The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density : The MESA study.

Retinopathy and albuminuria are associated with hip fracture risk. We investigated whether these disorders and endothelial dysfunction (which underlies microvascular diseases) were associated with low trabecular bone density. No significant associations were found, suggesting that microvascular diseases are not related to fracture risk through low trabecular bone density. PURPOSE: Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. METHODS: Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5 min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. RESULTS: We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. CONCLUSION: We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures.

Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.

Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture. INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture. METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive). RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90). CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4+CD28- T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

Predictors of lower extremity fracture-related amputation in persons with traumatic spinal cord injury: a case-control study.

STUDY DESIGN: This is a retrospective case-control study. OBJECTIVES: To identify predictors of lower extremity (LE) long bone fracture-related amputation in persons with traumatic spinal cord injury (tSCI). SETTING: US Veterans Health Administration facilities (2005-2015). METHODS: Fracture-amputation sets in Veterans with tSCI were considered for inclusion if medical coding indicated a LE amputation within 365 days following an incident LE fracture. The authors adjudicated each fracture-amputation set by electronic health record review. Controls with incident LE fracture and no subsequent amputation were matched 1:1 with fracture-amputation sets on site and date of fracture (±30 days). Multivariable conditional logistic regression determined odds ratios (OR) and 95% confidence intervals (CI) for potential predictors (motor-complete injury; diabetes mellitus (DM); peripheral vascular disease (PVD); smoking; primary (within 30 days) nonsurgical fracture management; pressure injury and/or infection), controlling for age and race. RESULTS: Forty fracture-amputation sets from 37 Veterans with LE amputations and 40 unique controls were identified. DM (OR = 26; 95% CI, 1.7-382), PVD (OR = 30; 95% CI, 2.5-371), and primary nonsurgical management (OR = 40; 95% CI, 1.5-1,116) were independent predictors of LE fracture-related amputation. CONCLUSIONS: Early and aggressive strategies to prevent DM and PVD in tSCI are needed, as these comorbidities are associated with increased odds of LE fracture-related amputation. Nonsurgical fracture management increased the odds of LE amputation by at least 50%. Further large, prospective studies of fracture management in tSCI are needed to confirm our findings. Physicians and patients should consider the potential increased risk of amputation associated with non-operative management of LE fractures in shared decision making.

Reasons for Initiation and Discontinuation of Pharmacological Therapies for Osteoporosis in Veterans with Spinal Cord Injury and Disorders.

INTRODUCTION: Medications for osteoporosis have not been reported to reduce fracture rates in patients with spinal cord injury and disorders (SCI/D), yet these medications are still prescribed. Clinical decision-making underscoring the initiation and discontinuation of osteoporosis medications in SCI/D remains poorly understood. METHODOLOGY: Veterans with a SCI/D with at least one prescription for an osteoporosis medication (bisphosphonate, calcitonin, denosumab, raloxifene, and teriparatide) who received healthcare within Veterans Affairs (VA) from 2005 to 2015 were identified using VA administrative databases. A 10% subsample of Veterans was selected for electronic health record review. RESULTS: Two hundred and sixty-seven Veterans with 330 prescriptions underwent electronic health record review. Bisphosphonates were the most frequently prescribed medication for osteoporosis (n = 223, 67.6%). Of the 187 Veterans with prescriptions for prevention or treatment of osteoporosis, the primary reason for initiation was Dual Energy X-ray Absorptiometry (DXA) scan with osteopenia or osteoporosis (n = 119, 63.6% of Veterans), primarily at the hip (81.0% of DXAs). The majority (79.0%) of DXAs were "screening tests," with SCI/D being the sole reason for the scan. Fractures (n = 51, 27.3%) and fall risk concerns (n = 29, 15.5%) were other major reasons for initiation. On average, oral bisphosphonates were filled for <3 yr, with medication-related side effects (n = 23, 15.8% of bisphosphonates discontinued), predominately gastrointestinal (n = 17, 73.9% of reported side effects), the most common reason for discontinuation. Drug holidays occurred in 14.3% of 35 oral bisphosphonates used for ≥5 yr. No cases of osteonecrosis of the jaw were found. There was one case of an atypical femoral fracture which could not be confirmed. CONCLUSIONS: The decision to initiate pharmacological therapies in SCI/D is primarily based on osteopenia or osteoporosis at the hip by screening DXAs. Gastrointestinal side effects are the major reason for discontinuation of oral bisphosphonates. New therapies for osteoporosis in SCI/D are needed.

Factors influencing providers' decisions on management of bone health in people with spinal cord injury.

