Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39–6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.

Purpose of Review: In this narrative review, we have summarized the literature on fracture risk in T1DM and T2DM with a special focus on fracture site, time patterns, glucose-lowering drugs, and micro- and macrovascular complications. Recent Findings: T1DM and T2DM were associated with an overall increased fracture risk, with preferent locations at the hip, vertebrae, humerus, and ankle in T1DM and at the hip, vertebrae, and likely humerus, distal forearm, and foot in T2DM. Fracture risk was higher with longer diabetes duration and the presence of micro- and macrovascular complications. In T2DM, fracture risk was higher with use of insulin, sulfonylurea, and thiazolidinediones and lower with metformin use. Summary: The increased fracture risk in T1DM and T2DM concerns specific fracture sites, and is higher in subjects with longer diabetes duration, vascular complications, and in T2DM with the use of specific glucose-lowering medication.

To examine whether GLP1-RA is associated with increased fracture risk, we compared 337,648 people with fractures to 675,296 people without fractures. Our adjusted analysis found that people with fractures tended to use GLP1-RA less often than people without fractures. This suggests that GLP1-RA may reduce fracture risk. Glucagon-like peptide-1 (GLP-1) receptor agonists were introduced as a treatment for type 2 diabetes mellitus with weight loss as a beneficial side effect. Since then, the medications have been approved as weight-loss medication. However, rapid and substantial weight loss can lead to bone loss and increased fracture risk. We identified persons aged 30-90 years with a fracture between 2017 and 2021 and matched them 1:2 with fracture-free controls by sex and year of birth. Conditional logistic regression models were used to estimate odds ratios (ORs) for any fracture and major osteoporotic fracture (MOF) associated with GLP-1 receptor agonist use. Analyses were adjusted for relevant risk factors. A total of 337,648 fracture cases and 675,296 fracture-free controls were included. In the unadjusted analyses, GLP-1 receptor agonist use did not differ between cases and controls (any fracture OR [confidence intervals (CI)], 1.00 [0.97-1.04]; MOF OR [CI], 0.96 [0.90-1.02]). In the adjusted analyses, GLP-1 receptor agonists were used less frequently in the group that sustained any fracture (OR [CI], 0.94 [0.90-0.97]) or MOF (OR [CI], 0.88 [0.83-0.94]) compared to the controls. GLP-1 receptor agonists may reduce fracture risk, suggesting a potential protective effect on bone health.

The incidence of major osteoporotic fractures has declined in men and women in Western countries over the last two decades. Although fracture risk is higher in persons with diabetes mellitus, trends of fractures remain unknown in men and women with diabetes. We investigated the trends in fracture incidence rates (IRs) in men and women with type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) in Denmark between 1997 and 2017. We identified men and women aged 18+ years who sustained a fracture (excluding skull and facial fractures) between 1997 and 2017 using the Danish National Patient Registry. We calculated sex‐specific IRs of fractures per 10,000 person‐years separately in persons with T1D, T2D, or without diabetes. Furthermore, we compared median IRs of the first 5 years (1997–2002) to the median IRs of the last 5 years (2012–2017). We identified 1,235,628 persons with fractures including 4863 (43.6% women) with T1D, 65,366 (57.5% women) with T2D, and 1,165,399 (54.1% women) without diabetes. The median IRs of fractures declined 20.2%, 19.9%, and 7.8% in men with T1D, T2D, and without diabetes, respectively (p‐trend <0.05). The median IRs decreased 6.4% in women with T1D (p‐trend = 0.35) and 25.6% in women with T2D (p‐trend <0.05) but increased 2.3% in women without diabetes (p‐trend = 0.08). Fracture IRs decreased in men with both diabetes types and only in women with T2D, highlighting the need for further attention behind the stable trend observed in women with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

To examine postural control in people with type 2 diabetes mellitus (T2DM) with and without diabetic neuropathy (DN) using center of pressure (CoP) measures under varying sensory and cognitive conditions. In this cross-sectional study, adults aged ≥ 40 years with T2DM for at least one year. Neuropathy was classified as severe peripheral neuropathy (DPN) or autonomic neuropathy (DAN), defined by vibration perception threshold ≥ 50 V, ≥2 abnormal cardiac autonomic reflex tests, or orthostatic hypotension. Postural control was assessed by CoP^Area and CoP^Velocity under different sensory and cognitive conditions. Regression analyses were adjusted for demographic factors, physical performance, and fall-associated medication. Exploratory analyses were performed by neuropathy subtype. 99 participants were included, 49 with DN and 50 without. The DN group was older (66.8 vs. 60.8 years) and more often male (75.5% vs. 52%). DN was associated with greater CoP^Area (β = 0.56, p = 0.006). Exploratory analyses suggested larger CoP^Area in participants with DAN alone (β = 0.76, 95% CI 0.36-1.16) or combined with DPN (β = 0.70, 95% CI 0.13-1.34), whereas DPN alone was not associated with CoP^Area. DN was linked to impaired postural control, with indications of differences by neuropathy subtype. CoP assessment may help identify people with T2DM at increased risk of falls.

Objective: Balance impairment is an underrecognized complication of acromegaly with potentially serious consequences for affected patients. In this study, we aimed to assess the balance in patients with long‐term acromegaly compared to non‐acromegalic controls.Design: Cross‐sectional study.Patients and Measurements: Seventeen patients with acromegaly and 17 age‐ and sex‐matched controls were examined using a force platform measuring the Centre of Pressure area (CoP_area) and velocity (CoP_velocity), the timed up‐and‐go (TUG) test, hand grip and knee extension dynamometry, nerve conduction measurements, visual acuity tests, and questionnaires concerning fear of falling and joint pain (Falls Efficacy Scale [FES‐I] and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]). Descriptive statistics and linear regression analyses were used to compare groups.Results: Compared to controls, participants with acromegaly (mean acromegaly duration 13 [±8.8] years, latest mean IGF‐I standard deviation score 1.2 [±1.59]) had significantly increased CoP_area adjusted for neural and visual function. When performing a difficult executive task, the CoP_area was impaired, both with (β: 2.24 [1.29; 3.92], p = 0.01) and without (β: 2.09 [1.02; 4.26], p = 0.04) a cushion under their feet, as compared to controls. Mean TUG time was significantly higher in patients with acromegaly than controls (β: 1.24 [0.07; 2.42], p = 0.04), and correlated with self‐reported joint pain (β: 0.04 [0.0004; 0.08], p = 0.05).Conclusions: Both static and dynamic balance is impaired in patients with long‐term controlled acromegaly, warranting clinical attention. Further studies are needed to address therapeutic options for this overlooked and potentially serious complication.