bluuebunny/crossref_metadata_2025_split huggingface dataset:
9236 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study
Authors: Rouach Vanessa , Gortler Hillary , Greenman Yona , Gabriel Chodick , inbalL Goldshtein 
Published: October 2024

Abstract
Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None.
Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p&lt;0.01), had longer diabetes duration (8.4 vs 7.2, p&lt;0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p&lt;0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored.
Presentation: 6/1/2024
8455 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study
Authors: Rouach V , Gortler H , Greenman Y , Gabriel C , inbalL G 
Published: October 2024

Abstract
Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None.
Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p&lt;0.01), had longer diabetes duration (8.4 vs 7.2, p&lt;0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p&lt;0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored.
Presentation: 6/1/2024
6483 Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma: A Rare Skeletal Dysplasia/Sarcoma Syndrome
Authors: Grover A , Ferreira C R , Gafni R I , Jumani S , Collins M T , Roszko K L , Hartley I R 
Published: October 2024

Abstract
Disclosure: A. Grover: None. C.R. Ferreira: None. R.I. Gafni: None. S. Jumani: None. M.T. Collins: None. K.L. Roszko: None. I.R. Hartley: None.
Introduction: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is a rare autosomal dominant syndrome associated with pathologic fractures, myopathy, premature hair graying, and aggressive osteosarcomas. DMS-MFH has been linked to genetic variants in the methylthioadenosine phosphorylase (MTAP) gene, which encodes an enzyme in the methionine salvage and polyamine synthesis pathway. This pathway is implicated in other skeletal fragility disorders, such as Snyder-Robinson syndrome, suggesting a still undefined role of this pathway in bone biology. We describe a kindred with DMS-MFH and identify diagnostic challenges. Case: A 53-year-old perimenopausal woman presented with four fragility fractures over one year. Relevant history included premature hair graying, esophageal strictures, and nephrolithiasis. The patient’s bone formation markers were slightly elevated; bone resorption markers were within reference range. Her only osteoporosis risk factor was perimenopausal status. Bone series showed a diffuse heterogeneous appearance of the long bones with a mixed lytic/sclerotic appearance. DEXA scan revealed osteopenia. Family history was significant for 2 sons with aggressive osteosarcomas diagnosed in their late teens; one died at age 20. The other son is currently 39-years-old with recurrent osteosarcomas in three different limbs. The family also has a multigenerational history of severe bone fragility, muscle weakness, and premature hair graying. The patient, her living son, and his father underwent genome sequencing that identified a variant in MTAP (c.885A&gt;G; p.(R295=)) in the patient and son. This variant was previously reported in three other families with DMS-MFH and has been shown to alter splicing. Notably, commercial genetic testing did not report this as a relevant variant, and diagnosis required independent analysis of the raw sequence data. Based on these findings, the patient and her son were diagnosed with DMS-MFH. Given the bone fragility with elevated bone turnover markers we treated the patient with yearly zoledronic acid infusions with no subsequent fractures. Surveillance for osteosarcoma is also being performed with annual whole-body MRI. Conclusion: DMS-MFH has been reported in only five families to date. The sixth family described here has clinical characteristics similar to the other kindreds. Due to high risk of aggressive osteosarcoma, timely diagnosis is imperative to decrease morbidity and mortality. Commercial genome sequencing may miss this diagnosis, so targeted genetic testing should be pursued. As more cases are identified, characterization of affected families may enhance our understanding of the natural history of the disease and guide surveillance and treatment strategies.
Presentation: 6/2/2024
8279 Dimeric [Cys25]PTH(1-34) Induces Differential Transcriptional Responses Versus Monomeric PTH(1-34)
Authors: Noh Minsoo , Jieun Kim Hani , Kim Jinseok , Kang Mikyung , Young Lee Soo , Lee Hunsang , Lee Sihoon 
Published: October 2024

