Role of RANKL inhibition in osteoporosis

When the rate of bone resorption exceeds that of bone formation, destruction of bone tissue occurs, resulting in a fragile skeleton. The clinical consequences, namely osteoporosis and fragility fractures, are common and costly problems. Treatments that normalize the balance of bone turnover by inhibiting bone resorption preserve bone mass and reduce fracture risk. The discovery of receptor activator of nuclear factor-κB ligand (RANKL) as a pivotal regulator of osteoclast activity provides a new therapeutic target. Early studies have demonstrated that denosumab, an investigational, highly specific anti-RANKL antibody, rapidly and substantially reduces bone resorption. Pharmacokinetics of the antibody allow dosing by subcutaneous injection at an interval of 6 months. Inhibiting RANKL appears to be a promising new treatment for osteoporosis and related disorders. More information about the effectiveness of denosumab in reducing fracture risk, its tolerability and safety, and the response to discontinuing therapy will be provided by ongoing clinical studies

Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential

Sclerostin is an osteocyte-derived glycoprotein that inhibits Wnt/β-catenin signaling and activation of osteoblast function, thereby inhibiting bone formation. It plays a vital role in the regulation of skeletal growth. In adults, sclerostin secretion is modulated by skeletal loading (increased secretion with immobilization; less with weight bearing) and by hormonal/cytokine actions on the osteocyte. Sclerostin deficiency syndromes in humans and animals are characterized by high bone mass of normal quality. In animal models of osteoporosis, inhibition of sclerostin by monoclonal antibodies induces osteoblast activity and new bone formation, normalizing bone mass and improving bone architecture and strength. In recently completed clinical trials, anti-sclerostin antibody therapy results in marked increases in bone mineral density and rapid and substantial reduction in fracture risk. This review will focus on these recent studies and anticipate the role of anti-sclerostin therapy in the management of patients with osteoporosis

Denosumab rapidly increases cortical bone in key locations of the femur: a 3D bone mapping study in women with osteoporosis.

Women with osteoporosis treated for 36 months with twice-yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60 mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One-third of the increase came from increasing cortical density, and two-thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab-treated women at increased risk of fracture.This study was funded by Amgen Inc., Thousand Oaks, CA, USA. Cambridge Bone Group is supported by Arthritis Research UK, The Evelyn Trust, and Cambridge NIHR Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/jbmr.232

Comparison of snow pressure measurements and theoretical predictions

Measurements of snow pressures from the centre section of a 3.4 m high and 15 m long avalanche-defence supporting structure located on a mountain in western Norway are presented. The site has a deep snow cover and an average slope angle of 250. The measurement configuration corresponds to plane-strain conditions and the data, along with measured snowpack parameters, allow comparision with simple theoretical predictions. The analysis shows that the average pressure on the structure may be calculated fairly accurately using linear, viscous modelling for the snow deformation. The maximum pressure proved to be higher than that provided by a linear model and this is considered characteristic of nonlinear material. The implications of these results for estimates of design loads are discussed.Larsen, Jan Ott

Reducing hip fracture risk with risedronate in elderly women with established osteoporosis

Tahir Masud1, Michael McClung2, Piet Geusens31Nottingham University Hospitals NHS Trust, Nottingham, UK; 2Oregon Osteoporosis Center, Portland, Oregon, USA; 3Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, BelgiumBackground: There is limited evidence to support the efficacy of current pharmaceutical agents in reducing the risk of hip fracture in older postmenopausal women with established osteoporosis.Objective: To clarify the efficacy of risedronate in reducing the risk of hip fracture in elderly postmenopausal women aged ≥70 years with established osteoporosis, i.e., those with bone mineral density-defined osteoporosis and a prevalent vertebral fracture.Methods: Post hoc analysis of the Hip Intervention Program (HIP) study, a randomized controlled trial comparing risedronate with placebo for reducing the risk of hip fracture in elderly women. Women aged 70 to 100 years with established osteoporosis (baseline femoral neck T-score ≤ −2.5 and ≥ 1 prior vertebral fracture) were included. The main outcome measure was 3-year hip fracture incidence in the risedronate and placebo groups.Results: A total of 1656 women met the inclusion criteria. After 3 years, hip fracture had occurred in 3.8% of risedronate-treated patients and 7.4% of placebo-treated patients (relative risk 0.54; 95% confidence interval 0.32–0.91; P = 0.019).Conclusion: Risedronate significantly reduced the risk of hip fracture in women aged up to 100 years with established osteoporosis.Keywords: osteoporosis, postmenopausal, hip fracture, risedronat

Plant responses to photoperiod

Photoperiod controls many developmental responses in animals, plants and even fungi. The response to photoperiod has evolved because daylength is a reliable indicator of the time of year, enabling developmental events to be scheduled to coincide with particular environmental conditions. Much progress has been made towards understanding the molecular mechanisms involved in the response to photoperiod in plants. These mechanisms include the detection of the light signal in the leaves, the entrainment of circadian rhythms, and the production of a mobile signal which is transmitted throughout the plant. Flowering, tuberization and bud set are just a few of the many different responses in plants that are under photoperiodic control. Comparison of what is known of the molecular mechanisms controlling these responses shows that, whilst common components exist, significant differences in the regulatory mechanisms have evolved between these responses

Effects of commercially available colored lenses on color perception in a normal population

Effects upon color perception were studied using the Corning Medical Optics CPF lenses and the Younger Optics PLS lenses. Measurements were obtained using the Farnsworth 15-hue (D-15) color test. Color perception errors associated with the respective lenses were statistically analyzed. Comparisons of these individual lens errors were then made among all the lenses included in the study. All the lenses significantly altered color perception in some or all of the visible spectrum. In all cases, the Corning CPF lenses had either equal or lesser effects upon color perception errors than did the Younger PLS lenses

Propagating compaction bands in confined compression of snow

Some materials are strong in response to a slowly applied deformation, yet weak when subject to rapid deformations—a materials property known as strain-rate softening1. Snow exhibits such behaviour: it is comparatively strong at low deformation rates, where it is quasi-plastic, but weak at high rates, where it deforms in a quasi-brittle manner2. During deformation, strain-rate-softening materials ranging from metals3, 4 to micellar systems5 exhibit complex spatio-temporal deformation patterns, including regular or chaotic deformation-rate oscillations and travelling deformation waves6. Here we report a systematic investigation of such phenomena in snow and show that snow can deform with the formation and propagation of localized deformation bands accompanied by oscillations of the driving force. We propose a model that accounts for these observations. Our findings demonstrate that in snow, strain localization can occur even in initially homogeneous samples deforming under homogeneous loads