Chinese-American women have lower rates of hip and forearm fracture than white women despite lower areal bone density (aBMD) by dual X-ray absorptiometry (DXA). We recently reported higher trabecular (Dtrab) and cortical (Dcomp) bone density as well as greater trabecular (Tb.Th) and cortical thickness (C.Th) but smaller bone area (CSA), as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in premenopausal Chinese-American compared with white women. These findings may help to account for the lower fracture rate among Chinese-American women but were limited to measurements in premenopausal women. This study was designed to extend these investigations to postmenopausal Chinese-American (n = 29) and white (n = 68) women. Radius CSA was 10% smaller in the Chinese-American versus the white group (p = .008), whereas their C.Th and Dcomp values were 18% and 6% greater (p < .001 for both). Tibial HR-pQCT results for cortical bone were similar to the radius, but Tb.Th was 11% greater in Chinese-American versus white women (p = .007). Tibial trabecular number and spacing were 17% lower and 20% greater, respectively, in Chinese-American women (p < .0001 for both). There were no differences in trabecular or whole-bone stiffness estimated by microstructural finite-element analysis, but Chinese-American women had a greater percentage of load carried by the cortical bone compartment at the distal radius and tibia. There was no difference in load distribution at the proximal radius or tibia. Whole-bone finite-element analysis may indicate that the thicker, more dense cortical bone and thicker trabeculae in postmenopausal Chinese-American women compensate for fewer trabeculae and smaller bone size.

Quinine, a quinoline derivative, is an ancient antipyretic drug with antimalarial properties that has been phased out by more effective synthetic candidates. In previous studies we discovered that hydroxychloroquine (HCQ), a synthetic antimalarial with structural similarities to quinine, reduced the binding of antiphospholipid (aPL) immune complexes to phospholipid bilayers. We performed ellipsometry and atomic force microscopy (AFM) studies to measure the effect of quinine on dissociation of anti-β2-glycoprotein I (anti-β2GPI) immune complexes. We found that quinine desorbed pre-formed β2GPI-aPL immunoglobulin (Ig)G complexes from phospholipid bilayers at significantly lower molar concentrations than HCQ. Quinine also inhibited the formation of immune complexes with a higher efficacy than HCQ at equivalent drug concentrations of 0.2 mg/ml (0.192 ± 0.025 µg/cm(2) for quinine vs. 0.352 ± 0.014 µg/cm(2) for HCQ, p < 0.001). Furthermore, AFM imaging experiments revealed that addition of quinine disintegrated immune complexes bound to planar phospholipid layers. The desorptive and inhibitory effects of the old drug, quinine, toward β2GPI-aPL IgG complexes and β2GPI were significantly more pronounced compared to the synthetic antimalarial, HCQ. The results suggest that the quinoline core of the molecule is a critical domain for this activity and that side chains may further modulate this effect. The results also indicate that there may yet be room for considering new activities of very old drugs in devising clinical trials on potential non-anticoagulant treatments for antiphospholipid syndrome (APS).

3423 Background: Quinine, an old drug extracted from bark of the cinchona tree, was the first effective antimalarial. Hydroxychloroquine (HCQ), a synthetic antimalarial developed over 60 years ago was subsequently found to be effective for treating autoimmune disorders and is widely used to treat systemic lupus erythematosus (SLE). Observational clinical studies have indicated that HCQ is associated with reduced risk of thrombosis in SLE and the antiphospholipid (aPL) syndrome (APS). Autoimmune recognition of β2-glycoprotein I (β2GPI) by aPL autoantibodies is a key thrombogenic step in the mechanism for APS. We recently demonstrated that HCQ targets aPL immune complexes and disrupts their assembly on membranes. Objective: Since quinine shares structural similarities to HCQ, we wondered whether it might have a similar effect on aPL immune complexes in vitro. Furthermore, structural differences between the two drugs could affect their activities and provide valuable information on therapeutic targeting of APS disease process. Methods: Phospholipid bilayers containing 70% phosphatidyl choline (PC) and 30 % phosphatidyl serine (PS) were formed on reflective silicon slides. Adsorption of β2GPI and the formation of aPL-β2GPI immune complexes on the supported lipid bilayers were measured using ellipsometry. Dose response of quinine and HCQ were performed and adsorption was measured in real time. The efficacy of the two drugs at desorbing immune complexes was quantified by half maximal effective concentrations (EC50) values. Experiments were also performed to gauge the ability of the drugs at preventing complex formation. Furthermore, atomic force microscopy (AFM) was used to gauge the morphological changes associated with addition of quinine to lipid-supported aPL-β2GPI immune complexes. Results: Quinine inhibited the formation of immune complexes with a higher efficacy than HCQ at equivalent drug concentrations of 0.2 mg/mL (0.192 ± 0.025 μg/cm2 for quinine vs. 0.352 ± 0.011 μg/cm2 for HCQ, p<0.001; for untreated immune complexes, 0.447 ± 0.013 μg/cm2) (Figure 1A). EC50 values for desorption of phospholipid-bound β2GPI-aPL IgG immune complexes revealed that the concentrations of quinine required for desorption of 50% of immune complexes (0.139 ± 0.003 mg/mL for quinine vs. 0.580 ± 0.006 mg/mL for HCQ, p<0.001) and β2GPI (0.129 ± 0.004 mg/mL for quinine vs. 0.440 ± 0.040 mg/mL for HCQ, p<0.001) were significantly lower than those for HCQ (Figure 1B). Furthermore, AFM experiments revealed that addition of quinine disintegrated immune complexes bound to phospholipid bilayers. Conclusions: Quinine is more effective than HCQ in impeding the formation of aPL-β2GPI immune complexes in vitro and in disintegrating immune complexes after they form. The disruptive effect that quinine and HCQ have on immune complexes suggests that the quinolone core of the molecule is an essential moiety conferring unique pharmacologic properties to the two drugs. Quinine and analogous molecules may offer novel approaches to targeting the APS disease mechanism and to reducing the thrombotic complications of APS without the inherent hemorrhagic risks of anticoagulant therapy. Disclosures: No relevant conflicts of interest to declare.