FRAX® assessment of osteoporotic fracture probability in Switzerland

Summary: A Swiss-specific FRAX® model was developed. Patient profiles at increased probability of fracture beyond currently accepted reimbursement thresholds for bone mineral density (BMD) measurement by dual X-ray absorptiometry (DXA), and osteoporosis treatment were identified. Introduction: This study aimed to determine which constellations of clinical risk factors, alone, or combined with BMD measurement by DXA, contribute to improved identification of Swiss patients with increased probability of fracture. Methods: The 10-year probability of hip and any major osteoporotic fracture was computed for both sexes, based on Swiss epidemiological data, integrating fracture risk and death hazard, in relation to validated clinical risk factors, with and without BMD values. Results: Fracture probability increased with age, lower body mass index (BMI), decreasing BMD T-score, and all clinical risk factors used alone or combined. Several constellations of risk factor profiles were identified, indicating identical or higher absolute fracture probability than risk factors currently accepted for DXA reimbursement in Switzerland. With identical sex, age and BMI, subjects with parental history of hip fracture had as high a probability of any major osteoporotic fracture as patients on oral glucocorticoids or with a prevalent fragility fracture. The presence of additional risk factors further increased fracture probability. Conclusions: The customised FRAX® model indicates that a shift from the current DXA-based intervention paradigm, toward a fracture risk continuum based on the 10-year probability of any major osteoporotic fracture may improve identification of patients at increased fracture ris

Remaining lifetime and absolute 10-year probabilities of osteoporotic fracture in Swiss men and women

Summary: Remaining lifetime and absolute 10-year probabilities for osteoporotic fractures were determined by gender, age, and BMD values. Remaining lifetime probability at age 50years was 20.2% in men and 51.3% in women and increased with advancing age and decreasing BMD. The study validates the elements required to populate a Swiss-specific FRAX® model. Introduction: Switzerland belongs to high-risk countries for osteoporosis. Based on demographic projections, burden will still increase. We assessed remaining lifetime and absolute 10-year probabilities for osteoporotic fractures by gender, age and BMD in order to populate FRAX® algorithm for Switzerland. Methods: Osteoporotic fracture incidence was determined from national epidemiological data for hospitalised fractured patients from the Swiss Federal Office of Statistics in 2000 and results of a prospective Swiss cohort with almost 5,000 fractured patients in 2006. Validated BMD-associated fracture risk was used together with national death incidence and risk tables to determine remaining lifetime and absolute 10-year fracture probabilities for hip and major osteoporotic (hip, spine, distal radius, proximal humerus) fractures. Results: Major osteoporotic fractures incidence was 773 and 2,078 per 100,000 men and women aged 50 and older. Corresponding remaining lifetime probabilities at age 50 were 20.2% and 51.3%. Hospitalisation for clinical spine, distal radius, and proximal humerus fractures reached 25%, 30% and 50%, respectively. Absolute 10-year probability of osteoporotic fracture increased with advancing age and decreasing BMD and was higher in women than in men. Conclusion: This study validates the elements required to populate a Swiss-specific FRAX® model, a country at highest risk for osteoporotic fracture

Cost-effective intervention thresholds against osteoporotic fractures based on FRAX® in Switzerland

Summary: FRAX-based cost-effective intervention thresholds in the Swiss setting were determined. Assuming a willingness to pay at 2× Gross Domestic Product per capita, an intervention aimed at reducing fracture risk in women and men with a 10-year probability for a major osteoporotic fracture at or above 15% is cost-effective. Introduction: The fracture risk assessment algorithm FRAX® has been recently calibrated for Switzerland. The aim of the present analysis was to determine FRAX-based fracture probabilities at which intervention becomes cost-effective. Methods: A previously developed and validated state transition Markov cohort model was populated with Swiss epidemiological and cost input parameters. Cost-effective FRAX-based intervention thresholds (cost-effectiveness approach) and the cost-effectiveness of intervention with alendronate (original molecule) in subjects with a FRAX-based fracture risk equivalent to that of a woman with a prior fragility fracture and no other risk factor (translational approach) were calculated based on the Swiss FRAX model and assuming a willingness to pay of 2 times Gross Domestic Product per capita for one Quality-adjusted Life-Year. Results: In Swiss women and men aged 50years and older, drug intervention aimed at decreasing fracture risk was cost-effective with a 10-year probability for a major osteoporotic fracture at or above 13.8% (range 10.8% to 15.0%) and 15.1% (range 9.9% to 19.9%), respectively. Age-dependent variations around these mean values were modest. Using the translational approach, treatment was cost-effective or cost-saving after the age 60years in women and 55 in men who had previously sustained a fragility fracture. Using the latter approach leads to considerable underuse of the current potential for cost-effective interventions against fractures. Conclusions: Using a FRAX-based intervention threshold of 15% for both women and men should permit cost-effective access to therapy to patients at high fracture probability based on clinical risk factors and thereby contribute to further reduce the growing burden of osteoporotic fractures in Switzerlan

Eccentric endurance training in subjects with coronary artery disease: a novel exercise paradigm in cardiac rehabilitation?

