Validity of Major Osteoporotic Fracture Diagnoses in the Danish National Patient Registry.

Objective: To evaluate the validity of diagnosis codes for Major Osteoporotic Fracture (MOF) in the Danish National Patient Registry (NPR) and secondly to evaluate whether the fracture was incident/acute using register-based definitions including date criteria and procedural codes. Methods: We identified a random sample of 2400 records with a diagnosis code for a MOF in the NPR with dates in the year of 2018. Diagnoses were coded with the 10th revision of the International Classification of Diseases (ICD-10). The sample included 2375 unique fracture patients from the Region of Southern Denmark. Medical records were retrieved for the study population and reviewed by an algorithmic search function and medical doctors to verify the MOF diagnoses. Register-based definitions of incident/acute MOF was evaluated in NPR data by applying date criteria and procedural codes. Results: The PPV for MOF diagnoses overall was 0.99 (95% CI: 0.98;0.99) and PPV=0.99 for the four individual fracture sites, respectively. Further, analyses of incident/acute fractures applying date criteria, procedural codes and using patients' first contact in the NPR resulted in PPV=0.88 (95% CI: 0.84;0.91) for hip fractures, PPV=0.78 (95% CI: 0.74;0.83) for humerus fractures, PPV=0.78 (95% CI: 0.73;0.83) for clinical vertebral fractures and PPV=0.87 (95% CI: 0.83;0.90) for wrist fractures. Conclusion: ICD-10 coded MOF diagnoses are valid in the NPR. Furthermore, a set of register-based criteria can be applied to qualify if the MOF fracture was incident/acute. Thus, the NPR is a valuable and reliable data source for epidemiological research on osteoporotic fractures.

Opportunistically identifiable vertebral fractures on routine radiological imaging predict mortality: observational cohort study.

In men and women with opportunistically identifiable vertebral fractures (VFs) on routine CT scans including the chest and/or abdomen, the risk of death is 51% higher than in those with no VF on the CT scan, and 325% higher than an age- and sex-matched general population cohort. PURPOSE: There is little knowledge about the risk of death in patients with VFs present on routine radiological imaging. We evaluated the risk of death in men and women aged 50 years or older with opportunistically identifiable VFs on routine CT scans and not treated with osteoporosis medications. METHODS: Thoracic and lumbar VFs were identified through a blinded, two-step approach on CT scans performed as part of normal clinical care in a Danish hospital in 2010 or later. Subjects with VF were matched on age and sex against those with no VF (1:2-ratio) and a general population cohort (1:3-ratio), respectively, and followed for up to 7 years through the national Danish registers. Subjects treated with an osteoporosis medication in the year prior to baseline were excluded. RESULTS: Subjects with VF had a significantly higher risk of death during follow-up as compared to subjects with no VF on the CT scan (adjusted hazard ratio [HR] 1.51 [95% confidence interval 1.27-1.79; p < 0.001]) and even more so when compared to the general population cohort (HR 4.25 [3.53-5.12; p < 0.001]). In subjects with versus without VF on the CT scan, the risk was higher in those with moderate or severe VF, in those with no malignancy prior to baseline, and in those with a lower Charlson comorbidity index score. CONCLUSION: Subjects with VF available for identification on routine CT scans face a substantially increased risk of death. Opportunistic identification and reporting of VF is important to identify these patients to allow intervention if indicated.

A multidisciplinary, shared care clinic using personalized medicine and coordinated care in patients with concomitant type 2 diabetes and cardiovascular disease. Protocol and baseline characteristics.

