Bone Mass Research Articles

Osteoporosis in postmenopausal women is associated with disturbances in gut microbiota and migration of peripheral immune cells

BackgroundPostmenopausal osteoporosis (PMO) results from a reduction in bone mass and microarchitectural deterioration in bone tissue due to estrogen deficiency, which may increase the incidence of fragility fractures. In recent years, the “gut-immune response-bone” axis has been proposed as a novel potential approach in the prevention and treatment of PMO. Studies on ovariectomized murine model indicated the reciprocal role of Th17 cells and Treg cells in the aetiology of osteoporosis. However, the relationship among gut microbiota, immune cells and bone metabolic indexes remains unknown in PMO.MethodsA total of 77 postmenopausal women were recruited for the study and divided into control (n = 30), osteopenia (n = 19), and osteoporosis (n = 28) groups based on their T score. The frequency of Treg and Th17 cells in lymphocytes were analyzed by flow cytometry. The serum levels of interleukin (IL)-10, 17 A, 1β, 6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) were determined via enzyme-linked immunosorbent assay. Additionally, 16S rRNA gene V3-V4 region sequencing analysis was performed to investigate the gut microbiota of the participants.ResultsThe results demonstrated decreased bacterial richness and diversed intestinal composition in PMO. In addition, significant differences of relative abundance of the gut microbial community in phylum and genus levels were found, mainly including increased Bacteroidota, Proteobacteria, and Campylobacterota, as well as reduced Firmicutes, Butyricicoccus, and Faecalibacterium. Intriugingly, in the osteoporosis group, the concentration of Treg cells and associated IL-10 in peripheral circulation was negatively regulated, while other chronic systemic proinflammatory cytokines and Th17 cells showed opposite trends. Moreover, significantly elevated plasma lipopolysaccharide (LPS) in patients with osteoporosis indicated that disrupted intestinal integrity and permeability. A correlation analysis showed close relationships between gut bacteria and inflammation.ConclusionsCollectively, these observations will lead to a better understanding of the relationship among bone homeostasis, the microbiota, and circulating immune cells in PMO. The elevated LPS levels of osteoporosis patients which not only indicate a breach in intestinal integrity but also suggest a novel biomarker for assessing osteoporosis risk linked to gut health.

8410 Lipid modification enhances the calcemic and bone building effects of injected PTH(1-14) and PTH(1-11) fragment peptides in mice

Abstract 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

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

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

12480 REMS Technology For The Bone Health Assessment After Hormonal Therapy In Transgender Subjects

Abstract Disclosure: F.A. Lombardi*: None. A. Russo: None. P. Pisani*: None. C. Stomaci*: None. F. Conversano*: None. R. Franchini*: None. M. Di Paola*: None. V. Racanelli*: None. S. Casciaro: None. Introduction: Sex steroid hormones play crucial roles in bone metabolism and the musculoskeletal system. These hormones interact with specific nuclear receptors, such as estrogen and androgen receptors, which are expressed in bone tissue. This interaction regulates the ongoing process of bone remodeling and induces positive effects on bone health.In this regard, it is crucial to examine the long-term impact of gender affirming hormone therapy (GAHT) on bone metabolism. Radiofrequency Echographic Multi-spectrometry (REMS) is a radiation-free technology for assessing bone mineral density (BMD) and fracture risk prediction by the analysis of the reference axial sites: lumbar spine (LS) and femoral neck (FN). REMS has been widely validated in comparison with Dual Energy X-ray Absorptiometry (DXA), showing good accuracy and precision (>90%), thereby representing a valid technology to monitor bone health status (BHS) in a short-term period. In this context, the goal of this preliminary clinical study was to track the bone health of transgender subjects for one year after starting treatment, using REMS, in order to comprehend the effects of GAHT on BHS. Methods: 7 transgender patients were recruited at Endocrinology Unit of Internal Medicine Department of Santa Chiara Hospital Trento (Italy). Among them were 4 individuals assigned male at birth (AMAB) undergoing therapy with oestradiol valerate 2 g/day and cyproterone acetate 25 mg/day, as well as 3 individuals assigned female at birth (AFAB) undergoing therapy with testosterone 25 mg/day. Before starting GAHT, patients underwent LS-DXA scan, followed by monitoring of BHS by REMS technology after 12 months from the start of treatment. Results: The results show an increase of T-score values in AMAB (-0,3 ± 0,3 REMS vs -1,8 ± 1,8 DXA) after estrogen treatment starting, and no effect on bone in AFAB subjects after GAHT (0.5 ± 0.4 REMS vs 0.9 ± 0.4 DXA); this is due to:-the protective effect of estrogen therapy in AMAB subjects against bone loss;-the combined effect of the decrease of estrogen together with the increase of testosterone in AFAB ones. Conclusions In summary, these initial findings indicate that REMS could be appropriate for monitoring the bone health status of these individuals, confirming the anticipated beneficial effects of estrogen therapy on bone loss in AMAB individuals. The limitation of the study is the lack of REMS data at the beginning of the treatment, but the possibility of carrying out the technique in subsequent evaluation times will allow us to evaluate the change in bone mass during hormonal reaffirmation therapy and compare it with the progress of the measurements obtained with DXA data ones. Presentation: 6/2/2024

