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

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

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

Effects of E2/P4 oral capsules on bone turnover in women with vasomotor symptoms

Objective: To evaluate bone turnover markers (BTM) in the REPLENISH trial (NCT01942668). Methods: REPLENISH evaluated oral estradiol/progesterone (E2/P4) for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women with a uterus. Eligible women for this analysis had ≥50 moderate to severe VMS/wk, were <5 years since last menstrual period, and had BTM measurements at baseline, and months 6 and 12. Percent changes for three BTM (bone-specific alkaline phosphatase [BSAP], C-terminal telopeptide of type I collagen [CTX-1], and N-terminal propeptide of type I procollagen [P1NP]) assessed by immunoassay methods were evaluated from baseline to months 6 and 12 for the 1 mg E2/100 mg P4, 0.5 mg E2/100 mg P4, and placebo groups. Results: A total of 157 women (40-61 y, 69% White) were analyzed. Mean baseline values ranged from 14.0 to 14.3 U/L for BSAP, 0.34 to 0.39 ng/mL for CTX-1, and 76.9 to 79.3 ng/mL for PINP. Mean differences in percent change from baseline for both E2/P4 doses versus placebo significantly decreased at months 6 and 12 and ranged from −8% to −16% for BSAP (all, P < 0.05), −30% to −41% for CTX-1 (all, P ≤ 0.001), and −14% to −29% for PINP (all, P < 0.01). Conclusions: REPLENISH data provide support for a potential skeletal benefit of E2/P4 when it is used for the treatment of moderate to severe VMS. Further studies are warranted

Updated trabecular bone score accounting for the soft tissue thickness (TBSTT) demonstrated significantly improved bone microstructure with denosumab in the FREEDOM TBS post hoc analysis

TBS algorithm has been updated to account for regional soft tissue noise. In postmenopausal women with osteoporosis, denosumab improved tissue thickness-adjusted TBS vs placebo independently of bone mineral density over 3 years, with the magnitude of changes from baseline or placebo numerically greater than body mass index-adjusted TBS. Introduction: To evaluate the effect of denosumab on bone microarchitecture assessed by trabecular bone score (TBS) in the FREEDOM study using the updated algorithm that accounts for regional soft tissue thickness (TBSTT) in dual-energy X-ray absorptiometry (DXA) images and to compare percent changes from baseline and placebo with classical body mass index (BMI)-adjusted TBS (TBSBMI). Methods: Postmenopausal women with lumbar spine or total hip bone mineral density (BMD) T score < - 2.5 and ≥ - 4.0 received placebo or denosumab 60 mg subcutaneously every 6 months. TBSBMI and TBSTT were assessed on lumbar spine DXA scans at baseline and months 1, 12, 24, and 36 in a subset of 279 women (129 placebo, 150 denosumab) who completed the 3-year FREEDOM DXA substudy and rolled over to open-label extension study. Results: Baseline characteristics were similar between groups. TBSTT in the denosumab group showed numerically greater changes from both baseline and placebo than TBSBMI at months 12, 24, and 36. Denosumab led to progressive increases in BMD (1.2, 5.6, 8.1, and 10.5%) and TBSTT (0.4, 2.3, 2.6, and 3.3%) from baseline to months 1, 12, 24, and 36, respectively. Both TBS changes were significant vs baseline and placebo from months 12 to 36 (p < 0.0001). As expected, BMD and TBSTT were poorly correlated both at baseline and for changes during treatment. Conclusion: In postmenopausal women with osteoporosis, denosumab significantly improved bone microstructure assessed by TBSTT over 3 years. TBSTT seemed more responsive to denosumab treatment than TBSBMI and was independent of BMD

The role of osteoanabolic agents in the management of patients with osteoporosis

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis

Type II Protein Arginine Methyltransferase 5 (PRMT5) Is Required for Circadian Pperiod Determination in Arabidopsis Thaliana

Posttranslational modification is an important element in circadian clock function from cyanobacteria through plants and mammals. For example, a number of key clock components are phosphorylated and thereby marked for subsequent ubiquitination and degradation. Through forward genetic analysis we demonstrate that protein arginine methyltransferase 5 (PRMT5; At4g31120) is a critical determinant of circadian period in Arabidopsis. PRMT5 is coregulated with a set of 1,253 genes that shows alterations in phase of expression in response to entrainment to thermocycles versus photocycles in constant temperature. PRMT5 encodes a type II protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues (Rsme2). Rsme2 modification has been observed in many taxa, and targets include histones, components of the transcription complex, and components of the spliceosome. Neither arginine methylation nor PRMT5 has been implicated previously in circadian clock function, but the period lengthening associated with mutational disruption of prmt5 indicates that Rsme2 is a decoration important for the Arabidopsis clock and possibly for clocks in general