Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay.

Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.

Associations of Type 2 Diabetes, Body Composition, and Insulin Resistance with Bone Parameters: The Dubbo Osteoporosis Epidemiology Study.

Type 2 diabetes (T2D) may be associated with increased risk of fractures, despite preserved bone mineral density (BMD). Obesity and insulin resistance (IR) may have separate effects on bone turnover and bone strength, which contribute to skeletal fragility. We characterized and assessed the relative associations of obesity, body composition, IR, and T2D on bone turnover markers (BTMs), BMD, and advanced hip analysis (AHA). In this cross-sectional analysis of Dubbo Osteoporosis Epidemiology Study, 525 (61.3% women) participants were grouped according to T2D, IR (homeostasis model assessment insulin resistance [HOMA-IR]

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Contributors to impaired bone health in type 2 diabetes.

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.

Assessment and treatment of osteoporosis and fractures in type 2 diabetes.

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.

Fractures in type 2 diabetes confer excess mortality: The Dubbo osteoporosis epidemiology study.

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.

Natural language processing of radiology reports for the identification of patients with fracture.

Text-search software can be used to identify people at risk of re-fracture. The software studied identified a threefold higher number of people with fractures compared with conventional case finding. Automated software could assist fracture liaison services to identify more people at risk than traditional case finding. PURPOSE: Fracture liaison services address the post-fracture treatment gap in osteoporosis (OP). Natural language processing (NLP) is able to identify previously unrecognized patients by screening large volumes of radiology reports. The aim of this study was to compare an NLP software tool, XRAIT (X-Ray Artificial Intelligence Tool), with a traditional fracture liaison service at its development site (Prince of Wales Hospital [POWH], Sydney) and externally validate it in an adjudicated cohort from the Dubbo Osteoporosis Epidemiology Study (DOES). METHODS: XRAIT searches radiology reports for fracture-related terms. At the development site (POWH), XRAIT and a blinded fracture liaison clinician (FLC) reviewed 5,089 reports and 224 presentations, respectively, of people 50 years or over during a simultaneous 3-month period. In the external cohort of DOES, XRAIT was used without modification to analyse digitally readable radiology reports (n = 327) to calculate its sensitivity and specificity. RESULTS: XRAIT flagged 433 fractures after searching 5,089 reports (421 true fractures, positive predictive value of 97%). It identified more than a threefold higher number of fractures (421 fractures/339 individuals) compared with manual case finding (98 individuals). Unadjusted for the local reporting style in an external cohort (DOES), XRAIT had a sensitivity of 70% and specificity of 92%. CONCLUSION: XRAIT identifies significantly more clinically significant fractures than manual case finding. High specificity in an untrained cohort suggests that it could be used at other sites. Automated methods of fracture identification may assist fracture liaison services so that limited resources can be spent on treatment rather than case finding.

Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline.

BACKGROUND: There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. RESULTS: Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. CONCLUSIONS: Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions.

Bone Turnover Is Suppressed in Insulin Resistance, Independent of Adiposity.

CONTEXT: The contribution of insulin resistance vs adiposity to bone mineral density (BMD), bone turnover, and fractures in humans remains unclear. OBJECTIVE: To evaluate BMD and bone turnover markers (BTMs) in lean (n = 18) and overweight/obese individuals with (n = 17) and without (n = 34, insulin-sensitive [Obsensitive, n=15] or insulin-resistant [Obresistant, n=19] by homeostasis model assessment insulin resistance) diabetes mellitus. DESIGN: Observational study. OUTCOME MEASURES: Insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp; whole body BMD and fat mass (FM) using dual energy X-ray absorptiometry; and by measurement of BTMs [osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and collagen type 1 cross-linked C-terminal telopeptide (CTx)], with the patient fasting and during clamp hyperinsulinemia. RESULTS: Fasting BTMs correlated with glucose infusion rate/fat-free mass (GIR/FFM) and adiponectin and, inversely, with fasting insulin and visceral fat (P ≤ 0.04 for all). Obsensitive, Obresistant, and diabetic individuals were matched by their FM percentage. Clamp GIR/FFM was similar in the lean and Obsensitive subjects (P = 1) and approximately twofold greater (P < 0.001) than in the Obresistant and diabetic subjects. BMD was greater in Obresistant than in Obsensitive (P = 0.04) and lean (P = 0.001) subjects. At baseline, compared with Obsensitive and lean subjects, Obresistant and diabetic individuals had lower OC, P1NP, and CTx levels. This reached statistical significance for Obresistant vs lean and Obresistant vs Obsensitive for both OC and CTx and for diabetic vs lean for CTx (P ≤ 0.04 for all). During hyperinsulinemia, lean individuals suppressed CTx more than did diabetic individuals (P = 0.03). On multiple regression analysis, visceral adiposity explained 16.7% and 19.3% of the baseline OC and CTx variability, respectively. CONCLUSIONS: Increased visceral adiposity and higher fasting insulin in insulin-resistant states are associated with lower fasting OC and CTx and failure to further suppress with more insulin.

The prevalence of Vitamin D deficiency is higher in adult survivors of childhood cancer.

