This is in line with other large cohort

This is in line with other large cohort studies which reported either a gradual Selleck Capmatinib increase or decrease in risk ratios for higher physical activity categories [12, 14]. In this study, physical activity was not significantly associated with fall risk. Three other cohort studies reported an increased fall risk in men [12] and a decreased fall risk in women [14] or in persons living in a residential care setting [13] in higher physical activity categories as compared with the lowest category. Perhaps lack of an association in our study is

due to an interaction with sex. However, the interaction term for physical activity by sex was not significant (p = 0.89). A second explanation may be that in our study, participants with high levels of physical activity were underrepresented causing an underestimation of the actual relationship. However, our sample is representative for the community-dwelling older population find more in the Netherlands. Third, these three studies and the current study differed in population (men [12] vs women [14] vs residential care setting [13]), physical activity measures (validated questionnaires [12] vs operational definitions

[14]), and outcome measures (4-month fall risk [12] vs proportion fallers [14]). It is likely that the contrasting findings are explained by differences in population and methodology. The association between physical activity and recurrent falling C646 has been studied only once before. A study among persons (70+ years) living in a residential care setting showed that the risk of recurrent falling decreased at higher levels of physical Adenosine triphosphate activity [13]. Our findings in community-dwelling older persons are in line with this study: an increase of 100 units led to a 4% lower risk of recurrent falling. One hundred units equal 30 min per day of walking, 20 in of swimming, or 40 min

of billiards. Thus, if all older persons increase their physical activity level with 100 units, 4% may be prevented to become recurrent fallers. In addition, given the beneficial effects of physical activity on other health outcomes, it is important to observe that, other than expected in the literature, highly active persons do not have an increased risk of falling. Clinical trials are necessary to test whether increasing physical activity leads to a decrease in falls. Two recently published systematic reviews showed that multiple component exercise programs did reduce the fall risk in community-dwelling older persons [34, 35]. Increasing daily physical activity may be an important component of these exercise programs. It has been suggested that in this type of study adjustment should be made for baseline mobility [9]. Like physical performance and functional limitations, mobility is a measure of physical functioning. In the current study, physical functioning did not modify the relationship between physical activity and (recurrent) falling.

The sequences displayed high homology (97-99%) to those of known

The sequences displayed high homology (97-99%) to those of known mesophilic Streptomyces and/or thermophilic Streptomyces species. A phylogenetic tree was drawn by using a neighbor-joining

Ro 61-8048 research buy check details method [24]. The chosen 11 newly isolated strains have distinct phenotypes when cultured on R2YE and MS media, and the reference strains utilized for comparison are well-classified Streptomyces species. As shown in Figure 1, all 11 newly isolated strains (4F, T6C-1, T1A, T6E-2. X4-3, T6-1-4, X3-3, 2C, T5A-1, T6A-2 and T6A-3) resembled known thermophilic Streptomyces species (e.g., S. thermocarboxydus, S. thermoviolaceus and S. glaucescens). Moderately thermophilic Streptomyces species form at least two distinct

clades [[12, 23, 25]], containing strains related to S. megasporus AZ 628 and S. thermodiastaticus, respectively. The phylogenetic tree of the 11 newly isolated strains reveals more clades (e.g., T5A-1 and T6E-2; see Figure 1). These results indicate that moderately thermophilic Streptomyces species are diverse in natural habitats. Figure 1 Identification of thermophilic Streptomyces strains. Phylogenetic tree for 11 newly identified strains and some known mesophilic and thermophilic Streptomyces species (Genbank numbers in parentheses). The tree is drawn to scale using the neighbor-joining method, with branch lengths in the same units as those of the evolutionary distances. Numbers next to the branches are the percentage of replicate trees (the bootstrap test is 500 replicates). Like typical Streptomyces species, these newly isolated strains produced spores on R2YE and MS media. Scanning electron microscopy showed that strains 4F and 2C formed long chains of smooth-surfaced spores after growth on MS medium at 42°C for 2 d (data not shown). Thus strains 4F and 2C were classified in the genus Streptomyces.

