Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12 months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55 years received denosumab 60 mg subcutaneously every 6 months or risedronate 150 mg orally every month for 12 months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3 ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p<0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of -78% vs -17%; p<0.0001) and month 6 (-61% vs -23%; p<0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover.

Phe-NH, have been studied in aqueous and dimethyl sulphoxide solutions. From an analysis of the 1H spectra of the Asp and Phe C(a)H-C(P)H, side-chains the vicinal coupling constants were obtained and used to calculate the rotational populations. There are no significant differences in the Phe side-chain rotamer populations between the tripeptide Met-Asp-Phe-NH, and gastrin pentapeptide PAla-Trp-Met-Asp-Phe-N H, , but the Asp residue shows some small changes.The presence of only small ring-current shielding contributions to the Phe aromatic protons from the aromatic ring in Trp can be taken to indicate that the aromatic rings are well separated ( > 5 8 ) in the most populated conformers of gastrin pentapeptide in aqueous solution.For dimethyl sulphoxide solutions, NH doublets could be observed for the peptides studied; the large values of the vicinal JNa coupling constants for Met, Asp, and Phe in the tetrapeptide Trp-Met-Asp-Phe-NH, are shown to be consistent with the most populated conformations, having a C $ angle of ca. -95". from considerations of potential energy diagrams and the Bystrov-modified Karplus curve which relates dihedral angles to vicinal coupling constants.

In a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures. Although bisphosphonate therapy usage improved over time, a substantial gap remains.

BackgroundWe previously reported that 1 year of treatment with the sclerostin antibody romosozumab (Romo) was associated with increased bone mineral density (BMD) and bone formation and with decreased bone resorption in postmenopausal women with low BMD.1 Here, we report the results of 2 years of treatment with Romo, followed by 1 year of denosumab (DMAb) or placebo.MethodsThis phase 2 study enrolled 419 postmenopausal women age 55 to 85 years with a lumbar spine, total hip, or femoral neck T-score ≤ –2.0 and ≥ –3.5. For the results described here, women received 1 of 5 regimens of Romo (70 mg QM, 140 mg QM, 210 mg QM, 140 mg Q3M, 210 mg Q3M; data for the 210 mg QM group are shown in the figure) or placebo for 2 years. At the end of 2 years, eligible women entered a 1-year extension phase and were re-randomized 1:1 within their original treatment group to placebo or DMAb 60 mg Q6M. Only women who entered the extension were included in these analyses.ResultsRomo led to rapid and marked increases in lumbar spine and total hip BMD during year 1 and continued increases through year 2. The largest gains were observed with Romo 210 mg QM, with BMD increases of 15.7% (lumbar spine) and 6.0% (total hip) (Figure). Women receiving Romo 210 mg QM who transitioned to DMAb continued to accrue BMD at a rate similar to that in the second year of Romo; in those who transitioned to placebo, BMD returned toward pretreatment levels. Romo induced rapid stimulation of bone formation (P1NP) and decreased bone resorption (CTX). Increases in P1NP were transitory, returning toward baseline within 6 to 12 months and remaining below baseline through year 2. CTX remained below baseline through year 2. In women receiving Romo 210 mg QM who transitioned to DMAb, P1NP and CTX decreased; in those who transitioned to placebo, P1NP gradually returned to pretreatment levels, while CTX initially increased above baseline and gradually returned toward baseline. Adverse events were balanced between the placebo and Romo groups during the first 2 years of the study (with the exception of injection site reactions, most reported as mild) and in the placebo and DMAb groups during year 3.ConclusionsRomo led to rapid and marked increases in lumbar spine and total hip BMD over 2 years, which continued with DMAb and resolved after transition to placebo. These data suggest that the treatment effects observed with Romo are further augmented by follow-on treatments like DMAb.ReferencesMcClung MR, et al. N Engl J Med. 2014;370:412-420Disclosure of InterestM. McClung Grant/research support from: Amgen, Merck, Consultant for: Amgen, Lilly, Merck, A. Chines Shareholder of: Amgen, Employee of: Amgen, J. Brown Grant/research support from: Actavis, Amgen, Eli Lilly, Merck, Novartis, Consultant for: Amgen, Eli Lilly, Speakers bureau: Amgen, Eli Lilly, A. Diez-Perez Shareholder of: Active Life Scientific, Grant/research support from: Amgen, Consultant for: Amgen, Eli Lilly, Speakers bureau: Amgen, Eli Lilly, GSK, Novartis, ViiV, H. Resch: None declared, J. Caminis Sharehol...

Hydrogenation of citrinin is accompanied by aromatisation of the nucleus, giving rise to dihydrocitrinin which on esterification and methylation yields methyl 0-dimethyldihydrocitrinin. On oxidation the latter compound furnished a lactone, methyl 0-dimethylcitrinone, and the acid obtained by the hydrolysis of the carbmethoxy-group of this lactone underwent simultaneous decarboxylation and demethylation when heated with glycerol, yielding a phenolic lactone, identical with the product formed by the action of hot hydriodic acid on methyl 0-dimethyldihydrocitrinone. On being boiled with aqueous sodium hydroxide this lactone gave rise to phenol (A) by simultaneous hydration and loss of carbon dioxide. These reactions in conjunction with the conversion of dihydrocitrinin into (VIII) by means of hydriodic acid have made it possible to deduce rational structural formulae for the phenolic lactone (VI), methyl 0-dimethyldihydrocitrinone (V; R = Me), 0-dimethyldihydrocitrinin (IV; R = H), and for dihydrocitrinin (111; R = H). The expression (11) appears best to represent the properties of citrinin.Methylation of methyl citrinin gave a complex mixture from which a crystalline compound (M), C,,H,,O,(OMe), has been isolated in comparatively small yield. On alkaline hydrolysis this substance yielded acetaldehyde, diethyl ketone, and formic acid, together with a phenolic * As in the analogous case of the methyl ester of the carboxylic acid citromycetin (Part 111, this vol., p. 848) we refer to the methyl ester of citrinin as methyl citrinin. The composition of trivial names for derivatives of these acids in so far as they are necessary and convenient would have been much easier and more systematic had the originators of the names followed the normal custom in naming acids, e.g., citrinic and citromycetinic acid. This also applies to the more recently isolated unsaturated ketone, trichothecin (Freeman and Morrison, Nature, 1948, 162, 30), for which a more appropriate name would have been, e.g., trichothecenone."