Incident peptic ulcers and concomitant treatment of direct oral anticoagulants and oral bisphosphonates-a real-world cohort study.

Oral bisphosphonates and direct oral anticoagulants are related to upper gastrointestinal ulcers. The present study investigated whether concomitant use of these drugs increase the risk of upper gastrointestinal ulcers and report no increased risk of upper gastrointestinal ulcers compared to the use of either drug alone, when individuals with previous upper gastrointestinal ulcers are excluded. INTRODUCTION: This study examines whether concomitant use of oral bisphosphonates (oBP) and direct oral anticoagulants (DOAC) increases the risk of peptic ulcers more than any drug alone. METHODS: A population-based cohort study was performed. We sampled a cohort of oBP and DOAC users from a sample of 2,622,742 individuals, consisting of diabetes patients and age- and gender-matched controls, obtained from the Danish National Patient Register. The exposures were concomitant use of oBP and DOAC and single use of DOAC and single use of oBP. The primary endpoint was the first incident peptic ulcer. Information on exposure and outcome were collected from national registries. The period of observation was from 01.01.2008 until 31.12.2018. Unadjusted and adjusted Cox regressions were performed. RESULTS: 8077 individuals received concomitant treatment with DOAC and oBP; 96,451 individuals used DOAC and no oBP; and 118,675 used oBP and no DOAC. The mean duration of follow-up was 1.9 years for concomitant users, 2.5 years for DOAC users, and 4.5 years for oBP users. A total of 4742 individuals with incident peptic ulcers were collected. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to single DOAC treatment in the adjusted analysis (HR = 1.23, 95% CI: 1.03; 1.48). However, the effects were abolished when excluding individuals with a previous ulcer. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to users of oBP in the adjusted model (HR = 1.34, 95% CI: 1.11; 1.63). CONCLUSION: Based on our results, concomitant use of oBP and DOAC is associated with a slight increase in the risk of peptic ulcers compared to either drug alone. The prescribing physician should weigh the slight increased risk of ulcer in concomitant users of oBP and DOAC with beneficial reductions in stroke and fractures.

The pattern of incident fractures according to fracture site in people with T1D.

Higher incidences of fractures are seen in people with type 1 diabetes (T1D), but knowledge on different fracture sites is sparse. We found a higher incidence mainly for distal fracture sites in people with T1D compared to controls. It must be further studied which fractures attributed to the higher incidence rates (IRs) at specific sites. INTRODUCTION: People with T1D have a higher incidence of fractures compared to the general population. However, sparse knowledge exists on the incidence rates of individual fracture sites. Therefore, we examined the incidence of various fracture sites in people with newly treated T1D compared to matched controls. METHODS: All people from the UK Clinical Practice Research Datalink GOLD (1987-2017), of all ages with a T1D diagnosis code (n = 6381), were included. People with T1D were matched by year of birth, sex, and practice to controls (n = 6381). Fracture IRs and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex. RESULTS: The IR of all fractures was significantly higher in people with T1D compared to controls (IRR: 1.39 (CI95%: 1.24-1.55)). Compared to controls, the IRR for people with T1D was higher for several fracture sites including carpal (IRR: 1.41 (CI95%: 1.14-1.75)), clavicle (IRR: 2.10 (CI95%: 1.18-3.74)), foot (IRR: 1.70 (CI95%: 1.23-2.36)), humerus (IRR: 1.46 (CI95%: 1.04-2.05)), and tibia/fibula (IRR: 1.67 CI95%: 1.08-2.59)). In women with T1D, higher IRs were seen at the ankle (IRR: 2.25 (CI95%: 1.10-4.56)) and foot (IRR: 2.11 (CI95%: 1.27-3.50)), whereas in men with T1D, higher IRs were seen for carpal (IRR: 1.45 (CI95%: 1.14-1.86)), clavicle (IRR: 2.13 (CI95%: 1.13-4.02)), and humerus (IRR: 1.77 (CI95%: 1.10-2.83)) fractures. CONCLUSION: The incidence of carpal, clavicle, foot, humerus, and tibia/fibula fractures was higher in newly treated T1D, but there was no difference at other fracture sites compared to controls. Therefore, the higher incidence of fractures in newly treated people with T1D has been found mainly for distal fracture sites.

Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial.

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. INTRODUCTION: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. METHODS: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. RESULTS: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) - 2.4 [- 3.5, - 1.4] kg, p value < 0.001) and FM (- 1.5 [- 2.3, - 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. CONCLUSION: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

Impact of season on the association between vitamin D levels at diagnosis and one-year remission in early Rheumatoid Arthritis.

The study evaluates associations between serum vitamin D metabolites at diagnosis and one-year remission, in early diagnosed rheumatoid arthritis(RA). The CIMESTRA-cohort comprised 160 newly diagnosed RA patients, treated aiming at remission. Vitamin D supplementation was recommended according to national guidelines. Dtotal(25OHD2 + 25OHD3) was dichotomized at 50 nmol/L, 1,25(OH)2D was categorized in tertiles. Primary outcome was remission(DAS28-CRP ≤ 2.6) after one year. Associations were evaluated using logistic regression, further adjusted for pre-specified potential confounders: Age, sex, symptom-duration before diagnosis, DAS28-CRP and season of diagnosis. Results are presented as Odds Ratios(OR) with 95% Confidence Intervals(95%CIs). In univariate analyses, neither Dtotal nor 1,25(OH)2D were associated with remission. In adjusted analyses, low Dtotal was associated with higher odds for remission; OR 2.6, 95%CI (1.1; 5.9) p = 0.03, with season impacting results the most. One-year remission was lower in patients with diagnosis established at winter. In conclusion, low Dtotal at diagnosis was associated with increased probability of achieving one-year remission in early RA when adjusting for covariates. Diagnosis in winter was associated with lower odds for one-year remission. Results suggest that season act as a contextual factor potentially confounding associations between vitamin D and RA disease-course. The finding of low Dtotal being associated with higher one-year remission remains speculative.

Twenty years with diabetes and amputations: a retrospective population-based cohort study.

AIM: To investigate the trends in non-traumatic lower limb amputation in people with and without diabetes. METHODS: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans-femoral amputations, trans-tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least-squares linear regression. RESULTS: The yearly mean decrease in incidence rate of amputation per 1000 person-years was -0.032 [95% CI: -0.062, -0.001], -0.022 [-0.032, -0.012] and -0.006 [-0.009, -0.003] for trans-femoral amputation, -0.072 [-0.093, -0.052], -0.090 [-0.102, -0.078] and -0.015 [-0.016, -0.013] for trans-tibial amputation, and -0.055 [-0.080, -0.020], -0.075 [-0.090, -0.060] and -0.011 [-0.014, -0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively. CONCLUSIONS: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

Diabetes and fractures: new evidence of atypical femoral fractures?

Patients with diabetes have an increased risk of fractures. In this study, subtrochanteric and femoral shaft fractures were increased in patients with type 1 diabetes compared with the general population. In the light of this, more evidence points towards an association between diabetes and atypical femoral fractures. INTRODUCTION: Patients with diabetes have an increased risk of femoral fractures, but little is known about the risk of atypical femoral fractures (AFFs). The aim of this study was to identify the risk of subtrochanteric and femoral shaft (ST/FS) fractures and estimate the risk of AFFs in patients with type 1 (T1D) and type 2 diabetes (T2D). METHODS: From the nationwide Danish National Patient Register, we identified patients with T1D (n = 19,896), T2D (n = 312,188), and sex- and aged-matched controls without diabetes (n = 996,252) from the general population and all ST/FS fractures (n = 7509). Data were analyzed using a Cox proportional-hazards model and the incidence rate and rate ratio of ST/FS fractures were estimated. RESULTS: The incidence rate of ST/FS fractures in T1D was 52.14 events per 100,000 person years and 73.21 per 100,000 person years in T2D. T1D was associated with an increased risk of ST/FS (HR 2.07 (95% CI 1.68-2.56)), whereas T2D was not (HR 0.99 (95% CI 0.94-1.10)). Previous ST/FS fractures were associated with an increased risk of subsequent ST/FS fractures (HR 6.95 (95% CI 6.00-8.05)) and the use of bisphosphonates with an increased risk of ST/FS fractures (HR 1.72 (95% CI 1.54-1.91)). CONCLUSION: Patients with T1D have a higher risk of ST/FS fractures compared with sex- and age-matched controls. Since a proportion of ST/FS fractures are classified as AFFs, this could point towards the fact that AFFs also are increased in patients with T1D, but not T2D.

