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This paper studies the effect of oral risedronate on osteoclast precursors, osteoclast formation, and cytokine production in 25 osteoporotic women. Risedronate is effective in reducing the number of osteoclast precursors, their formation, vitality, and activity and the level of RANKL and TNF-␣ in cultures.Introduction: Bisphosphonates inhibit bone resorption by acting against osteoclasts. Some in vitro studies suggest that they induce osteoclast apoptosis; others suggest that they exert an effect on the production of pro-osteoclastogenic cytokines. The effect of risedronate on osteoclastogenesis by peripheral blood mononuclear cells (PBMCs) in postmenopausal osteoporosis has not been previously studied. This paper examined the influence of risedronate on the formation of osteoclast precursors and cytokine production within the compass of osteoclastogenesis in osteoporosis. Materials and Methods: This study was conducted on 38 osteoporotic women; 25 patients were treated with risedronate 5 mg/d, whereas 13 were treated with calcium 1 g/d and vitamin D 800 UI/d. The following parameters were assessed: changes in bone turnover, circulating osteoclast precursors, formation of osteoclasts in PBMC cultures, their activity and vitality, and variations in the production of pro-osteoclastogenic cytokines before and after therapy. Results: After 3 mo of risedronate, there was a significant reduction in the number and degree of differentiation of osteoclast precursors, osteoclast formation, vitality and activity, and in the level of RANKL and TNF in cultures and of TNF and osteoprotegerin (OPG) in serum, whereas in the group treated with calcium and vitamin D, there were no significant changes. Conclusions: Our data show that risedronate is effective in lowering the number of circulating osteoclast precursors, their formation, vitality, and activity in cultures, and in reducing the level of pro-osteoclastogenic cytokines in culture supernatants and in serum.

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IntroductionInterferon-␥ (IFN-␥), produced by T and natural killer (NK) cells, is considered the principal effector cytokine of cell-mediated immunity and exerts its effects on target cells through a highaffinity receptor complex linked to a specific Janus kinase (Jak)/ signal transducer and activator of transcription (STAT) signaling cascade. 1,2 The IFN-␥ receptor (IFN-␥R) complex consists of 2 chains: an IFN-␥R1 binding chain and an IFN-␥R2 signaling chain. 1 The intracellular portions of the 2 chains provide the Jak1 and Jak2 docking sites. Upon phosphorylation, Jak1 and Jak2 activate STAT1: Following phosphorylation and dimerization, STAT1 is translocated into the nucleus where it activates transcription of numerous sets of IFN-␥-inducible genes. 2 The IFN-␥/STAT1 pathway plays an essential role in controlling the expansion of normal and neoplastic cell types of different origin. Activation of this pathway switches on many proapoptotic and antiproliferative genes such as interferon regulatory factor 1 (IRF1), p21 waf/cip , Fas and FasL, and activates caspases. [3][4][5][6][7][8][9][10] However, the signals transduced by IFN-␥ do not always induce apoptosis or block proliferation, and lymphoid cells become resistant to the antiproliferative effects of IFN-␥. Resting, malignant, or normal T cells that develop toward the T helper 1 (Th1) pathway become resistant to the antiproliferative effects of the IFN-␥/STAT1 pathway 9,11,12 or rather, IFN-␥ favors their proliferation and differentiation. [13][14][15] The refractoriness of T cells to the IFN-␥/STAT1 pathway has been attributed mainly to down-regulation of the IFN-␥R chains, especially IFN-␥R2, which protects these cells from the antiproliferative/proapoptotic effects of [16][17][18][19] Both IFN-␥-dependent and -independent mechanisms have been reported to downregulate IFN-␥R2 expression in T lymphocytes. During murine Th cell differentiation, IFN-␥ itself induces IFN-␥ resistance by down-regulating IFN-␥R2, 16 whereas in human T lymphocytes, IFN-␥R2 internalization occurs mostly in clathrin-coated pits independently from IFN-␥ 17 and is selectively induced by insulinlike growth factor 1 (IGF1). 20 Since the IFN-␥/STAT1 pathway is usually down-regulated in T lymphocytes, information on the mechanisms that maintain low IFN-␥R2 expression in these cells might prove useful for devising therapeutic approaches centered on selectively reinstating the IFN-␥/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells.Besides T-cell receptor (TCR) engagement, 9,12 up-regulation of surface IFN-␥R2 in T cells may also be induced by serum deprivation, 5 exposure to nitric oxide (NO), 21 Among the plethora of factors present in serum, iron has profound effects on numerous critical cell functions, such as electron and oxygen transport, mitochondrial energy metabolism, and detoxification, thus requiring tight homeostatic regulation. 24 Iron binds to cytoplasmic iron regulatory protein 1 (IRP1) and IRP2 which in turn regulate expression of proteins such as fe...