Treatment Of Osteoporosis Research Articles

ALKBH5 regulates etoposide-induced cellular senescence and osteogenic differentiation in osteoporosis through mediating the m6A modification of VDAC3.

Osteoporosis, a common bone disease in older individuals, involves the progression influenced by N6-methyladenosine (m6A) modification. This study aimed to elucidate the effects of VDAC3 m6A modification on human bone mesenchymal stromal cell (BMSC) senescence and osteogenic differentiation. BMSCs were treated with etoposide to induce senescence. Senescence was assessed by β-galactosidase staining and quantitative real-time PCR (qPCR), and osteogenic differentiation was evaluated using Western blot, alkaline phosphatase, and alizarin red S staining. VDAC3 and ALKBH5 expression were quantified by qPCR, and their interaction was assessed by RNA immunoprecipitation (RIP) and luciferase reporter assay. m6A methylation was analyzed using the Me-RIP assay. VDAC3 expression was significantly decreased in etoposide-treated BMSCs (1.00 ± 0.13 vs. 0.26 ± 0.06). VDAC3 overexpression reduced etoposide-induced senescence and promoted osteogenic differentiation. ALKBH5 overexpression inhibited VDAC3 m6A modification (1.00 ± 0.095 vs. 0.233 ± 0.177) and its stability. ALKBH5 knockdown decreased etoposide-induced senescence and promoted osteogenic differentiation, effects that were reversed by VDAC3 knockdown. YTHDF1 was identified as the m6A methylation reader, and its overexpression inhibited VDAC3 stability. We demonstrated that ALKBH5 inhibited osteogenic differentiation of etoposide-induced senescent cells through the inhibition of VDAC3 m6A modification, and YTHDF1 acted as the m6A methylation reader. These findings provide a novel theoretical basis for the treatment of osteoporosis.

IMPC-based screening revealed that ROBO1 can regulate osteoporosis by inhibiting osteogenic differentiation.

The utilization of denosumab in treating osteoporosis highlights promising prospects for osteoporosis intervention guided by gene targets. While omics-based research into osteoporosis pathogenesis yields a plethora of potential gene targets for clinical transformation, identifying effective gene targets has posed challenges. We first queried the omics data of osteoporosis clinical samples on PubMed, used International Mouse Phenotyping Consortium (IMPC) to screen differentially expressed genes, and conducted preliminary functional verification of candidate genes in human Saos2 cells through osteogenic differentiation and mineralization experiments. We then selected the candidate genes with the most significant effects on osteogenic differentiation and further verified the osteogenic differentiation and mineralization functions in mouse 3T3-E1 and bone marrow mesenchymal stem cells (BMSC). Finally, we used RNA-seq to explore the regulation of osteogenesis by the target gene. We identified PPP2R2A, RRBP1, HSPB6, SLC22A15, ADAMTS4, ATP8B1, CTNNB1, ROBO1, and EFR3B, which may contribute to osteoporosis. ROBO1 was the most significant regulator of osteogenesis in both human and mouse osteoblast. The inhibitory effect of Robo1 knockdown on osteogenic differentiation may be related to the activation of inflammatory signaling pathways. Our study provides several novel molecular mechanisms involved in the pathogenesis of osteoporosis. ROBO1 is a potential target for osteoporosis intervention.

Novel Delivery Systems of Raloxifene Hydrochloride for Improved Bioavailability and Therapeutic Efficacy: A Review