Background: Concomitant type 2 diabetes (T2DM) and cardiovascular disease (CVD) is frequent with a poor prognosis with high risk of comorbidities. Strict risk factor control reduces the risk for complications - yet many people do not achieve treatment targets. The complexity and fragmentation of the healthcare system may, together with the vulnerability of these patients, be a reason. Objective: The purpose of this paper is to describe the protocol of a non-randomized interventional pilot study testing the feasibility and effect of a multidisciplinary, shared care clinic using personalized medicine and coordinated care in people living with concomitant T2D and CVD. Methods: Participants were included from the Holbaek area in Denmark. People suffered from T2DM and CVD and were dysregulated regarding to HbA1c, cholesterol, micro/macroalbuminuaria or blood pressure. Participants went through a thorough evaluation to identify their needs and resources and received consultations every three months for one year. Results: A total of 63 participants with T2DM and CVD were enrolled in the clinic. The participants had a mean age of 69 years and a BMI of 30.9 kg/m2. Almost 50 % had heart failure, 95 % dyslipidemia and 91 % hypertension. Around 54 % received GLP-1 agonists and 39 % received SGLT-2-inhibitors. Perspectives: To our knowledge, a similar study with a multidisciplinary, shared care, outpatient clinic treating people living with concomitant T2DM and CVD, has not been performed previously. This study will provide information about the feasibility and efficacy of a multidisciplinary clinic based on changes in cardiovascular risk factors and medication.

Excess mortality following a first and subsequent osteoporotic fracture: a Danish nationwide register-based cohort study on the mediating effects of comorbidities.

OBJECTIVES: This study aimed to examine the risk of mortality following incident and subsequent osteoporotic fractures, the effect of different fracture type combinations, and the mediating role of postfracture morbidity in a Danish population. METHODS: We used the National Patient Registry to identify patients ≥60 years with incident major osteoporotic fracture of the hip, vertebrae, wrist or humerus between 2013 and 2018, and controls matched 1:10 on age and sex. Possible mediators were identified using International Classification of Diseases, 10th Revision codes registered in the 6 months following index fracture. HRs were estimated using Cox regression analyses with 95% CIs. The effect of possible mediators was estimated using mediation analyses. RESULTS: The study included 106 303 patients and 1 062 988 controls. Mortality following index fracture was highest in the month following hip fractures (HR 10.98 (95% CI 10.23 to 11.79) in women and HR 16.40 (95% CI 15.00 to 17.93) in men). Subsequent hip fractures resulted in the highest HRs for all fracture type combinations. In women, the highest HR was observed in patients with index wrist/subsequent hip fractures (HR 2.43 (95% CI 2.12 to 2.78)). In men, the highest HR was observed in patients with index humerus/subsequent hip fractures (HR 2.69 (95% CI 2.04 to 3.54)). Pneumonia mediated the largest proportion of mortality, but dehydration, urinary tract infection and sepsis were also important factors. CONCLUSIONS: The highest mortality risk was found in the month immediately following both index and subsequent fracture. The combination of index and subsequent fractures at different skeletal sites had a substantial impact on the risk of mortality. Postfracture morbidities were found mediate the association.

An enhanced version of FREM (Fracture Risk Evaluation Model) using national administrative health data: analysis protocol for development and validation of a multivariable prediction model.

BACKGROUND: Osteoporosis poses a growing healthcare challenge owing to its rising prevalence and a significant treatment gap, as patients are widely underdiagnosed and consequently undertreated, leaving them at high risk of osteoporotic fracture. Several tools aim to improve case-finding in osteoporosis. One such tool is the Fracture Risk Evaluation Model (FREM), which in contrast to other tools focuses on imminent fracture risk and holds potential for automation as it relies solely on data that is routinely collected via the Danish healthcare registers. The present article is an analysis protocol for a prediction model that is to be used as a modified version of FREM, with the intention of improving the identification of subjects at high imminent risk of fracture by including pharmacological exposures and using more advanced statistical methods compared to the original FREM. Its main purposes are to document and motivate various aspects and choices of data management and statistical analyses. METHODS: The model will be developed by employing logistic regression with grouped LASSO regularization as the primary statistical approach and gradient-boosted classification trees as a secondary statistical modality. Hyperparameter choices as well as computational considerations on these two approaches are investigated by an unsupervised data review (i.e., blinded to the outcome), which also investigates and handles multicollinarity among the included exposures. Further, we present an unsupervised review of the data and testing of analysis code with respect to speed and robustness on a remote analysis environment. The data review and code tests are used to adjust the analysis plans in a blinded manner, so as not to increase the risk of overfitting in the proposed methods. DISCUSSION: This protocol specifies the planned tool development to ensure transparency in the modeling approach, hence improving the validity of the enhanced tool to be developed. Through an unsupervised data review, it is further documented that the planned statistical approaches are feasible and compatible with the data employed.

