Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra

Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone. INTRODUCTION: The collagen matrix contributes significantly to a bone's fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment. METHODS: Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of alpha/beta C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links. RESULTS: All doses of both RIS and ALN increased PEN (+34-58%) and the ratio of PYD/DPD (+14-26%), and decreased the ratio of alpha/beta CTX (-29-56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = -0.664), alpha/beta CTX (R = 0.586), and PYD/DPD (R = -0.470). CONCLUSIONS: Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.The authors thank Dr. Keith Condon, Diana Jacob, Mary Hooser, and Lauren Waugh for histological preparation. This work was supported by NIH Grants AR047838 and AR007581 and research grants from The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis), and Lilly Research Laboratories, as well as an unrestricted grant from Eli Lilly to INSERM. Merck and Co. kindly provided the alendronate. This investigation utilized an animal facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR10601-01 from the National Center for Research Resources, National Institutes of Health

Mineral maturity and crystallinity index are distinct characteristics of bone mineral

The purpose of this study was to test the hypothesis that mineral maturity and crystallinity index are two different characteristics of bone mineral. To this end, Fourier transform infrared microspectroscopy (FTIRM) was used. To test our hypothesis, synthetic apatites and human bone samples were used for the validation of the two parameters using FTIRM. Iliac crest samples from seven human controls and two with skeletal fluorosis were analyzed at the bone structural unit (BSU) level by FTIRM on sections 2–4 lm thick. Mineral maturity and crystallinity index were highly correlated in synthetic apatites but poorly correlated in normal human bone. In skeletal fluorosis, crystallinity index was increased and maturity decreased, supporting the fact of separate measurement of these two parameters. Moreover, results obtained in fluorosis suggested that mineral characteristics can be modified independently of bone remodeling. In conclusion, mineral maturity and crystallinity index are two different parameters measured separately by FTIRM and offering new perspectives to assess bone mineral traits in osteoporosis

Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis

The structural basis of the antifracture efficacy of strontium ranelate and alendronate is incompletely understood. We compared the effects of strontium ranelate and alendronate on distal tibia microstructure over 2 years using HR-pQCT. In this pre-planned, interim, intention-to-treat analysis at 12 months, 88 osteoporotic postmenopausal women (mean age 63.7 ± 7.4) were randomized to strontium ranelate 2 g/day or alendronate 70 mg/week in a double-placebo design. Primary endpoints were changes in microstructure. Secondary endpoints included lumbar and hip areal bone mineral density (aBMD), and bone turnover markers. This trial is registered with http://www.controlled-trials.com, number ISRCTN82719233. Baseline characteristics of the two groups were similar. Treatment with strontium ranelate was associated with increases in mean cortical thickness (CTh, 5.3%), cortical area (4.9%) and trabecular density (2.1%) (all P < 0.001, except cortical area P = 0.013). No significant changes were observed with alendronate. Between-group differences in favor of strontium ranelate were observed for CTh, cortical area, BV/TV and trabecular density (P = 0.045, 0.041, 0.048 and 0.035, respectively). aBMD increased to a similar extent with strontium ranelate and alendronate at the spine (5.7% versus 5.1%, respectively) and total hip (3.3% versus 2.2%, respectively). No significant changes were observed in remodeling markers with strontium ranelate, while suppression was observed with alendronate. Within the methodological constraints of HR-pQCT through its possible sensitivity to X-ray attenuation of different minerals, strontium ranelate had greater effects than alendronate on distal tibia cortical thickness and trabecular volumetric density

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 mu M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 mu M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) and selective (SI = >313 to 550) molecules toward T brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 mu M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTRI), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V

Technical Note: New ground-based FTIR measurements at Ile de La Réunion: observations, error analysis, and comparisons with independent data

