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Type 2 diabetes (T2D) is associated with numerous complications, including increased risk of fragility fractures, despite seemingly protective factors [e.g., normal bone mineral density and increased body mass index(BMI)]. However, fracture risk in T2D is underestimated by current fracture risk calculators. Importantly, post-fracture mortality is worse in T2D following any fracture, highlighting the importance of identifying high-risk patients that may benefit from targeted management. Several diabetes-related factors are associated with increased fracture risk, including exogenous insulin therapy, vascular complications, and poor glycaemic control, although detailed comprehensive studies to identify the independent contributions of these factors are lacking. The underlying pathophysiological mechanisms are complex and multifactorial, with different factors contributing during the course of T2D disease. These include obesity, hyperinsulinaemia, hyperglycaemia, accumulation of advanced glycation end products, and vascular supply affecting bone-cell function and survival and bone-matrix composition. This review summarises the current understanding of the contributors to impaired bone health in T2D, and proposes an updated approach to managing these patients.

Context Bisphosphonates have been reported to be cardioprotective in some, but not all, studies. It is unknown whether denosumab (Dmab) use protects against cardiovascular events (CVEs). Objective To determine whether oral bisphosphonate (oBP) or Dmab use is associated with CVEs in persons with incident fracture. Methods Participants with an incident minimal trauma fracture from the Sax Institute’s 45 and Up Study, a population-based cohort from NSW, Australia, were followed between 2005/2009 and 2017. Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection [APDC]) by the Centre for Health Record Linkage). Medicare Benefit Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data sets were provided by Services Australia. Data was stored in a secure computing environment (Secure Unified Research Environment). Fractures, CVEs, and comorbidities were identified from the APDC and oBP and Dmab medication from the PBS. oBP and Dmab users were matched to never users (NoRx) by propensity scores. The main outcome measures were association between oBP and Dmab with CVE (acute myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) and were determined using a stratified Cox's proportional hazards model. Results There were 880 pairs of oBP and NoRx (616 women) and 770 pairs of Dmab and NoRx (615 women) followed for ∼4.3 years. CVE risk was similar for oBP and NoRx Hazard Ratios (HR) women, 0.88 [95% CI 0.65-1.18]; men, 1.07 [95% CI 0.72-1.57]). Similar findings were obtained for Dmab (Hazard Ratios (HR) women, 1.08 [95% CI 0.78-1.50]; men, 1.55 [95% CI 0.96-2.48]). Conclusion oBP and Dmab use was not associated with CVEs.

Fracture liaison services (FLS) are considered to be the most effective organizational approach for secondary fracture prevention. In this study, we evaluated whether FLS care was associated with reduced subsequent fracture and mortality risk over 3 years of follow-up. In total, 8682 consecutive patients aged 50-90 years with a recent fracture were included. Before FLS introduction, regular fracture treatment procedures were followed (pre-FLS). After FLS introduction, patients were invited to the FLS and FLS attenders were assessed for osteoporosis, prevalent vertebral fractures, metabolic bone disorders, medication use, and fall risk, and treatment for fracture prevention was initiated according to Dutch guidelines. All fractures were radiographically confirmed and categorized into major/hip (pelvis, proximal humerus or tibia, vertebral, multiple rib, distal femur) and non-major/non-hip (all other fractures). Mortality risk was examined using age and sex adjusted Cox proportional hazard models. For subsequent fracture risk, Cox proportional hazard models were adjusted for age, sex, and competing mortality risk (subdistribution hazard [SHR] approach). The pre-FLS group consisted of 2530 patients (72% women), of whom 1188 (46.9%) had major/hip index fractures, the post-FLS group consisted of 6152 patients (69% women), of whom 2973 (48.3%) had major/hip index fractures. In patients with a non-major/non-hip fracture there was no difference in subsequent non-major/non-hip fracture risk or mortality between pre-FLS and post-FLS. In patients with a major/hip index fracture, mortality risk was lower post-FLS (hazard ratio [HR] 0.84; 95% confidence interval [CI], 0.73-0.96) and subsequent major/hip fracture risk was lower in the first 360 days after index fracture post-FLS compared to pre-FLS (SHR 0.67; 95% CI, 0.52-0.87). In conclusion, FLS care was associated with a lower mortality risk in the first 3 years and a lower subsequent major/hip fracture risk in the first year in patients with a major/hip index fracture but not in patients with a non-major/non-hip fracture. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This study was funded by the research foundation of VieCuri Medical Center Noord-Limburg, The Netherlands and Stichting de Wijerhorst.

Context Fragility fracture is a significant public health problem because it is associated with increased mortality. We want to find out whether the risk of fracture can be predicted from the time of birth. Objective To examine the association between a polygenic risk score (PRS) and lifetime fracture risk. Methods This population-based prospective study involved 3515 community-dwelling individuals aged 60+ years who have been followed for up to 20 years. Femoral neck bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry. A PRS was created by summing the weighted number of risk alleles for each single nucleotide polymorphism using BMD-associated coefficients. Fragility fractures were radiologically ascertained, whereas mortality was ascertained through a state registry. Residual lifetime risk of fracture (RLRF) was estimated by survival analysis. Results The mortality-adjusted RLRF for women and men was 36% (95% CI, 34%-39%) and 21% (18%-24%), respectively. Individuals with PRS > 4.24 (median) had a greater risk (1.2-fold in women and 1.1-fold in men) than the population average risk. For hip fracture, the average RLRF was 10% (95% CI, 8%-12%) for women and ∼5% (3%-7%) for men; however, the risk was significantly increased by 1.5-fold and 1.3-fold for women and men with high PRS, respectively. Conclusion A genetic profiling of BMD-associated genetic variants is associated with the residual lifetime risk of fracture, suggesting the potential for incorporating the polygenic risk score in personalized fracture risk assessment.