9175 Pretransplant Clinical Characteristics Related To Change In Bone Mineral Density In Adults 1 Year After Allogeneic Hematopoietic Stem Cell Transplantation At Bucaramanga, Colombia Reference Center

Abstract Disclosure: G.A. Parra-Serrano: None. C.L. Sossa: None. K.J. Moreno Medina: None. M. Ochoa: None. A. Reyes Gonzalez: None. A. Plata: None. P. Mantilla Mantilla: None. Introduction: Hematopoietic stem cell transplantation (HSCT) , refractory to pharmacological management, increases 10-year survival by 80%, Chronic complications include alterations in bone metabolism, that increase appearance of osteoporosis (13.8 - 17%), non traumatic fractures, and loss of Bone mineral density (BMD) at the hip -4.2%, L1L4 -2% and femoral neck-9%. Methods Calculate Change at (BMD) in adults undergoing allogenic (HSCT) after 1y and determine pretransplant factors related to this change. Composite endpoint osteoporosis/lowbonemass (osteoporosis Tscore<-2.5 and/or low bone mass Zscore-2.0) 1 year after transplant, Adult patients Retrospective cohort study, ethical comittee approval, anonymized database, undergoing allogeneic (HSCT) between 2009 and 2022, (BMD) measured at lumbar spine (L1L4) and femoral neck before and one year after transplant; Also paraclinical variables: TSH, vitaminD, kidney function, glucocorticoid, Graft vs host disease, disease relapse, diabetes. Descriptive analisis performed, simple linear regresion analisis for delta L1L4 and femoral neck BMD before and 1 year after transplant, and multivariate regresion analisis for variables p<0.2 on simple lineal regression analysis . Results 123 patients, (48 included, 73 excluded (22 died, 50 densitometry data not suitable)). BMD change At lumbar spine, -4.7% (NS) , and at femoral neck -9.8% (p<0.05), Simple regression analysis no correlation for preclinical variables at lumbar spine. negative correlation between prednisolone dose at femoral neck BMD (p 0.007, coefficient B -0.0086 [IC95% -0.014, 0.0025]). Mutivariate regression analysis performed for BMD diference at femoral neck, after adjusting for variables p<0.2 on simple regression analysis, model that include (prednisone dose, diabetes and relapse before transplant showed Rsquare 0.19 coefficient 0.0092 p 0.003. For every gram of glucocorticoid (prednisolone) bone loss decrease -0.9% of BMD at femoral neck at 1 year follow up. Proportion of patients with composite osteoporosis/lowbonemass at femoral neck pre-transplant (n2) 4.17%, postransplant (n14) 29.17%. * p 0.0005. no difference observed at lumbar spine. Fracture incidence n2 (4%) at lumbar spine and n1 (2%) at femoral neck. Conclusions At femoral neck, People with HSCT present significant decrease in (BMD) and higuer incidence of Osteoporosis or low bone mass, not observed at lumbar spine, after adjusting for multiple variables. for every 1gr of prednisolone equivalent dose, (BMD) decrease -0.9%, at femoral neck p0.003. The model only explain 19% of change of BMD at femoral neck, that suggest immune response caused by allogenic transplantation might be responsible, in part, of BMD change. Presentation: 6/3/2024

