Bone loss in Crohn's disease: exercise as a potential countermeasure

Crohn's disease (CD) is associated with a number of secondary conditions including osteoporosis, which increases the risk of bone fracture. The cause of metabolic bone disease in this population is believed to be multifactorial and may include the disease itself and associated inflammation, high-dose corticosteroid use, weight loss and malabsorption, a lack of exercise and physical activity, and an underlying genetic predisposition to bone loss. Reduced bone mineral density has been reported in between 5% to 80% of CD sufferers, although it is generally believed that approximately 40% of patients suffer from osteopenia and 15% from osteoporosis. Recent studies suggest a small but significantly increased risk of fracture compared with healthy controls and, perhaps, sufferers of other gastrointestinal disorders such as ulcerative colitis. The role of physical activity and exercise in the prevention and treatment of CD-related bone loss has received little attention, despite the benefits of specific exercises being well documented in healthy populations. This article reviews the prevalence of and risk factors for low bone mass in CD patients and examines various treatments for osteoporosis in these patients, with a particular focus on physical activity.     

Secondary osteoporosis and glucocorticoid-induced osteoporosis

In order to assess properly the diagnosis of osteoporosis, a short clinical investigation is required to address potential causes for bone loss. Osteoporosis used to be suspected in a patient with vertebral demineralization, but nowadays it is often diagnosed in a patient with a low bone mass on a screening dual-energy X-ray absorptiometry (DEXA). In this setting, it is important for the clinician to look for secondary osteoporosis, especially in men in whom secondary osteoporosis is more frequent than in women, before discussing any specific therapy. The major causes are longterm glucocorticoid therapy, endocrine (hypogonadism, primary hyperparathyroidism, hyperthyroidism), or digestive diseases.     

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.     

Osteoporosis: the evolution of a diagnosis

The global trend towards increased longevity has resulted in ageing populations and a rise in diseases or conditions that primarily affect older persons. One such condition is osteoporosis (fragile or porous bones), which causes an increased fracture risk. Vertebral and hip fractures lead to increased morbidity and mortality and result in enormous healthcare costs. Here, we review the evolution of the diagnosis of osteoporosis. In an attempt to separate patients with normal bones from those with osteoporosis and to define the osteoporosis diagnosis, multiple factors and characteristics have been considered. These include pathology and histology of the disease, the endocrine regulation of bone metabolism, bone mineral density (BMD), fracture type or trauma severity, risk models for fracture prediction, and thresholds for pharmacological intervention. The femoral neck BMD ?2.5 SDs cut‐off for the diagnosis of osteoporosis is arbitrarily chosen, and there is no evidence to support the notion that fracture location (except vertebral fractures) or severity is useful to discriminate osteoporotic from normal bones. Fracture risk models (including factors unrelated to bone) dissociate bone strength from the diagnosis, and treatment thresholds are often based on health‐economic considerations rather than bone properties. Vertebral fractures are a primary feature of osteoporosis, characterized by decreased bone mass, strength and quality, and a high risk of another such fracture that can be considerably reduced by treatment. We believe that the 2001 definition of osteoporosis by the National Institutes of Health Consensus Development Panel on Osteoporosis is still valid and useful: ‘Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture’.     

Low bone mass in children and adolescents

Osteoporosis is a disease characterized by low bone mass and micro architectural alterations of bone tissue leading to enhanced bone fragility and increased fracture risk. Although research in osteoporosis has focused mainly on the role of bone loss in the elderly population, it is becoming increasingly clear that the amount of bone that is gained during growth is also an important determinant of future resistance to fractures. Thus, considerable interest is being placed on defining preventive strategies that optimize the gain of bone mass during childhood and adolescence. Knowledge of the determinants accounting for the physiologic and genetic variations in bone accumulation in children will provide the best means toward the early diagnosis and treatment of osteoporosis. This article reviews the techniques available for bone mass measurements in children and the major determinants and diseases influencing bone accretion during childhood and adolescence.     

