Higher prevalence of thyroid-specific autoantibodies (TPOAb and TgAb) is related to a higher prevalence of fractures in females: results from NHANES 2007-2010.

A retrospective analysis was conducted using data from the NHANES. Bone mineral density (BMD) was compared in different thyroid-specific autoantibodies groups. Strengths of associations were calculated by using binary logistic regression models. Higher titers of thyroid-specific autoantibodies (TgAb and/or TPOAb) may lead to decreased BMD. Higher prevalence of TgAb and TPOAb significantly associated with fractures in females but not in males. PURPOSE: Hashimoto's thyroiditis is characterized by elevated thyroid-specific autoantibodies. It is currently believed that osteoporosis is not only a disease with abnormal mineral metabolism but also with immune abnormalities. This study investigated the relationship between thyroid-specific autoantibodies and osteoporosis, including the bone mineral density (BMD) values and fractures. METHODS: A retrospective analysis was conducted using data from the National Health and Nutrition Examination Survey (2007-2010). BMD was compared in different thyroid-specific autoantibodies groups. The associations between thyroid-specific autoantibodies and fractures were explored. Strengths of associations were calculated by binary logistic regression models. Candidate variables for binary logistic regression model were selected after screened in univariate analysis (variables with P < 0.05). RESULTS: A total of 3865 study participants were included in this analysis; 224 participants were TgAb positive and 356 were TPOAb positive. A total of 392 participants reported hip, spine or wrist fractures. Participants with higher prevalence of TgAb or TPOAb had lower BMD. In females, significant cigarettes use, higher prevalence of TgAb and TPOAb, and the BMD of the total femur and femoral neck were significantly associated with fractures. Higher prevalence of TPOAb was particularly associated with a higher possibility of hip or spine fractures. In males, significant cigarettes use, 25OHD3, the BMD values of the total femur, femoral neck and total spine were significantly associated with fractures. CONCLUSION: Higher prevalence of thyroid-specific autoantibodies may lead to decreased BMD. In females, higher prevalence of TgAb and TPOAb significantly associated with fractures and TPOAb especially relating to the fractures of hip and spine. Males patients with vitamin D deficiency or insufficiency associated a higher possibility of fractures.

Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway.

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

Inflammatory cytokines IL-6 and TNF-α in patients with hip fracture.

Mortality and remaining bedridden following the hip fracture surgery are not rare. We tried to measure the levels of inflammatory markers tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) following the hip fracture surgery and compare their levels with controls. We aimed to show a relationship between the levels of these markers and post-operative mortality and walking capability. INTRODUCTION: Osteoporosis is a condition, causing the hip fractures in the elderly. Hip fractures have a high rate of overall mortality up to 30% following the incident. Cytokines such as IL-6 and TNF-α are suggested to play a role in bone resorption and, thus, in the etiology of osteoporosis. METHODS: Plasma levels of IL-6 and TNF-α were measured pre-operatively and on the first and second days after the surgery in 40 Turkish hip fracture patients. The levels of these cytokines were compared with 40 Turkish age-matched healthy controls. The levels of these cytokines were compared between the deceased and surviving patients, as well as the existence of walking capability following the surgery. RESULTS: Significantly higher IL-6 levels were shown on the first and second days after the surgery (p = 0.005; p = 0.01, respectively). The overall death rate of our study group within the 2-year follow-up time was found to be 35%. No statistical significance was found in the means of 2-year follow-up mortality between the patients. Presence of walking capability did not differ between the patients, as well. CONCLUSION: We demonstrated an association between IL-6 levels and hip fracture in our study group following the surgery. We also suggest that TNF-α and IL-6 levels are not related to the occurrence of death and walking capability after the surgery. However, these findings need further functional and clinical confirmation.

Bone Disease in Connective Tissue Disease/Systemic Lupus Erythematosus.

This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2-4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies.

Functional block of IL-17 cytokine promotes bone healing by augmenting FOXO1 and ATF4 activity in cortical bone defect model.

