bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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<0.001, P<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<0.001), TH (4.8% vs. -0.2%, P<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

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 > -2.0. Compared with the control group, LS BMD 0.93 ± 0.16 g/cm2 and FN BMD 0.73± 0.13g/cm2 (p >0.05) were not improved significantly. BMI of study population 23.09 ± 4.21 kg/m2 (p <0.05) and FMI 6.11 ± 4.25 kg/m2 (p <0.05) increased significantly; however, there was a decrease in FFMI 9.60 ± 1.44 kg/m2 (p <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

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>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<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>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
8709 FABP4+ Bone Marrow Endothelial Cells Support Hematopoietic Stem Cell Niches And Osteogenesis In Response To Vascular Insufficiency
Authors: Kim Y , Song M K , Sun H , Cho S
Published: October 2024

Disclosure: Y. Kim: None. M. Song: None. H. Sun: None. S. Cho: None.

Background: Numerous non-communicable and aging-related diseases are linked to systemic vascular insufficiency. The consequences of vascular insufficiency in bone marrow extend to compromising osteogenesis and hematopoiesis, with a more pronounced impact on aging individuals compared to younger counterparts affected by these conditions. Recent advances in scRNA-seq have shed light on the cellular taxonomy in bone marrow; however, a comprehensive understanding of cellular complexity requires further elucidation, and there are limitations in delineating impaired osteogenesis and hematopoiesis resulting from vascular insufficiency. In this study, we employed a combined approach of scRNA-seq and intensive ex vivo investigations to elucidate the regeneration process of bone marrow microenvironment following vascular insufficiency. Method Female C57BL/6 mice at different ages (6-wkks and 14 weeks) were subjected to sham (sham group) or right femoral artery ligation surgery (ischemia group). Reperfusion duration was quantified by color laser doppler. Osteogenesis was assessed by H&E staining, DXA and microCT scan. Flow cytometry was employed to count the number of type H endothelial cell (THEC, Endomucinhi). Bone marrow regeneration capacity was examined in vitro by treating with conditioned medium (CM) of THEC and in vivo via THEC injection. scRNA-seq was performed on the bone marrow of both sham and ischemia group 7 days post-ischemia. Result In young mice, reperfusion occurred within 7 days and osteogenesis was not different between sham and ischemia group. However, in old mice, reperfusion extended to 6 weeks, and accompanied by a reduction in osteogenesis, which did not recover until 12 weeks post-ischemia compared to sham group. The percentage of THEC increased after ischemia in young mice from 1.01% to 3.12 % (n=10, p<0.05), while those were comparable between sham and ischemia group in old mice (from 0.66% to 1.02%, n = 10, p=0.56). in MC3T3-E1 preosteoblast cell line, treatment with THEC-CM upregulated gene expressions associated with bone formation such as Alpl, Bglap, and Col1a1. In vivo THEC injection in old mice following ischemia surgery resulted in a reduction in reperfusion duration and an improvement in osteogenesis. scRNA-seq of bone marrow identified a significant increase of bone marrow stromal cells (BMSCs) and Cxcl12-abundant reticular (CAR) cells 7-days post-ischemia, which provides favorable microenvironment for dormant hematopoietic stem cells (HSCs). The number of FABP4+ THEC synchronized with the increase in BMSCs and CARs. In addition, FABP4+ THEC expressed Col1a1 and Col1a2, associated with osteogenesis, along with Cxcl12 and Foxc1, linked to HSC niches. Conclusion: FABP4+ THECs contribute to favorable microenvironment for HSCs and play a pivotal role in angiogenesis-osteogenesis coupling following vascular insufficiency.

Presentation: 6/1/2024
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

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
6487 Hypercalcemia In Pregnancy Due To An Ectopic Parathyroid Adenoma: A Diagnostic Dilemma
Authors: Patel S S , Sharma M B
Published: October 2024

Disclosure: S.S. Patel: None. M.B. Sharma: None.