Bone mineral density directly correlates with duodenal Marsh stage in newly diagnosed adult celiac patients

Abstract Objectives. To estimate the prevalence of low bone mineral density (BMD) in a prospective series of adult celiac patients and to identify nutritional and metabolic factors associated with osteoporosis and osteopenia. Methods. Patients over 18 years of age who were consecutively and newly diagnosed with celiac disease (CD) were recruited. A bone density scan with dual-energy X-ray absorptiometry was carried out on the left hip and lumbar spine; nutritional parameters were analyzed and a hormone study conducted in order to exclude secondary low BMD. Results. 40 patients (36 females/4 males) between the ages of 18 and 68 (mean 44.25 years) were recruited. Overall, at the moment of diagnosis 45% of patients exhibited low BMD at both demarcations. Risk of hip fracture was generally low, but ascended to mild in patients with villous atrophy (p = 0.011). Differences in major fracture risk were also observed depending on Marsh stage (p = 0.015). Significant differences were observed in nutritional status between patients with and without duodenal villous atrophy, with body mass index and blood levels of prealbumin, iron, vitamin D and folic acid significantly lower in Marsh III stage patients. No differences were found in blood hormone levels between Marsh stages or BMDs. The degree of bone mass loss in the lumbar spine directly correlated to Marsh stage. In the hip, a parallel association between BMD and Marsh stage was also observed, but did not reach statistical significance. Conclusion. Duodenal villous atrophy, through malabsorption, was the main determinant factor for low BMD in adult-onset CD patients.     

Risk factors for low bone density in Crohn's disease

Osteopenia and osteoporosis are prevalent in patients with Crohn's disease (CD). We conducted a cross-sectional study on consecutive patients with CD to assess the prevalence and factors associated with low bone mass density (BMD).One hundred sixty-eight patients with CD were evaluated. Baseline demographics, medical and surgical history, calcium intake, physical activity, steroid use, Harvey Bradshaw Index, blood and urine tests, and dual-energy X-ray absorptiometry were obtained. Sixty-seven (40%) and seventy-five (45%) patients had osteopenia of the femur and spine, respectively. Ten to 11% of patients had osteoporosis. Of the 40 patients who never used steroids, 19 (48%) had osteopenia of the femur and 12 (30%) of the spine. Significant associations were found between BMD and age, body mass index, and serum magnesium. Lifetime steroid use was a weaker predictor of bone loss. Duration of disease did not correlate with BMD when adjusted for age. At follow-up at a mean of 2 years, BMD declined in the femur but not the spine. However, those with ongoing steroid use had lower spine BMD. A significant number of patients with CD have osteopenia. Age was the most important predictor of bone loss. Significant proportion of steroid naive patients had osteopenia, which implies that mechanisms other than steroid use are also involved in bone loss in CD. Disease activity, systemic inflammation, and hormonal and genetic factors may all be important determinants of bone loss in CD.     

Lymphoplasmacytoid lymphoma presenting as severe osteoporosis

We report four cases presenting with severe osteoporosis which on further investigation were found to have an underlying lymphoplasmacytoid lymphoma (LPL). Common secondary causes of osteoporosis were excluded in each case. Three of the cases responded to treatment with a biphosphonate. As these lymphomas share some common pathological and clinical features with multiple myeloma (MM) an association with osteoporosis is likely to represent more than a coincidental finding. The incidence of osteoporosis occurring with LPL will become clearer if routine imaging is carried out in patients at presentation. Issues relating to the treatment of the osteoporosis as well as the lymphoma arise in patients that present in this way. Based on the model of bone disease in MM, correlating serum levels of osteoclast activating cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor (TNF) with the actual finding of bone disease provides a basis for future research into the pathogenesis and management of bone disease in these rare forms of low grade non-Hodgkin's lymphoma.     

Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition

Fetal and postnatal bone development is by tradition viewed as a process of bone mineral accretion or an increase in bone mass. Accordingly, previous approaches to bone development in neonatology and early childhood have emphasized the determinants of peak bone mass and their relationship to osteopenia, osteoporosis and fractures in later life. This suggests that the neonatal period and early childhood is an important period for bone mineral accrual, and that peak bone mass may be correlated with subsequent skeletal health. Nevertheless, describing fetal and postnatal bone development just in terms of changes in mass or density means looking at bones as if they were amorphous heaps of calcium and phosphorus. In reality, of course, bones are complex three-dimensional structures. It is therefore important to create conditions that stimulate bones to become more stable. We suggest that functional bone physiology can be used to explain fetal and postnatal bone development and to devise strategies for improved bone development in both premature infants and neonates.     

Osteoporosis and inflammatory bowel disease: prevalence and risk factors in Tunisian patients

OBJECTIVES: The study was aimed to evaluate osteoporosis prevalence in a group of Tunisian patients with inflammatory bowel disease (IBD), to determine its risk factors, and to describe its mechanisms. SUBJECTS AND METHODS: We included 67 IBD patients, 43 patients with Crohn's disease (CD) and 24 with ulcerative colitis (UC). Bone mineral density was measured at the lumbar spine and left femoral neck by dual-energy X-ray absorptiometry. We used T score to express bone loss (osteopenia: -2.5 SD 2 years and active disease tended to be associated with lumbar osteoporosis; the ORs were respectively 4.87 [0.92-25.80] (P=0.06), 4.21 [0.87-20.57] (P=0.06), and 2.33 [0.78-6.67] (P=0.13). No association was found with cumulated dose of steroids even when considering only CD. Patients with osteoporosis showed significant increased CrossLaps and interleukin-6 levels that indicate both high bone resorption and inflammatory activity. CONCLUSIONS: Osteoporosis is frequent in IBD patients, especially in CD patients. Female gender, malnutrition (body mass index <20 kg/m2), disease course (> 2 years) and active disease would be risk factors of bone mineral loss in IBD. Osteoporosis is associated with enhanced bone resorption, that seems be linked to excessive intestinal inflammation.     

Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis

BACKGROUND: There is an increased prevalence of osteoporosis among patients with celiac disease. However, the relative prevalence of celiac disease among osteoporotic and nonosteoporotic populations is not known, and the benefit of screening the osteoporotic population for celiac disease remains controversial. METHODS: We evaluated 840 individuals, 266 with and 574 without osteoporosis, from the Washington University Bone Clinic by serologic screening for celiac disease. Individuals with positive serologic test results for antitissue transglutaminase or antiendomysial antibody were offered endoscopic intestinal biopsy to confirm the diagnosis of celiac disease. Individuals with biopsy-proven celiac disease were treated with a gluten-free diet and followed up for improvement in bone mineral density. RESULTS: Twelve (4.5%) of 266 patients with osteoporosis and 6 (1.0%) of 574 patients without osteoporosis tested positive by serologic screening for celiac disease. All but 2 serologically positive individuals underwent in-testinalbiopsy. Nine osteoporotic patients and 1 nonosteoporotic patient had positive biopsy results. The prevalence of biopsy-proven celiac disease was 3.4% among the osteoporotic population and 0.2% among the nonosteoporotic population. All biopsy-positive individuals tested positive by antitissue transglutaminase and antiendomysial antibody. The antitissue transglutaminase levels correlated with the severity of osteoporosis as measured by T score, demonstrating that the more severe the celiac disease the more severe the resulting osteoporosis. Treatment of the patients with celiac disease with a gluten-free diet resulted in marked improvement in T scores. CONCLUSIONS: The prevalence of celiac disease among osteoporotic individuals (3.4%) is much higher than that among nonosteoporotic individuals (0.2%). The prevalence of celiac disease in osteoporosis is high enough to justify a recommendation for serologic screening of all patients with osteoporosis for celiac disease.     

