Increased Fracture Risk Research Articles

The impact of novel hormonal agents on fracture risk in prostate cancer patients: a nationwide population-based cohort study

Prostate cancer (PC) treatment, particularly androgen deprivation therapy (ADT), remains pivotal, albeit linked to increased fracture risk due to osteoporosis. The advent of novel hormonal agents (NHAs) has spurred inquiries into their influence on bone health. This study aimed to evaluate the impact of NHAs on bone health in patients receiving combination therapy. We conducted a retrospective analysis using Taiwan’s National Health Insurance Research Database, encompassing men aged 45 and above diagnosed with PC without bone metastasis and undergoing ADT between 2000 and 2018. The study involved 25,949 patients, categorized into those receiving standard ADT (n = 25,166) and those on NHA combination therapy (n = 783). Our analysis delved into fracture risk, comorbidities, and osteoporosis treatments. Patients on NHA combination therapy faced significantly higher risks of any osteoporotic fracture and major osteoporotic fracture than those on ADT alone (HR = 1.29, 95% CI 1.04–1.61; HR = 1.37, 95% CI 1.06–1.75, respectively). Notably, age emerged as a critical factor, with the highest risk observed in those aged 90 or above. The 5-year overall survival rates were lower for patients who experienced any osteoporotic fracture, major osteoporotic fracture, and hospitalization due to osteoporotic fracture compared to those who did not experience these fractures (51.5% vs. 56.5%, 47.1% vs. 56.7%, and 48.2% vs. 56.3%, respectively, p < 0.001). Furthermore, patients not using any bone-modifying agents had the highest risk for all fracture types. In conclusion, NHA combination therapy in PC patients potentially escalates the risk of osteoporotic fractures, especially in older individuals. Our findings underscore the pivotal role of osteoporosis treatments in preventing fractures, emphasizing the importance of evaluating fracture risk in patients undergoing NHA combination therapy.

Bone block options for treating glenoid bone loss and glenohumeral instability: A systematic review

Background To systematically review the literature assessing glenoid bone loss restoration by different bone block options and compare their dimensions. Methods Systematic examination of articles in PubMed and EMBASE databases was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to find studies of bone grafts for treating anterior glenohumeral instability. Statistical analyses were conducted via Review Manager, and a p-value of &lt;0.05 was statistically significant. Results Our review included 25 studies evaluating 870 shoulders. Traditional arc Latarjet (TL) had more depth than congruent arc Latarjet (CAL; p = 0.003). The coronal radii of curvature of TL, CAL, distal tibia, and iliac crest bone blocks were similar to native glenoid ( p = 0.400, 0.817, 0.467, 0.216, respectively). CAL coracoid bone blocks restored significantly more glenoid surface area (30.3%) than TL bone blocks ( p = 0.012). The glenoid width and surface area restoration by distal clavicle bone blocks were equivalent to TL ( p = 0.058 and p = 0.103, respectively). Discussion The CAL technique restored higher percentages of glenoid surface area than TL but has less depth, which may increase fracture risk during screw insertion. The distal clavicle bone block is a suitable substitute to TL as it was equivalent regarding glenoid width and surface area restoration.

Effect of walking and bone joint exercise on enhancing bone remodeling in menopausal women: A randomized controlled trial

Osteoporosis increases fracture risk and reduces quality of life in menopausal women. Although physical activity, such as walking and bone joint exercise, is known to help maintain bone health, its effectiveness needs further examination. The aim of this study was to analyze the effects of physical activity, in particular walking and bone joint exercise, on enhancing bone remodeling in menopausal women. A randomized controlled trial was conducted among menopausal women and allocated into three groups: walking, bone joint exercise, and control groups. The intervention was provided for eight weeks, with the outcomes measured before and after the intervention. The study assessed five bone remodeling biomarkers: estrogen, parathyroid hormone (PTH), receptor activator of nuclear factor kappa-β ligand (RANKL), tumor necrosis factor-alpha (TNF-α), and bone mineral density (BMD). The paired sample student t-test and ANOVA were used to assess the effects of the interventions. The results indicated that, compared to pre-intervention, both walking and bone joint exercise significantly increased the estrogen (p=0.026 and p=0.023, respectively), decreased RANKL (p=0.019 and p=0.002, respectively), decreased PTH levels (p=0.022 and p=0.048, respectively) and increased the BMD scores (p=0.001 and p&lt;0.001, respectively). In the control group, none of the remodeling biomarkers significantly changed except the mean level of TNF-α, which was increased significantly (p=0.001). This study highlights that structured exercise, such as walking and bone joint exercise, can significantly enhance bone remodeling markers in menopausal women. Therefore, implementing such physical activities into management may provide benefits to menopausal women.

