Purpose:To evaluate the real-world effectiveness of antiresorptive osteoporosis pharmacologic treatments on fracture incidence and survival in patients with type 2 diabetes mellitus (T2DM), with subgroup analysis by treatment route. Methods:We conducted a retrospective cohort study using a national registry of patients with T2DM and osteoporosis. Patients receiving antiresorptive treatments (oral or intravenous/subcutaneous [IV/SC]) were compared to untreated individuals using propensity score matching. The primary outcomes were major osteoporotic fracture (MOF) and all-cause mortality. Cox proportional hazards models were used to assess associations, including subgroup analyses by BMI and HbA1c. Results:Among 8,788 matched patients, treatment was associated with significantly lower mortality (adjusted HR 0.86; 95% CI: 0.78-0.94) but not with reduced fracture incidence (HR 1.11; 95% CI: 0.96-1.29). In the treated subgroup (N = 2,960), IV/SC therapy was associated with reduced fracture risk (HR 0.58; 95% CI: 0.35-0.94) but increased mortality (HR 1.63; 95% CI: 1.35-1.96) compared to oral treatment. Conclusion:In this real-world cohort of patients with type 2 diabetes and obesity, osteoporosis treatment was associated with improved survival but not reduced fracture risk. Injectable therapies offered greater fracture protection but were linked to higher mortality, likely due to confounding by indication. Poor adherence may limit the effectiveness of oral treatments in routine care. These findings underscore the need for individualized osteoporosis management strategies in high-risk diabetic populations and raise important considerations regarding the optimal route of administration in real-world settings.

Abstract Background Monitoring developmental milestones is essential for identifying at-risk populations and for guiding effective intervention programs. Our previous report examined milestone attainment among Israeli children from 2016 to 2020. Using a similar methodology, this study analyzes trends in developmental milestone attainment in the Israeli population from 2019 to 2024, with primary focus on 2019 to 2023 because of changes in evaluation policy. This follow-up report complements the earlier analysis by providing updated estimates for the post-COVID period and enabling assessment of temporal trends and potential changes in socioeconomic and regional disparities that could not be evaluated previously. Methods The dataset included over 1 million children with more than 5 million developmental assessments conducted at Maternal and Child Health Clinics (MCHCs) across Israel. These assessments were used to calculate failure rates across four developmental domains: language, social, gross motor, and fine motor skills, along with parental concern about child development. Data were stratified by maternal characteristics, such as age, education, employment, and marital status, and by family sociodemographic factors, including ethnicity, degree of Haredi observance and socioeconomic status. We applied multivariable logistic regression to estimate associations between sociodemographic factors and the odds of failure to attain milestones, while controlling for confounding. Results A mild overall increase in milestone failure rates was observed from 2019 to 2023. Disparities based on maternal characteristics, particularly lower education, divorce status, unemployment, advanced maternal age, and immigration background, widened notably during periods of national disruption (COVID-19 and the war). In contrast, gaps associated with ethnicity and socioeconomic status remained stable or narrowed. Parental concern increased across most groups, particularly among Bedouin parents, suggesting growing awareness. Conclusions Maternal-level characteristics were strongly associated with elevated developmental risk from 2019 to 2023, and may be particularly sensitive to national crises. The findings underscore the importance of strengthening parental awareness, prioritizing early identification of high-risk families, and maintaining access to developmental services during emergencies. The study’s insights can support decision-makers in education, health, welfare, and local authorities in developing evidence-based strategies to promote equity and resilience in early childhood development systems.

Evidence supporting osteoporosis screening in older men remains limited. In a large real-world cohort of 29,906 men aged ≥ 70 undergoing DXA screening, osteoporosis was identified in 16.5

[This corrects the article DOI: 10.3389/fendo.2026.1688669.].