Characterization of the fast-growing and moderately-thermophilic Streptomyces strains 4F and 2C As shown in Figure 2, strains 4F and 2C were able to grow from 30 to 50°C, while two mesophilic Streptomyces strains (S. coelicolor M145 and S. venezuelae ISP5230) grew at 30°C and 37°C. 4F and 2C grew well at 45°C Carnitine palmitoyltransferase II and 50°C but poorly at 55°C, while M145 and ISP5230 could not grow at 45°C and 50°C (data not shown). Thus, 4F and 2C were concluded to be moderately thermophilic Streptomyces strains. Figure 2 Growth of strains 4F, 2C, M145 and ISP5230 on MS medium at different temperatures in a time-course. A series of 10× dilutions of spore suspensions were inoculated onto MS medium and incubated at 30, 37, 45 and 50°C in a time-course at 20, 30, 40 and 60 h. The numbers of spores of the four strains inoculated on plates are shown.

Serum LDL decreased slightly in response to creatine loading in t

Serum LDL decreased slightly in response to creatine loading in the CrM group but returned to baseline after ingesting Epigenetics inhibitor maintenance doses of CrM suggesting these changes were transient. Additionally, no significant differences were observed among groups in markers of catabolism (BUN, BUN:CRN, AST, ALT, Total Protein, TBIL), markers of bone status (bone mineral content, ALB, GLOB, ALB:GLOB, calcium, ALK) or whole blood markers (WBC, RBC, Hematocrit, Smad inhibitor Hemoglobin, MCV, MCH, MCHC, RBCDW, platelet counts). Moreover, values remained within normal levels for active individuals. These findings are consistent with other studies that have examined the safety of creatine supplementation in active individuals

[1, 3, 21, 26, 27, 38]. Consequently, present findings do not support claims learn more that KA is a safer form of creatine to ingest than creatine monohydrate.

Conclusion In summary, supplementation of the diet with recommended doses of a purported buffered form of creatine (1.5 g/d) for 28-days or equivalent loading (20 g/d for 7-days) and maintenance doses (5 g/d for 21-days) of CrM did not promote greater increases in muscle creatine content or training adaptations in comparison to creatine monohydrate (20 g/d for 7-days, 5 g/d for 21-days). Additionally, there was no evidence to support claims that the buffered form of creatine was associated with fewer side effects or was a safer form of creatine to consume than creatine monohydrate. While it could be argued that supplementing the diet with any form of creatine may provide some health and/or 3-mercaptopyruvate sulfurtransferase ergogenic benefits over time as long as it delivers sufficient amounts of creatine to increase muscle creatine content; present findings do not support claims

that KA is a more efficacious and/or safer form of creatine than creatine monohydrate. With this said, some limitations of this study should be noted. For example, this study did not have a control group and depended on participants to self-report side effects. Therefore, while the safety profile of short and long-term creatine monohydrate supplementation has been well established, safety and efficacy could only be compared to ingesting different levels and forms of creatine and not controls. There is also variability in conducting muscle and blood assays as well as variability in conducting performance tests. In some instances, large mean differences among groups were either not statistically significant or only approached significance. It is possible that some of these differences would have been significant if a control group was included in the study design and/or more subjects were studied to increase statistical power. Nevertheless, results from the present study do not support claims that KA is a more efficacious and/or safer form of creatine to consume than creatine monohydrate. Funding Supported by AlzChem AG, Germany.