BACKGROUND: It is unclear whether the rate of vitamin D deficiency in paediatric cancer survivors is higher than in the background population, and whether this is of pathological significance. PATIENTS AND METHODS: 25OHD was measured in a previously studied group of 208 survivors (n = 108 paediatric 5-17 years, n = 99 adults 18-39 years) and compared with paediatric (5-17 years; n = 132) and adult controls (25-35 years; n = 1393 from the AusDiab cohort) adjusted for age and gender. Relationships with treatment factors (irradiation, bone marrow transplantation and intensity of treatment) along with overweight/obesity (defined by BMI), abdominal adiposity (waist:height ratio >0·5) and hyperinsulinism or abnormal glucose tolerance (HI/aGT) were sought. RESULTS: 25OHD concentrations were similar in paediatric survivors compared with controls (64·3 ± 21·6 nmol/l vs 66·3 ± 22·8 nmol/l), with no effect of age or gender. Adjusted for gender, rates of 25OHD deficiency (<50 nmol/l) were higher in adult survivors compared with AusDiab controls (42·4% vs 20·8%; P < 0·001). Apart from time since diagnosis (P = 0·03), no relationship with treatment factors was detected. In multivariate regression analysis, abdominal adiposity (P = 0·001), but not overweight/obesity by BMI status nor HI/aGT, was associated with significantly lower 25OHD concentrations. CONCLUSIONS: Adult survivors are at increased risk of abnormalities in vitamin D compared to the background population, probably reflecting longer time since diagnosis. Like others, we have not identified any contributory treatment-related factors. Vitamin D deficiency does not appear to be associated with the development of abnormal glucose tolerance in this population.

Contribution of the collagen I alpha1 and vitamin D receptor genes to the risk of hip fracture in elderly women.

CONTEXT AND OBJECTIVE: Hip fracture is partially genetically determined. The present study was designed to examine the contributions of vitamin D receptor (VDR) and collagen I alpha1 (COLIA1) genotypes to the liability to hip fracture in postmenopausal women. DESIGN: The study was designed as a prospective population-based cohort investigation. SUBJECTS: Six hundred seventy-seven postmenopausal women of Caucasian background, aged 70 +/- 7 yr (mean +/- SD), have been followed for up to 14 yr. Sixty-nine women had sustained a hip fracture during the period. MAIN OUTCOME: Atraumatic hip fractures were prospectively identified through radiologists' reports. Bone mineral density (BMD) at the hip and lumbar spine was measured by dual-energy x-ray absorptiometry. GENOTYPES: The TaqI and SpI COLIA1 polymorphisms of the VDR and COLIA1 genes were determined. Using the Single Nucleotide Polymorphism database, VDR TT, Tt, and tt genotypes were coded as TT, TC, and CC, whereas COLIA1 SS, Ss, and ss were coded as GG, GT, and TT. RESULTS: Women with VDR CC genotype (16% prevalence) and COLIA1 TT genotype (5% prevalence) had an increased risk of hip fracture [odds ratio (OR) associated with CC, 2.6; 95% confidence interval (CI), 1.2-5.3; OR associated with TT, 3.8; 95% CI, 1.3-10.8] after adjustment for femoral neck BMD (OR, 3.4 per SD; 95% CI, 2.3-5.0) and age (OR, 1.4 per 5 yr; 95% CI, 1.1-1.7). Approximately 20 and 12% of the liability to hip fracture was attributable to the presence of the CC genotype and TT genotype, respectively. CONCLUSION: The VDR CC genotype and COLIA1 TT genotype were associated with increased hip fracture risk in Caucasian women, and this association was independent of BMD and age.

Insulin expressing hepatocytes not destroyed in transgenic NOD mice.

BACKGROUND: The liver has been suggested as a suitable target organ for gene therapy of Type 1 diabetes. However, the fundamental issue whether insulin-secreting hepatocytes in vivo will be destroyed by the autoimmune processes that kill pancreatic beta cells has not been fully addressed. It is possible that the insulin secreting liver cells will be destroyed by the immune system because hepatocytes express major histocompatibility complex (MHC) class I molecules and exhibit constitutive Fas expression; moreover the liver has antigen presenting activity. Together with previous reports that proinsulin is a possible autoantigen in the development of Type 1 diabetes, the autoimmune destruction of insulin producing liver cells is a distinct possibility. METHODS: To address this question, transgenic Non-Obese Diabetic (NOD) mice which express insulin in the liver were made using the Phosphoenolpyruvate Carboxykinase (PEPCK) promoter to drive the mouse insulin I gene (Ins). RESULTS: The liver cells were found to possess preproinsulin mRNA, translate (pro)insulin in vivo and release it when exposed to 100 nmol/l glucagon in vitro. The amount of insulin produced was however significantly lower than that produced by the pancreas. The transgenic PEPCK-Ins NOD mice became diabetic at 20-25 weeks of age, with blood glucose levels of 24.1 +/- 1.7 mmol/l. Haematoxylin and eosin staining of liver sections from these transgenic NOD PEPCK-Ins mice revealed the absence of an infiltrate of immune cells, a feature that characterised the pancreatic islets of these mice. CONCLUSIONS: These data show that hepatocytes induced to produce (pro)insulin in NOD mice are not destroyed by an ongoing autoimmune response; furthermore the expression of (pro)insulin in hepatocytes is insufficient to prevent development of diabetes in NOD mice. These results support the use of liver cells as a potential therapy for type 1 diabetes. However it is possible that a certain threshold level of (pro)insulin production might have to be reached to trigger the autoimmune response.