Abaloparatide treatment significantly increased BMD at the LS, TH, and FN compared with placebo in men with osteoporosis in the phase 3 ATOM trial. The current study used 3D-DXA modeling to evaluate the effects of abaloparatide on cortical and trabecular compartments of the proximal femur in ATOM study participants. Proximal femur DXA images were retrospectively analyzed using 3D-DXA (3D-Shaper software v2.12.0, 3D-Shaper Medical, Barcelona, Spain) to evaluate changes in bone parameters from baseline at months 6 and 12 in all randomized men from the ATOM trial. Between-group comparisons were made for percent change from baseline data based on a mixed-effect repeated-measure model with treatment, visit, treatment-by-visit interaction, and type of DXA scanner as fixed effects. Other covariates include BMI, age, and baseline values of bone parameters. Abaloparatide treatment significantly increased integral volumetric BMD (vBMD) (3.7%), trabecular vBMD (7.0%), cortical thickness (1.1%), and cortical surface BMD (1.7%) at 12 mo compared to baseline (p < .0001). Changes were greater for abaloparatide compared to placebo for all 4 parameters (p < .01). Significant increases from baseline compared to placebo in integral vBMD (2.7% vs -0.1%, p < .0001) and trabecular vBMD (6.1% vs -0.6%, p < .0001) were also observed at 6 mo. In conclusion, in men with osteoporosis, abaloparatide improved proximal femur 3D-DXA parameters broadly consistent with results in postmenopausal women in the ACTIVE study, adding to the growing data on abaloparatide bone structure effects at the hip.

Sex specific differences in the determinants, occurrence, and distribution of osteoporosis and osteoporotic fractures play a pivotal role in the implementation of timely surveillance, prevention and effective treatment approaches. This review is aimed at synthesizing recently published scientific evidence on disparities in the epidemiology and management of osteoporosis and related fragility fractures in men. Several studies have identified race-, sex-, geographic-, socioeconomic-, and comorbidity-based disparities in osteoporosis care. Over the last decade, the awareness and imperative for identifying osteoporosis in men have increased. Nonetheless, the treatment gap is increasing and osteoporosis in men remains severely underappreciated and undertreated. Fewer studies in men have focused on the factors beyond osteoporosis awareness. Recent data of individuals aged 50 years and older show an alarmingly greater increase in hip fractures in men compared to women. This coupled with the existing knowledge of greater disability burden and excess mortality due to fragility fractures in men is a cause of public health concern. This review offers a comprehensive examination of widespread and profound disparities across the spectrum of osteoporosis care and post-fracture management in men and highlights the considerable health economic aspect of this burden. We call for targeted multifaceted interventions: develop novel methods to engage patients and health professionals, increase screening and treatment of osteoporosis in men, conduct epidemiological studies focused on disease phenotyping and risk factor assessment, studies on the identification of perceptions and barriers to effective screening and treatment, expansion and further evaluation of cost-effective therapies and primary prevention strategies for fractures, implementation of fracture liaison services to address the treatment gap in secondary prevention, and promote inclusivity in outcome studies and therapeutic trials. These interventions are paramount to reduce inequities in osteoporosis care and post-fracture care in men.

Context Trabecular bone score (TBS), a gray-level texture index derived from lumbar spine (LS) dual-energy x-ray absorptiometry (DXA) scans, is decreased in patients with diabetes and is associated with increased fracture risk, independent of areal bone mineral density (aBMD), but potentially influenced by abdominal fat tissue.Objective Evaluate effect of romosozumab (210 mg monthly) for 12 months followed by alendronate (70 mg weekly) for 24 months vs alendronate alone (70 mg weekly) for 36 months on LS aBMD and TBS in women with type 2 diabetes (T2D) enrolled in the ARCH study.Methods This post hoc analysis included women from ARCH who had T2D at baseline and LS DXA scans at baseline and >= 1 postbaseline visit (romosozumab-to-alendronate, n = 165; alendronate-to-alendronate, n = 195). aBMD and TBS (determined by an updated tissue thickness-adjusted TBS algorithm [TBSTT]) were assessed on LS DXA scans at baseline and >= 1 postbaseline visit (months 12, 24, and 36).Results Romosozumab led to significantly greater gains in LS aBMD and TBSTT at month 12 vs alendronate, and the greater gains with romosozumab were maintained after transition to alendronate and persisted significantly at months 24 and 36 vs alendronate alone. TBSTT percentage changes weakly correlated to LS aBMD percentage changes from baseline to month 36 (romosozumab-to-alendronate, R2 = 0.1493; alendronate-to-alendronate, R2 = 0.0429).Conclusion In postmenopausal women with osteoporosis and T2D, 12 months of romosozumab followed by 24 months of alendronate vs alendronate alone significantly improved LS aBMD and TBSTT (independently of abdominal fat) and to a greater extent. Hence, romosozumab may improve bone strength in patients with T2D.Trial registration ClinicalTrials.gov-NCT01631214