自身免疫性甲状腺疾病与骨代谢

甲状腺素对骨骼的生长发育及骨重建过程有着非常重要的作用.甲状腺功能亢进症引起骨量减少,增加骨折风险已经得到公认,而甲状腺功能减退症及亚临床甲状腺疾病与骨量的关系则存在争议.既往对其机制的研究主要着眼于甲状腺素(thyroid hormone,TH)及促甲状腺素(thyroid stimulating hormone,TSH)对骨代谢的影响.自身免疫性甲状腺疾病(autoimmune thyroid disease,AITD)是导致甲状腺功能亢进症或甲状腺功能减退症的最常见病因,随着骨免疫学说的提出,在AITD中免疫因素对骨量的影响,也逐渐成为研究的另一个关注点.本文将从以上3个因素对AITD与骨质疏松的关系进行综述.     

Bone Homeostasis in Intestinal Disorders

Diagnosis and therapy of osteoporosis associated with gastrointestinal diseases is a remarkable problem. Osteoporosis is most common in celiac disease, Crohn’s disease, chronic liver disease, and in postgastrectomy patients. Protocols regarding prevention, diagnosis and therapy are based on results gained from patients with osteoporosis in the general population. This review aims to summarize the special aspects and most important clinical data regarding the bone loss associated with gastrointestinal diseases.     

Association between bone mineral density of the general skeletons and jaw bones

Associations between bone mineral density (BMD) of the general skeletons and jaw bones have been investigated to clarify the influences of skeletal low BMD or osteoporosis on periodontitis and tooth loss, especially in women. Some studies reported the significant associations between general skeletal BMD and BMD (or bone mass) of the jaw bones, however, the others failed to find this association. It is likely that the differences in the methods and regions in measuring BMD (or bone mass) of the jaw bones and in study sample size may contribute to this contradiction. Further systematical investigation in the large populations would be necessary in cooperation with medical professionals.     

Osteoporosis in men

Osteoporosis is characterized by a reduction in bone density, associated with skeletal fragility and an increased risk of fracture after minimal trauma. Although osteoporosis is generally considered to be a condition affecting post-menopausal women, it is now clear that substantial bone loss occurs with advancing age in men, such that up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men. This chapter highlights the incidence and prevalence of osteoporotic fractures in men and reviews the associated morbidity, excess mortality and health and social service expenditure. The determinants of peak bone mass and bone loss in men are discussed, as is the pathogenesis of osteoporosis and vertebral and hip fractures. The criteria for the diagnosis of osteoporosis in men are reviewed, together with the most appropriate investigations for secondary osteoporosis. The management of osteoporosis in men is also discussed, highlighting the most appropriate treatment options.     

Positive IgA against transglutaminase 2 in patients with distal radius and ankle fractures compared to community-based controls

Background: Patients with celiac disease (CD), including adults with subclinical disease, have low bone mineral density (BMD), deteriorated bone microarchitecture and meta-analysis show an increased risk of fracture. Immunoglobulin A (IgA) against transglutaminase 2 (IgA TG2) is a highly reliable marker to detect CD.

Main objective: To explore the prevalence of positive IgA TG2 and CD in patients with distal radius and ankle fracture compared to community-based controls.

Methods: Four hundred patients aged 40 years or above with distal fractures were included in a case–control study. About 197 controls were identified from the National Population Registry, those included had never suffered a fracture. BMD was measured, and comorbidities, medications, physical activity, smoking habits, body mass index (BMI) and nutritional factors were registered. Blood analysis to detect common causes of secondary osteoporosis was performed.

Results: About 2.5% of the fracture patients had positive IgA TG2, compared to 1% in the control group. The odds ratio, adjusted for sex and age, of having positive IgA TG2 was 2.50 (95% CI 0.54–11.56).

Conclusions: There were no significantly increased odds of CD in adult patients with fractures compared to controls; however, results imply that positive IgA TG2 is more prevalent in fracture patients than in controls. This study indicates that universal screening for CD in fracture patients is not warranted, but supports current clinical practice in Norway to suspect and investigate for CD in patients with fracture, osteoporosis and other risk factors for CD.     

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.     