Hypoglycaemia and type 1 diabetes are associated with an increased risk of fractures.

People with diabetes have an increased risk of fractures, and in this study, the effect of hypoglycaemia and insulin on this risk was investigated. Type 1 diabetes and hypoglycaemia did increase the fracture risk, and prevention of hypoglycaemia is thus an important focus area in the prevention of fractures. INTRODUCTION: Studies have shown that type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with increased risk of fractures. Especially, subjects with T1D have an increased risk of fractures. The purpose of this study was to investigate the association of T1D, hypoglycaemia and insulin on fracture risk. METHODS: A cohort study with T1D subjects (n = 19,896) and T2D subjects (n = 312,188) matched with subjects from the general populated (n = 996,252) and a nested case-control study with T1D subjects with fracture (n = 895) as cases and T1D subjects without (n = 2685) as controls were conducted based on subjects from the Danish National Patient Registry (DNPR). RESULTS: T1D (HR = 2.47, 95% CI 2.37 to 2.59), age (HR = 1.05, 95% CI 1.05 to 1.05), previous fracture (HR = 1.95, 95% CI 1.92 to 1.99) and being female (HR = 2.06, 95% CI 2.04 to 2.09) increased the risk of fractures. Also, T2D (HR = 1.14, 95% CI 1.11 to 1.18) increased the risk of proximal upper arm and shoulder fractures. T1D (HR = 2.41, 95% CI 2.20 to 2.65) increased the risk of hip and femoral region fractures. Hypoglycaemia (OR = 1.58, 95% CI 1.27 to 1.97) increased the risk of fractures, whereas insulin use did not change the risk. CONCLUSIONS: Hypoglycaemic episodes are associated with increased fracture risk, and the frequency of hypoglycaemic episodes leading to hospital admission was above 16% for T1D subjects. Prevention of hypoglycaemia is thus an important focus area in the prevention of fractures.

The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). METHODS: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. RESULTS: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). CONCLUSIONS: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00657943).

Social inequality and fractures-secular trends in the Danish population: a case-control study.

We examined links between markers of social inequality and fracture risk in the Danish population, demonstrating that high income and being married are associated with a significantly lower risk. INTRODUCTION: We explored whether the risk of hip, humerus, and wrist fracture was associated with markers of inequality using data from Danish health registries. METHODS: All patients 50 years or older with a primary hip (ICD10 S720, S721, S722, and S729) humerus (ICD10 S422, S423, S424, S425, S426, and S427), or wrist (ICD10: S52) fracture were identified from 1/1/1995 to 31/12/2011. Fracture patients were matched 1:1 by age, sex, and year of fracture, to a non-fracture control. Markers of inequality were as follows: income (fifths); marital status (married, divorced, widowed, or unmarried); area of residence (remote, rural, intermediate, or urban). Conditional logistic regression was used to investigate associations between these exposures, and risk of fracture, adjusting for covariates (smoking, alcohol, and Charlson co-morbidity). Interactions were fitted between exposure and covariates where appropriate. RESULTS: A total of 189,838 fracture patients (37,500 hip, 45,602 humerus, and 106,736 wrist) and 189,838 controls were included. Mean age was 73.9 years (hip), 67.5 years (humerus), and 65.3 years (wrist). High income (5th quintile) was significantly associated with a lower odds ratio of all three fractures, compared to average income (3rd quintile). Married subjects had a significantly decreased odds ratio across all three fractures. However, no overall secular difference was observed regarding the influence of the markers of inequality. CONCLUSION: In conclusion, we have demonstrated important, stable associations between social inequality, assessed using income, marital status, and area of residence, and fracture at the population level. These findings can inform approaches to healthcare, and suggest that much thought should be given to novel interventions aimed especially at those living alone, and ideally societal measures to reduce social inequality.

Predicting mortality and incident immobility in older Belgian men by characteristics related to sarcopenia and frailty.

