Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3–6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.

In conclusion, we have found that B-cell depletion increases bone formation and decreases bone resorption in RA patients; this may be a direct effect on osteoblasts and osteoclasts, respectively, and be at least partially explained by the decreased inflammation and disease activity.

IntroductionB-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.MethodsIn this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.ResultsFixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.ConclusionBy studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.

Data describing the effect of in vivo B cell depletion on general bone loss in patients with rheumatoid arthritis (RA) are limited. Given the pathogenetic role of B cells in RA, it is tempting to speculate that B cell depletion might have a beneficial effect on bone loss. We prospectively investigated the changes in bone mineral density (BMD), bone turnover, inflammation and disease activity before and after rituximab in 45 RA patients over a 12 month period, 36 patients of whom completed the study and were included in the analysis. There was no significant change in our primary endpoint; lumbar spine BMD after 12 months. However, we found a significant decrease in neck of femur (mean -0.017 g/cm2, 95% CI -0.030, -0.004 p = 0.011) and total femur BMD (mean -0.016 g/cm2, 95% CI -0.025, -0.007 p = 0.001). Additionally, there was a significant increase in procollagen type 1 amino-terminal propeptide (P1NP) and bone specific alkaline phosphatase (BAP); biomarkers of bone formation (median change from baseline to 12 months; P1NP 11.3 μg/L, 95% CI -1.1, 24.8 p = 0.025; BAP 2.5 μg/L, 95% CI 1.2, 3.6 p = 0.002), but no significant change in bone resorption or osteocyte markers. The fall in BMD occurred despite improvement in disease control. Post-menopausal women had the lowest mean lumbar spine, femoral and forearm BMD at baseline and after 12 months, additionally they had a higher level of bone turnover throughout the study. In conclusion, BMD was maintained at the lumbar spine and forearm, but fell at the femur sites. A high prevalence of vitamin D deficiency was observed and these patients had lower BMD and evidence of higher bone turnover.