Raloxifene hydrochloride belongs to the selective estrogen receptor modulator category. Initially, US FDA approved its use for the prevention and treatment of osteoporosis in postmenopausal women. Later, raloxifene hydrochloride was also approved for the prevention of invasive breast carcinoma in post-menopausal women under the high-risk category. Despite its immense and diverse therapeutic potential, the oral bioavailability of raloxifene hydrochloride is only ~ 2%. The factors responsible for the poor bioavailability of raloxifene hydrochloride include its amphiphobic nature, para-glycoprotein pump-mediated efflux in the intestine, and high pre-systemic glucuronidation. In the past two decades, multiple novel delivery systems, viz. lipid-based nanocarriers, polymeric nanoparticles, polymer-lipid hybrid nanoparticles, micelles, and mixed micelles, have been developed to overcome its drawbacks. Moreover, inclusion complex, phospholipid complex, and solid dispersion have also been developed to improve its solubility and dissolution rate. Further, some research groups successfully explored non-peroral routes like nasal and transdermal for augmenting the raloxifene hydrochloride bioavailability and its therapeutic efficacy. Hence, the principal objective of this review paper is to critically analyze all the delivery systems developed for raloxifene hydrochloride with their advantages and limitations. In addition, a detailed discussion of the physicochemical and pharmacokinetic parameters of raloxifene hydrochloride has been included in this paper. An in-depth understanding of these parameters will assist formulation scientists in developing efficient delivery systems in the future. In conclusion, the literature review revealed that the nanoparticulate systems successfully augmented the raloxifene hydrochloride bioavailability and therapeutic efficacy in pre-clinical experiments. However, future clinical trials should be conducted to assess their safety and therapeutic efficacy for rapid preclinical to clinical translation.

Geriatric traumatological management of osteoporosis : "Let the first fracture be the last"

In Germany more than 800,000 osteoporotic fractures occur every year, with severe medical, social and health economic consequences. Nevertheless, as in many other countries there is alarge gap in care. Fractures frequently occur in older geriatric patients, who are increasingly being (or should be) treated in geriatric trauma centers. This multidisciplinary approach offers the opportunity not only to restore the patient's mobility and independence but also to set the course for preventing further fractures. Diagnosing osteoporosis and initiating treatment early after afracture is particularly important as there is an imminently high risk of further fractures in the months and years following afracture. This review article describes apragmatic, guideline-based approach to osteoporosis management for geriatric trauma patients. It discusses fracture risk assessment, current treatment thresholds and treatment strategies as well as the individual osteoporosis drugs, the indications and contraindications. This review aims to show that the treatment of osteoporosis within the framework of ageriatric traumatology team is feasible in the majority of cases. It is suggested that atreatment decision can be systematically made based on afew questions or aflow chart.

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<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<0.0001) and also hip fracture (7.2±4.1% versus 1.9±2.7%, p<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

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells

Background/ObjectiveActive vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells. MethodsBone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/−) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups. ResultsABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins. ConclusionABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency. The translational potential of this articleThis study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

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

12453 Osteoporosis Screening In A Primary Care Clinic: Barriers And Solutions

Abstract Disclosure: B.M. Laquidara: None. S. Mistry: None. L. Guo: None. Purpose/Objective: Osteoporosis is a prevalent bone disorder that affects over 10 million people in the United States. The US Preventive Services Task Force (USPSTF) recommends screening females aged 65 and older with a baseline DEXA scan and to screen postmenopausal females younger than age 65 who have an increased risk of osteoporosis. Despite these guidelines, the screening rate for osteoporosis remains very low. Our quality improvement project seeks to first identify at what rate eligible patients in our residency primary care clinic are being screened for osteoporosis and what barriers (patient, provider, or clinical factors) to screening may decrease this rate. Methods: We reviewed a random sample medical records of 300 female patients aged >/= 50 years who visited our clinic within the last two years. We collected patient demographics, insurance status, presence of ≥1 risk factor of osteoporosis (fracture, heavy alcohol use, tobacco use, steroid use, BMI<19), MyChart activity, provider training level, diagnosis code, and whether a baseline DEXA was ordered and/or completed. We compared patient characteristics by DEXA order status using descriptive statistics, and used multivariable regression models to determine odds of DEXA order and completion. Results: The patients who were at high risk for osteoporosis were more likely to have an order without completion (OR 6.11, p <0.001). Increased age was associated with increased odds of having an order (OR 1.09, p<0.001). Increasing BMI was associated with decreased odds of having an order. Black patients and current smokers were less likely to have a DEXA scan ordered and completed after controlling for age and other confounding factors (p= 0.002 and 0.001 respectively). Among the 96 patients who had a completed DEXA scan, 74 had osteoporosis. The only significant predictor for having osteoporosis was low BMI (OR 0.87%, p<0.001). Conclusion: The results of this study suggest that while patients with a clinically high risk for osteoporosis are more likely to have an order placed for a DEXA scan, these patients often do not have a completed scan. Patients who have an ICD-10 diagnosis of high-risk for osteoporosis or osteoporosis in their electronic medical record are more likely to have both an ordered and completed scan. Utilizing this data, we will develop a variety of interventions such as a clinical didactic case for osteoporosis, a flow-sheet summary of proper osteoporosis screening and treatment initiation to be distributed in the clinic setting, and a short presentation during noon didactics where we review the proper screening method for osteoporosis. Following our intervention, we will re-examine the screening rate in our residency clinic to evaluate the effect of our intervention. Presentation: 6/3/2024

