Significant Increase In Fracture Risk Research Articles

P1116 Risk of fractures in children and adults with inflammatory bowel disease: A report from the epi-IIRN

Abstract Background Both adult and pediatric patients with inflammatory bowel disease (IBD) are at risk of osteopenia and osteoporosis, nevertheless, whether patients with IBD are subjected to a higher risk for bone fractures is debated. Thus, we aimed to assess the risk for bone fractures, osteopenia and osteoporosis in IBD vs non-IBD patients, using the epi-Israeli IBD Research Nucleus (IIRN) data. Methods Data of patients with IBD and non-IBD matched controls (approximately 3 non-IBD controls per case) were retrieved from the epi-IIRN cohort (January 2005- June 2020) that maintain data on all patients with IBD from the four Israeli HMOs. Data included demographics, osteoporosis medications, fracture data and IBD related characteristics. Patients were stratified by age group (0-17,18-49, and ≥50). Patients with known osteopenia or osteoporosis before IBD diagnosis were excluded. Results We included 32,263 patients with IBD and 89,423 non-IBD controls [48% female, 56% Crohn’s disease (CD)]. Time to first fracture was significantly shorter in female pediatric patients (p=0.01), in both female (p=0.0004) and male (p=0.003) adult and elderly patients (p<0.0001) (Figure 1). Time to diagnosis of osteopenia/osteoporosis in patients with IBD was significantly shorter in all age groups and genders. Rate of fractures was significantly higher in patients with IBD versus controls for all groups, and rate of osteopenia/osteoporosis was also higher in patients with IBD in all groups (Table 1). In a subgroup analysis, fracture rate did not significantly differ between CD and ulcerative colitis (UC) for all age groups, but osteopenia and osteoporosis were significantly higher in CD compared to UC in all age groups. The hazard ratio for fractures in the pediatric IBD population was 1.02 (0.88-1.16) for males and 1.17(0.95-1.44) for females, in adults 1.08 (0.99-1.16) for males and 1.12 (1.02-1.21) for females, and in the elderly 1.2 (1.08-1.32) for males and 1.19 (1.08-1.31) for females. Arthritis was significantly associated with fracture risk [HR: children 1.47 (1.15-1.88); adults 1.3 (1.17-1.44); elderly 1.19 (1.07-1.30)]. In adults and elderly, older age at diagnosis, chronic obstructive pulmonary disease, diabetes and long-term proton pump inhibitors usage were also associated with a significant increase in fracture risk. Conclusion In this large nationwide cohort, patients with IBD had significantly higher risk for bone fractures than matched controls in almost all age groups, with no difference between CD and UC. Additionally, the rate of osteopenia and osteoporosis was higher in patients with IBD, suggesting that further efforts need to be invested in bone health of this at-risk population.

Fracture Risk and Association With TDF Use Among People With HIV in Large Integrated Health Systems.

Greater decline in bone health among people with HIV (PWH) has been documented but fracture risk and the impact of specific antiretroviral therapy (ART) regimens remain unclear. Retrospective analyses of electronic health record data from 3 US integrated health care systems. Fracture incidence was compared between PWH aged 40 years or older without prior fracture and demographically matched people without HIV (PWoH), stratified by age, sex, and race/ethnicity. Multivariable Cox proportional hazards models were used to estimate fracture risk associated with HIV infection. The association of tenofovir disoproxil fumarate (TDF) use and fracture risk was evaluated in a subset of PWH initiating ART. Incidence of fracture was higher in PWH [13.6/1000 person-years, 95% confidence interval (CI): 13.0 to 14.3, n = 24,308] compared with PWoH (9.5, 95% CI: 9.4 to 9.7, n = 247,313). Compared with PWoH, the adjusted hazard ratio (aHR) for fracture among PWH was 1.24 (95% CI: 1.18 to 1.31). The association between HIV infection and fracture risk increased with age, with the lowest aHR (1.17, 95% CI: 1.10 to 1.25) among those aged 40-49 years and the highest aHR (1.89, 95% CI: 1.30 to 2.76) among those aged 70 years or older. Among PWH initiating ART (n = 6504), TDF was not associated with significant increase in fracture risk compared with non-TDF regimens (aHR: 1.18, 95% CI: 0.89 to 1.58). Among people aged 40 years or older, HIV infection is associated with increased risk of fractures. Bone health screening from the age of 40 years may be beneficial for PWH. Large cohort studies with longer follow-up are needed to evaluate TDF effect and the potential benefit of early screening.