Abstract
Disclosure: M. Noh: None. H.J. Kim: None. J. Kim: None. M. Kang: None. S. Lee: None. H. Lee: None. S. Lee: None.
Introduction: Patients with hypoparathyroidism caused by the homozygous mutation that changes arginine to cysteine at position 25 in parathyroid hormone (PTH) exhibit high bone densities, which suggests a potential influence of the mutant hormone on bone formation. We also have found that [Cys25]PTH forms homodimers, and that the dimeric peptide exhibits altered functionality versus monomeric PTH. Dimeric [Cys25]PTH(1-34) (Dimer) thus displays selective binding to the G protein-coupled PTH1R conformation (RG) in vitro and markedly diminished cAMP-inducing capability in vivo. Despite these alterations, Dimer induced bone anabolic effects in both calvarial injection assays and after injection in ovariectomized osteoporotic mice, closely mimicking the effects of PTH(1-34) (wtPTH). Our current objective is to explore the downstream signaling pathways activated by Dimer vs wtPTH to help elucidate the bone anabolic effects of the Dimeric analog and its therapeutic potential. Methods: A phospho-protein antibody array assay developed for G protein-coupled receptor (GPCR) downstream target proteins was employed in HEK293/hPTH1R (GP-2.3) cells following treatment with chemically synthesized wtPTH or Dimer. We further conducted RNA-seq analysis of transcriptome changes in primary cells collected from calvarial bones of mice treated with wtPTH or Dimer at 6, 12, and 24-hours post-injection. Finally, we used quantitative reverse transcription PCR (qRT-PCR) to analyze changes in specific marker genes in tibiae and kidney isolated from mice after treatment with Dimer vs. wtPTH. Results: The number of phosphorylated proteins significantly regulated by PTH1R upon exposure to Dimer was remarkably enhanced, relative to the number regulated upon exposure to wtPTH. RNA-seq analysis revealed that the early effects of wtPTH and Dimer on transcriptional regulation were similar, whereas marked differences in expression levels became apparent over time. qRT-PCR analyses of RNA expression levels in kidneys versus tibiae from mice treated with wtPTH or Dimer revealed in bone that the expression of genes associated with bone catabolism, particularly RANKL, was significantly lower in response to Dimer as compared to wtPTH treatment, while in kidney there was an overall reduced response to Dimer as compared to wtPTH. Conclusions: Our study supports the hypothesis that as compared to PTH(1-34), dimeric [Cys25]PTH (1-34) induces altered signaling responses in vivo and has a lower effect on bone catabolism. Dimeric [Cys25]PTH(1-34) thus holds interest as a potential bone anabolic agent that utilizes a distinct mechanism of action.
Presentation: 6/3/2024
7050 Effect of Spironolactone On Reducing Sugar-Induced Cellular Damage In MC3T3-E1 Osteoblastic Cells
Authors: Jin Yun Soo , Sang Hyunji , Young Park So , Sik Suh Kwang , Kim Hyun-Sook , Ouk Chin Sang 
Published: October 2024

Abstract
Disclosure: S. Yun: None. H. Sang: None. S. Park: None. K. Suh: None. H. Kim: None. S. Chin: None.
Background: In diabetes, prolonged hyperglycemia causes oxidative stress, resulting in pancreatic beta cells' dysfunction and diabetic complications. Oxidative stress can inhibit osteoblast differentiation and induce dysfunction and apoptosis. Spironolactone is an aldosterone antagonist used to treat hypertension and heart failure. In this study, we observed whether spironolactone can reduce osteoblast cytotoxicity and differentiation caused by oxidative stress induced by 2-deoxy-d-ribose (dRib). Methods: MC3T3-E1 cells were treated with spironolactone (0-100 uM) in the presence of 15 mM dRib. The cytotoxicity (lactate dehydrogenase, LDH) and differentiation (collagen content, alkaline phosphatase [ALP] activity, and mineralization) of osteoblasts, inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-6), oxidative stress (reactive oxygen species [ROS], mitochondrial superoxide), endoplasmic reticulum (ER) stress (activating transcription factor 6 [ATF-6], inositol-requiring 1 [IRE1]), mitochondrial function (mitochondrial membrane potential [MMP], adenosine triphosphate [ATP]), glyoxalase I activity, and glutathione (GSH) were measured. Results: Pretreatment of MC3T3-E1 osteoblastic cells with spironolactone prevented the dRib-induced cytotoxicity of osteoblasts and promoted differentiation of osteoblasts suppressed by dRib. Spironolactone significantly reduced dRib-induced inflammatory cytokines, ROS, mitochondrial superoxide, and ER stress. dRib-induced mitochondrial dysfunction was significantly improved by treatment with spironolactone. dRib is detoxified by the glyoxalase system. Pretreatment with spironolactone also increased the level of reduced GSH and the activity of glyoxalase I in dRib. Conclusion: Spironolactone could reduce dRib-induced cytotoxicity and promote differentiation in MC3T3-E1 osteoblastic cells by reducing oxidative stress and inflammatory cytokines, increasing mitochondrial biogenesis, and detoxifying dRib. These results suggest that spironolactone can be useful in the prevention and treatment of diabetic bone disease.
Presentation: 6/1/2024
7250 Effects of Romosozumab According To Prior Anti-Resorptive Treatments In Korean Postmenopausal Women From The Real-World Data: A Multi-Center Retrospective Study
Authors: Kim Y , Ahn S , Lee S E , Lee S , Kim H , Hong S 
Published: October 2024

