Reduce Fracture Risk Research Articles

Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes

AbstractSclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25–85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors.

D-limonene suppresses RANKL-induced osteoclast differentiation and promotes osteoblast activity in-vitro

Abstract Treatments for osteoporosis are typically given post-fracture. Therefore, identifying safe prophylactic interventions to reduce fracture risk would be beneficial. One approach is to utilise the bioactive properties of natural compounds to modify osteoclast and osteoblast activity. D-limonene a well-tolerated, anti-inflammatory monoterpene found in citrus fruits holds promise due to its suppressive effect on NFκB, a key regulator of bone cell activity. We found that limonene promoted osteoblast differentiation and bone nodule formation and inhibited RANKL-indued osteoclast formation and bone resorption in-vitro. Limonene also reduced the pro-resorptive signal provided by osteoblast, augmenting markers of osteoblast differentiation (alkaline phosphatase, osterix and osteocalcin) and significantly decreased osteoclastogenic cytokine production (PTHrP, IL-1β and TNF-α). Therefore, limonene supplementation represents a potential route in combination with current interventions to optimise bone cell activity to maintain or enhance bone mass.

Plating after tumor curettage in human femora does not efficiently improve torsional stability ex vivo

BackgroundSurgical treatments of benign primary bone tumors of the femur face the challenge of limiting tissue damage and contamination while providing sufficient stabilization to avoid fracture. While no clear treatment guidelines exist, surgical treatment commonly consists of femoral fenestration and curettage with optional filling and plating of the defect. Mono- or bicortical plating of distal femoral defects aim to reduce fracture risk and have been shown to increase axial stability. However, it remains unclear whether plating increases torsional stability of the affected femur. Questions/purposesThis biomechanical study aimed to determine how much additional stability can be achieved by mono- or bicortical plating of femoral defects after fenestration. The following hypotheses were investigated: 1. Preventive plating of distal femur bone defects enhances torsional stability when compared to femoral fenestration alone. 2. A condition close to the intact (nonpathological) bone can be achieved by bone plating. 3. Defect shape influences torsional stability. Patients and methodsThiel embalmed human femora (n = 24) were left intact or subjected to the following surgical treatments (A) defect creation via fenestration, (B) defect with short monocortical plating, (C) defect with long bicortical plating. All femora were torsion tested in midstance position using pre-cycling and testing until failure. Quantitative computed tomography pre and post testing allowed bone mineral density calculation and crack path analysis. Finite element analysis provided insight into defect shape variations. ResultsTorsion experiments showed no relevant enhancement of torsional stability due to mono- or bicortical plating. There were no significant differences in maximum torque between unplated and plated femora with defect (defect: 35.38 ± 7.53 Nm, monocortical plating: 37.77 ± 9.82 Nm, bicortical plating: 50.27 ± 9.72 Nm, p > 0.05). Maximum torque for all treatment groups was significantly lower compared to intact femora (155–200 Nm, p < 0.001). Cracks originated predominantly from the proximal posterior corner of the defect and intersected with screw holes in plated femora. The influence of variations of the defect corner shapes had no significant influence on maximum torque and angle. ConclusionThis biomechanical study shows that mono- or bicortical plating is not an effective preventive treatment against torsional failure of femora with distal defects as the resulting maximum torque was drastically reduced compared to intact femora. Thus, the initial hypotheses have to be rejected. As habitual loading of the femur includes a combination of axial and torsional loading, the observed lack of prevention against torsional failure might help to explain the occurrence of fractures despite plating. Future research towards ameliorating clinical outcome should address the role of defect filling with bone cement or bone grafts regarding the improvement of torsional stability after primary bone tumor treatment in the femur.

Romosozumab for the treatment of osteoporosis - a systematic review.