There is an increasing awareness of sarcopenia in older people. We applied machine learning principles to predict mortality and incident immobility in older Belgian men through sarcopenia and frailty characteristics. Mortality could be predicted with good accuracy. Serum 25-hydroxyvitamin D and bone mineral density scores were the most important predictors. INTRODUCTION: Machine learning principles were used to predict 5-year mortality and 3-year incident severe immobility in a population of older men by frailty and sarcopenia characteristics. METHODS: Using prospective data from 1997 on 264 older Belgian men (n = 152 predictors), 29 statistical models were developed and tuned on 75% of data points then validated on the remaining 25%. The model with the highest test area under the curve (AUC) was chosen as the best. From these, ranked predictor importance was extracted. RESULTS: Five-year mortality could be predicted with good accuracy (test AUC of .85 [.73; .97], sensitivity 78%, specificity 89% at a probability cut-off of 22.3%) using a Bayesian generalized linear model. Three-year incident severe immobility could be predicted with fair accuracy (test AUC .74 [.57; .91], sensitivity 67%, specificity 78% at a probability cut-off of 14.2%) using a multivariate adaptive regression splines model. Serum 25-hydroxyvitamin D levels and hip bone mineral density scores were the most important predictors of mortality, while biochemical androgen markers and Short-Form 36 Physical Domain questions were the most important predictors of immobility. Sarcopenia assessed by lean mass estimates was relevant to mortality prediction but not immobility prediction. CONCLUSIONS: Using advanced statistical models and a machine learning approach 5-year mortality can be predicted with good accuracy using a Bayesian generalized linear model and 3-year incident severe immobility with fair accuracy using a multivariate adaptive regression splines model.

Use of systemic glucocorticoids and the risk of major osteoporotic fractures in patients with sarcoidosis.

This study revealed the risk of major osteoporotic fracture in patients with sarcoidosis exposed to glucocorticoids. Current use of glucocorticoids was associated with a risk of fracture, with no difference between patients with and without sarcoidosis. Sarcoidosis per se was not associated with an increased fracture risk. INTRODUCTION: Sarcoidosis is a multi-organ, chronic inflammatory, granulomatous disorder that most frequently affects the lungs, lymph nodes, skin, eyes, and liver, but may occur in any organ, including the bones. While oral glucocorticoids (GCs) are commonly used as initial treatment, little is known about the risk of major osteoporotic fractures in patients with sarcoidosis exposed to GCs. METHODS: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1995 and December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) of major osteoporotic fractures in subjects with and without sarcoidosis stratified by average daily and cumulative dose exposures. RESULTS: A total of 376,858 subjects with a major osteoporotic fracture and the same number of subjects without this event were identified (mean age 64.2 ± 19.5 years, 69% female). In patients with sarcoidosis (n = 124), current use of GC was associated with an increased risk of major osteoporotic fracture (adjusted (adj.) OR 1.74; 95% CI 1.17-2.58), which dropped to baseline levels after discontinuation. In subjects without sarcoidosis, this risk was comparable (adj. OR 1.36; 95% CI 1.32-1.40). In sarcoidosis patients, cumulative dose 1.0-4.9 g and >10 g prednisolone equivalents were associated with increased risk of major osteoporotic fracture (adj. OR 2.75; 95% CI 1.06-7.14 and 2.22; 95% CI 1.17-4.22, respectively), whereas a cumulative dose of <1.0 g and 5.0-9.9 g was not associated with major osteoporotic fracture risk. CONCLUSION: Both in subjects with and without sarcoidosis, current expose to GC is associated with increased risk of major osteoporotic fractures, with no between-group difference. Sarcoidosis per se was not associated with increased fracture risk. Having sarcoidosis per se, i.e., if not treated with GC, is not a risk factor for fracture, and such patients may only need risk assessment when they commence GC therapy.

Association between baseline vitamin D metabolite levels and long-term cardiovascular events in patients with rheumatoid arthritis from the CIMESTRA trial: protocol for a cohort study with patient-record evaluated outcomes.

