Firefighter- and fire department-level barriers and promoters of physical activity and fitness among volunteer firefighters: a qualitative study using semi-structured interviews.

OBJECTIVE: To describe volunteer firefighters' perspectives on how firefighter- and fire department-level factors influence their physical activity and fitness. METHODS: Firefighters (n = 28) were interviewed, stratified by their years of firefighting, using an interview guide. Thematic analysis and systematic coding were employed to analyze the interview transcripts. RESULTS: Five themes were identified: (1) health and firefighting performance; (2) firefighter time and availability; (3) responsibility of the fire department to support volunteer members' physical fitness; (4) fire training drills as a form of functional physical activity, and (5) fitness initiatives at the department. Interviewing by years of experience showed varied perspectives which converged towards similar conclusions. CONCLUSIONS: Incorporating fitness discussions into department meetings and trainings, and identifying fitness advocates within the department, may contribute to overcoming barriers to physical fitness among volunteer firefighters.

The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Fracture risk prediction in postmenopausal women with traditional and machine learning models in a nationwide, prospective cohort study in Switzerland with validation in the UK Biobank.

Fracture prediction is essential in managing patients with osteoporosis and is an integral component of many fracture prevention guidelines. We aimed to identify the most relevant clinical fracture risk factors in contemporary populations by training and validating short- and long-term fracture risk prediction models in 2 cohorts. We used traditional and machine learning survival models to predict risks of vertebral, hip, and any fractures on the basis of clinical risk factors, T-scores, and treatment history among participants in a nationwide Swiss Osteoporosis Registry (N = 5944 postmenopausal women, median follow-up of 4.1 yr between January 2015 and October 2022; a total of 1190 fractures during follow-up). The independent validation cohort comprised 5474 postmenopausal women from the UK Biobank with 290 incident fractures during follow-up. Uno's C-index and the time-dependent area under the receiver operating characteristics curve were calculated to evaluate the performance of different machine learning models (Random survival forest and eXtreme Gradient Boosting). In the independent validation set, the C-index was 0.74 [0.58, 0.86] for vertebral fractures, 0.83 [0.7, 0.94] for hip fractures, and 0.63 [0.58, 0.69] for any fractures at year 2, and these values further increased for longer estimations of up to 7 yr. In comparison, the 10-yr fracture probability calculated with FRAX Switzerland was 0.60 [0.55, 0.64] for major osteoporotic fractures and 0.62 [0.49, 0.74] for hip fractures. The most important variables identified with Shapley additive explanations values were age, T-scores, and prior fractures, while number of falls was an important predictor of hip fractures. Performances of both traditional and machine learning models showed similar C-indices. We conclude that fracture risk can be improved by including the lumbar spine T-score, trabecular bone score, numbers of falls and recent fractures, and treatment information has a significant impact on fracture prediction.

Fracture prediction is essential in managing patients with osteoporosis. We developed and validated traditional and machine learning models to predict short- and long-term fracture risk and identify the most relevant clinical fracture risk factors for vertebral, hip, and any fractures in contemporary populations. We used data from 5944 postmenopausal women in a Swiss Osteoporosis Registry and validated our findings with 5474 women from the UK Biobank. Our machine learning models performed well, with C-index values of 0.74 for vertebral fractures, 0.83 for hip fractures, and 0.63 for any fractures at year 2, and these values further increased for longer estimations of up to 7 years. In contrast, FRAX Switzerland had lower C-index values (0.60 for major fractures and 0.62 for hip fracture probabilities over 10 years). Key predictors identified included age, T-scores, prior fractures, and number of falls. We conclude that incorporating a broader range of clinical factors, as well as lumbar spine T-scores, fall history, recent fractures, and treatment information, can improve fracture risk assessments in osteoporosis management. Both traditional and machine learning models showed similar effectiveness in predicting fractures.

Disruption of central and peripheral circadian clocks and circadian controlled estrogen receptor rhythms in night shift nurses in working environments.

