Intraoperative Seizure Under General Anesthesia Not Detected by EEG: A Case Report.

Intraoperative seizures under general anesthesia are infrequent. However, seizure activity under general anesthesia confirmed by contemporaneous EEG has been reported. We describe the case of a 39-year-old female undergoing right frontal brain tumor resection who experienced an intraoperative seizure. Intraoperative neuromonitoring was utilized and included four channels of EEG, somatosensory evoked potentials (SSEP), and transcranial motor evoked potentials (MEP). During this operation, characteristic motor manifestations of a seizure occurred. However, the EEG did not demonstrate seizure activity due to limitations in EEG lead placement. Post-operatively in the ICU, motor manifestations of seizure activity continued, and subsequent EEG recordings demonstrated classic seizure activity. Due to the previous hemicraniectomy, corkscrew EEG electrodes were not placed over the right skull defect, thereby failing to detect the intraoperative seizure. Anesthesiologists should be aware that limitations with EEG electrode placement can fail to detect intraoperative seizures, and treatment to extinguish the seizure should proceed in an emergent fashion.

Electrocardiogram Changes Following Intravenous Bisphosphonate Infusion: A Systematic Review and Meta-Analysis.

Bisphosphonates are first-line treatments for several bone and mineral disorders. Studies have reported an increased incidence of serious atrial fibrillation in patients receiving bisphosphonates; however, uncertainty remains as to whether electrical disturbances are precipitated by bisphosphonates. We aimed to review the literature for studies reporting electrocardiogram (ECG) findings in patients receiving intravenous bisphosphonates for any indication. We searched MEDLINE and EMBASE from inception until January 14, 2023, for studies reporting ECG parameters after intravenous bisphosphonate infusion. We excluded studies that only reported atrial fibrillation. Study quality was assessed using the Newcastle-Ottawa scale. Continuous data were meta-analyzed if reported in at least two studies. Random-effects models were fitted and reported as standardized mean difference (SMD) with 95% confidence intervals (95% CIs). We found 1083 unique records, of which 11 met our inclusion and exclusion criteria. Studies had a low to low/moderate risk of bias. Six prospective cohort studies were included in the meta-analysis. Five studies used zoledronic acid, whereas one study used pamidronate. Most studies (n = 4) were conducted in postmenopausal women with osteoporosis, one study was conducted in patients with bone metastases, and one study in children with osteoporosis secondary to cerebral palsy. Study populations ranged from n = 15 to n = 116. Heart rate-corrected QT (QTc) was significantly longer post-infusion (SMD = 0.46 ms [95% CI 0.80 to 0.11]; n = 67 patients, k = 2 studies, τ2 = 0). There were no differences in heart rate, P wave (maximum), P wave (minimum), P wave dispersion, PR interval, QRS duration, QTc, QTc (maximum), QTc (minimum), and QTc dispersion. The correlation between pre- and post-infusion QTc was not significant (p = 0.93). Overall, there is a weak association between intravenous bisphosphonate infusion and a QTc interval prolongation. However, there is insufficient evidence to support an association between intravenous bisphosphonate and any ECG variable changes, which may precipitate atrial fibrillation. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Association between high-sensitivity cardiac troponin I and fall-related hospitalisation in women aged over 70 years.