Abaloparatide treatment significantly increased bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck compared with placebo in men with osteoporosis in the phase 3 ATOM trial. The current study used 3D-DXA modeling to evaluate the effects of abaloparatide on cortical and trabecular compartments of the proximal femur in ATOM study participants. Proximal femur DXA images were retrospectively analyzed using 3D-DXA (3D-Shaper software v2.12.0, 3D-Shaper Medical, Barcelona, Spain) to evaluate changes in bone parameters from baseline at months 6 and 12 in all randomized men from the ATOM trial. Between-group comparisons were made for percent change from baseline data based on a mixed-effect repeated-measure model with treatment, visit, treatment-by-visit interaction, and type of DXA scanner as fixed effects. Other covariates include BMI, age, and baseline values of bone parameters. Abaloparatide treatment significantly increased integral volumetric BMD (vBMD) (3.7%), trabecular vBMD (7.0%), cortical thickness (1.1%), and cortical surface BMD (1.7%) at 12 mo compared to baseline (p < .0001). Changes were greater for abaloparatide compared to placebo for all four parameters (p < .01). Significant increases from baseline compared to placebo in integral vBMD (2.7% vs −0.1%, p < .0001) and trabecular vBMD (6.1% vs −0.6%, p < .0001) were also observed at 6 mo. In conclusion, in men with osteoporosis, abaloparatide improved proximal femur 3D-DXA parameters broadly consistent with results in postmenopausal women in the ACTIVE study, adding to the growing data on abaloparatide bone structure effects at the hip.

Context Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility. Objective To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes. Methods An observational cohort study was conducted in a well-characterized cohort from Health, Aging, and Body Composition study. Participants Older Black and White ambulatory adults with baseline plasma F2-isoprostanes measurements (baseline age 70-79 years, T2D: N = 132; nondiabetes: N = 571) were selected from the study cohort of 3075 individuals. Risk of incident clinical fractures was assessed. Results In the Cox proportional hazard model with multivariate adjustments (including BMD, medications, and other risk factors), a 93% increase in incident clinical fracture risk was significantly associated with each SD increase in log plasma F2-isoprostanes in the T2D group (hazard ratio [HR] = 1.93 [95% CI, 1.26-2.9] P = .002), but there was no evidence of an association in the nondiabetes group (HR = 0.98 [95% CI 0.81-1.18] P = .79, P for interaction <.001). Log plasma F2-isoprostanes were moderately correlated with a decline in baseline total hip BMD (r = -0.25, P = .003), and with a 4-year decrease in total hip BMD (r = -0.28, P = .008) in T2D. There was no evidence of correlation between log plasma F2-isoprostanes and circulating glycoxidation markers or bone turnover markers in either group. Conclusion Plasma F2-isoprostanes levels in individuals with diabetes are associated with increased incident clinical fracture risk independently of baseline BMD.