INTRODUCTION: Cardiovascular morbidity and mortality is increased in patients with rheumatoid arthritis (RA), and among these patients, the prevalence of hypovitaminosis D is high. Moreover, low vitamin D levels have been associated with increased cardiovascular risk in healthy subjects. OBJECTIVE: To evaluate the long-term risk of cardiovascular events in patients having low total 25-hydroxyvitamin D levels at baseline compared with patients with normal levels, in an efficiently treated, closed cohort of patients with an early diagnosis of RA. METHODS AND ANALYSIS: This study is a prospective, closed, blinded endpoint cohort study, based on secondary analyses from a previous randomised trial (CIMESTRA study; NCT00209859, approved September 1999) including 160 patients with an early diagnosis of RA from Danish University clinics. Primary outcome will be the proportion of patients with any cardiovascular event in the follow-up period, evaluated using systematic journal audits. Logistic regression models will test the hypothesis that there are more cardiovascular events in enrolled patients with a low level of vitamin D (< 50 nmol/L). Secondarily, Cox regression models, based on survival analysis, will determine the extent to which independent variables (including different levels of vitamin D at baseline) predict whether a cardiovascular event will occur, and also when this will be. ETHICS AND DISSEMINATION: All patients have received verbal and written information before enrolment, and have given written consent at baseline. To disseminate comprehension of factors of prognostic importance to cardiovascular outcome in RA, we will attempt to have a first draft ready no later than 1 year after the adjudication process has finished. If low vitamin D levels can predict cardiovascular events in RA, it is relevant to take into account in a prediction model, to be considered by patients, physicians and other decision-makers. TRIAL REGISTRATION NUMBER: The parental controlled trial is registered as NCT00209859.

Subjects with osteoporosis to remain at high risk for fracture despite benefit of prior bisphosphonate treatment-a Danish case-control study.

The benefits of pharmaceutical treatment for osteoporosis may be limited for a number of patients, as they continue to experience fractures. Alternative treatments may be considered for subjects whom remain at high risk for future fractures. INTRODUCTION: Previous studies have investigated the effects of good adherence to anti-osteoporosis medication. However, very few studies have described why some patients experience fractures and loss of BMD despite adherence to treatment. The aim of this study was to estimate the proportion of patients at high risk for fracture despite being compliant to bisphosphonate treatment and examine which factors influence why some osteoporotic patients remain at a high risk for fracture despite being compliant to bisphosphonate treatment. METHODS: This case-control study is based on Danish national health registry data. The subjects had to have either one BMD test or a fracture prior to inclusion. "High-risk" subjects (cases) were defined as BMD t-score < =-2.5 SD, any drop in BMD from baseline or a fracture 24-36 months following inclusion. RESULTS: A total of 2406 subjects (66.3 % women; 33.7 % men) fulfilled the inclusion criteria, and of these, 352 (14.6 %) were identified as high risk subjects. A multiple logistical regression analysis showed that high risk subjects were more likely to have lower plasma calcium and/or vitamin D levels (OR: 2.9) and were more frequently diagnosed with hyperparathyroidism (OR: 2.6). CONCLUSION: Based on Danish national health registry data, 14.6 % patients were identified as patients remaining at high risk for fracture despite being compliant to bisphosphonate treatment. Lower plasma calcium and/or vitamin D level is the greatest predictor of high risk for fracture despite persistent bisphosphonate treatment. Secondary causes of osteoporosis should be considered and alternative treatments may be advised for subjects whom remain at high risk.

Clinical fracture risk evaluated by hierarchical agglomerative clustering.

Clustering analysis can identify subgroups of patients based on similarities of traits. From data on 10,775 subjects, we document nine patient clusters of different fracture risks. Differences emerged after age 60 and treatment compliance differed by hip and lumbar spine bone mineral density profiles. INTRODUCTION: The purposes of this study were to establish and quantify patient clusters of high, average and low fracture risk using an unsupervised machine learning algorithm. METHODS: Regional and national Danish patient data on dual-energy X-ray absorptiometry (DXA) scans, medication reimbursement, primary healthcare sector use and comorbidity of female subjects were combined. Standardized variable means, Euclidean distances and Ward's D2 method of hierarchical agglomerative clustering (HAC), were used to form the clustering object. K number of clusters was selected with the lowest cluster containing less than 250 subjects. Clusters were identified as high, average or low fracture risk based on bone mineral density (BMD) characteristics. Cluster-based descriptive statistics and relative Z-scores for variable means were computed. RESULTS: Ten thousand seven hundred seventy-five women were included in this study. Nine (k = 9) clusters were identified. Four clusters (n = 2886) were identified based on low to very low BMD with differences in comorbidity, anthropometrics and future bisphosphonate compliance. Two clusters of younger subjects (n = 1058, mean ages 30 and 51 years) were identified as low fracture risk with high to very high BMD. A mean age of 60 years was the earliest that allowed for separation of high-risk clusters. DXA scan results could identify high-risk subjects with different antiresorptive treatment compliance levels based on similarities and differences in lumbar spine and hip region BMD. CONCLUSIONS: Unsupervised HAC presents a novel technology to improve patient characteristics in bone disease beyond traditional T-score-based diagnosis. Technological and validation limitations need to be overcome to improve its use in internal medicine. Current DXA scan indication guidelines could be further improved by clustering algorithms.