We determine the effect of interleukin (IL)-17 neutralizing antibody on new bone regeneration. Anti-IL-17 antibody promoted new bone regeneration in cortical bone defect model by augmenting FOXO1 and ATF4 activity thereby decreasing oxidative stress. Our study demonstrates the bone healing and regeneration potential of neutralizing IL-17antibody in osteoporotic fractures. INTRODUCTION: The immune system plays important role in the fracture healing process. However, fracture healing is prolonged in disorders associated with systemic inflammation. Fracture healing is decelerated in osteoporosis, condition linked with systemic inflammation. Bone regeneration therapies like recombinant human BMP2 are associated with serious side effects. Studies have been carried out where agents like denosumab and infliximab enhance bone regeneration in osteoporotic conditions. Our previous studies show the osteoprotective and immunoprotective effects of neutralizing IL-17 antibody. Here, we determine the effect of IL-17 neutralizing antibody on new bone regeneration and compare its efficacy with known osteoporotic therapies. METHODS: For the study, female BALB/c mice were ovariectomized or sham operated and left for a month followed by a 0.6-mm drill-hole injury in femur mid-diaphysis. The treatment was commenced next day onwards with anti-IL-17, anti-RANKL (Receptor activator of nuclear factor kappa-B ligand), parathyroid hormone (PTH), or alendronate for a period of 3, 10, or 21 days. Animals were then autopsied, and femur bones were dissected out for micro-CT scanning, confocal microscopy, and gene and protein expression studies. RESULTS: Micro-CT analysis showed that anti-IL-17 antibody promoted bone healing at days 10 and 21, and the healing effect observed was significantly better than Ovx, anti-RANKL antibody, and ALN, and equal to PTH. Anti-IL-17 also enhanced new bone regeneration as assessed by calcein-labeling studies. Additionally, anti-IL-17 therapy enhanced expression of osteogenic markers and decreased oxidative stress at the injury site. CONCLUSION: Overall, our study demonstrates bone healing and regeneration potential of neutralizing IL-17 antibody in osteoporotic fractures.

Osteoporotic Vertebral Fractures as Part of Systemic Disease.

Our understanding of the genetic control of skeletogenesis and bone remodeling is expanding, and normally, bone resorption and bone formation are well balanced through regulation by hormones, growth factors, and cytokines. Osteoporosis is considered a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue. Consequent increased bone fragility results in higher fracture risk. The most common osteoporotic fractures are located in the spine, and they form a significant health issue. A large variety of systemic diseases are associated with risk of osteoporotic vertebral fractures, illustrating its multifactorial etiology. Prevalences of these conditions vary from common to extremely rare, and incidence peaks differ according to etiology. This review appreciates different aspects of osteoporotic vertebral fractures as part of systemic disease, including genetic, immunologic, inflammatory, metabolic, and endocrine pathways. It seems impossible to be all-comprehensive on this topic; nevertheless, we hope to provide a reasonably thorough overview. Plenty remains to be elucidated in this field, identifying even more associated diseases and further exposing pathophysiological mechanisms underlying osteoporotic vertebral fractures.

Impaired healing of fragility fractures in type 2 diabetes: clinical and radiographic assessments and serum cytokine levels.

BACKGROUND: Diabetes induces bone alterations accompanied by altered cytokine expression patterns. These alterations lead to modified fracture healing, contributing to musculoskeletal fragility in the elderly. AIMS: We evaluated the inflammatory immune response in diabetic patients during fracture healing relative to clinical and radiographic assessments. METHODS: Fifty patients of both sexes with fragility fractures were studied: 30 diabetics (group A, mean age 73.4 ± 11.2 years) and 20 normoglycemic controls (group B, mean age 75.1 ± 16.9 years). Two subgroups comprised those with hip or wrist fragility fractures (25 and 16 patients, respectively). We evaluated serum concentrations of tumor necrosis factor α, interleukins 4 and 8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor, and epidermal growth factor (EGF) before and at 4 and 8 weeks after surgery. We also determined the Radiographic Union Score for Hips and the Radius Union Scoring System score and applied the Physical Activity Scale for the Elderly test at the same time points. Each patient underwent bone densitometry. RESULTS: MCP-1 and EGF levels were higher in group A than in group B at 4 weeks after surgery (p > 0.05). Radiographic evaluation showed lower scores in group A (p < 0.05). The main difference between the groups was evident 4 weeks after surgery. Changes in the serum concentrations of chemotactic and angiogenic factors could explain the radiographically proved impaired fracture healing in diabetic patients. CONCLUSIONS: Fragility fracture healing is impaired in diabetic patients. Radiographic and molecular patterns confirmed that the most compromised fracture-healing phase is at 4 weeks after surgery, during callus mineralization.

Toll-Like Receptor 4 Gene Polymorphism C1196T in Polish Women with Postmenopausal Osteoporosis - Preliminary Investigation.