6577 National Trends in Fragility Hip Fractures Among Community Dwelling Women With Low Femoral Neck Bone Mineral Density

Abstract Disclosure: A. Atri: None. C. Anastasopoulou: None. Introduction: Fragility hip fractures are a major public health burden and are considered a good measure of the quality of healthcare. However, contemporary trends in fragility hip fractures in women with low femoral neck bone mineral density (BMD) in the United States are not known. 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 ≥ 60 years with bone mineral density (BMD) T score ≤ -1 at the femur neck, which was measured by dual energy x-ray absorptiometry (DEXA) on Hologic Discovery Model A Densitometers (Hologic, Inc., Bedford, Massachusetts). Fragility fracture at the hip was defined as self-reported hip fracture resulting from a fall from standing height or less. Participants with missing BMD and fracture data were excluded. ANOVA was used for comparing means. The Cochran-Armitage test was utilized for trend analysis. Results: Overall, in women aged ≥ 60 years with femoral neck T score ≤ -1, the average age of women of low BMD decreased from 71(±7.2) years to 69.6 (±6.7) years, whereas the mean T-score modestly worsened from – 1.96 (±0.62) to -2.04 (±0.77) from 2009-10 to 2017-18. Similarly, the prevalence of women with T score ≤ -2.5 increased from 18.1% to 21.3%. We also found no significant change in proportion of women who reported treatment for osteoporosis (2009-10: 19.8%, 2013-14: 18.5%, 2017-18: 19.7%; p trend = 0.052). However, proportion of women who experienced fragility hip fractures decreased significantly (2009-10: 2.4%, 2013-14: 1.5%, 2017-18: 1.2%; p trend = 0.001). The mean age of index fragility hip fracture was 70.6 years in 2009-10, 68.3 years in 2013-14 and 71.7 years in 2017-18 (p = 0.001). Age stratified analysis showed a decreasing trend in proportion of women ≥ 80 years who experienced their index fragility hip fracture (2009-10: 25.9%, 2013-14: 14.7%, 2017-18: 15%; p trend = 0.001) and 70-79 years (2009-10: 40.9%, 2013-14: 21.1%, 2017-18: 35.8%; p trend = 0.001), while an increasing trend was seen in women 60–69 years (2009-10: 33.2%, 2013-14: 64.2%, 2017-18: 49.2%; p trend = 0.001). Discussion In this nationally representative cohort of community-dwelling US women with a low femoral neck BMD, we found a 50% decrease in burden of fragility hip fractures over a 10-year period from 2009-10 to 2017-18. This trend was observed despite worsening mean femoral neck T-scores, T score ≤ -2.5, and similar rates of osteoporosis treatment. Interestingly, the proportion of women who experienced their index fragility hip fracture showed a declining trend among the 70-79 years and ≥ 80 years age-groups. This change may be due to increasing awareness and utilization of measures to decrease falls such as exercise, nutrition, health education and environment modifications targeted towards the elderly population. Presentation: 6/2/2024

9288 National Trends in Fragility Hip Fractures Among Community Dwelling Women With Low Femoral Neck Bone Mineral Density

