Intravenous iron infusions (particularly ferric carboxymaltose) are associated with hypophosphatemia. This is mediated by increased fibroblast growth factor 23 (FGF-23), resulting in decreased activation of 25(OH)vitamin D to 1,25(OH)2 vitamin D and increased urinary phosphate excretion. Similarly, parenteral antiresorptive agents can lead to hypocalcemia due to reduced bone calcium mobilization, increasing parathyroid hormone (PTH) secretion, and exacerbating kidney phosphate excretion. When given concurrently, electrolyte disturbances can be severe and refractory to treatment, necessitating intravenous replacement, frequent monitoring, and prolonged hospitalization. We describe a case series of six patients with severe hypophosphatemia and hypocalcemia from concurrent administration of intravenous iron and antiresorptive therapy. The average time to hypophosphatemia following iron therapy in the presence of antiresorptives was 17.5 days. This is consistent with the nadir of phosphate 2 weeks following iron infusion and appears to be prolonged and exacerbated by antiresorptive therapy, increasing urinary phosphate loss through increased PTH activity. With the increasing popularity of intravenous iron infusions and parenteral antiresorptive agents, the interplay of these medications is an important consideration for clinicians. The emerging administration of these agents in the community and fragmentation of care across primary and specialist networks create the risk of unintentional concurrent use. Increased awareness of their impact on calcium-phosphate homeostasis is needed to mitigate the risk of severe electrolyte derangements with consideration of alternate iron formulations preferentially in those receiving medications for osteoporosis.

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.

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.

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.

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] >= 2.5), and BMI (>= 25 kg/m(2)): insulin-sensitive lean (IS-L), insulin-sensitive overweight/obese (IS-O), insulin-resistant (IR), and T2D. BMD, AHA, and body composition, including visceral adipose tissue (VAT) (on dual-energy x-ray absorptiometry scan) and fasting BTMs, were assessed. Analyses performed using Bayesian model averaging and principal component analysis. T2D was associated with low BTMs (by 26%-30% [95% confidence interval [CI] 11%-46%] in women, 35% [95% CI 18%-48%] in men compared to IS-L), which persisted after adjustment for VAT. BTMs were similar among IR/IS-O/IS-L. BMD was similar among T2D/IR/IS-O; BMD was low only in IS-L. All groups were similar after adjustment for BMI. Similarly, AHA components were lowest in IS-L (attenuated following adjustment). On multivariate analysis, T2D was independently associated with BTMs. IR was also associated with C-terminal telopeptide of type 1 collagen in men. Age and body size were the strongest independent contributors to BMD and AHA. VAT was inversely associated with section modulus, cross-sectional area, cross-sectional moment of inertia in women, and hip axis length in men. Low bone turnover is associated with T2D and IR (in men), while BMD and hip strength/geometry are predominantly associated with body size. VAT, indicative of dysglycemia, is also associated with impaired bone geometry. Establishing the role of BTMs and AHA fracture risk may improve skeletal assessment in T2D people. (c) 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background: 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. Objectives: 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. Methods: A literature search was conducted in Embase, CINAHL, Scopus, MEDLINE, andWeb 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 patientdirected 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). Results: 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. Conclusion: 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. (c) 2022 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

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.

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.

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.

Aims The aim of this study was to establish the pharmacokinetic profile of serum oestriol (E 3 ) concentrations over 24 h following application of vaginal E 3 in chronic users (>12 weeks of E 3 use). The interindividual and intraindividual differences before and after E 3 were examined. Methods Ten women participated. Vaginal cream was omitted for ≥36 h prior to the study days. Blood sampling was performed for E 3 , oestradiol and oestrone concentrations prior to cream application and at 1, 2, 3, 5, 8, 10, 12 and 24 h afterwards. In five women, all samples were repeated on a separate day. Results E 3 was absorbed rapidly in most women. Peak serum E 3 concentration occurred around 2 h (range 1–5 h). The decline in E 3 concentrations was also rapid: falling <100 pmol L −1 in six out of ten women within 8 h and returning to ≤ 10 pmol L −1 at 24 h in nine out of the ten patients. Interindividual variability for peak concentrations was considerable (mean 546 pmol L −1 ; 95% CI 349–743). Area under the concentration–time curve (AUC) values over a dosage interval also varied widely: mean 2145 pmol.h L −1 ; 95% CI 1422–3233. However, repeated measurements in the same woman were highly (peaks: ρ = 0.94) or moderately (AUC: P = 0.74) correlated. Conclusions Postmenopausal E 3 concentrations are negligible. Serum E 3 concentrations of chronic users of E 3 cream varied greatly; however, concentrations declined rapidly within 8 h, generally reaching ‘postmenopausal’ levels by 24 h. The basis for the variation between subjects needs further elucidation. Additional research is required to establish the safety of topical E 3 .

We assessed two electronic search tools that screen medical records for documented fractures. Both programs reliably identified patients with any fracture but missed individuals with minimal trauma fracture to different degrees. A hybrid tool combining the methodology of both tools is likely to improve the identification of those with osteoporosis. Purpose Most patients who suffer a minimal trauma fracture remain undiagnosed, placing them at high risk of refracture. Case finding can be improved by electronic search tools that screen medical records for documented fractures. Here, we assessed the efficacy of two new programs, AES and XRAIT, in identifying patients with minimal trauma fracture. Methods Each tool was applied to search the electronic medical record and/or radiology reports at two tertiary hospitals in Sydney, Australia, from 1 July to 31 December 2018. Samples of the extracted reports were then manually reviewed to determine the sensitivity of each program in detecting minimal trauma fractures. Results At the two centers, AES detected 872 and 1364 cases, whereas XRAIT identified 1414 and 2180 patients with fractures, respectively. The true positive rate for "any fracture" was similar for both instruments (77-88%). However, the ability to detect "minimal trauma fractures" differed between programs and centers (53-75% accuracy), with each tool identifying separate subsets of patients. Concordance between both tools was less than half of the combined total number of minimal trauma fractures (43-45%). Considering the total number of minimal trauma fractures detected by both tools combined, AES correctly identified 52-55% of cases while XRAIT identified 88-93% of cases. Conclusion Both programs reliably identified patients with any fracture but missed individuals with minimal trauma fracture to different degrees. Hybrid tools combining the methodology of XRAIT and AES are likely to improve the identification of patients who require investigation and treatment for osteoporosis.

Abstract Fracture liaison services (FLS) address the treatment gap for those with osteoporosis (OP) who fracture and are not treated. Given the limited human resources in FLS, screening high volumes of radiology reports for fractures with Natural Language Processing (NLP) could identify patients that have not been recognized or treated. This study is an analytical and clinical validation of X-Ray Artificial Intelligence Tool software (XRAIT) at its development site (a tertiary hospital) and external validation in an adjudicated cohort from the Dubbo Osteoporosis Epidemiology Study (DOES).Methods: XRAIT uses NLP to perform a Boolean search of radiology reports for fracture and related terms. It can be trained for site-specific reporting styles and use rules to refine identification (e.g. age>50y; bone involved; etc). At the development site, XRAIT was used to search the emergency patient presentations of people over 50 years of age and compared to referrals to FLS (usual care) during the same 3-month period. XRAIT analyzed all plain radiographs and CT scans (n = 5089) while n = 224 were referred to FLS for usual care. External validation: XRAIT was used to analyze digitally readable radiology reports in an untrained cohort from DOES (n = 327) to calculate sensitivity and specificity.Results: XRAIT identified a 5-fold higher number of potential significant fractures (349/5089) compared to manual case finding (70/224). 339/349 were confirmed fractures (97.1%). Only 29% of those eligible were started or recommended anti-resorptive therapy, including those seen by the fracture liaison service. XRAIT unadjusted for the local radiology reporting styles in DOES had a sensitivity of 69.6% and specificity of 95%. Conclusion: XRAIT identifies clinically significant fractures efficiently with minimal additional human resources. Its high specificity in an untrained cohort suggests it could be used at other sites. Automated methods of patient identification may assist fracture liaison services to identify fractures that still remain largely untreated.

Aims To quantify estriol serum concentrations in "new" and "chronic users" of topical estriol cream using quantitative liquid chromatography tandem mass spectrometry. Methods In this singlecentre prospective observational study, postmenopausal women with urogynaecological complaints were enrolled: 40 had not used topical estriol previously ("new users") and 50 had been applying estriol cream for more than 12 weeks ("chronic users"). In "new users," serum estriol levels were measured at baseline and after 12 weeks use. Estriol cream 1 mg/g was used daily for 3 weeks, then twice weekly with applicator (group 1A) or digitally (group 1B) or three times per week digitally (group 1C). "Chronic users" applied the cream twice (n = 7) or three (n = 43) times per week. Serum samples were taken in the morning after using cream the previous night. The main outcome measures were estriol serum concentrations in "new" and "chronic users" of estriol cream. Results Baseline serum estriol concentrations were less than 5 pmol/L in all 40 "new users." At 12 weeks, the 12-hour serum estriol levels ranged from less than 5 to 494 pmol/L (median 22.8; Interquartile range [IQR] 9.2-108.5). Seven "new users" had levels more than 100 pmol/L. Most of the 50 "chronic users" also had 12-hour levels less than 100 pmol/L (median 15.1 pmol/L [IQR 2.7-33.9]: three had levels more than 100 pmol/L. Conclusions This study reports serum estriol concentrations in a large number of "new" and "chronic users" of vaginal estriol cream, employing a novel highly sensitive and specific technique. Overall, the results are reassuring: 87% had 12-hour estriol levels less than 100 pmol/L.