STUDY DESIGN: Survey. OBJECTIVES: Managing osteoporosis in persons with chronic spinal cord injury (SCI) is difficult as little evidence exists regarding effective strategies. We examined the effect of key factors on providers' bone health management decisions in persons with SCI. SETTING: USA. METHODS: Providers reviewed blocks of 9 hypothetical cases that varied on four factors: osteoporosis, osteopenia, or normal bone mineral density using dual-energy X-ray absorptiometry (DXA); DXA region of interest (lumbar spine, hip, knee), prior lower extremity fracture; and no or limited ambulation. They indicated how likely they would recommend pharmacological management, what treatment(s) they would recommend, and whether they would request another DXA before treatment. RESULTS: Eighty-two healthcare providers completed the survey. Treatment recommendations for bisphosphonates and Vitamin D/calcium supplements, respectively, were more likely if there was a prior fracture (OR: 2.65, 95%CI: 1.76-3.99, p < 0.0001; OR: 2.96, 95%CI: 1.40-6.26, p = 0.004) and if a DXA scan found osteopenia (OR: 2.23, 95%CI: 1.41-3.54, p = 0.001; OR: 6.56, 95%CI: 2.71-15.85, p < 0.0001) or osteoporosis (OR: 12.08, 95%CI: 7.09-20.57, p < 0.0001; OR: 4.54, 95%CI: 2.08-9.90, p < 0.0001). Another DXA scan was more likely to be requested if there was a prior fracture (OR: 1.75, 95%CI: 1.10-2.78, p = 0.02) but less likely if the person was nonambulatory (OR: 0.41, 95%: 0.19-0.90, p = 0.03). CONCLUSIONS: Prior fracture and DXA findings influenced treatment recommendations for bone health management in SCI. Reliance on lumbar spine scans to determine bone loss and treatment identifies a knowledge gap for which future education is required.

Association of Bisphosphonate Therapy With Incident of Lower Extremity Fractures in Persons With Spinal Cord Injuries or Disorders.

OBJECTIVE: To investigate the association between prescriptions for bisphosphonates; calcium and vitamin D supplements; and receipt of dual-energy x-ray absorptiometry (DXA) screening, and incident fracture risk in men and women with a spinal cord injury (SCI) or disorder (SCID). DESIGN: Propensity-matched case-control analyses. SETTING: United States Veterans Affairs (VA) facilities. PARTICIPANTS: A total of 7989 men and 849 women with an SCID included in VA administrative databases between October 1, 2005 and October 1, 2015 were identified (N=8838). Cases included 267 men and 59 women with a bisphosphonate prescription propensity matched with up to 4 controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incident lower extremity fractures. RESULTS: There was no significant association between prescriptions for bisphosphonates and incident lower extremity fractures in men (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.62-1.77) or women (OR, 1.02; 95% CI, 0.28-3.75). In men, similar null associations were seen among those who were adherent to bisphosphonate therapy (OR, 1.25; 95% CI, 0.73-2.16), were concomitant users of vitamin D and calcium and a bisphosphonate (OR, 1.05; 95% CI, 0.57-1.96), had more than 1 fracture on different dates during the study period (OR, 0.13; 95% CI, 0.02-1.16) and in those who had undergone DXA testing prior to the date of the bisphosphonate prescription and incident fracture (OR, 1.26; 95% CI, 0.69-2.32). CONCLUSIONS: In men with a traumatic SCI and women with a traumatic SCID, bisphosphonate therapies for osteoporosis do not appear to significantly affect fracture risk. Adequately powered randomized controlled trials are needed to definitively demonstrate efficacy of bisphosphonates for fracture prevention in this population. There is a compelling need to identify new medications to prevent fractures in this high-risk population.

Rheumatoid Arthritis and Mortality in End Stage Renal Disease.

OBJECTIVE: To determine whether rheumatoid arthritis (RA) is a risk factor for cardiovascular disease (CVD) events, all-cause mortality and cardiovascular mortality in End Stage Renal Disease (ESRD). METHODS: Cohort study of adult patients with ESRD in the United States Renal Data System (USRDS) with RA and a 5% random sample of those without RA. CVD events, all-cause mortality and cardiovascular mortality were determined in those with RA compared to those without RA using Cox Proportional Hazards modeling. RESULTS: 2,824 subjects, 407 with RA and 2,417 without RA, were included in the analyses. The duration of the study was up to 5 years, depending on mortality and initiation of dialysis. There were no significant differences in CVD events by RA status (n = 311 [76.4% RA] vs. n = 1936 [80.1% without RA], p = 0.09). Subjects with RA had a significantly shorter mean time in months from start of dialysis to an incident CVD event (20.1 ± 12.2 vs. 21.2 ± 14.1, p < 0.01) than those without RA. In multivariable adjusted models, RA was not associated with an increased risk for all-cause mortality (aHR = 1.09, 95%CI 0.94-1.27) or cardiovascular mortality (aHR = 0.95, 95% CI 0.74-1.22) within 5 years. Risk factors for all-cause mortality and cardiovascular mortality in RA included older age and a higher Charlson comorbidity index (CCI). CONCLUSIONS: Clinicians should be aware that persons with RA who develop ESRD incur cardiac events sooner than the general population. However, RA is not an independent risk factor for all-cause or cardiovascular mortality in ESRD.

The Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.

In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p ≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.

Psychosis as an adverse effect of monoclonal antibody immunotherapy.

Immunotherapy is a "hot" area in schizophrenia research. Monoclonal antibodies (mAbs) target specific immune molecules, and therefore offer an unparalleled opportunity to directly test the hypothesis that immune dysfunction plays a causal role in psychopathology in schizophrenia. Cytokine-based immunotherapy for other disorders has been associated with a range of neuropsychiatric adverse effects, including psychosis. The purpose of the present study was to investigate the prevalence of spontaneously-reported adverse drug reactions of psychotic symptoms for mAbs, and to calculate odds of psychosis for individual mAbs, compared to bevacizumab, which does not directly target the immune system. We searched the publicly available VigiBase, a World Health Organization global individual case safety report database from inception through February 2019 for which a mAb was the suspected agent of an adverse drug reaction (ADR). We investigated 43 different mAbs, comprising 1,298,185 case reports and 2025 psychosis ADRs. For individual mAbs, the prevalence of psychosis ADRs ranged from 0.1 to 0.4%. Seven mAbs were associated with a significantly increased odds of psychosis (OR = 1.42-2.22), including two agents that target CD25. Eight mAbs were associated with a significantly decreased odds of psychosis (OR = 0.28-0.75), including 4 anti-TNF-α agents. Our results suggest that psychosis is a relatively rare adverse effect of mAb treatment, but risks vary by specific agents. Findings indicate that modulating the immune system may sometimes lead to the development of psychosis. Ongoing clinical trials of adjunctive mAb immunotherapy in schizophrenia will provide valuable insights into the role of the immune system in psychosis.

Bone Mineral Density Testing in Spinal Cord Injury: 2019 ISCD Official Position.

Spinal cord injury (SCI) causes rapid osteoporosis that is most severe below the level of injury. More than half of those with motor complete SCI will experience an osteoporotic fracture at some point following their injury, with most fractures occurring at the distal femur and proximal tibia. These fractures have devastating consequences, including delayed union or nonunion, cellulitis, skin breakdown, lower extremity amputation, and premature death. Maintaining skeletal integrity and preventing fractures is imperative following SCI to fully benefit from future advances in paralysis cure research and robotic-exoskeletons, brain computer interfaces and other evolving technologies. Clinical care has been previously limited by the lack of consensus derived guidelines or standards regarding dual-energy X-ray absorptiometry-based diagnosis of osteoporosis, fracture risk prediction, or monitoring response to therapies. The International Society of Clinical Densitometry convened a task force to establish Official Positions for bone density assessment by dual-energy X-ray absorptiometry in individuals with SCI of traumatic or nontraumatic etiology. This task force conducted a series of systematic reviews to guide the development of evidence-based position statements that were reviewed by an expert panel at the 2019 Position Development Conference in Kuala Lumpur, Malaysia. The resulting the International Society of Clinical Densitometry Official Positions are intended to inform clinical care and guide the diagnosis of osteoporosis as well as fracture risk management of osteoporosis following SCI.

Associations of Biomarker-Calibrated Sodium and Potassium Intakes With Cardiovascular Disease Risk Among Postmenopausal Women.

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

Association of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

Screening and Treatment of Latent Tuberculosis Among Patients Receiving Biologic Agents: A National and International Survey of Rheumatologists.