Muscle strength and physical performance are associated with incident fractures and mortality. However, their role in the risk of subsequent fracture and postfracture mortality is not clear. We assessed the association between muscle strength (grip strength) and performance (gait speed and chair stands time) and the risk of subsequent fracture and mortality in 830 men with low-trauma index fracture, who participated in the Osteoporotic Fractures in Men (MrOS) USA Study and had their index measurements assessed within 5 years prior to the index fracture. The annual decline in muscle strength and performance following index fracture, estimated using linear mixed-effects regression, was also examined in relation to mortality. The associations were assessed using Cox proportional hazards models adjusted for age, femoral neck bone mineral density (FN BMD), prior fractures, falls, body mass index (BMI), index fracture site, lifestyle factors, and comorbidities. Over a median follow-up of 3.7 (interquartile range [IQR], 1.3-8.1) years from index fracture to subsequent fracture, 201 (24%) men had a subsequent fracture and over 5.1 (IQR, 1.8-9.6) years to death, and 536 (65%) men died. Index measurements were not associated with subsequent fracture (hazard ratios [HRs] ranging from 0.97 to 1.07). However, they were associated with postfracture mortality. HR (95% confidence interval [CI]) per 1 standard deviation (1-SD) decrement in grip strength: HR 1.12 (95% CI, 1.01-1.25) and gait speed: HR 1.14 (95% CI, 1.02-1.27), and 1-SD increment in chair stands time: HR 1.08 (95% CI, 0.97-1.21). Greater annual declines in these measurements were associated with higher mortality risk, independent of the index values and other covariates. HR (95% CI) per 1-SD annual decrement in change in grip strength: HR 1.15 (95% CI, 1.01-1.33) and in gait speed: HR 1.38 (95% CI, 1.13-1.68), and 1-SD annual increment in chair stands time: HR 1.28 (95% CI, 1.07-1.54). Men who were unable to complete one or multiple tests had greater risk of postfracture mortality (24%-109%) compared to those performed all tests. It remains to be seen whether improvement in these modifiable factors can reduce postfracture mortality. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

There is substantial, and growing, evidence that type 2 diabetes (T2D) is associated with skeletal fragility, despite often preserved bone mineral density. As post-fracture outcomes, including mortality, are worse in people with T2D, bone management should be carefully considered in this highly vulnerable group. However, current fracture risk calculators inadequately predict fracture risk in T2D, and dedicated randomised controlled trials identifying optimal management in patients with T2D are lacking, raising questions about the ideal assessment and treatment of bone health in these people. We synthesise the current literature on evaluating bone measurements in T2D and summarise the evidence for safety and efficacy of both T2D and anti-osteoporosis medications in relation to bone health in these patients.

To examine an impact of three types of bariatric surgery compared with dietary intervention (DIET), on concurrent changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and appetite hormones over 3 years. Fifty-five adults were studied during phase of weight loss (0–12 months) and during weight stability (12–36 months) post intervention. Measurements of HOMA-IR, fasting and postprandial PYY and GLP1, adiponectin, CRP, RBP4, FGF21 hormones and dual-Xray absorptiometry were performed throughout the study. All surgical groups achieved significant reductions in HOMA-IR with greatest difference between Roux-en-Y gastric bypass and DIET (− 3.7; 95% CI − 5.4, − 2.1; p = 0.001) at 12–36 months. Initial (0–12 months) HOMA-IR values were no different to DIET after adjustment for the lost weight. During 12–36 months, after controlling for treatment procedure and weight, for every twofold increase in postprandial PYY and adiponectin, HOMA-IR decreased by 0.91 (95% CI − 1.71, − 0.11; p = 0.030) and by 0.59 (95% CI − 1.10, − 0.10; p = 0.023) respectively. Initial, non-sustained changes in RBP4 and FGF21 were not associated with HOMA-IR values. While initial rapid weight loss reduces insulin resistance, the enhanced secretions of PYY and adiponectin may contribute to weight-independent improvements in HOMA-IR during weight stability.Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000188730.

ImportanceLimited knowledge about interactions among health disorders impedes optimal patient care. Because comorbidities are common among patients 50 years and older with fractures, these fractures provide a useful setting for studying interactions among disorders.ObjectiveTo define multimorbidity clusters at the time of fracture and quantify the interaction between multimorbidity and fracture in association with postfracture excess mortality.Design, Setting, and ParticipantsThis nationwide cohort study included 307 870 adults in Denmark born on or before January 1, 1951, who had an incident low-trauma fracture between January 1, 2001, and December 31, 2014, and were followed up through December 31, 2016. Data were analyzed from February 1 to March 31, 2022.Main Outcomes and MeasuresFracture and 32 predefined chronic diseases recorded within 5 years before the index fracture were identified from the Danish National Hospital Discharge Register. Death was ascertained from the Danish Register on Causes of Death. Latent class analysis was conducted to identify multimorbidity clusters. Relative survival analysis was used to quantify excess mortality associated with the combination of multimorbidity and fractures at specific sites.ResultsAmong the 307 870 participants identified with incident fractures, 95 372 were men (31.0%; mean [SD] age at fracture, 72.3 [11.2] years) and 212 498 were women (69.0%; mean [SD] age at fracture, 74.9 [11.2] years). During a median of 6.5 (IQR, 3.0-11.0) years of follow-up, 41 017 men (43.0%) and 81 727 women (38.5%) died. Almost half of patients with fractures (42.9%) had at least 2 comorbidities. Comorbidities at fracture were categorized as low-multimorbidity (60.5% in men and 66.5% in women), cardiovascular (23.7% in men and 23.5% in women), diabetic (5.6% in men and 5.0% in women), malignant (5.1% in men and 5.0% in women), and mixed hepatic and/or inflammatory (5.1% in men only) clusters. These clusters distinguished individuals with advanced, complex, or late-stage disease from those with earlier-stage disease. Multimorbidity and proximal or lower leg fractures were associated with increased mortality risk, with the highest excess mortality found in patients with hip fracture in the malignant cluster (1-year excess mortality: 40.8% [95% CI: 38.1%-43.6%]). The combination of multimorbidity and fracture compounded the association with mortality, conferring much greater risk than either alone.Conclusions and RelevanceConcomitant illnesses were common and clustered into distinct multimorbidity clusters that were associated with excess postfracture mortality. The compound contribution of multimorbidity to postfracture excess mortality highlights the need for more comprehensive approaches in these high-risk patients. The analytical approach applied to fracture could also be used to examine other sentinel health events.