OBJECTIVE: To examine the association between high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of myocardial injury, muscle function decline and 14.5-year fall-related hospitalisation risk in women aged over 70 years. METHODS: 1179 ambulatory community-dwelling women aged over 70 years with subclinical levels of hs-cTnI (ie, <15.6 ng/L), who were followed up for 14.5 years, were included. Samples for hs-cTnI were obtained in 1998. Fall-related hospitalisations were retrieved from linked health records. Muscle function measures, including handgrip strength and the Timed-Up-and-Go (TUG) test, were assessed in 1998 and 2003. RESULTS: Mean±SD age was 75.2±2.7 years. Over 14.5 years of follow-up, 40.4% (476 of 1179) experienced fall-related hospitalisation. Participants were categorised into four approximate hs-cTnI quartiles: quartile 1 (<3.6 ng/L), quartile 2 (3.6-4.4 ng/L), quartile 3 (4.5-5.8 ng/L) and quartile 4 (≥5.9 ng/L). Compared with those in Q1, women in Q4 were likely to experience fall-related hospitalisation (36.0% vs 42.8%). In a multivariable-adjusted model that accounted for CVD and fall risk factors, compared with women in Q1, those in Q4 had a 46% higher risk of fall-related hospitalisation (HR 1.46, 95% CI 1.08 to 1.98). Additionally, women in Q4 had slower TUG performance compared with those in Q1 (10.3 s vs 9.5 s, p=0.032). CONCLUSION: Elevated level of hs-cTnI was associated with slower TUG performance and increased fall-related hospitalisation risk. This indicates subclinical level of hs-cTnI can identify clinically relevant falls, emphasising the need to consider cardiac health during fall assessment in women aged over 70 years. TRIAL REGISTRATION NUMBER: ACTRN12617000640303.

Cardiovascular disease, muscle function, and long-term falls risk: The Perth Longitudinal Study of Ageing Women.

BACKGROUND: A few cross-sectional studies have highlighted inconsistent associations between cardiovascular disease (CVD) and musculoskeletal conditions. We sought to investigate the relationship between clinical CVD including subtypes, compromised muscle function, as well as incident self-reported and injurious falls in older women. MATERIALS AND METHODS: 1431 community-dwelling older women (mean age ± SD; 75.2 ± 2.7 years) were included in over 14.5 years of a prospective study, the Perth Longitudinal Study of Ageing in Women. CVD (up to 18-years prior to the baseline visit) and injurious fall hospitalizations over 14.5 years were obtained from linked health records. Self-reported falls for five years were obtained via a written adverse event diary posted every four months. Timed-Up-and-Go (TUG) test and hand grip strength were used to assess mobility and muscle strength, respectively. Mobility impairment was defined as TUG performance >10.2 sec and muscle weakness characterized as grip strength <22 kg. RESULTS: Over 5-years, 411 (28.7%) women reported a falls, while 567 (39.6%) were hospitalized due to an injurious fall over 14.5 years. Prior CVD events were associated with 32% (HR 1.32 95%CI, 1.06-1.64) and 29% (HR 1.29 95%CI, 1.07-1.56) increased risk of self-reported and injurious falls, respectively, in multivariable-adjusted models. When considering subtypes of CVD, only cerebrovascular disease was related to self-reported (HR 1.77; 95%CI, 1.15-2.72) and injurious falls requiring hospitalization (HR 1.51; 95%CI, 1.00-2.27). CVD was also associated with cross-sectional and prospective mobility impairments. However, no evidence for such relationships was observed for muscle weakness. CONCLUSIONS: Prevalent CVD events, particularly cerebrovascular disease, are related to an increased risk of long-term falls. These findings highlight the need to recognize increased falls risk in patients with CVD. Further, there is a need to understand whether incorporating prevalent CVD into falls screening tools improves risk stratification or affects model calibration.

Cardiac adverse events in bisphosphonate and teriparatide users: An international pharmacovigilance study.

