Association between recurrent fracture risk and implementation of fracture liaison services in four Swedish hospitals: A cohort study

Structured secondary preventions programs, called fracture liaison services (FLSs), increase the rate of evaluation with bone densitometry and use of osteoporosis medication after fracture. However, the evidence regarding the effect on the risk of recurrent fracture is insufficient. The aim of this study was to investigate if implementation of FLS was associated with reduced risk of recurrent fractures. In this retrospective cohort study, electronic health records during 2012 to 2017 were used to identify a total of 21,083 patients from four hospitals in Western Sweden, two with FLS (n = 15,449) and two without (n = 5634). All patients aged 50 years or older (mean age 73.9 [SD 12.4] years, 76% women) with a major osteoporotic index fracture (hip, clinical spine, humerus, radius, and pelvis) were included. The primary outcome was recurrent major osteoporotic fracture. All patients with an index fracture during the FLS period (n = 13,946) were compared with all patients in the period before FLS implementation (n = 7137) in an intention‐to‐treat analysis. Time periods corresponding to the FLS hospitals were used for the non‐FLS hospitals. In the hospitals with FLSs, there were 1247 recurrent fractures during a median follow‐up time of 2.2 years (range 0–6 years). In an unadjusted Cox model, the risk of recurrent fracture was 18% lower in the FLS period compared with the control period (hazard ratio = 0.82, 95% confidence interval [CI] 0.73–0.92, p = .001), corresponding to a 3‐year number needed to screen of 61, and did not change after adjustment for clinical risk factors. In the hospitals without FLSs, no change in recurrent fracture rate was observed. Treatment decisions were made according to the Swedish treatment guidelines. In conclusion, implementation of FLS was associated with a reduced risk of recurrent fracture, indicating that FLSs should be included routinely at hospitals treating fracture patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

Type 2 diabetes and risk of hip fractures and non-skeletal fall injuries in the elderly: A study from the Fractures and Fall Injuries in the Elderly Cohort (FRAILCO)

Questions remain about whether the increased risk of fractures in patients with type 2 diabetes (T2DM) is related mainly to increased risk of falling or to bone‐specific properties. The primary aim of this study was to investigate the risk of hip fractures and non‐skeletal fall injuries in older men and women with and without T2DM. We included 429,313 individuals (aged 80.8 ± 8.2 years [mean ± SD], 58% women) from the Swedish registry “Senior Alert” and linked the data to several nationwide registers. We identified 79,159 individuals with T2DM (45% with insulin [T2DM‐I], 41% with oral antidiabetics [T2DM‐O], and 14% with no antidiabetic treatment [T2DM‐none]) and 343,603 individuals without diabetes. During a follow‐up of approximately 670,000 person‐years, we identified in total 36,132 fractures (15,572 hip fractures) and 20,019 non‐skeletal fall injuries. In multivariable Cox regression models where the reference group was patients without diabetes and the outcome was hip fracture, T2DM‐I was associated with increased risk (adjusted hazard ratio (HR) [95% CI] 1.24 [1.16–1.32]), T2DM‐O with unaffected risk (1.03 [0.97–1.11]), and T2DM‐none with reduced risk (0.88 [0.79–0.98]). Both the diagnosis of T2DM‐I (1.22 [1.16–1.29]) and T2DM‐O (1.12 [1.06–1.18]) but not T2DM‐none (1.07 [0.98–1.16]) predicted non‐skeletal fall injury. The same pattern was found regarding other fractures (any, upper arm, ankle, and major osteoporotic fracture) but not for wrist fracture. Subset analyses revealed that in men, the risk of hip fracture was only increased in those with T2DM‐I, but in women, both the diagnosis of T2DM‐O and T2DM‐I were related to increased hip fracture risk. In conclusion, the risk of fractures differs substantially among patients with T2DM and an increased risk of hip fracture was primarily found in insulin‐treated patients, whereas the risk of non‐skeletal fall injury was consistently increased in T2DM with any diabetes medication. © 2016 American Society for Bone and Mineral Research

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.ISSN:0092-8674ISSN:1097-417

A fold-recognition approach to loop modeling

A novel approach is proposed for modeling loop regions in proteins. In this approach, a prerequisite sequence-structure alignment is examined for regions where the target sequence is not covered by the structural template. These regions, extended with a number of residues from adjacent stem regions, are submitted to fold recognition. The alignments produced by fold recognition are integrated into the initial alignment to create an alignment between the target sequence and several structures, where gaps in the main structural template are covered by local structural templates. This one-to-many (1:N) alignment is used to create a protein model by existing protein-modeling techniques. Several alternative approaches were evaluated using a set of ten proteins. One approach was selected and evaluated using another set of 31 proteins. The most promising result was for gap regions not located at the C-terminus or N-terminus of a protein, where the method produced an average RMSD 12% lower than the loop modeling provided with the program MODELLER. This improvement is shown to be statistically significant.The original publication is available at www.springerlink.com</p

On the Systematicity of Internal Representations in Connectionist Networks

It is frequently claimed that connectionist architectures, because they cannot support structured items, cannot provide an alternative cognitive architecture. For an architecture to be cognitive, there must be systematicity (as well as compositionality and productivity), and systematicity, it is claimed, depends crucially on the ability of the system to represent and use structured items. This paper introduces the idea of grouped hyperplanes, where such groups designate abstractions located in an n-dimensional space criss-crossed by simple decision lines. This lead to the idea of emergent primitives supporting complex internal representations, both of which --- in addition to exemplifying characteristics of connectionist systematicity --- are grounded in computable mathematical regions in a hyperspace. 1 Systematicity and compositionality Symbolists and connectionists can agree that any non-trivial cognitive system must be able to represent complex structured items (CSIs). A CSI is ty..

Association between alendronate use and hip fracture risk in older patients using oral prednisolone

Importance Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. Objective To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. Design, Setting, and Participants Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. Exposures Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. Main Outcomes and Measures The primary outcome was incident hip fracture. Results Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of −17.6 (95% CI, −24.8 to −10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group. Conclusions and Relevance Among older patients using medium to high doses of prednisolone, alendronate treatment was associated with a significantly lower risk of hip fracture over a median of 1.32 years. Although the findings are limited by the observational study design and the small number of events, these results support the use of alendronate in this patient group