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.

Establishing consensus recommendations for long-term osteoporosis care for patients who have attended an Australian fracture liaison service: a Delphi study.

Coordinating healthcare activities between fracture liaison services (FLS) and primary care is challenging. Using a Delphi technique, we developed 34 consensus statements to support improved care coordination across this healthcare transition. PURPOSE: Evidence supporting an optimal coordination strategy between fracture liaison services (FLS) and primary care is lacking. This study aimed to develop consensus statements to support consistency and benchmarking of clinical practice to improve coordination of care for patients transitioning from FLS to primary care following an osteoporotic fracture. METHODS: A Delphi technique was used to develop consensus among a panel of experts, including FLS clinicians (medical and non-medical), general practitioners (GPs), and consumers. RESULTS: Results of a preparatory questionnaire (n = 33) informed the development of 34 statements for review by expert panellists over two Delphi rounds (n = 25 and n = 19, respectively). The majority of participants were from New South Wales (82%), employed as FLS clinicians (78.8%) and working in metropolitan centres (60.6%). Consensus was achieved for 24/34 statements in round one and 8/10 statements in round two. All statements concerning patient education, communication, and the GP-patient relationship achieved consensus. Expert opinions diverged in some areas of clinician roles and responsibilities and long-term monitoring and management recommendations. CONCLUSION: We found clear consensus among experts in many key areas of FLS integration with primary care. While experts agreed that primary care is the most appropriate setting for long-term osteoporosis care, overall confidence in primary care systems to achieve this was low. The role of (and responsibility for) adherence monitoring in a resource-limited setting remains to be defined.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

The association between multimorbidity and osteoporosis investigation and treatment in high-risk fracture patients in Australia: A prospective cohort study.

BACKGROUND: Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture. METHODS AND FINDINGS: The Sax Institute's 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively; >40% had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62); males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99); males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy; therefore, the impact of multimorbidity on osteoporosis management may have been underestimated. CONCLUSIONS: Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.

Exploring barriers and opportunities to improve osteoporosis care across the acute-to-primary care interface: a qualitative study.

This qualitative study interviewed general practitioners, patients, and FLS clinicians and identified key challenges facing stakeholders seeking to improve post-fracture osteoporosis care. Local policies and care pathways as an initial strategy may address information and service delivery issues across the acute-primary care divide. INTRODUCTION: Fracture liaison services (FLS) can be effective for secondary fracture prevention, but long-term adherence to therapies remains suboptimal. Few studies have explored how services manage the transition between tertiary and primary post-fracture care. This study mapped service processes and factors influencing integration of post-clinic care, identifying barriers, supports, and opportunities for seamless healthcare. METHODS: Qualitative descriptive study using semi-structured interviews with FLS stakeholders at two metropolitan hospitals in New South Wales (NSW) and surrounding general practices. RESULTS: Seven FLS clinicians, 11 general practitioners (GPs), and seven patients were interviewed. Six key themes emerged on the transition of patient care from tertiary to primary care (PC). Interprofessional communication issues and role ambiguity posed threats to seamless care. Delayed, absent, inaccessible, or poor-quality communication frustrated GPs, while FLS clinicians lacked confidence in existing communication systems and desired bidirectional communication with PC. GPs were confident managing osteoporosis, but FLS clinicians had limited confidence that patients would discuss osteoporosis with their GP and that GPs would action recommendations. Effective PC follow-up required a positive GP-patient relationship and that patients perceived a need to engage with PC. Patient understanding of osteoporosis (influenced by patient education, knowledge, beliefs, and health behaviours) affected PC attendance. Limited public awareness of osteoporosis and healthcare policy deficits contributed to care gaps. CONCLUSION: Key challenges were identified facing stakeholders seeking to improving post-clinic osteoporosis care. Development and implementation of local, integrated acute-community policies and care pathways as an initial intervention may address information and service delivery issues across the acute-PC divide.

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.

The role of community pharmacists in delivering interventions for osteoporosis: A systematic review.

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, 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). 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.

Roux-en-Y gastric bypass and gastric sleeve surgery result in long term bone loss.

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.

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Vitamin D deficiency and supplementation in critical illness-the known knowns and known unknowns.

The burgeoning literature on vitamin D deficiency and supplementation over the past decade or so has generated a greater understanding of some areas but also an appreciation of the many areas of equipoise. This is particularly relevant in the field of critical care with the heterogeneous patient populations, the severity and duration of illness and the frequency of comorbid conditions.This review aims to summarise the current knowledge base of vitamin D deficiency within the context of critical illness-"the known knowns"-and also highlight the areas of recognised uncertainty-"the known unknowns". It acknowledges the fact that there may well be other knowledge gaps of clinical relevance of which we are currently unaware-"the unknown unknowns".

Nonstandard Lumbar Region in Predicting Fracture Risk.

