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Among postmenopausal women with osteoporosis and a high risk of fracture, treatment with the monoclonal antibody romosozumab for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate for 12 months followed by alendronate.

Summary This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. Purpose To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. Methods This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients ( N  = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80–125% (for 95% CIs associated with geometric LS mean ratios). Results Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: − 0.139 [− 0.826, 0.548] in the full analysis set and − 0.280 [− 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. Conclusions CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to teriparatide received denosumab (teriparatide to denosumab group), those originally assigned to denosumab received teriparatide (denosumab to teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00926380. Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9–21·8) in 27 women in the teriparatide to denosumab group, 14·0% (10·9–17·2) in 27 women the denosumab to teriparatide group, and 16·0% (14·0–18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the teriparatide to denosumab group vs the denosumab to teriparatide group, p=0·30 for the teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the teriparatide to denosumab group (6·6% [95% CI 5·3–7·9]) than in the denosumab to teriparatide group (2·8% [1·3–4·2], p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% [7·1–10·0]; p=0·0446 vs the teriparatide to denosumab group, p<0·0001 vs the denosumab to teriparatide group). Similarly, femoral neck bone mineral density increased more in the teriparatide to denosumab group (8·3% [95% CI 6·1–10·5]) and the combination to denosumab group (9·1% [6·1–12·0]) than in the denosumab to teriparatide group (4·9% [2·2–7·5]; p=0·0447 for teriparatide to denosumab vs denosumab to teriparatide, p=0·0336 for combination to denosumab vs denosumab to teriparatide). Differences between the combination to denosumab group and the teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the teriparatide to denosumab group (0·0% [95% CI −1·3 to 1·4]), whereas it decreased by −1·8% (−5·0 to 1·3) in the denosumab to teriparatide group, and increased by 2·8% (1·2–4·4) in the combination to denosumab group (p=0·0075 for the teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to teriparatide group vs the combination to denosumab group). One participant in the denosumab to teriparatide group had nephrolithiasis, classified as being possibly related to treatment. In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. Amgen, Eli Lilly, and National Institutes of Health.

\"Imagine waking up to the gentle noises of the city, and moving through your day with complete confidence that you will get where you need to go quickly and efficiently. Soft City is about ease and comfort, where density has a human dimension, adapting to our ever-changing needs, nurturing relationships, and accommodating the pleasures of everyday life. How do we move from the current reality in most cites-separated uses and lengthy commutes in single-occupancy vehicles that drain human, environmental, and community resources-to support a soft city approach? In Soft City David Sim, partner and creative director at Gehl, shows how this is possible, presenting ideas and graphic examples from around the globe. He draws from his vast design experience to make a case for a dense and diverse built environment at a human scale, which he presents through a series of observations of older and newer places, and a range of simple built phenomena, some traditional and some totally new inventions. Sim shows that increasing density is not enough. The soft city must consider the organization and layout of the built environment for more fluid movement and comfort, a diversity of building types, and thoughtful design to ensure a sustainable urban environment and society. Soft City begins with the big ideas of happiness and quality of life, and then shows how they are tied to the way we live. The heart of the book is highly visual and shows the building blocks for neighborhoods: building types and their organization and orientation; how we can get along as we get around a city; and living with the weather. As every citizen deals with the reality of a changing climate, Soft City explores how the built environment can adapt and respond. Soft City offers inspiration, ideas, and guidance for anyone interested in city building. Sim shows how to make any city more efficient, more livable, and better connected to the environment\"-- Publisher's website.

This study shows that in postmenopausal women with low bone mineral density, the monoclonal antibody romosozumab, which binds to sclerostin, an osteoblast-activity inhibitor, was associated with increased bone mineral density and bone formation and decreased bone resorption. Osteoporosis is characterized by low bone mass and defects in microarchitecture that are responsible for decreased bone strength and increased risk of fracture. 1 Antiresorptive drugs for osteoporosis increase bone mineral density and prevent the progression of structural damage but may not restore bone structure. Stimulation of bone formation is necessary to achieve improvements in bone mass, architecture, and strength. Sclerostin, encoded by the gene SOST, is an osteocyte-secreted glycoprotein that has been identified as a pivotal regulator of bone formation. By inhibiting the Wnt and bone morphogenetic protein signaling pathways, sclerostin impedes osteoblast proliferation and function, thereby decreasing bone formation. . . .

Summary The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. Introduction This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. Methods Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. Results Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. Conclusions Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.