Osteoporosis Associated with Neutralizing Autoantibodies against Osteoprotegerin

Riches, Philip L.; McRorie, Euan; Fraser, William D.; Determann, Catherine; Hof, Rob J van 't; Ralston, Stuart H.

doi:10.1056/nejmoa0810925

Cited by 88 publications

(53 citation statements)

References 16 publications

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“…It is also possible that, besides malabsorption, indirect factors such as serum antibodies contribute to the bone loss in celiac disease. 30,31 The mucosal inflammation measured by CD3ϩ IEL density proved a poor predictor of the clinical outcomes. This partly could be explained by the fact that the inflammation is not always remedied by a gluten-free diet and very often celiac patients evince persistent mucosal inflammation despite a strict diet.…”

Section: Discussionmentioning

confidence: 99%

Degree of Damage to the Small Bowel and Serum Antibody Titers Correlate With Clinical Presentation of Patients With Celiac Disease

Taavela¹,

Kurppa²,

Collin³

et al. 2013

Clinical Gastroenterology and Hepatology

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Section: Discussionmentioning

confidence: 99%

Degree of Damage to the Small Bowel and Serum Antibody Titers Correlate With Clinical Presentation of Patients With Celiac Disease

Taavela¹,

Kurppa²,

Collin³

et al. 2013

Clinical Gastroenterology and Hepatology

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“…Autoantibodies neutralising the bone regulatory cytokine osteoprotegerin (OPG) have previously been described in a patient with severe osteoporosis and an incidental finding of autoimmune thyroid and coeliac disease (2).…”

Section: Introductionmentioning

confidence: 99%

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

et al. 2015

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ObjectivesAutoantibodies 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. MethodsA 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. ResultsRaised 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 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). ConclusionPolyclonal 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.3

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“…33 Recently, a novel mechanism of osteoporosis has been described due to the development of neutralising antibodies to OPG. 34 These antibodies block the inhibitory effect of OPG on RANK signalling (Figure 2). The index case was a 40-year-old man who presented with a low trauma fracture and severe osteoporosis (lumbar spine T score of -6.6).…”

Section: Osteoporosismentioning

confidence: 99%

“…34 This raises the possibility that these antibodies might contribute to the pathogenesis of osteoporosis in coeliac disease more widely, although the clinical relevance of these findings remains to be established. …”

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confidence: 99%

Recent insights into the biology of bone turnover

Riches

Ralston²

2010

JRCPE

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Recent insights into the biology of bone turnover J R Coll Physicians Edinb educationAutoantibodies to OPG were found in about 20% of a small cohort of patients with coeliac disease. 34 This raises the possibility that these antibodies might contribute to the pathogenesis of osteoporosis in coeliac disease more widely, although the clinical relevance of these findings remains to be established. clInIcAl ImplIcAtIonsThe identification of the RANK pathway has opened up novel therapeutic targets in the management of osteoporosis. An Fc-OPG construct showed effectiveness in reducing bone turnover, 35 although this is no longer being developed in clinical trials. More recently denosumab, a fully humanised anti-RANKL antibody has shown effectiveness in the treatment of post-menopausal osteoporosis. 36 Alternatively, the signalling cascade induced by RANK binding may be targeted by small molecule inhibitors, as has been demonstrated in other members of the TNF superfamily. 37The observation that neutralising antibodies to OPG cause severe osteoporosis raises the possibility that screening for OPG antibodies, particularly in patients with autoimmune disease, may be a valuable method for detecting patients at risk of osteoporosis and guiding their subsequent management. Such patients would be expected to have high bone turnover and therefore be particularly suitable for treatment with antiresorptive drugs. It is also possible that specific treatments may be developed to block the neutralising antibody itself.Since RANK signalling has been shown to be a critical regulator of diverse functions such as lymph node organogenesis, 7 thymic development 38 and temperature regulation, 39 there will need to be careful evaluation of any novel therapy targeting this pathway. . The addition of OPG (100 ng/ml) blocks this signalling (green). Patient serum (1/40 dilution) reversed this inhibition (blue), but this could be overcome by the addition of excess OPG (400 ng/ml) (purple). There was no effect on signalling in the absence of RANKL stimulation (grey).

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Osteoporosis Associated with Neutralizing Autoantibodies against Osteoprotegerin

Cited by 88 publications

References 16 publications

Degree of Damage to the Small Bowel and Serum Antibody Titers Correlate With Clinical Presentation of Patients With Celiac Disease

Degree of Damage to the Small Bowel and Serum Antibody Titers Correlate With Clinical Presentation of Patients With Celiac Disease

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

Recent insights into the biology of bone turnover

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