BACKGROUND: Cardiovascular effects of osteoporosis medications have recently been highlighted. Although oral and intravenous bisphosphonates are assumed to have similar cardiovascular safety, few head-to-head comparisons exist. The cardiovascular safety of teriparatide is unknown. Aim We conducted a pharmacovigilance safety study of cardiac events using real-life adverse event reports from alendronate, zoledronic acid and teriparatide users. METHODS: Adverse drug reactions were obtained from Vigibase, a WHO database of individual case safety reports (ICSRs) from 130 countries (1967-2020). ISCRs for atrial fibrillation (AF), angina pectoris, arteriosclerosis coronary artery (ACA), cardiac arrhythmias, coronary artery disease (CAD), thromboembolic events (TE), ischaemic heart disease (IHD), torsade de pointes/QT prolongation (TDP) associated with alendronate, zoledronic acid and teriparatide use were extracted. Data were included in a disproportionality analysis where the lower end of the 95 % credibility interval for the information component (IC025), showing a statistical association when >0. Head-to-head comparisons of ISCRs were estimated by age-adjusted odds ratios and 95 % confidence intervals. RESULTS: 465 episodes of angina, 287 ACA, 13,385 arrhythmias, 792 CAD, 6743 TE, 3264 IHD, 1037 myocardial infarcts, and 3714 TDP events were recorded across 50,365 alendronate, 52,436 zoledronic acid and 137,629 teriparatide users. There was a significant association between alendronate and zoledronate with all outcomes except MI. Teriparatide use was associated with AF, arrythmias and angina only. In head-to-head comparisons, teriparatide use was associated with fewer ACA and CAD events than alendronate and fewer ACA than zoledronic acid. DISCUSSION: Osteoporosis medication use is associated with adverse cardiac events, except for MI, and these appear to be more common with oral and intravenous bisphosphonates than teriparatide. Our data do not support differential effects of oral and intravenous bisphosphonates on cardiac events. Mechanisms whereby teriparatide may be cardio-protective warrant further investigation.

Measures of carotid atherosclerosis and fall-related hospitalization risk: The Perth Longitudinal Study of Ageing Women.

BACKGROUND AND AIMS: We and others have identified links between cardiovascular conditions and poor musculoskeletal health. However, the relationship between measures of carotid atherosclerosis such as focal carotid plaque and common carotid intima media thickness (CCA-IMT) and falls remains understudied. This study examined the association between measures of carotid atherosclerosis and fall-related hospitalization over 11.5 years in community dwelling older women. METHODS AND RESULTS: 1116 older women recruited in 1998 to a five-year randomized controlled trial to examine the effect of calcium supplementation in preventing fracture and who had undertaken B-mode ultrasound in 2001 (three years after the baseline clinical visit) were included in this study. The participants were followed for over 11.5 years as Perth Longitudinal Study of Ageing Women (PLSAW). Over the follow up period, 428 (38.4%) women experienced a fall-related hospitalization. Older women with carotid plaque had 44% a higher relative hazard for fall-related hospitalization (HR 1.44; 95%CI, 1.18 to 1.76) compared to those without carotid plaque. The association persisted after adjustment for established falls risk factors such as measures of muscle strength and physical function.Each SD increase in the mean and maximum CCA-IMT was also associated with a higher risk of fall-related hospitalizations (HR 1.10; 95%CI, 1.00 to 1.21 and HR 1.11; 95%CI, 1.01 to 1.22, respectively). CONCLUSIONS: Measures of carotid atherosclerosis are associated with a higher risk of fall-related hospitalization independent of established falls risk factors. These findings suggest the importance of vascular health when considering falls risk.

Evidence for the cardiovascular effects of osteoporosis treatments in randomized trials of post-menopausal women: A systematic review and Bayesian network meta-analysis.

Osteoporosis medications have been reported to have beneficial and harmful cardiovascular effects. Much of this evidence stems from single reports and as such, a comprehensive examination of the evidence is needed. We conducted a network meta-analysis (NMA) of cardiovascular adverse event (CAE) data from randomized trials of osteoporosis medications in postmenopausal women. Trials were identified from recent NMAs of osteoporosis treatment for fracture reduction with an updated literature search (December 2020). Included studies were randomized, included over 100 participants, and reported skeletal primary outcomes. We investigated three-point major adverse cardiovascular events (MACE3), four- (MACE4) and five-point MACE (MACE5), as well as myocardial infarction (MI) and stroke. Data were synthesized in a random-effects network meta-analysis using Bayesian modelling. Probabilistic ranking of treatment safety was performed. Relative to placebo, point estimates for the odds ratios (OR) with 95 % credible intervals (CrI) were also generated. We identified 75 trials (n = 136,940 women), of which 27 (68,699 women, nine arms) reported CAEs. In women randomized to placebo, the overall event rate for the MACE3 outcome was 2.58 % compared with 1.99 % in those randomized to all other active comparators. Probabilistic ranking found abaloparatide, oral bisphosphonates, teriparatide, and menopausal hormone therapy were less likely to have increased risk of CAEs than placebo, while romosozumab ranked more likely to have increased risk of CAEs than placebo for all outcomes. Compared with placebo, abaloparatide (one trial, n = 1642) was associated with a reduced odds for MACE3 (OR = 0·31; 95%CrI: 0·06 to 0·99), MACE4 (0·28; 0·06 to 0·88) and MACE5 (0·25; 0·06 to 0·79). When all PTH analogues were grouped together, magnitude and direction of effects were consistent but no longer statistically significant. We did not find pooled direct and indirect evidence that osteoporosis treatments significantly increased the risk of adverse cardiovascular events relative to placebo. (PROSPERO: CRD42020178702).

