AIMS:No cardiovascular risk prediction model dedicated to individuals aged ≥70 years with diabetes is currently recommended by the European Society of Cardiology. We aimed to develop a new model, CArdiovascular Risk Estimation-Diabetes Mellitus (CARE-DM), to predict the risk of cardiovascular disease (CVD) in older adults with type 2 diabetes. METHODS AND RESULTS:We developed a model to predict the risk of incident CVD in participants aged ≥65 years with diabetes using data from four population-based prospective cohorts, accounting for the competing risk of non-cardiovascular death. Pre-specified predictors were age, gender, smoking status, alcohol consumption, body mass index, total and HDL cholesterol, use of antihypertensive, cholesterol-lowering and glucose-lowering medication, diabetes duration, and glycated haemoglobin. We assessed model performance using measures of calibration and discrimination. We used a 10-fold cross-validation and a bootstrapping approach to correct estimates for optimism and conducted an internal-external cross-validation. A total of 6943 participants (median age 72 years, 56% women) with diabetes were included in the model development. Over a median follow-up of 6.3 (interquartile range 3.7, 7.2) years, 1204 (17.3%) participants experienced a CVD event. Internal validation with optimism correction showed adequate model performance with a C-index of 0.65 (95% confidence interval 0.63-0.67), an observed-to-expected ratio of 1.01 (0.95-1.08), and a calibration slope of 1.13 (0.95-1.31) at 5 years. CONCLUSION:The new CARE-DM model allows prediction of the incident CVD risk in older adults with type 2 diabetes. Independent external validation should be conducted to confirm the model's performance before implementation in clinical practice.

To characterize fracture circumstances by age at time of fracture among community-dwelling older men, we analyzed incident clinical fractures in the Osteoporotic Fractures in Men study. Participants were contacted every 4 mo to identify fractures confirmed by radiographic reports. Fractures were classified as fall- or non-fall-related and further categorized by degree of trauma: minimal (fall from ≤ standing height), moderate (fall on stairs, steps or curb), or severe (fall from > standing height) for fall-related fractures; and minimal (eg, coughing), moderate (eg, collisions with objects during normal activity without falling), or severe (eg, motor vehicle accident) for non-fall-related fractures. Of 2351 clinical fractures in 1424 men during an average follow-up of 9.9 yr, 12.7% occurred at age <75 yr, 15.7% at age 75-79 yr, 26.1% at age 80-84 yr, and 45.5% at age ≥85 yr. A total of 1891 fractures (80.4% of all fractures) were the result of a fall. The proportion of fall-related fractures steadily rose with increasing age at time of fracture, ranging from 65.8% in men <75 yr rising to 84.7% in men ≥85 yr (p < .001). Most fall-related fractures (76.4%) were due to minimal trauma; the proportion of all fractures due to a fall with minimal trauma steadily rose with increasing age (p < .001). In contrast, approximately half of non-fall-related fractures (53.5%) were due to severe trauma. The proportion of all fractures due to severe trauma (whether fall-related or not) declined with advancing age (p < .001). In conclusion, the most frequently occurring fracture circumstance in older men was a fall from ≤standing height. This circumstance was increasingly common with advancing age occurring in 7 of every 10 fractures in men ≥85 yr, while a fracture (fall-related or not) due to severe trauma was less common with advancing age. Findings have implications for development of fracture prevention strategies in older men.

Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events. Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex. Design and setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration. Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l). Interventions: None as this is an observational study. Main outcome measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP. Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05). Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies.