The effect of defect size and location on the fracture risk of proximal tibia, following tumor curettage and cementation: An in-silico investigation

Even though, proximal tibia is a common site of giant cell tumor and bone fractures, following tumor removal, nonetheless very little attention has been paid to affecting factors on the fracture risk. Here, nonlinear voxel-based finite element models based on computed tomography images were developed to predict bone fracture load with defects with different sizes, which were located in the medial, lateral, anterior, and posterior region of the proximal tibia. Critical defect size was identified using One-sample t-test to assess if the mean difference between the bone strength for a defect size was significantly different from the intact bone strength. Then, the defects larger than critical size were reconstructed with cement and the mechanics of the bone-cement interface (BCI) was investigated to find the regions prone to separation at BCI. A significant increase in fracture risk was observed for the defects larger than 20 mm, which were located in the medial, lateral and anterior regions, and defects larger than 25 mm for those located in the posterior region of the proximal tibia. Furthermore, it was found that the highest and lowest fracture risks were associated with defects located in the medial and posterior regions, respectively, highlighting the importance of selecting the initial location of a cortical window for tumor removal by the surgeon. The results of the BCI analysis showed that the location and size of the cement had a direct impact on the extent of damage and its distribution. Identification of critical regions susceptible to separation at BCI, can provide critical comments to surgeons in selecting the optimal cement augmentation technique, which may ultimately prevent unnecessary surgical intervention, such as using screws and pins.

Fracture risks associated with sodium-glucose cotransporter-2 inhibitors in type 2 diabetes patients across eGFR and albuminuria categories: A population-based study in Hong Kong

AimsTo evaluate major osteoporotic fracture (MOF) risk among type 2 diabetes patients treated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) across eGFR and albuminuria categories. MethodsA population-based cohort of type 2 diabetes patients started on SGLT2i or dipeptidyl peptidase-4 inhibitors (DPP4i) during 2007–2020 was identified from Hong Kong Hospital Authority database. One-to-one propensity score matching was applied to match each SGLT2i user with one DPP4i user. The primary outcomes were 180- and 365-day risks of MOF. Cox proportional hazard regression models were used to estimate hazard ratios (HR). ResultsA total of 28,696 patients (14,348 in each group) were included. Over 180-day follow-up, MOF occurred in 25 (0.17 %) SGLT2i users and 24 (0.17 %) DPP4i users (incidence of 4.07 and 3.63/1,000 person-years, respectively). At 365 days, MOF occurred in 43 (0.30 %) SGLT2i users and 44 (0.31 %) DPP4i users (incidence of 4.16 and 3.64/1,000 person-years, respectively). Risks of MOF were comparable between two groups at both 180 days (HR = 1.13, 95 %CI 0.65–1.98, P = 0.67) and 365 days (HR = 1.15, 95 %CI 0.75–1.75, P = 0.52). Subgroup analyses were consistent across age, sex, eGFR, albuminuria, or KDIGO categories. ConclusionsOur study did not reveal a statistically significant increase in fracture risk with SGLT2i use compared with DPP4i among type 2 diabetes patients, across eGFR and albuminuria categories.

Smoking and fracture risk in men: a meta-analysis of cohort studies, using both frequentist and Bayesian approaches

