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Context Individualized fracture risk may help to select patients requiring a pharmacological treatment for osteoporosis. FRAX and the Garvan fracture risk calculators are the most used tools, although their external validation has shown significant differences in their risk prediction ability. Objective and Methods Using data from the Fracture Risk Brussels Epidemiological Enquiry study, a cohort of 3560 postmenopausal women aged 60 to 85 years, we aimed to construct original 5-year fracture risk prediction models using validated clinical risk factors (CRFs). Three models of competing risk analysis were developed to predict major osteoporotic fractures (MOFs), all fractures, and central fractures (femoral neck, shoulder, clinical spine, pelvis, ribs, scapula, clavicle, sternum). Results Age, a history of fracture, and hip or spine BMD were predictors common to the 3 models. Excessive alcohol intake and the presence of comorbidities were specific additional CRFs for MOFs, a history of fall for all fractures, and rheumatoid arthritis for central fractures. Our models predicted the fracture probability at 5 years with an acceptable accuracy (Brier scores ≤ 0.1) and had a good discrimination power (area under the receiver operating curve of 0.73 for MOFs and 0.72 for central fractures) when internally validated by bootstrap. Three simple nomograms, integrating significant CRFs and the mortality risk, were constructed for different fracture sites. In conclusion, we derived 3 models predicting fractures with an acceptable accuracy, particularly for MOFs and central fractures. The models are based on a limited number of CRFs, and we constructed nomograms for use in clinical practice.

We registered 1336 incident-validated fractures in a prospective cohort of 3560 postmenopausal (60-85 years) Belgian women (mean follow-up of 9.1 years). The increase of fracture incidence with age varied widely depending on the fracture site and was significantly steeper for central than for peripheral fractures (e.g., not significant for the ankle).The epidemiology of fracture sites other than MOFs has been less studied. We examined the incidence of fractures according to their sites in a prospective cohort of postmenopausal Belgian women.Three thousand five hundred sixty postmenopausal women, aged 60-85 years old, were recruited from 2007 to 2013 and surveyed yearly (FRISBEE). The number of validated incident fractures was recorded and analyzed in relation to age and the fracture site.One thousand three hundred thirty-six fractures were recorded after a mean follow-up of 9.1 years. Seven hundred fifty-six fractures (57%) were MOFs and 580 (43%) non-MOFs, while 813 (61%) were central and 523 (39%) peripheral. The increase of fracture incidence with age differed between fracture sites and was steeper for central than for peripheral fractures. The ratio of MOFs to non-MOFs increased significantly with age, from 1.10 (95% CI: 0.83-1.45) for the 60-69 to 1.69 [1.42-2.01] for the 80-89-year subgroup (P = 0.017). This was also true for central versus peripheral fracture. We differentiated three groups of fracture incidence evolution with age: fractures with a mean increase/decade (compared to the 60-69 age group) of less than 1.5, 1.5-2.0, and 2.0-3.0. The lowest increase was seen for most peripheral fractures, whereas the greatest increase included hip, scapula, pelvis, ribs, and spine fractures.The increase of fracture incidence with age varied widely depending on the fracture site, and the ratio of MOFs to non-MOFs rose significantly with age. Some peripheral fractures, such as the ankle, did not increase significantly with age, suggesting that bone fragility does not play a major role in their occurrence.