BACKGROUND:Falls are a major concern in the older population. An important cause of falls is fall-risk-increasing drugs (FRID). However, it is not known if the discontinuation of FRID leads to a reduction of falls. Therefore, the aim of this study was to assess the association between discontinuation of FRID and the occurrence of falls and recurrent falls. METHODS:This study included adults aged ≥ 70 years with multimorbidity and polypharmacy who were enrolled in a cluster randomized controlled trial assessing hospital pharmacotherapy optimization (OPERAM). Participants who were using FRID at baseline, were alive after 2 months of follow-up, and provided data on fall occurrence were included. FRID discontinuation was defined as discontinuation of ≥ 1 FRID within 2 months after inclusion, including the following groups: antidepressants, antiepileptics, antihistamines, antipsychotics, benzodiazepines and z-drugs, diuretics, opioids, and alpha-blockers. Multivariable cox regression analysis, using inverse probability weighting, was performed to assess the association between FRID discontinuation and the occurrence of falls. RESULTS:Our analysis included 1546 participants, with a median age of 79 years (IQR 74-84) and 45% female. After 2 months of follow-up, FRID were discontinued in 878 (57%) participants. Among all participants, 378 (24%) experienced a fall within 1 year of follow-up, with 137 (9%) of the participants experiencing two or more falls, and 199 (13%) participants experiencing a serious fall. No association was found between FRID discontinuation and the occurrence of falls. In a subgroup of participants with a previous fall, discontinuation of antipsychotics was associated with a lower occurrence of falls (HR 0.32 [CI 0.12-0.84], p = 0.02). CONCLUSIONS:In multimorbid older patients using FRID, falls are highly prevalent. No association was found between discontinuation of FRID and the risk of falls, except for the discontinuation of antipsychotics in patients who experienced a previous fall.

Introduction Statins are among the most widely used drugs. While they are effective for primary and secondary prevention of cardiovascular (CV) disease in middle-aged subjects, their benefits for prevention in older adults (aged ≥70 years) without CV disease are uncertain, particularly for those with multimorbidity. Statin side effects and drug interactions are common in older patients and may negatively impact quality of life. To date, the only randomised controlled trial (RCT) investigating statin discontinuation in older adults has demonstrated no difference in survival but did note a small improvement in quality of life for those who discontinued statins. However, this trial exclusively enrolled patients with a life expectancy <1 year. Therefore, the present RCT aims to assess the safety and potential benefits of statin discontinuation in primary prevention for the ever-growing population of multimorbid older adults.Methods and analysis This study is a multicentre, randomised, non-inferiority trial conducted in both inpatient and outpatient settings in Switzerland, France and the Netherlands, targeting patients using statins for primary prevention. 1800 participants are randomly assigned 1:1 to either discontinue (intervention arm) or continue (control arm) statin therapy. The primary objective is to compare the primary composite endpoint of major CV events (non-fatal myocardial infarction or non-fatal ischaemic stroke) and all-cause death between the control and intervention groups over a follow-up duration of up to 48 months. We hypothesise that discontinuing statins does not result in shorter event-free survival, with a non-inferiority margin set at 5.2 weeks over a 2-year observation period. Secondary objectives are to compare patient-centred outcomes (health-related quality of life, muscle pain symptoms, falls and sarcopenia) and all-cause death, non-CV death, major CV events and coronary and peripheral artery revascularisation. The study is open-labelled, with blinded outcome adjudication of the primary endpoints.Ethics and dissemination The trial protocol has received approval from the local ethics committees in Switzerland, France and the Netherlands. Results will be published in a peer-reviewed journal.Trial registration number Clinicaltrials.gov: NCT05178420; BASEC (Swiss Ethics Commission): 2021-01513; FOPH (Swiss national portal): SNCTP000005172; Netherlands Trial Register: NL83907.058.23; France Trial Register: 22.04747.000158– IDRCB 2022-A02481-42.