Further experiments will focus on the upgrade of these protocols

Further experiments will focus on the upgrade of these protocols for the in planta detection of these bacteria as endophytes, encouraged by the results here obtained with the pathovar-specific TaqMan® probes. Moreover because of their multiplexing activity, these probes are already available to yield new important insights into the epidemiology of Psv, Psn and Psf and of the diseases they caused. Methods Bacterial strains AZD5582 and pathogenicity tests P. savastanoi strains used in this study are listed

in Table 1. P. savastanoi strains were routinely grown on King’s B agar (KB) [59], incubated at 26°C for 48 h. For liquid culture, bacteria were grown overnight on KB at 26°C on a rotary shaker (160 rpm). Bacterial suspensions were prepared from liquid cultures: after centrifugation (10 min at 7,000 g), the pellets were washed twice with sterile saline water (SSW, 0.85% NaCl in distilled water) and then resuspended in an appropriate volume of SSW to give the desired concentration [expressed as Colony Forming Units (CFU) per ml]. The concentration of each suspension was

verified by plating on KB agar plates 100 μl of SSW serial dilutions and counting single colonies after 2 days of incubation at 26°C. Bacterial epiphytes naturally occurring on P. savastanoi host plants (olive, oleander and ash) were also isolated and included in this study. To this selleck screening library purpose two chemically untreated plants for each species were sampled, randomly removing three Thiamet G leaves per plant from one-year-old twigs. Each leaf was then resuspended in SSW (50 ml in a 100 cc Erlenmeyer flask) and incubated at 26°C on a rotatory shaker (200 rpm) for 18 hours. The leaves washings were then separately centrifuged (8,000 g, 15 min), each pellet resuspended in 200 μl of SSW, and then used for plating

on KB agar, containing cycloheximide (50 μg/ml) to avoid fungal growth. After an incubation of 2 days at 26°C, 50 individual and different bacterial colonies from each leaf washing were randomly isolated and submitted as unidentified pool to DNA extraction. For long term storage bacteria were maintained at -80°C on 20% (v/v) glycerol. In order to confirm their previous identification, almost-full-length 16S rRNA genes were Crenolanib cell line amplified from all these isolates and amplifications were performed as described elsewhere [23]. The P. savastanoi strains used were also inoculated into 1-year-old olive, oleander and ash stems and tested for their pathogenicity and their virulence, as already described [21]. DNA extraction from bacteria and plants Genomic DNA was extracted and purified from 1 ml of bacterial titrated cultures (from 106 to 1010 CFU/ml), using Puregene® DNA Isolation Kit (Gentra System Inc., MN, USA), according to manufacturers’ instructions.

To determine the quality of repetitions performed, the number of

To determine the quality of repetitions performed, the number of repetitions performed at 90% of peak and mean power was also calculated. Test-retest reliability for the Tendo unit in our laboratory has consistently shown R > 0.90. Anaerobic Power Measures To quantify anaerobic power performance all subjects performed a Wingate anaerobic power test (Lode Excalibur, Groningen, The Netherlands). After a warm-up

period of 5 min of pedaling at 60 rpm interspersed with an three all-out sprints lasting 5 s, the subjects pedaled for 30 s at maximal speed against a constant force (1.2 Nm·kg-1). Subjects then performed an active rest for 5-minutes (repeat warm-up period) and then performed a second Wingate GANT61 clinical trial Blebbistatin in vitro test. Peak power, mean power, total work and rate of fatigue were determined. Peak power was defined as the highest mechanical power output elicited during the test and mean power was defined as the average mechanical power during each 30-s test. To quantify vertical jump power subjects performed a 3-jump power test. Following a brief warm-up period that included pedaling on a cycle ergometer for 5 min at 60 rpm, subjects stood on a portable force plate (Advanced Medical Technology Inc., Watertown, MA). The subject’s hands were placed on his waist at all times. Upon cue each subject performed 3 consecutive vertical jumps with

a standardized countermovement. The subject was instructed to maximize the height of each jump while minimizing the contact time with the force plate between jumps. Computer analysis was used to calculate power output. The highest power outputs were recorded. To quantify upper jump power subjects performed 3-repetitions with the bench press throw exercise. All bench press throws were performed on a Cormax bench throw device (Cormax Strength Power Systems; Valley City, ND) using 30% of the subject’s previously measured 1-RM bench press. The Cormax bench press throw

second apparatus provides a hydraulic mechanism that can unload the eccentric phase of contraction. Subjects performed all repetitions with the eccentric phase unloaded. During the concentric phase subjects were instructed to press the weight as fast as possible and release the bar as they reached the end of the range of motion. Power output during the bench press throw was measured for each repetition with the Tendo™ Power Unit as described above. Both peak power and peak force outputs were calculated and the highest outputs were recorded. THZ1 chemical structure Dietary Recall Three-day dietary records were completed during the week prior to the onset of the study. Subjects were instructed to record as accurately as possible everything they consumed during the day and between meal and late evening snacks. FoodWorks Dietary Analysis software (McGraw Hill, New York, NY) was used to analyze dietary recalls. Questionnaires The profile of mood states (POMS) was administered on the second day of each testing session.

The reaction products were examined by electron microscopy and X-

The reaction products were examined by electron microscopy and X-ray diffraction in order to identify their chemical compositions and microstructures. Methods Alumina-passivated Al nanoparticles with a diameter range of 50 to 120 nm were purchased from Sigma-Aldrich Corporation (St. Louis, MO, USA). These nanoparticles were handled in an argon-filled glove box before being mixed with the oxidizer. The thickness of the oxide shell was about 5 to 8 nm which agrees with the Mocetinostat research buy reported data on passivated Al nanoparticles [41, 42]. By assuming the averaged nanoparticle diameter of 80 nm, this shell thickness indicates that the content of Al is about 50%. NiO nanowires were synthesized by

a hydrothermal method; their average diameters were approximately 20 nm, and their lengths were several microns. Hydrothermal synthesis involved two check details major steps. First, NiOH nanostructures were formed at 120°C in a weak selleck compound alkaline solution when Ni(NO3) reacted with a Ni source. NiO nanowires were then produced by annealing NiOH nanostructures at 500°C

for 1 h at ambient atmosphere. The two reactants were then mixed together and ground in a 50-mL beaker in air; 10 mL of isopropanol was then added to the beaker, and the suspension was mixed in an ultrasound bath for 2 h. The suspension was then stir dried on a hot-plate stirrer. The dried powder was carefully scraped from the beaker wall and ground in an alumina mortar. Subsequently, the powder was pressed into

a stainless steel die to make a pellet with a diameter of 3 mm and a height of 0.7 mm. It is worthwhile to mention that a few thermogravimetric analysis (TGA) trails were made in order to fully oxidize the Al nanoparticles in air for determining the content of Al in those particles. The results were however quite uncertain due to the low penetration of O2 into the core of these nanoparticles. Six different compositions indicated in Table 1 were prepared. For each composition, two selleck kinase inhibitor samples were tested. The weight ratios of NiO in these composites were used to calculate the fuel-to-oxidizer equivalence ratio Φ, defined in this study by the following: (1) where is the measured mass ratio of the fuel to oxidizer and is the stoichiometric ratio calculated from the following thermite reaction between Al and NiO: (2) Table 1 Compositions of six Al nanoparticle and NiO nanowire composites Sample Composition Weight percentage of NiO nanowires (%) Equivalence ratio ( Φ )a A Al-NiO 9 18 B Al-NiO 20 7 C Al-NiO 26 5 D Al-NiO 33 3.5 E Al-NiO 38 2.8 F Al-NiO 50 1.7 aCalculated by the Al content of 42%. In this study, the equivalence ratios were calculated from the mass ratio of Al nanoparticles to oxidizer nanowires by taking into account the mass of the alumina shell. For this purpose, a base hydrolysis method was used to determine the amount of active aluminum in Al nanoparticles [43].

Xylanase activity The cells were grown in medium supplemented wi

Xylanase activity. The cells were grown in medium supplemented with 0.5% xylan [52]. Xylanase activity was indicated Selleck ABT-888 by a clear halo around the colony. Pectinase activity. The cells were grown in 0.67% YNB medium, pH 7.0, Chk inhibitor containing 1% pectin [26]. The plates were flooded with 1% hexadecyltrimethylammonium bromide, and activity was indicated by a clear halo around the colony on a red background [48]. Esterase activity. The cells were grown in medium composed of 1% bacto peptone,

0.5% NaCl, 0.4% CaCl2*2H2O and 1% Tween 80 [53], and esterase activity was indicated by a white precipitate around the colony. Acknowledgements We thank Ricardo Jaña (Departamento Científico – Instituto Antártico Chileno) for compiling the maps. This work was supported by grant T_23-09 from check details the Instituto Antártico Chileno. Electronic supplementary material Additional file 1: Molecular identification of yeast isolates obtained in this work. Summary of Blast search results obtained for D1/D2 and ITS1-5.8S-ITS2 rDNA sequences. The closets Blast-hits corresponding to uncultured yeasts were not considered. (PDF 62 KB) Additional file 2: Colony morphology of Leuconeurospora sp . isolates. Yeasts were cultivated on YM plates supplemented with glucose. The isolates T11Cd2 and T27Cd2 possess identical D1/D2 and ITS sequences,

yet are morphologically different. (PDF 2 MB) Additional file 3: Carbon source assimilation by yeast isolates obtained in this work. Determinations were performed using the API ID 32C gallery (bioMérieux, Lyon, France) according to manufacturer′s instructions. Gal, D-galactose; Sac, D-sucrose; 17-DMAG (Alvespimycin) HCl Nag, N-acetyl-glucosamine; Lat, lactic acid; Ara, L-arabinose; Cel, D-cellobiose; Raf, D-raffinose;

Mal, maltose; Tre, D-trehalose; 2kg, 2-ketoglutamate; Mdg, Methyl-αD-glucopiranoside; Man, D-mannitol; Lac, D-lactose; Ino, Inositol; Sor, D-sorbitol; Xyl, D-xylose; Rib, D- ribose; Gly, Gycerol; Rha, L-rhamnnose; Ple, pallatinose; Ery, erytritol; Mel, mellibiose; Grt, glucoronate; Mlz, D-mellicitose; Gnt, gluconate; Lvt, levulinic acid; Glu, D-glucose; Sbe, L-sorbose; Gln, glucosamine. +, assimilation; -, no assimilation. Determinations for each yeast were performed twice. (PDF 73 KB) References 1. Margesin R, Miteva V: Diversity and ecology of psychrophilic microorganisms. Res Microbiol 2011, 162:346–361.PubMedCrossRef 2. Robinson CH: Cold adaptation in Arctic and Antarctic fungi. New Phytol 2001, 151:341–353.CrossRef 3. Gounot AM: Psychrophilic and psychrotrophic microorganisms. Experientia 1986, 42:1192–1197.PubMedCrossRef 4. D’Amico S, Collins T, Marx JC, Feller G, Gerday C: Psychrophilic microorganisms: challenges for life. EMBO reports 2006, 7:385–389.PubMedCrossRef 5. Gerday C, Aittaleb M, Bentahir M, Chessa JP, Claverie P, Collins T, D’Amico S, Dumont J, Garsoux G, Georlette D: Cold-adapted enzymes: from fundamentals to biotechnology. Trends Biotechnol 2000, 18:103–107.PubMedCrossRef 6.

Using a TECNAI F30 transmission electron microscope (TEM), FEI, H

Using a TECNAI F30 transmission electron microscope (TEM), FEI, Hillsboro, OR, USA, operating at 300 kV and point-to-point resolution of 0.205 nm, the structural characterization of the samples deposited on carbon-coated copper grids was also executed. Finally, rheological measurements were carried out by a parallel plate rheometer stress tech HR at 200°C. Samples of MEH-PPV

and CdS/MEH-PPV nanocomposites, with a relative weight ratio of 1:4, were prepared by casting of solution in chloroform to obtain 1-mm thick films in order to evaluate the influence of CdS NCs inclusion on MEH-PPV film mechanical properties. Results and discussion Thermolytic process and thermogravimetric FK228 analysis The thermolytic process to obtain CdS NCs is described by the following scheme: (1) Thermogravimetric analysis, reported elsewhere [13], shows that the imidazole ligand is broken when the temperature reaches about 100°C, while the remaining metal bis(thiolates) decompose in a second step forming cadmium sulphide when temperature reaches 180°C. Our studies demonstrated that annealing temperatures of about 180°C to 200°C are required for the formation of CdS NCs. However, this finding implies that the thermal E7080 order stability of the polymer

at these annealing temperatures must be also assured. In fact, the thermal stability of polymers is one of the most important properties for CP673451 ic50 both processing and application [20]. Thermogravimetric (TG) and differential scanning calorimerty (DSC) signals of MEH-PPV film show the polymer degradation in the temperature range 25°C to 600°C, in inert atmosphere (Figure 2). The first weight loss on TG curve in the temperature range Ketotifen 200°C to 300°C is associated to the decomposition of MEH group (first broad exothermic peak on DSC curve). The

weight loss occurred at higher temperature is associated to a double exothermic peak and corresponds to the decomposition of PPV structure. Consequently, our results show that MEH-PPV films are still stable at the used annealing temperatures and the polymer decomposition becomes critical at temperatures >200°C consistent with the decomposition of MEH side groups and PPV backbone at low and high temperatures, as reported in the literature [21]. Figure 2 TG and DSC signals of MEH-PPV film. In argon atmosphere and recorded in the temperature range 25°C to 600°C (heating rate, 10°C/min). Optical spectroscopy analysis The absorption spectra of the [Cd(SBz)2]2·MI/MEH-PPV samples with a weight/weight ratio of 1:4 recorded before and after the annealing process are shown in Figure 3.

PubMedCentralPubMedCrossRef 37 Helming L, Gordon S: Molecular me

PubMedCentralPubMedCrossRef 37. Helming L, Gordon S: Molecular mediators of macrophage fusion.

Trends Cell Biol 2009, 19:514–522.PubMedCrossRef 38. Jay SM, Skokos E, Laiwalla F, Krady MM, Kyriakides TR: Foreign body giant cell formation is preceded OSI-906 chemical structure by lamellipodia formation and can be attenuated by inhibition of Rac1 activation. Am J Pathol 2007, 171:632–640.PubMedCentralPubMedCrossRef 39. Helming L, Tomasello E, Kyriakides TR, Martinez FO, Takai T, Gordon S, eFT508 mouse Vivier E: Essential role of DAP12 signaling in macrophage programming into a fusion-competent state. Sci Signal 2008, 1:ra11.PubMedCentralPubMedCrossRef 40. Helming L, Winter J, Gordon S: The scavenger receptor CD36 plays a role in cytokine-induced macrophage

fusion. J Cell Sci 2009, 122:453–459.PubMedCentralPubMedCrossRef 41. MacLauchlan S, Skokos EA, Meznarich N, Zhu DH, Raoof S, Shipley JM, Senior GS-1101 nmr RM, Bornstein P, Kyriakides TR: Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9. J Leukoc Biol 2009, 85:617–626.PubMedCentralPubMedCrossRef 42. Van den Bossche J, Bogaert P, Van Hengel J, Guerin CJ, Berx G, Movahedi K, Van den Bergh R, Pereira-Fernandes A, Geuns JM, Pircher H, Dorny P, Grooten J, De Baetselier P, Van Ginderachter JA: Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes. Blood 2009, 114:4664–4674.PubMedCrossRef 43. Yu M, Qi X, Moreno JL, Farber PAK5 DL, Keegan AD: NF-kappaB signaling participates in both RANKL- and IL-4-induced macrophage fusion: receptor cross-talk leads to alterations in NF-kappaB pathways. J Immunol 2011, 187:1797–1806.PubMedCentralPubMedCrossRef 44. French CT, Toesca IJ, Wu TH, Teslaa T, Beaty SM, Wong W, Liu M, Schroder I, Chiou PY, Teitell MA, Miller JF: Dissection of the Burkholderia intracellular life cycle using a photothermal nanoblade. Proc Natl Acad Sci U S A 2011, 108:12095–12100.PubMedCentralPubMedCrossRef