ObjectivesTo evaluate the risk of subsequent fractures in patients who attended the Fracture Liaison Service (FLS), with and without incident falls after the index fracture.DesignA 3-year prospective observational cohort study.SettingAn outpatient FLS in the Netherlands.ParticipantsPatients aged 50+ years with a recent clinical fracture.Outcome measuresIncident falls and subsequent fractures.ResultsThe study included 488 patients (71.9% women, mean age: 64.6±8.6 years). During the 3-year follow-up, 959 falls had been ascertained in 296 patients (60.7%) (ie, fallers), and 60 subsequent fractures were ascertained in 53 patients (10.9%). Of the fractures, 47 (78.3%) were fall related, of which 25 (53.2%) were sustained at the first fall incident at a median of 34 weeks. An incident fall was associated with an approximately 9-fold (HR: 8.6, 95% CI 3.1 to 23.8) increase in the risk of subsequent fractures.ConclusionThese data suggest that subsequent fractures among patients on treatment prescribed in an FLS setting are common, and that an incident fall is a strong predictor of subsequent fracture risk. Immediate attention for fall risk could be beneficial in an FLS model of care.Trial registration numberNL45707.072.13.

Osteoporosis is a major public health concern, given that disease prevalence is expected to substantially increase due to the aging population. Community pharmacists can play a key role in the identification and management of chronic diseases.The purpose of this systematic review was to present an overview of the literature on the role of community pharmacists in providing osteoporosis interventions to patients. The secondary objective was to assess the impact of these interventions on patient outcomes.A literature search was conducted in Embase, CINAHL, Scopus, MEDLINE, and Web of Science from database inception to March 2021. The search was limited to human studies in the English language. Primary studies were included if they described or assessed a patient-directed osteoporosis intervention conducted by community pharmacists. The following data were extracted and tabulated: citation, study location, study design, subject, number of participants, nature of intervention, classification of intervention, outcome measures, measurement methods, findings, and effect. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2) and Risk of Bias in Non-randomized Studies (ROBINS-I).Twenty-one studies were included in this review. The main interventions were education, screening, and medication management. Nineteen of these studies reported patient outcomes, all yielding positive outcomes. Outcomes included increased physician follow-up, risk factor reduction, increased osteoporosis knowledge, increased medication adherence, identification of medication-related problems, and positive patient-reported experience measures (PREMs). Three studies were considered to have a moderate risk of bias, whereas the remaining 18 studies had a high risk of bias.There is some evidence that pharmacist-led osteoporosis interventions have a positive impact on patient outcomes. More high-quality studies using objective outcome measures are needed to determine whether this translates into clinical outcomes such as decreased hospitalization and fractures.

Fracture risk evaluation of postmenopausal women is suboptimal, but most women undergo screening mammography. Digital X-radiogrammetry (DXR) determines bone mineral density (BMD) at the metacarpal shaft and can be performed on mammography equipment. This study examined correlations between DXR and dual-energy X-ray absorptiometry (DXA) in women undergoing mammography, to identify optimal DXR thresholds for triage to osteoporosis screening by central DXA. Postmenopausal women over age 50 years, recruited from Westmead Hospital's Breast Cancer Institute, underwent mammography, DXR and DXA. Agreements were determined using the area under the receiver operator characteristic (AUC ROC) curve and Lin's concordance correlation coefficient. Optimal DXR T-scores to exclude osteoporosis by DXA were determined using the Youden's method. Of 200 women aged 64 ± 7 years (mean ± standard deviation [SD]), 82% had been diagnosed with breast cancer and 37% reported prior fracture. DXA T-scores were ≤ -1 at the spine, hip or forearm in 77.5% and accorded with DXR T-scores in 77%. For DXR and DXA T-scores ≤ -2.5, the AUC ROC was 0.87 (95% confidence interval [CI], 0.81-0.94) at the 1/3 radius, and 0.74 (95% CI, 0.64-0.84) for hip or spine. DXR T-scores > -1.98 provided a negative predictive value of 94% (range, 88%, 98%) for osteoporosis by central DXA. In response to a questionnaire, radiography staff responded that DXR added 5 minutes to patient throughput with minimal workflow impact. In the mammography setting, triaging women with a screening DXR T-score < -1.98 for DXA evaluation would capture a significant proportion of at-risk women who may not otherwise be identified and improve current low rates of osteoporosis screening. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

