Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-␣/␤) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7and TLR-9). Enhanced TLR-7-mediated IFN-␣ production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7-mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17␤-estradiol markedly enhances TLR-7-and TLR-9-dependent production of IFN-␣ by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) ␣. IntroductionDendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and play a crucial role in orchestrating the immune responses. In response to viral infection, a specialized DC subset, plasmacytoid DCs (pDCs), produces a large amount of type I IFNs (IFN-␣/␤), which are potent anti-viral and immunostimulatory cytokines. 1 pDCs become activated to produce IFN-␣/␤ through Toll-like receptors (TLR-7 and TLR-9) within endosomal compartments that can sense viral nucleic acids. In the context of autoimmune diseases, such as systemic lupus erythematosus (SLE), these TLRs can also be inappropriately activated by self-nucleic acids complexed with autoreactive antibodies, resulting in IFN-␣ production by pDCs. 2 Activation of pDCs by endogenous DNA and RNA has been suggested to play a critical role in promoting and exacerbating SLE. 2-4 SLE patients show increased serum levels of IFN-␣ and overexpression of IFN-␣-regulated genes in blood cells, suggesting a central role for type I IFNs in disease pathogenesis. [5][6][7][8] This is supported by the observation that antinuclear antibody and SLE syndrome can develop during IFN-␣ treatment in patients with nonautoimmune disorders. 9 Likewise, IFN-␣ administration accelerates disease development and enhances disease severity in lupus-prone mouse strains. 10,11 In addition to IFN-␣, TNF-␣ has been shown to be increased in the serum of patients with active SLE disease and correlates with IFN-␣ levels. 12,13 Although pDCs can also produce TNF-␣, it is not clear whether they represent the unique source of this cytokine in SLE. 14 Cumulative evidence supports a role for sex-based differences in the pathogenesis of autoimmune and infectious diseases, which may be the result of sex hormones through their effects on innate and adaptive immunity. 15,16 A strong sex bias is observed in SLE, whose incidence is approximately 9 times higher in women relative to men. 15 Because disease onset is much more frequent in women of childbearing age, it has been hypothesized that sex steroid hormones, such as estro...

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The aim of this prospective study was (1) to identify significant and independent clinical risk factors (CRFs) for major osteoporotic (OP) fracture among peri-and early postmenopausal women, (2) to assess, in this population, the discriminatory capacity of FRAX and bone mineral density (BMD) for the identification of women at high risk of fracture, and (3) to assess whether adding risk factors to either FRAX or BMD would improve discriminatory capacity. The study population included 2651 peri-and early postmenopausal women [mean age (AE SD): 54 AE 4 years] with a mean follow-up period of 13.4 years (AE1.4 years). At baseline, a large set of CRFs was recorded, and vertebral BMD was measured (Lunar, DPX) in all women. Femoral neck BMD also was measured in 1399 women in addition to spine BMD. Women with current or past OP treatment for more than 3 months at baseline (n ¼ 454) were excluded from the analyses. Over the follow-up period, 415 women sustained a first low-energy fracture, including 145 major OP fractures (108 wrist, 44 spine, 20 proximal humerus, and 13 hip). In Cox multivariate regression models, only 3 CRFs were significant predictors of a major OP fracture independent of BMD and age: a personal history of fracture, three or more pregnancies, and current postmenopausal hormone therapy. In the subsample of women who had a hip BMD measurement and who were not receiving OP therapy (including hormone-replacement therapy) at baseline, mean FRAX value was 3.8% (AE2.4%). The overall discriminative value for fracture, as measured by the area under the Receiver Operating Characteristic (ROC) curve (AUC), was equal to 0.63 [95% confidence interval (CI) 0.56-0.69] and 0.66 (95% CI 0.60-0.73), respectively, for FRAX and hip BMD. Sensitivity of both tools was low (ie, around 50% for 30% of the women classified as the highest risk). Adding parity to the predictive model including FRAX or using a simple risk score based on the best predictive model in our population did not significantly improve the discriminatory capacity over BMD alone. Only a limited number of clinical risk factors were found associated with the risk of major OP fracture in peri-and early postmenopausal women. In this population, the FRAX tool, like other risk scores combining CRFs to either BMD or FRAX, had a poor sensitivity for fracture prediction and did not significantly improve the discriminatory value of hip BMD alone. ß

Discontinuation of bisphosphonates should be considered in all patients who have beentreated for more than five years with alendronate, risedronate or zoledronic acid. In view of the limited evidence, no robust recommendations can be made for ibandronate and denosumab. If the patient has not experienced fractures before or during therapy and the fracture risk is low, a "drug holiday" canbe recommended. Although there is no solid evidence, 1-2 years for risedronate, 3-5 years for alendronate and 3-6 years for zoledronic acid are suggested. After this time, the patient should be reassessed. If a new fracture is experienced, or fracture risk has increased or BMD remains low (femoral neck T-score ≤-2.5), anti-osteoporotic treatment should be resumed. In the case of denosumab discontinuation, close monitoring is suggested, due to the possibility of rebound fractures.

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Two hundred and thirty women aged 45-66 years were divided into three groups according to their menopausal status and were followed to assess the changes in vertebral bone mineral density (BMD). These included 71 premenopausal, 42 perimenopausal, and 117 postmenopausal women. Menopausal status was assessed through menstrual history and plasma concentrations of 17 beta estradiol and luteinizing hormone. BMD was measured by dual photon absorptiometry between 2 and 5 times over an average period of 27 months, and annual rates of changes were calculated by linear regression. BMD decreased significantly (P < 0.0001) in the three groups during the follow-up. Mean (+/- SD) annual rate of change was -0.79 +/- 1.5% for premenopausal, -2.35 +/- 1.5% for perimenopausal, and -1.24 +/- 1.5% for postmenopausal women. There was no difference in the rates of bone loss between the perimenopausal group and the postmenopausal group within 3 years after menopause (1-2 years: -2.34 +/- 2.1%; 2-3 years: -1.9 +/- 1.5%). Thereafter, rates decreased exponentially with time since menopause to fall out at the same level as the premenopausal level. These longitudinal data indicate that vertebral bone loss begins before menopause and accelerates sharply during menopause to decline exponentially with time after 3 years.

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