7172 Osteoporosis Associated with Antiretroviral Therapy - Case report

Abstract Disclosure: C.E. Guillen Lopez: None. L.A. Sanchez Ato: None. A. Patel: None. A. Molkina: None. T. Ayub: None. L. Robles: None. A. Arce Gastelum: None. Osteoporosis presents a substantial public health challenge, contributing significantly to morbidity and mortality through fractures. While postmenopausal osteoporosis is common, secondary osteoporosis affects a significant number of patients, including over 30% of postmenopausal and 50-80% of men. People living with HIV (PLWH) experience age-related medical comorbidities earlier and more extensively than those without HIV. The compromised bone health in PLWH is attributed to factors associated with the virus, antiretroviral therapy (ART) side effects, and health disparities such as inadequate nutrition, low body weight, hypogonadism, vitamin D deficiency, and increased recreational substance use. More recently, it has become apparent that vertebral fractures are more common in PLWH, with a prevalence of 11.1% and a 2.30-fold more significant risk than the general population. Low bone mass density (BMD) is twice as common in PLWH, increasing to 3 times as common in PLWH on ART. ART initiation leads to transient bone loss with nucleotide reverse transcriptase inhibitors such as tenofovir disoproxil fumarate (TDF) and protease inhibitors, causing higher BMD loss. In contrast, integrase and specific reverse-transcriptase inhibitors have minimal adverse effects on BMD. The newer formulation, tenofovir alafenamide (TAF), is believed to have a more favorable impact on bone health than TDF. The repercussions of diminished bone health, particularly osteoporotic fractures, have significant medical and economic implications. They are leading to early mortality, disability, and a loss of independence. The HIV Medicine Association (HIVMA) and Infectious Diseases Society of America (IDSA) recommend BMD screening for all HIV-infected patients at 50 years. 58-year-old male PLWH reveals a history of osteoporosis with multiple spinal (L1, L4-5, S1) and bilateral wrist fractures on TDF for 15 years. The patient has been treated with bisphosphonates. Alendronate was initially prescribed, but due to acid reflux side effects, zoledronic acid was a better option. Despite various ART regimens, Dolutegravir/Lamivudine was started four years ago without further fractures. Recent bone density assessments showed improvement in the lumbar spine, returning to a normal range with a T-score of 0.6. However, the left femoral neck remains at -2.5, and the right femoral neck is at -2.2, showing minimal change. To enhance BMD in PLWH on ART, transitioning to alternatives with lower bone loss associations and using bisphosphonates as tolerated are suggested. As the HIV-infected population ages, proactive screening for low BMD is vital to manage evolving health needs and prevent bone-related complications. A holistic approach includes evaluation for secondary etiologies of osteoporosis, medical treatment, and vitamin D and calcium supplementation. Presentation: 6/3/2024

12538 Blocking Oxidized Phospholipids Improves Bone Mass In Mice By Transcriptional Reprogramming Of Osteoblastic Cells: Analysis At The Single Cell Level

Abstract Disclosure: M. Palmieri: None. I. Nookaew: None. M. Almeida: None. T.E. Joseph: None. C. O'Brien: None. E. Ambrogini: None. Oxidized phospholipids containing phosphatidylcholine (PC-OxPLs), present on oxidized low-density lipoproteins (OxLDL) and apoptotic cells, are pathogenic in many diseases, including osteoporosis. The E06 IgM antibody binds PC-OxPLs and blocks their adverse effects. In our studies, six-month-old female and male mice overexpressing a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv) have high cancellous and cortical bone mass. In addition, E06-scFv transgenic mice are protected against high fat diet- and age-induced bone loss. E06-scFv increases osteoblast number, bone formation rate and reduces osteoblast apoptosis. To investigate the effect of E06-scFv on osteoblastic cells transcriptional reprogramming, we performed single cell RNA-sequencing (scRNA-seq) of mesenchymal cells from long bones of 6-months old WT and E06-scFv transgenic female and male mice. Based on the total of over 7,500 osteoblastic cells, we focused the analysis on 3 cell clusters, pre-osteoblasts, identified by high levels of osteopontin (Spp1), osteoblasts, identified by high expression of osteocalcin (Bglap) and adipo-CAR expressing the adipogenic marker Adipoq in addition to high expression of the stromal marker Cxcl12. In both males and female transgenic mice, the relative number osteoblasts increased [12.0 % in females and 23.7 % in males; conversely, the relative number of adipo-CAR cells decreased [18.2 % in females and 15.1 % in males] compared to WT. We performed the analysis of functional enrichment-based gene ontology by piano software package and found that, in the three clusters of both male and female transgenic mice, there was an upregulation of gene expression, with a range of 37-125 genes per cluster, related to extracellular matrix organization [p range 0.0003-3.95E-09], bone mineralization [p range 0.04-0.0022] and cell adhesion [p range 0.019-0.00008]. Consistent with these results, bulk RNA sequencing indicated that these ontology terms were downregulated in calvaria-derived osteoblasts treated with OxLDL [extracellular matrix organization p= 1.19E-13; bone mineralization p= 0.0018655; cell adhesion p= 2.73E-12]. Based on these results, we conclude that PC-OxPLs not only affect osteoblast number but also decrease osteoblast activity on a single cell basis. Presentation: 6/1/2024

