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The theorems at the core of density functional theory (DFT) state that the energy of a many-electron system in its ground state is fully defined by its electron density distribution. This connection is made via the exact functional for the energy, which minimizes at the exact density. For years, DFT development focused on energies, implicitly assuming that functionals producing better energies become better approximations of the exact functional. We examined the other side of the coin: the energy-minimizing electron densities for atomic species, as produced by 128 historical and modern DFT functionals. We found that these densities became closer to the exact ones, reflecting theoretical advances, until the early 2000s, when this trend was reversed by unconstrained functionals sacrificing physical rigor for the flexibility of empirical fitting.

To the best of our knowledge, no systematic review and meta-analysis has evaluated the cholesterol-lowering effects of intermittent fasting (IF) and energy-restricted diets (ERD) compared with control groups. The aim of this review and meta-analysis was to summarize the effects of controlled clinical trials examining the influence of IF and ERD on lipid profiles. A systematic review of four independent databases (PubMed/Medline, Scopus, Web of Science and Google Scholar) was performed to identify clinical trials reporting the effects of IF or ERD, relative to non-diet controls, on lipid profiles in humans. A random-effects model, employing the method of DerSimonian and Laird, was used to evaluate effect sizes, and results were expressed as weighted mean difference (WMD) and 95% confidence intervals (CIs). Heterogeneity between studies was calculated using Higgins I2, with values ≥50% considered to represent high heterogeneity. Subgroup analyses were performed to examine the influence of intervention type, baseline lipid concentrations, degree of energy deficit, sex, health status, and intervention duration. For the outcomes of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triacylglycerols (TG), there were 34, 33, 35, and 33 studies meeting all inclusion criteria, respectively. Overall, results from the random-effects model indicated that IF and ERD interventions resulted significant changes in TC (WMD, –6.93 mg/dL; 95% CI, –10.18 to –3.67; P < 0.001; I2 = 78.2%), LDL-C (WMD, –6.16 mg/dL; 95% CI, –8.42 to –3.90; P ˂ 0.001; I2 = 52%), and TG concentrations (WMD, –6.46 mg/dL; 95% CI, –10.64 to –2.27; P = 0.002; I2 = 61%). HDL-C concentrations did not change significantly after IF or ERD (WMD, 0.50 mg/dL; 95% CI, –0.69 to 1.70; P = 0.411; I2 = 80%). Subgroup analyses indicated potentially differential effects between subgroups for one or more lipid parameters in the majority of analyses. Relative to a non-diet control, IF and ERD are effective for the improvement of circulating TC, LDL-C, and TG concentrations, but have no meaningful effects on HDL-C concentration. These effects are influenced by several factors that may inform clinical practice and future research. The present results suggest that these dietary practices are a means of enhancing the lipid profile in humans. •Other than Ramadan intermittent fasting, specific intermittent fasting strategies may be adopted into clinical scenario.•Intermittent fasting and energy-restricted diets are effective in improving circulating total cholesterol, low-density lipoprotein cholesterol, and triacylglycerol levels.•However, intermittent fasting and energy-restricted diets have no meaningful effects on high-density lipoprotein cholesterol levels.

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.

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.

Summary Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D 3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Let$\\mathcal {P}(\\mathbf{N})$be the power set of N . We say that a function$\\mu ^\\ast : \\mathcal {P}(\\mathbf{N}) \\to \\mathbf{R}$is an upper density if, for all X , Y ⊆ N and h , k ∈ N + , the following hold: ( f1 )$\\mu ^\\ast (\\mathbf{N}) = 1$; ( f2 )$\\mu ^\\ast (X) \\le \\mu ^\\ast (Y)$if X ⊆ Y ; ( f3 )$\\mu ^\\ast (X \\cup Y) \\le \\mu ^\\ast (X) + \\mu ^\\ast (Y)$; ( f4 )$\\mu ^\\ast (k\\cdot X) = ({1}/{k}) \\mu ^\\ast (X)$, where k · X : = kx : x ∈ X ; and ( f5 )$\\mu ^\\ast (X + h) = \\mu ^\\ast (X)$. We show that the upper asymptotic, upper logarithmic, upper Banach, upper Buck, upper Pólya and upper analytic densities, together with all upper α -densities (with α a real parameter ≥ −1), are upper densities in the sense of our definition. Moreover, we establish the mutual independence of axioms ( f1 )–( f5 ), and we investigate various properties of upper densities (and related functions) under the assumption that ( f2 ) is replaced by the weaker condition that$\\mu ^\\ast (X)\\le 1$for every X ⊆ N . Overall, this allows us to extend and generalize results so far independently derived for some of the classical upper densities mentioned above, thus introducing a certain amount of unification into the theory.

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. . . .

Wnt signaling is a major regulator during development. Genetic mutations affecting main regulators of this pathway have also emphasized the relevance of Wnt signaling in bone homeostasis after birth and diseases involving bone loss and fragility, such as osteoporosis. New therapies targeting Wnt signaling to increase bone formation are now under development. Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high–bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

SummaryGiven the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped.IntroductionThe aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab.MethodsSystematic review.ResultsDiffering pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20–40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture.ConclusionsThe view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.