This study evaluated the effects of 8weeks of eccentric endurance training (EET) in male subjects (age range 42-66years) with coronary artery disease (CAD). EET was compared to concentric endurance training (CET) carried out at the same metabolic exercise intensity, three times per week for half an hour. CET (n=6) was done on a conventional cycle ergometer and EET (n=6) on a custom-built motor-driven ergometer. During the first 5weeks of the training program the metabolic load was progressively increased to 60% of peak oxygen uptake in both groups. At this metabolic load, mechanical work rate achieved was 97 (8)W [mean (SE)] for CET and 338 (34)W for EET, respectively. Leg muscle mass was determined by dual-energy X-ray absorptiometry, quadriceps strength with an isokinetic dynamometer and muscle fibre composition of the vastus lateralis muscle with morphometry. The leg muscle mass increased significantly in both groups by some 3%. Strength parameters of knee extensors improved in EET only. Significant changes of +11 (4.9)%, +15 (3.2)% and +9 (2.5)% were reached for peak isometric torque and peak concentric torques at 60°s−1 and 120°s−1, respectively. Fibre size increased significantly by 19% in CET only. In conclusion, the present investigation showed that EET is feasible in middle-aged CAD patients and has functional advantages over CET by increasing muscle strength. Muscle mass increased similarly in both groups whereas muscle structural composition was differently affected by the respective training protocols. Potential limitations of this study are the cautiously chosen conditioning protocol and the restricted number of subject

Effect of calcium-channel blockers on calcium—phosphate metabolism in patients with end-stage renal disease

Background After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect. Methods To test this hypothesis, seven patients with ESRD on chronic haemodialysis (3 women and 4 men) with serum levels of intact PTH ranging from 204 to 675 pg/ml were studied both before and during the first 180 min of haemodialysis against a dialysate with low calcium concentration (0.75 mmol/1, n=6 and 1 mmol/1, n=1) under the following three experimental conditions: control, felodipine (10 mg/day) and diltiazem (120 mg b.i.d.). Results At onset of dialysis, plasma phosphorus level was higher on diltiazem (2.03±0.08 mM) than on felodipine (1.64±0.10, P<0.02), and on the latter it was lower than in control condition (1.88±0.16, P<0.02). As a probable consequence, blood ionized calcium concentration was lower on diltiazem (1.14 mM±0.02, mean±SEM) than on felodipine (1.2±0.03, P<0.05) or in control condition (1.17±0.01, NS). There was a trend for intact PTH to be higher on diltiazem (324±47 pg/ml) than on felodipine (246±55) or in control condition (305±49) and 1,25-dihydroxyvitamin D was higher indeed on diltiazem (6.70±0.92 pg/ml) than on felodipine (4.75±0.91, P<0.02) or control (3.87±0.62, P<0.05). Area under the curve PTH over the first 60 min of dialysis was higher by 16±7% on diltiazem than on felodipine (P<0.05). Conclusions While on diltiazem rather than on felodipine, patients with ESRD display higher plasma phosphorus levels, and slightly aggravate the degree of severity of hyperparathyroidism recorded during haemodialysis against low-calcium dialysate. The longterm effect of this new observation remains to be evaluate

Composition Effects on Kilonova Spectra and Light Curves: I

The merger of neutron star binaries is believed to eject a wide range of heavy elements into the universe. By observing the emission from this ejecta, scientists can probe the ejecta properties (mass, velocity and composition distributions). The emission (a.k.a. kilonova) is powered by the radioactive decay of the heavy isotopes produced in the merger and this emission is reprocessed by atomic opacities to optical and infra-red wavelengths. Understanding the ejecta properties requires calculating the dependence of this emission on these opacities. The strong lines in the optical and infra-red in lanthanide opacities have been shown to significantly alter the light-curves and spectra in these wavelength bands, arguing that the emission in these wavelengths can probe the composition of this ejecta. Here we study variations in the kilonova emission by varying individual lanthanide (and the actinide uranium) concentrations in the ejecta. The broad forest of lanthanide lines makes it difficult to determine the exact fraction of individual lanthanides. Nd is an exception. Its opacities above 1 micron are higher than other lanthanides and observations of kilonovae can potentially probe increased abundances of Nd. Similarly, at early times when the ejecta is still hot (first day), the U opacity is strong in the 0.2-1 micron wavelength range and kilonova observations may also be able to constrain these abundances

In major joint diseases the human synovium retains its potential to form repair cartilage.

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-β1 (TGF-β1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-β1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies

Clinical observation of diminished bone quality and quantity through longitudinal HR-pQCT-derived remodeling and mechanoregulation.

High resolution peripheral quantitative computed tomography (HR-pQCT) provides methods for quantifying volumetric bone mineral density and microarchitecture necessary for early diagnosis of bone disease. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone formation and resorption (i.e., remodeling) and the relationship between this remodeling and mechanical loading (i.e., mechanoregulation) at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9-12 months follow-up: 16 patients were prescribed vitamin D3 with/without calcium supplement based on a blood biomarker measures of bone metabolism and dual-energy X-ray absorptiometry image-based measures of normative bone quantity which indicated diminishing (n = 9) or poor (n = 7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element analysis was then used to predict local bone strains and derive rules for mechanoregulation. Remodeling volume fractions were predicted by both average values of trabecular and cortical thickness and bone mineral density (R2 > 0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p < 0.05). Overall, longitudinal, extended HR-pQCT analysis enabled the identification of changes in bone quantity and quality too subtle for traditional measures