Ground-based high spectral resolution Fourier-transform infrared (FTIR) solar absorption spectroscopy is a powerful remote sensing technique to obtain information on the total column abundances and on the vertical distribution of various constituents in the atmosphere. This work presents results from two FTIR measurement campaigns in 2002 and 2004, held at Ile de La Réunion (21° S, 55° E). These campaigns represent the first FTIR observations carried out at a southern (sub)tropical site. They serve the initiation of regular, long-term FTIR monitoring at this site in the near future. To demonstrate the capabilities of the FTIR measurements at this location for tropospheric and stratospheric monitoring, a detailed report is given on the retrieval strategy, information content and corresponding full error budget evaluation for ozone (O3), methane (CH4), nitrous oxide (N2O), carbon monoxide (CO), ethane (C2H6), hydrogen chloride (HCl), hydrogen fluoride (HF) and nitric acid (HNO3) total and partial column retrievals. Moreover, we have made a thorough comparison of the capabilities at sea level altitude (St.-Denis) and at 2200 m a.s.l. (Maïdo). It is proved that the performances of the technique are such that the atmospheric variability can be observed, at both locations and in distinct altitude layers. Comparisons with literature and with correlative data from ozone sonde and satellite (i.e., ACE-FTS, HALOE and MOPITT) measurements are given to confirm the results. Despite the short time series available at present, we have been able to detect the seasonal variation of CO in the biomass burning season, as well as the impact of particular biomass burning events in Africa and Madagascar on the atmospheric composition above Ile de La Réunion. We also show that differential measurements between St.-Denis and Maïdo provide useful information about the concentrations in the boundary layer.Peer reviewe

The Global Longitudinal Study of Osteoporosis in Women (GLOW): rationale and study design

SUMMARY: The Global Longitudinal study of Osteoporosis in Women (GLOW) is a prospective cohort study involving 723 physicians and 60,393 women subjects \u3eor=55 years. The data will provide insights into the management of fracture risk in older women over 5 years, patient experience with prevention and treatment, and distribution of risk among older women on an international basis. INTRODUCTION: Data from cohort studies describing the distribution of osteoporosis-related fractures and risk factors are not directly comparable and do not compare regional differences in patterns of patient management and fracture outcomes. METHODS: The GLOW is a prospective, multinational, observational cohort study. Practices typical of each region were identified through primary care networks organized for administrative, research, or educational purposes. Noninstitutionalized patients visiting each practice within the previous 2 years were eligible. Self-administered questionnaires were mailed, with 2:1 oversampling of women \u3eor=65 years. Follow-up questionnaires will be sent at 12-month intervals for 5 years. RESULTS: A total of 723 physicians at 17 sites in ten countries agreed to participate. Baseline surveys were mailed (October 2006 to February 2008) to 140,416 subjects. After the exclusion of 3,265 women who were ineligible or had died, 60,393 agreed to participate. CONCLUSIONS: GLOW will provide contemporary information on patterns of management of fracture risk in older women over a 5-year period. The collection of data in a similar manner in ten countries will permit comparisons of patient experience with prevention and treatment and provide insights into the distribution of risk among older women on an international basis

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p &lt; 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM &gt; 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM &gt; 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Microarchitecture Influences Microdamage Accumulation in Human Vertebral Trabecular Bone

It has been suggested that accumulation of microdamage with age contributes to skeletal fragility. However, data on the age-related increase in microdamage and the association between microdamage and trabecular microarchitecture in human vertebral cancellous bone are limited. We quantified microdamage in cancellous bone from human lumbar (L2) vertebral bodies obtained from 23 donors 54–93 yr of age (8 men and 15 women). Damage was measured using histologic techniques of sequential labeling with chelating agents and was related to 3D microarchitecture, as assessed by high-resolution μCT. There were no significant differences between sexes, although women tended to have a higher microcrack density (Cr.Dn) than men. Cr.Dn increased exponentially with age (r = 0.65, p < 0.001) and was correlated with bone volume fraction (BV/TV; r = −0.55; p < 0.01), trabecular number (Tb.N; r = −0.56 p = 0.008), structure model index (SMI; r = 0.59; p = 0.005), and trabecular separation (Tb.Sp; r = 0.59; p < 0.009). All architecture parameters were strongly correlated with each other and with BV/TV. Stepwise regression showed that SMI was the best predictor of microdamage, explaining 35% of the variance in Cr.Dn and 20% of the variance in diffuse damage accumulation. In addition, microcrack length was significantly greater in the highest versus lowest tertiles of SMI. In conclusion, in human vertebral cancellous bone, microdamage increases with age and is associated with low BV/TV and a rod-like trabecular architecture

The effects of tibolone in older postmenopausal women

Robert Norman and Alastair MacLennan were investigators in the LIFT TrialSteven R. Cummings, Bruce Ettinger, Pierre D. Delmas, Peter Kenemans, Victoria Stathopoulos, Pierre Verweij, Mirjam Mol-Arts, Lenus Kloosterboer, Lori Mosca, Claus Christiansen, John Bilezikian, Eduardo Mario Kerzberg, Susan Johnson, Jose Zanchetta, Diederich E. Grobbee, Wilfried Seifert and Richard Eastell for the LIFT Trial Investigator