BACKGROUND: Postmenopausal osteoporosis is a systemic bone disease characterized by low bone mass after menopause. Bone remodeling is regulated by a number of factors, including the immune system. Toll-like receptors 4 (TLR4) are expressed on bone cells and modify the immune response. TLR4 gene polymorphism may take part in the development of chronic inflammation in women after menopause, which is the cause of severe bone resorption. OBJECTIVES: To examine the frequency of TLR4 C1196T genotypes in postmenopausal osteoporotic and non-osteoporotic Polish women and to investigate the possible relationship between C1196T polymorphism, bone mineral density (BMD) and the incidence of osteoporotic fractures in this group of patients. MATERIAL AND METHODS: The study involved 40 postmenopausal women with osteoporosis and 63 healthy postmenopausal non-osteoporotic women. BMD measurements were performed by dual-energy X-ray absorptiometry. DNA was extracted from peripheral blood. Genotyping was performed by real-time PCR using LightSNiP tests with SimpleProbe probes. Melting curve analysis of PCR amplicons enabled the identification of individual C1196T genotypes. RESULTS: C1196T genotype frequencies in the osteoporotic group were 88% for CC and 12% for CT. In the control group, respectively 86% and 14%. We did not observe the TT genotype. There was no association of C1196T genotypes and BMD nor the incidence of fractures but there was a correlation between genotypes and body height (p=0.035, r=0.415). Homozygous subjects for the C-allele had a lower body height with respect to heterozygous subjects. CONCLUSIONS: It is unlikely that TLR4 C1196T polymorphism is related to bone mineral density and fracture incidence in Polish osteoporotic women after menopause. However, our data suggests that the C allele may be associated with lower body height in this group. Due to the small number of participants, our observations should be considered as preliminary. Larger studies are needed to confirm our findings.

[Osteoporosis - inflammatory effects on bone metabolism and fracture risk]. / Osteoporose - inflammatorische Effekte auf den Knochenstoffwechsel und das Frakturrisiko.

There is a large body of evidence that proinflammatory cytokines, particularly interleukin-1, interleukin-6, and tumour necrosis factor-α, play an important role in bone metabolism. Moreover, it is suspected that proinflammatory cytokines are also important in the pathogenesis of age- and estrogen deficiency-related bone loss. Although an accelerated decrease in bone mass is observed in patients with chronic inflammatory disorders, the definite meaning of proinflammatory cytokines in the aetiology of osteoporosis is still unclear. Some studies suggest a relationship between increased concentrations of proinflammatory cytokines and a decrease in bone mineral density, as well as an increased risk of fracture. In sum, the evidence is rather scarce and does not permit any clear conclusions about the effects of single cytokines in bone metabolism. To be able to define more exactly at which stage of the pathogenesis of osteoporosis parameters of a systemic inflammation take effect, further studies will be necessary, particularly for developing suitable diagnostic markers for clinicians. These diagnostic markers may be able to identify patients at risk for osteoporosis and therefore predict fracture risks. Thus, early interventions to preserve bone health, for example, by anti-cytokine therapy, could be more effective and efficient.

Skeletal manifestations of systemic autoimmune diseases.

PURPOSE OF REVIEW: There is an increased risk of osteoporotic fractures and osteonecrosis often at a young age among patients with certain systemic autoimmune diseases. The loss of bone mineral density and bone integrity seen with these diseases often cannot be explained by traditional risk factors alone. In this review, we focus on rheumatoid arthritis and systemic lupus erythematosus, two systemic autoimmune diseases in which skeletal manifestations have been well described. RECENT FINDINGS: There is recent evidence that autoimmunity and its associated inflammation and vitamin D deficiency play key roles in the pathogenesis of adverse skeletal effects. SUMMARY: Understanding these processes carries implications for the prevention and treatment of osteoporosis and osteonecrosis among patients with autoimmune diseases.

Immune changes in post-menopausal osteoporosis: the Immunos study.

UNLABELLED: The phenotypic and functional characteristics of immune cells of osteoporotic women compared to healthy controls similar for age and estrogen level showed for the first time significant changes in several B lymphocytes populations in postmenopausal osteoporosis, related to bone mineral density (BMD) and fractures, and a significant lower basal secretion of interferon-gamma (IFN-gamma) by CD4(+). INTRODUCTION: To investigate the interactions between bone and immune system, we studied the phenotypic and functional characteristics of immune cells of 26 postmenopausal women with osteoporotic (OP) fractures compared to 24 healthy controls. METHODS: We analyzed surface markers of peripheral B, CD4(+) and CD8(+) lymphocytes and cytokine secretion in supernatants of these cells cultured with or without stimulation. Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: The two groups were similar for age and estrogen level. OP women had a significantly lower body mass index, fat mass, and lean mass. The number of CD19(+), CD19(+)/CD27(+), CD19(+)/CD27(+)/CD5(-)/CD38(+) and CD19(+)/CD27(+)/RANK(+), CD4(+)/CD27(+)/CD45RA(-)/RANK(+), and CD4(+)/CD27(+)/CD45RA(-)/CD28(+) was lower in OP women and positively correlated to BMD. In OP women, under basal conditions, CD4(+) secreted less IFN-gamma and B lymphocytes more granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF was positively correlated to fracture rate and negatively to BMD. CONCLUSIONS: Our results suggest that, regardless of age and estrogen status, postmenopausal OP is associated with immune changes, highlighting a possible role of IFN-gamma in the pathophysiology of OP and reporting, for the first time, changes in several B lymphocyte populations. These alterations may reflect the frailty observed after fracture, providing new insight into the mechanisms of morbidity and mortality associated with OP fractures.