Introduction: Hypercalcemia is a rare complication of pregnancy, with the most common cause being primary hyperparathyroidism due to a parathyroid adenoma. Ultrasound is the primary modality used for localization, as sestamibi and computed tomography (CT) carry the risk of potential harm to the fetus. We present the case of hypercalcemia in a pregnant female that failed to resolve after two gland parathyroidectomy, necessitating a sestamibi parathyroid scan to localize an ectopic parathyroid adenoma. Case: A 40-year-old pregnant woman at 12 weeks of gestation presented with hypercalcemia, with a corrected calcium level of 12.5 mg/dL (8.7-10.4 mg/dL). She complained of nausea and vomiting but denied any personal or family history of hypercalcemia. Further evaluation revealed primary hyperparathyroidism as the etiology, with Intact PTH of 429.2 pg/mL (18.5-88.0 pg/mL), ionized calcium of 1.45 mmol/L (1.12-1.32 mmol/L), 25-OH vitamin D of 16.4 ng/mL (30-100 ng/mL), phosphorus of 1.3 mg/dL (2.4-5.1 mg/dL), and creatinine of 0.71 mg/dL (0.5-0.8 mg/dL). Notably, her calcium level had been 19.2 mg/dL two weeks earlier during an episode of hyperemesis gravidarum. Hypercalcemia proved relatively resistant to treatment with intravenous hydration and subcutaneous calcitonin. Ultrasound of the neck failed to reveal a parathyroid adenoma. The patient then underwent surgical neck exploration, during which two parathyroid glands were removed, resulting in an intraoperative PTH drop from 440 to 340 pg/mL. Postoperative calcium levels remained elevated at 12.9 mg/dL, prompting the resumption of treatment. Oral sodium and potassium phosphate was added to bind dietary calcium. After an extensive multidisciplinary discussion, a 99mTc-sestamibi parathyroid scan with a lower dose of sestamibi and without CT was recommended. This revealed an ectopic parathyroid adenoma in the anterior mediastinum. Surgical removal of the ectopic parathyroid adenoma in the second trimester finally led to a significant intraoperative PTH drop from 315 to 28 pg/mL. The postoperative course was complicated by hypocalcemia and hypomagnesemia, requiring calcium, vitamin D, and magnesium supplements. These complications resolved over the following days. The patient remained normocalcemic for the remaining pregnancy and delivered a healthy male infant at 34 weeks. Conclusion: Hypercalcemia in pregnancy is associated with fetal and maternal complications, warranting adequate management and close follow-up. The use of 99mTc-sestamibi parathyroid scan is typically not recommended in pregnancy due to concern for fetal harm; however, there are a few studies showing no association with increased birth defects or adverse pregnancy outcomes at low radiotracer doses. Hence, a sestamibi parathyroid scan can be considered during pregnancy to localize an adenoma after a careful review of the benefits versus risks.

Presentation: 6/2/2024
6734 Hypercalcemia Of Immobilization (HCOM) Responding To COVID Treatment: A Mere Coincidence Or More?
Authors: Shafiq Ramsha , Javed Ammad , Haider Adnan
Published: October 2024

Disclosure: R. Shafiq: None. A. Javed: None. A. Haider: None.

A paraplegic patient who developed HCOM and subsequently received steroids for COVID-19 pneumonia with improvement in calcium levels. After completing steroid treatment his hypercalcemia relapsed and received IV bisphosphonates with normalization of calcium levels. Case: A 58-year-old male who became paraplegic after a fall in August, of 2022. In October 2022, during admission for sepsis related to an Indwelling foley catheter, his corrected calcium was 12 mg/dl. Despite IV hydration calcium remained elevated. In December 2022, the patient was readmitted for COVID-19 pneumonia & received Decadron 6 mg daily. On admission calcium was 13.2mg/dl with pertinent labs of PTH 4 (8.5-77 pg/ml), Vitamin D 1,25 was 31 (18-72 pg/ml), and PTHrp was normal. C- telopeptide was 1068 (87-345 pg/ml) which improved to 877 pg/ml after completing Decadron for COVID pneumonia. Also, Calcium transiently improved from 13.2mg/dl on admission to 9.8 mg/dl. Calcium levels were noted to be elevated again up to 14 mg/dl a month after discharge. February 2023, after IV bisphosphonate infusion corrected calcium normalized. In June 2023 calcium was high again at 14.4 mg/dl. IV hydration with a brief 3-day course of dexamethasone before receiving the second dose of zoledronic normalized corrected calcium. Discussion: Dysregulation in bone formation & resorption is due to the absence of mechanical stress in prolonged bed rest which is essential for bone remodeling. Lack of mechanical stress results in increased secretion of Sclerostin, a protein secreted by mature osteocytes that inhibits the Wnt signaling pathway resulting in increased bone resorption & decreased bone formation. Steroids reduce sclerostin production causing an improvement in calcium levels due to reduced bone resorption. His C telopeptide level was 1068 pg/ml) which improved to 877 pg/ml after steroids also supported Sclerostin-mediated bone resorption as a cause of hypercalcemia. Antiresorptive agents like IV bisphosphonates and Denosumab especially in patients with renal failure are the first-line treatments for HCOM. He did require an additional dose of IV zoledronic acid 4 months after the initial dose to maintain normocalcemia. Conclusion: HCOM is managed by physical therapy, IV hydration, and IV bisphosphonates. Since hypercalcemia of immobilization is a sclerostin-mediated bone resorption process, a short course of steroids or the use of anti-sclerostin monoclonal antibody Romosozumab can be a reasonable treatment consideration however more research is needed for that.