Romosozumab, a new treatment of osteoporosis, is a monoclonal antibody that targets sclerostin and thereby exhibits a dual mechanism of action by stimulating bone formation and inhibiting bone resorption. This systematic review aims to assess the clinical efficacy and safety of romosozumab for treatment of primary and secondary osteoporosis. A comprehensive literature search was conducted in October 2023 across multiple databases including Embase, PubMed and Cochrane Library. Randomized controlled trials (RCTs) and observational studies evaluating the impact of romosozumab on BMD, bone turnover markers (BTM), fracture outcomes, and its safety profile were included. Data extraction and quality assessment were performed independently by two reviewers in accordance with PRISMA guidelines. A total of 36 articles met the inclusion criteria. Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared to placebo and active comparators in patients with primary osteoporosis. Sequential therapy with romosozumab followed by antiresorptives maintained or further increased BMD and reduced fracture risk. Romosozumab was generally well tolerated, however, an imbalance in cardiovascular adverse event was observed in one large clinical trial. Observational studies supported these findings. Specific subgroups of patients with secondary osteoporosis were assessed, demonstrating overall positive outcomes with romosozumab treatment. Romosozumab effectively increases BMD and reduces fracture risk, particularly when used as initial therapy in high fracture-risk patients. Sequential therapy with subsequent antiresorptive treatment optimizes long-term benefits. While generally well-tolerated, its cardiovascular safety profile requires further long-term studies to ensure its safety in clinical practice. Additional studies are needed to confirm efficacy and safety in patients with secondary osteoporosis.

Mediterranean Diet and Risk of Hip Fracture: A Systematic Review and Dose-Response Meta-Analysis.

Hip fractures are a major public health concern. Understanding their epidemiologic and biological links with diet and cardiovascular risk may have important implications for prevention. To assess the dose-response association of Mediterranean diet (MD) adherence with the risk of hip fracture. A systematic search was conducted in the PubMed, Scopus, and Web of Science databases for prospective studies. Search terms were "Mediterranean Diet" and "Fracture." Data were extracted from 8 studies, encompassing 15 cohorts that included 503 174 individuals. Methodological quality was assessed using the Risk of Bias in Nonrandomized Studies of Interventions. The "meta" and "dosresmeta" packages were used in R Studio Software. The results demonstrated that high and moderate MD adherence were associated with a reduced risk of hip fracture (relative risk [RR] = 0.71 [95% CI, 0.55-0.91]; and RR = 0.78[(95% CI, 0.65-0.93], respectively). The effect of the association was similar in men and women. The dose-response pattern of the association was linear: each point increase in MD adherence was associated with a 5.25% reduction in hip fracture risk. Adherence to MD is associated with a reduction in hip fracture risk, following a linear dose-response pattern. This supports the promotion of this dietary pattern for improving bone health. PROSPERO registration no. CRD42023402284.

Rapid reduction in fracture risk after the discontinuation of long-term oral glucocorticoid therapy: a retrospective cohort study using a nationwide health insurance claims database in Japan.

We investigated changes in fracture risk following discontinuation of long-term oral glucocorticoids (GCs) using Japan's nationwide health insurance claims database (NDBJ). We identified patients aged ≥ 50 years who initiated GC therapy in 2012-2019. Those receiving ≥ 5mg (prednisolone or equivalent, PSL)/day for ≥ 72days in the initial 90days of GC therapy were classified as the GC-exposure group, and those receiving < 5mg PSL/day for < 30days were classified as the reference group. Patients discontinuing GC after 90days of GC therapy were classified as the GC-discontinuation group; all others were classified as the GC-continuation group. We tracked the incidence rates of hip and clinical vertebral fractures for up to 990days, and assessed fracture risk after GC discontinuation by hazard ratios (HR) adjusted by inverse probability weighting using propensity scores for GC discontinuation. There was a total of 52,179 GC-discontinuation, 91,969 GC-continuation, and 43,138 reference group women, and 57,560, 93,736, and 33,696 men in the corresponding groups, respectively. According to adjusted HRs, incidence rates of fractures were significantly lower in the GC-discontinuation group than in the GC-continuation group in the initial 90days after GC discontinuation and remained significant for 360days, except for hip fracture in men. HRs for hip fractures remained significantly higher in the GC-discontinuation group compared to the reference group for 720days post-discontinuation. Fracture risk declines rapidly in the first year after GC discontinuation, but vigilance is necessary as the increased risk persists for two years post-discontinuation.

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect.