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

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

6408 Familial Hypoparathyroidism With Elevated Parathyroid Hormone Due To A PTH Mutation Responsive To Teriparatide

Abstract Disclosure: N. Mukhtar: None. B. Alghamdi: None. M. Alswailem: None. A.S. Alzahrani: None. Introduction: Apart from vitamin D disorders, causes of congenital hypocalcemia (HypoCa) include genetic defects causing familial hypoparathyroidism (FH), and defects in PTH receptor or its signalling pathway (PTH resistance). The former is typically characterized by low plasma PTH and the latter by elevated PTH levels. In this report, we describe a family with FH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic impact of recombinant human PTH (teriparatide) therapy on HypoCa in one of these siblings who was not well controlled on calcitriol and calcium replacement. Case description: The proband is a 34-year-old lady who has history of chronic HypoCa since birth with several admissions for severe HypoCa and recurrent seizures during childhood. She and her three brothers (a 32-year-old male twin and an 18-year-old male) were diagnosed to have Pseudohypoparathyroidism type 1b based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Laboratory workup of the proband recently showed: PTH 514 ng/L (NR 15-65) , calcium 1.81 mmol/l (NR 2.1-2.6), phosphate 1.67mmol/L (NR 0.8-1.4), magnesium 0.73 mmol/L (NR 0.7-1.0), albumin 38 g/L (NR 40-50), Alkaline phosphatase 56 U/L, eGFR >60 ml/min/1.73 m2, creatinine 78 umol/L and 25-hydroxyvitamin D 77 nmol/l (NR 50-120). Daily excretion of calcium was normal at 3.38 mmol and an ultrasound of the kidneys suggest nephrocalcinosis. Skeletal X-rays and bone mass densitometry were normal. Molecular studies: WES showed no potentially pathogenic variants in GNAS, PTHR, CASR, VDR, and CYP27B1 but a previously reported homozygous variant in the PTH, exon 3 (NM_000315.4: c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and two of her brothers. This variant was assessed to be likely pathogenic or likely damaging by several in silico analysis tools including Polyphen2, MutPred, PROVEAN, DEOGEN2 and VUS by ACMG, SIFT, Mutation Assessor and FATHMM. Management: Because the patient’s HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily resulted in normalization of calcium and PTH levels. The patient reported significant improvement in her general wellbeing with loss of numbness, tingling, muscle spasms and tetany of the fingers. She has been on teriparatide for the last year with excellent improvement in her quality-of-life Conclusion: High PTH in the presence of congenital hypoCa is not always due to receptor or post-receptor defect and can be due to a mutated biologically inactive PTH. In such cases, treatment with Teriparatide may result in stabilization of biochemical profile and improve quality of life. Presentation: 6/2/2024

6820 Assessing The Efficacy And Safety Of Setrusumab For Osteogenesis Imperfecta: Updated Phase 2 Data From The Phase 2/3 Orbit Study

Abstract Disclosure: G.S. Gottesman: Advisory Board Member; Self; Ultragenyx, Kyowa Kirin, Inc. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Ultragenyx. T.O. Carpenter: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. M. Wallace: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Novosteo. P. Smith: Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. E.A. Imel: Consulting Fee; Self; Ultragenyx. Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. H. Wang: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. H.M. Byers: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. S. Krolczyk: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. E.M. Lewiecki: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Grant Recipient; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Research Investigator; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Speaker; Self; Amgen Inc, Kyowa Kirin, Inc. Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and low bone mass with no universally accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that improved bone mineral density (BMD), bone strength, and bone turnover markers in adults with OI (ASTEROID; NCT03118570). In the ongoing Phase 2/3 Orbit study (NCT05125809), Phase 2 evaluated the efficacy and safety of setrusumab in pediatric and young-adult cohorts with OI based on PK/PD, safety, and BMD data, to determine the dosing strategy for the Phase 3 portion. Subjects with OI Types I, III, or IV, ages 5 to <26 years, were randomized 1:1 to receive 20 or 40 mg/kg setrusumab intravenously monthly. Six-month data as of August 2023 are presented. Twenty-four subjects (50% female, 75% <18 years of age) with OI Type I (n=17/24, 71%) or III/IV (n=7/24, 29%) were enrolled and randomized to receive 20 mg/kg (n=14/24) or 40 mg/kg (n=10/24) of setrusumab. The mean (SD) baseline-corrected area under the effect curve (AUEC) for serum P1NP in the 20 mg/kg setrusumab group was 4153 (4407) µg/(L*day) over month one of treatment, and 5256 (5521) µg/(L*day) in the 40 mg/kg group. Mean (SE) change from baseline in lumbar spine BMD in the 20 mg/kg group was 9.1% (1.8%) and 12.8% (2.5%) at M3 and M6, respectively (all p<0.05 vs baseline) and 9.3% (2.4%) and 16.1% (3.9%) in the 40 mg/kg group (M6 p<0.05 vs baseline). Mean (SE) baseline BMD Z-score in the 20 mg/kg group of 2.1 (0.8) improved by 0.6 (0.8) at M3 and 0.9 (0.8) at M6, and improved from 1.1 (0.4) at baseline by 0.5 (0.4) and 0.9 (0.4) at M3 and M6, respectively, in the 40 mg/kg group (all p<0.05 vs baseline). The median annualized fracture rate (excluding fingers, toes, face, and skull) was reduced significantly from 0.7 to 0 (p=0.042) after setrusumab initiation (calculated reduction of 67%). No new radiographically confirmed fractures excluding fingers, toes, face, and skull were reported in 20/24 (83%) subjects after starting setrusumab, while only 4/24 (17%) reported fractures (precipitating events: one subject: slipped on ice, stubbed toe, one subject each: fell off of tricycle, bending over in bed, tripped and fell). Setrusumab treatment resulted in no unexpected adverse events. Treatment-related adverse events included infusion-related reaction (7/24, 29%), headache (3/24, 13%) infusion site pain, bone pain, and upper respiratory tract infection (each 1/24, 4%). In Orbit Phase 2, we observed significant improvements from baseline in lumbar spine BMD at M3 and M6 at both 20 and 40 mg/kg doses, with no marked differences between dose groups. Fracture rates significantly decreased with setrusumab initiation, with 83% of subjects reporting no new fractures. Presentation: 6/1/2024

