Autoantibodies to osteoprotegerin are associated with increased bone resorption in rheumatoid arthritis
Authors: Barbara Hauser, Philip L Riches, Tamara Gilchrist, Micaela R Visconti, James F Wilson, Stuart H Ralston
Journal: Annals of the Rheumatic Diseases (2015)

Osteoporosis is a common complication of many autoimmune diseases that is typically attributed to disease specific factors rather than a direct autoimmune process.This thesis arises from the investigation of a patient with severe high bone turnover osteoporosis who was identified as having autoimmune disease but whose osteoporosis deteriorated despite appropriate treatment.This presentation led to the hypothesis that neutralising autoantibodies to the bone protective cytokine osteoprotegerin (OPG) may have developed.Serum from the index patient, but not healthy controls, was able to immunoprecipitate recombinant OPG protein, demonstrating that OPG had become the target of an autoimmune response.Purified immunoglobulins from the index case were able to inhibit the function of OPG in vitro, by suppressing OPG-mediated inhibition of a luciferase reporter cell line.This represents the first description of disease associated with neutralising antibodies to OPG.Whilst the immunoprecipitation assay did identify OPG antibodies in further patients these results were difficult to quantify.A more robust enzyme linked immunosorbent assay for OPG antibodies was developed using OPG as a capture antigen, which allowed the screening of patient cohorts.Presence of OPG antibodies was defined as a titre greater than the mean plus three standard deviations of 101 healthy volunteers.A low prevalence of 14/864 (1.6%) was seen in a general population cohort and no association with bone density or turnover was seen.An association with higher vascular calcification score in this cohort requires replication.A prevalence of 37/315 (11.7%) was seen in an osteoporosis cohort though no association was seen with bone density or response to treatment.In a coeliac cohort OPG antibodies were identified in 14/282 (5.0%) patients and presence of antibody was independently associated with reduced spine bone density.Functional inhibition of OPG was shown in vitro in 3/14 (21.4%) of the positive cases.Case finding of osteoporosis in the coeliac cohort was not improved by identification of OPG antibodies.These results are consistent with OPG antibodies being pathological in a small number of patients with osteoporosis but a clinical utility of measuring OPG antibodies has not been established.iii Lay Summary of ThesisOsteoporosis, or thinning of the bones, is a common complication of many autoimmune diseases but is usually thought to be caused by the underlying disease itself.This study describes a patient with autoimmune coeliac and thyroid disease who developed very severe osteoporosis due to a protein in the blood that caused rapid bone breakdown.The protein was an antibody which blocked the function of a key protector of bone called osteoprotegerin.This patient did not respond to treatment of his thyroid and coeliac disease, but instead needed a powerful medicine to reduce bone breakdown.We have developed a test for this antibody and found levels to be raised in some patients attending routine osteoporosis and coeliac disease clinics, though in the general population levels of this protein are low.These results suggest that antibodies to osteoprotegerin might cause osteoporosis in a small number of patients, however it was not possible to show that finding antibodies to OPG will help better identify patients with osteoporosis, or influence their response to treatment with osteoporosis medicines.Further work will be needed before this better understanding of disease can lead to better care of patients.