Femoral neck (FN) bone mineral density (BMD) is the most commonly used skeletal site to estimate fracture risk. The role of lumbar spine (LS) BMD in fracture risk prediction is less clear due to osteophytes that spuriously increase LS BMD, particularly at lower levels. The aim of this study was to compare fracture predictive ability of upper L1-L2 BMD with standard L2-L4 BMD and assess whether the addition of either LS site could improve fracture prediction over FN BMD. This study comprised a prospective cohort of 3016 women and men over 60 yr from the Dubbo Osteoporosis Epidemiology Study followed up for occurrence of minimal trauma fractures from 1989 to 2014. Dual-energy X-ray absorptiometry was used to measure BMD at L1-L2, L2-L4, and FN at baseline. Fracture risks were estimated using Cox proportional hazards models separately for each site. Predictive performances were compared using receiver operating characteristic curve analyses. There were 565 women and 179 men with a minimal trauma fracture during a mean of 11 ± 7 yr. L1-L2 BMD T-score was significantly lower than L2-L4 T-score in both genders (p < 0.0001). L1-L2 and L2-L4 BMD models had a similar fracture predictive ability. LS BMD was better than FN BMD in predicting vertebral fracture risk in women [area under the curve 0.73 (95% confidence interval, 0.68-0.79) vs 0.68 (95% confidence interval, 0.62-0.74), but FN was superior for hip fractures prediction in both women and men. The addition of L1-L2 or L2-L4 to FN BMD in women increased overall and vertebral predictive power compared with FN BMD alone by 1% and 4%, respectively (p < 0.05). In an elderly population, L1-L2 is as good as but not better than L2-L4 site in predicting fracture risk. The addition of LS BMD to FN BMD provided a modest additional benefit in overall fracture risk. Further studies in individuals with spinal degenerative disease are needed.

Acute hypocalcaemia following denosumab in heart and lung transplant patients with osteoporosis.

BACKGROUND: 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). AIM: To explore the risk of hypocalcaemia in a heart and lung transplant cohort prescribed denosumab for osteoporosis. METHODS: 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. RESULTS: 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. CONCLUSIONS: In heart and lung transplant patients, denosumab should be used judiciously in patients with advanced renal disease due to the risk of hypocalcaemia.

High prevalence of diabetes before and after lung transplantation: target for improving outcome?

BACKGROUND: Diabetes increases morbidity and mortality of lung transplantation. However, the reported prevalence of diabetes varies post-transplantation partly due to lack of detection protocols. AIM: To determine the prevalence of diabetes in patients (i) waitlisted for lung transplant and (ii) early post-transplantation. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Fracture Burden: What Two and a Half Decades of Dubbo Osteoporosis Epidemiology Study Data Reveal About Clinical Outcomes of Osteoporosis.

PURPOSE OF THE REVIEW: This review aims to highlight important clinical findings from the over 25 year-long Dubbo Osteoporosis Epidemiology Study particularly focusing on outcomes post fracture. RECENT FINDINGS: Every low trauma fracture in the elderly is associated with an increased risk of a subsequent fracture, with a higher risk in men than women. All major or proximal fractures and even minor fractures in the very elderly or minor fractures that are then followed by re-fracture are associated with premature mortality, greatest in the first 5 years post fracture. Having a subsequent fracture further increases this high mortality risk, but if an individual survives the high risk period, their risk returns to that of the background population. Non-hip non-vertebral fractures account for a significant proportion of the premature mortality. Despite an improvement in overall health and population mortality over the years, excess mortality post fracture has not changed in the last 2 decades. All low trauma, fractures in the elderly herald a high risk of poor outcomes, particularly in the first few years post fracture. Early intervention should be initiated.

Determinants of mortality risk following osteoporotic fractures.

PURPOSE OF REVIEW: Increased mortality risk is accepted for hip and vertebral fracture. Recent data suggest that other fracture types have also been linked to excess mortality. This article reviews the existing evidence on the pattern and determinants of postfracture mortality. RECENT FINDINGS: The pattern of mortality over time following hip and vertebral fractures has recently been clarified. Nonhip nonvertebral fractures at major, and even minor sites in older individuals have also been associated with excess mortality. Studies have revealed the higher excess mortality in men and in younger age groups for all fracture types. Despite the increasing knowledge on the fracture-mortality association, little is known about its cause. The role of co-morbidities is inconsistent across studies. Recent findings suggest low bone mass, bone loss and muscle weakness are linked to both fracture and mortality risk, and thus may play a role in postfracture mortality. SUMMARY: Nonhip nonvertebral fractures have recently been associated with mortality risk. Larger studies are needed to better understand which specific fractures and factors contribute to fracture-associated mortality risk. The role of bone loss in postfracture mortality needs to be validated in more studies, because of its potential reversibility with antifracture therapies.

Bone Failure in Critical Illness.