PURPOSE: Diabetes and fractures are both associated with increased mortality, however the effect of the combination is not well-established. We examined the mortality risk following all types of fractures in type 2 diabetes (T2D). METHODS: In the Dubbo Osteoporosis Epidemiology Study (1989-2017), participants were grouped according to T2D and/or incident fracture. Study outcome was all-cause mortality. First incident radiological fragility fracture and incident T2D diagnosis were time-dependent variables. Cox's proportional hazards models quantified mortality risk associated with T2D and incident fracture overall, as well as by fracture site, T2D duration and T2D medication type. RESULTS: In 3618 participants (62% women), 272 had baseline and 179 developed T2D over median 13.0 years (IQR 8.2-19.6). 796 women (56 with T2D) and 240 men (25 with T2D) sustained a fracture. Compared to those without T2D or fracture, mortality risk increased progressively, in T2D without fracture, then no T2D with fracture, and was highest in those with T2D with fracture (adjusted hazard ratio (aHR) (95% CI) for women 2.62 (1.75-3.93) and men 2.61 (1.42-4.81)). Within T2D participants, incident fracture was associated with increased mortality (aHR for women 1.87 (1.10-3.16) and men 2.83 (1.41-5.68)), especially following hip/vertebral fractures in men (aHR 2.97 (1.29-6.83)) and non-hip non-vertebral fractures in women (aHR 2.42 (1.24-4.75)), and in T2D duration >5 years. CONCLUSION: Any fracture in T2D conferred significant excess mortality. Individuals with T2D should be carefully monitored post-fracture, especially if T2D >5 years. Optimising fracture prevention and post-fracture management in T2D is critical and warrants further studies.

Bisphosphonates are first line agents used to treat osteoporosis and reduce fracture rate. They bind to areas of exposed calcium in the skeleton and cause osteoclast apoptosis, thereby leading to a reduction in remodelling rates. They are also used to decrease skeletal complications of some cancers including a reduction in bone metastases. Following the landmark randomised controlled trial of zoledronate post hip fracture (HORIZON) in which an unexpected survival benefit was found, there has been increasing interest in their potential ability to increase lifespan. This review will consider the clinical evidence for their effect on mortality in both the osteoporosis and non-osteoporosis settings, the latter including studies in intensive care, cancer and cardiovascular disease. Where evidence exists, this review will briefly discuss some of the postulated mechanisms for this survival benefit.

Pharmacoepidemiology is used extensively in osteoporosis research and involves the study of the use and effects of drugs in large numbers of people. Randomized controlled trials are considered the gold standard in assessing treatment efficacy and safety. However, their results can have limited external validity when applied to day‐to‐day patients. Pharmacoepidemiological studies aim to assess the effect/s of treatments in actual practice conditions, but they are limited by the quality, completeness, and inherent bias due to confounding. Sources of information include prospectively collected (primary) as well as readily available routinely collected (secondary) (eg, electronic medical records, administrative/claims databases) data. Although the former enable the collection of ad hoc measurements, the latter provide a unique opportunity for the study of large representative populations and for the assessment of rare events at relatively low cost. Observational cohort and case‐control studies, the most commonly implemented study designs in pharmacoepidemiology, each have their strengths and limitations. However, the choice of the study design depends on the research question that needs to be answered. Despite the many advantages of observational studies, they also have limitations. First, missing data is a common issue in routine data, frequently dealt with using multiple imputation. Second, confounding by indication arises because of the lack of randomization; multivariable regression and more specific techniques such as propensity scores (adjustment, matching, stratification, trimming, or weighting) are used to minimize such biases. In addition, immortal time bias (time period during which a subject is artefactually event‐free by study design) and time‐varying confounding (patient characteristics changing over time) are other types of biases usually accounted for using time‐dependent modeling. Finally, residual “uncontrolled” confounding is difficult to assess, and hence to account for it, sensitivity analyses and specific methods (eg, instrumental variables) should be considered. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Data on long-term consequences of non-hip non-vertebral (NHNV) fractures, accounting for approximately two-thirds of all fragility fractures, are scanty. Our study aimed to quantify the population-wide impact of NHNV fractures on mortality. The national population-based prospective cohort study (Canadian Multicentre Osteoporosis Study) included 5526 community dwelling women and 2163 men aged 50 years or older followed from July 1995 to September 2013. Population impact number was used to quantify the average number of people for whom one death would be attributable to fracture and case impact number to quantify the number of deaths out of which one would be attributable to a fracture. There were 1370 fragility fractures followed by 296 deaths in women (mortality rate: 3.49; 95% CI, 3.11 to 3.91), and 302 fractures with 92 deaths in men (5.05; 95% CI, 4.12 to 6.20). NHNV fractures accounted for three-quarters of fractures. In women, the population-wide impact of NHNV fractures on mortality was greater than that of hip and vertebral fractures because of the greater number of NHNV fractures. Out of 800 women, one death was estimated to be attributable to a NHNV fracture, compared with one death in 2000 women attributable to hip or vertebral fracture. Similarly, out of 15 deaths in women, one was estimated to be attributable to a NHNV fracture, compared with one in over 40 deaths for hip or vertebral fracture. The impact of forearm fractures (ie, one death in 2400 women and one out of 42 deaths in women attributable to forearm fracture) was similar to that of hip, vertebral, or rib fractures. Similar, albeit not significant, results were noted for men. The study highlights the important contribution of NHNV fractures on mortality because many NHNV fracture types, except for the most distal fractures, have serious adverse consequences that affect a significant proportion of the population. © 2017 American Society for Bone and Mineral Research.