Both trabecular and cortical bone undergo changes at multiple scales. We previously demonstrated the multi-scale changes in trabecular bone quality that contribute to bone fragility in type 2 diabetes (T2D). The link between increased fragility in T2D and multi-scale changes in cortical bone and their interaction with glycation remains unclear. This study presents, first-ever, multi-scale cortical bone quality parameters in T2D patients after their first hip fracture. The study objective was to determine the association between cortical porosity (Ct.Po.), mechanical, material, and bone compositional properties in T2D. Inferomedial femoral neck (FN) bone tissue specimens were collected from patients (n = 10 with T2D, n = 25 age- and sex-matched non-diabetes controls) who underwent hip replacement surgery following the first hip fragility fracture. Bone mineral density at FN was found to be similar between groups. In T2D, Ct.Po was higher (p = 0.038), while ultimate stress (p = 0.021), ultimate strain (p = 0.040), post-yield strain (p = 0.011), toughness (p = 0.005), yield energy (p = 0.003), and post-yield energy (p = 0.004) were notably lower. Tissue compositional differences included lower gravimetric mineral/matrix (p = 0.017), higher non-enzymatic collagen cross-link ratio (NE-xLR) (p = 0.049) and higher sugar/matrix ratio (p = 0.042) in T2D. Fluorescent advanced glycation end-products (fAGEs) content was higher in T2D bone (p = 0.043). At the mesoscale, the fAGEs in the bone matrix are inversely related to the yield- and ultimate strain of T2D bone, and NE-xLR is negatively correlated with yield- and ultimate- stress in the T2D group. In conclusion, study findings demonstrate that elevated glycation weakens the mechanical integrity of cortical bone by reducing its ability to absorb energy and resist deformation, thereby contributing to bone fragility in T2D. The strong association of fAGEs with lower yield strain, along with the association of NE-xLR with lower yield- and ultimate stress, establishes a causal link between AGEs and the deterioration of cortical bone mechanical properties. These findings underscore the need for strategies targeting glycation and collagen quality to mitigate fracture risk in T2D patients.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n = 20) and without (n = 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17 yr. Despite the matched range of treatment duration (4-17 yr), AFF patients received alendronate for significantly longer time (10.7 yr) than non-AFF patients (8.0 yr) (P = .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6 mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Advanced Glycation End-products (AGEs) are seen in long-lived proteins and were not expected to accumulate in the bone that turnovers and renews itself. Here, we provide a commentary on the contrary, highlighting the Special Issue of AGEs in Bone. An outcome of hyperglycemia and increased oxidative stress, AGEs form and accumulate by altering the bone resorption and formation processes. Accumulation of various AGEs species in bone increases bone fragility through the stiffening of the collagen network and, potentially, through the changes in collagen-mineral interactions. Evidence from both preclinical and clinical studies is leading to new translational approaches wherein measurement, inhibition, or removal of AGEs show the potential to diagnose, manage, and treat bone fragility associated with multiple conditions and diseases.

The excess fracture risk observed in adults with type 1 diabetes (T1D) is inexplicable in the presence of only modest reductions in areal bone mineral density (BMD). Accumulation of advanced glycation endproducts (AGEs) in bone has been invoked as one explanation for the increased bone fragility in diabetes. The evidence linking AGEs and fractures in individuals with T1D is sparse, although the association has been observed in individuals with type 2 diabetes. Recent data show that in T1D, AGEs as measured by skin intrinsic fluorescence, are a risk factor for lower BMD. Further research in T1D is needed to ascertain whether there is a causal relationship between fractures and AGEs. If confirmed, this would pave the way for finding interventions that can slow AGE accumulation and thus reduce fractures in T1D.