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

7867 Treatment-Related Changes in Total Hip Bone Mineral Density and Fracture Risk Reduction for Drugs With Different Mechanisms of Action: The FNIH-ASBMR-SABRE Project

Abstract Disclosure: T. Vilaca: None. M.T. Schini: None. A.R. Thompson: None. E. Vittinghoff: None. L. Lui: None. S.K. Ewing: None. D.C. Bauer: None. D.M. Black: None. M. Bouxsein: None. R. Eastell: Consulting Fee; Self; Immunodiagnostic Systems, CL Bio, CureTeQ, Biocon, Takeda, UCB. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Osteolabs. Speaker; Self; Pharmacosmos, Alexion Pharmaceuticals, Inc., Amgen Inc, UCB. Introduction: To date, trials of new anti-osteoporosis therapies have used fractures as primary endpoints. In the FNIH-ASBMR-SABRE project, we posited that the treatment-related change in total hip BMD (THBMD) could be used as a surrogate endpoint for fractures in future clinical trials of new osteoporosis therapies. To demonstrate this, we compiled a large dataset of individual patient data (IPD) from randomized trials and showed a strong association between the change in THBMD at 24 months and reduction in fracture risk. To further explore the use of THBMD as a surrogate endpoint, here we examine whether the association is robust across drugs with different mechanisms of action. Methods: We used IDP (n&amp;gt;120,000 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications (17 anti-resorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab). We calculated the treatment-related difference (active-placebo) in mean % change in THBMD at 12, 18, and 24 months for each trial. We determined the treatment-related fracture risk reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for all clinical fractures (a combination of non-vertebral and clinical vertebral fractures). We used meta-regression to estimate the study-level association (r2) between treatment-related differences in THBMD changes and fracture risk reduction, including only the 17 trials of anti-resorptive drugs and then using the entire set of 22 trials. Since there were only 3 trials of anabolic drugs, we did not perform separate analyses for the anabolic trials. Results: The r2 values were similar between all trials and antiresorptive trials only for both fracture outcomes at all time points. Specifically, for vertebral fractures, the r2 was 0.59 vs 0.70 at 12 mo, 0.69 vs 0.74 at 18 mo, and 0.73 vs 0.78 at 24 mo for all trials vs anti-resorptive trials only. For all clinical fractures, the r2 was 0.46 vs 0.51 at 12 mo, 0.64 vs 0.60 at 18 mo, and 0.71 vs 0.65 at 24 mo for all trials vs anti-resorptive trials only. Conclusion: These results demonstrate that the associations between treatment-related changes in THBMD and fracture risk reductions are robust across anti-osteoporosis therapies with varying mechanisms of action. We conclude that the treatment-related difference in THBMD change would predict fracture reduction equally well for drugs with different mechanisms of action. Presentation: 6/2/2024

8455 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study

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

9236 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study

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

6683 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

9275 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

7581 Periodic Administration of Quercetin and Dasatinib Alleviates Skeletal Fragility in the INS2AKITA Mouse Model of Type 1 Diabetes

Abstract Disclosure: R. Dresner-Pollak: Consulting Fee; Self; Opko Biologics LTD.. Speaker; Self; Medison Pharma. N. Lishinsky: None. I. Gurt: None. J. Stokar: None. V. Temkin: None. P. Shivam: None. G. Zatarah: None. J. Milgram: None. R. Shahar: None. Skeletal fragility is a recognized complication of type 1 diabetes (T1D). The risk of hip and non-vertebral fractures is significantly higher in people living with T1D compared to age- and sex-matched non-diabetic controls and those living with type 2 diabetes (T2D). Hip fracture risk is up to six-fold higher in T1D patients; hip fractures occur 10-15 years earlier and the outcome is poorer compared to non-diabetics. Alterations in bone quality are considered major contributors to T1D-related skeletal fragility. As people with T1D live longer, there is a growing need to discover new therapeutics to reduce fracture risk. TID is associated with accelerated biological aging. Cellular senescence is a fundamental mechanism of aging. Senescent cells stop dividing, are resistant to apoptosis and acquire a distinct phenotype that includes secretome changes termed “senescence-associated secretory phenotype” (SASP). Clearing senescent cells with senolytics is recognized as a promising therapeutic approach for multiple conditions in mice and humans We explored the ability of senolytics dasatinib (D), a tyrosine kinase inhibitor, and quercetin (Q), a flavanol, present in fruit and vegetables, drug combination, to alleviate femur fragility in mice with T1D. Ins2Akita mice show a sexual dimorphic effect of the mutant Ins2 allele causing severe hyperglycemia in males. We treated Ins2Akita male and female mice and C57BL/6 wild type (WT) male mice with D + Q administered once monthly for four months beginning at age 3 months. 3-month-old Ins2Akita male mice had higher blood levels of the SASPs components HMGB1, PAI-1, MMP12, and increased gene expression of p53 and senescence effectors p16, p15 and SASPs Il1b, Mmp3, Mmp9, Mmp13, Serpineb2 at the femur diaphysis and in bone marrow mesenchymal stem cells, respectively compared to age-matched WT male mice. In vitro, exposure to glucose levels equivalent to those observed in blood in Ins2Akita male mice induced cellular senescence in IDG-SW3 osteocyte-like cells including a 4-5-fold increase in gene expression of p16INK4a, p21Cip[1], p53, double percentage of SA-β-gal+ cells and P21 protein level. Ingenuity pathway analysis of differentially expressed proteins revealed enrichment for the senescence pathway (Z=1.213; P=1.11E-05). D+Q administration did not affect bone microarchitecture at the spine (L2), distal femur metaphysis and diaphysis assessed by µCT. D+Q administration significantly increased femur resistance to fracture assessed by the 3-point-bending test by increasing whole femur work-to-fracture, the ultimate parameter of bone resistance to failure, and post-yield displacement, an index of matrix composition, organization, and bone quality in Ins2Akita males. No effect was observed in Ins2Akita females or WT male mice, indicating that the intervention is specific for T1D. Senolyitcs D+Q show promise in improving bone health in T1D. Presentation: 6/1/2024

