RESUMEN
BACKGROUND: Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density. METHODS: The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis. RESULTS: Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD -0.220; SE 3.379), followed by pamidronate (SMD -5.662; SE 2.635) and zoledronate (SMD -10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD -0.256; SE 3.184), followed by alendronate (SMD -17.032; SE 3.191) and ibandronate (SMD -17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD -16.030; SE 1.702) and ibandronate (SMD -17.000; SE 1.679). CONCLUSION: Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD. LEVEL OF EVIDENCE: Level I, Bayesian network meta-analysis of RCTs.
Asunto(s)
Conservadores de la Densidad Ósea , Osteoporosis Posmenopáusica , Osteoporosis , Preparaciones Farmacéuticas , Alendronato/química , Teorema de Bayes , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Denosumab/fisiología , Femenino , Humanos , Ácido Ibandrónico/química , Metaanálisis en Red , Osteoporosis Posmenopáusica/diagnóstico por imagen , Osteoporosis Posmenopáusica/tratamiento farmacológicoRESUMEN
The natural product sesquisabinene is a key component of the fragrant essential oil of the sandalwood tree, currently valued at $5,000/L. Sesquisabinene contains a highly strained [3.1.0] bicyclic ring system and is generated from farnesyl diphosphate in a reaction catalyzed by a class I terpenoid cyclase. To understand how the enzyme directs the formation of a strained hydrocarbon ring system, we now report the X-ray crystal structure of sesquisabinene synthase 1 (SQS1) from the Indian sandalwood tree ( Santalum album). Specifically, we report the structure of unliganded SQS1 at 1.90 Å resolution and the structure of its complex with three Mg2+ ions and the inhibitor ibandronate at 2.10 Å resolution. The bisphosphonate group of ibandronate coordinates to all three metal ions and makes hydrogen bond interactions with basic residues at the mouth of the active site. These interactions are similarly required for activation of the substrate diphosphate group to initiate catalysis, although partial occupancy binding of the Mg2+B ion suggests that this structure represents the penultimate metal coordination complex just prior to substrate activation. The structure of the liganded enzyme enables a precise definition of the enclosed active site contour that serves as a template for the cyclization reaction. This contour is very product-like in shape and readily fits an extended conformation of sesquisabinene and its precursor, the homobisabolyl cation. Structural comparisons of SQS1 with epi-isozizaene synthase mutants that also generate sesquisabinene suggest that [3.1.0] ring formation is not dependent on the isoprenoid tail conformation of the homobisabolyl cation.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Liasas de Carbono-Carbono/química , Catálisis , Dominio Catalítico , Enlace de Hidrógeno , Ácido Ibandrónico/química , Magnesio/química , Conformación MolecularRESUMEN
To face the high costs of developing new drugs, researchers in both industry and academy are looking for ways to repurpose old drugs for new uses. In this sense, bisphosphonates that are clinically used for bone diseases have been studied as agents against Trypanosoma cruzi, causative parasite of Chagas disease. In this work, the development of first row transition metal complexes (M = Co2+, Mn2+, Ni2+) with the bisphosphonate ibandronate (iba, H4iba representing the neutral form) is presented. The in-solution behavior of the systems containing iba and the selected 3d metal ions was studied by potentiometry. Mononuclear complexes [M(Hxiba)](2-x)- (x = 0-3) and [M(Hiba)2]4- together with the formation of the neutral polynuclear species [M2iba] and [M3(Hiba)2] were detected for all studied systems. In the solid state, complexes of the formula [M3(Hiba)2(H2O)4]·6H2O were obtained and characterized. All obtained complexes, forming [M(Hiba)]- species under the conditions of the biological studies, were more active against the amastigote form of T. cruzi than the free iba, showing no toxicity in mammalian Vero cells. In addition, the same complexes were selective inhibitors of the parasitic farnesyl diphosphate synthase (FPPS) enzyme showing poor inhibition of the human one. However, the increase of the anti-T. cruzi activity upon coordination could not be explained neither through the inhibition of TcFPPS nor through the inhibition of TcSPPS (T. cruzi solanesyl-diphosphate synthase). The ability of the obtained metal complexes of catalyzing the generation of free radical species in the parasite could explain the observed anti-T. cruzi activity.