Vitamin D supplementation and exercise for improving physical function, body composition and metabolic health in overweight or obese older adults with vitamin D deficiency: a pilot randomized, double-blind, placebo-controlled trial.

PURPOSE: Vitamin D supplementation may have non-skeletal health benefits and enhance exercise responsiveness, particularly in those with low vitamin D levels. We determined whether, compared with placebo, vitamin D supplementation taken prior to and during a 12-week exercise program improves physical function, body composition or metabolic health, in overweight and obese older adults with vitamin D deficiency. METHODS: Fifty overweight or obese older adults (mean ± SD age: 60 ± 6 years; BMI 30.6 ± 5.7 kg/m2) with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] < 50 nmol/L) were recruited. Participants were randomly allocated to receive either vitamin D3 (4000 IU/day) or matching placebo for 24 weeks. Between weeks 12 and 24, all participants completed multi-modal exercise three days per week while continuing with vitamin D/placebo. Mean changes in physical function (primary outcome: gait speed), body composition and biochemical parameters at weeks 12 and 24 were compared between groups. RESULTS: Vitamin D supplementation, with or without exercise, had no effect on gait speed. From baseline to week 12, vitamin D supplementation increased serum 25(OH)D levels (placebo: 2.5 ± 14.7 nmol/L; treatment: 43.4 ± 18.4 nmol/L; P < 0.001) and reduced stair climb times (placebo: 0.3 ± 1.0 s; treatment: - 0.2 ± 1.0 s; P = 0.046). From 12 to 24 weeks, vitamin D supplementation combined with exercise decreased waist circumference (placebo: 1.3 ± 7.3 cm; treatment: - 3.0 ± 6.1 cm; P = 0.02) and waist-to-hip ratio (placebo: 0.01 ± 0.05; treatment: - 0.03 ± 0.05; P = 0.01) relative to placebo. Vitamin D supplementation, with or without exercise, had no effect on other physical function, body composition or metabolic health outcomes. CONCLUSION: Vitamin D supplementation had no effect on most physical function, body composition or metabolic health parameters when taken alone, or during exercise, in overweight or obese older adults with vitamin D deficiency. Vitamin D-related improvements in stair climb times and waist circumference suggest that future trials should explore the effects of vitamin D on muscle power, and its effects on body composition when combined with exercise, in populations with moderate or severe vitamin D deficiency.

Abdominal Aortic Calcification, Bone Mineral Density, and Fractures: A Systematic Review and Meta-analysis of Observational Studies.

BACKGROUND: Abdominal aortic calcification (AAC) has been inconsistently associated with skeletal health. We aimed to investigate the association of AAC with bone mineral density (BMD) and fracture risk by pooling the findings of observational studies. METHODS: MEDLINE, EMBASE, Web of Science, and Google Scholar were searched (August 2021). All clinical studies that assessed the association between AAC and BMD or fracture were included. AAC was categorized into any/advanced (all higher reported groups) versus no/less advanced (lowest reported group). Pooled standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CI) were determined for BMD and fracture, respectively, using random-effects models. RESULTS: Of 2 192 articles screened, 86 (61 553 participants) were included in the review, while 42 provided data for meta-analysis. AAC was associated with lower BMD at the total hip (SMD = -1.05 [95%CI: -1.47 to -0.63]; 16 studies), femoral neck (-0.25 [-0.46 to-0.04]; 10), and lumbar spine (-0.67 [-1.21 to -0.12]; 20). AAC was associated with a greater risk of any fracture (RR = 1.73 [95%CI: 1.48-2.02]; 27). AAC was also associated with vertebral, non-vertebral, and hip fractures. In dose-response analysis, the highest AAC group had greater risks of any, vertebral and non-vertebral fractures. CONCLUSIONS: AAC is associated with lower BMD and increased fracture risk at multiple sites, underscoring the potential importance of vascular disease on skeletal health. Detection of AAC at the time of BMD testing may provide clinicians with prognostic information about bone health to enhance osteoporosis screening programs and fracture risk prediction.