Osteoporotic fracture increases the risk of premature mortality. Muscle weakness is associated with both increased fracture risk and low bone mineral density (BMD). However, the role of muscle strength in post-fracture mortality is not well understood. This study examines the change of muscle strength measured at quadriceps (QS) before and after fracture and defines the relationship between muscle strength and post-fracture mortality. The study involved 889 women and 295 men (who were participating in the Dubbo Osteoporosis Study) who had at least one low-trauma fracture (ascertained from X-ray reports) after the age of 50 years. Median follow-up time was 11 years (range 1 to 24). To determine the change in muscle strength before and after a fracture, we selected a subset of 344 women and 99 men who had had at least two muscle strength measurements before the fracture event and a subset of 407 women and 105 men who had had at least two measurements after the fracture. During the follow-up period, 366 (41.2%) women and 150 (50.9%) men died. The annual rate of decrease in height-adjusted muscle strength before fracture was 0.27 kg/m (1.85%) in women and 0.40 kg/m (1.79%) in men. Strength loss after fracture was not significantly different from that before fracture. In women, after adjusting for baseline age and BMD, each SD (5 kg/m) lower height-adjusted pre- and post-fracture quadriceps strength was associated with a 27% (hazard ratio [HR] = 1.27; 95% confidence interval [CI] 1.07, 1.50) and 18% (HR = 1.18; 95% CI 1.01, 1.38) increase in post-fracture mortality risk, respectively. Similarly, in men, each SD (5 kg/m) lower height-adjusted pre- and post-fracture QS was associated with increased mortality before fracture (HR = 1.33; 95% CI 1.09, 1.63) and after fracture (HR = 1.43; 95% CI 1.16, 1.78). Muscle weakness accounted for 15% (95% CI 0.05, 0.24) of premature deaths after fracture in women and 23% (95% CI 0.11, 0.35) in men. These results indicate that in the older individuals, lower muscle strength is an independent risk factor for post-fracture mortality. © 2017 American Society for Bone and Mineral Research.

Background: Vitamin D deficiency is associated with active Crohn’s disease (CD). However, it remains unclear if lower 25-hydroxyvitamin D [25(OH)D] concentration is the cause, or consequence, of intestinal inflammation. Existing literature has focused on circulating 25(OH)D rather than the active metabolite 1,25(OH)2D, or its breakdown product, 24,25(OH)2D. We aimed to characterise vitamin D metabolism in a cohort of patients with active and inactive CD. Methods: Fifty-four patients with CD and not on corticosteroids or vitamin D supplements, were enrolled in a 6-month prospective cohort study. Sera were collected on enrolment and at 6 months and tested for 25(OH)D, 1,25(OH)2D, 24,25(OH)2D using liquid chromatography tandem mass spectroscopy as well as vitamin-D-binding protein. Results: There were no differences in 25(OH)D or 1,25(OH)2D levels between participants with active versus inactive disease. Levels of 24,25(OH)2D were significantly lower in those with active compared with inactive disease (mean 3.9 versus 6.0 µmol/l; p = 0.007) and therefore the ratio of 25(OH)D:24,25(OH)2D was higher (mean 17.3 versus 11.1; p = 0.001). In those patients with active disease who achieved remission, there was a mean increase in 25(OH)D of 32.3 nmol/l (i.e. to a level in the sufficient range) and 24,25(OH)2D of 2.1 µmol/l. These increases were not seen in patients with persistently active or inactive disease. Conclusion: Levels of 24,25(OH)2D, but not 25(OH)D, were lower in patients with active CD, and spontaneously increased with resolution of underlying inflammation. The utility of 24,25(OH)2D as a biomarker of disease activity and vitamin D status in CD warrants further exploration.

IntroductionOsteoporosis is a systemic skeletal disease that is characterised by reduced bone strength and increased fracture risk. Osteoporosis-related fractures impose enormous disease and economic burden to the society. Although many treatments and health interventions are proven effective to prevent fractures, health economic evaluation adds evidence to their economic merits. Computer simulation modelling is a useful approach to extrapolate clinical and economic outcomes from clinical trials and it is increasingly used in health economic evaluation. Many osteoporosis health economic models have been developed in the past decades; however, they are limited to academic use and there are no publicly accessible health economic models of osteoporosis.Methods and analysisWe will develop the Australian osteoporosis health economic model based on our previously published microsimulation model of osteoporosis in the Chinese population. The development of the model will follow the recommendations for the conduct of economic evaluations in osteoporosis by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the US branch of the International Osteoporosis Foundation. The model will be a state-transition semi-Markov model with memory. Clinical parameters in the model will be mainly obtained from the Dubbo Osteoporosis Epidemiology Study and the health economic parameters will be collected from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study. Model transparency and validates will be tested using the recommendations from Good Research Practices in Modelling Task Forces. The model will be used in economic evaluations of osteoporosis interventions including pharmaceutical treatments and primary care interventions. A user-friendly graphical user interface will be developed, which will connect the user to the calculation engine and the results will be generated. The user interface will facilitate the use of our model by people in different sectors.Ethics and disseminationNo ethical approval is needed for this study. Results of the model validation and future economic evaluation studies will be submitted to journals. The user interface of the health economic model will be publicly available online accompanied with a user manual.

Although the susceptibility to fracture is partly determined by genetic factors, the contribution of newly discovered genetic variants to fracture prediction is still unclear. This study sought to define the predictive value of a genetic profiling for fracture prediction. Sixty-two bone mineral density (BMD)-associated single-nucleotide polymorphisms (SNPs) were genotyped in 557 men and 902 women who had participated in the Dubbo Osteoporosis Epidemiology Study. The incidence of fragility fracture was ascertained from X-ray reports between 1990 and 2015. Femoral neck BMD was measured by dual-energy X-ray absorptiometry. A weighted polygenic risk score (genetic risk score [GRS]) was created as a function of the number of risk alleles and their BMD-associated regression coefficients for each SNP. The association between GRS and fracture risk was assessed by the Cox proportional hazards model. Individuals with greater GRS had lower femoral neck BMD (p < 0.01), but the variation in GRS accounted for less than 2% of total variance in BMD. Each unit increase in GRS was associated with a hazard ratio of 1.20 (95% CI, 1.04 to 1.38) for fracture, and this association was independent of age, prior fracture, fall, and in a subset of 33 SNPs, independent of femoral neck BMD. The significant association between GRS and fracture was observed for the vertebral and wrist fractures, but not for hip fracture. The area under the receiver-operating characteristic (ROC) curve (AUC) for the model with GRS and clinical risk factors was 0.71 (95% CI, 0.68 to 0.74). With GRS, the correct reclassification of fracture versus nonfracture ranged from 12% for hip fracture to 23% for wrist fracture. A genetic profiling of BMD- associated genetic variants could improve the accuracy of fracture prediction over and above that of clinical risk factors alone, and help stratify individuals by fracture status. © 2016 American Society for Bone and Mineral Research.