Potential Risks Associated With Long-term Use of Proton Pump Inhibitors and the Maintenance Treatment Modality for Patients With Mild Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) significantly affects the health-related quality of life and healthcare costs. The prevalence of this disease is increasing in Asia, leading to a rapid increase in the demand of proton pump inhibitors (PPIs). Despite effective symptom management during initial treatment, relapse rates after PPI cessation remain high in patients with GERD, warranting longterm maintenance therapy. Concerns regarding potential side effects related to the long-term use of PPIs are escalating with increased usage. Studies have reported diverse side effects of PPIs, such as increased fracture risk, cardiovascular concerns, enteric infections, neurological diseases, and potential associations with gastric cancer. However, definitive causal relationships remain unclear. This review comprehensively summarizes the latest knowledge on the potential risks associated with long-term use of PPIs. Continuous or noncontinuous therapy can be used as a maintenance treatment modality for GERD. For patients with mild GERD, including those with nonerosive and mildly erosive reflux disease, on-demand therapy following a sufficient period of continuous maintenance therapy is recommended as a long-term maintenance treatment option.

Risk of first hip fracture under treatment with zoledronic acid versus alendronate: a NOREPOS cohort study of 88,000 Norwegian men and women in outpatient care

SummaryWe aimed to investigate the risk of hip fracture associated with zoledronic acid treatment compared to alendronate on a population level. The risk of hip fracture was lower in women using zoledronic acid and higher in women who had discontinued treatment. The findings support the effectiveness of intravenous bisphosphonate.PurposeTo investigate whether zoledronic acid (ZOL) was associated with a lower risk of the first hip fracture than alendronate (ALN) in Norway using real-world data.MethodsNationwide data on drugs dispensed in outpatient pharmacies were individually linked with all hospital-treated hip fractures. Individuals aged 50–89 years without previous hip fracture were included at their first filling of a prescription for ALN or ZOL during 2005–2016. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for first hip fracture by time-varying exposure to ZOL versus ALN were estimated in sex-stratified flexible parametric survival analyses. Covariates included time-varying accumulated ALN exposure and comorbidity level expressed by the prescription-based Rx-Risk Comorbidity Index, marital status, education, and residential urbanity.ResultsOf 75,250 women who initiated treatment, 72,614 (96.5%) were exposed to ALN and 6366 (8.5%) to ZOL. Of 12,739 men who initiated treatment, 12,311 (96.6%) were exposed to ALN and 784 (6.2%) to ZOL. In women, the HR for first hip fracture was 0.75 (95% CI: 0.61–0.91) for ZOL versus ALN. In men, the corresponding HR was 0.59 (95% CI: 0.32–1.07). Discontinued treatment was associated with increased risk compared with current ALN treatment in women (HR: 1.33; 95% CI: 1.24–1.42, men: HR 1.13 (95% CI: 0.95–1.35)).ConclusionsIn women, the risk of first hip fracture when treated with ZOL was 25% lower than when treated with ALN. Discontinued treatment was associated with a 33% increase in hip fracture risk. Similar, albeit statistically non-significant, results were observed in men.

Identification of osteoporosis genes using family studies.

Osteoporosis is a multifactorial bone disease characterised by reduced bone mass and increased fracture risk. Family studies have made significant contribution in unravelling the genetics of osteoporosis. Yet, most of the underlying molecular and biological mechanisms remain unknown prompting the need for further studies. This review outlines the proper phenotyping and advanced genetic techniques in the form of high-throughput DNA sequencing used to identify genetic factors underlying monogenic osteoporosis in a family-based setting. The steps related to variant filtering prioritisation and curation are also described. From an evolutionary perspective, deleterious risk variants with higher penetrance tend to be rare as a result of negative selection. High-throughput sequencing (HTS) can identify rare variants with large effect sizes which are likely to be missed by candidate gene analysis or genome-wide association studies (GWAS) wherein common variants with small to moderate effect sizes are identified. We also describe the importance of replicating implicated genes, and possibly variants, identified following HTS to confirm their causality. Replication of the gene in other families, singletons or independent cohorts confirms that the shortlisted genes and/or variants are indeed causal. Furthermore, novel genes and/or variants implicated in monogenic osteoporosis require a thorough validation by means of in vitro and in vivo assessment. Therefore, analyses of families can continue to elucidate the genetic architecture of osteoporosis, paving the way for improved diagnostic and therapeutic strategies.

From Genomics to Metabolomics: Molecular Insights into Osteoporosis for Enhanced Diagnostic and Therapeutic Approaches.

Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mineral density (BMD) and increased fracture risk. The advancements in omics technologies-genomics, transcriptomics, proteomics, and metabolomics-have provided significant insights into the molecular mechanisms driving OP. These technologies offer critical perspectives on genetic predispositions, gene expression regulation, protein signatures, and metabolic alterations, enabling the identification of novel biomarkers for diagnosis and therapeutic targets. This review underscores the potential of these multi-omics approaches to bridge the gap between basic research and clinical applications, paving the way for precision medicine in OP management. By integrating these technologies, researchers can contribute to improved diagnostics, preventative strategies, and treatments for patients suffering from OP and related conditions.

Puerarin alleviates osteoporosis in rats by targeting the JAK2/STAT3 signaling pathway.