OBJECTIVES: The origin of systemic inflammatory response syndrome and multiple organ dysfunction syndrome is poorly understood but remains a fundamental concern in the ICU. This paper provides a critical appraisal on whether bone failure may represent an unrecognized component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome. DATA SOURCES, DATA SELECTION, AND DATA EXTRACTION: Search of the PubMed database and manual review of selected articles investigating bone pathophysiology in critical illness. DATA SYNTHESIS: Bone hyperresorption is highly prevalent among critically ill patients. Bone breakdown releases numerous systemically active cytokines and bone-sequestered toxins, with the capacity to fuel inflammatory hypercytokinaemia and metabolic toxaemia. Anti-resorptive medication inhibits bone break down and preadmission anti-resorptive use is associated with superior survival among critically ill patients. CONCLUSIONS: We propose that hyperresorptive bone failure is an unrecognised component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome that is causal to critical illness progression. If this hypothesis is valid, bone preservative strategies could reduce the risk of osteoporosis/fractures among ICU survivors, as well as decreasing critical illness mortality.

A Randomized Study of a Single Dose of Intramuscular Cholecalciferol in Critically Ill Adults.

OBJECTIVES: 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. DESIGN: Prospective randomized interventional study. SETTING: Tertiary, academic adult ICU. PATIENTS: Fifty critically ill adults with the systemic inflammatory response syndrome. INTERVENTION: 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. MEASUREMENTS AND MAIN RESULTS: 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 (p<0.01). 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. CONCLUSIONS: 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.

Relationship between Serum Testosterone and Fracture Risk in Men: A Comparison of RIA and LC-MS/MS.

BACKGROUND: Serum testosterone can be measured by LC-MS/MS and RIA. We investigated whether the testosterone-fracture relationship was affected by the method of measurement. METHODS: We measured total testosterone (TT) by LC-MS/MS (TTLC-MS/MS) and RIA (TTRIA) in serum samples collected from 602 men whose incident fractures had been continuously ascertained by x-ray reports from 1989 to 2010. We measured bone mineral density (BMD) by dual-energy x-ray absorptiometry. The association between TT and fracture risk was assessed by the Cox proportional hazards model, taking into account the effect of age and BMD. RESULTS: Mean TTLC-MS/MS was higher than TTRIA by 27 ng/dL (95% CI 13-41). The concordance correlation coefficient between TTLC-MS/MS and TTRIA was 0.72 (95% CI 0.68-0.76). The Deming regression equation linking the 2 measurements was ln(TTLC-MS/MS + 10) = 0.87 + 0.87 × ln(TTRIA + 10). The hazard ratio of fracture per SD decrease in TT was 1.32 (95% CI 1.12-1.54) for TTLC-MS/MS and 1.23 (1.06-1.43) for TTRIA. The correlation between predicted probabilities of fracture by TTLC-MS/MS and TTRIA was r = 0.96, with the mean difference being 0.01% (95% CI -6.1% to 6.2%). Slightly more patients were classified as having hypogonadism if TTRIA was used (29% vs 26%). CONCLUSIONS: The concordance between LC-MS/MS and RIA in the measurement of serum TT was moderate. Moreover, the magnitude of association between testosterone and fracture risk in older men was largely unaffected by the method of measurement.

Association between fat-mass-and-obesity-associated (FTO) gene and hip fracture susceptibility.

OBJECTIVE: Common variants in the fat-mass-and-obesity-associated (FTO) gene are related to body mass index (BMI), which is a predictor of hip fracture risk. This study sought to examine the association between variants in the FTO gene and hip fracture risk. DESIGN AND PARTICIPANTS: This is a prospective study including 934 postmenopausal women aged 60 years and above living in Dubbo, Australia (Dubbo Osteoporosis Epidemiology Study), followed up between 1989 and 2007. MEASUREMENTS: Six single nucleotide polymorphisms (SNPs) (rs1421085, rs1558902, rs1121980, rs17817449, rs9939609 and rs9930506) of the FTO gene were genotyped using Taqman assay. Bone mineral density at the lumbar spine and femoral neck was measured by DXA (GE-Lunar) at baseline. Incidence of hip fractures during the follow-up was ascertained by reviewing X-ray reports. We used Cox's models to estimate the association between the genetic variants and hip fracture risk. We also utilized Bayes factor to evaluate the association. RESULTS: One hundred and two women (11%) had sustained a hip fracture. The incidence of hip fracture was greater in women homozygous for the minor allele of all SNPs. Women homozygous for the minor allele (AA) of rs1121980 had significantly higher risk of hip fracture (hazard ratio, 2.06; 95% CI 1.17-3.62) than women homozygous for the major allele (TT). The observed data favoured the hypothesis of FTO gene and fracture association over the hypothesis of nonassociation by a factor of nine. CONCLUSION: Common variations in the FTO gene are associated with hip fracture risk in women and that FTO gene may help improve the predictive value of hip fracture risk.