osteoprotegerin and Celiac-Disease

Bone health, characterized by its mass, density, and micro-architectural qualities, is maintained by a balanced system of remodeling. The lack of these qualities, caused by an uncoupling of the remodeling process, leads to bone fragility and an increased risk for fracture. The prime regulator of bone remodeling is the RANK/RANKL/OPG system. The common origin of both bone and immune stem cells is the key to understanding this system and its relationship to the transcription factor nuclear factor kappaB in bone loss and inflammation. Via this coupled osteo-immune relationship, a catabolic environment from heightened proinflammatory cytokine expression and/or a chronic antigen-induced activation of the immune system can initiate a switch-like diversion of osteoprogenitor-cell differentiation away from monocyte-macrophage and osteoblast cell formation and toward osteoclast and adipocyte formation. This disruption in bone homeostasis leads to increased fragility. Dietary and specific nutrient interventions can reduce inflammation and limit this diversion. Common laboratory biomarkers can be used to assess changes in body metabolism that affect bone health. This literature review offers practical information for applying effective strategic nutrition to fracture-risk individuals while monitoring metabolic change through serial testing of biomarkers. As examples, the clinician may recommend vitamin K and potassium to reduce hypercalciuria, _-lipoic acid and N-acetylcysteine to reduce the bone resorption marker N-telopeptide (N-Tx), and dehydroepiandrosterone (DHEA), whey, and milk basic protein (the basic protein fraction of whey) to increase insulin-like growth factor-1 (IGF-1) and create a more anabolic profile.

Topics: Absorptiometry, Photon; Acidosis; Biomarkers; Bone Density; Bone Remodeling; C-Reactive Protein; Calcium; Celiac Disease; Dehydroepiandrosterone; Female; Gonadal Steroid Hormones; Humans; Hydrocortisone; Hyperhomocysteinemia; Male; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Thyroid Diseases; Vitamin D; Vitamin K

Skeletal demineralization and mineral metabolism derangement are well-recognized features of untreated celiac disease (CD). Although treatment with a gluten-free diet appears to prevent bone loss while correcting skeletal demineralization in childhood, there is evidence that bone mineral density does not return to normal in celiacs diagnosed in adulthood. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, and ligand of receptor activator of NFkB (RANKL) are involved in the process of bone turnover and have been implicated in the pathogenesis of osteoporosis and other metabolic bone diseases. We measured OPG, RANKL, bone mineral density (BMD), and biochemical markers of bone turnover in 32 adult female premenopausal celiac patients on a gluten-free diet, and thirty age-matched healthy women. We correlated the OPG/RANKL ratio with the severity of bone loss. Celiac patients had a mean BMD lower than controls in lumbar spine and in the femoral neck. Serum levels of bone alkaline phosphatase (BAP, marker of bone formation), and urinary excretion of telopeptides of type I collagen (a marker of bone resorption) were significantly higher than in controls. Serum OPG and RANKL levels were significantly higher in CD patients than in controls, while the OPG/RANKL ratio was significantly lower in CD patients than in controls and was positively correlated with BMD at the spine. The role of elevated OPG in CD patients is unclear, but it might represent a compensatory mechanism against other factors that promote bone damage. Further studies are required to assess a possible therapeutic potential of osteoprotegerin in optimally treated celiacs with persistent osteopenia.

Topics: Adult; Biomarkers; Bone Density; Bone Resorption; Carrier Proteins; Case-Control Studies; Celiac Disease; Female; Follow-Up Studies; Glutens; Glycoproteins; Humans; Long-Term Care; Membrane Glycoproteins; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