Osteoporosis (OP) is a common chronic progressive bone disease that increases fracture risk in postmenopausal women. Research suggests that puerarin (Pue) may be an effective treatment for OP. This study examined the effects and underlying mechanisms of Pue in treating postmenopausal osteoporosis (PMOP) in rats. Sprague-Dawley (SD) rats underwent bilateral ovariectomy to simulate PMOP and were then treated with subcutaneous injections of Pue. Bone mineral density (BMD) was measured using a bone densitometer. Micro-CT scans assessed femur bone structure and various parameters were calculated: bone volume fraction (BV/TV), bone surface density (BS/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and bone surface area-to-bone volume ratio (BS/BV). Hematoxylin-eosin (HE) staining was employed to observe femoral tissue pathology. Serum levels of bone formation metabolism-related markers-osteocalcin (OC), bone alkaline phosphatase (BALP), and procollagen type I N-terminal propeptide (PINP)-were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in bone tissue were evaluated using Western blotting assay. The results showed improved bone density and reduced bone loss in rats treated with Pue. There were also significant increases in serum levels of OC and BALP, indicating enhanced osteogenesis. Furthermore, there was a decrease in activation of the JAK2/STAT3 pathway in femoral tissue, suggesting a pathway inhibition. These findings indicate that Pue may combat osteoporosis by promoting osteogenesis and inhibiting activation of the JAK2/STAT3 pathway activation.

The effect of antidiabetic drugs on bone metabolism: a concise review.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.

New Challenges: Use and Interpretation of Radius Bone Mineral Density.

It is unknown if isolated low bone mineral density (BMD) "osteoporosis" at the radius is associated with increased fracture risk, not only at the wrist but elsewhere and whether it reflects more generalized skeletal fragility. To review the association of radius BMD and fracture risk, the epidemiology of wrist fractures, isolated osteoporosis at the radius and the concordance between radial BMD and femoral neck BMD. We completed a narrative literature review on radius BMD and fracture risk and current recommendations for measurement of radial BMD. We updated results of radial BMD and fracture results from the Study of Osteoporotic Fractures over 20 years and examined the concordance of BMD at the distal and proximal radius with femoral neck BMD T -scores. Radius BMD is a robust predictor of all types of fractures including hip and wrist but there is insufficient evidence to suggest that radius BMD predicts wrist fractures better than fractures at other sites. Fractures of the wrist tend to occur in younger, healthier women compared with hip and spine fractures. Nevertheless, wrist fractures are associated with an increased risk of future fractures and represent a missed opportunity for intervention. On a population level, the discordance between radius BMD and femoral neck BMD is small. But women with isolated osteoporosis at the radius had biochemical and microarchitecture deterioration that were similar to women with hip osteoporosis. Future research should address the clinical implications of isolated osteoporosis at the radius and whether treatment is warranted.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin with Incident Fractures in Middle-Aged to Older Men.

As men age, circulating testosterone (T) decreases, circulating sex-hormone binding globulin (SHBG) increases, and risk of fracture increases. It is unclear if circulating T, independently of comorbidities, is associated with fracture risk in men. To determine associations for T and SHBG with incident fractures in men. We utilized the large (n=205,973 participants, 11,088 any fracture cases, 1,680 hip fracture cases, 1,366 forearm fracture cases) and well-characterized UK Biobank cohort. Associations were modelled using Cox regressions, adjusting for multiple comorbidities/covariates, imputing for missing information, and assessing non-linearity using cubic splines. For T, not considering SHBG, there was a non-linear association with hip but not forearm fractures, with the lowest risk in the second quintile. However, in models adjusted for SHBG or using calculated free T, lower T was associated with higher risk for fractures at all evaluated bone sites. Lower SHBG was strongly associated with lower risk of hip and forearm fractures (Q1 vs Q5, hip 0.55, 0.47-0.65; forearm 0.62, 0.52-0.74). Low circulating SHBG is strongly associated with low risk of fracture at all evaluated bone sites, while the associations of circulating T with fracture risk are of lesser magnitude, non-linear, inconsistent among fracture site, and affected by adjustment for SHBG. These findings demonstrate that circulating SHBG, rather than T, is a major independent biomarker of fracture risk in men. Consequently, both total T and SHBG should be assessed when examining the relationship of endogenous T concentrations with fractures in middle-aged to older men.

