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.

Australian Patient Preferences for Discussing Spiritual Issues in the Hospital Setting: An Exploratory Mixed Methods Study.

While there is high patient acceptance for clinical staff discussing issues regarding spirituality with hospital inpatients, it is not clear which staff member patients prefer for these discussions. This unique exploratory study investigated inpatient preferences regarding which staff member should raise the topic of spirituality. A cross-sectional survey was conducted with inpatients at six hospitals in Sydney, Australia (n = 897), with a subset invited to participate in qualitative interviews (n = 41). Pastoral care staff (32.9%) were the preferred staff members with whom to discuss spiritual issues, followed by doctors (22.4%). Qualitative findings indicated that individual characteristics of the staff member are more important than their role.

Measurement of Spiritual Wellbeing in an Australian Hospital Population Using the Functional Assessment of Chronic Illness Therapy: Spiritual Wellbeing Scale (FACIT-Sp-12).

Spiritual wellbeing is known to be a predictor of increased patient coping in hospital settings. Therefore, access to a valid and reliable measure of spiritual wellbeing amongst general hospital patients is highly recommended. The aim of this study was to investigate the dimensionality, reliability, and validity of the Functional Assessment of Chronic Illness Therapy Spiritual Wellbeing scale (FACIT-Sp-12) in a heterogeneous cohort of hospital patients. A cross-sectional survey was administered to 897 adult patients across six hospitals in Sydney, Australia. Confirmatory factor analysis for the three-factor FACIT-12-Sp indicated a poor fit, but after removal of Item 12, the three-factor FACIT-11-Sp presented a good fit to the data. Reliability testing indicated acceptable to good internal consistency. Validity was supported by statistically significant differences between patients who considered themselves 'both spiritual and religious' and 'not religious or spiritual'. While some caution should be taken when using the FACIT-Sp due to several limitations, nevertheless, in a general hospital population in Australia, the three-factor FACIT-11-Sp indicated good dimensionality, reliability, and validity.

Fracture risk in women with osteoporosis initiated on gastro-resistant risedronate versus immediate release risedronate or alendronate: a claims data analysis in the USA.

The study results indicate that women with osteoporosis initiated on gastro-resistant risedronate have a lower risk of fracture than those initiated on immediate release risedronate or alendronate. A large proportion of women discontinued all oral bisphosphonate therapies within 1 year of treatment start. PURPOSE: Using a US claims database (2009-2019), we compared risk of fractures between women with osteoporosis initiated on gastro-resistant (GR) risedronate and those initiated on (a) immediate release (IR) risedronate or (b) immediate release alendronate. METHODS: Women aged ≥ 60 years with osteoporosis who had ≥ 2 oral bisphosphonate prescription fills were followed for ≥ 1 year after the first observed bisphosphonates dispensing (index date). Fracture risk was compared between the GR risedronate and IR risedronate/alendronate cohorts using adjusted incidence rate ratios (aIRRs), both overall and in subgroups with high fracture risk due to older age or comorbidity/medications. Site-specific fractures were identified based on diagnosis codes recorded on medical claims using a claims-based algorithm. Persistence on bisphosphonate therapy was evaluated for all groups. RESULTS: aIRRs generally indicated lower fracture risk for GR risedronate than IR risedronate and alendronate. When comparing GR risedronate to IR risedronate, statistically significant aIRRs (p < 0.05) were observed for pelvic fractures in the full cohorts (aIRRs = 0.37), for any fracture and pelvic fractures among women aged ≥ 65 years (aIRRs = 0.63 and 0.41), for any fracture and pelvic fractures among women aged ≥ 70 years (aIRRs = 0.69 and 0.24), and for pelvic fracture among high-risk women due to comorbidity/medications (aIRR = 0.34). When comparing GR risedronate to alendronate, statistically significant aIRRs were observed for pelvic fractures in the full cohorts (aIRR = 0.54), for any fracture and wrist/arm fractures among women aged ≥ 65 years (aIRRs = 0.73 and 0.63), and for any fracture, pelvic, and wrist/arm fractures among women aged ≥ 70 years (aIRRs = 0.72, 0.36, and 0.58). In all cohorts, ~ 40% completely discontinued oral bisphosphonates within 1 year. CONCLUSIONS: Discontinuation rates of oral bisphosphonate therapy were high. However, women initiated on GR risedronate had a significantly lower risk of fracture for several skeletal sites than women initiated on IR risedronate/alendronate, particularly those aged ≥ 70 years.

Prevalence of osteoporosis and incidence of related fractures in developed economies in the Asia Pacific region: a systematic review.

Robust data on osteoporosis in the Asia Pacific region could improve healthcare decision-making. Osteoporosis affects 10-30% of women aged 40 + , and up to 10% of men in 7 developed economies in Asia Pacific. Fractures affect 500-1000 adults aged 50 + per 100,000 person-years. Policymakers and clinicians must address this problem. PURPOSE: Osteoporosis and associated fractures result in considerable morbidity, loss of productivity, early mortality, and increased healthcare expenses. Many countries in the Asia Pacific (AP) region, especially middle- and higher-income economies, are faced with aging and increasingly sedentary populations. It is critical to consolidate and analyze the available information on the prevalence and incidence of the disease in these countries. METHODS: We systematically reviewed articles and gray literature for Australia, China, Hong Kong, Japan, Singapore, South Korea, and Taiwan. We searched PubMed, ScienceDirect, JSTOR, Cochrane, Google Scholar, and other databases for data published 2009-2018. We included articles with prevalence or incidence estimates for adults with osteoporosis or related fractures. RESULTS: All locations had data available, but of widely varying quantity and quality. Most estimates for osteoporosis prevalence ranged from 10 to 30% for women ages 40 and older, and up to 10% for men. Osteoporotic fracture incidence typically ranged between 500 and 1000 per 100,000 person-years among adults aged 50 and older. Both outcomes typically increased with age and were more common among women. CONCLUSION: Osteoporosis and associated fractures affect significant portions of the adult population in developed economies in the AP region. Governments and healthcare systems must consider how best to prevent and diagnose osteoporosis, and manage affected individuals, to reduce healthcare costs and mortality associated with fractures.