Disclosure: T. Vilaca: Pharmacosmos. L. Lui: None. M. Schini: UCB. S. Ewing: None. A.R. Thompson: None. E. Vittinghoff: None. D. Bauer: None. D. Bauer: None. D.M. Black: None. M. Bouxsein: Angitia Bio, Keros Therapeutics. R. Eastell: Alexion Pharmaceuticals, Inc., Sandoz, Immunodiagnostic Systems,, Angitia, CL Bio, Cureteq. Objectives In the SABRE Study, we showed that treatment-related differences in 24-month total hip bone mineral density (THBMD) changes are strongly associated with reduced fracture risk in placebo-controlled trials. We also determined the surrogate threshold effect (STE): the minimum THBMD change in a trial that would predict a significant reduction in fracture risk in trials. However, the availability of osteoporosis therapies limits use of placebo-controlled trials, and the need to sustain bone mineral density gains after anabolic therapies leads to the use of sequential therapy. This analysis aimed to determine if these associations and STEs apply to trials using active control or sequential therapies.Material and methods We used individual patient data from 19 trials: 16 randomized, placebo-controlled trials (14 anti-resorptive, 1 teriparatide, 1 odanacatib), and 3 trials with active control or sequential therapy (1 abaloparatide/alendronate and 2 romosozumab/alendronate or denosumab).For each trial, we calculated the treatment-related difference in mean percentage change in THBMD at 24 months and the risk reductions for the entire follow-up period. We used logistic regression for radiologic vertebral fractures and Cox regression for all clinical fractures (combination of non-vertebral and clinical vertebral fractures). We performed linear meta-regression to estimate the study-level association (r2 and 95% CI) between treatment-related differences in THBMD changes and fracture risk reduction, including the 16 placebo-controlled trials only and all the trials including 3 active control/sequential therapy trials and verified if the change in THBMD observed in the trials with active control or sequential therapy was greater than the STE calculated from placebo-controlled trials.Results We found consistent associations between treatment-related THBMD changes and fracture risk reduction for placebo-controlled trials only and all trials for vertebral fractures [r2 (CI)= 0.73 (0.33, 0.84) vs. 0.71 (0.36, 0.82)] and for all clinical fractures [0.71 (0.32, 0.83) vs.0.72 (0.39, 0.83)] respectively. In trials with active control or sequential therapy, the increase in THBMD was greater than STE and associated with a significant decrease in fracture risk: the increase in THBMD was 4.57%; 3.69% and 3.12% respectively for romosozumab/denosumab, romosozumab/alendronate and abaloparatide/alendronate trials, and the STE was 1.43% for vertebral and 2.04% for all clinical fractures. Conclusion Our findings show that treatment-related changes in THBMD predict anti-fracture efficacy equally well, regardless of the trial design. Presentation: Saturday, July 12, 2025

As populations are aging, the number of older patients with multiple chronic diseases demanding complex care increases. Although clinical guidelines recommend care to be personalized accounting for life expectancy, there are no tools to estimate life expectancy among multimorbid patients. Our objective was therefore to develop and internally validate a life expectancy estimator specifically for older multimorbid adults. We analyzed data from the OPERAM (OPtimising thERapy to prevent avoidable hospital admissions in multimorbid older people) study in Bern, Switzerland. Participants aged 70 years old or more with multimorbidity (3 or more chronic medical conditions) and polypharmacy (use of 5 drugs or more for > 30 days) were included. All-cause mortality was assessed during 3 years of follow-up. We built a 3-year mortality prognostic index and transformed this index into a life expectancy estimator. Mortality risk candidate predictors included demographic variables (age, sex), clinical characteristics (metastatic cancer, number of drugs, body mass index, weight loss), smoking, functional status variables (Barthel-Index, falls, nursing home residence), and hospitalization. We internally validated and optimism corrected the model using bootstrapping techniques. We transformed the mortality prognostic index into a life expectancy estimator using the Gompertz survival function. Eight hundred five participants were included in the analysis. During 3 years of follow-up, 292 participants (36

Emerging anti-osteoporosis therapies might present varied mechanisms of action and demand active control groups or sequential therapies due to ethical or mechanistic reasons. We previously showed a strong association between treatment-induced changes in total hip BMD (THBMD) at 12 and 24 mo and reduced fracture risk in placebo-controlled trials. We determined the surrogate threshold effect: the minimum THBMD difference (active-placebo) in a trial that would predict a significant reduction in fracture risk in trials. In this analysis, we investigated whether these associations are influenced by drug mechanism of action or trial design, including treatment with an anabolic followed by an antiresorptive compared to active control or placebo. We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 antiresorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and 3 trials of an anabolic followed by an antiresorptive (1 PTH analog and 2 romosozumab). We established treatment-related differences in THBMD changes, calculated fracture risk reductions for radiologic vertebral and all clinical fractures, and estimated study-level associations between these features via meta-regression. We found consistent associations between treatment-related THBMD changes and fracture risk reduction across different drug mechanisms and trial designs. Among placebo-controlled trials, the r(2) values for vertebral fractures were 0.73 (p = .0001) and 0.78 (p = .0002) at 24 mo, and 0.59 (p = .0003) and 0.70 (p = .0007) at 12 mo for all drugs vs only antiresorptive drugs, respectively. Similarly, for all clinical fractures, the r(2) were 0.71 (p < .0001) and 0.65 (p = .0009) at 24 mo and 0.46 (p = .0007) and 0.51 (p = .002) at 12 mo for all drugs vs only antiresorptive drugs. For trials of an anabolic followed by an antiresorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design.