12213 Is Atrial Fibrillation An Adverse Cardiovascular Effect Of Romosozumab

Abstract Disclosure: S. Martinez: None. D. Anez: None. M. Shahid: None. Osteoporosis and cardiovascular disease are both common in older populations. Therefore, it is not uncommon to find the two disorders in a single individual and yet it may be difficult to establish whether the diseases are coincident or the result of complex hormonal processes interacting with multiple systems, including possibly sclerostin. Indeed, pre-existent cardiovascular disease predisposes to osteoporotic bone loss and increased fracture risk. To date, a number of studies have linked the incidence of major adverse cardiovascular events (MACE) with various osteoporosis treatments while other treatments have demonstrated no associated or a reduced cardiovascular risk. Here we discuss the possibility of romosozumab-induced sudden, new onset atrial fibrillation (a fib) in a 70-year-old female with no known risk factors other than age. A 70-year-old female with a 20-year history of osteoporosis presented to establish care. After 5 years of alendronate therapy, she was switched to denosumab injections, 60 mg every 6 months. During Covid the patient’s physicians closed their office and denosumab therapy was interrupted for approximately 18 months. Therefore, when the patient established care with a new rheumatologist she was started on romosozumab. After 6 months of romosozumab the patient developed new onset atrial fibrillation. The cardiovascular safety of romosozumab, in particular, has been adjudicated in two large trials describing predominantly major cardiovascular events such as myocardial infarction, stroke, heart failure and cardiovascular death. In one of those trials, two reports of atrial fibrillation were also included in the adverse events but further details were not available. These increased MACEs prompted a safety warning from the FDA such that use of romosozumab in patients who have experienced a myocardial infarction or stroke within the year prior to its use is contraindicated. Recently atrial fibrillation and congestive heart failure were documented in 78-year-old woman who had been receiving romosozumab for three months for the treatment of osteoporosis. Our case represents a second report of a temporal relationship between the initiation of romosozumab and the onset of atrial fibrillation raising the question of a possible cause and effect. Disclaimer: This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. Presentation: 6/3/2024

7858 Increasing Severity of Growth Hormone Deficiency is Associated with Lower Vertebral Strength

Abstract Disclosure: R. Boutin: None. M. Haines: None. R. Shahid: None. C. Mark: None. C. Gill: None. M. Bredella: None. K.K. Miller: Other; Self; Pfizer, Inc. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Grant Recipient; Self; Lumos Pharma, Perspectum Ltd. Research Investigator; Self; Recordati, Novo Nordisk. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. Objective: Growth hormone (GH) stimulates osteoblast differentiation, while insulin-like growth factor-1 (IGF-1) stimulates osteoblast proliferation and bone formation. Retrospective studies have demonstrated a 2-to-3-fold increased fracture risk in adults with GH deficiency (GHD) due to organic hypothalamic or pituitary disease, particularly at vertebral sites. Adults with overweight/obesity produce relatively less GH than lean individuals, and serum IGF-1 levels are associated positively with BMD in adults with obesity. Yet, no published studies have examined the relationship between degree of GHD across these groups and vertebral strength, an understudied measure of bone quality in part because HR-pQCT cannot image this skeletal site. We hypothesized that there would be an inverse association between degree of GHD and vertebral strength, independent of age and BMI. Methods: Cross-sectional study of 134 estrogen-replete (with regular menses or taking estrogen) women: 16 with GHD secondary to hypopituitarism (HP, severe GHD), 91 with obesity (OB) without a hypothalamic/pituitary disorder (relative GHD), and 37 lean controls (LC) without a hypothalamic/pituitary disorder (normal GH production). Peak-stimulated GH was assessed by GHRH-arginine testing. CT imaging at the L4 vertebra was performed to determine vertebral cross-sectional area and total integrated volumetric bone mineral density (Int.vBMD), from which estimates of vertebral strength were calculated. Results: Mean age [44±9 (mean±SD) (HP) vs. 35±7 (OB) vs. 30±7 (LC) y, p&amp;lt;0.005] and BMI [30±6 (HP) vs. 34±6 (OB) vs. 22±2 (LC) kg/m2, p&amp;lt;0.004] differed between all groups. As expected, peak-stimulated GH was highest in LC (28.3 ± 9.5 ng/mL) followed by OB (12.4 ± 8.9 ng/mL) and HP (2.4 ± 1.7 ng/mL), p&amp;lt;0.0001. IGF-1 Z-scores were higher in LC (0.0 ± 0.6) and OB (0.0 ± 0.7) vs. HP (-1.4 ± 0.7), p&amp;lt;0.0001. Int.vBMD and vertebral strength were higher in LC and OB vs. HP [Int.vBMD (g/cm3) LC 0.21±0.04 and OB 0.21±0.04 vs. HP 0.16±0.03, and vertebral strength (N) LC 4540±850 and 4743±91 vs. HP 3542±651, both p&amp;lt;0.0001], which remained significant when adjusted for age and BMI (p≤0.01). Peak-stimulated GH and IGF-1 Z-scores were positively associated with vertebral strength (GH R=0.33, p=0.003 and IGF-1 Z-score R=0.41, p&amp;lt;0.0001) and Int.vBMD (GH R=0.46, p&amp;lt;0.0001 and IGF-1 Z-score R=0.40, p&amp;lt;0.0001), which remained significant when adjusted for age and BMI. Among the subset of patients without organic pituitary disease (LC and OB only), IGF-1 Z-scores remained positively associated with vertebral strength (R=0.24, p&amp;lt;0.03) and Int.vBMD (R=0.22, p&amp;lt;0.05). Conclusions: These findings suggest that severe GHD is associated with impaired vertebral volumetric bone density and strength. Moreover, the relative GHD of obesity may contribute to lower vertebral bone density and strength in otherwise healthy adults with overweight/obesity. Presentation: 6/3/2024