Presentation: 6/2/2024
8732 Hypercalcemia: When It’s Not PTH, Why Not Blame Your Neighbor?
Authors: Misra Daniel , Roger Brennan Michael , Misra Lynda
Published: October 2024

Disclosure: D. Misra: None. M.R. Brennan: None. L. Misra: None.

A 60-year-old female with a history of recently diagnosed hyperthyroidism, hypertension, and seizure disorder presents with a four-month history of neck swelling and pain. The patient was diagnosed with hyperthyroidism four months prior to admission and was started on methimazole 10 mg three times a day for two months, then instructed to decreased to 10 mg daily. In addition to the four months of neck swelling and pain, the patient also endorsed difficulty swallowing, palpitations, constipation, and bilateral ankle edema. Vital signs were stable other than a heart rate in the low 100s. Physical exam revealed a fixed painful L sided neck mass with no signs of airway compromise and bilateral exophthalmos. Labs revealed TSH <0.01 uIU/mL, Free T4 2.1 ng/dL, TSI was elevated (>40) IU/L. potassium 3.2 mmol/L, hypomagnesemia 1.3 mg/dL, troponin of 55 ng/l and hemoglobin 9.3 g/dL. The patient had a calcium of 10.6 mg/dL and an ionized calcium of 5.73 mg/dL with a normal PTH (34 pg/mL) and a low Vitamin D (22 ng/mL). A CT of the neck was performed showing marked thyromegaly with innumerable subcentimeter hypodense nodules in both lobes and a dominant 1.1 nodule in right lobe. Initial therapy involved correction of the electrolytes, telemetry monitoring, and a consultation to the endocrine service. The endocrine team started the patient on methimazole 10mg/daily and ordered a thyroid scan. Scintigraphy was performed and was consistent with Graves’ disease. On Day #2 the patient’s vital signs had normalized and the patient was able to swallow and tolerate a regular diet, The scan showed an enlarged thyroid with diffuse nodular character and moderate hyperemia consistent with diffuse thyroiditis. The scan also described a multinodular goiter with the largest nodule measuring 2.2 cm. She was discharged on Day #3 on methimazole 10mg daily and asked to follow up with endocrinology. Graves’ disease is a common cause of hyperthyroidism and is caused by autoantibodies that increase the production of thyroid hormone. Along with classic symptoms of hyperthyroidism, our patient had hypercalcemia. This was non-PTH mediated and in the absence of other signs or symptoms of a malignancy or granulomatous process, the hypercalcemia is likely due to her hyperthyroid state. Hyperthyroidism-associated hypercalcemia is a rare complication in hyperthyroid patients but should not be forgotten when evaluating non-PTH mediated hypercalcemia as it can be corrected easily with appropriate medications or in this case with the correction of the hyperthyroidism. Consideration of this etiology may also reduce the number of extraneous labs and imaging when no other common etiology is found.

Presentation: 6/2/2024
8541 Hypocalcemia In Setting Of Hypoparathyroidism And Gastric Bypass
Authors: Abrahimi Nora , Abrahimi Aryan
Published: October 2024

Disclosure: N. Abrahimi: None. A. Abrahimi: None.