In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2

The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73 = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

Importance:There are limited data regarding adolescent weight among healthy individuals and their trajectory through early adulthood with respect to bone health. Objective:To assess the association between adolescent body mass index (BMI) and osteoporosis risk while accounting for BMI change during early adulthood. Design, Setting, and Participants:A retrospective population-based cohort study from 1967 to 2019. Participants were Israeli-born adolescents aged 16 to 19 years who were evaluated for military service. Data were analyzed from January 2023 to March 2025. Exposure:Weight and height were measured to calculate BMI at adolescence, and additional sociodemographic and medical data were collected. Health status at baseline and incident cancer and diabetes throughout adulthood were strictly controlled. Main Outcomes and Measures:Osteoporosis diagnosis until 2022, recorded in the osteoporosis registry of Maccabi Healthcare Services (the second-largest Israeli health care system). Cox proportional hazard models were applied. Adult BMI measurement was available for 74% of the study population and was used to assess the association between adolescence-to-adulthood weight trajectory and incident osteoporosis. Results:In this cohort study of 1 083 491 adolescents, 21 497 (4.58%) women and 6929 (1.13%) men were enrolled in the osteoporosis registry during a cumulative follow-up of 19 400 208 person-years (mean [SD] age at follow-up, 23.7 [8.5] years). There was a consistent inverse association between adolescent BMI and osteoporosis risk in adulthood. The crude incidence rate of osteoporosis decreased from 330.2 per 100 000 person-years among those with extreme underweight (<3rd percentile) to 78.9 among those with obesity (≥95th percentile). Adjusted hazard ratios for osteoporosis ranged from 1.88 (95% CI, 1.74-2.04) to 0.83 (95% CI, 0.77-0.89) in women and from 1.82 (95% CI, 1.64-2.01) to 1.04 (95% CI, 0.93-1.16) in men, using normal BMI as the reference. A sex-specific difference in osteoporosis risk was notable, with obesity not showing a protective association in men compared with women. The findings were robust across multiple models and sample restrictions, and the highest risk was observed in individuals who remained underweight from adolescence into adulthood. Conclusions and Relevance:In this cohort study, BMI at a young age and its trajectory to adulthood were significantly associated with risk for osteoporosis in adult life.

PurposeTo assess the comparative effectiveness of zoledronic acid vs. denosumab in prevention of major osteoporotic fractures and mortality among patients with type 2 diabetes.MethodsThe study population was identified by crosslinking the diabetes and osteoporosis registries of a large healthcare organization in Israel. Demographics, Charlson Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins and anti-resorptive agents were collected. Exposure groups were matched using propensity score. Kaplan-Meier curves were generated to assess the time from treatment initiation to outcomes. Multivariable Cox’s proportional hazards survival models estimated hazard ratios (HR) and 95% CIs for each outcome.ResultsAmong 27503 patients with concurrent osteoporosis and type 2 diabetes, 627 (4.7%) received zoledronic acid and 502 (3.7%) denosumab. Prior to matching, the denosumab-treated patients were older (mean age 75.7 vs 71.9, p<0.01), had longer diabetes duration (mean 8.4 vs 7.2 years, p<0.01), and had a lower baseline eGFR (59.4 vs 75.3, p<0.01) than the zoledronic acid-treated patients. After matching, 415 pairs of subjects were included. The incidence of all examined outcomes was similar in the Zol and Dmab treatment groups, including 5-year cumulative incidence of fractures (38% vs 31%), death events (36% vs 41%), overall fracture risk (HR=1.17, 95% CI: 0.78 to 1.75), death risk (HR= 1.12, 95% CI:0.87 to 1.44), and mortality after a hip fracture (HR= 0.92, 95% CI:0.37-2.29).ConclusionsOur findings suggest comparability of Zoledronic Acid and Denosumab in managing osteoporotic fractures and mortality among patients with type 2 diabetes.

The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3

The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

PURPOSE:Blepharitis is a prevalent ocular condition, associated with significant discomfort and linked to other ocular and systemic pathologies such as dermatological conditions. The pathophysiology of blepharitis is multifactorial, and the potential correlation with systemic conditions including blood test abnormalities is still not fully known. We aimed to identify systemic conditions and routine laboratory abnormalities independently associated with blepharitis in a large screening-clinic cohort. METHODS:This case-control study analyzed electronic medical records from adults who underwent routine ophthalmic and systemic evaluations at a single Medical Screening Institute between 2001 and 2020. Patients with blepharitis were compared with controls after accounting for age and sex differences via inverse probability weighting. The outcome measures were systemic conditions and blood tests results. P values were adjusted for multiple testing using the false discovery rate (q-values). RESULTS:Overall, 35,678 individuals were included in the study. Among them, 4797 (13.4%) were diagnosed with blepharitis. Blepharitis cases were characterized by a higher rate of dermatological conditions (15.7% vs. 12.2%, q < 0.001), and neurological disorders (7.2% vs. 5.7%, q = 0.013) compared with controls. No significant correlations were observed between blepharitis blood test abnormalities, including complete blood count and chemistry. CONCLUSIONS:This study supports the association between blepharitis and dermatological conditions and highlights a possible link with neurological disorders.