Osteoporotic fracture is a growing public health problem worldwide. Because of the ageing of most populations, the number of people who will sustain a fracture is predicted to increase significantly over the next few decades. This chapter reviews the epidemiology of osteoporotic fracture and its outcomes, including subsequent fracture and associated premature mortality. All osteoporotic fractures are associated with an approximate twofold increased risk of a subsequent fracture, with the greatest risk of refracture occurring close in time to the initial fracture. This risk is higher in men than in women. Although hip and vertebral fractures are considered the most serious of fracture types, nonhip nonvertebral fractures account for more than 50% of initial and subsequent fractures. In addition, all proximal fractures are associated with an increased mortality risk, which is highest close to the fracture event and persists for at least 5 years before declining to the background population mortality rate. A subsequent fracture further increases this risk. Antiresorptive medication may be associated with improved survival in those at fracture risk. It is now clear that osteoporotic fracture is associated with poor outcomes, and early intervention is essential to reduce the subsequent fracture and possibly also mortality risk.

© 2018 Elsevier Inc. Purpose: Low trauma rib fracture (hereinafter, rib fracture) is common in the elderly, but its risk factors and mortality consequence are rarely studied. We sought to define the epidemiology of rib fracture and the association between rib fracture and postfracture mortality. Methods: The study was part of the Dubbo Osteoporosis Epidemiology Study, which was designed as a population-based prospective study, and consisted of 2041 women and men (aged ≥ 60). The incidence of rib fracture was ascertained from X-ray reports. Bone mineral density (BMD) was measured by DXA (GE-Lunar). The time-dependent Cox model was used to access the relationship between rib fracture and mortality. Results: During the median follow-up of 13 years, 59 men and 78 women had sustained a rib fracture, making the annual incidence of 4.8/1000 person-years. Each SD (0.15 g/cm 2 ) lower in femoral neck BMD was associated with ~2-fold increase in the hazard of fracture (hazard ratio [HR] 1.9; 95% CI, 1.4 to 2.6 in men; and HR 2.1; 95% CI, 1.6 to 2.8 in women). Among those with a rib fracture, the incidence of subsequent fractures was 10.2/100 person-years. Compared with those without a fracture, the risk of mortality among those with a fracture was increased by ~7.8-fold (95% CI, 2.7 to 22.5) in men and 4.9-fold (95% CI 2.0 to 11.8) in women within the first year postfracture. Conclusions: A rib fracture signifies an increased risk of subsequent fractures and mortality. The increased risk of mortality during the first 2.5 years postfracture suggests a window of opportunity for treatment.

To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints: calcium, phosphate, parathyroid hormone, C-reactive protein, interleukin-6, and cathelicidin in critically ill adults.Prospective randomized interventional study.Tertiary, academic adult ICU.Fifty critically ill adults with the systemic inflammatory response syndrome.Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU) cholecalciferol.Pharmacokinetic, pharmacodynamic parameters, and outcome measures were collected over a 14-day period or until ICU discharge, whichever was earlier. Prior to randomization, 28 of 50 patients (56%) were classified as vitamin D deficient. By day 7 after randomization, 15 of 23 (65%) and 14 of 21 patients (67%) normalized vitamin D levels with 0.15 and 0.3 mU, respectively (p=0.01) and by day 14, 8 of 10 (80%) and 10 of 12 patients (83%) (p=0.004), respectively. Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p0.01). Inflammatory markers (C-reactive protein and interleukin-6) fell significantly over the study period. Greater increments in 25-hydroxy-vitamin-D were significantly associated with greater increments in cathelicidin at days 1 and 3 (p=0.04 and 0.004, respectively). Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p=0.05). No significant adverse effects were observed.A single dose of either dose of intramuscular cholecalciferol corrected vitamin D deficiency in the majority of critically ill patients. Greater vitamin D increments were associated with early greater cathelicidin increases, suggesting a possible mechanism of vitamin D supplementation in inducing bactericidal pleiotropic effects.

Nonhip, nonvertebral (NHNV) fractures constitute the majority of osteoporotic fractures, but few studies have examined the association between these fractures, comorbidity, and mortality. Our objective was to examine the relationship between individual nonhip, nonvertebral fractures, comorbidities, and mortality. The prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 to 2013. Associations between fracture and mortality were examined using multivariate, time-dependent Cox models, adjusted for age, prior fracture, body mass index, smoking, and comorbidities (cardiovascular disease, diabetes, stroke, thrombosis, and cancer), and survival function curves. Population attributable fraction was calculated for each level of risk exposure. During 1,490,651 person-years, women and men experienced 7571 and 4571 fractures and 7064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men were associated with increased multivariable-adjusted mortality hazard ratios ranging from 1.3 to 3.4. Comorbidity independently added to mortality such that a woman with a humeral fracture and 1 comorbidity had a similarly reduced 5-year survival as that of a woman with a hip fracture and no comorbidities. Population mortality attributable to any fracture without comorbidity was 9.2% in women and 5.3% in men. All proximal nonhip, nonvertebral fractures in women and men were associated with increased mortality risk. Coexistent comorbidities independently further increased mortality. Population attributable risk for mortality for fractures was similar to cardiovascular disease and diabetes, highlighting their importance and potential benefit for early intervention and treatment. © 2018 American Society for Bone and Mineral Research.

