bone mass was weakly correlated with body mass index (BMI), serum estradiol-17beta, and N-telopeptide, but not with testosterone, alkaline phosphatase, bone-specific alkaline phosphatase, or osteocalcin. CONCLUSION: Patients with CLD should be considered for bone densitometry screening regardless of glucocorticoid use. Those patients with a low BMI and/or decreased serum estradiol-17beta comprise a subgroup with increased risk for osteoporosis.     

Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications

Nonalcoholic fatty liver disease (NAFLD) and osteoporosis are two highly prevalent metabolic diseases. Increasing experimental evidence supports a pathophysiological link between NAFLD and osteoporosis. A key feature could be chronic, low-grade inflammation, which characterizes NAFLD and possibly affects bone metabolism. In this context, several factors, including but not limited to receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, osteopontin and osteocalcin, may serve as mediators. In the clinical setting, most but not all epidemiological evidence indicates that NAFLD is associated with lower bone mineral density or osteoporosis in adults. Although an association between NAFLD and osteoporosis has not yet been established, and thus remains speculative, pharmacological considerations already exist. Some of the current and emerging pharmacological options for NAFLD have shown possible anti-osteoporotic properties (eg, vitamin E, obeticholic acid, semaglutide), while others (eg, pioglitazone, canagliflozin) have been associated with increased risk of fractures and may be avoided in patients with NAFLD and concomitant osteoporosis, especially those at high fracture risk. Conversely, some anti-osteoporotic medications (denosumab) might benefit NAFLD, while others (raloxifene) might adversely affect it and, consequently, may be avoided in patients with osteoporosis and NAFLD. If an association between NAFLD and osteoporosis is established, a medication that could target both diseases would be a great advancement. This review summarizes the main experimental and clinical evidence on the potential association between NAFLD and osteoporosis and focuses on treatment considerations derived from this potential association.     

Osteopenia and osteoporosis in gastrointestinal diseases: diagnosis and treatment

An increased awareness of the higher incidence of osteopenia and osteoporosis associated with a number of gastrointestinal disease states has occurred over the last few years. High rates of bone loss have been reported in luminal diseases such as inflammatory bowel disease and celiac disease as well as in cholestatic liver diseases and in the post-liver transplant setting. The post-gastrectomy state and chronic pancreatitis are also associated with decreased bone density. Publications over the last year have provided a better understanding of the true incidence of osteoporosis and fracture risk in these gastrointestinal disease states. Dual-energy x-ray absorptiometry remains the diagnostic procedure of choice. Biochemical markers of bone resorption have a role in identifying those patients with ongoing bone loss and monitoring their response to therapy. Identification of patients at risk and initiation of measures to prevent bone loss form the optimal therapeutic strategy. This article reviews advancements in the understanding of the development and activation of osteoblasts and osteoclasts. It also reviews the recent data concerning the diagnosis and treatment of bone loss associated with various gastrointestinal disease states.     

Progression of osteoporosis in patients with COPD: a 3-year follow up study

Currently, our knowledge on the progression of osteoporosis and its determinants is limited in patients with chronic obstructive pulmonary disease (COPD). Bone mineral density generally remains stable in patients with COPD over a period of 3 years. Nevertheless, the progression of vertebral fractures was not assessed, while an increase of vertebral fractures over time may be reasonable. Aims of the current study were to determine the percentage of newly diagnosed osteoporotic patients after a follow up of 3 years and to identify baseline risk factors for the progression of osteoporosis in COPD. Clinically stable COPD outpatients were included. Lung function parameters, body composition measures, six minute walk distance, DXA-scan and X-spine were assessed at baseline and repeated after 3 years. Prevalence of osteoporosis in COPD patients increased from 47% to 61% in 3 years mostly due to an increase of vertebral fractures. Lower baseline T-score at the trochanter independently increased the risk for the development of osteoporosis. Additionally, baseline vitamin D deficiency increased this risk 7.5-fold. In conclusion, the prevalence of osteoporosis increased over a 3-year period in patients with COPD. Baseline risk factors for the development of osteoporosis are osteopenia at the trochanter and vitamin D deficiency.