Past studies indicate that men are more likely to smoke and be at higher risk of smoking-related conditions than women. Our research aimed, through meta-analysis, to assess the association between smoking and fracture risk in men. The following databases were searched, including MEDLINE, EMBASE, Scopus, PsycINFO, ISI Web of Science, Google Scholar, WorldCat, and Open Grey, for identifying related studies. A random-effects model was used to pool the confounder-adjusted relative risk (R.R.). Frequentist and Bayesian hierarchical random-effects models were used for the analysis. The heterogeneity and publication bias were evaluated in this study. Twenty-seven studies met the inclusion criteria. Overall, smoking is associated with a significantly increased risk of fracture in both the frequentist approach (R.R., 1.37; 95% confidence interval: 1.22, 1.53) and the Bayesian approach (R.R., 1.36; 95% credible interval: 1.22, 1.54). Significant heterogeneity was observed in the meta-analysis (Higgin's I2 = 83%) and Cochran's Q statistic (p < 0.01). A significant association was also observed in multiple pre-specified sensitivity and subgroup analyses. Similar results were observed in the group containing a large sample size (≥ 10,000 participants), and the group has a small sample size (< 10,000 participants); the pooled R.R was 1.23 (95% confidence interval, 1.07–1.41) and 1.56 (95% confidence interval, 1.37–1.78), respectively. With the Bayesian method, the effect size was 1.23 (95% credible interval, 1.05, 1.45) for the large sample size group and 1.57 (95% credible interval, 1.35, 1.82) for the small sample size group. Smoking is associated with a significant increase in fracture risk for men. Thus, smoking cessation would also greatly reduce fracture risk in all smokers, particularly in men.

Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis.

Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis. A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002-2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1-30, 31-60, and>60days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications. A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66-2.12), in the 31-60-day period (1.73, 95% CI 1.48-2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47-1.91). The risks of fracture were greater in men and older patients. The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.

Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis

Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage. Systematic review and meta-analysis. Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D. Observational studies. Data extraction was conducted by 1 reviewer and checked by a second reviewer. MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs. 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients (<65 years) had higher relative risk (RR, 7.66; 95% CI, 2.76-21.26) than older patients (>65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures. We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures. Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.

High Plasma Sphingosine 1-phosphate Levels Predict Osteoporotic Fractures in Postmenopausal Women: The Center of Excellence for Osteoporosis Research Study.

BackgroundHigher sphingosine 1-phosphate (S1P) plasma levels are associated with decreased bone mineral density (BMD), and increased risk of prevalent vertebral fracture. So, we hypothesized that postmenopausal women with increased baseline plasma S1P levels have a greater risk for future incident fracture (osteoporosis-related fractures [ORFs]).MethodsThis study was conducted in a prospective longitudinal cohort of 707 women recruited in 2004 and followed up annually for a mean period of 5.2±1.3 years. They were postmenopausal (aged ≥50 years). The primary outcome measure was the time to the first confirmed ORF event using radiographs and/or a surgical report.ResultsThe plasma S1P levels (µmol/L) were significantly higher in the women with incident fracture (7.23±0.79) than in those without ORFs (5.02±0.51; P<0.001). High S1P levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the hazard ratio (HR) was 6.12 (95% confidence interval [CI], 4.92−7.66) for each 1-standard deviation increase in plasma S1P levels. The women in the highest quartile of S1P levels had a significant increase in fracture risk (HR, 9.89; 95% CI, 2.83−34.44). Results were similar when we compared plasma S1P levels at the 1-year visit.ConclusionsThe associations between plasma S1P levels and fracture risk were independent of BMD and other confounders. These findings demonstrate that high plasma S1P level at baseline and at years 1 to 5 is a strong and independent risk factor for future [ORFs] among postmenopausal women and could be a useful biomarker for fracture risk assessment in this population.

Antidepressant Exposure and Risk of Fracture Among Medicaid-Covered Youth.

This study examines the association between antidepressant use and risk of fracture in depressed youth and assesses whether fracture incidence varies over the course of antidepressant treatment. A retrospective cohort analysis of Ohio Medicaid claims data was conducted for youth ages 6-17 years with a new episode of ICD-9-diagnosed depression from 2001-2009. The primary outcome variable was time to fracture. Fracture rates were compared between depressed youth treated with antidepressant medication and untreated depressed youth. Time categories of no use, past use, and current use were compared. Of 50,673 depressed youths, 5,872 (11.6%) experienced a fracture. Of those who had a fracture, 2,228 (37.9%) were exposed to antidepressants, 80% of which were selective serotonin reuptake inhibitors. The adjusted hazard ratio (HR) was 3% higher in those currently prescribed antidepressants (HR = 1.03; 95% CI, 1.00-1.06; P = .03). The risk ratio (RR) for adjusted fracture rates per 10,000 persons was twice as high during the first 30 days of antidepressant use compared to the other time periods (RR = 2.0; 95% CI, 1.2-3.3; P = .007). The number of fractures for those with past antidepressant use did not differ from those with no history of antidepressant use. Antidepressant use may be associated with a small but significant increase in fracture risk, particularly within the first 30 days of treatment. Findings underscore a need for additional prospective and mechanistic research. Prescribers should consider other risks for fracture in antidepressant-treated youth, particularly disability and the concomitant use of other medications that increase fracture risk.