Importance Detecting and addressing potentially modifiable factors associated with healthy development is key to optimizing a child’s potential. When investigating the outcomes of child development, it is important to account for disparities in feeding practices and avoid confounding bias. Objectives To estimate the independent association between breastfeeding and attainment of developmental milestones or neurodevelopmental conditions. Design, Setting, and Participants This retrospective cohort study used data from a national network for routine child development surveillance in Israel linked with national social insurance financial entitlements for neurodevelopmental deficiencies. Participants were children born between January 2014 and December 2020 after at least 35 weeks’ gestation without severe morbidity and with at least 1 follow-up surveillance visit at 2 to 3 years of age. Outcome data were collected in March 2023. Exposures Duration and exclusivity of breastfeeding in infancy. Main Outcomes and Measures The primary outcomes were delays in attainment of developmental milestones and diagnosis of prespecified neurodevelopmental conditions. Multivariable regression, matching, and within-family analyses were used to estimate adjusted odds ratios (AORs) after accounting for potential confounding factors related to the child (gestational age, birth weight, multiple gestation, and child order in the family) and mother (age, socioeconomic status, educational level, marital status, employment, nationality, and postpartum depression). Results Of 570 532 children (291 953 [51.2%] male), 20 642 (3.6%) were preterm, 38 499 (6.7%) were small for gestational age, and 297 571 (52.1%) were breastfed for at least 6 months (123 984 [41.7%] were exclusively breastfed). Children who were breastfed for at least 6 months exhibited fewer delays in attaining language and social or motor developmental milestones compared with children exposed to less than 6 months of breastfeeding (AOR, 0.73 [95% CI, 0.71-0.76] for exclusive breastfeeding; AOR, 0.86 [95% CI, 0.83-0.88] for nonexclusive breastfeeding). Among 37 704 sibling pairs, children who were breastfed for at least 6 months were less likely to demonstrate milestone attainment delays (OR, 0.91 [95% CI, 0.86-0.97]) or be diagnosed with neurodevelopmental conditions (OR, 0.73 [95% CI, 0.66-0.82]) compared with their sibling with less than 6 months of breastfeeding or no breastfeeding. Conclusions and Relevance In this cohort study, exclusive or longer duration of breastfeeding was associated with reduced odds of developmental delays and language or social neurodevelopmental conditions. These findings may guide parents, caregivers, and public health initiatives in promoting early child development.

Objective To determine whether Xanthelasma palpebrarum (XP) is associated with dyslipidemia, cardiovascular disease (CVD) and other systemic conditions in a large population. Design Case-control study conducted at a single tertiary care center. Participants Individuals who were examined at a medical screening institute from 2001 to 2020. Methods Medical records were reviewed to extract data on ophthalmic evaluations, blood tests, and systemic diagnoses. Patients identified with XP in at least one eye comprised the study group. A control group without XP was established matched by age and sex at a 10:1 ratio to allow robust statistical analysis. Main Outcome Measures Associations between XP and dyslipidemia and CVD. Lipid profiles, diagnosis of dyslipidemia and CVD were compared between the case and control groups. Results The database included 35,452 individuals, 24,287 males (69%), mean age 52.2±12.2 years. The study population included 203 XP patients (0.6%) and 2030 matched controls. The prevalence of dyslipidemia diagnosis and the usage rates of statins, fibrates, or other cholesterol-lowering medications was similar between the two groups. Lipid profiles were similar between the groups, including median total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels (187 controls vs. 192 XP, 48 controls vs. 47 XP, 120 controls vs. 125 XP, 111 controls vs. 105 XP, respectively, P>0.05 for all). The rate of CVD was similar as well (10% controls vs. 8.9%, XP P=0.56). The prevalences of related conditions, including hypertension, diabetes mellitus, and history of cerebrovascular accident, were similar between groups (24% controls vs. 23% XP, 14% controls vs. 10% XP, 1.3% controls vs. 1% XP, respectively P>0.05). Conclusions XP was not associated with increased rates of dyslipidemia or CVD. This questions the extent to which XP serves as an indicative marker for heightened systemic risk.Introduction