8353 Impact of a plant-based protein diet on bone health and body composition in Sprague Dawley rats

Abstract Disclosure: M.M. Gomes: None. I.M. de Araújo: None. S.V. Rodriguez: None. F.R. Jorge: None. F.J. de Paula: None. Introduction:Vegetarian and vegan diets are associated with some health benefits; this has contributed to their growing popularity. Although studies remain limited, there is evidence that these patients may be at greater risk of reduced bone mineral density (BMD) and increased fracture risk. The general objective of this study was to analyze the impact of a high-protein, plant-based diet on bone tissue and body composition in male Sprague Dawley rats. Methodology: The study was approved by the Animal Ethics Committee. This study was done with 10 rats in the control group (CG), which received a standard AIN-93M diet; 11 in the normoprotein vegetarian group (NVG), with a normoprotein AIN-93 diet modified with pea protein and methionine; and 11 in the high-protein vegetarian group (HVG), with a modified AIN-93 diet with 40% pea protein and methionine. The dietary intervention lasted 8 weeks. The weight of the animals was measured weekly. Basal blood glucose levels were measured at baseline. At the end of the study, 6 rats from the CG, 6 rats from the NVG, and 5 rats from the HVG were subjected to a glucose tolerance test (GTT). The dual-energy X-ray absorptiometry (DXA) technique was applied in the baseline and final periods of the experiment to evaluate body composition, bone mineral content (BMC) and BMD. After sacrifice, bone strength was measured via a three-point flexion mechanical test on the tibia; brown adipose, epididymal, and retroperitoneal tissues, as well as the liver, were weighed on an analytical balance. Blood was used to measure circulatory levels of insulin, CTX, and P1NP (n=6/group). Results: Basal weight was similar between the groups, but the final weight was lower in the HVG as compared to the CG. In the DXA evaluation, the final lean mass was not different between the groups. On the other hand, total fat mass was lower in the HVG than in the CG and the NVG and the fat percentage was lower in the HVG than in the CG. The weight of epididymal adipose tissue was lower in the HVG than in the NVG, but retroperitoneal and brown adipose tissues were lower in HVG than CG. Liver weight was similar between groups. BMD was similar between groups; however, BMC was lower in the HVG than in the CG and the NVG. Bone strength was similar between groups. There was no difference in glycemia at baseline or during GTT at the eighth week. Serum levels of insulin, CTX, and P1NP were similar between groups. Discussion and Conclusion: A normoprotein vegetarian diet that includes all essential amino acids appears to have no negative impact on body composition or BMD in rats. On the other hand, a high-protein diet with plant protein appears to have a negative impact on bone mineral content, in addition to reducing the amount of body fat and weight. This finding expands on previous results by showing that high-protein diets have a negative impact on bone even when the protein is of plant origin. Presentation: 6/1/2024

6536 National Trends in Prevalence of Prediabetes and Diabetes Among Women With Low Bone Mineral Density: 2009-2018

Abstract Disclosure: A. Atri: None. C. Anastasopoulou: None. Introduction: In recent years, bone fragility has emerged as a complication of prediabetes (preDM) and diabetes mellitus (DM), resulting in reduced bone mass and increased fracture risk, and is an important, though under-studied risk factor for osteoporosis. However, the converse relationship, trends in prevalence of preDM and DM in women with low bone mineral density (BMD) in the United States, are not well established. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) for the years 2009-10, 2013–14 and 2017–18 to include U.S. women aged ≥ 50 years with T-score ≤ -1. Osteoporosis assessment in NHANES was not completed in 2011–12 and 2015–16, and therefore not included in the analysis. Osteopenia and osteoporosis were defined by a femoral neck BMD ≤1 to 2.5, and ≤2.5 standard deviations (SDs) below the BMD of a young female adult mean (T-score). Femur neck BMD was measured by dual energy x-ray absorptiometry (DEXA). PreDM and DM were defined using HbA1c values of 5.7 - 6.4% and ≥ 6.5% respectively. Participants with missing HbA1c and BMD data were excluded. Descriptive statistics were used for comparing means and medians. The Cochran-Armitage test was utilized for trend analysis. Results: In this nationally representative sample of US women with low BMD, the median (IQR) T-score at femoral neck worsened from -1.74 (-1.4 to -2.17) in 2009-10 to -1.87 (-1.43 to -2.32) in 2017-18 (trend p = 0.001). Similarly, the prevalence of osteoporosis increased from 13.7% to 16.9% (trend p = 0.001). Overall, in this cohort, the national prevalence of both preDM and DM decreased from 40% to 32.9% and 9.6% to 9%, respectively (trend p = 0.001). Along with a reduction in the overall prevalence of osteopenia (86.3% to 83.1%, p=0.001), the prevalence of both preDM and DM decreased from 39.2% to 32.6% and 10% to 9% (p = 0.001). In those with osteoporosis, the prevalence of preDM decreased from 45.2% to 34.4% (p trend=0.001), however, the prevalence of DM increased from 7.5% to 8.7% (p trend =0.001). Overall rates of uncontrolled DM (HbA1c &amp;gt; 7%) in women with osteoporosis showed significant improvement (5.8% to 3.5%, p = 0.001). Discussion Despite worsening trend in femoral neck BMD among US women age ≥ 50 years from 2009-10 to 2017-18, the overall prevalence of preDM and DM improved by 7.1% and 0.6% respectively. However, this favorable trend was not observed among women with osteoporosis, where the overall prevalence of DM increased by 1.2%, though the rate of uncontrolled DM significantly decreased by 2.3%. Targeted interventions to improve blood glucose control among women with low BMD, especially those with osteoporosis are warranted, to improve bone health, as well as reduce fall and fracture risk. Presentation: 6/2/2024