7522 Effects of Trikafta On Bone Mineral Density And Body Composition In Patients With Cystic Fibrosis

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. G. Bakeerathan: None. L. Healy: None. E. Favier: None. S. Foushee: None. Background: Cystic fibrosis related bone disease (CFBD) is a common complication of adult Cystic fibrosis (CF) patients due to calcium, vitamin D and K malabsorption from exocrine pancreatic insufficiency, increased inflammatory cytokines, glucocorticoid therapy, delayed puberty, physical inactivity, and hypogonadism. Newer CF transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (Trikafta) has proven benefit in pulmonary and nutritional outcomes. There is limited data on effects of Trikafta on bone health and body composition. The aim is to examine the effects of Trikafta on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), and body composition in terms of fat free mass index (FFMI) and fat mass index (FMI) in our CF patients. Method: We conducted a cross sectional and retrospective review of 38 adults with CF (Ages 20-59, 28 males and 10 females) in our CF clinic. Body Mass Index (BMI), Body composition measured by bioelectric impedance analysis, BMD of LS and FN by Dual-energy X-ray absorptiometry, Vitamin D level, and forced expiratory volume in one second (FEV1 % predicted) in patients taking Trikafta were analyzed and compared with control CF group who were not on Trikafta. Results: 38 subjects on Trikafta, aged 33.29 ± 10.36 years with FEV1 % predicted 65.11± 28.14% were studied. Serum 25-hydroxyvitamin D level was 35.92 ± 18.52 ng/dL. Of the 38 study patients, 23 (60.53%) had a diagnosis of CF related diabetes (CFRD). Among the Trikafta cohort, 18 (50%) had low BMD with Z-scores ≤ -2.0 and 7 (19.44%) of them had Z score ≤ -1.0 and > -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

8693 Dexamethasone Increases Bone Mass In Mice

Abstract Disclosure: F. Sultana: None. M.L. Temple: None. S. Kim: None. V. Ryu: None. F. Korkmaz: None. A. Gumerova: None. P. Georgii: None. U. Cheliadinova: None. D. Vasilyeva: None. V. Laurencin: None. R. Witztum: None. O. Barak: None. L. Cullen: None. A.R. Pallapati: None. S. Rojekar: None. J. Gimenez Roig: None. D. Lizneva: None. W. Zhou: None. T. Yuen: None. M. Zaidi: None. Severe osteoporosis and bone fractures are strongly associated with long-term or recurring glucocorticoid use in people. Steroids have traditionally been used as an anti-inflammatory and immunosuppressive agent, and while their use has been widely implicated in causing bone loss by suppressing osteoblastic bone formation, recent data have consistently shown mixed results in mice. It is also important to stress that dexamethasone (DEX) in particular has been used for over three decades in cell cultures to stimulate osteoblast formation. We therefore posit that mechanisms other than direct steroid effects on osteoblasts contribute to bone loss, and that, at least physiologically, steroids stimulate (rather than inhibit) bone formation. Here, we have aimed to clarify the effects of DEX on bone metabolism. We first studied the effects of low and high doses of DEX (1 mg/kg and 10 mg/kg), given daily as intraperitoneal injections to 8-week-old C57BL/6 mice. Micro-CT showed that DEX markedly increased bone microarchitecture, including the bone volume fraction, connectivity density, and trabecular number, while decreasing trabecular spacing in femoral epiphyses compared with vehicle-injected controls. Serum levels of adrenocorticotropic hormone (ACTH) and corticosterone did not change following DEX. These findings suggest that both low and high DEX doses are anabolic to the skeleton. Reaffirming these data, we found that adrenalectomy (with salt replacement) caused a significant decline in bone mineral density. Likewise, Tpit-/- mice, in which ACTH and corticosterone are both reduced, display reduced bone microarchitectural parameters, together with low mineralizing surface and bone formation rates on dynamic histomorphometry, impaired osteoblast formation in Cfu-f cultures, and lowered expression of the osteoblastogenesis genes Bmp2, Ibsp, Runx2 and Sp7. Finally, deleting the glucocorticoid receptor (Gr) specifically in osteoclasts in Acp5-Cre;Grfl/fl mice had no effect on microarchitectural parameters at the spine or proximal tibial metaphysis. However, and importantly, absent GR in the osteoclast, DEX increased bone mass significantly, suggesting that its notable anabolic action was mediated by the osteoblast. Our findings challenge the longstanding premise that steroids directly impact the osteoblast to cause bone loss, and that other mechanisms, such as reduced ACTH levels and/or central effects of DEX, may play a key role. Presentation: 6/1/2024