Background: Hypocalcemia secondary to hypoparathyroidism is a known complication for patients who undergo thyroidectomy. (1) Additionally, patients who undergo bariatric surgery are similarly at risk for developing hypocalcemia. (2) Clinical Case: 52-year-old female with past medical history of thyroid carcinoma status post total thyroidectomy complicated by post operative hypoparathyroidism and history of gastric bypass presented to the hospital with paresthesia and fatigue. On presentation, calcium measured at 6.9 mg/dL, EKG showed Qtc prolongation at 503. Physical exam was positive for Chvostek sign and Trousseau sign. The patient received 1 g of intravenous calcium gluconate and was admitted to medicine for management of symptomatic hypocalcemia. Calcium initially improved to 8.2 mg/dL with a subsequent drop to 7.5 mg/dL. An additional 1 g of intravenous calcium gluconate was administered, calcium then corrected to 8.0 mg/dL, symptoms and Qtc prolongation resolved. The patient endorsed compliance with daily calcium supplementation of oral calcitriol prior to presentation. Prior to discharge, calcitriol dosage was increased, and patient was instructed to follow up calcium levels in one week outpatient with endocrinologist. Conclusion: Bariatric surgery, specifically gastric bypass or Roux-en-Y bypass reduces absorption of vitamin D and calcium as the primary sites for absorption are bypassed. (3) Although not commonly studied, severe hypocalcemia is linked to an increased risk for development of serious cardiac arrhythmias. (4) This emphasizes the importance of close calcium monitoring in patient with history of bariatric surgery and hypoparathyroidism.

References:

1. Lee YS, Nam KH, Chung WY, Chang HS, Park CS . Postoperative complications of thyroid cancer in a single center experience. J Korean Med Sci. 2010;25(4):541. Epub 2010 Mar 19.

2. Slater GH, Ren CJ, Siegel N, Williams T, Barr D, Wolfe B, Dolan K, Fielding GA. Serum fat-soluble vitamin deficiency and abnormal calcium metabolism after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8:48-55. doi: 10.1016/j.gassur.2003.09.020

3. Panazzolo DG, Braga TG, Bergamim A, Pires B, Almeida H, Kraemer-Aguiar LG. J Med Case Rep. 2014; 8: 357. Epub 2014 Oct 28. doi: 10.1186/1752-1947-8-357

4. Khalid S, Albaba I, Neu K. Hypocalcemia: A Little Known Cause of Supraventricular Tachyarrhythmia. Cureus. 2023;15(5):e38456. Published 2023 May 2. doi:10.7759/cureus.38456

Presentation: 6/1/2024
8025 Hypocalcemia Secondary To Relative Hypoparathyroidism After Parathyroidectomy For Tertiary Hyperparathyroidism
Authors: Solanki Naisargee N , Bahrou Mohamad A , Taha Wael
Published: October 2024

Disclosure: N.N. Solanki: None. M.A. Bahrou: None. W. Taha: None.

Parathyroidectomy is one of the treatment options for patients with tertiary hyperparathyroidism. Hypocalcemia following parathyroidectomy is a well-known occurrence due to a sudden drop in parathyroid levels, commonly to normal levels. We describe a case of hypocalcemia following subtotal parathyroidectomy for tertiary hyperparathyroidism with elevated parathyroid hormone (PTH) levels but relatively low compared to baseline. A 56-year-old female with a history of end-stage renal disease status post renal graft rejection presents for elective parathyroidectomy for tertiary hyperparathyroidism. Pre-operative investigations showed serum calcium levels of 11.6 mg/dL, normal value (NV): 9-10.5 mg/dL, serum phosphorus levels of 5.6 mg/dL, NV: 2.7-4.5 mg/dL, very high levels of serum intact PTH of 1257 pg/mL, NV: 10-65pg/mL and high level of alkaline phosphatase of 376 U/L, NV: 40-150 U/L. The patient underwent right and left inferior parathyroidectomy. Postoperatively, the patient's intact PTH levels remained elevated [895 pg/mL]; however, they decreased compared to baseline, but she developed hypocalcemia requiring intravenous and oral calcium supplementation. On postoperative day seven, she was discharged on oral calcitriol and calcium carbonate. Hypocalcemia following parathyroidectomy is well-described in cases where the PTH levels drop to the normal range. This case highlights that hypocalcemia can also occur when there is a relatively lower PTH level while the absolute value remains elevated.

