A theoretical

concern is the possible effect of denosumab on the susceptibility to infectious diseases and on the risk of cancer. A deregulation of the immune system could also lead to the appearance of atopic disease MX69 in vivo or autoimmune diseases. Conversely, there could be a benefit in inflammatory diseases. However, though RANK and RANK-L are essential in mice for ontogeny of the lymphoid tissues [227], patients with a mutation of the RANKL gene did not present immunological defects [230]. Suppression of RANKL does not interfere with inflammatory or immune response in mature individuals, and RANKL inhibition did not prevent inflammatory disease in several rat and mice models, except in the IL-2-deficient mice whose lymphocytes over express

RANKL [229, 231]. The only human model of inflammatory disease in which denosumab has been used is RA. The authors followed at MRI for 12 months 143 patients receiving 60 or 180 mg injections of denosumab every 6 months. All patients were treated with methotrexate. At 12 months, the MRI erosion score was less increased from baseline in both denosumab 4SC-202 manufacturer groups than in the patients receiving a placebo (p < 0.012 and 0.007, respectively), but there was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity [232]. Thus, denosumab cannot substitute for DMARDs or anti-TNF in RA but could be an interesting

adjuvant in patients with progression of bone erosions; beside, Inositol monophosphatase 1 it could prevent osteoporosis associated with RA, particularly in patients requiring glucocorticoid treatment [233]. Concerning the problem of atopic disease and susceptibility to infections, Stolina et al. have shown that mice treated with OPG, the natural inhibitor of RANKL signalling, did not differ from controls with regard to contact hypersensitivity or infectious load induced by mycobacterial infection [234]. There was no decrease of humoral or cellular immunity. Another study in mice showed that inhibition of RANK signalling by a single dose of RANK-Fc 100 or 500 μg, which inhibits hypercalcaemia induced by 1, 25-dihydroxyvitamin D, did not decrease the immune response to influenza infection [235]. In the first clinical study in postmenopausal women with low bone density [236], the 1.9% of neoplasms in the denosumab group versus none in the placebo or alendronate groups was intriguing though not significant. However, in the FREEDOM study, including nearly 4,000 patients treated for 3 years with denosumab, the incidence of neoplasia did not differ significantly from the placebo group (3.7% versus 3.2%) [237]. In this study, the authors found a significant increase of eczema (3.0% versus 1.7%) and of cellulitis (0.3% versus <0.