45. Horton RE, Grant GD, Matthews B, Batzloff M, Owen SJ, Kyan S, Flegg CP, Clark AM, Ulett GC, Morrison N, Peak IR, Beacham IR: Quorum sensing negatively regulates multinucleate cell formation during intracellular growth of Burkholderia pseudomallei in macrophage-like cells. PLoS One 2013, 8:e63394.PubMedCentralPubMedCrossRef 46. Kespichayawattana W, Rattanachetkul S, Wanun T, Utaisincharoen P, Sirisinha S: Burkholderia pseudomallei induces cell fusion and actin-associated membrane protrusion: a possible mechanism for cell-to-cell spreading. Infect Immun 2000, 68:5377–5384.PubMedCentralPubMedCrossRef 47. Wong KT, Puthucheary SD, Vadivelu J: The histopathology of human melioidosis. Histopathology 1995, 26:51–55.PubMedCrossRef 48.

Table 1 Effect on vertebral fracture rates (from randomized contr

Table 1 Effect on vertebral fracture rates (from randomized controlled trials)   Osteopenia Osteoporosis (without prevalent vertebral fractures) Established osteoporosis (with prevalent vertebral fractures) Raloxifene ● ■ ■ Alendronate NA ■ ■ Risedronate NA ● ■ Ibandronate NA ■ ■ Zoledronate NA ■ ■ SB202190 Teriparatide NA NA ■ Strontium ranelate ● ■ ■ Denosumab NA ■ ■ NA No evidence available ■ Denotes a preplanned analysis in the entire study population ● Denotes

a post hoc analysis Table 2 Effect on nonvertebral/hip fracture rates (from randomized controlled trials) MEK inhibitor side effects   Nonvertebral Hip Osteoporosis (without prevalent vertebral fractures) Established osteoporosis (with prevalent vertebral fractures) Osteoporosis (without prevalent vertebral fractures) Established osteoporosis (with prevalent vertebral fractures) Raloxifene NA ● NA NA Alendronate ■ ■ NA ■ Risedronate NA ■ NA ■ Ibandronate NA ● NA NA Zoledronate ■ NA ■ NA Teriparatide NA ■ NA NA Strontium Ranelate ● ■ ● ▲ Denosumab ■ NA ■ ICG-001 NA NA no evidence available ■ Denotes a preplanned analysis in the entire study population ▲ Denotes a preplanned analysis on a subset

of the study population ● Denotes a post hoc analysis Calcium and vitamin D supplementation should be a first-line strategy for the management of osteoporosis. Based on the very low mean dietary intake of calcium in the Belgian population, a systematic pharmacological supplementation (1,000–1,200 mg of calcium ion daily) in postmenopausal women appears to be an appropriate strategy (unless an individual dietary assessment reveals a satisfactory intake). The high prevalence of vitamin D deficiency in elderly Belgian subjects, combined

with the low marginal cost of a calcium–vitamin D supplementation compared with calcium alone, suggest that, after the age of 65, calcium and (800–1,000 IU) vitamin D should be systematically offered to all postmenopausal women, either alone or, if needed, in combination with another therapeutic regimen. HRT can no longer be considered as a first-line treatment for osteoporosis. It should only be considered in women experiencing Non-specific serine/threonine protein kinase climacteric symptoms, for the shortest possible duration and with the lowest effective doses. Selective-estrogen receptor modulators are a first-line option for women with low BMD, with or without fractures. Their effect on vertebral fracture is unequivocal, across different degrees of skeletal fragility, ranging from osteopenia to severe osteoporosis. Evidence of antifracture efficacy against nonvertebral fractures is limited to a post hoc analysis performed in a high-risk subset of the population. Breast benefits have been documented and should be taken into account when assessing the overall risk/benefit ratio of SERMs. Bisphosphonates reduce vertebral, nonvertebral, and hip fractures in women with established osteoporosis (low BMD and prevalent fractures).