Cost and health care resource use associated with noncompliance with oral bisphosphonate therapy: an analysis using Danish health registries.

We estimated the rate of compliance with oral bisphosphonates among Danish women and examined its association with health care resource use and cost. Approximately 30 % of Danish females aged >55 who take bisphosphonates are noncompliant, and noncompliance is significantly associated with increased health care resource use and cost. INTRODUCTION: Two objectives of this study were to estimate the rate of oral bisphosphonate compliance among Danish women and to examine the association of noncompliance with health care resource use and cost. METHODS: Women ≥55 with an index prescription claim for an oral bisphosphonate were identified from Danish national health registries between 2003 and 2008. Compliance was measured as the medication possession ratio (MPR) during the first 12 months post-index. Cost and health care resource use were collected for the following 12 months. RESULTS: Among the 38,234 women meeting the study inclusion criteria, 29.9 % were noncompliant (MPR <70 %). Younger age was associated with higher odds of compliance (OR [95 % CI] 1.22 [1.15-1.29] for ages 55-64 and 1.18 [1.12-1.24] for ages 65-74; reference age group ≥75 years). Rates of all-cause health care resource use were significantly higher in noncompliant subjects: 28.9 versus 23.0 % had inpatient admissions, 16.5 versus 13.0 % had emergency room visits, and 48.7 versus 43.3 % used outpatient services (P < 0.001 for all comparisons). The total mean (SD) all-cause cost per patient (excluding office visits) was €626 (2344) and €4178 (7854), respectively. The mean (SD) osteoporosis-related cost per patient (excluding office visits) was €572 (2085) and €754 (2857) for compliant and non-compliant subjects, respectively. The compliant subjects accrued significantly lower all-cause and OP-related cost than noncompliant subjects, regardless of whether the total cost or medical cost only was considered. CONCLUSIONS: Approximately 30 % of Danish females aged 55 or older who take bisphosphonates are noncompliant. Noncompliance is significantly associated with increased health care resource use and cost.

The epidemiology of fractures in Denmark in 2011.

UNLABELLED: In the present study, we used national health care databases to estimate fracture incidence rates (IRs) and compared these IRs based on imputed data. We showed that imputation could lead to both over- and underestimation of IRs, and future research should therefore focus on how to improve those imputations. INTRODUCTION: Osteoporosis is a major public health burden through associated (osteoporotic) fractures. In Denmark, the incidence rates (IRs) of hip fracture are widely available. However, there is limited data about other fracture sites. A recent report could only provide imputed IRs, although nationwide data is readily available in electronic healthcare databases. Therefore, our aim was to estimate fracture site-specific IRs for Denmark in 2011 and to compare those to the previously reported imputed data. METHODS: Data from the Danish National Hospital Discharge Register was used to estimate age- and gender-specific IRs for any fracture as well as for different fracture sites in the Danish population aged 20 years and older in 2011. Hip fracture IRs were stratified to sub-sites, and IRs were determined for all hip fractures which were confirmed by surgery. RESULTS: The total number of incident fractures in 2011 was 80,760 (IR 191, 95 % confidence interval (CI) 190-192 (per 10,000 person-years)), of which 35,398 (43.8 %, IR 171, 95 % CI 169-173) occurred in men and 45,362 (56.2 %, IR 211, 95 % CI 209-213) in women. The majority of the fractures occurred in the population aged 50 years and older (n = 50,470, IR 249, 95 % CI 247-251). The numbers of any hip fracture were lower than the previously imputed estimates, whereas the number of forearm fractures was higher. CONCLUSION: We showed age- and gender-specific fracture rates for any fracture as well as for different fracture sites. The IRs of most fracture sites increased with age. Estimating the number of fractures for Denmark based on imputation of data from other countries led to both over- and underestimation. Future research should therefore focus on how to improve those imputations as not all countries have nationwide registry data.

Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk.

BACKGROUND: Data from observational studies have suggested that thiazide diuretics protect against fractures. Few studies have investigated time frames from initiation of treatment to fracture occurrence. OBJECTIVE: To evaluate the time to spinal, hip, femur, wrist and upper extremity fracture occurrence before and after thiazide exposure. METHODS: A matched retrospective cohort study of patient information from national Danish patient databases was conducted. Patients with reimbursed prescriptions for noncompounded thiazide diuretics with potassium supplementation (Anatomical Therapeutic Chemical classification system code C03AB) between 1996 and 2011 were matched with nonexposed control subjects by date of birth and gender. Weekly odds ratios (ORs) of fracture occurrence and total incidence rates (IRs) and incidence rate ratios (IRRs) of fracture risk were calculated for the periods before treatment initiation, weeks 1-42 and weeks 43-780. RESULTS: A total of 1,602,141 'thiazide exposure periods' (46,8271 individuals) and 1,530,233 'nonexposure periods' (655,399 individuals) were included in the analysis. Thiazide use was associated with factors of increased de novo fracture risk. Weekly adjusted fracture risk between exposure and nonexposure was increased prior to commencing thiazide therapy, further increasing from weeks 1-42 weeks and then decreasing gradually from weeks 43-780. There was a decreasing trend in total age-adjusted risk during these periods: IRR [95% confidence interval 1.44 [1.42; 1.47], 1.27 [1.24; 1.29] and 1.14 [1.11; 1.18], respectively. Prescription patterns showed several treatment breaks amongst thiazide users. CONCLUSIONS: It appears that thiazides reduce the background risk of fracture that is increased prior to commencing therapy. Long duration and continuity of thiazide exposure seems to be important to obtain this protective effect on fracture risk, but we have found in this study that this approach is not always used in clinical practice.

Treatment of osteoporosis after alendronate or risedronate.

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti-resorptive treatment to prevent a loss of the bone gained. There are only few studies-of short duration-that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long-term studies are needed.

Optimal age of commencing and discontinuing thiazide therapy to protect against fractures.

UNLABELLED: A study of national Danish patient data with regard to thiazide diuretics vs. non-treatment. We find that after age 83 years, thiazides increase the 10-year risk of major fractures. We also find that thiazides can be stopped after 63 years old to possibly protect against fracture occurrence. INTRODUCTION: The purpose of this study was to retrospectively examine the optimal age for commencing and discontinuing thiazide therapy to protect from osteoporotic fractures. METHODS: A population-based, retrospective matched cohort study was done using national data of 2.93 million Danish subjects. Ten-year crude and adjusted age-grouped hazard ratios (HRs) of fracture occurrence were stratified by age of commencing thiazides compared to non-exposure. Separate analyses were done on Anatomical Therapeutic Chemical Classification System (ATC) codes C03AA and C03AA + C03AB compiled. Ten-year crude HRs of fracture occurrence for discontinuing vs. continuing thiazides were estimated and stratified by age for the two groups. RESULTS: For C03AB alone (97.1 % of thiazide prescriptions), adjusted 10-year HRs of fracture occurrence were significantly increased for thiazide commencement after age 83 years and comparable to non-exposure for commencement between ages 50 and 83 years. For C03AA + C03AB, 10-year adjusted HRs of fracture occurrence were significantly increased from ages 73 years and upwards. Crude 10-year HRs of fracture occurrence were significantly decreased for discontinuing vs. continuing thiazides at or after age 63 years for C03AB and age 77 years for C03AA + C03AB. CONCLUSIONS: No significantly protective effect of thiazides was found on fracture occurrence compared to non-users, but evidence that thiazides increase the 10-year adjusted HR risk of fractures if prescribed after the age of 83 years for C03AB and 73 years for C03AA + C03AB. Discontinuing thiazides at or after age 63 years for C03AB or 77 years for C03AA & C03AB significantly decreases the 10-year risk of fractures compared to continuing thiazides. Further prospective studies are warranted.