Evaluating the relationship between glycemic control and bone fragility within the UK Biobank: observational and one-sample Mendelian randomization analyses.

We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA1c was used to classify patients into "adequately-" (ACD; n = 17 078; HbA1c < 7.0%/53mmol/mol) and "inadequately-" (ICD; n = 10 682; HbA1c ≥ 7.0%/53mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11mmol/mol) increase in HbA1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA1c. Fracture risk between the T2D ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA1c and eBMD. We obtained evidence that lower HbA1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.

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.

Physician-dentist dual referral model concept for coordinated bone anabolic therapy

BackgroundBone anabolic drugs used for the pharmacologic treatment of osteoporosis have the potential to enhance alveolar bone regeneration to improve implant success. There are no US Food and Drug Administration–approved drugs indicated to improve oral bone density around teeth or implants. MethodsThe authors summarized expert opinions on a novel coordinated treatment approach leveraging the effects of systemic bone anabolic drugs to enhance dental implant therapy in patients with osteoporosis and a dual referral model for physicians and dentists to address the clinical needs of patients with osteoporosis from a comprehensive perspective of oral-systemic health. Interviews of key opinion leaders were conducted with a bone health specialist group consisting of specialists in orthopedic surgery, internal medicine, geriatrics, endocrinology, and clinical densitometry and a surgical dental specialist group consisting of periodontists and oral surgeons. ResultsOverall, both groups shared positive feedback on the idea of strategically timing administration of anabolic osteoporosis drugs with dental treatment. Both groups expressed interest in the dual referral model. ConclusionsThe feedback of key opinion leaders supported the coordinated bone anabolic therapy concept and identified a need for improved interdisciplinary collaboration, education, and communication to realize the synergies of physician-dentist clinical cooperation. Practical ImplicationsStrategic timing of osteoporosis therapy could improve skeletal bone health and reduce fracture risk while offering adjunctive dental benefits.

Individuals with a fragility fracture and a prescription for bone active medication have a positive perception of the medication but do not associate it with fracture risk reduction.

Our purpose was to examine perceptions about bone active medication from individuals with a fragility fracture and a prescription for bone active medication. In this qualitative description study, eligible participants were those who attended an Osteoporosis Canada education session, and reported sustaining a previous fragility fracture and receiving a prescription for bone active medication. We conducted one-on-one interviews and analyzed the data using the analytic hierarchy approach. We interviewed 32 female participants (age range 58-89years). Based on our analysis, two themes were developed: (1) most participants spoke positively about bone active medication, indicating they were willing to start, or continue to take, their medication. Positive perceptions were held by participants who sustained a fracture while taking bone active medication, participants whose healthcare provider had stopped the prescription, and participants who reported side effects from the medication; (2) most participants did not discuss bone activemedication in relation to their fracture and did not appear to connect the medication to the concept of fracture risk. Instead, participants talked about themedication in relation to bone health in general, or to bone density. Participants appeared to have positive perceptions of bone active medication, despite sustaining a fracture while taking the medication, reporting medication side effects, or having a healthcare provider stop the prescription. Participants did not connect bone active medication to the concept of fracture risk, illustrating the need for healthcare providers to emphasize the connection between fracture risk and bone active medication.