A clinically meaningful impairment of bone mass secondary to malabsorption is frequent in untreated celiac disease. In adult patients, a rigorous gluten-free diet (GFD) significantly improves, but does not always normalize, bone mineral density (BMD). The reason for this marginal response is unclear. Accordingly, we evaluated the role of both local and systemic factors for bone loss in celiac patients on long-term GFD.. In a prospective cohort, 22 patients with low lumbar and/or femoral BMD and 22 with normal BMD underwent bone and mineral metabolism evaluation: we tested calcium, phosphate, parathyroid hormone, and vitamin D; telopeptide of type I collagen, a bone resorption index; propeptide of type I procollagen, a bone neoformation index; receptor antagonist of NF-kB ligand, an osteoclast-stimulating factor; osteoprotegerin (OPG), a decoy receptor for RANKL. Sunlight exposure and physical exercise were measured.. Patients with bone loss showed prevalently osteopenia, severe osteoporosis was rare. In comparison with normal BMD patients, they showed higher serum OPG, telopeptide, and lower serum propeptide, suggesting an increased bone turnover. Lumbar T-score was negatively correlated with OPG, telopeptide and RANKL and positively with propeptide. Propeptide was negatively correlated with OPG and telopeptide. OPG was positively correlated with telopeptide.. The persistent activation of inflammation should be considered the main pathophysiological mechanism for bone defect in celiac disease patients with bone loss on long-term GFD. High levels of OPG, an attempt at protective mechanism, and low levels of propeptide of type I procollagen, reflecting an insufficient matrix production, characterize this subgroup of patients.

Topics: Adult; Bone Density; Bone Diseases, Metabolic; Celiac Disease; Cohort Studies; Diet, Gluten-Free; Female; Humans; Inflammation; Osteoporosis; Osteoprotegerin; Peptide Fragments; Procollagen; Prospective Studies

Autoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. A direct enzyme-linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. Raised titres of antibodies to OPG were found in 7/71 (9.8 %) patients with coeliac disease, compared with 1/72 (1.4 %) non-coeliac osteoporosis clinic control patients (p < 0.05). Our results suggest that a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z-score of the hip in coeliac patients on univariate (p < 0.05) and multivariate analysis including age, sex height and weight as covariates (p < 0.01). Polyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z-scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies.

Topics: Absorptiometry, Photon; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Blotting, Western; Bone Density; Celiac Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Osteoprotegerin; Young Adult

To investigate risk factors for low bone mineral density (BMD) in celiac disease (CD) patients, focusing on circulating autoantibodies against osteoprotegerin (OPG).. Seventy asymptomatic CD adult patients on gluten-free diet (GFD) and harbouring persistent negative CD-related serology were recruited. Conventional risk factors for osteoporosis (e.g., age, sex, menopausal status, history of fractures, smoke, and body mass index) were checked and BMD was assessed by dual energy X ray absorptiometry. Serum calcium and parathyroid hormone (PTH) levels were evaluated. Thirty-eight patients underwent repeat duodenal biopsy. Serum samples from a selected sub-group of 30 patients, who were also typed for human leukocyte antigen (HLA) DQ2 and DQ8 haplotype, were incubated with homodimeric recombinant human OPG and tested by western blotting with an anti-OPG antibody after immunoprecipitation.. Despite persistent negative CD-related serology and strict adherence to GFD, 49 out of the 70 (74%) patients displayed low BMD. Among these patients, 13 (24%) showed osteoporosis and 36 (76%) osteopenia. With the exception of age, conventional risk factors for osteoporosis did not differ between patients with normal and low BMD. Circulating serum calcium and PTH levels were normal in all patients. Duodenal mucosa healing was found in 31 (82%) out of 38 patients who underwent repeat duodenal biopsy with 20 (64%) still displaying low BMD. The remaining 7 patients had an incomplete normalization of duodenal mucosa with 6 (84%) showing low BMD. No evidence of circulating antibodies against OPG was found in the serum of 30 celiac patients who were tested for, independent of BMD, duodenal histology, and HLA status.. If any, the role of circulating autoantibodies against OPG in the pathogenesis of bone derangement in patients with CD is not a major one.