Presentation: 6/1/2024
5071 Impact of Estrogen Replacement Therapy on Bone Health in a Novel Non-human Primate Model of Postmenopausal Women Living with HIV
Authors: Sauter K , Takahashi D L , Webb G , Hofmeister H , Varlamov O , Sacha J , Kievit P
Published: October 2024

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
8810 Improvement in bone mineral density in tertiary hyperparathyroidism after renal transplant treated with parathyroidectomy
Authors: Zakher Mariam , Barnett Braden G
Published: October 2024

Disclosure: M. Zakher: None.

55 year old man with past medical history of end-stage renal disease (ESRD) and alcoholic cirrhosis who underwent simultaneous liver-kidney transplant (SLKT) seven months prior to presentation to endocrinology who was referred for management of hypophosphatemia as low as 1.0 mg/dl. Prior to the transplant, he had hyperphosphatemia and hyperparathyroidism with phosphate and parathyroid hormone (PTH) levels as high as 8.2 mg/dL and 682 pg/mL, respectively. PTH remained elevated at 244 pg/mL and vitamin D was 35 ng/mL the week of the initial endocrinology visit. Initial DXA scan six months after SLKT showed osteoporosis of the lumbar spine, total left proximal femur, and left femoral neck with T-scores of -3.4, -4.9, -5.6, respectively. Alendronate was started three weeks prior to the initial visit. Urine studies confirmed phosphate wasting with urinary phosphate excretion significantly higher than 100 mg/24h, FEPO4 greater than 70%, and TmP/GFR less than 2 mg/dL. Increased urinary excretion of phosphate was consistent with hyperparathyroidism. The extremely low urinary calcium in the setting of normocalcemia and the history of renal transplant suggested a tertiary hyperparathyroidism. Alendronate was discontinued eight months after the initial visit to reduce the risk of post-parathyroidectomy hypocalcemia and post-parathyroidectomy bone remodeling inhibition.One year after the initial visit, the patient had a bilateral neck exploration with total parathyroidectomy and auto transplantation of the parathyroid. Pathology showed hypercellular parathyroid tissue. He was hospitalized one week after surgery for symptomatic hypolcalcemia (calcium 5.8 mg/dL). He was taking one tablet of calcium carbonate three times daily at home instead of three tablets three times daily as prescribed. He was discharged on calcitriol 0.5 mcg once daily, magnesium oxide 800 mg twice daily, calcium carbonate 1 g three times daily, and cholecalciferol 5000 units once daily. He remained on these for eleven months as well as calcitriol for fifteen months with dose adjustments during visits. Calcitriol was discontinued when calcium was found to be 8.9 mg/dL and the patient was asymptomatic. Repeat DXA scan two years after the baseline DXA showed osteoporosis of the left femoral neck with a T score of -2.5. There was a tremendous improvement from the baseline DXA scan from +20% in the total lumbar spine to +170% in the left femoral neck. DXA scan four years after the baseline DXA scan showed osteopenia of the lumbar spine, total left proximal femur, and left femoral neck with T-scores of -1.7, -2.4, -1.9.This is a 55 year old man who underwent SLKT seven months prior to presentation to endocrinology who was referred for management of hypophosphatemia as low as 1.0 mg/dL found with tertiary hyperparathyroidism who underwent a parathyroidectomy that resulted in significant improvement in bone mineral density test.

Presentation: 6/2/2024
7630 Incidental Calvarial Brown Tumor in an ESRD patient with seizures
Authors: Nikita Pereira Kristal , mehta vidhi , Sekaran Sruthi , Renzu Mahvish
Published: October 2024

Disclosure: K.N. Pereira: None. V. mehta: None. S. Sekaran: None. M. Renzu: None.

Brown Tumor [BT], also known as Osteitis fibrosa cystica [OFC], is a rare tertiary manifestation of hyperparathyroidism [HPTH]. BT commonly affects the maxilla/mandible, long bones and spine and presents as lytic bone lesions on imaging. Among the crania-facial bones, the maxilla, palate, temporal bone, nasal cavity, orbital bone and paranasal sinuses are affected. We describe a case of a 37 year old African-American female with extensive medical history including ESRD on hemodialysis who initially presented to the hospital with hypertensive emergency in the setting of 1 week of missed dialysis. During her presentation, she had an unexplained seizure which led to further workup with imaging. CT head revealed findings suspicious of renal osteodystrophy as well as a discrete lucency at the calvarial vertex suggestive of a brown tumor. Endocrinological studies were noted to have very high PTH levels with hypercalcemia, hyperphosphatemia and vitamin D deficiency indicative of tertiary hyperparathyroidism. Based on her clinical presentation, labs and imaging, her bone disease including BT and pathologic fractures, was deemed to be due to tertiary hyperparathyroidism in the setting of ESRD, which were not amenable to surgical intervention. Extensive literature review did not reveal any reported BTs in the calvarial vertex. This case emphasizes on the holistic approach to diagnosis of BTs and underlines that fact that BT can occur in any cortical bone including unusual presentation sites like the calvarial vertex.

Presentation: 6/3/2024
8519 Investigating the Role of Protein Inhibitor of Activated STAT1 (Pias1) in Growth Plate Chondrocyte Maturation
Authors: Baronas John , Ahmed Usman , Hirschhorn Joel N , Renthal Nora E
Published: October 2024

Disclosure: J. Baronas: None. U. Ahmed: None. J.N. Hirschhorn: None. N.E. Renthal: None.

Development of growth plate chondrocytes is a complex process that involves a wide array of regulatory elements. Recently our laboratory conducted a genome wide CRISPR knockout (KO) screen of growth plate chondrocyte maturation to discover novel genes and gene networks in the proliferation and maturation of chondrocytes. Among targets uncovered is Protein Inhibitor of Activated STAT 1 (Pias1), an E3 SUMO ligase that plays a multi-faceted role in genetic regulation, driving post-translational modifications, directly binding to transcription factors, and functioning as a DNA-binding protein. While Pias1 has been shown to be involved in the regulation of many cellular processes across multiple tissues, its function in growth plate development and chondrocyte maturation has been previously unstudied. In our genome-wide screen, our laboratory identified that loss of Pias1 led to early maturation of chondrocytes. This project seeks to investigate the role of Pias1 in chondrocyte maturation and differentiation. We first developed a Pias1-KO chondrocyte cell line, observing upregulation of hypertrophic markers Cd200 and Col10a1 in KOs relative to control via qPCR, in addition to proliferative regulators IHH and Pth1R. Through Bulk-RNAseq of the same cell line, we identified additional chondrocyte markers as upregulated in KO, as well as osteoblast marker Sp7. Members of the HoxD family, regulators of limb development, were downregulated. Cell culture data suggests that loss of Pias1 leads to increased cell proliferation and increased matrix production, indicating dysregulation of multiple chondrocyte processes. Immunohistochemistry of micromass culture sections also suggests morphological differences between KO and control, with KO cells significantly larger in diameter. Early SUMO-1 profiling yields limited evidence of decreased global SUMOylation in KO cells, one possible mechanistic explanation for the observed dysregulation. Ongoing studies are focused on identifying specific SUMOylation targets of Pias1 in chondrocytes, analyzing proteomic differences in KO and control, seeking putative DNA-binding sites of Pias1, and observing in vivo murine Pias1-KO growth plates. Our findings suggest that PIAS1 plays a crucial role in the growth plate by prolonging growth and delaying terminal hypertrophy. Our study aims to provide a better understanding of the regulatory pathways involved in growth plate development and related phenotypes such as height, and contribute to the development of novel therapies for growth-related disorders, such as achondroplasia and hypochondroplasia.

Presentation: 6/1/2024
5144 Lessons Learned: Evaluation of a Fracture Liaison Service Quality Improvement Efforts
Authors: Sara Rothman Micol , Fixen Danielle R , Schilling Lisa M , Mahmoud Elsheikh Arwa , Marcus Alexandra M , Billups Sarah J
Published: October 2024

Disclosure: M.S. Rothman: None. D.R. Fixen: None. L.M. Schilling: None. A.M. Elsheikh: None. A.M. Marcus: None. S.J. Billups: None.

Background: The Fracture Liaison Service (FLS) care model, a care coordination program for patients experiencing a fragility fracture, is proven to improve management of patients with an osteoporotic fracture, but treatment initiation gaps persist. We describe the evolution of a centralized FLS within a university-based healthcare system, including impact of adding clinical pharmacist consultation and describe circumstances surrounding continued care gaps. Design: Cohort analysis of osteoporosis medication initiation before FLS, after initial implementation, and after addition of pharmacist consultation. Patients: Individuals aged 65 and older experiencing any fragility fracture between 7/1/16 - 3/31/22. Intervention: A centralized team outreached eligible patients, ordered dual x-ray absorptiometry and laboratory tests as needed, and scheduled an osteoporosis-focused primary care appointment. Three years after FLS implementation, clinical pharmacist consultative review was added prior to the primary care visit. Main Measures: Initiation of osteoporosis pharmacologic therapy, completion of DXA, primary care follow-up rate, and description of circumstances where therapy was not initiated. Key Results: Of 1204 new fractures between 7/1/16-3/31/22, 315 patients were enrolled in one of two FLS phases, and 89 eligible historical controls were identified. Medication initiation rates went from 22/89 (25%) pre-FLS to 201/428 (47%) after-FLS phase 1 [POST1], (p<0.001) and to 106/187 (57%) after FLS phase 2 (POST2), when clinical pharmacist consultation was added (p=0.03 versus POST1). DXA was completed in 56/89 (67%) of pre-FLS patients, 364/428 (85%) POST1 patients (p<0.001 versus pre), and 163/187 (87%) POST2 (p< 0.001 versus PRE, p=0.59 versus POST1). Of 375 patients who did not initiate osteoporosis medication, more in the combined post-FLS cohorts attended a follow-up primary care appointment (233/308, 76% attended, versus pre-FLS 41/67, 61% , p=0.016). Conclusion: An FLS including centralized outreach and care coordination significantly improved patient follow-up, DXA, and medication initiation. Addition of de-centralized pharmacist consultation further improved medication initiation rates.

Presentation: 6/3/2024
8410 Lipid modification enhances the calcemic and bone building effects of injected PTH(1-14) and PTH(1-11) fragment peptides in mice
Authors: Höppner Jakob , Noda Hiroshi , Khatri Ashok , Jüppner Harald , James Gardella Thomas
Published: October 2024

Disclosure: J. Höppner: None. H. Noda: None. A. Khatri: None. H. Jüppner: None. T.J. Gardella: None.

PTH analogs with improved actions in vivo are of interest as potential treatment options for bone and mineral ion diseases such as hypoparathyroidism and osteoporosis. The efficacies in vivo of conventional PTH peptides are generally limited by rapid rates of clearance from the circulation (t1/2 = ∼ 5-30 minutes) and relatively short-dwell times on the receptor (PTH1R). This is especially true for small fragment analogs, such as M (modified)-PTH(1-14), and M-PTH(1-11), which have only been shown to be active in vitro. We explored whether PTH fragment peptide efficacy in vivo could be enhanced by addition of a lipid chain (e.g., a C15 palmitoyl chain (palm)) to either the peptide C-terminus or to the side chain of the amino acid residue at position 11 or 13. The C-tail lipid modifications were specifically designed to promote binding to serum albumin, and hence extend circulation half-life, while the lipid chains at sidechains of residue positions 11 and 13 were designed, based on structural models, to anchor the ligand to the receptor in situ -- i.e. by projection of the acyl chain between two adjacent transmembrane helices and into the surrounding plasma membrane -- to thereby extend receptor dwell time. Assessment of cAMP signaling potencies in HEK293/hPTH1R/glosensor cells revealed that both types of lipid modifications can preserve agonist potency, and that the lipid extensions at position 11 or 13 can indeed prolong receptor dwell times, as shown by extended durations of cAMP signaling after initial binding of Palm 11 or 13-modified M-PTH(1-14) and M-PTH(1-11) peptide fragment. Single subcutaneous injection of either Palm-13-M-PTH(1-14) or Palm-11-M-PTH(1-11) into mice resulted in prolonged increases in blood serum calcium levels, while 14 days of daily injection resulted in profound increases in bone mass, as measured by uCT, and marked increases in blood levels of the bone turnover markers CTX1 and P1NP, whereas non-lipidated M-PTH(1-14) control peptides were inactive in vivo. Peptide lipidation thus holds promise as a strategy to employ in the design of new PTH analogs with improved efficacies in vivo.

Presentation: 6/1/2024