Towards Improved Identification of Vertebral Fractures in Routine Computed Tomography (CT) Scans: Development and External Validation of a Machine Learning Algorithm.

Vertebral fractures (VFs) are the hallmark of osteoporosis, being one of the most frequent types of fragility fracture and an early sign of the disease. They are associated with significant morbidity and mortality. VFs are incidentally found in one out of five imaging studies, however, more than half of the VFs are not identified nor reported in patient computed tomography (CT) scans. Our study aimed to develop a machine learning algorithm to identify VFs in abdominal/chest CT scans and evaluate its performance. We acquired two independent data sets of routine abdominal/chest CT scans of patients aged 50 years or older: a training set of 1011 scans from a non-interventional, prospective proof-of-concept study at the Universitair Ziekenhuis (UZ) Brussel and a validation set of 2000 subjects from an observational cohort study at the Hospital of Holbaek. Both data sets were externally reevaluated to identify reference standard VF readings using the Genant semiquantitative (SQ) grading. Four independent models have been trained in a cross-validation experiment using the training set and an ensemble of four models has been applied to the external validation set. The validation set contained 15.3% scans with one or more VF (SQ2-3), whereas 663 of 24,930 evaluable vertebrae (2.7%) were fractured (SQ2-3) as per reference standard readings. Comparison of the ensemble model with the reference standard readings in identifying subjects with one or more moderate or severe VF resulted in an area under the receiver operating characteristic curve (AUROC) of 0.88 (95% confidence interval [CI], 0.85-0.90), accuracy of 0.92 (95% CI, 0.91-0.93), kappa of 0.72 (95% CI, 0.67-0.76), sensitivity of 0.81 (95% CI, 0.76-0.85), and specificity of 0.95 (95% CI, 0.93-0.96). We demonstrated that a machine learning algorithm trained for VF detection achieved strong performance on an external validation set. It has the potential to support healthcare professionals with the early identification of VFs and prevention of future fragility fractures. © 2023 UCB S.A. and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Healthcare costs associated with opportunistically identifiable vertebral fractures.

PURPOSE: Vertebral fractures (VFs) are often available on radiological imaging undertaken during daily clinical work, yet the healthcare cost burden of these opportunistically identifiable fractures has not previously been reported. In this study, we examine the direct healthcare costs of subjects with vertebral fractures available for identification on routine CT scans. METHODS: Thoracolumbar vertebral fractures were identified from 2000 routine CT scans. Subjects with VF on the scan were matched 1:2 against subjects with no VF on the scan, and similarly in a 1:3-ratio against a general population cohort. We excluded those subjects who received treatment with osteoporosis medication(s) in the year prior to baseline. Direct healthcare costs, identified from the national Danish registers, were accrued over up to 6 years of follow-up, and reported per day at risk and per year. RESULTS: In subjects undergoing a CT scan, costs were initially high, yet declined over time. Comparing subjects with prevalent vertebral fracture (n = 321) against those subjects with no vertebral fracture (n = 606), mean total healthcare costs per day at risk was numerically higher in the first three years after baseline, while healthcare costs per year were similar between the cohorts. No differences reached statistical significance. When compared to the general population cohort, costs were significantly higher in the vertebral fracture cohort. CONCLUSION: Subjects with vertebral fractures available for identification on routine CT scans incur substantially higher healthcare costs than matched subjects representing the general population, and numerically, albeit non-significantly, higher healthcare costs per day at risk in the short term, as compared to subjects with no visible VF on the CT scan.

Fracture Risk in Men and Women With Vertebral Fractures Identified Opportunistically on Routine Computed Tomography Scans and Not Treated for Osteoporosis: An Observational Cohort Study.