Chronic disruption of circadian rhythms by night shift work is associated with an increased breast cancer risk. However, little is known about the impact of night shift on peripheral circadian genes (CGs) and circadian-controlled genes (CCGs) associated with breast cancer. Hence, we assessed central clock markers (melatonin and cortisol) in plasma, and peripheral CGs (PER1, PER2, PER3, and BMAL1) and CCGs (ESR1 and ESR2) in peripheral blood mononuclear cells (PBMCs). In day shift nurses (n = 12), 24-h rhythms of cortisol and melatonin were aligned with day shift-oriented light/dark schedules. The mRNA expression of PER2, PER3, BMAL1, and ESR2 showed 24-h rhythms with peak values in the morning. In contrast, night shift nurses (n = 10) lost 24-h rhythmicity of cortisol with a suppressed morning surge but retained normal rhythmic patterns of melatonin, leading to misalignment between cortisol and melatonin. Moreover, night shift nurses showed disruption of rhythmic expressions of PER2, PER3, BMAL1, and ESR2 genes, resulting in an impaired inverse correlation between PER2 and BMAL1 compared to day shift nurses. The observed trends of disrupted circadian markers were recapitulated in additional day (n = 20) and night (n = 19) shift nurses by measurement at early night and midnight time points. Taken together, this study demonstrated the misalignment of cortisol and melatonin, associated disruption of PER2 and ESR2 circadian expressions, and internal misalignment in peripheral circadian network in night shift nurses. Morning plasma cortisol and PER2, BMAL1, and ESR2 expressions in PBMCs may therefore be useful biomarkers of circadian disruption in shift workers.

Comparison of COVID-19 Symptoms in Correctional Health Care Workers During the Initial and Omicron Surges.

There is a dearth of medical literature that characterizes the experience of correctional health care workers (HCWs) during the COVID-19 pandemic. We performed a retrospective chart review of the results of an ongoing universal SARS-CoV-2 testing program for New Jersey correctional system HCWs and describe their presenting symptoms, perceived exposure, and demographic characteristics during the initial (March 15, 2020, to August 31, 2020) and Omicron (March 1, 2022, to August 31, 2022) COVID-19 surges. Analysis included 123 eligible records. In both surges, nurses had a high proportion of infections and cough was the most commonly reported symptom. Fever was more than twice as commonly reported in the initial surge. During the Omicron surge, nasal symptoms predominated (39.5% [95% CI: 28.4-51.4]) compared with the initial surge (8.5% [95% CI: 2.4-20.4]). Perceived exposure source was predominantly work related during the initial surge and multiple other sources of exposure were identified during the Omicron surge. Ninety-six percent of HCWs received a COVID-19 booster shot by February 2022. The reinfection rate was less than 10% for our initial cohort. Presenting symptoms correlated with the circulating variant. Mass vaccination of staff, the lower virulence of the Omicron variant, and possibly prior infection likely contributed to the milder illness experienced during the Omicron surge.

Firefighting, per- and polyfluoroalkyl substances, and DNA methylation of genes associated with prostate cancer risk.

Prostate cancer is the leading incident cancer among men in the United States. Firefighters are diagnosed with this disease at a rate 1.21 times higher than the average population. This increased risk may result from occupational exposures to many toxicants, including per- and polyfluoroalkyl substances (PFAS). This study assessed the association between firefighting as an occupation in general or PFAS serum levels, with DNA methylation. Only genomic regions previously linked to prostate cancer risk were selected for analysis: GSTP1, Alu repetitive elements, and the 8q24 chromosomal region. There were 444 male firefighters included in this study, with some analyses being conducted on fewer participants due to missingness. Statistical models were used to test associations between exposures and DNA methylation at CpG sites in the selected genomic regions. Exposure variables included proxies of cumulative firefighting exposures (incumbent versus academy status and years of firefighting experience) and biomarkers of PFAS exposures (serum concentrations of 9 PFAS). Proxies of cumulative exposures were associated with DNA methylation at 15 CpG sites and one region located within FAM83A (q-value <0.1). SbPFOA was associated with 19 CpG sites (q < 0.1), but due to low detection rates, this PFAS was modeled as detected versus not detected in serum. Overall, there is evidence that firefighting experience is associated with differential DNA methylation in prostate cancer risk loci, but this study did not find evidence that these differences are due to PFAS exposures specifically.

Prevalence and predictors of colon and prostate cancer screening among volunteer firefighters: The United States Firefighter Cancer Assessment and Prevention Study.