The European Society of Cardiology recommends the use of the SCORE2-Diabetes cardiovascular risk prediction model in primary prevention for persons with diabetes aged 40–69 years; however, no model is currently recommended for older individuals. Our objective was to develop a new risk prediction model (CARE-DM, CArdiovascular Risk Estimation - Diabetes Mellitus) for the estimation of incident cardiovascular disease (CVD) risk in older adults (aged ≥65 years) with type 2 diabetes. We used individual participant data of persons aged ≥65 years with diabetes and without prior CVD from four population-based cohorts (CoLaus, HRS, Health ABC, SHARE) to develop a model to predict the risk of incident CVD event (a composite of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction), accounting for the competing-risk of non-cardiovascular death. We defined 5-year CVD risk categories as low (<2.5%), moderate (2.5-<5%), high (5-<10%) and very high (≥10%) risk. We assessed calibration (observed-to-expected ratio and calibration slope) and discrimination (c-index) of the model, and corrected estimates for optimism using bootstrapping and 10-fold cross-validation. We also conducted an internal-external cross-validation. The model was developed using data from 6’943 participants with diabetes (median age 72 years, 56% women). During a median follow-up time of 6.3 [interquartile range 3.7, 7.2] years, 1’204 (17.3%) participants experienced a CVD event and 1’524 (22.0%) died of non-cardiovascular causes. Using the model, 0% of participants were classified as low-risk, 3% as moderate risk, 39% as high-risk and 58% as very high risk (Figure 1). Agreement between observed and predicted 5-year risks was adequate (Figure 2). The optimism-corrected observed-to-expected ratio and calibration slope were 1.01 (95% CI 0.95-1.08) and 1.13 (95% CI 0.95-1.31), respectively. The optimism-corrected c-index for discriminative performance at 5-years was 0.65 (95% CI 0.63-0.67). Discriminative performance was similar across age groups, 65-74 years (c-index 0.61, 95% CI 0.58 to 0.64) and 75+ years (c-index 0.63, 95% CI 0.60 to 0.65), as well as between men (c-index 0.64, 95% CI 0.61 to 0.66) and women (c-index 0.65, 95% CI 0.63 to 0.68). A model including an indicator for low-, moderate- or high-risk geographical region, classified as in SCORE2-Diabetes, showed similar performance to the main model. The new CARE-DM model allows prediction of the incident risk of CVD in older adults with type 2 diabetes. Further external validation should be conducted to verify its performance prior to clinical implementation.Figure 1.CI curves by risk groupFigure 2.Calibration plot at 5-years

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip BMD (TH BMD) at 2 yr could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the Foundation for the National Institutes of Health-American Society for Bone and Mineral Research- A Study to Advance BMD as a Regulatory Endpoint (FNIH-ASBMR-SABRE) project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN), and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups, which included data from 46 666 placebo participants in 25 RCTs. We estimated the relative risk (RR) of fracture per SD decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, "all," and "all clinical" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 +/- 7.2 yr, mean TH BMD T-score -1.97 +/- 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43), and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race, and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs. Bone mineral density (BMD) is the standard of care for the diagnosis of osteoporosis. In this study, we analyzed data from more than 40 000 placebo participants in 25 RCTs of medications used for osteoporosis. We showed that there is a strong relationship between low total hip BMD (TH BMD) and high risk of fractures.