Osteoporosis is highly prevalent in the heart and lung transplant population. Given high rates of concurrent renal impairment, there is increasing use of denosumab in this population. However, denosumab may be associated with hypocalcaemia, particularly in patients with chronic kidney disease (CKD).To explore the risk of hypocalcaemia in a heart and lung transplant cohort prescribed denosumab for osteoporosis.We performed a retrospective database review of all surviving heart and lung transplant patients who had received denosumab for osteoporosis between January 2012 and November 2015. We assessed the rates of hypocalcaemia in this cohort and collected baseline clinical data to determine associated factors.Ten patients received denosumab and had laboratory results available within 3 months of the dose. Of these, three patients developed severe (grade 4) hypocalcaemia, while two patients developed mild (grade 1) hypocalcaemia. In comparison to the five patients who remained normocalcaemic, patients with hypocalcaemia had significantly lower baseline mean estimated glomerular filtration rate but similar baseline mean corrected serum calcium. Unexpectedly, patients developing hypocalcaemia had non-significantly higher levels of 25-hydroxyvitamin D and lower baseline doses of prednisone.In heart and lung transplant patients, denosumab should be used judiciously in patients with advanced renal disease due to the risk of hypocalcaemia.

Diabetes increases morbidity and mortality of lung transplantation. However, the reported prevalence of diabetes varies post-transplantation partly due to lack of detection protocols.To determine the prevalence of diabetes in patients (i) waitlisted for lung transplant and (ii) early post-transplantation.We analysed patients on the St Vincent's Heart Lung database from 1 April 2014 to 30 September 2015 on the waitlist (Study 1) and those transplanted (Study 2). Standard of care required all non-diabetic patients to have an oral glucose tolerance test (modified for patients with cystic fibrosis (CF) to screen for CF-related hyperglycaemia (CFRH) (plasma glucose ≥8.2 mmol/L at 60 or 90 min).Study 1 included 114 patients (32 with CF and 82 without CF). Of 30 CF patients with glycaemic data, 27 (90%) had abnormal glucose metabolism: 18 had diabetes and nine had CFRH. In 50 patients without CF, 20 (40%) had abnormal glucose metabolism: eight had diabetes and 12 had impaired fasting glucose and/or impaired glucose tolerance. Study 2 included 78 transplanted patients (25 with CF and 53 without CF). Fourteen CF patients had pre-existing diabetes and seven had pre-existing CFRH. All but one patient were diagnosed with diabetes post-transplantation. Hence, diabetes prevalence in CF patients post-transplantation was 96%. Among 53 transplanted patients without CF, seven (13%) had abnormal glucose metabolism but 30 (57%) were diagnosed with post-transplant diabetes.There is a high prevalence of diabetes in lung transplant patients. Earlier endocrine participation in lung transplant services is likely to lower diabetes-related morbidity and mortality further.

The relationship between body mass index (BMI) and fracture risk is controversial. We sought to investigate the effect of collinearity between BMI and bone mineral density (BMD) on fracture risk, and to estimate the direct and indirect effect of BMI on fracture with BMD being the mediator. The study involved 2199 women and 1351 men aged 60 years or older. BMI was derived from baseline weight and height. Femoral neck BMD was measured by dual-energy X-ray absorptiometry (DXA; GE-LUNAR, Madison, WI, USA). The incidence of fragility fracture was ascertained by X-ray reports from 1991 through 2012. Causal mediation analysis was used to assess the mediated effect of BMD on the BMI-fracture relationship. Overall, 774 women (35% of total women) and 258 men (19%) had sustained a fracture. Approximately 21% of women and 20% of men were considered obese (BMI ≥ 30). In univariate analysis, greater BMI was associated with reduced fracture risk in women (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.85 to 0.99) and in men (HR 0.77; 95% CI, 0.67 to 0.88). After adjusting for femoral neck BMD, higher BMI was associated with greater risk of fracture in women (HR 1.21; 95% CI, 1.11 to 1.31) but not in men (HR 0.96; 95% CI, 0.83 to 1.11). Collinearity had minimal impact on the BMD-adjusted results (variance inflation factor [VIF] = 1.2 for men and women). However, in mediation analysis, it was found that the majority of BMI effect on fracture risk was mediated by femoral neck BMD. The overall mediated effect estimates were −0.048 (95% CI, −0.059 to −0.036; p

After fracture there is increased risk of refracture and premature mortality. These outcomes, particularly premature mortality following refracture, have not previously been studied together to understand overall mortality risk. This study examined the long-term cumulative incidence of subsequent fracture and total mortality with mortality calculated as a compound risk and separated according to initial and refracture. Community-dwelling participants aged 60+ years from Dubbo Osteoporosis Epidemiology Study with incident fractures, followed prospectively for further fractures and deaths from 1989 to 2010. Subsequent fracture and mortality ascertained using cumulative incidence competing risk models allowing four possible outcomes: death without refracture; death following refracture; refracture but alive, and event-free. There were 952 women and 343 men with incident fracture. Within 5 years following initial fracture, 24% women and 20% men refractured; and 26% women and 37% men died without refracture. Of those who refractured, a further 50% of women and 75% of men died, so that total 5-year mortality was 39% in women and 51% in men. Excess mortality was 24% in women and 27% in men. Although mortality following refracture occurred predominantly in the first 5 years post-initial fracture, total mortality (post-initial and refracture) was elevated for 10 years. Most of the 5-year to 10-year excess mortality was associated with refracture. The long-term (>10 years) refracture rate was reduced, particularly in the elderly as a result of their high mortality rate. The 30% alive beyond 10 years postfracture were at low risk of further adverse outcomes. Refractures contribute substantially to overall mortality associated with fracture. The majority of the mortality and refractures occurred in the first 5 years following the initial fracture. However, excess mortality was observed for up to 10 years postfracture, predominantly related to that after refracture.