Abstract Disclosure: A. Atri: None. C. Anastasopoulou: None. Introduction: Fragility hip fractures are a major public health burden and are considered a good measure of the quality of healthcare. However, contemporary trends in fragility hip fractures in women with low femoral neck bone mineral density (BMD) in the United States are not known. 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 ≥ 60 years with bone mineral density (BMD) T score ≤ -1 at the femur neck, which was measured by dual energy x-ray absorptiometry (DEXA) on Hologic Discovery Model A Densitometers (Hologic, Inc., Bedford, Massachusetts). Fragility fracture at the hip was defined as self-reported hip fracture resulting from a fall from standing height or less. Participants with missing BMD and fracture data were excluded. ANOVA was used for comparing means. The Cochran-Armitage test was utilized for trend analysis. Results: Overall, in women aged ≥ 60 years with femoral neck T score ≤ -1, the average age of women of low BMD decreased from 71(±7.2) years to 69.6 (±6.7) years, whereas the mean T-score modestly worsened from – 1.96 (±0.62) to -2.04 (±0.77) from 2009-10 to 2017-18. Similarly, the prevalence of women with T score ≤ -2.5 increased from 18.1% to 21.3%. We also found no significant change in proportion of women who reported treatment for osteoporosis (2009-10: 19.8%, 2013-14: 18.5%, 2017-18: 19.7%; p trend = 0.052). However, proportion of women who experienced fragility hip fractures decreased significantly (2009-10: 2.4%, 2013-14: 1.5%, 2017-18: 1.2%; p trend = 0.001). The mean age of index fragility hip fracture was 70.6 years in 2009-10, 68.3 years in 2013-14 and 71.7 years in 2017-18 (p = 0.001). Age stratified analysis showed a decreasing trend in proportion of women ≥ 80 years who experienced their index fragility hip fracture (2009-10: 25.9%, 2013-14: 14.7%, 2017-18: 15%; p trend = 0.001) and 70-79 years (2009-10: 40.9%, 2013-14: 21.1%, 2017-18: 35.8%; p trend = 0.001), while an increasing trend was seen in women 60–69 years (2009-10: 33.2%, 2013-14: 64.2%, 2017-18: 49.2%; p trend = 0.001). Discussion In this nationally representative cohort of community-dwelling US women with a low femoral neck BMD, we found a 50% decrease in burden of fragility hip fractures over a 10-year period from 2009-10 to 2017-18. This trend was observed despite worsening mean femoral neck T-scores, T score ≤ -2.5, and similar rates of osteoporosis treatment. Interestingly, the proportion of women who experienced their index fragility hip fracture showed a declining trend among the 70-79 years and ≥ 80 years age-groups. This change may be due to increasing awareness and utilization of measures to decrease falls such as exercise, nutrition, health education and environment modifications targeted towards the elderly population. Presentation: 6/2/2024

7250 Effects of Romosozumab According To Prior Anti-Resorptive Treatments In Korean Postmenopausal Women From The Real-World Data: A Multi-Center Retrospective Study

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<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

7002 Building Poor Bone, A Rare Presentation Of Skeletal Fluorosis

Abstract Disclosure: C. Pham: None. J.S. Lopresti: None. Skeletal fluorosis is a rare disease associated with osteosclerosis and fractures. Case: 26 year old male presented with a history of multiple traumatic fractures but no childhood or family history of fractures. Initial labs revealed a corrected calcium of 8.1 mg/dL (8.5-10.3), ALP 1,504 U/L (40-129), PTH 131 pg/ml (15-65), 25-OH D 14 ng/ml (30-100), PO4 3.7 mg/dl (2.5-4.5) and normal creatinine. X-Rays demonstrated osteosclerosis and cortical expansion of bone and nuclear bone scan demonstrated diffuse increased uptake. Further history revealed huffing of computer inhalants (10 cans daily) for years. Due to these findings, urine fluoride 16.88 mg/L (0.20-3.20 mg/L) and serum fluoride 0.40 mg/L (<0.05 mg/L) were obtained and vitamin D was started. 4 months later, his vitamin D level improved to 21 while calcium levels normalized despite ongoing inhalant use. ALP (878) and PTH (92) continued to be elevated albeit at improved levels. Conclusion: Exposure to fluoride leads to a rare condition called skeletal fluorosis causing accelerated osteogenesis and bone turnover leading to weak bone. Symptoms include bony pain, fractures, and osteosclerosis on radiographs. Differential diagnosis includes other conditions associated with osteosclerosis such as Paget’s disease and myelofibrosis. However, diffuse osteosclerosis and vertebral osteophytosis are noted only in skeletal fluorosis compared to other potential causes, though our patient did not have a CT spine done to assess for osteophytes. Biochemical studies can include hypocalcemia and hyperparathyroidism. It is thought that low calcium intake contributes to the hyperparathyroidism. Elevated serum and urine fluoride levels are also diagnostic and can persist for months after cessation of fluoride intake. Sodium fluoride has been posited as a treatment for osteoporosis due to its tremendous ability to build bone; however, the quality of bone made is poor leading to unacceptable fracture rates. Skeletal fluorosis should be suspected in any patient with history of diffuse osteosclerosis and hyperparathyroidism; and vitamin D supplementation should be initiated. In our case, hypocalcemia and PTH levels were improved despite active inhalant use after vitamin D supplementation. This suggests that Vitamin D deficiency and fluoride may be two independent driving factors in hyperparathyroidism in patients with fluorosis. Increased calcium absorption with vitamin D provides therapeutic benefit in both cases. Presentation: 6/1/2024