This dissertation examines the dynamic interrelationship between MNEs and cities. First, it examines cities as MNEs' foreign direct investment location choice and imitation processes within these FDI location choices. Imitation not only enhances the attractiveness of the city by contributing to the generation of agglomeration economies and by encouraging additional imitation, but it also contributes to the further development of the international connectivity of the city and the creation of global knowledge networks. Second, this dissertation introduces a new measure of international connectivity of cities in terms of collaboration on innovation. In addition, it elaborates on the interrelated roles of different types of international connectivity on city economic growth and the influence of this connectivity on the surrounding areas of the city. The dissertation has four contributing chapters, in addition to an introduction (Chapter 1) and general conclusion (Chapter 6). Chapter 2 examines the role of domestic cultural characteristics and investor heterogeneity in shaping imitation of foreign direct investment location choices by MNEs. While existing research has indicated that firms may imitate their peers in order to gain legitimacy among stakeholders, a national cultural dimension has rarely been included. The chapter argues that imitation processes depend on the presence of three cultural traits of home countries, i.e. collectivism, power distance and uncertainty avoidance, which can jointly act as domestic conformity forces strengthening the incentive to imitate. This influence is most salient in particular for firms that lack substantial domestic legitimacy and those that have limited multinational operations. The empirical findings, using a conditional logit model on a sample of 1050 greenfield manufacturing investments in the United States by 662 firms based in 35 different home countries, confirm that the tendency to engage in imitation is stronger for firms based in home countries characterized by greater collectivism and overall national conformity forces. Furthermore, the empirical findings conclude that less legitimate firms and firms with limited multinational operations are significantly responsive to two domestic cultural traits, i.e. collectivism and power distance. This may imply that targeted policies in attracting FDI from countries with such domestic conformity forces may prove to be more effective by follow up investments, yet it will attract in particular smaller and younger firms and firms with limited multinational operations. Chapter 3 puts forward a new measurement of international connectivity of global cities focusing on collaborations in innovation, by drawing on a novel and extensive database of geocoded patent inventor addresses. While existing research has mainly measured international connectivity by the worldwide office networks of advanced producer services firms (e.g. consulting, accounting and insurance firms) in cities, a more inclusive understanding of city connectivity remains absent. Hence, this chapter looks at international connectivity based on another central function of global cities, i.e. their role as prominent spaces for knowledge exchange and collaboration on innovation. The findings of this chapter, focusing on the 125 cities in 46 countries, confirm the role of global cities as prominent places for knowledge exchange and collaboration of innovation and the growing importance of international collaboration for innovation. Chapter 4 compares the new measure of connectivity based on innovation collaboration to the traditional indicator on advanced producer services for 129 cities in 76 countries. The findings suggest broadly similar trends, but also highlight some important differences suggesting specialization advantages of a strong position in one of the two networks. When analyzing the simultaneous and interrelated influences of the knowledge network and the advanced producer services network of cities on their economic growth using a fixed effects panel regression, the findings suggest that both aspects of cities' international connectivity may allow their economies to grow, but that they reduce each other's association with city economic growth. This suggest that specialization in one type of network and connectivity and building on existing strengths may be more beneficial. Chapter 5 analyses the influence of global city international connectivity on collaborative linkages of the city with the surrounding area of these global cities. It argues that the international connectivity may render global cities less likely to establish intensive local innovation linkages with surrounding areas, but that the nature of this relationship may depend on the characteristics of the global city and their surroundings. More specifically, we argue that global linkages are more detrimental to the establishment of local linkages if the global city is a technology leader, but less so if the surrounding area has a greater absorptive capacity and features a smaller travel distance to the global city. The findings, based on the collaborative linkages of 21 US global cities and 614 surrounding counties using a fixed effects Poisson regression model, provide clear indications of international connectedness being associated with local disconnectedness. However, it also suggests that the relationship between global city international connectivity and their local linkages depends on the characteristics of both the global city and their surrounding area. This illustrates that knowledge exchange does not always cause an equal spread of opportunities across geographies and calls for innovation policies focusing on improving the knowledge convergence between the surrounding areas and cities. status: published

Purpose To provide a summarized state of the art of the relative efficacy and rapidity of action of pharmacological treatments to prevent imminent osteoporotic fractures. Methods We reviewed metanalyses (MA) and network metaanalyses (NMA) published during the last 10 years concerning the pharmacological treatment of osteoporosis. We compared the anti-fracture efficacy and the rapidity of action of various agents versus placebo and versus risedronate. Results All bisphosphonates decrease the incidence of vertebral fractures compared with placebo. Ibandronate is the only one without demonstrated efficacy against non-vertebral and hip fractures. Zoledronate, denosumab and anabolic therapy are associated with a higher fracture risk reduction than oral bisphosphonates. Compared with risedronate, which significantly reduces the rate of hip fractures, zoledronate, denosumab, teriparatide, abaloparatide and romosozumab are more efficient for vertebral fractures but not for non-vertebral or hip fractures reduction. No studies have compared bone anabolic treatments with zoledronate or denosumab. Oral