Topics: Adult; Aged; Autoantibodies; Bone Diseases, Metabolic; Calcium; Celiac Disease; Diet, Gluten-Free; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoprotegerin

Autoantibodies against osteoprotegerin, which block the inhibitory effect of osteoprotegerin on signaling by the receptor activator of nuclear factor (NF)-kappaB (RANK), were identified in a man with celiac disease who presented with severe osteoporosis and high bone turnover. The osteoporosis did not respond to the treatment of his celiac disease but was completely reversed by bisphosphonate therapy. Autoantibodies against osteoprotegerin were detected in three additional patients with celiac disease. Such autoantibodies may be associated with the development of high-turnover osteoporosis, but whether autoantibodies against osteoprotegerin commonly contribute to the pathogenesis of osteoporosis in patients with celiac disease remains to be determined.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Biomarkers; Bone Density; Bone Remodeling; Celiac Disease; Diet, Gluten-Free; Humans; Hypothyroidism; Immunoglobulin A; Male; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Transglutaminases

Bone turnover impairement and low bone density in 25-year-old man with active celiac disease was presented. The patient refused gluten-free diet compliance and clinically showed doughy abdomen, hyperpigmentation, finger clubbing and koilonychia. In serum, we obtained about 2-fold of formation markers (osteocalcin, bone alkaline phosphatase) and and 5-fold higher levels of resorption marker (collagen type I crosslinked C-telopeptide). The concentration of osteoprotegerin was slightly above normal range. We observed the trace amounts of 25-(OH)D in serum whereas the level of parathormone was 2-fold higher than in controls. Serum calcium and phosphorus were often below normal range. In dual X-ray absorptiometry (DXA) whole-body bone density was remarkably reduced. Our results suggest, that on gluten-containing diet the patient will develop lower bone mineral density and higher risk of fractures and skeletal deformities.

Topics: Absorptiometry, Photon; Adult; Alkaline Phosphatase; Bone and Bones; Bone Density; Calcium; Celiac Disease; Glycoproteins; Humans; Male; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Phosphates; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Celiac disease is an autoimmune disorder characterized by atrophy of the intestine villi triggered by ingestion of gluten in genetically susceptible individuals. The association between celiac disease and low BMD has been recognized, but the mechanisms of disturbance are poorly understood. We show imbalance of cytokines relevant to bone metabolism in celiac patients' sera and the direct effect of these sera on in vitro bone cell activity.. Celiac disease is associated with mineral metabolism derangement and low BMD. We investigated whether imbalance of serum factors in celiac patients could affect human bone cell activity in vitro.. We studied two groups of celiac patients--one on a gluten-free diet and another before the diet--both with decreased bone mass. Patients were investigated for bone turnover markers, and their sera were used for culturing bone cells from healthy donors and evaluate changes in cell activity.. The N-terminal telopeptide of procollagen type I and interleukin (IL)-6 were higher than normal in patients not on the gluten-free diet. IL-1beta and TNF-alpha/beta were normal in all patients. IL-12 was reduced in all patients, whereas IL-18 was reduced only in patients on the diet. The RANKL/osteoprotegerin (OPG) ratio was increased in patients not on the gluten-free diet. Persistently increased osteoclast numbers were obtained from peripheral blood mononuclear cells of healthy donors on incubation with sera of patients not on the gluten-free diet versus control sera and sera from patients on the diet. In human osteoblasts from healthy individuals, IL-18 was reduced on incubation with sera from all patients, whereas OPG expression was lower when sera from patients not on the diet were used. Proliferation, alkaline phosphatase, and nodule mineralization were increased in osteoblast cultures containing sera from all celiac patients, either on or not on the gluten-free diet.. We conclude that bone loss in celiac disease might also be caused by a cytokine imbalance directly affecting osteoclastogenesis and osteoblast activity.

Topics: Adult; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Resorption; Carrier Proteins; Celiac Disease; Collagen; Collagen Type I; Cytokines; Female; Glutens; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Glycoproteins; Humans; Leukocytes, Mononuclear; Male; Membrane Glycoproteins; Osteoblasts; Osteoclasts; Osteoprotegerin; Parathyroid Hormone-Related Protein; Peptides; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor