Replication stress impairs chromosome segregation and preimplantation development in human embryos.

Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies. Entry into mitosis with incomplete replication results in chromosome breakage, whole and segmental chromosome errors, micronucleation, chromosome fragmentation, and poor embryo quality. Sites of spontaneous chromosome breakage are concordant with sites of DNA synthesis in G2 phase, locating to gene-poor regions with long neural genes, which are transcriptionally silent at this stage of development. Thus, DNA replication stress in mammalian preimplantation embryos predisposes gene-poor regions to fragility, and in particular in the human embryo, to the formation of aneuploidies, impairing developmental potential.

Transcription-mediated replication hindrance: a major driver of genome instability.

Genome replication involves dealing with obstacles that can result from DNA damage but also from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops. Experimental evidence reveals that an engaged transcription machinery at the DNA can either enhance such obstacles or be an obstacle itself. Thus, transcription can become a potentially hazardous process promoting localized replication fork hindrance and stress, which would ultimately cause genome instability, a hallmark of cancer cells. Understanding the causes behind transcription-replication conflicts as well as how the cell resolves them to sustain genome integrity is the aim of this review.

Histone Mutants Separate R Loop Formation from Genome Instability Induction.

R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA), versus RNA-DNA hybrids alone, were demonstrated using ssDNA-specific human AID and bisulfite. Notably, they are similar size regardless of whether or not they induce genome instability. Contrary to mutants causing R loop-mediated instability, these histone mutants do not accumulate H3 serine-10 phosphate (H3S10-P). We propose a two-step mechanism in which, first, an altered chromatin facilitates R loops, and second, chromatin is modified, including H3S10-P, as a requisite for compromising genome integrity. Consistently, these histone mutations suppress the high H3S10 phosphorylation and genomic instability of hpr1 and sen1 mutants. Therefore, contrary to what was previously believed, R loops do not cause genome instability by themselves.

Delineating the mechanism of fragility at BCL6 breakpoint region associated with translocations in diffuse large B cell lymphoma.

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into non-B DNA. Results revealed that the Cluster II sequence folded into overlapping hairpin structures and identified sequences that undergo base pairing at the stem region. Further, the formation of cruciform DNA blocked DNA replication. The sodium bisulfite modification assay revealed the single-strandedness of the region corresponding to hairpin DNA in both strands of the genome. Further, we report the formation of intramolecular parallel G4 and triplex DNA, at Cluster II. Taken together, our studies reveal that multiple non-canonical DNA structures exist at the BCL6 cluster II breakpoint region and contribute to the fragility leading to BCL6 translocation in DLBCL patients.

Hyperglycaemia, diabetes and risk of fragility fractures: observational and Mendelian randomisation studies.

AIMS/HYPOTHESIS: Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality. METHODS: In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses. RESULTS: Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither. CONCLUSIONS/INTERPRETATION: Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.

Fibroblast growth factor 23 and its role in bone diseases.

Fibroblast growth factor 23 (FGF23) has been casually linked to numerous hypophosphatemic bone diseases, however connection with bone loss or fragility fractures is still a matter of debate. The purpose of this review is to explore and summarise the known actions of FGF23 in various pathological bone conditions. Besides implication in bone mineralisation, elevated FGF23 showed a pathological effecton bone remodelling, primarily by inhibiting osteoblast function. Unlike the weak association with bone mineral density, high values of FGF23 have been connected with fragility fracture prevalence. This review shows that its effects on bone are concomitantly present on multiple levels, affecting both qualitative and quantitative part of bone strength, eventually leading to impaired bone strength and increased tendency of fractures. Recognising FGF23 as a risk factor for the development of bone diseases and correcting its levels could lead to the reduction of morbidity and mortality in specific groups of patients.

Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma.

BACKGROUND: The clinical benefit of systemic anticancer therapies can be unclear despite positive trials, and outcomes may not translate to real-world practice. This study evaluated the benefit of soft tissue sarcoma (STS) treatments using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (MCBS) v1.1 and measured the robustness of STS trial results using Fragility Index (FI). METHODS: Database searches for adult phase II or III trials in advanced STS (January 1998-December 2023) were performed. Therapies with trial outcomes that met the criteria for MCBS were scored 1-5 (≥4 represents substantial clinical benefit). For randomized clinical trials with positive time-to-event endpoints, the number of additional events that would render results nonsignificant, FI, was calculated and expressed as a proportion of the experimental arm size (fragility quotient [FQ]). Higher FI/FQ implies more robust results. RESULTS: Among 194 trials, 19 (9.8%) were phase III. Most phase II trials (146/175; 83.4%) had single-arm or non-comparative design. Trials that were eligible for MCBS scoring (n = 78; 40.2%) evaluated 56 different agents/regimens. Median MCBS score was 2. Only three agents/regimens (all cytotoxic therapies) had an MCBS score ≥4. Among 47 randomized clinical trials, 16 (8 phase II; 8 phase III) trials had positive outcomes. Median FI was 7 (range, 2-52) and 10 trials (62.5%) had an FQ < 10%, with median of 7% (range, 1%-59%). CONCLUSIONS: Most systemic therapies in STS trials did not confer substantial clinical benefit per European Society of Medical Oncology-MCBS. Additionally, positive randomized trials were often fragile. Novel STS therapy trials should use clinically meaningful endpoints and real-world efficacy confirmation is essential, especially for less robust trials.

A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE.

By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.

Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review.

Regulatory T cells (Tregs) expressing the transcription factor FoxP3 are essential for maintaining immunological balance and are a significant component of the immunosuppressive tumor microenvironment (TME). Single-cell RNA sequencing (ScRNA-seq) technology has shown that Tregs exhibit significant plasticity and functional diversity in various tumors within the TME. This results in Tregs playing a dual role in the TME, which is not always centered around supporting tumor progression as typically believed. Abundant data confirms the anti-tumor activities of Tregs and their correlation with enhanced patient prognosis in specific types of malignancies. In this review, we summarize the potential anti-tumor actions of Tregs, including suppressing tumor-promoting inflammatory responses and boosting anti-tumor immunity. In addition, this study outlines the spatial and temporal variations in Tregs function to emphasize that their predictive significance in malignancies may change. It is essential to comprehend the functional diversity and potential anti-tumor effects of Tregs to improve tumor therapy strategies.

Relationship between red blood cell lifespan and endogenous carbon monoxide in the common bottlenose dolphin and beluga.

Certain deep-diving marine mammals [i.e., northern elephant seal (Mirounga angustirostris), Weddell seal (Leptonychotes weddellii)] have blood carbon monoxide (CO) levels that are comparable with those of chronic cigarette smokers. Most CO produced in humans is a byproduct of heme degradation, which is released when red blood cells (RBCs) are destroyed. Elevated CO can occur in humans when RBC lifespan decreases. The contribution of RBC turnover to CO concentrations in marine mammals is unknown. Here, we report the first RBC lifespans in two healthy marine mammal species with different diving capacities and heme stores, the shallow-diving bottlenose dolphin (Tursiops truncatus) and deep-diving beluga whale (Delphinapterus leucas), and we relate the lifespans to the levels of CO in blood and breath. The belugas, with high blood heme stores, had the longest mean RBC lifespan compared with humans and bottlenose dolphins. Both cetacean species were found to have three times higher blood CO content compared with humans. The estimated CO production rate from heme degradation indicates some marine mammals may have additional mechanisms for CO production, or delay CO removal from the body, potentially from long-duration breath-holds.NEW & NOTEWORTHY This is the first study to determine the red blood cell lifespan in a marine mammal species. High concentrations of carbon monoxide (CO) were found in the blood of bottlenose dolphins and in the blood and breath of belugas compared with healthy humans. Red blood cell turnover accounted for these high levels in bottlenose dolphins, but there may be alternative mechanisms of endogenous CO production that are contributing to the CO concentrations observed in belugas.

Usmani-Riazuddin syndrome can have a recognizable phenotype: Report of a novel AP1G1 variant.

Usmani-Riazuddin syndrome (USRISR, MIM# 619548; USRISD, MIM#619467) is a very rare genetic condition. recently associated with deleterious variants in AP1G1 (MIM* 603533). It is characterized by multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, muscular tone disorders, seizures, limb defects, and unspecified facial gestalt. In this report, we describe this syndrome for the second time, in association to a novel AP1G1 variant identified in a toddler with multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, arrhythmias, hearing loss, skin changes, and limb defects. Next generation sequencing (NGS) analysis through clinical exome disclosed AP1G1: c.1969C>G (p.Leu657Val), de novo, likely pathogenic variant, according to ACMG classification criteria. Proband's facial features resembled the spectrum of chromatinopathies. Clinical pictures were analyzed and a clinical overlap was supported by DeepGestalt analysis (www.face2gene.com). The system identified 6 chromatin disorders out of 30 possible diagnoses. The remaining 24 included 9 miscellaneous cryptic chromosomal abnormalities (excluded due to normal microarray study). To the best of our knowledge, this is the first description of likely distinctive facial features in a patient with Usmani-Riazuddin syndrome. Further multicentric analyses are needed for a better definition of this aspect.

Assessing the robustness of positive vascular surgery randomized controlled trials using their fragility index.

OBJECTIVE: The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. METHODS: In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. RESULTS: Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P = .035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P = .01, respectively). The FI did not vary between disease states (P = .285) or between index and follow-up trials (P = .147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). CONCLUSIONS: A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery.

Family/caregiver influence on osteoporosis management for older people: an integrative review.

An integrative literature review was conducted to understand family/caregiver influence on osteoporosis management for older people. Findings include caregivers' overprotection, caregivers' risks for fragility fractures due to caregiving role, poor bone health in caregivers, and caregivers' burden and facilitators. Caregivers should be included in bone health and discharge planning. Literature on family/caregiver influence on osteoporosis management for older people is sparse. Older people are prone to osteoporosis and fragility fractures due to their age, often triggering the need for a caregiver after experiencing a fragility fracture. These fractures pose significant costs to the patient and health systems and are projected to increase with the aging population. This study applied an integrative literature review methodology to key literature findings on family/caregiver influence on osteoporosis management for older people. Key findings include caregivers' tendency to overprotect persons who experience hip fracture by limiting mobilization, thus impeding recovery, caregivers' risks for their own fragility fractures due to the demands of their caregiving role, risks of poor bone health in caregivers, and caregivers' experience of significant burden for which facilitators have been identified. Family caregivers of older people with osteoporosis have unique needs and require support and resources, especially after their loved one experiences a hip fracture. Informal caregivers must be considered in bone health education and discharge planning. They should be considered in the creation of osteoporosis guidelines and within the work of fracture liaison services. More research is needed to increase understanding about family caregiver influence on osteoporosis management.

The incremental risk of fragility fractures in aging men.

INTRODUCTION: While the United States Preventative Services Task Force recommends osteoporosis screening for women 65 years and older, there is no definitive recommendation for routine osteoporosis screening in men. The purpose of this study was to determine the age at which the odds of fragility fractures (FFx) increase in men to help guide future policy discussions evaluating an optimal screening strategy in this population. METHODS: Men older than 49 years were identified in the PearlDiver Patient Records Database. Patients were excluded if they had a prior fragility fracture, if they were at high risk for osteoporosis due to comorbidities, or if they carried a diagnosis of and/or were on treatment for osteoporosis. The prevalence of FFx was trended for each age group. A stratum-specific likelihood ratio (SSLR) analysis was conducted to identify data-driven strata that maximize the incremental FFx risk by age for men. Logistic regression analyses controlling for potential confounders were conducted to test these identified strata. RESULTS: The incidence of FFx started to increase after the age of 64 years for men. Further, the identified data-driven age strata associated with a significant and incremental difference in fragility fractures were the following: 50-64, 65-69, 70-72, 73-75, 76-78, 79-80, and 81+. When compared to the youngest age stratum (50-64 years), multivariable regression showed the risk of fragility fracture incrementally increased starting in those aged 70-72 (RR, 1.31; 95% CI. 1.21-1.46; p < 0.001) with the highest risk in those aged 81+ (RR, 5.35; 95% CI, 5.10-5.62; p < 0.001). CONCLUSION: In men without a pre-existing history of osteoporosis, the risk of fragility fractures starts to increase after the age of 70. Further work building upon these data may help to identify a specific age at which routine bone health screening in males can help to minimize fractures and their associated morbidity and mortality.

Evaluation of costs, osteoporosis treatment, and re-fractures in German collaborative orthogeriatric care after fragility fractures.

Orthogeriatric co-management (OGCM) may provide benefits for geriatric fragility fracture patients in terms of more frequent osteoporosis treatment and fewer re-fractures. Yet, we did not find higher costs in OGCM hospitals for re-fractures or antiosteoporotic medication for most fracture sites within 12 months, although antiosteoporotic medication was more often prescribed. PURPOSE: Evidence suggests benefits of orthogeriatric co-management (OGCM) for hip fracture patients. Yet, evidence for other fractures is rare. The aim of our study was to conduct an evaluation of economic and health outcomes after the German OGCM for geriatric fragility fracture patients. METHODS: This retrospective cohort study was based on German health and long-term care insurance data. Individuals were 80 years and older, sustained a fragility fracture in 2014-2018, and were treated in hospitals certified for OGCM (ATZ group), providing OGCM without certification (OGCM group) or usual care (control group). Healthcare costs from payer perspective, prescribed medications, and re-fractures were investigated within 6 and 12 months. We used weighted gamma and two-part models and applied entropy balancing to account for the lack of randomization. All analyses were stratified per fracture site. RESULTS: We observed 206,273 patients within 12-month follow-up, of whom 14,100 were treated in ATZ, 133,353 in OGCM, and 58,820 in other hospitals. Total average inpatient costs per patient were significantly higher in the OGCM and particularly ATZ group for all fracture sites, compared to control group. We did not find significant differences in costs for re-fractures or antiosteoporotic medication for most fracture sites, although antiosteoporotic medication was significantly more often observed in the OGCM and particularly ATZ group for hip, pelvic, and humerus fractures. CONCLUSION: The observed healthcare costs were higher in ATZ and OGCM hospitals within 12 months. Antiosteoporotic medication was prescribed more often in both groups for most fracture sites, although the corresponding medication costs did not increase.

Epidemiology of forearm fractures in women and men in Norway 2008-2019.

The purpose of this paper is to describe rates of forearm fractures in adults in Norway 2008-2019. Incidence rate of distal forearm fractures declined over time in both sexes. Forearm fracture constitute a significant health burden and prevention strategies are needed. PURPOSE: To assess age- and sex-specific incidence rates, and time trends for forearm fractures in Norway, and compare these with incidence rates in other Nordic countries. METHODS: Data on all patients aged 20-107 years with forearm fractures treated in Norwegian hospitals from 2008 to 2019 was retrieved from the Norwegian Patient Registry. Fractures were identified based on International Classification of Disease 10th revision code S52. Age- and sex-specific incidence rates and changes in incidence rates were calculated. RESULTS: We identified 181,784 forearm fractures in 45,628,418 person-years. Mean annual forearm fracture incidence rates per 100,000 person-years were 398 (95% CI 390-407) for all, 565 (95% CI 550-580) for women, and 231 (95% CI 228-234) for men above 20 years. Mean annual number of forearm fractures was 15,148 (95% CI 14,575-15,722). From 2008 to 2019, age-adjusted total incidence rates of forearm fractures S52 diagnoses declined by 3.5% (incidence rate ratio (IRR) of 0.997 (95% CI 0.994-0.999)) in men. The corresponding decline in women was not significant (IRR: 0.999 (95% CI 0.997-1.002)). In the same period, the age-adjusted incidence rates of distal forearm fractures declined by 7.0% in men (IRR = 0.930; 95% CI 0.886-0.965) and 4.7% in women (IRR = 0.953; 95% CI 0.919-0.976). The incidence rates of distal forearm fractures were similar to rates in Sweden and Finland. CONCLUSION: Age-adjusted incidence rates of distal forearm fractures in both sexes declined over time.

Undiagnosed vertebral fragility fractures in patients with distal radius fragility fractures: an opportunity for prevention of morbimortality in osteoporotic patients in developing countries.

Our study investigates vertebral fractures in individuals with distal radius fractures. Among 512 patients, 41.21% had vertebral fractures, predominantly in the lumbar spine. These findings highlight the importance of screening for vertebral fractures in this population, informing early intervention strategies to mitigate risks associated with osteoporosis. PURPOSE: This study's main goal was to look into the frequency, location, kind, and severity of asymptomatic vertebral fragility fractures (VFF) in people who had fractures of the fragility of the distal radius. Although VFF is frequently misdiagnosed, it is linked to higher mortality, morbidity, and hip fracture risk. The study also attempted to investigate the relationship between VFF and certain demographic and lifestyle factors, as well as FRAX data, in this patient population. METHODS: Between January, 2021, and January, 2022, individuals with low-energy distal radial fractures who presented to the emergency room of tertiary care hospital of Karachi, Pakistan, were the subject of a cross-sectional study and were 45 years of age or older except those who fitted the exclusion criteria (n = 208). The thoracic and/or lumbar spine was imaged using radiology, and information on demographics, way of life, and FRAX (Fracture Risk Assessment Tool) was gathered. Using the Genant semiquantitative approach, an impartial and blinded orthopaedist identified VF in the images and determined their severity. SPSS version 20 was used to analyse the data. RESULTS: Two hundred eleven (41.21%) of them were found to have radiographic VFF and only 12 (2.34%) of the 512 patients who were tested were getting osteoporotic therapy. The thoracic spine (32.7%), followed by the lumbar spine (43.12%), was the area most frequently afflicted. In 24.17% of the patients, multiple fractures of the thoracolumbar spine were found. The wedge form (54.5%), followed by biconcave (30.81%) and crush (14.7%), was the most prevalent VFF type. The majority of detected VFF were rated as having a 25-40% height loss (64.9%) then severe (> 40%) fractures (35.1%), according to the Genant grading method. Notably, there were no variations in smoking, drinking, BMI, or FRAX score between patients with and without VFF that were statistically significant. CONCLUSION: Based on our study's findings, it is clear that osteoporotic vertebral fragility fractures occur in almost half of individuals with distal radius fractures. The lumbar spine is notably the most affected region, predominantly with wedge fractures. Given the high prevalence of asymptomatic vertebral fragility fractures (VFF), proactive measures are necessary to mitigate associated risks. Prioritising comprehensive fall risk assessments for these patients and interventions to enhance bone mineral density and strength are crucial. Early identification of asymptomatic VFF enables timely intervention, optimising patient care and minimising the risk of complications in this vulnerable population.

The Healing and therapeutic effects of perioperative bisphosphonate use in patients with fragility fractures: meta-analysis of 19 clinical trials.