Background/Objectives: Hyponatremia has been associated with mortality and hospital readmissions. Although multimorbid older patients are particularly affected, specific data on this group are lacking. Methods: A prospective cohort was used based on the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial, a European multicenter, cluster-randomized trial among hospitalized patients aged ≥70 years with ≥3 chronic medical conditions taking ≥5 long-term medications, with documented sodium values at admission, excluding participants with hypernatremia (>145 mmol/L). The primary outcome was all-cause 1-year mortality, and secondary outcomes were 30-day mortality and readmission at 1 year and at 30 days. We examined the association between hyponatremia and mortality in comparison to normonatremia using a mixed-effects survival model, with adjustment for age, sex, comorbidities, study intervention arm, study site and cluster; and the association between hyponatremia and readmission using competing risk models with death as the competing risk. Subgroup analyses were performed across sodium hyponatremia categories (mild 134–130 mmol/L, moderate 129–125 mmol/L, severe < 125 mmol/L). Results: Of 2008 OPERAM participants, 1968 had a sodium value at admission, and 33 were excluded due to hypernatremia. In the 1935 participants, the mean age was 79.4 years (standard deviation 6.3), 866 (44.8%) were female, the median number of comorbidities was 11 (IQR 8–16), the median number of drugs was 10 (IQR 7–13), and 401 (20.7%) had hyponatremia at admission. The multivariate-adjusted hazard ratio (HR) for 1-year mortality with hyponatremia was 1.41 (95% confidence interval [CI] 1.11–1.78, 364 deaths) and for 30-day mortality was 1.20 (95%CI 0.74–1.94, 89 deaths). The adjusted sub-HR for 1-year readmission was 0.94 (95%CI 0.79–1.11), and that for 30-day readmission was 1.1 (95%CI 0.78–1.59). There was a linear increase in 1-year mortality across hyponatremia categories (HR from 1.31 to 2.64, p for trend = 0.001). Conclusions: Hyponatremia at admission is associated with increased 1-year mortality in multimorbid older adults, with increasing risk for lower sodium values. These findings support sodium as a useful prognostic marker in this setting, while its potential independent impact on survival remains to be clarified in prospective studies.

This Clinical Insights discusses factors clinicians should consider when prescribing denosumab among postmenopausal women with osteoporosis.

BACKGROUND:Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults. METHODS:We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D. RESULTS:The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98]). CONCLUSIONS:T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults.

To the Editor: One in five men older than 50 years of age will have an osteoporosis-related fracture, which is often associated with high risks of complications and death and high costs.(1) Guidelines from the Endocrine Society suggest that men with hypogonadism should have their bone mineral density measured,(2) given that hypogonadism causes a decrease in bone mineral density,(3) whereas testosterone-replacement therapy increases bone mineral density when used in concert with calcium and vitamin D supplementation.(4) A recent study showed that only approximately 7% of men who begin receiving testosterone-replacement therapy have their bone mineral density assessed.(5) This situation is . . .

Objective: Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages. Design: This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study. Methods: Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses. Results: Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (-57.2 pmol/L [95% confidence interval, -69.4, -44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2 , but decreased among men with BMI > 23.6 kg/m2 (-24.7 pmol/L [-29.1, -20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (-18.4 pmol/L [-27.6, -9.3]) and in men who formerly smoked (-5.7 pmol/L [-8.9, -2.6]), were in poor general health (-14.0 pmol/L [-20.1, -7.8]), and had diabetes (-19.6 pmol/L [-23.0, -16.3]), cardiovascular disease (-5.8 pmol/L [-8.3, -3.2]), or cancer (-19.2 pmol/L [-24.4, -14.1]) Conclusions: Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values.

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on BMD differ in people ≥70 compared to those <70 yr. We used individual patient data from 23 RCTs of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. We assessed the following fractures: radiographic vertebral, non-vertebral, hip, all clinical, and all fractures. We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes, logistic regression for the radiographic vertebral fracture outcome, and linear regression to estimate treatment effect on 24-mo change in hip and spine BMD in each age subgroup. The analysis included 123 164 (99% female) participants; 43% being ≥70 yr. Treatment with anti-osteoporosis drugs significantly and similarly reduced fractures in both subgroups (eg, odds ratio [OR] = 0.47 and 0.51 for vertebral fractures in those below and above 70 yr, interaction P = .19; hazard ratio [HR] for all fractures: 0.72 vs 0.70, interaction P = .20). Results were similar when limited to bisphosphonate trials with the exception of hip fracture risk reduction which was somewhat greater in those <70 (HR = 0.44) vs ≥70 (HR = 0.79) yr (interaction P = .02). Allocation to anti-osteoporotic drugs resulted in significantly greater increases in hip and spine BMD at 24 mo in those ≥70 compared to those <70 yr. In summary, anti-osteoporotic medications similarly reduced the risk of fractures regardless of age, and the few small differences in fracture risk reduction by age were of uncertain clinical significance.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low BMD measured by DXA. This study used data from a large set of randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into FN BMD T-score subgroups (≤-2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all-fracture outcome reached statistical significance (interaction P = .001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all, and all clinical fractures in the lower BMD quintiles (all interaction P ≤ .03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.