ObjectivesWe assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND‐LINE study.MethodsWe measured concentrations of procollagen type 1 pro‐peptide (P1NP), carboxyl‐terminal collagen crosslinks (CTX), high‐sensitivity C‐reactive protein (hs‐CRP), D‐dimer, interleukin (IL)‐6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND‐LINE dual‐energy X‐ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression.ResultsThe mean age was 38 years, the mean CD4 T‐cell count was 252 cells/µL and the mean viral load was 4.2 log HIV‐1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]‐based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)‐containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1–27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0–27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking.ConclusionsIn a diverse cohort of viraemic HIV‐infected patients, switching to second‐line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at‐risk patients.

Department of Urogynaecology, St. George Hospital, School of Women's and Children's Health, University of New South Wales, Sydney, Australia Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia St. Vincent's Clinical School, University of New South Wales, Sydney, Australia Department of Clinical Chemistry and Endocrinology, New South Wales Health Pathology East, Prince of Wales Hospital, Sydney, Australia

AIM:To determine the relationship between bone microarchitecture, as measured by trabecular bone score, and advanced glycation end-product accumulation, as assessed by skin autofluorescence.METHODS:This was a cross-sectional study. Participants were 64 post-menopausal women with type 2 diabetes and 175 post-menopausal women without diabetes. Trabecular bone score and skin autofluorescence data were obtained at time of bone density measurement.RESULTS:Trabecular bone score and skin autofluorescence were inversely correlated in women with type 2 diabetes (r = -0.34, P = 0.006); no correlation was seen in post-menopausal women without diabetes (r = -0.029, P = 0.707). After adjustment, neither skin autofluorescence nor a diagnosis of diabetes were associated with trabecular bone score, but HbA1c and waist circumference were independently associated with trabecular bone score.CONCLUSION:Skin autofluorescence did not predict trabecular bone score. In contrast, glycaemia, as reflected by HbA1c , and visceral adiposity, as reflected by waist circumference, were independently associated with trabecular bone score.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

Objectives Little is known about the long-term skeletal impact of bariatric procedures, particularly the increasingly commonly performed gastric sleeve surgery (GS). We examined bone density (BMD) change following three types of bariatric surgery Roux-en-Y gastric bypass (RYGB), GS and laparoscopic adjustable gastric banding (LAGB), compared with diet, over 36 months. Methods Non-randomized, prospective study of participants with severe obesity ( n = 52), undergoing weight-loss interventions: RYGB ( n = 7), GS ( n = 21), LAGB ( n = 11) and diet ( n = 13). Measurements of calciotropic indices, gut hormones (fasting and post prandial) peptide YY (PYY), glucagon-like peptide 1 (GLP1) and adiponectin together with dual-X-ray absorptiometry and quantitative computed tomography scans were performed thorough the study. Results All groups lost weight during the first 12 months. Despite weight stability from 12 to 36 months and supplementation of calcium and vitamin D, there was progressive bone loss at the total hip (TH) over 36 months in RYGB −14% (95% CI: −12, −17) and GS −9% (95% CI: −7, −10). In RYGB forearm BMD also declined over 36 months −9% (95% CI: −6, −12) and LS BMD declined over the first 12 months −7% (95% CI: −3, −12). RYGB and GS groups experienced significantly greater bone loss until 36 months than LAGB and diet groups, which experienced no significant BMD loss. These bone losses remained significant after adjustment for weight loss and age. RYGB and GS procedures resulted in elevated postprandial PYY, adiponectin and bone turnover markers up to 36 months without such changes among LAGB and diet participants. Conclusions RYGB and GS but not LAGB resulted in ongoing TH bone loss for three postoperative years. For RYGB, bone loss was also observed at LS and non-weight-bearing forearms. These BMD changes were independent of weight and age differences. We, therefore, recommend close monitoring of bone health following RYGB and GS surgeries.