Vertebral fractures (VFs) have been associated with future fractures, yet few studies have evaluated whether this pertains to VFs available for identification on routine radiological imaging. We sought to evaluate the risk of subsequent fractures in subjects with VF identified opportunistically on computed tomography (CT) scans performed as part of routine clinical practice. From the radiology database of Holbæk Hospital we identified the first CT scan including the thorax and/or abdomen of 2000 consecutive men and women aged 50 years or older, performed from January 1, 2010 onward. The scans were assessed in a blinded approach to identify chest and lumbar VF, and these data linked to national Danish registers. Subjects were excluded if treated with an osteoporosis medication (OM) in the year prior to baseline (date of CT), and the remaining subjects with VF matched on age and sex in 1:2 ratio against subjects with no VF. We found that the risk of major osteoporotic fractures (hip, non-cervical vertebral, humerus, and distal forearm fractures) was higher for subjects with VF than without VF: incidence rates (IRs) were 32.88 and 19.59 fractures per 1000 subject-years, respectively, and the adjusted hazard ratio (HRadj) was 1.72 (95% confidence interval [CI], 1.03-2.86). Subsequent hip fracture IRs were 16.75 and 6.60; HRadj 3.02 (95% CI, 1.39-6.55). There were no significant differences in other fracture outcomes (including a pooled estimate of any subsequent fracture, except face, skull, and fingers: IRs 41.52 and 31.38; HRadj 1.31 [95% CI, 0.85-2.03]). Our findings suggest that subjects undergoing routine CT scans including the chest and/or abdomen are a high risk population in terms of fracture risk. Even within this group, subjects with VF are at higher risk of future major osteoporotic fracture (MOF), in particular hip fracture. Hence, systematic opportunistic screening for VF and subsequent fracture risk management is important to reduce the risk of new fractures. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

New Insights in the Pathophysiology, Epidemiology, and Response to Treatment of Osteoporotic Vertebral Fractures.

CONTEXT: Vertebral fractures (VFs) make up an important but challenging group of fractures often caused by osteoporosis. Osteoporotic fractures pose unique diagnostic challenges in generally requiring imaging for diagnosis. The objective of this narrative mini-review is to provide an overview of these recent advances in our knowledge of VF pathophysiology and epidemiology with particular focus on endocrine diseases, prevention, and treatment. EVIDENCE ACQUISITION: We searched PubMed on May 23, 2022, for studies of VFs in humans. Results were limited to papers available as full-text publications in English, published from 2020 and onward. This yielded 3457 citations. This was supplemented by earlier publications selected to add context to the recent findings. EVIDENCE SYNTHESIS: Studies addressed VF risk in hyperthyreosis, hyperparathyroidism, acromegaly, Cushing syndrome, primary aldosteronism, and diabetes. For pharmaceutical treatment, new studies or analyses were identified for romosozumab and for weekly teriparatide. Several studies, including studies in the immediate pipeline, were intervention studies with vertebroplasty or kyphoplasty, including combination with stem cells or pharmaceuticals. CONCLUSIONS: Endocrinologists should be aware of the high likelihood of osteoporotic VFs in patients with endocrine diseases. Though licensed treatments are able to substantially reduce the occurrence of VFs in patients with osteoporosis, the vast majority of recent or ongoing randomized controlled trials in the VF area focus on advanced invasive therapy of the fracture itself.

Side effects of drugs for osteoporosis and metastatic bone disease.

Osteoporosis is a common condition that leads to substantial morbidity and mortality and affects an increasing number of persons worldwide. Several pharmacological therapies that inhibit bone resorption, promote bone formation, or both, are available for the treatment of osteoporosis. The osteoanabolic treatment spectrum was recently expanded by the introduction of a novel bone-forming agent in the United States, and clinical trials indicate that a new class of bone anabolic therapy may become available. Both antiresorptive and bone anabolic therapies are associated with common and rare adverse effects, which are particularly important to address as these drugs are used for long-term treatment in numerous patients with a large proportion being elderly and/or having multimorbidity. In addition, antiresorptive drugs are used to inhibit bone resorption in patients with malignant hypercalcaemia or to prevent skeletal events in cancer patients, and bisphosphonates have been repurposed as a cancer preventive therapy. However, therapeutic doses are generally higher when antiresorptive drugs are used in the oncological setting, which influence the prevalence of adverse effects significantly. This review highlights key issues and controversies regarding adverse effects of currently available and emerging drugs used for osteoporosis and metastatic bone diseases.