5071 Impact of Estrogen Replacement Therapy on Bone Health in a Novel Non-human Primate Model of Postmenopausal Women Living with HIV

Abstract Disclosure: K. Sauter: None. D.L. Takahashi: None. G. Webb: None. H. Hofmeister: None. O. Varlamov: None. J. Sacha: None. P. Kievit: None. Current antiretroviral therapy (ART) regimens have rendered HIV a manageable chronic condition rather than a fatal disease, with people who initiate ART soon after infection achieving nearly normal life expectancy. As a consequence of increased survival, more women living with HIV (WLWH) will now undergo menopause and be subject to a disease burden that reflects age along with adverse skeletal consequences of postmenopausal estrogen deficiency. In addition to known bone loss and increased fracture risk in postmenopausal women, ART also causes decreased bone mineral density. Therefore ART-suppressed WLWH may have a compounded detrimental effect on bone due to long-term ART treatment combined with menopause that may be attenuated with estrogen replacement. Eleven rhesus macaques were infected intravenously with SIVmac239M and received ART two weeks post-infection (PI). All animals were ovariectomized (OVX) at 35 weeks PI and received estrogen implants (n=6) or cholesterol implants (n=5). Weekly blood samples were collected and animals were monitored longitudinally for body composition including bone mineral content (BMC) via dual x-ray absorptiometry (DEXA). Infection with SIV caused a significant decrease, -8.2%, in pelvis BMC after 14 days of peak viremia with SIV. These changes were not observed in the BMC of spine or extremities. BMC remained suppressed by ∼7% for an additional 25 weeks PI during ART treatment. Measurement of circulating bone turnover markers (BTMs), osteocalcin and C-terminal telopeptide of type 1 collagen (CTX), decreased post infection without significant improvement after ART suppression. Induction of menopause via OVX and loss of estrogen induced a drastic increase in BTMs with a much larger increase in CTX, indicating potential global bone loss due to OVX. Post-implant, the control animals’ pelvis BMC continued to decrease to -20.9% and pelvis BMD to -9.3% indicating that OVX further exacerbated the effect of SIV and ART. However, animals that received estrogen implants demonstrated marked improvement in both measures to greater than baseline. SIV and subsequent long-term ART negatively impact pelvic BMC and BMD and this effect is compounded by menopause in our model of post-menopausal WLWH. However, estrogen replacement post-menopause may attenuate these detrimental bone effects despite long-term ART treatment. Presentation: 6/1/2024

7281 Increased Incidence Of Fracture And Predicted Fracture Risk In Patients With Mild Autonomous Cortisol Secretion

Abstract Disclosure: R. Sagar: None. A. Saadulla: None. A. Abbas: None. Background: Mild autonomous cortisol secretion (MACS) is common in patients presenting with adrenal incidentalomas (AI) and has been associated with cardiovascular and metabolic co-morbidities. Whilst there is growing evidence to support the increased risk of cardiometabolic co-morbidity in this cohort, the bone health effects are less well characterised. Our study evaluated the prevalence of fragility fracture and fracture risk in patients with AI and MACS compared with a cohort of patients with benign, non-functional AI. Methods: Retrospective observational data were collected on 391 patients with MACS and an AI along with 626 patients with a benign, non-functional AI. Demographic, biochemical, radiological and bone health data were recorded. FRAX, a validated fracture risk stratifying tool, was used to calculated risk scores for all patients aged between 40 and 90 and risk category according to national guidance were also recorded. Results: MACS cohort (mean age 69±10 and 53% female) had a mean cortisol on overnight dexamethasone suppression test of 76.6±21nmol/l. Benign, non-functional patients had a mean age 61.4±12 and 57% female. Both cohorts had predominantly unilateral lesions (76% in MACS versus 84%). Patients with MACS had a significantly higher prevalence of all fragility fractures, 15.9% compared with 6.7% in the benign, non-functional group, p&amp;lt;0.0001. Patients with MACS had a significantly higher 10-year risk of major osteoporotic fracture (10.6±3.8% versus 7.1±5.4%, p&amp;lt;0.0001) and also hip fracture (7.2±4.1% versus 1.9±2.7%, p&amp;lt;0.0001). 17% of MACS cohort were classed as either high or very high fracture risk, with a further 28% classed as intermediate risk requiring further assessment of bone health compared with 3% high/very high risk in the non-functional group. Despite this only 31% of the MACS group had undergone DEXA scan to assess bone mineral density compared to 13% of the non-MACS group. Only 5% of MACS patients were on osteoporosis treatment (3% in non-MACS cohort). Conclusions: Patients with MACS make up a large proportion of those presenting with adrenal incidentaloma. Our study suggests an increased prevalence of fragility fractures along with increased fracture risk in patients with MACS compared to those with non-functional AI. However, we also demonstrate an unmet need, with less than 1/3 of patients with MACS undergoing formal bone health assessment and just 5% of the total cohort on treatment for osteoporosis despite a significant proportion meeting intervention thresholds. Presentation: 6/1/2024