Bone mineral mass is associated with interleukin 1 receptor autoantigen and TNF-alpha gene polymorphisms in post-menopausal Mediterranean women

Bone mass is known to be under genetic control. Interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-alpha are strong inductors of bone resorption. The estrogenic deficiency that occurs during menopause leads to an increase in the production of these cytokines. We analyzed the genetic susceptibility of several polymorphisms of the interleukin-1 receptor antagonist (IL-1ra), IL-6 and TNF-alpha genes in lumbar spine and hip bone mass in a sample of post-menopausal Caucasian Mediterranean women with osteoporosis. 104 post-menopausal osteoporotic women (58.6+/-4.8 yr) and 51 post-menopausal women without osteoporosis as the control group (57.2+/-4.5 yr) were studied. The osteoporotic group was in turn sub-classified into severe and non-severe osteoporosis. The variable number of tandem repeats IL1-ra, IL-6 SfaNI and TNF-alpha NcoI genetic polymorphisms were studied. Biochemical markers of bone turnover were measured in blood and urine. Women carrying the A2 allele (A2+) of the IL-1ra gene showed greater BMD in the lumbar spine (p=0.02) and hip (p=0.006), compared to those not carrying the allele (A2-). The IL-6 polymorphism studied in its 5' flanking region did not show any association with BMD values. The TNF-alpha gene G allele was associated with a greater bone mass in the non-severe osteoporotic subgroup, both in the lumbar spine (p=0.0007) and in the hip (p=0.02). Likewise, genotype combination A2+GG was associated to a greater hip BMD at the femoral neck and Ward triangle levels (p=0.02). We conclude that both IL-1ra and TNF-alpha can be candidate loci to be studied in the susceptibility to develop post-menopausal osteoporosis.     

Aging bones as a paradigm for individual differences in aging

The physiological fate of every organism and its organ systems is aging which--as general opinion has it--after the age of 50 leads to a measurable mass of bone loss in the human skeletal system. This so-called physiological osteoporosis, however, affects the individual bones differently: Thus, the volumetric density in the neck of the femur and in the lower three lumbar vertebral bodies (LVB) decreases by 30%, but not in the lower three cervical vertebral bodies (CVB), while in the thyroid cartilage it increases constantly from the age of 15/20 years onwards. From the functional point of view, the so-called osteoporosis of old age is thus an expression of an aging bone adapting to the physical activity of the body, which, as such--just like the bone of the younger adult--merely reflects the current stressing of the cancellous bone by the locomotor system. Osteoporosis proper, in contrast, is a manifestation of disease of the bone causing clinical symptoms, in which underlying osteopenia results in fractures and spontaneous deformations.     

Evaluation and management of skeletal health in celiac disease: Position statement

OBJECTIVE:

To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients.

METHODS:

A multidisciplinary team developed clinically relevant questions for review. An electronic search of the literature was conducted using the MEDLINE and EMBASE databases from 1996 to 2010. All original studies, reviews and guidelines, both pediatric and adult, were included. A document summarizing the results of the review and proposed recommendations was prepared and underwent multiple revisions until consensus was reached.

RESULTS:

At diagnosis, approximately one-third of adult CD patients have osteoporosis, one-third have osteopenia and one-third have normal BMD. Children with CD have low bone mass at diagnosis. Adult and pediatric CD patients are at increased risk of fractures.

DISCUSSION:

For adults, serum calcium, albumin, 25(OH) vitamin D₃, parathyroid hormone and 24 h urine calcium testing should be performed at diagnosis; patients with ‘classic’ CD and those at risk for osteoporosis should undergo a dual x-ray absorptiometry scan. An abnormal baseline dual x-ray absorptiometry scan should be repeated one to two years after initiation of a gluten-free diet (GFD). For children, BMD should be assessed one year after diagnosis if GFD adherence is not strict. A GFD is the most important treatment for bone loss. Supplemental antiresorptives may be justified in those who remain at high fracture risk (eg, postmenopausal women, older men) after implementation of a GFD.

CONCLUSION:

Current evidence does not support the screening of all CD patients for low BMD at diagnosis. Follow-up BMD assessment should be performed one to two years after initiation of a GFD.