The Effect of Quantitative Computed Tomography Acquisition Protocols on Bone Mineral Density Estimation.

Osteoporosis is characterized by bony material loss and decreased bone strength leading to a significant increase in fracture risk. Patient-specific quantitative computed tomography (QCT) finite element (FE) models may be used to predict fracture under physiological loading. Material properties for the FE models used to predict fracture are obtained by converting grayscale values from the CT into volumetric bone mineral density (vBMD) using calibration phantoms. If there are any variations arising from the CT acquisition protocol, vBMD estimation and material property assignment could be affected, thus, affecting fracture risk prediction. We hypothesized that material property assignments may be dependent on scanning and postprocessing settings including voltage, current, and reconstruction kernel, thus potentially having an effect in fracture risk prediction. A rabbit femur and a standard calibration phantom were imaged by QCT using different protocols. Cortical and cancellous regions were segmented, their average Hounsfield unit (HU) values obtained and converted to vBMD. Estimated vBMD for the cortical and cancellous regions were affected by voltage and kernel but not by current. Our study demonstrated that there exists a significant variation in the estimated vBMD values obtained with different scanning acquisitions. In addition, the large noise differences observed utilizing different scanning parameters could have an important negative effect on small subregions containing fewer voxels.

Comparison between frailty index of deficit accumulation and fracture risk assessment tool (FRAX) in prediction of risk of fractures

A frailty index (FI) of deficit accumulation could quantify and predict the risk of fractures based on the degree of frailty in the elderly. We aimed to compare the predictive powers between the FI and the fracture risk assessment tool (FRAX) in predicting risk of major osteoporotic fracture (hip, upper arm or shoulder, spine, or wrist) and hip fracture, using the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort. There were 3985 women included in the study, with the mean age of 69.4years (standard deviation [SD]=8.89). During the follow-up, there were 149 (3.98%) incident major osteoporotic fractures and 18 (0.48%) hip fractures reported. The FRAX and FI were significantly related to each other. Both FRAX and FI significantly predicted risk of major osteoporotic fracture, with a hazard ratio (HR) of 1.03 (95% confidence interval [CI]: 1.02–1.05) and 1.02 (95% CI: 1.01–1.04) for per-0.01 increment for the FRAX and FI respectively. The HRs were 1.37 (95% CI: 1.19–1.58) and 1.26 (95% CI: 1.12–1.42) for an increase of per-0.10 (approximately one SD) in the FRAX and FI respectively. Similar discriminative ability of the models was found: c-index=0.62 for the FRAX and c-index=0.61 for the FI. When cut-points were chosen to trichotomize participants into low-risk, medium-risk and high-risk groups, a significant increase in fracture risk was found in the high-risk group (HR=2.04, 95% CI: 1.36–3.07) but not in the medium-risk group (HR=1.23, 95% CI: 0.82–1.84) compared with the low-risk women for the FI, while for FRAX the medium-risk (HR=2.00, 95% CI: 1.09–3.68) and high-risk groups (HR=2.61, 95% CI: 1.48–4.58) predicted risk of major osteoporotic fracture significantly only when survival time exceeded 18months (550days). Similar findings were observed for hip fracture and in sensitivity analyses. In conclusion, the FI is comparable with FRAX in the prediction of risk of future fractures, indicating that measures of frailty status may aid in fracture risk assessment and fracture prevention in the elderly. Further evidence from randomized controlled trials of osteoporosis medication interventions is needed to support the FI and FRAX as validated measures of fracture risk.

Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management.

Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6–12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation.

P233 Long-term Impact Of Inhaled Corticosteroids On Bone Mineral Density And Fracture Risk In Patients With Asthma: Systematic Review And Meta-analysis

Background A recent meta-analysis of 16 randomised controlled trials (RCTs) and 7 observational studies demonstrated a modest but statistically significant increase in fracture risk with inhaled corticosteroid (ICS) use in chronic obstructive pulmonary disease. However, it is not clear whether ICS use has similar skeletal adverse effects in patients with asthma. We aimed to evaluate the association between ICS and fractures and changes in bone mineral density when used for >12 months in asthma. Methods We initially searched MEDLINE and EMBASE in July 2013, and performed an updated PubMed search in June 2014. We used a combination of search terms involving drug name and adverse effects of interest, and we also hand-searched reference lists of existing systematic reviews and trial reports. We selected RCTs and controlled observational studies of any ICS vs non-ICS control treatment for asthma (at least 52 weeks duration). Meta-analysis of odds ratios was conducted using RevMan 5.3 with the primary outcome measure being fracture events. We also analysed mean differences in bone mineral density (gram per cm squared) using inverse variance method. Heterogeneity was assessed using the I2 statistic. Results We selected nine RCTs and 11 observational studies for the meta-analysis. There was no significant association between ICS and fractures in children in one RCT, or in a pooled analysis of two observational studies, (OR 1.02, 95% CI 0.94–1.10). No significant fracture risk in adults was reported in 4 observational studies (pooled OR 1.09, 95% CI 0.45–2.62). Meta-analysis of bone mineral density at the lumbar spine did not show significant reductions with ICS use in children (three RCTs and three observational studies), or in adults (three RCTs and four observational studies). Similarly, meta-analysis of bone mineral density at the neck of femur in adults did not demonstrate significant reductions compared to control (three RCTs and four observational studies). Conclusion In our systematic review of 20 studies, use of ICS for >12 months in patients with asthma was not associated with statistically significant adverse effects on bone mineral density or fractures.

Association between use of antiepileptic drugs and fracture risk: A systematic review and meta-analysis

BackgroundIt has been shown that antiepileptic drugs (AEDs) may have a detrimental effect on bone health and translate into an increased risk of bone fracture. We aimed to comprehensively evaluate the association between use of AEDs and fracture risk. MethodsWe searched NCBI (PubMed), ISI Web of Science, the Cochrane Library and EMBASE databases for studies reporting fracture risk among users of AEDs. Random-effects meta-analysis was used to pool results across studies. ResultsTwenty-two studies met the inclusion criteria. Overall, there was a significant increase in fracture risk among users of AEDs involving 1,292,910 participants, with a mean/median age of 36–82years (relative risk (RR)=1.86; 95% confidence interval (CI) 1.62–2.12). When we limited the studies to those on osteoporosis-related fractures, the RR was still significant. Both liver enzyme-inducing antiepileptic drugs (LEI AEDs) and non-LEI AEDs were associated with an increase in fracture risk, although the estimate for LEI AEDs was higher than that of non-LEI AEDs (RR=1.18; 95% CI 1.11–1.25). For some specific AEDs, use of phenobarbiturate (PB), topiramate (TPM) and phenytoin (PHT) suggested an increase in fracture risk of 78%, 39% and 70%, respectively. ConclusionsThe study suggests a robust association between use of AEDs and fracture risk (particularly for LEI AEDs). It also suggests that several specific AEDs such as PB, TPM and PHT may be associated with an increased risk of fracture.