7500 Effect Of Orchiectomy On Bone Microarchitecture In Male Mice With Kidney Disease

Abstract Disclosure: D. Wu: None. A. Patwardhan: None. O. Marks: None. Y. Komaru: None. E. Kefalogianni: None. R. Aurora: None. S. Dhindsa: None. A. Herrlich: None. Background: Chronic kidney disease (CKD) leads to decreased bone density and increased fracture risk. In males, an additional factor contributes to the low bone density. Around half of the men with CKD have low serum testosterone concentrations. We hypothesized that CKD and low testosterone would have an additive and detrimental effect on bone. Methods: Forty male C57BL/6 mice were divided into 4 groups: 1) renal injury, induced by ischemia-induced reperfusion (IRI) and sham orchidectomy (IRI-sham, N=8) at 2 months of age; 2) orchidectomy (ORX), performed 4 weeks after IRI (IRI + ORX, N=11); 3) sham-ORX, N=9; and 4) sham-sham surgery, N=12. 12 weeks after IRI, the mice developed renal fibrosis and decreased glomerular filtration rate, indicative of CKD. The mice were sacrificed when they were 7 months old. Femur and tibia were harvested for both histology and μCT analysis. Results: Bone volume to total volume fraction (BV/TV) was lower in the IRI-ORX (0.06±0.02) and sham-ORX (0.08±0.02), as compared to IRI-sham (0.10±0.03, p&amp;lt;0.05) and sham-sham group (0.14±0.03, p&amp;lt;0.05) respectively. Similarly, the volumetric bone mineral density (vBMD) in IRI-ORX (93±27 mgHA/cm3) and sham-ORX (112±39 mgHA/cm3) groups were lower than IRI-sham (150±43 mgHA/cm3, p&amp;lt;0.05) and sham-sham (187±30 mgHA/cm3, p&amp;lt;0.05) mice. Trabecular number (Tb.N) was decreased in the IRI-ORX group (2.7±0.7 #/mm) compared to IRI-sham group (4.1±1.1 #/mm, p&amp;lt;0.05). Tb.N was also lower in sham-ORX (3.2±1.1 #/mm) mice than sham-sham (4.5±0.2 #/mm), but not IRI-sham mice. In contrast, trabecular thickness (Tb.Th) was lower in IRI-ORX (0.035±0.002 mm) and IRI-sham (0.038±0.002 mm) compared to sham-ORX (0.045±0.005 mm) and sham-sham (0.047±0.005 mm, p&amp;lt;0.05). Trabecular spacing (Tb.Sp) was increased by 47% in IRI-ORX group compared to IRI-sham group (0.26±0.09 mm). Decreased trabecular numbers and increased spacing results in reduced connectivity density (Conn.Den), which was decreased by 60% in the IRI-ORX sham-ORX groups as compared to sham-sham group (423±58 #/mm3, p&amp;lt;0.05). 2 way ANOVA analysis showed that ORX significantly contributed to the variance in BV/TV (p&amp;lt;0.001), vBMD (p&amp;lt;0.001), Tb.N (p&amp;lt;0.01), Tb.Sp (p&amp;lt;0.01) and Conn.Den (p&amp;lt;0.001), while IRI contributed to Tb.Th (p&amp;lt;0.0001). There was no significant interaction between IRI and ORX in all endpoints. Conclusions: Taken together, these data indicate that even in the presence of established CKD, ORX has a greater effect on bone mass. ORX decreased trabecular number (Tb.N) and increased trabecular spacing (Tb.Sp) to a greater extent than IRI. IRI decreased trabecular thickness (Tb.Th) while ORX had no effect on that parameter. Trabecular bone loss starts by trabecular thinning. Eventually, the trabeculae will be completely resorbed, resulting in decreased trabecular numbers and increased spacing. Our data indicate that IRI and ORX affect bone at different time points. Presentation: 6/1/2024