bisphosphonates significantly reduce fracture risk only after more than one year of therapy. A faster reduction of fracture risk is observed with zoledronate and denosumab, or with anabolic agents. For denosumab and anabolic agents, a sequential treatment is required to keep gains after treatment withdrawal. Conclusions In patients at high risk of imminent fracture, starting therapy with potent antiresorptive agents or with an anabolic agent seems most appropriate to promptly reduce the fracture risk. Available NMA/MA suggest that, compared to zoledronate and denosumab, anabolic agents have a higher efficacy for vertebral fractures but head-to-head studies are lacking., Highlights • The concept of imminent fracture has implications for the choice of therapy • We reviewed metanalyses and network metaanalyses published in the last 10 years • We compared the efficacy and rapidity of treatments to prevent imminent fractures • Potent antiresorptive and anabolic agents are most appropriate to promptly reduce fracture risk • Anabolic agents seem to be more efficient to reduce vertebral fracture risk

This dissertation examines the dynamic interrelationship between MNEs and cities. First, it examines cities as MNEs��� foreign direct investment location choice and imitation processes within these FDI location choices. Imitation not only enhances the attractiveness of the city by contributing to the generation of agglomeration economies and by encouraging additional imitation, but it also contributes to the further development of the international connectivity of the city and the creation of global knowledge networks. Second, this dissertation introduces a new measure of international connectivity of cities in terms of collaboration on innovation. In addition, it elaborates on the interrelated roles of different types of international connectivity on city economic growth and the influence of this connectivity on the surrounding areas of the city. The dissertation has four contributing chapters, in addition to an introduction (Chapter 1) and general conclusion (Chapter 6). Chapter 2 examines the role of domestic cultural characteristics and investor heterogeneity in shaping imitation of foreign direct investment location choices by MNEs. While existing research has indicated that firms may imitate their peers in order to gain legitimacy among stakeholders, a national cultural dimension has rarely been included. The chapter argues that imitation processes depend on the presence of three cultural traits of home countries, i.e. collectivism, power distance and uncertainty avoidance, which can jointly act as domestic conformity forces strengthening the incentive to imitate. This influence is most salient in particular for firms that lack substantial domestic legitimacy and those that have limited multinational operations. The empirical findings, using a conditional logit model on a sample of 1050 greenfield manufacturing investments in the United States by 662 firms based in 35 different home countries, confirm that the tendency to engage in imitation is stronger for firms based in home countries characterized by greater collectivism and overall national conformity forces. Furthermore, the empirical findings conclude that less legitimate firms and firms with limited multinational operations are significantly responsive to two domestic cultural traits, i.e. collectivism and power distance. This may imply that targeted policies in attracting FDI from countries with such domestic conformity forces may prove to be more effective by follow up investments, yet it will attract in particular smaller and younger firms and firms with limited multinational operations. Chapter 3 puts forward a new measurement of international connectivity of global cities focusing on collaborations in innovation, by drawing on a novel and extensive database of geocoded patent inventor addresses. While existing research has mainly measured international connectivity by the worldwide office networks of advanced producer services firms (e.g. consulting, accounting and insurance firms) in cities, a more inclusive understanding of city connectivity remains absent. Hence, this chapter looks at international connectivity based on another central function of global cities, i.e. their role as prominent spaces for knowledge exchange and collaboration on innovation. The findings of this chapter, focusing on the 125 cities in 46 countries, confirm the role of global cities as prominent places for knowledge exchange and collaboration of innovation and the growing importance of international collaboration for innovation. Chapter 4 compares the new measure of connectivity based on innovation collaboration to the traditional indicator on advanced producer services for 129 cities in 76 countries. The findings suggest broadly similar trends, but also highlight some important differences suggesting specialization advantages of a strong position in one of the two networks. When analyzing the simultaneous and interrelated influences of the knowledge network and the advanced producer services network of cities on their economic growth using a fixed effects panel regression, the findings suggest that both aspects of cities��� international connectivity may allow their economies to grow, but that they reduce each other���s association with city economic growth. This suggest that specialization in one type of network and connectivity and building on existing strengths may be more beneficial. Chapter 5 analyses the influence of global city international connectivity on collaborative linkages of the city with the surrounding area of these global cities. It argues that the international connectivity may render global cities less likely to establish intensive local innovation linkages with surrounding areas, but that the nature of this relationship may depend on the characteristics of the global city and their surroundings. More specifically, we argue that global linkages are more detrimental to the establishment of local linkages if the global city is a technology leader, but less so if the surrounding area has a greater absorptive capacity and features a smaller travel distance to the global city. The findings, based on the collaborative linkages of 21 US global cities and 614 surrounding counties using a fixed effects Poisson regression model, provide clear indications of international connectedness being associated with local disconnectedness. However, it also suggests that the relationship between global city international connectivity and their local linkages depends on the characteristics of both the global city and their surrounding area. This illustrates that knowledge exchange does not always cause an equal spread of opportunities across geographies and calls for innovation policies focusing on improving the knowledge convergence between the surrounding areas and cities.���