Abstract
Disclosure: Y. Kim: None. S. Ahn: None. S. Lee: None. S. Lee: None. H. Kim: None. S. Hong: None.
Objectives: This study investigated the effects of romosozumab in Korean postmenopausal women based on their prior anti-resorptive treatments for osteoporosis from real-world data. Methods: A retrospective analysis of 145 postmenopausal women (66 drug-naïve [45.5%], 27 prior bisphosphonate [BP, 18.6%], 11 prior selective estrogen receptor modulator [SERM, 7.6%], and 41 prior denosumab [DMAB, 28.3%] groups) who received a 12-month romosozumab treatment between March 2020 and June 2023 at four hospitals in Korea was conducted. Changes in bone mineral densities (BMDs) at the lumbar spine (LS), total hip (TH), and femoral neck (FN), as well as bone turnover markers (C-telopeptide [CTX] and N-terminal type I procollagen propeptide [P1NP]), were evaluated. Results: Significant differences in BMD changes at all skeletal sites were observed between the groups (LS, TH, and FN: P&lt;0.001, P&lt;0.001, and P=0.018, respectively). Especially, the drug-naïve group showed a significantly greater increase in BMD change than the prior DMAB group at LS (17.5% vs. 6.5%, P&lt;0.001), TH (4.8% vs. -0.2%, P&lt;0.001), and FN (5.7% vs. 1.4%, P=0.015). The highest levels of P1NP were observed in the drug-naïve, prior BP, and prior SERM groups after one month of romosozumab treatment, while it was observed after six months in the prior DMAB group. Additionally, CTX levels decreased in the drug-naïve, prior BP, and prior SERM groups during romosozumab treatment, while an increase was observed in the prior DMAB group. Conclusion: The efficacy of romosozumab treatment is influenced by prior anti-resorptive therapies. Further investigation is necessary to develop personalized strategies for optimizing romosozumab's effectiveness based on prior osteoporosis medications, especially in prior DMAB group.
Presentation: 6/3/2024
7522 Effects of Trikafta On Bone Mineral Density And Body Composition In Patients With Cystic Fibrosis
Authors: Mon Nandar , Krishnasamy Sathya S , Bakeerathan Gunaratnam , Healy Lila , Favier Elizabeth , Foushee Sarah 
Published: October 2024

Abstract
Disclosure: N. Mon: None. S.S. Krishnasamy: None. G. Bakeerathan: None. L. Healy: None. E. Favier: None. S. Foushee: None.
Background: Cystic fibrosis related bone disease (CFBD) is a common complication of adult Cystic fibrosis (CF) patients due to calcium, vitamin D and K malabsorption from exocrine pancreatic insufficiency, increased inflammatory cytokines, glucocorticoid therapy, delayed puberty, physical inactivity, and hypogonadism. Newer CF transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (Trikafta) has proven benefit in pulmonary and nutritional outcomes. There is limited data on effects of Trikafta on bone health and body composition. The aim is to examine the effects of Trikafta on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), and body composition in terms of fat free mass index (FFMI) and fat mass index (FMI) in our CF patients. Method: We conducted a cross sectional and retrospective review of 38 adults with CF (Ages 20-59, 28 males and 10 females) in our CF clinic. Body Mass Index (BMI), Body composition measured by bioelectric impedance analysis, BMD of LS and FN by Dual-energy X-ray absorptiometry, Vitamin D level, and forced expiratory volume in one second (FEV1 % predicted) in patients taking Trikafta were analyzed and compared with control CF group who were not on Trikafta. Results: 38 subjects on Trikafta, aged 33.29 ± 10.36 years with FEV1 % predicted 65.11± 28.14% were studied. Serum 25-hydroxyvitamin D level was 35.92 ± 18.52 ng/dL. Of the 38 study patients, 23 (60.53%) had a diagnosis of CF related diabetes (CFRD). Among the Trikafta cohort, 18 (50%) had low BMD with Z-scores ≤ -2.0 and 7 (19.44%) of them had Z score ≤ -1.0 and &gt; -2.0. Compared with the control group, LS BMD 0.93 ± 0.16 g/cm2 and FN BMD 0.73± 0.13g/cm2 (p &gt;0.05) were not improved significantly. BMI of study population 23.09 ± 4.21 kg/m2 (p &lt;0.05) and FMI 6.11 ± 4.25 kg/m2 (p &lt;0.05) increased significantly; however, there was a decrease in FFMI 9.60 ± 1.44 kg/m2 (p &lt;0.05). Conclusion: Treatment with Trikafta in CF patients was associated with increases in BMI and fat mass index but decrease in fat free mass index. There was no statistically significant difference in BMD at LS and FN in our study cohort. This study has limitations in terms of gender differences within the study cohort, duration of Trikafta use in relation to bone mass, and also extent of glucocorticoid use among the study subjects. Larger prospective clinical trials are needed to study efficacy of Trikafta on CFBD.
Presentation: 6/3/2024
8115 Evaluation Of The Incidence Of Hypoparathyroidism In Patients Undergoing Anterior Cervical Surgery
Authors: Dos Santos Lívia Marcela , Oliveira Martins Graziela , Viana Lima Jose , Azevedo Alvares Leonardo , de Lemos Manuela Nascimento , Costa Figueiredo Luis Felipe , Naomi Sakane Eliane , Scalissi Nilza 
Published: October 2024

