Acute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism... Show moreAcute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). ZOL, however, has also been reported to inhibit the proliferation of regulatory T cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a negative regulator of T cell activation that is increased in patients with autoimmune diseases. There are, however, no data on the relationship between ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations or in vitro with the use of assays relevant to the mechanism of action of N-BPs. The objectives of the present study were firstly, to characterize the ZOL-induced APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship with changes in circulating sCTLA-4 and secondly, to investigate the effects of ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous ZOL 5 mg. Five women experienced APR (APR + ) associated with significant decreases in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 values were increased in all patients before ZOL administration and decreased significantly 72 h after the ZOL infusion (from 30.0 +/- 2.9 to 6.3 +/- 1.8 ng/ml; p < 0.001) with no differences between APR + and APR- patients. Consistent with the results of the in vivo study, ZOL (1 mu M) decreased the production of sCTLA-4 by 87% and 57% after 3 and 5 days in cultures of peripheral blood mononuclear cells (PBMCs) in vitro, respectively, and inhibited the expression of both cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel immunoregulatory action of ZOL that is not related to its action on bone resorption but might be associated with reported clinically significant extraskeletal outcomes of ZOL treatment. Show less
Atypical fractures of the femur below the lesser trochanter have been reported in patients treated with bisphosphonates. We performed a systematic literature search of case/case series studies to... Show moreAtypical fractures of the femur below the lesser trochanter have been reported in patients treated with bisphosphonates. We performed a systematic literature search of case/case series studies to better define the clinical presentation and to identify characteristics that may predispose patients to such fractures. We considered only women treated with a bisphosphonate at a dosing regimen used for the prevention or treatment of osteoporosis and we included also eight own unpublished cases. We identified 141 women with atypical fractures of the femur, mean age of 67.8 +/- 11.0 years, who were treated with bisphosphonate for 71.5 +/- 40.0 months (range = 3-192 months). The results of this analysis allow identification of patients on bisphosphonate treatment at risk of developing atypical fractures, define fractures better as predominantly insufficiency fractures, illustrate that long-term bisphosphonate treatment is not a prerequisite for their development, recognize the use of glucocorticoids and proton pump inhibitors as important risk factors, but do not provide insights in the pathogenesis of these fractures and raise questions that need to be addressed in properly designed studies. (C) 2010 Elsevier Inc. All rights reserved. Show less