Erratum: Cardiovascular Safety of Antifracture Medications in Patients With Osteoporosis: A Narrative Review of Evidence From Randomized Studies.

[This corrects the article DOI: 10.1002/jbm4.10522.].

Cardiovascular Safety of Antifracture Medications in Patients With Osteoporosis: A Narrative Review of Evidence From Randomized Studies.

Osteoporosis and cardiovascular (CV) disease share common risk factors and pathophysiology. Low bone mineral density (BMD) and fractures appear to increase the risk for multiple CV diseases. Equally, prevalent CV disease appears to predispose to bone loss and increase fracture rates. This relationship has naturally provoked the hypothesis that stopping bone loss may result in some CV benefit. Secondary analyses of safety and adverse event data from many randomized controlled trials (RCTs) have attempted to clarify this putative association. Recently, the discontinuation of odanacatib (anti-cathepsin K monoclonal antibody) over stroke concerns and the imbalance in ischemic events in romosozumab-treated (anti-sclerostin monoclonal antibody) women compared to bisphosphonate-treated women, has provided further justification to better characterize potential CV benefits and harms of osteoporosis medications. This review delves into the seminal, and other major RCTs of osteoporosis medications and, using both published data and additional information provided on trial registration pages, examines the evidence for CV safety and harms of these medications. Accepted and emerging "off-target" effects are explored for validity, biological plausibility, and clinical importance. A brief research agenda is provided to stimulate the next wave of clinical development and CV understanding of osteoporosis medications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abdominal aortic calcification is associated with a higher risk of injurious fall-related hospitalizations in older Australian women.

BACKGROUNDS AND AIMS: Abdominal aortic calcification (AAC) is associated with weaker grip strength, an established risk factor for fall-related hospitalizations. However, its association with long-term fall-related hospitalisations remains unknown. This study investigated the association between AAC and long-term fall-related hospitalizations in community-dwelling older women. METHODS: Fall-related hospitalizations were obtained from linked data over 14.5-years in a prospective cohort of 1053 older women (mean age 75.0 ± 2.6 years). At baseline (1998/99), AAC was assessed from lateral spine images obtained using dual-energy X-ray absorptiometry, and scored using a semi-quantitative method (AAC24, range 0-24). The presence of any AAC was defined by AAC24 ≥ 1. RESULTS: Over 14.5-years, 413 (39.2%) women experienced a fall-related hospitalization. In the multivariable-adjusted model, each unit increase in baseline AAC24 was associated with a 3% increase in relative hazards for a fall-related hospitalization (HR 1.03 95%CI, 1.01 to 1.07). Compared to women with no AAC, women with any AAC had a 40% (HR 1.40 95%CI, 1.11 to 1.76) and 39% (HR 1.39 95%CI, 1.10 to 1.76) greater risk for fall-related hospitalizations in the minimal and multivariable-adjusted models, respectively. This relationship was not attenuated by including measures of muscle function such as grip strength and timed-up-and-go. CONCLUSIONS: The presence of AAC is associated with long-term fall-related hospitalizations risk, independent of muscle function, in community-dwelling older women. Concurrent assessment of AAC may be a simple and cost-effective way to identify older women at higher risk of falling as part of routine osteoporosis screening.

The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation.

OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis. DESIGN: Retrospective cohort study. SETTING: Academic hospital. PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018). INTERVENTION: FEIBA administered to control perioperative hemorrhage. MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 × 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk. CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (∼1,000 units, ∼13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

Exercise attenuates bone mineral density loss during diet-induced weight loss in adults with overweight and obesity: A systematic review and meta-analysis.

BACKGROUND: Weight-loss-induced fat loss improves cardiometabolic health in individuals with overweight and obesity; however, weight loss can also result in bone loss and increased fracture risk. Weight-loss-induced bone loss may be attenuated with exercise. Our aim was to compare changes in bone mineral density (BMD) in adults with overweight and obesity who undertook diet-induced weight loss alone or in combination with exercise. METHODS: We included randomized controlled trials (RCTs) in adults with overweight or obesity (aged ≥18 years; body mass index ≥25 kg/m2) that prescribed diet-induced weight loss alone or in combination with supervised exercise, and measured any bone structural parameters. Risk of bias was assessed using the Cochrane Risk of Bias tool. Random-effects meta-analyses determined mean changes and net mean differences (95% confidence intervals (95%CIs)) in the percentage of areal BMD (aBMD) change between groups. RESULTS: We included 9 RCTs. Diet-induced weight loss led to significant losses in femoral neck aBMD (mean change: -1.73% (95%CI: -2.39% to -1.07%), p < 0.001) and total hip aBMD (-2.19% (95%CI: -3.84% to -0.54%), p = 0.009). Femoral neck aBMD losses were significantly greater in the diet-induced weight loss group compared to the exercise plus diet-induced weight loss group (net difference: -0.88% (95%CI: -1.73% to -0.03%)); however, there were no differences in aBMD changes at any other skeletal site: total hip (-1.96% (95%CI: -4.59% to 0.68%)) and lumbar spine (-0.48% (95%CI: -1.81% to 0.86%)). aBMD changes did not differ significantly according to exercise modality (resistance exercise, aerobic exercise, or a combination of the two) during diet-induced weight loss. CONCLUSION: Diet-induced weight loss led to greater femoral neck bone loss compared to diet-induced weight loss plus exercise. Bone loss at the total hip and lumbar spine was not attenuated by exercise during diet-induced weight loss. The lack of consistent skeletal benefits may be due to the insufficient duration and/or training intensities of most exercise interventions. Additional RCTs with appropriate, targeted exercise interventions should be conducted.

Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized Trials.

The cardiovascular safety of denosumab has not yet been evaluated in a systematic review. This systematic review and meta-analysis sought to quantify the number of randomized controlled trials (RCTs) of denosumab (against comparators) reporting cardiovascular adverse events (CAEs) and examine the balance of CAEs between treatment arms. MEDLINE, Embase, and clinicaltrials.gov were searched from inception to October 26, 2019, for RCTs of denosumab versus comparators for any indication. Included trials were randomized, enrolled ≥100 participants, and reported bone-related outcomes. Primary outcome for analysis was all CAEs, a composite endpoint representing summation of all CAEs as reported by included trials. Secondary outcomes included major adverse cardiovascular events (MACE). Data were pooled using a fixed effects model to determine relative risk (RR) and 95% confidence interval (95% CI). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 554 records screened, 49 were included, while 36 reported CAEs. Twenty-seven included trials (12 eligible for meta-analysis) were conducted in 13,202 postmenopausal women. Compared with bisphosphonates, there was a 46% (95% CI 1.05 to 2.02) increase in CAEs (85/2136 events in denosumab-treated versus 58/2131 events in bisphosphonate-treated; seven trials). There was a similar imbalance in a five-point (stroke, myocardial infarction, cardiovascular death, heart failure, atrial fibrillation) MACE endpoint (28/2053 versus 12/2050; RR = 2.33 [1.19 to 4.56]). Compared with placebo-treated women, there was no imbalance in total CAEs (439/4725 events in denosumab versus 399/4467 in placebo; RR = 0.79 [0.41 to 1.52]; seven trials). No imbalance in total AEs (versus bisphosphonates: 0.98 [0.92 to 1.04]; versus placebo: 0.99 [0.98 to 1.01]) occurred. Other indications showed no statistically significant results. The excess CAEs in postmenopausal women treated with denosumab compared with bisphosphonates, but not placebo, indirectly supports claims that bisphosphonates may suppress CAEs. Future trials should use standardized CAE reporting to better describe cardiovascular effects of bone active medications. (PROSPERO: CRD42019135414.) © 2020 American Society for Bone and Mineral Research (ASBMR).

Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density.

CONTEXT: The cardiovascular (CV) safety of oral bisphosphonates (oBPs) is uncertain. OBJECTIVE: Determine the risk of CV events in oBP users referred for bone mineral density (BMD) testing compared with matched controls. DESIGN: Cohort study. SETTING: Danish national prescription registry enriched with local hospital data from Odense. PARTICIPANTS: Individuals aged ≥45 years referred for BMD testing. EXPOSURE: oBP. OUTCOMES: Hospitalization for any CV event. Secondary study outcomes were specific CV events. Negative (inguinal hernia surgery and ingrown toenail) and positive (fragility fracture) control outcomes assessed systemic bias. Cox proportional hazards models were fitted to estimate hazard ratio (HR) and 95% confidence intervals. RESULTS: There were 2565 oBP users (82.6% women) and 4568 (82.3% women) propensity score-matched controls. Alendronate accounted for 96% of oBP prescription. A total of 406 (15.8%) CV events occurred in oBP users (rate = 73.48 [66.67-80.98]); rate = events divided by person-time; and 837 (18.3%) events in controls (rate = 104.73 [97.87-112.07]) with an adjusted HR of 0.68 (95% CI 0.60-0.77). Additional adjustment for BMD did not attenuate estimates (HR 0.67; 95% CI 0.58-0.78]. Similar results were seen for secondary outcomes where risk reductions were seen regarding atrial fibrillation, stroke, heart failure, and aneurysms. Positive and negative control outcome analyses identified minimal residual confounding. CONCLUSION: Oral BP users experienced a 33% reduced risk of CV events. This observational real-world study adds to a growing body of evidence for cardioprotection by oBP that warrants testing in a randomized setting.

Abdominal aortic calcification, bone mineral density and fractures: a systematic review and meta-analysis protocol.

INTRODUCTION: Abdominal aortic calcification (AAC) is associated with low bone mass and increased fracture risk. Two previous meta-analyses have investigated the association between AAC and fracture. However, these meta-analyses only identified articles until December 2016, undertook limited searches and did not explore potential sources of between-study heterogeneity. We aim to undertake a sensitive and comprehensive assessment of the relationship between AAC, bone mineral density (BMD) as well as prevalent and incident fractures. METHODS: We will search MEDLINE, EMBASE, Web of Science core collection and Google Scholar (top 200 articles sorted by relevance) from their inception to 1 June 2018. Reference lists of included studies and previous systematic reviews will be hand searched for additional eligible studies. Retrospective and prospective cohort studies (cross-sectional, case-control and longitudinal) reporting the association between AAC, BMD and fracture at any site will be included. At least two investigators will independently: (A) evaluate study eligibility and extract data, with a third investigator to adjudicate when discrepancies occur, (B) assess study quality by the Newcastle-Ottawa Scale for each cohort/study. The meta-analysis will be reported in adherence to the Meta-analysis of Observational Studies in Epidemiology criteria. AAC will be grouped as either: (1) AAC present or absent, (2) AAC categorised as 'low' (referent-lowest reported group) versus 'high' (all other groups) or (3) dose-response when AAC was assessed in ≥3 groups. Where primary event data were reported in individual studies, pooled risk differences and risk ratios with 95% CI will be calculated, from which, a summary estimate will be determined using DerSimonian-Laird random effects models. For the AAC and BMD pooled analyses, estimates will be expressed as standardised mean difference with 95% CI. We will examine the likelihood of publication bias and where possible, investigate potential reasons for between-study heterogeneity using subgroup analyses and meta-regression. ETHICS AND DISSEMINATION: The study will be submitted to a peer- reviewed journal and disseminated via research presentations. PROSPERO REGISTRATION NUMBER: CRD42018088019.