Hip Fracture Risk and Cadmium in Erythrocytes: A Nested Case–Control Study with Prospectively Collected Samples

Several studies have investigated the relation between bone mass density and cadmium exposure, but only few studies have been performed on fractures and biomarkers of cadmium. This study analyzed the association between hip fracture risk and cadmium in erythrocytes (Ery-Cd). Prospective samples from the Northern Sweden Health and Disease Study's biobank were used for 109 individuals who later in life had sustained a low-trauma hip fracture, matched with two controls of the same age and gender. The mean concentration of Ery-Cd (±SD) in case samples was 1.3 ± 1.4 versus 0.9 ± 1.0 μg/L in controls. The odds ratio (OR) was 1.63 [95% confidence interval (CI) 1.10-2.42] for suffering a hip fracture for each microgram per liter increase in Ery-Cd. However, when taking smoking into consideration (never, former, or current), neither Ery-Cd nor smoking showed a statistically significant increase in fracture risk. Using multiple conditional logistic regression with BMI, height, and smoking, the estimated OR for a 1-μg/L increase in Ery-Cd was 1.52 (95% CI 0.77-2.97). Subgroup analysis showed an increased fracture risk among women (OR = 1.94, 95% CI 1.18-3.20, for a 1 μg/L increase), which also remained in the multiple analysis (OR = 3.33, 95% CI 1.29-8.56). This study shows that fracture risk is associated with Ery-Cd. It is, however, not possible to draw firm conclusions on whether cadmium is the causal factor or whether other smoking-related factors cause this association. Subgroup analysis shows that cadmium is a risk factor for hip fracture among women.

Association between use of benzodiazepines and risk of fractures: a meta-analysis

Benzodiazepines (BZDs) are some of the most commonly prescribed drugs in the world. It has been shown that BZD use could be associated with increased fracture risk. However, studies on the use of BZDs and fracture risk have yielded inconsistent results. Results from the present meta-analysis show that BZD use is associated with a moderate and clinically significant increase in the risk of fractures. The relationship between the use of BZDs and fracture risk has been neither well identified nor summarized. This meta-analysis reports on the use of BZDs, especially short-acting BZDs, and their correlation with a moderate and clinically significant increase in fracture risk. This analysis will provide evidence for clinicians to consider fracture risk when prescribing BZDs among the elderly population. This study was conducted to determine whether people who take BZDs are at an increased fracture risk. A systematic search of studies published through January 2013 was conducted using MEDLINE, EMBASE, OVID, and ScienceDirect. Case-control and cohort studies that assessed the relationship between BZD use and the risk of fractures were identified. Literature searches, study selections, methodological assessments, and data mining were independently conducted by two reviewers. Disagreements were resolved by consensus. STATA 12.0 software was used for the meta-analysis. Random effects models were used for pooled analysis due to heterogeneity among the studies. There were 25 studies, including 19 case-control studies and 6 cohort studies, that met the inclusion criteria. Overall, the results of the meta-analysis indicated that BZD use was associated with a significantly increased fracture risk (relative risk (RR) = 1.25; 95% confidence intervals (CI), 1.17-1.34; p < 0.001). Increased fracture risk associated with BZD use was observed in participants aged ≥65 years old (RR = 1.26; 95% CI, 1.15-1.38; p < 0.001). When only hip fractures were included as the outcome measure, the RR increased to 1.35. However, subgroup meta-analyses showed that there was no significant association between BZD use and fracture risk in Eastern countries (RR = 1.27; 95% CI, 0.76-2.14; p = 0.362) as well as between long-acting BZD use and risk of fractures (RR = 1.21; 95% CI, 0.95-1.54; p = 0.12). After accounting for publication bias, we observed that the overall association between BZD use and fracture risk to be slightly weaker (RR = 1.21; 95% CI, 1.13-1.30) but still significant. The results of this meta-analysis demonstrate that the use of BZD, especially short-acting BZD, is associated with a moderate and clinically significant increase in fracture risk. However, large prospective studies that minimize selection bias are necessary to determine a more accurate fracture risk associated with BZD use.

Association of Antiepileptic Drugs With Nontraumatic Fractures

To explore the relationship between antiepileptic drug (AED) use and nontraumatic fractures in those aged 50 years and older. Retrospective matched cohort study. A total of 15,792 persons, identified through the Population Health Research Data Repository from Manitoba, Canada, with nontraumatic fractures of the wrist, hip, and vertebra occurring between 1996 and 2004. Each patient was matched for age, sex, ethnicity, and comorbidity with up to 3 controls (n = 47,289). Prior AED use (carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin) was determined from pharmacy data in the repository. Odds ratios (OR) for fracture from AED exposure were adjusted for sociodemographic and comorbidity factors known to affect fracture risk. A significant increase in fracture risk was found for most of the AEDs being investigated (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted ORs ranged from 1.24 (95% confidence interval [CI], 1.05-1.47) for clonazepam to 1.91 (95% CI, 1.58-2.30) for phenytoin. The only AED not associated with increased fracture risk was valproic acid (adjusted OR, 1.10; 95% CI, 0.70-1.72). Most AEDs were associated with an increased risk of nontraumatic fractures in individuals aged 50 years or older. Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population.