The risk of subsequent fracture is increased after initial fractures; however, proper understanding of its magnitude is lacking. This population-based study examines the subsequent fracture risk in women and men by age and type of initial incident fracture. All incident nonvertebral fractures between 1994 and 2009 were registered in 27,158 participants in the Tromso Study, Norway. The analysis included 3108 subjects with an initial incident fracture after the age of 49 years. Subsequent fracture (n = 664) risk was expressed as rate ratios (RR) and absolute proportions irrespective of death. The rates of both initial and subsequent fractures increased with age, the latter with the steepest curve. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age-adjusted RR of subsequent fracture was 1.3 (95% CI, 1.2–1.5) in women, and 2.0 (95% CI, 1.6–2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased with age; from 9% to 30% in women and from 10% to 26% in men, between the age groups 50–59 to 80+ years. The type of subsequent fracture varied by age from mostly minor fractures in the youngest to hip or other major fractures in the oldest age groups, irrespective of type and severity of initial fracture. In women and men, 45% and 38% of the subsequent hip or other major fractures, respectively, were preceded by initial minor fractures. The risk of subsequent fracture is high in all age groups. At older age, severe subsequent fracture types follow both clinically severe and minor initial incident fractures. Any fragility fracture in the elderly reflects the need for specific osteoporosis management to reduce further fracture risk. © 2013 American Society for Bone and Mineral Research.

PURPOSE OF REVIEW: Fragility fracture is a major public health burden, because it is associated with a substantial morbidity and mortality. Risk prediction models, including the Fracture Risk Assessment Tool (FRAX) and Garvan Fracture Risk Calculator (GFRC), have been developed to provide a useful clinical framework for communicating the risk of fracture. The present review examines the validation of risk prediction models in osteoporosis and identifies some major challenges. RECENT FINDINGS: Recent validation studies suggested that the area under the ROC curve in fracture discrimination ranged from 0.61 to 0.83 for FRAX, and from 0.63 to 0.88 for GFRC, with hip fracture having a better discrimination than fragility fractures as a group. FRAX substantially underestimated the risk of fracture, whereas the predicted risk by GFRC was close to or slightly higher than the actual risk. Results of post-hoc analyses of clinical trials indicated the antifracture efficacy of alendronate, coronate, bazedoxifene, and denosumab was greater in patients with higher predicted risk of fracture. However, there was no correlation between antifracture efficacy and predicted fracture risk among patients on raloxifene and strontium ranelate. SUMMARY: The prognostic performance of FRAX and GFRC for fracture prediction is not perfect, but these predictive models can aid patients and doctors to communicate about fracture risk in the medium term and to make rational decisions. However, the application of these predictive models in making decisions for an individual should take into account the individual's perception of the importance of the risk of fracture and its severity outcomes. © 2013 Wolters Kluwer Health / Lippincott Williams & Wilkins.

Data on long-term consequences of non-hip non-vertebral (NHNV) fractures, accounting for approximately two-thirds of all fragility fractures, are scanty. Our study aimed to quantify the population-wide impact of NHNV fractures on mortality. The national population-based prospective cohort study (Canadian Multicentre Osteoporosis Study) included 5526 community dwelling women and 2163 men aged 50 years or older followed from July 1995 to September 2013. Population impact number was used to quantify the average number of people for whom one death would be attributable to fracture and case impact number to quantify the number of deaths out of which one would be attributable to a fracture. There were 1370 fragility fractures followed by 296 deaths in women (mortality rate: 3.49; 95% CI, 3.11 to 3.91), and 302 fractures with 92 deaths in men (5.05; 95% CI, 4.12 to 6.20). NHNV fractures accounted for three-quarters of fractures. In women, the population-wide impact of NHNV fractures on mortality was greater than that of hip and vertebral fractures because of the greater number of NHNV fractures. Out of 800 women, one death was estimated to be attributable to a NHNV fracture, compared with one death in 2000 women attributable to hip or vertebral fracture. Similarly, out of 15 deaths in women, one was estimated to be attributable to a NHNV fracture, compared with one in over 40 deaths for hip or vertebral fracture. The impact of forearm fractures (ie, one death in 2400 women and one out of 42 deaths in women attributable to forearm fracture) was similar to that of hip, vertebral, or rib fractures. Similar, albeit not significant, results were noted for men. The study highlights the important contribution of NHNV fractures on mortality because many NHNV fracture types, except for the most distal fractures, have serious adverse consequences that affect a significant proportion of the population. © 2017 American Society for Bone and Mineral Research.

Manuscript. Published version available at http://dx.doi.org/10.1007/s11657-016-0294-z Summary: This study describes childhood fracture rates in Norway, a country known for high fracture rates in the adult population. Fracture rates correspond with other reports from Scandinavia, although with a slightly higher proportion in girls. Indications of increased vulnerability during stages of puberty require further exploration. Introduction: Fractures are common injuries during childhood. Incidence rates and patterns vary, but population-based data are scarce. The aim of this study was to describe the sex-, age- and maturation-specific incidence of fractures in a representative population-based sample from a region in Norway. Methods: All fractures in the population based convenient cohort Fit Futures, comprising 961 adolescents under 18 years, were recorded retrospectively from the local hospital. Details on individual’s age and fracture site were recorded. A radiologist confirmed all fractures. Results: In the period from birth to cohort scanning, the register recorded 316 fractures in 253 individuals. Fractures were more common in boys (35%) than in girls (31%). The overall annual fracture incidence was 204 per 10,000 persons-year under the age of 18 and 205 under the age of 16. The majority of fractures involved the upper extremities and the most common site of fracture was the forearm with 24% of the fractures followed by phalanges with 23% of the fractures. Fractures peaked in girls at sexual maturation stage 3. Boys had a peak in stage 2. Timing of subsequent fractures was also consistent with stages of sexual maturation. Conclusions: The overall incidence of fractures in childhood in Northern Norway corresponds with other reports from Scandinavia, although the proportion of fractures in girls is higher than in other studies. Both sexes seem especially vulnerable at stages related to sexual maturation. Whether this reflects bone vulnerability or other changes related to puberty requires further investigation.