OBJECTIVE: We sought to understand the current practice patterns of both US and international members of the American College of Rheumatology (ACR) in this regard. METHODS: A set of questionnaires developed by a focus group of faculties and fellows of the Rheumatology Division of University of Tennessee Health Science Center, Memphis, TN, was sent electronically using an online survey tool to 4433 rheumatologists who are ACR members in the United States and internationally. RESULTS: Seven hundred sixty-eight physicians out of 4433 ACR members responded to the electronic survey, with a response rate of 17.32%. The preferred screening method by most of the respondents was either tuberculin skin test (19%) or interferon γ release assay (32%) or both. For treatment of latent tuberculosis infection (LTBI) overall, 49% of the respondents would refer management to infectious disease specialist or the health department, 37% would initiate isoniazid for 9 or 12 months, and 14% would use isoniazid for 6 months. Approximately 60% of respondents would initiate anti-tumor necrosis factor therapy after being on LTBI treatment for 1 month. The other respondents were almost equally divided among the 3 responses: 2, 3, 6, or 9 months. CONCLUSIONS: There is a large disagreement regarding the method used and how often to screen for LTBI after initiating biologic therapy and how soon biologic treatment would be started after initiating LTBI therapy. Another disagreement exists regarding the duration of LTBI therapy. The information obtained from the survey can be taken into account when ACR or other international member organizations formulate future recommendations regarding screening and treatment of LTBI.

Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in Western societies. Despite its significance, there are no well-proven pharmacological treatments. Two novel classes of potential pharmacotherapies are the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4I), collectively known as incretin-based therapies. These have several metabolic and anti-inflammatory actions that may be of benefit in NAFLD. The aim of this meta-analysis was to evaluate their efficacy via a structured retrieval and pooled analysis of relevant studies. METHODS: Studies were sourced from electronic databases and meeting abstracts. Main inclusion criteria were original studies investigating treatment of adults with NAFLD using GLP-1 RA/DPP-4I. Key outcomes were a change in serum alanine transaminase (ALT), as a marker of liver inflammation, and improvement in disease status measured by imaging or histology. RESULTS: Initial searching retrieved 1357 peer-reviewed articles and abstracts. Four studies met all inclusion and exclusion criteria. There were a total of 136 participants with NAFLD and concomitant type 2 diabetes mellitus (T2DM). Meta-analysis (random-effects model) revealed a significant decrease in serum ALT following treatment (mean reduction 14.1 IU/L, 95% confidence intervals [CI] 8.3-19.8, P < 0.0001). In two studies with imaging and tissue data, treatment was found to significantly reduce steatosis, inflammation, and fibrosis. CONCLUSION: The significant decrease in a key biochemical marker of hepatic inflammation following treatment with incretin-based therapies, as well as improvements in imaging and histology, suggests these agents may be effective options for managing NAFLD with comorbid T2DM.

Bone turnover in long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: We investigated the effects of demographic, lifestyle (self-reported smoking status and physical activity levels), cancer-related treatment factors (radiation and chemotherapy), and diet (calcium and vitamin D intake) on bone turnover and the relationship of bone turnover to lumbar spine bone mineral density (BMD) Z-scores (LS-BMD Z-scores) determined by quantitative computed tomography (QCT) in 418 ≥5-year survivors of childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Bone turnover was assessed by biomarkers including serum bone-specific alkaline phosphatase (BALP), osteocalcin (OC), and urinary N-telopeptide of type I collagen indexed to creatinine (NTX/Cr). The 215 males ranged in age from 9 to 36 years (median age 17 years). RESULTS: Age and tanner score were inversely associated with all biomarkers (BALP, OC, NTX/Cr) (P < 0.001). Males had higher BALP and OC than females (P < 0.001). Body mass index (BMI) was inversely associated with OC and NTX/Cr (P < 0.001). There was no significant association of biomarkers with lifestyle related factors, ALL treatment-related factors, dietary calcium, vitamin D, or LS-BMD Z-score. CONCLUSIONS: In this population of long-term survivors of ALL, bone turnover was significantly associated with age, gender, tanner stage, and BMI. ALL-related treatments did not influence bone turnover and bone turnover was not predictive of volumetric LS-BMD Z-score.

Thiazide use is associated with reduced risk for incident lower extremity fractures in men with spinal cord injury.

OBJECTIVE: To determine the association between thiazide use and lower extremity fractures in patients who are men with a spinal cord injury (SCI). DESIGN: Cohort study from fiscal years 2002 to 2007. SETTING: Medical centers. PARTICIPANTS: Men (N=6969) with an SCI from the Veterans Affairs (VA) Spinal Cord Dysfunction (SCD) Registry, including 1433 users of thiazides and 5536 nonusers of thiazides. INTERVENTION: Thiazide use versus nonuse. MAIN OUTCOME MEASURE: Incident lower extremity fractures. RESULTS: Among the men, 21% in the VA SCD Registry (fiscal years 2002-2007) included in these analyses used thiazide diuretics. There were 832 incident lower extremity fractures over the time period of this study: 110 fractures (7.7%) in 1433 thiazide users and 722 fractures (13%) in 5536 nonusers of thiazides. In unadjusted and adjusted models alike, thiazide use was associated with at least a one-quarter risk reduction in lower extremity fracture at any given point in time (unadjusted: hazard ratio (HR)=.75; 95% confidence interval (CI), .59-.94; adjusted: HR=.74; 95% CI, .58-.95). CONCLUSIONS: Thiazide use is common in men with SCI and is associated with a decreased likelihood for lower extremity fractures.