Abstract Disclosure: D. Segura Torres: None. K. Raygoza: None. M. Garcia: None. J.P. Brito: None. M.E. McDonnell: None. M. Corrigan: None. C.R. McCartney: None. R. Dhaliwal: None. N.M. Singh Ospina: None. Clinical practice guidelines (CPG) improve healthcare quality by guiding decision making. Recent trends in CPG development emphasize incorporating race/ethnicity terms and health equity considerations. However, the appropriateness of how race/ethnicity is utilized remains uncertain. Objective This study seeks to evaluate the use of race/ethnicity in published Endocrine Society (ES) CPG and elucidate the context in which race and ethnicity terms are used. Methods: We identified 30 active clinical practice guidelines from ES up to January 2023. Two reviewers independently and in duplicate: a) located statements addressing race/ethnicity using an electronic search with 24 keywords, b) determined the statements' location within guidelines, and c) classified them based on content using frameworks by Cerdena and Gilliam. Disagreements were resolved by consensus. Exclusions were made for statements not addressing race and ethnicity terms in the appropriate context (e.g., “minority” of the panel disagreed), as well as for those in references or duplicates. Results: We reviewed 30 clinical practice guidelines, with 19 of them containing statements related to race or ethnicity. After applying exclusion criteria, we identified a final analytic sample of 114 statements. The majority of these statements were found in the body of the clinical guidelines (79%), followed by the evidence-to-decision framework (14%), and clinical recommendations (7%).The predominant classification were statements in which there was biologization of race/ethnicity 55% (n=63). Discussions on racial/ethnic disparities accounted for 23% (n=26) of the statements, with 31% (n=8) of these including explicit considerations of social context. Additionally, there were descriptions of race-specific treatment or diagnosis/screening in 14% (n=16) and 9% (n=10) of the statements, respectively.Less commonly statements of race/ethnicity reflected the consideration of ancestry as a code for race/ethnicity (n=7, 6%), identified ancestry as a risk factor for disease (n=19, 6%), highlighted racial/ethnic groups as understudied n=6, 5%), normalized findings to the majority group (White centeredness) (n=7, 6%), and other categories (7%). None of the statements employed race/ethnicity terms to emphasize cultural humility or the value of inclusivity in guideline committees. Conclusion: We systematically analyzed how race and ethnicity terms are used in ES CPGs. Our findings align with prior assessments made in non-ES CPG, highlighting the prevalent biologization of race and ethnicity constructs. Addressing this trend and incorporating socio-structural context considerations could bolster the impact of clinical guidelines in promoting health equity. Presentation: 6/1/2024

Dual-energy X-ray absorptiometry (DXA) is the gold standard method for measuring bone mineral density (BMD) which is most strongly associated with fracture risk. BMD is therefore the basis for the World Health Organization's densitometric definition of osteoporosis. The International Society for Clinical Densitometry (ISCD) promotes best densitometry practices and its official positions reflect critical review of current evidence by domain experts. This document reports new official positions regarding follow-up DXA examinations based on a systematic review of literature published through December 2022. Adoption of official positions requires consensus agreement from an expert panel following a modified RAND protocol. Unless explicitly altered by the new position statements, prior ISCD official positions remain in force. This update reflects increased consideration of the clinical context prompting repeat examination. Follow-up DXA should be performed with pre-defined objectives when the results would have an impact on patient management. Testing intervals should be individualized according to the patient's age, sex, fracture risk and treatment history. Incident fractures and therapeutic approach are key considerations. Appropriately ordered and interpreted follow-up DXA examinations support diagnostic and therapeutic decision making, thereby contributing to excellent clinical care. Future research should address the complementary roles of clinical findings, imaging and laboratory testing to guide management.

AIMS:Evaluate changes in circulating biomarkers as predictors of kidney disease, and cardiac/vascular dysfunction in participants from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS:Candidate biomarkers were assessed annually in 507 participants over a mean follow-up of 6.9 ± 2.4 years. Moderate albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g and hyperfiltration as eGFR ≥ 135 mL/min/1.73 m2 at two consecutive visits. Echocardiography (n = 256) and pulse wave velocity (n = 193) were evaluated twice, 5 years apart. Adjusted Cox proportional hazard models and logistic regression models were used to examine associations between biomarkers and outcomes. RESULTS:At baseline, 35.7% were male, with a mean age 13.9 years, diabetes duration 7.8 months, and HbA1c 6.0%. Higher concentrations of E-selectin and proinsulin were associated with incident moderate albuminuria and hyperfiltration. Higher concentrations of FGF-23 were associated with lower risk of hyperfiltration and negatively correlated with eGFR. No candidate biomarkers predicted a decline in cardiac or vascular function. CONCLUSIONS:Circulating biomarkers of endothelial dysfunction and markers of β-cell dysfunction and insulin sensitivity could be used in a more personalized risk assessment of kidney disease in youth-onset type 2 diabetes. However, biomarkers studied have limited value in predicting cardiac dysfunction or vascular stiffness.