Different Effects of Biologics on Systemic Bone Loss Protection in Rheumatoid Arthritis: An Interim Analysis of a Three-Year Longitudinal Cohort Study

ObjectiveTo compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis factor-α inhibitors (TNFi), and abatacept.MethodsPatients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD.ResultsA total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA.ConclusionCompared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy.

Effects of Autoantibodies on Osteoclasts

The balance between bone forming osteoblasts and bone resorbing osteoclasts can be disturbed in autoimmune diseases resulting in local and systemic bone loss. It was long time believed that autoantibodies only indirectly contribute to bone loss by fueling the overall inflammation. However, in the last decade, more and more evidence emerged that autoantibodies and immune complexes directly activate osteoclasts and pre-osteoclasts by binding to Fcγ receptors (FcγRs) on the (pre)-osteoclast cell surface. This pro-osteoclastogenic effect seems to be dependent on the absence of sialic acid in the IgG Fc glycan, which is a typical feature of many autoantibodies. Clinical studies revealed the importance of autoantibody-mediated bone loss mainly in rheumatoid arthritis, but also in other diseases, such as celiac disease. In summary, the gained knowledge about autoantibody-mediated bone loss helps to better understand bone pathologies of autoimmune diseases. However, studies are still relatively limited and more research is needed to fully understand the impact of autoantibodies on bone and to develop future therapeutic strategies.

Getting to the heart of bone loss

Heart attack leads to systemic bone loss in mice, indicating fracture risk as a clinical comorbidity of heart attack.

Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis

Background The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model. Methods TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis. Results TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.