9397 Shatter Proofing Bones: Revamping Osteoporosis Screening

Abstract Disclosure: R. Subramani: None. T. Gupta: None. M. Anwar: None. J. Pamula: None. Background: Osteoporosis is a common disease characterized by low bone mass, structural deterioration of bone tissue, and increased risk of fractures. The World Health Organization (WHO) has defined osteoporosis based on bone density measurements. According to their definition, osteoporosis is diagnosed when the bone density at the hip or spine is at least 2.5 standard deviations (SDs) below the mean bone density of a reference population of young, healthy women (T score ≤ -2.5). According to NHANES data from 2017-2018, the overall prevalence of osteoporosis among adults over 50 was found to be 12.6%. It was observed that the prevalence of osteoporosis was higher among women (19.6%) compared to men (4.4%). According to US Preventative Services Task Force (USPSTF), the guidelines for screening are as follows: BMD Testing (DEXA) for all women aged 65 and older, postmenopausal women younger than 65 with clinical risk factors for fracture including advancing age, previous fracture, glucocorticoid therapy, parental history of hip fracture, low body weight, current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, secondary osteoporosis. BMD Testing for Men is not recommended. The most used bone measurement test to screen for osteoporosis is central DXA which measures BMD at the hip and lumbar spine. Goal: To improve the osteoporosis screening using DXA scan in the outpatient internal medicine resident patient panel by 5% Study Design:Subjects were identified by an EPIC report and will include retrospective chart review of records from July 2022 and prospective screening until April 2024 for the outpatient IM clinic list of patients including both resident panel. Methods: Pre-intervention data analysis of current rates; Educating residents about appropriate screening; Utilization of osteoporosis screening as care-gap in EPIC ;Calling patients who are due for screening from IM residents patient panels; Post-interventional data analysis Results: The total number of patients on the residents panel was 196. Before interventions, screening rate for osteoporosis were 71.2% among residents' patients. After intervention, screening rates increased to 75.5%. There was a 4.3 % improvement in screening rate. Conclusion: Resident education, addressing Osteoporosis care gaps in EPIC and patient outreach are effective interventions to improve screening rates. Discussion: Osteoporosis screening remains an area of needed improvement in IM clinic. EPIC system should not only take age for prompting osteoporosis screening but also other factors such as family history, pre-mature fractures, steroid use, etc. Adding osteoporosis screening into the metric system are few steps to be considered for future directions. Presentation: 6/3/2024

Mechanical analysis of modified femoral neck system in the treatment of osteoporotic femoral neck fractures

BackgroundDespite the explicit biomechanical advantages associated with FNS, it is currently inconclusive, based on the existing literature, whether Femoral Neck System (FNS) outperforms Cannulated cancellous screws (CSS) in all aspects. Due to variances in bone morphology and bone density between the elderly and young cohorts, additional research is warranted to ascertain whether the benefits of FNS remain applicable to elderly osteoporosis patients. This study aimed to investigate the biomechanical properties of FNS in osteoporotic femoral neck fractures and propose optimization strategies including additional anti-rotation screw.MethodsThe Pauwels type III femoral neck fracture models were reconstructed using finite element numerical techniques. The CSS, FNS, and modified FNS (M-FNS) models were created based on features and parameterization. The various internal fixations were individually assembled with the assigned normal and osteoporotic models. In the static analysis mode, uniform stress loads were imposed on all models. The deformation and stress variations of the femur and internal fixation models were recorded. Simultaneously, descriptions of shear stress and strain energy were also incorporated into the figures.ResultsFollowing bone mass reduction, deformations in CSS, FNS, and M-FNS increased by 47%, 52%, and 40%, respectively. The equivalent stress increments for CSS, FNS, and M-FNS were 3%, 43%, 17%, respectively. Meanwhile, variations in strain energy and shear stress were observed. The strain energy increments for CSS, FNS, and M-FNS were 4%, 76%, and 5%, respectively. The shear stress increments for CSS, FNS, and M-FNS were 4%, 65% and 44%, respectively. Within the osteoporotic model, M-FNS demonstrated the lowest total displacement, shear stress, and strain energy.ConclusionModified FNS showed better stability in the osteoporotic model (OM). Using FNS alone may not exhibit immediate shear resistance advantages in OM. Concurrently, the addition of one anti-rotation screw can be regarded as a potential optimization choice, ensuring a harmonious alignment with the structural characteristics of FNS.

Vertebral body density role in determining vertebral osteoporotic fracture type and its progression.

Vertebral osteoporotic fractures (VOF) are among the most frequent fractures in the elderly, often leading to an impaired lifestyle and a high economic burden. Although a reduced bone mass density is considered one of the main risk factors for VOF, its role in determining the fracture type, using the AO spine-DGOU classification for osteoporotic thoracolumbar fractures, as well as its progression, is unknown. The current study aimed to: (1) reveal whether the bone density of the vertebral bodies of fractured and non-fractured vertebrae predicts the type of fracture, (2) examine whether bone density is associated with the initial and progressive collapse of the vertebral body, and (3) provide predictive measures for fracture progression. The study sample included 124 patients (40 males and 84 females) with an acute osteoporotic vertebral fracture who underwent a computerized tomography scan at the time of diagnosis and an x-ray at least 3 months later. The bone density of the fractured and adjacent (non-fractured) vertebrae was measured at diagnosis. The magnitude of the collapse and the progression of the fracture over time were calculated from height measurements of the vertebral bodies at diagnosis and follow-up. Age was a significant factor in predicting the fracture type and magnitude of collapse, whereas sex and bone density were not. The severity of the fracture was involved in predicting its progression, demonstrating that severe-type fractures tended to continue to collapse after diagnosis. However, when each type was examined independently, the density of the fractured vertebra had a protective effect on fracture progression. To conclude, identifying the type of fracture is beneficial in determining patient prognosis. Furthermore, the density of the fractured vertebra, the magnitude of collapse, and patient age are valuable predictors of fracture progression.

Physical Activity before and After Bariatric Surgery.

Lifestyle changes including reduced calorie intake and increased physical activity (PA) improve the prognosis associated with bariatric surgery (BS) and metabolic indices. Early implementation of exercise leads to improved physical performance, better glycemic control and lipid profile, reduces the risks associated with anesthesia, and accelerates recovery from surgery. Undertaking systematic exercise after BS is associated with a better quality of life, improves insulin sensitivity, results in additional weight loss, reduces adverse effects on bone mass, and results in better body composition. The aim of this review was to summarize recommendations for physical activity in patients undergoing BS and to highlight the key role of physical activity in this patient group.

Osteoporosis in older men

Osteoporosis, characterized by reduced bone mass and compromised skeletal microarchitecture, significantly increases the risk of fractures and is the most prevalent metabolic bone disease. While it is commonly associated with post-menopausal women, osteoporosis and subsequent fractures are also substantial concerns in men. Men experience sustained bone loss after the sixth decade, with estimates indicating that 20% of Americans with osteopenia or osteoporosis are men. Approximately one in eight men over 50 will suffer an osteoporotic fracture, with hip fractures in men leading to a two- to threefold increase in mortality compared to women. The prevalence of osteoporosis in men has risen, doubling in prevalence since the early 1990s. Men generally have higher peak bone mass and greater bone size, offering some protection against osteoporosis; however, aging leads to increased bone resorption and decreased bone formation, exacerbated by lower androgen and estrogen levels. Secondary causes, such as hypogonadism and chronic glucocorticoid use, are prevalent in men. Diagnosis primarily involves bone mineral density (BMD) measurements using dual-energy X-ray absorptiometry (DXA), with fracture risk assessment tools like FRAX and MORES aiding in clinical decisions. Treatment includes calcium and vitamin D supplementation, bisphosphonates, denosumab, and anabolic agents like teriparatide and abaloparatide. Special considerations are necessary for men undergoing androgen deprivation therapy for prostate cancer due to accelerated bone loss. Effective management requires early diagnosis, lifestyle modifications, and appropriate pharmacological interventions to reduce fracture risk and improve patient outcomes.

Between a Rock and a Short Place-The Impact of Nephrolithiasis on Skeletal Growth and Development Across the Lifespan.

The impact of nephrolithiasis on skeletal growth and bone health across the life span of kidney stone formers is reviewed. Bone disease is an early event among kidney stone formers (SF), with distinct phenotypes according to each age, sex, menopausal status, dietary, hormonal and genetic factors. Nephrolithiasis-associated bone disorder is characterized by reduced bone mineral density (BMD) and histologically discloses low bone formation, high bone resorption and abnormal mineralization. Although hypercalciuria has been presumed to be pathogenic for bone loss in SF, the association of BMD with urinary calcium is not uniform in all studies. Hypocitraturia, metabolic disturbances, cytokines and receptors, growth factors and acid-base status may all influence skeletal outcomes. The potential link of bone disease with vascular calcification and cardiovascular disease among SF is discussed. The unique vulnerability of the younger skeleton to the effects of nephrolithiasis on attainment of peak bone mass and strength is highlighted and the association of bone loss with kidney stone formation early in life indicate the opportunity for intervention to reduce the risk of future bone fractures.

Administration of low intensity vibration and a RANKL inhibitor, alone or in combination, reduces bone loss after spinal cord injury-induced immobilization in rats

We previously reported an ability of low-intensity vibration (LIV) to improve selected biomarkers of bone turnover and gene expression and reduce osteoclastogenesis but lacking of evident bone accrual. In this study, we demonstrate that a prolonged course of LIV that initiated at 2 weeks post-injury and continued for 8 weeks can protect against bone loss after SCI in rats. LIV stimulates bone formation and improves osteoblast differentiation potential of bone marrow stromal stem cells while inhibiting osteoclast differentiation potential of marrow hematopoietic progenitors to reduce bone resorption. We further demonstrate that the combination of LIV and RANKL antibody reduces SCI-related bone loss more than each intervention alone. Our findings that LIV is efficacious in maintaining sublesional bone mass suggests that such physical-based intervention approach would be a noninvasive, simple, inexpensive and practical intervention to treat bone loss after SCI. Because the combined administration of LIV and RANKL inhibition better preserved sublesional bone after SCI than either intervention alone, this work provides the impetus for the development of future clinical protocols based on the potential greater therapeutic efficacy of combining non-pharmacological (e.g., LIV) and pharmacological (e.g., RANKL inhibitor or other agents) approaches to treat osteoporosis after SCI or other conditions associated with severe immobilization.

Features of the state of bone tissue in children with cerebral palsy. Part 1. Etiological aspects. A literature review

BACKGROUND: The growth of the human body is the most significant period of development of the bone tissue, because it is during this period that the size, shape, and architectonics of bone are formed against the background of increasing body weight and increasing physical exertion. Considering a number of pathological factors of the underlying disease (alimentary, neurological, hormonal, stress, and physical), bone tissue in children with cerebral palsy grows and develops with deviations from the norm. АIM: To present up-to-date generalized information about the features of bone tissue in children with cerebral palsy to orthopedic traumatologists, neurologists, and physical therapy specialists. MATERIALS AND METHODS: Studies on the problem of bone tissue condition in patients with cerebral palsy were analyzed. Data published over the past 20 years were searched in the scientific databases PubMed, Google Scholar, Cochrane Library, Crossref, and eLibrary without language restrictions. RESULTS: In the last 20 years, the number of studies about pediatric osteoporosis has increased. The gold standard for determining the level of bone mineral density is dual-energy X-ray absorptiometry. However, its use in children has presented some difficulties and limitations. In children, the relationship between bone mineral density values and the risk of fractures has not been well studied, which does not allow us to discuss about osteoporosis based on densitometric bone mineral density data alone. In patients with cerebral palsy, a decrease in bone mineral density and bone mass during growth was found. Previous studies showed that the main factors associated with a decrease in bone mineral density in this group of patients include neuroendocrine causes due to growth retardation against the background of CNS damage, alimentary factors, decreased calcium and vitamin D concentrations, systemic use of glucocorticoids, intake of antiepileptic drugs, decreased motor activity, and low muscle mass. Increasing serum vitamin D concentrations does not have a positive effect on bone mass, although increasing serum calcium concentrations is associated with an increase in bone mineral density. CONCLUSIONS: Identifying and correcting factors leading to decreased bone mineral density in children with cerebral palsy can improve bone health in this group of patients. The absence of a relationship between bone mineral density values and the risk of fractures in children with cerebral palsy does not allow us to discuss about osteoporosis based only on bone mineral density densitometric data. There may be more factors leading to an increased risk of bone fractures in children with cerebral palsy that require further study.