BACKGROUND: Although firefighters have increased risk for colon and prostate cancer, limited information exists on screening practices for these cancers in volunteer firefighters who compose two-thirds of the US fire service. We estimated the prevalence of colon and prostate cancer screening among volunteer firefighters using eligibility criteria from 4 evidence-based screening recommendations and evaluated factors influencing screening. METHODS: We evaluated colon (n = 569) and prostate (n = 498) cancer screening prevalence in a sample of US volunteer firefighters using eligibility criteria from the US Preventive Services Taskforce (USPSTF), National Fire Protection Association, American Cancer Society, and National Comprehensive Cancer Network. We assessed associations with fire service experience, demographics, and cancer risk perception based on USPSTF guidelines. RESULTS: For those eligible based on USPSTF guidelines, colon and prostate cancer screening prevalence was 51.7% (95% CI: 45.7, 57.8) and 48.8% (95% CI: 40.0, 57.6), respectively. Higher odds of colon and prostate cancer screening were observed with older age and with some college education compared to those with less education. Fire service experience and cancer risk perception were not associated with screening practices. CONCLUSION: This is the first large study to assess colon and prostate cancer screening among US volunteer firefighters based on different screening guidelines. Our findings suggest gaps in cancer prevention efforts in the US volunteer fire service. Promoting cancer screening education and opportunities for volunteer firefighters by their fire departments, healthcare professionals, and public health practitioners, may help to address the gaps.

Comparison of Serum Per- and Polyfluoroalkyl Substances Concentrations in Incumbent and Recruit Firefighters and Longitudinal Assessment in Recruits.

OBJECTIVE: Firefighters are occupationally exposed to per- and polyfluoroalkyl substances (PFAS). This study objective was to compare serum PFAS concentrations in incumbent and recruit firefighters and evaluate temporal trends among recruits. METHODS: Serum PFAS concentrations were measured in 99 incumbent and 55 recruit firefighters at enrollment in 2015-2016, with follow-up 20 to 37 months later for recruits. Linear and logistic regression and linear mixed-effects models were used for analyses. Fireground exposure impact on PFAS concentrations was investigated using adjusted linear and logistic regression models. RESULTS: Incumbents had lower n-PFOA and PFNA than recruits and most PFAS significantly decreased over time among male recruits. No significant links were found between cumulative fireground exposures and PFAS concentrations. CONCLUSIONS: Serum PFAS concentrations were not increased in incumbent firefighters compared with recruits and were not associated with cumulative fireground exposures.

Associations Between Epigenetic Age Acceleration and microRNA Expression Among U.S. Firefighters.

Epigenetic changes may be biomarkers of health. Epigenetic age acceleration (EAA), the discrepancy between epigenetic age measured via epigenetic clocks and chronological age, is associated with morbidity and mortality. However, the intersection of epigenetic clocks with microRNAs (miRNAs) and corresponding miRNA-based health implications have not been evaluated. We analyzed DNA methylation and miRNA profiles from blood sampled among 332 individuals enrolled across 2 U.S.-based firefighter occupational studies (2015-2018 and 2018-2020). We considered 7 measures of EAA in leukocytes (PhenoAge, GrimAge, Horvath, skin-blood, and Hannum epigenetic clocks, and extrinsic and intrinsic epigenetic age acceleration). We identified miRNAs associated with EAA using individual linear regression models, adjusted for sex, race/ethnicity, chronological age, and cell type estimates, and investigated downstream effects of associated miRNAs with miRNA enrichment analyses and genomic annotations. On average, participants were 38 years old, 88% male, and 75% non-Hispanic white. We identified 183 of 798 miRNAs associated with EAA (FDR q < 0.05); 126 with PhenoAge, 59 with GrimAge, 1 with Horvath, and 1 with the skin-blood clock. Among miRNAs associated with Horvath and GrimAge, there were 61 significantly enriched disease annotations including age-related metabolic and cardiovascular conditions and several cancers. Enriched pathways included those related to proteins and protein modification. We identified miRNAs associated with EAA of multiple epigenetic clocks. PhenoAge had more associations with individual miRNAs, but GrimAge and Horvath had greater implications for miRNA-associated pathways. Understanding the relationship between these epigenetic markers could contribute to our understanding of the molecular underpinnings of aging and aging-related diseases.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.

Prevalence and predictors of skin cancer screening among a sample of US volunteer firefighters.

BACKGROUND: Firefighters have a higher risk of melanoma incidence and mortality compared to the general population. In the United States (US), the National Fire Protection Association recommends all firefighters receive annual skin cancer screening through visual skin examination by a clinician. However, there is limited information on skin cancer screening practices among volunteer firefighters who comprise two-thirds of the US fire service. METHODS: This cross-sectional study of 552 US volunteer firefighters estimated the prevalence of skin cancer screening and evaluated associations with their fire service experience, demographics, sun protection practices, and cancer risk perception. RESULTS: The prevalence of receiving skin cancer screening among volunteer firefighters was 26.1% (95% confidence interval [CI]: 22.4, 29.8). The odds of being screened for skin cancer, compared to not being screened, were twice as high for firefighters who used sunscreen (odds ratio [OR]: 2.35, 95% CI: 1.48, 3.73) and who perceived their skin likely to burn with prolonged sun exposure (OR: 1.81, 95% CI: 1.10, 3.00). Older age, some college education, and family history of skin cancer were also positively associated with skin cancer screening. A positive exposure-response relationship was observed between more monthly firefighting calls and receiving screening. Cancer risk perception was not associated with screening. CONCLUSION: To our knowledge, this is the first large study to assess skin cancer screening among US volunteer firefighters. Our findings suggest gaps in skin cancer prevention efforts in the volunteer fire service. Additional assessment of skin cancer prevention practices within volunteer fire departments could help address these gaps.

Comparison of anti-fracture effectiveness of zoledronate, ibandronate and alendronate versus denosumab in a registry-based cohort study.

This registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab. PURPOSE: To analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting. METHODS: This registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting. RESULTS: A total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab. CONCLUSIONS: When adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.

Firefighting and Cancer: A Meta-analysis of Cohort Studies in the Context of Cancer Hazard Identification.

Objective: We performed a meta-analysis of epidemiological results for the association between occupational exposure as a firefighter and cancer as part of the broader evidence synthesis work of the IARCMonographs program. Methods: A systematic literature search was conducted to identify cohort studies of firefighters followed for cancer incidence and mortality. Studies were evaluated for the influence of key biases on results. Random-effects meta-analysis models were used to estimate the association between ever-employment and duration of employment as a firefighter and risk of 12 selected cancers. The impact of bias was explored in sensitivity analyses. Results: Among the 16 included cancer incidence studies, the estimated meta-rate ratio, 95% confidence interval (CI), and heterogeneity statistic (I2) for ever-employment as a career firefighter compared mostly to general populations were 1.58 (1.14-2.20, 8%) for mesothelioma, 1.16 (1.08-1.26, 0%) for bladder cancer, 1.21 (1.12-1.32, 81%) for prostate cancer, 1.37 (1.03-1.82, 56%) for testicular cancer, 1.19 (1.07-1.32, 37%) for colon cancer, 1.36 (1.15-1.62, 83%) for melanoma, 1.12 (1.01-1.25, 0%) for non-Hodgkin lymphoma, 1.28 (1.02-1.61, 40%) for thyroid cancer, and 1.09 (0.92-1.29, 55%) for kidney cancer. Ever-employment as a firefighter was not positively associated with lung, nervous system, or stomach cancer. Results for mesothelioma and bladder cancer exhibited low heterogeneity and were largely robust across sensitivity analyses. Conclusions: There is epidemiological evidence to support a causal relationship between occupational exposure as a firefighter and certain cancers. Challenges persist in the body of evidence related to the quality of exposure assessment, confounding, and medical surveillance bias.

Incidence and Predictors of COVID-19 Infection in Prison Healthcare Workers.

OBJECTIVE: The aim of the study is to assess the predictors of SARS-CoV-2 infection among correctional healthcare workers (HCWs). METHODS: We conducted a retrospective chart review to describe the demographic and workplace characteristics of New Jersey correctional HCWs between March 15, 2020, and August 31, 2020, using univariate and multivariable analysis. RESULTS: Among 822 HCWs, patient-facing staff had the highest incidence of infection (7.2%). Associated risk factors include being Black and working in a maximum-security prison. There were few statistically significant findings due to small total numbers ( n = 47) that tested positive. CONCLUSIONS: Correctional HCWs' challenging work environment creates unique risk factors for infection with the SARS-CoV-2 virus. Administrative measures taken by the department of corrections may have a significant role in curbing the spread of infection. The findings can help focus preventive measures for reducing the spread of COVID-19 in this unique population.

Serum per- and polyfluoroalkyl substance concentrations in four municipal US fire departments.

BACKGROUND: Firefighters have occupational and environmental exposures to per- and polyfluoroalkyl substances (PFAS). The goal of this study was to compare serum PFAS concentrations across multiple United States fire departments to National Health and Nutrition Examination Survey (NHANES) participants. METHODS: Nine serum PFAS were compared in 290 firefighters from four municipal fire departments (coded A-D) and three NHANES participants matched to each firefighter on sex, ethnicity, age, and PFAS collection year. Only Departments A and C had sufficient women study participants (25 and six, respectively) to compare with NHANES. RESULTS: In male firefighters compared with NHANES, geometric mean perfluorohexane sulfonate (PFHxS) was elevated in Departments A-C, sum of branched perfluoromethylheptane sulfonate isomers (Sm-PFOS) was elevated in all four departments, linear perfluorooctane sulfonate (n-PFOS) was elevated in Departments B and C, linear perfluorooctanoate (n-PFOA) was elevated in Departments B-D, and perfluorononanoate (PFNA) was elevated in Departments B-D, but lower in A. In male firefighters compared with NHANES, perfluoroundecanoate (PFUnDA) was more frequently detected in Departments B and D, and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) was less frequently detected in Departments B-D. In female firefighters compared with NHANES, PFHxS and Sm-PFOS concentrations were elevated in Departments A and C. Other PFAS concentrations were elevated and/or reduced in only one department or not significantly different from NHANES in any department. CONCLUSIONS: Serum PFHxS, Sm-PFOS, n-PFOS, n-PFOA, and PFNA concentrations were increased in at least two of four fire departments in comparison to NHANES.

Incidence of Atypical Femoral Fractures in Patients on Osteoporosis Therapy-A Registry-Based Cohort Study.

Atypical femoral fractures (AFFs) have been reported in patients taking bisphosphonates (BPs) for osteoporosis therapy but also in patients with no exposure to these drugs. In contrast, less is known about the incidence of AFFs in patients taking denosumab. This registry-based cohort study analyzed the incidence of AFFs in patients with suspected or confirmed osteoporosis who were included in the osteoporosis register of the Swiss Society of Rheumatology between January 2015 and September 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for AFFs, and considered sequential therapies and drug holidays as time-dependent covariates. Among the 9956 subjects in the cohort, 53 had subtrochanteric or femoral shaft fractures. Ten fractures occurred under BP or denosumab treatment and two under teriparatide therapy. Five fractures were classified as AFFs based on the revised American Society of Bone and Mineral Research case definition of AFFs from 2014. Three AFFs occurred in women being treated with denosumab at the time of diagnosis, all with prior BP use (10, 7, and 1 years, respectively). One AFF developed in a woman receiving ibandronate and one arose in a woman receiving glucocorticoids rather than antiresorptive therapy. The incidence of AFFs per 10,000 observed patient-years was 7.1 in patients receiving denosumab and 0.9 in patients with BP-associated AFFs, yielding a rate ratio of 7.9 (95% confidence interval [CI] 0.63-413), p = 0.073. The risk of AFFs was not significantly higher in patients receiving denosumab therapy compared with BP therapy (hazard ratio = 7.07, 95% CI 0.74-68.01, p = 0.090). We conclude that the risk of AFFs is low in patients taking BPs, denosumab, or both sequentially. All three patients with AFFs under denosumab therapy had undergone prior BP therapy. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting.

BACKGROUND: The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. OBJECTIVE: This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. METHODS: We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6 months later. In patients with longer denosumab therapy (≥5 years), BTMs were measured every 3 months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2 years after the first zoledronate. RESULTS: Bone loss after switching from denosumab to zoledronate was higher in patients with 10 ± 2 denosumab injections (n = 84) compared to 5 ± 2 injections (n = 144, p < 0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15 ± 2 injections (n = 54, p = 0.35 and p = 0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6 months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6 months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p = 0.37 for lumbar spine and p = 0.97 for femoral neck). CONCLUSIONS: Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6 years, irrespective of the frequency of subsequent zoledronate therapy.