8136 Using High-Resolution Peripheral Quantitative Computed Tomography to Assess Bone Microarchitecture and Guide Osteoporosis Treatment

Abstract Disclosure: S.V. Rupani: None. J. Sfeir: None. L. Graeff-Armas: None. Bone microarchitecture is an important factor that impacts bone strength. Unlike other factors that affect bone strength, such as bone mineral density and bone turnover, assessment of bone microarchitecture is not yet widely accessible in clinical practice. Computed tomography is the primary method of non-invasively assessing bone microarchitecture. High-resolution peripheral quantitative CT (HR-pQCT) is an emerging imaging modality that provides a three-dimensional assessment of bone densitometry, morphometry, and microarchitecture with a low effective radiation dose. It provides a quantitative and qualitative assessment of cortical and trabecular structural and mechanical properties. We present two similar cases of osteoporosis in males, where knowledge of bone microarchitecture through HR-pQCT helped formulate two distinct and targeted therapeutic approaches. The first case is of a 46-year-old male with a history of idiopathic osteoporosis with multiple nontraumatic vertebral fractures. Given his presentation and age, anabolic therapy such as teriparatide was being considered. He underwent HR-pQCT scanning, which showed average radial trabecular parameters, but his cortical porosity was significantly above average, with similar findings in his tibial parameters. Since teriparatide has been shown to increase cortical porosity, this would not be the best option for our patient, given the risk of further weakening of the microarchitecture of his cortical bone. Therefore, denosumab, which has been shown to decrease cortical porosity, was chosen. Our second patient is a 52-year-old male with idiopathic osteoporosis with multiple nontraumatic vertebral fractures, whose HR-pQCT showed average cortical parameters at both the radius and tibia but low trabecular number and increased trabecular separation at both sites. Since teriparatide increases trabecular thickness and mass, we could confidently choose teriparatide for this patient, with less concern for significant deleterious effects on his cortical bone parameters. These case reports highlight the impact that the assessment of qualitative properties of bone, such as microarchitecture, can have in the management of osteoporosis. Currently, the lack of sufficient validated normative data for HR-pQCT limits its widespread use in the diagnosis of osteoporosis and fracture prediction. However, given that HR-pQCT can characterize the properties of trabecular and cortical bone, it may have a role in helping guide osteoporosis treatment, especially in challenging and atypical cases. Presentation: 6/3/2024