Abstract
Disclosure: L.D. Santos: None. G. Oliveira Martins: None. J.V. Lima: None. L.A. Alvares: None. M.N. Lemos: None. L. Costa Figueiredo: None. E.N. Sakane: None. N. Scalissi: None.
Introduction: The consensus published in 2022 suggests that a parathyroid hormone (PTH) level below 10 pg/mL may predict permanent hypoparathyroidism. However, these data have not yet been tested in the Brazilian population.Objective: To assess the clinical and laboratory characteristics of patients undergoing anterior cervical surgery, aiming to identify whether a postoperative PTH level below 10 pg/mL is associated with permanent hypoparathyroidism in a tertiary center in Brazil. Methods: We conducted a retrospective study with a chart review analysis. Results: We analyzed 59 patients who underwent anterior cervical surgery, with a mean age of 53 years (SD= +/- 17). 81% of the patients were alcohol consumers, and 76% were smokers. Regarding the surgical indication, 60.34% were for thyroid cancer, 17.24% for thyroid goiter, 13.79% for Graves' disease, 5.17% for glottic cancer, and 3.45% for primary hyperparathyroidism. Of the total operated patients, 49.15% were diagnosed with permanent hypoparathyroidism. The distribution of patients with permanent hypoparathyroidism was as follows: thyroid cancer 34.5%, Graves' disease 24.1%, goiter 24.1%, glottic cancer 10.3%, and primary hyperparathyroidism 7%. There was no significant difference in the occurrence of post-surgical hypoparathyroidism concerning the type of surgical indication (p&gt;0.05). Regarding PTH 24 hours after surgery, a significant difference was observed between the group with permanent hypoparathyroidism and the group without the disease, with a mean PTH of 5.0 pg/mL and 10 pg/mL, respectively (p&lt;0.05). As for serum calcium collected 24 hours post-surgery, there was no significant difference between the groups with and without permanent hypoparathyroidism (7.5 x 8.0 mg/dL; p&gt;0.05). Conclusion: The PTH measurement in the first 24 hours postoperatively has proven to be more discriminative than the serum calcium measurement during the same period in identifying patients with permanent hypoparathyroidism.
Presentation: 6/2/2024
7582 Genetic Profiling of Phosphaturic Mesenchymal Tumors Unravels Osterix's Significance in Tumor-Induced Osteomalacia
Authors: Imanishi Yasuo , Nagata Yuki , Ohara Masaya , Maeda-Tateishi Tomomi , Shoji Tetsuo , Emoto Masanori 
Published: October 2024

Abstract
Disclosure: Y. Imanishi: None. Y. Nagata: None. M. Ohara: None. T. Maeda-Tateishi: None. T. Shoji: None. M. Emoto: None.
Background & Purpose: Tumor-induced osteomalacia (TIO) is a rare condition caused by tumors releasing too much fibroblast growth factor 23 (FGF23). These tumors, specifically called phosphaturic mesenchymal tumors, mixed connective tissue variant (PMTMCT), lead to osteomalacia due to low serum phosphate levels. However, a detailed study regarding the genetic makeup of these tumors and their similarity to bone cells (osteoblasts/osteocytes) has been lacking. Methods: Nineteen PMTMCTs were analyzed and compared their gene expressions to 6 non-TIO tumors. Our focus was on genes usually found in bone cells. Additionally, we examined the relationship between FGF23 and these genes in PMTMCTs. One gene, Osterix, showing significant correlation was further studied using UMR106 osteoblast cells. Results: Fourteen genes related to bone cells expressed significantly higher in PMTMCTs compared to non-TIO tumors. Immunoblotting and Immunohistochemical examinations confirmed the presence of FGF23, Runx2, and Osterix in PMTMCTs. Particularly, Osterix showed the strongest link with FGF23 in PMTMCTs. Immunohistochemical tests revealed similar patterns of distribution for Osterix and FGF23, even co-localizing in some instances. However, the distribution of another gene, DMP1, differed from that of FGF23. In UMR106 cells, silencing Osterix expression led to decreased FGF23 expression, irrespective of DMP1 levels. Conclusions: PMTMCTs exhibit higher levels of genes associated with bone cell functions compared to other tumors. These tumors likely originated from mesenchymal stem cells and transformed into bone cells. Furthermore, Osterix might play a crucial role in the excessive release of FGF23 in PMTMCTs.
Presentation: 6/1/2024