Predictors of fracture in middle-aged and older adults with type 2 diabetes and overweight or obesity.

CONTEXT: Persons with type 2 diabetes have increased fracture risk that existing fracture risk assessment tools underestimate. OBJECTIVE: Identify fracture predictors in persons with type 2 diabetes and overweight or obesity, considering traditional and diabetes-related risk factors. DESIGN: Secondary analysis of the Look AHEAD: Action for Health in Diabetes randomized clinical trial, with randomization from 2001-2004 and fracture follow-up until 2015. SETTING: Multicenter U.S. study. PARTICIPANTS: Men and women 45-75 years old with type 2 diabetes and body mass index≥25 kg/m2. EXPOSURES: Potential fracture predictors ascertained at randomization included traditional and diabetes-related risk factors (diabetes duration, diabetic neuropathy, antidiabetic medication use, hemoglobin A1c, and renal function). Total hip bone mineral density (BMD) was measured in a subcohort. MAIN OUTCOME MEASURE: All incident clinical fractures, ascertained by self-report and centrally adjudicated with medical records review. RESULTS: Over a median 12.2 years follow-up, 649 of the 4,703 participants experienced at least one clinical fracture. Thiazolidinedione use [hazard ratio (HR):1.22, 95% confidence interval (CI):1.02-1.46] and insulin use [HR:1.34, 95% CI:1.08-1.66] were significant diabetes-related predictors of all clinical fractures. When measured in a subcohort (n=1,285), total hip BMD was the strongest modifiable predictor of all clinical fractures [Per 1 standard deviation (SD)=0.1 g/cm2 increase, HR:0.47, 95% CI:0.39-0.58]. CONCLUSIONS: Thiazolidinedione and insulin use predict clinical fracture in middle-aged and older persons with type 2 diabetes and overweight or obesity. Evaluating BMD is advisable if these medications are prescribed. Fracture risk prediction tools may consider including thiazolidinedione and insulin use to refine prediction in this population.

Malunions following lower extremity fractures in veterans with a spinal cord injury/disorder.

BACKGROUND: Nearly 50% of all persons with a spinal cord injury/disorder (SCI/D) will sustain an osteoporotic fracture sometime in their life, with lower extremity fractures being the most common. There are a number of complications that can occur post fracture, including fracture malunion. To date, there have been no dedicated investigations of malunions among persons with SCI/D. OBJECTIVES: The primary objective of this study was to identify risk factors associated with fracture malunion among fracture-related (type of fracture, fracture location, initial fracture treatment) and SCI/D-related factors. Secondary objectives were to describe treatment of fracture malunions and complications following these malunions. METHODS: Veterans with SCI/D with an incident lower extremity fracture and subsequent malunion from Fiscal Year (FY) 2005-2015 were selected from the Veteran Health Administration (VHA) databases using International Classification of Diseases, 9th edition (ICD-9) codes for lower extremity fractures and malunion. These fracture malunion cases underwent electronic health record (EHR) review to abstract information on potential risk factors, treatments and complications for malunion. Twenty-nine cases were identified with a fracture malunion with 28 of them successfully matched with Veterans with a lower extremity fracture during FY2005-FY2014 without a malunion (matched 1:4) based on having an outpatient utilization date of care within 30 days of the fracture case. There was trend towards more nonsurgical treatment in the malunion group (n = 27, 96.43%) compared to the control group (n = 101, 90.18%) (P = 0.05), though fracture treatment proved not to be not associated with developing a malunion in univariate logistic regression analyses (OR = 0.30; 95% CI: 0.08-1.09). In multivariate analyses, Veterans with tetraplegia were significantly less likely (approximately 3-fold) to have a fracture malunion (OR = 0.38; 95% CI: 0.14-0.93) compared to those with paraplegia. Fracture malunion was significantly less likely to occur for fractures of the ankle (OR = 0.02; 95% CI: 0-0.13) or the hip (OR = 0.15; 95% CI: 0.03-0.56) compared to femur fractures. Fracture malunions were rarely treated. The most common complications following malunions were pressure injuries (56.3%) followed by osteomyelitis (25.0%). CONCLUSIONS: Persons with tetraplegia as well as fractures of the ankle and hip (compared to the femur) were less likely to develop a fracture malunion. Attention to prevention of avoidable pressure injuries following a fracture malunion is important.