7293 An Unusual Case Of Adult-Onset Heterozygous HHRH In A Male With Normal Phosphorus And Severe Osteoporosis

Abstract Disclosure: M. El Najjar: None. A. Sabet: None. D. Willard: None. Introduction: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder characterized by renal phosphate wasting, which can affect bone metabolism. Although onset is typically in childhood, adult-onset forms have been described, and the manifestation depends on the zygosity of each patient. Most commonly, adults with HHRH demonstrate markedly reduced bone density and multiple fractures. Heterozygotes have milder presentations with mild hypophosphatemia, hypercalciuria, and nephrolithiasis, usually without bone disease; however, it is less well characterized. Case report: A 73-year-old man suffered an L1 vertebral compression fracture while playing golf. Bone mineral density testing revealed T-scores of -0.9 at the lumbar spine and -3.4 at the femoral neck (Z-score -2.6). He started alendronate 70 mg weekly for osteoporosis treatment. A year later, the patient sustained an L3 vertebral compression fracture while on treatment with no improvement in his bone density. His family history was remarkable for osteoporosis in his mother but no nephrolithiasis or hypercalcemia. Physical examination was unremarkable. Laboratory evaluation was notable for a 1,25-dihydroxyvitamin D of 87 pg/mL (18-72 pg/mL) , a 24-hour urine calcium of 240 mg/g Cr (30-210 mg/g),a serum PTH of 9 pg/mL (16-77 pg/ml) , but otherwise a normal serum calcium level of 9.4 mg/dL (8.6-10.3 mg/dL) and serum phosphate level of 2.2 mg/dl (2.1-4.3 mg/dl). Genetic testing revealed heterozygosity for SLC34A3 mutation, which is associated with HHRH. The patient discontinued alendronate and started 250 mg phosphorus supplementation 4 times daily. At 6 months follow up, he reported improvement in his body aches, and biochemical testing showed normalization of his 24-hour urine calcium to 171 mg/g Cr and serum PTH to 21 pg/mL. Repeat bone density scan after 1 year of phosphorus supplementation showed T-scores of -0.3 at the lumbar spine (5.8% increase) and -2.6 at the femoral neck (15.5% increase). Clinical Lesson: HHRH is an autosomal recessive hypophosphatemic rickets associated with mutations of the SLC34A3 sodium-phosphate cotransporter, where it is believed that selective phosphate wasting leads to increased calcitriol, in contrast to other forms of hypophosphatemic rickets, causing increased intestinal calcium absorption and resulting hypercalciuria. Adult-onset forms of HHRH have been described in heterozygous carriers of the SLC34A3 mutation and usually present with low to low-normal phosphate levels, hypercalciuria, and nephrolithiasis but without bone disease. However, clinical variations of heterozygous carriers have also been recognized, and therefore are likely underdiagnosed. Our patient’s serum phosphorus level was within the normal range, and hypophosphatemic rickets could have been missed if a more extensive laboratory evaluation had not been performed. Presentation: 6/1/2024

6986 Efficacy and Safety of Weekly Liquid Alendronate Sodium Trihydrate in Korean Postmenopausal Women with Osteoporosis: A 12-Month, Multi-Center, Randomized Trial

Abstract Disclosure: Y. Rhee: None. S. Ahn: None. N. Hong: None. D. Seo: None. S. Hong: None. Background: Although alendronate is the most prescribed oral bisphosphonate for osteoporosis treatment, it can lead to gastrointestinal problems, impacting treatment compliance and efficacy. This study aimed to assess the efficacy and safety of once-weekly alendronate sodium trihydrate (ALN-S), an oral solution, compared to once-weekly alendronate sodium (ALN-T), an oral tablet, in Korean postmenopausal women with osteoporosis. Methods: Conducted as a 12-month, multi-center, prospective, randomized, open-labeled, parallel trial at two hospitals in Korea, 170 postmenopausal women were randomized to ALN-S (N=85) or ALN-T (N=85). Bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) was measured at baseline and after 12 months. Bone turnover markers, including C-telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP), were assessed at baseline, 6 months, and 12 months. The primary outcome was the percentage change in LS BMD, evaluated for non-inferiority. Results: After 12 months, both ALN-S and ALN-T groups exhibited a significant increase in LS, FN, and TH BMD, with no significant intergroup differences (ALN-S: LS 5.0 ± 0.6%, FN 1.8 ± 0.6%, TH 2.2 ± 0.5%; ALN-T: LS 5.2 ± 0.6%, FN 1.6 ± 0.6%, TH 1.8 ± 0.5%). ALN-S was found to be non-inferior to ALN-T for BMD change at LS (treatment difference: -0.22%, 95% CI: -1.84 to 1.40%), excluding the predefined non-inferiority margin of -2.29%. Changes in both CTX and P1NP over time did not significantly differ between the groups. There was no significant difference in the frequency of adverse events between the groups. Conclusion: Weekly liquid alendronate sodium trihydrate demonstrated non-inferiority to weekly tablet alendronate sodium in increasing LS BMD in Korean postmenopausal women with osteoporosis. Presentation: 6/2/2024

Cost-effectiveness intervention thresholds for romosozumab and teriparatide in the treatment of osteoporosis in the UK.

To estimate the 10-year probability of a major osteoporotic fracture (MOF) at which sequential treatment with romosozumab or teriparatide followed by alendronate, compared with alendronate alone, becomes cost-effective in a UK setting. A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), in women receiving sequential treatment with either romosozumab or teriparatide followed by alendronate, compared with alendronate alone. Patients aged 50 to 90years with a recent MOF, hip or spine fracture were followed from the start of a 5-year treatment until the age of 100years or death. The analysis had a healthcare perspective. Efficacy of romosozumab, teriparatide and alendronate was derived from phase III randomised controlled trials. Resource use and unit costs were derived from the literature. Cost-effectiveness intervention threshold (CEIT), defined as the 10-year probability of a major osteoporotic fracture at which treatment becomes cost-effective, was compared with clinically appropriate intervention thresholds for bone-forming treatment in women with very high fracture risk as recommended by the UK National Osteoporosis Guideline Group (NOGG). The base case analysis showed that sequential romosozumab-to-alendronate treatment was cost-effective from a 10-year MOF probability of 18-35% and above depending on age and site of sentinel fracture at a willingness to pay (WTP) of £30,000. For teriparatide-to-alendronate, treatment was cost-effective at a 10-year MOF probability of 27-57%. The results were sensitive to pricing of the drugs but relatively insensitive to treatment duration, romosozumab persistence assumptions, and site of sentinel fracture. The CEITs for romosozumab-to-alendronate treatment were lower than the clinical thresholds from the age of 70years meaning that treatment could be considered both cost-effective and aligned with the NOGG treatment guidelines. By contrast, for teriparatide-to-alendronate the CEITs were higher than the clinical thresholds irrespective of age. However, cost-effective scenarios were found in the presence of strong clinical risk factors in addition to a recent sentinel fracture. The results of this study indicate that sequential romosozumab-to-alendronate or teriparatide-to-alendronate treatment can be a cost-effective treatment option for postmenopausal women at very high risk of fracture.

Current Treatment for Glucocorticoid-Induced Osteoporosis: Beyond Bisphosphonates

Current Treatment for Glucocorticoid-Induced Osteoporosis: Beyond Bisphosphonates

Integrated Single-cell RNA-seq and Bulk RNA-seq Identify Diagnostic Biomarkers for Postmenopausal Osteoporosis.

We aimed to explore diagnostic biomarkers of postmenopausal osteoporosis (PMOP). PMOP brings enormous physical and economic burden to elderly women. This study aims to screen new biomarkers for osteoporosis, providing insights for early diagnosis and therapeutic targets of osteoporosis. Weighted gene co-expression network analysis (WGCNA) was applied to identify osteoporosis-related hub genes. Single-cell transcriptomic atlas of osteoporosis was depicted and the heterogeneity of monocytes was analyzed, based on which the biomarkers for osteoporosis were screened. Gene set enrichment analysis (GSEA) was conducted on the biomarkers. The diagnostic model (nomogram) was established and evaluated based on the expression levels of biomarkers. Additionally, the transcription factor (TF) regulatory network was constructed to predict the potential TF and targeted miRNA of biomarkers. The drugs with significant correlation with biomarkers were identified by Spearman correlation analysis. We obtained 30 osteoporosis-associated hub genes. 9 cell types were identified, and the monocytes were subdivided to 4 subtypes. Three biomarkers, DHX29, LSM5, and UBE2V2, were screened. DHX29 and UBE2V2 were highly expressed in non-classical monocytes, while LSM5 exhibited the highest expression in other monocytes, followed by non-classical monocytes. GSEA indicated that osteoporosis may be correlated with vascular calcification and the biomarkers may be involved in the formation of immune cells. Then, nomogram was constructed and exhibited good robustness. In addition, MYC and SETDB1 were the shared IF in three biomarkers, which may play critical regulatory roles in the progression of osteoporosis. Moreover, 41, 49, and 68 drugs appeared significant correlations with DHX29, LSM5, and UBE2V2, respectively. This study provided a basis for early diagnosis and targeted treatment of osteoporosis.

Effect of recombinant irisin on recombinant human bone morphogenetic protein-2 induced osteogenesis and osteoblast differentiation

Osteoporotic fragility fractures substantially impact aging societies, necessitating long-term care and increasing healthcare costs. Myokine irisin, secreted by skeletal muscle, influences bone metabolism; however, a comprehensive understanding of the mechanisms by which irisin affects bone metabolism is still lacking. Therefore, this study aimed to explore the effects of irisin on osteogenesis and osteoblast differentiation triggered by bone morphogenetic protein-2 (BMP-2). We used 4-week-old male ICR mice and implanted polyethylene glycol pellets containing recombinant human BMP-2 (rh-BMP-2) into the left dorsal muscle pouch. Mice received weekly intraperitoneal injections of either phosphate-buffered saline or recombinant irisin (re-irisin). Ectopic bone formation was evaluated 3 weeks post-surgery using micro-computed tomography (μ-CT) and histological analysis. In vitro experiments, C2C12 cells were treated with or without rh-BMP-2 and re-irisin, and we assessed osteoblast differentiation markers, e.g., runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and osteopontin, using real-time reverse transcription-polymerase chain reaction. The μ-CT analyses showed that re-irisin significantly increased bone mineral content and bone volume of ectopic bones newly formed by rh-BMP-2. The gene expressions of the osteoblast markers were significantly increased by rh-BMP-2 and further upregulated by re-irisin. The treatment of cyclic AMP response element-binding protein (CREB) small interfering RNA attenuated these effects, suggesting that CREB signaling pathway was involved in rh-BMP-2/re-irisin-induced osteoblastic differentiation. This study demonstrates the potential of irisin to enhance osteogenesis through BMP signaling, offering insights for osteoporosis treatment and highlighting irisin as a promising therapeutic target for improving bone health and extending a healthy lifespan.

A-112 Reference Intervals for Serum Concentrations of N-Terminal Propeptide of Type-I Procollagen (PINP) for Greek Adult Population

Abstract Background PINP is a sensitive indicator of the synthesis of type-I collagen. Serum PINP levels are affected by changes in bone metabolism and is a useful indicator of disease activity in Paget's disease, bone metastases of osteoblastic nature and in monitoring osteoporosis treatment. To interpret PINP, method and population specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of PINP for the Greek adult population. Methods We collected samples from 431 apparently healthy Greeks (140 men as well as 150 pre- and 139 post-menopausal women), who volunteered to participate in our study. Data on socio-demographic characteristics, medical histories and medications were collected and subjects with conditions or receiving medications that affecting bone metabolism were excluded. Dual-energy x-ray absorptiometry (DXA) used to measure bone mineral density (BMD) in all participants. All blood collections were performed in the morning after overnight fast. Measurements were performed by an automated chemiluminescent immunoassay on the Maglumi-X3 analyzer (Snibe, Shenzhen, China). This method measures the total-PINP in serum. The reference interval was defined as the central 95% range and determined according to CLSI guide C28-A3 using the MedCalc Software Results The table summarizes our results. DXA results revealed that 348 participants had normal BMD, 74 had osteopenia and 9 had osteoporosis which excluded from analysis. Since our data were not normally distributed (Shapiro-Wilk test) in any group and after the exclusion of outliers (Tukey test), we used the non-parametric method suggested by the CLSI guide in order to determine the reference intervals. Multiple regression analysis revealed that sex and menopausal status were factors affecting PINP values. Conclusions We provide reference intervals for the determination of PINP concentrations in serum for the Greek adult population using an automated immunoassay. Our data may aid to interpret bone turnover in the Greek adult population.