OBJECTIVES: Previous evidence suggests that bisphosphonates (BPs) may lower the risk of recurrent fractures and enhance functional recovery in patients with fractures. However, there has been controversy regarding the optimal timing of treatment initiation for patients with fragility fractures. We conducted a meta-analysis to evaluate the available evidence on the use of BPs during the perioperative period and compared it to both non-perioperative periods and non-usage. METHODS: Electronic searches were performed using PubMed, EMBASE, Web of Science and the Cochrane Library published before February 2023, without any language restrictions. The primary outcomes included fracture healing rate, healing time, and new fractures. We also examined a wide range of secondary outcomes. Random effects meta-analysis was used. RESULTS: A total of 19 clinical trials involving 2543 patients were included in this meta-analysis. When comparing patients with non-perioperative BPs use in 4-6 weeks and approximately 10-12 weeks post-surgically, the overall risk ratios (RRs) of perioperative BPs use for healing rate were 1.06 (95% CI: 0.81, 1.38, p=0.69) and 1.02 (95% CI: 0.94, 1.11, p=0.65), respectively, suggesting no difference in healing rate between perioperative and non-perioperative BP initiation. For healing time, the overall mean difference between perioperative and non-perioperative periods was -0.19 week (95% CI: -1.03, 0.64, p=0.65) at approximately 10-12 weeks, indicating no significant impact of perioperative BP initiation on healing time. In terms of new fractures, the overall RR with BP use was 0.35 (95% CI: 0.17-0.73, p=0.005), when compared to patients without BPs use. This suggests a protective impact of BP use against new fractures compared to patients without BP use. Perioperative BP use was associated with a markedly higher likelihood of having adverse experiences, including fever (RR: 23.78, 95% CI: 8.29, 68.21, p< 0.001), arthralgia (RR: 10.20, 95% CI: 2.41, 43.16, p=0.002), and myalgia (RR: 9.42, 95% CI: 2.54, 34.87, p< 0.001), compared with non-BPs use. CONCLUSIONS: Treatment with BP during the perioperative period does not affect the healing process and has positive effects on therapy for patients with fragility fractures. These compelling findings underscore the potential efficacy of BP use during the perioperative period as a viable treatment option for patients with fragility fractures.

Examining treatment targets and equity in bone-active medication use within secondary fracture prevention: a systematic review and meta-analysis.

PURPOSE: This systematic review seeks to evaluate the proportion of fragility fracture patients screened in secondary fracture prevention programs who were indicated for pharmacological treatment, received prescriptions for bone-active medications, and initiated the prescribed medication. Additionally, the study aims to analyze equity in pharmacological treatment by examining equity-related variables including age, sex, gender, race, education, income, and geographic location. METHODS: We conducted a systematic review to ascertain the proportion of fragility fracture patients indicated for treatment who received prescriptions and/or initiated bone-active medication through secondary fracture prevention programs. We also examined treatment indications reported in studies and eligibility criteria to confirm patients who were eligible for treatment. To compute the pooled proportions for medication prescription and initiation, we carried out a single group proportional meta-analysis. We also extracted the proportions of patients who received a prescription and/or began treatment based on age, sex, race, education, socioeconomic status, location, and chronic conditions. RESULTS: This review included 122 studies covering 114 programs. The pooled prescription rate was 77%, and the estimated medication initiation rate was 71%. Subgroup analysis revealed no significant difference in treatment initiation between the Fracture Liaison Service and other programs. Across all studies, age, sex, and socioeconomic status were the only equity variables reported in relation to treatment outcomes. CONCLUSION: Our systematic review emphasizes the need for standardized reporting guidelines in post-fracture interventions. Moreover, considering equity stratifiers in the analysis of health outcomes will help address inequities and improve the overall quality and reach of secondary fracture prevention programs.

Developing fracture liaison service framework based on comparative analysis and scoping review.

This research conducts a comparative analysis and scoping review of 105 studies in the field of Fracture Liaison Service (FLS). The resulting two-dimensional framework represents a significant step toward FLS implementation. PURPOSE: The primary goal is to review interventions in real world settings in order to provide the FLS framework that specifies the essential elements of its implementation and offers different perspectives on that. METHOD: This study encompasses two phases: a comparative analysis of existing FLS models, including "Capture the Fracture," "5IQ," and "Ganda," and a scoping review from 2012 to 2022 in PubMed, Web of Science, Scopus, ProQuest, and IEEE databases limited to publications in English. RESULTS: The resulting model of comparative analysis identifies patient identification, investigation, intervention and integration or continuity of care as the four main stages of FLS. Additionally, the elements of quality and information span across all stages. Following comparative analysis, the framework is designed to be used for content analysis of the included studies in the scoping review. The intersection of columns (Who, Where, When, What, How, Quality) with rows (Identification, Investigation, Intervention, and continuity of care) yields a set of questions, answered in tabular form based on the scoping review. CONCLUSION: The framework offers potential benefits in facilitating the adoption of effective approaches for FLS implementation. It is recommended to undertake an in-depth review of each of these components in order to uncover novel and innovative approaches for improving their implementation.