7686 A Case Of A 66-Year-Old Male With Systemic Macrocytosis Complicated By Osteoporosis

Abstract Disclosure: J.M. Gri: None. M. Hillhouse: None. P. madhavan: None. Background: Osteoporosis in men is underestimated and warrants investigation for secondary causes of osteoporosis. Systemic mastocytosis is a rare secondary cause of osteoporosis. Clinical Case: This is a 66-year-old male with a past medical history of severe persistent asthma, eczema, hypertension, GERD with esophagitis, basal cell carcinoma, and systemic mastocytosis (diagnosed in 2010). Family history was significant for lung cancer in both of his parents. Patient was first noted to have hyperpigmented skin lesions on his legs, trunk and upper extremities in the early 1990s. The spots were biopsied and he was diagnosed with urticaria pigmentosa in 1998. Due to persistent symptoms of facial flushing and soft stool, he was referred to Hematology and was started on antihistamines. He later underwent a bone marrow biopsy in 2010 which showed multifocal mast cell aggregates but normal trilineage hematopoiesis. He endorsed back pain shortly after his diagnosis and a DXA scan was completed. The DXA scan showed osteopenia of the spine T score of -1.8, BMD 0.999 mg/mm3 and normal bone density in bilateral hips. He had no history of fractures. He was started on alendronate and remained on the medication from 2012 to 2015. It was stopped due to intolerable symptoms of acid reflux and he required proton pump inhibitors. DXA scan in 2017 showed normal bone density of the hips and osteopenia of the lumbar spine (T score -1.2). DXA scan in 2022 showed a decrease in spine BMD by 6% (T score -1.8) from 2017 to 2022 but unchanged from 2010. Hip bone mineral density was normal but decreased by 10% since 2010 and by 6% since 2017. Labs obtained in May 2022 showed normal serum electrophoresis, normal urine calcium and creatinine ratio, calcium and vitamin D level and urine NTX of 41 nM BCE/mM (21-83) and bone specific alkaline phosphatase level of 31.5 U/L (15-41.3). After discussion with the patient, conservative management with calcium, vitamin D and exercise has been implemented along with close follow up. Should the patient’s bone turnover markers increase or fracture risk increase, additional antiresorptive therapy will be initiated. Conclusion: This case study highlights the importance of screening for osteoporosis in patients with systemic macrocytosis. As this patient was diagnosed with osteopenia at age 53, this case also emphasizes the importance of early screening in both women and men with this rare condition. Presentation: 6/3/2024

7892 Longitudinal Changes in Bone Microarchitecture and Strength in Girls with Type 1 Diabetes

Abstract Disclosure: R. Dhaliwal: None. R.K. Saunders: None. M. Misra: None. M.L. Bouxsein: None. D.M. Mitchell: None. Introduction: Type 1 diabetes (T1D) confers an increased fracture risk, only partly explained by low areal bone mineral density (aBMD). We have previously shown in a cross-sectional study that bone microarchitecture is altered early in the course of T1D. The goal of this study is to evaluate how T1D influences longitudinal changes in volumetric BMD (vBMD) and microarchitecture. Methods: This is a 2-year prospective study of girls ages 10-16 years (62 with T1D and 59 controls). We used dual-energy x-ray absorptiometry (DXA) to measure aBMD, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius (7% site) and tibia (8% site) to measure vBMD and microarchitecture. We used linear mixed models to assess the effects of T1D on change in bone parameters over time, adjusting for bone age as an index of skeletal maturity, height, lean mass index (LMI), and fat mass index (FMI). Results: At baseline, mean duration of disease in T1D was 4.8 ± 3.2 years, and mean HbA1c was 8.6 ± 1.4%. The groups did not differ by age, bone age, and height, while T1D participants had higher LMI (p&amp;lt;0.001) and borderline higher FMI (p=0.107). Linear growth, weight gain, and changes in body composition over time did not differ between groups. Growth-mediated aBMD gains were observed in both groups at the subtotal body, total hip, femoral neck, and spine. While adjusted aBMD as well as trabecular bone score were lower in T1D, we did not observe between-group differences in changes in these endpoints over time. In both groups, at the distal radius, we observed significant increases over time in total and cortical vBMD, cortical thickness, trabecular (Tb) thickness, and estimated failure load, while cortical porosity decreased. While several microarchitectural parameters were altered in T1D participants, we did not observe significant between-group differences in changes in these measures over time. Of note, trabecular development was subtly altered, with T1D participants demonstrating a borderline significant decrease in Tb vBMD (-14.3 ± 9.0 mg HA/cm3, p=0.112) and Tb number (-0.14 ± 0.07 mm-[1], p=0.057), while control participants had no change in Tb vBMD or number, but a significant increase in Tb thickness (5.8 ± 2.5 µm, p=0.018). At the distal tibia, we observed similar overall detrimental effects of T1D at baseline. However, we did not observe between-group differences in microarchitectural change over time. Glycemic control as measured by HbA1c was not associated with changes in skeletal parameters among T1D participants. Conclusions: T1D leads to substantially altered areal and volumetric BMD as well as microarchitectural parameters in girls. While our data suggest that much of this deficit appears to occur early in the course of disease as prospective change is similar in T1D and controls, subtle changes in trabecular bone development at the radius may indicate ongoing impairment of bone accrual. Presentation: 6/3/2024