Performance of the Garvan Fracture Risk Calculator in Individuals with Diabetes: A Registry-Based Cohort Study.

Diabetes increases fracture and falls risks. We evaluated the performance of the Garvan fracture risk calculator (FRC) in individuals with versus without diabetes. Using the population-based Manitoba bone mineral density (BMD) registry, we identified individuals aged 50-95 years undergoing baseline BMD assessment from 1 September 2012, onwards with diabetes and self-reported falls in the prior 12 months. Five-year Garvan FRC predictions were generated from clinical risk factors, with and without femoral neck BMD. We identified non-traumatic osteoporotic fractures (OF) and hip fractures (HF) from population-based data to 31 March 2018. Fracture risk stratification was assessed from area under the receiver operating characteristic curves (AUROC). Cox regression analysis was performed to examine the effect of diabetes on fractures, adjusted for Garvan FRC predictions. The study population consisted of 2618 women with and 14,064 without diabetes, and 636 and 2201 men with and without the same, respectively. The Garvan FRC provided significant OF and HF risk stratification in women with diabetes, similar to those without diabetes. Analyses of OF in men were limited by smaller numbers; no significant difference was evident by diabetes status. Cox regression showed that OF risk was 23% greater in women with diabetes adjusted for Garvan FRC including BMD (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01-1.49), suggesting it slightly underestimated risk; a non-significant increase in diabetes-related HF risk was noted (HR 1.37, 95% CI 0.88-2.15). Garvan FRC shows similar fracture risk stratification in individuals with versus without diabetes, but may underestimate this risk.

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.

Establishing baseline absolute risk of subsequent fracture among adults presenting to hospital with a minimal-trauma-fracture.

BACKGROUND: One in three women and one in five men are expected to experience a minimal-trauma-fracture after the age of 50-years, which increases the risk of subsequent fracture. Importantly, timely diagnosis and optimal treatment in the form of a fracture liaison service (FLS), has been shown to reduce this risk of a subsequent fracture. However, baseline risk of subsequent fracture among this group of FLS patients has not been well described. Therefore, this study aims to estimate absolute risk of subsequent fracture, among women and men aged 50-years or more, presenting to hospital with a minimal-trauma-fracture. METHODS: Women and men aged 50-years or more with a minimal-trauma-fracture, presenting to hospitals across the South Western Sydney Local Health District between January 2003 and December 2017 were followed to identify subsequent fracture presentations to hospital. Absolute risk of subsequent fracture was estimated, by taking into account the competing risk of death. RESULTS: Between January 2003 and December 2017-15,088 patients presented to the emergency departments of the five hospitals in the SWSLHD (11,149, women [74%]), with minimal-trauma-fractures. Subsequent fractures identified during the follow-up period (median = 4.5 years [IQR, 1.6-8.2]), occurred in 2024 (13%) patients. Death during the initial hospital stay, or during a subsequent hospital visit was recorded among 1646 patients (11%). Women were observed to have 7.1% risk of subsequent fracture after 1-year, following an initial fracture; and, the risk of subsequent fracture after 1-year was 6.2% for men. After 5-years the rate among women was 13.7, and 11.3% for men, respectively. Cumulative risk of subsequent fracture when initial fractures were classified as being at proximal or distal sites are also presented. CONCLUSION: This study has estimated the baseline risk of subsequent fracture among women and men presenting to hospital with minimal trauma fractures. Importantly, this information can be used to communicate risk to patients deciding to attend an osteoporosis refracture prevention clinic, and highlight the need for screening, and initial of treatment when indicated, once a minimal-trauma-fracture has occurred.

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.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

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.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies.

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10(-6). By applying α = 5 × 10(-5) (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P = 7.67 × 10(-6) and 1.58 × 10(-5)) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P = 5.08 × 10(-3)) at α = 0.10/11 = 9.09 × 10(-3). PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 7.55 × 10(-6)) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P = 8.87 × 10(-12)). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.

Fracture Risk Assessment: From Population to Individual.

Fracture caused by osteoporosis remains a major public health burden on contemporary populations because fracture is associated with a substantial increase in the risk of mortality. Early identification of high-risk individuals for prevention is a priority in osteoporosis research. Over the past decade, few risk prediction models, including the Garvan Fracture Risk Calculator (Garvan) and FRAX®, have been developed to provide absolute (individualized) risk of fracture. Recent validation studies suggested that the area under the receiver operating characteristic curve in fracture discrimination ranged from 0.61 to 0.83 for FRAX® and from 0.63 to 0.88 for Garvan, with hip fractures having a better discrimination than fragility fractures as a group. Although the prognostic performance of Garvan and FRAX® for fracture prediction is not perfect and there is room for further improvement, these predictive models can aid patients and doctors 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 fracture relative to other diseases.

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

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.

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.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)

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.