The value of lateral vertebral assessment in patients receiving glucocorticoids referred for dual x-ray absorptiometry (DXA)

Glucocorticoids are widely used to treat a number of medical disorders. Prolonged steroid use can cause osteoporosis can lead to a significant increase in fracture risk of the hip and spine. Vertebral fractures can indicate higher risk of both subsequent vertebral and non-vertebral fractures. Lateral vertebral assessment (LVA) can highlight patients who have asymptomatic vertebral fractures.A retrospective audit of patients referred for DXA who have been taking oral glucocorticoids for >3 months. DXA was performed and included total hip, femoral neck, lumbar spine and LVA.657 patients on glucocorticoids for >3 months were reviewed. Overall, vertebral fractures were present in 19.3%. Mean age 59.8 (±18) yrs with 72.3% patients being female. Common reasons for being on glucocorticoids included rheumatoid arthritis (47.1%), COPD (25.1%), gastrointestinal disorder (14.7%), bone marrow and renal transplants (7.5%) and inflammatory disorders (5.6%). 44.7% of patients had osteoporosis with the spine being the most likely site to be affected (35.5%). 31.2% of these patients were on treatment on referral. Patients who had vertebral were older and had more severe osteoporosis (p<0.001). 7.3% of overall fractures occured in the osteopenic group.Vertebral fractures were present in almost 1/5 osteopenic patients. LVA identifed osteopenic patients who would be an increased risk of subsequent fracture. As substantial bone loss occurs in the first 6 months of glucocorticoid treatment, these high-risk patients should be prioritised for osteoporosis treatment. Disclosure of Interest: None declared

Recommendations for the Registration of Agents to be Used in the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis: Updated Recommendations from the Group for the Respect of Ethics and Excellence in Science

The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). Consensus discussion of the committee. With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.

Long-term fracture risk following renal transplantation: a population-based study.

Abnormal bone metabolism is a recognized complication of end-stage renal disease, but fracture risk following renal transplantation has not been well quantified. We followed the 86 Olmsted County, Minnesota, residents who underwent initial renal transplantation in 1965-1995 for 911 person-years (median, 10.6 years per subject) in a retrospective cohort study. Fractures, and possible risk factors, were assessed through review of each subject's complete community medical records. Altogether, 117 fractures were observed during follow-up extending to 33 years. The cumulative incidence of any fracture at 15 years was 60% versus 20% expected ( P<0.001). There was a significantly increased risk of fractures generally [standardized incidence ratio (SIR), 4.8; 95% CI, 3.6-6.4] and vertebral (SIR, 23.1; 95% CI, 12.3-39.6) and foot fractures (SIR, 8.4; 95% CI, 5.1-12.9) especially. Age at first transplantation, renal failure due to diabetes, pancreas transplantation, peripheral neuropathy, peripheral vascular disease and blindness were all associated with overall fracture risk. In a multivariate analysis, however, only age and diabetic nephropathy were independent predictors of fracture risk generally, while higher activity status was protective. Diabetes was the only independent predictor of lower limb fractures, whereas age and osteoporosis history predicted vertebral fractures. Cumulative corticosteroid dosage was not associated with increased fracture risk in this analysis. Despite the fact that our patients had few risk factors for preexisting bone disease attendant to postmenopausal osteoporosis, prior corticosteroid use or renal osteodystrophy, these data indicate that renal transplantation is associated with a significant increase in fracture risk among unselected patients in the community. Diabetic patients, particularly, experience excess lower limb fractures. Patients and their care providers should be aware of this elevated fracture risk, which continues long-term.