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). The resource comprised 906,359 women and men (66.9

We studied the association between non-osteoporotic fractures and future major osteoporotic fractures, using UK health records. Non-osteoporotic fractures were found to increase the risk of major osteoporotic fractures, although to a lesser extent than osteoporotic fractures. This highlights the importance of considering all previous fractures in assessing future fracture risk. PURPOSE:Previous studies demonstrated that osteoporotic fractures-minor and major-increase the risk for future major osteoporotic fractures; we test whether non-osteoporotic fractures are also associated with such increased risk. METHODS:The study is a retrospective cohort study using UK primary care electronic health records. Exposure groups were defined according to fracture location prior to the year 2011 (index date): major, minor, and non-osteoporotic. The outcome of incident major osteoporotic fractures following the index date was compared between the exposure groups and the general population. RESULTS:The general study population included 1,951,388 patients. The exposure groups included 39,931 patients with a prior major osteoporotic fracture, 19,397 with a prior minor osteoporotic fracture, and 50,115 patients with a prior non-osteoporotic fracture. The standardized Incidence Rate Ratio for future major osteoporotic fractures was 2.73 (95% confidence interval: 2.64-2.82), 2.43 (2.32-2.54), and 1.83 (1.74-1.92), respectively. CONCLUSION:Non-osteoporotic fractures are significantly associated with increased risk for future major osteoporotic fractures relative to the general population, yet to a lesser extent compared to major and minor osteoporotic fractures.

Objectives Increased acid-suppressive therapy (AST) usage during infancy is seen worldwide, while the data on the risk for paediatric fractures associated with these drugs are scarce. We aimed to evaluate the risk for fractures associated with early-life usage of AST.Methods This population-based retrospective propensity-matched cohort study included children born between 2005 and 2016 who used AST during the first year of life, and a 3:1 matched unexposed group. Study subjects were followed from the end of the first year of life until the earliest of the following: an outcome event (either fracture or non-fracture injury, separately), age of 10 or August 2022. The cumulative incidence of fractures and the HR of AST for fracture and non-fracture injury as negative control were calculated.Results A total of 13 894 eligible AST users and 41 418 propensity score-matched non-users were included in the analysis. The cumulative incidence of fracture among children with AST (23.7%) was significantly (p<0.001) higher than non-users (21.7%) corresponding to an HR of 1.11 (95% CI 1.06 to 1.16). The HR for one to two AST purchases versus none was 1.09 (95% CI 1.04 to 1.14) and the HR for 3+ AST purchases versus none was 1.25 (95% CI 1.13 to 1.39). AST was also associated with injuries by an HR of 1.09 (95% CI 1.04 to 1.13).Conclusions AST was associated with a small but statistically significant increased incidence of fractures. We cannot exclude reporting bias or residual confounders. The clinical inference is currently unclear.

BACKGROUND:The standard practice to account for expected developmental lags in preterm children is calculating their age as if born on their expected delivery date. We aimed to assess the accuracy of standard age correction in a large and diverse population. METHODS:Routine surveillance data was extracted from a national network of mother-child clinics covering over 70% of the Israeli population. We included children with no developmental delay at age 2 years old, to exclude chronic dysfunctions. For each milestone assessed before age 2 years old we calculated the age of 90% and 95% population-milestone attainment, and compared attainment age between term and preterm children, before and after age correction. RESULTS:The study consisted of n = 656,986 and n = 52,662 term and preterm children respectively. Without age correction extensive gaps were observed in all domains, all degrees of prematurity and persisted throughout the first 2 years of life. With age correction most gaps were resolved among moderate/late preterm children, but not among extreme and very preterm, with residual gaps of at least 2 months for motor and 1 month for language-social development. CONCLUSION:While standard age correction accounts for maturational delay in late/moderate preterm children, it may underestimate the maturational delay among very/ extremely preterm children. IMPACT:Standard age correction is sufficient for late/moderate preterm children, and underestimates the maturational delay of extreme and very preterm children. Prior evidence on the accuracy of standard age correction across developmental domains and degrees of prematurity was limited to dated, small-scale data. Maturational delays persist throughout the first 2 years of life across all developmental domains and in all levels of prematurity. Developmental assessments without age correction may lead to unnecessary parental anxiety.