Epidural Steroid Injections and Fracture Incidence Among Older Individuals with Radiculopathy.

Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.

An Audit of the Fifth Irish Hip Fracture Standard in patients &amp;gt;=70 years following hip fracture

Abstract Background Hip fractures are a significant cause of morbidity and mortality in older adults. Bone health assessment is key in the reduction of future fracture risk. The aim of our study was to examine the adherence to the fifth Irish Hip Fracture Standard in patients &amp;gt;=70 years presenting to Letterkenny University Hospital (LUH) with a hip fracture and to examine the number of patients who were commenced on bone protection. Methods We included patients &amp;gt;=70 years who were admitted under the Orthopaedic service following a hip fracture between January and June 2023 in LUH and were identified the database maintained by the using Fracture Liaison Nurse. Data collected included age, month in which hip fracture occurred, patient resident in Ireland, patient alive/deceased, patient on bone protection prior to fracture, patient commenced on bone protection or patient declined treatment. Data was recorded in a Microsoft excel spreadsheet and was analysed by the clinical audit facilitator. We measured our data against the British Geriatric Society guideline on the use of IV zoledronate following hip fracture. Results 76 patients were admitted to LUH with a hip fracture &amp;gt;=70 years between January and June 2023. 100% of patients were reviewed by the fracture liaison service and following this it was recommended that 46 patients (60%) be commenced on bone protection. A letter was sent to each patient’s General Practitioner outlining the recommendation for bone protection. On follow up only 7/46 (15.2%) had been started on treatment. Conclusion The fracture liaison service is appropriately identifying patients who require treatment, despite this, patients are not starting the necessary bone protection in the community. This has prompted our service to establish an IV zoledronate clinic for patients following hip fracture and to generate a plan for ongoing treatment of this patient cohort.

Integrated model of secondary fracture prevention in primary care (INTERCEPT): protocol for a cluster randomised controlled multicentre trial

BackgroundOsteoporotic fractures signal severely compromised bone strength and are associated with a greatly increased risk of refracture. Despite the availability of effective and safe medications that reduce fracture risk, 70–80% of patients are inadequately investigated or treated for osteoporosis following an initial fracture, constituting a significant ‘osteoporosis care gap’. Optimal methods of bridging this gap with primary care at the forefront of secondary fracture prevention remain undetermined. This protocol describes a cluster randomised controlled trial to evaluate the effectiveness of a novel integrated model of secondary fracture prevention and management in primary care.MethodsThe cluster randomised controlled trial involves multiple branches of a community-based radiology provider (CRP), a hospital-based secondary fracture prevention program (SFPP) and numerous primary care practices in metropolitan Sydney that refer to either the CRP or SFPP. Using natural language processing tools, patients diagnosed with a potential osteoporotic fracture will be identified by automatically screening radiology reports generated at the CRP or SFPP. The primary care practices that these patients attend will be randomised (1:1) to either the intervention or usual care. The intervention consists of (i) electronic and fax alerts informing the practice/primary care physician that their patient has been diagnosed with a potential osteoporotic fracture; (ii) provision of osteoporosis management guidelines and (iii) follow-up surveys at 4 weeks and 6 months. Practices in the usual care (control) group will receive no alerts and provide usual care. The primary outcome is the proportion of patients undergoing a bone density scan and/or filling a prescription for osteo-protective pharmacotherapy within 3 months of the initial diagnostic imaging report. Secondary outcomes are the proportion of patients: (i) undergoing an osteoporosis-related blood test within 3 months of the initial diagnostic imaging report; (ii) initiated on a chronic disease management plan within 3 months of the diagnostic report, and (iii) filling a second prescription for osteo-protective pharmacotherapy within 9 months post initial diagnostic imaging report. Outcomes will be obtained through de-identified linked data from Medical Benefits Schedule and Pharmaceutical Benefits Scheme held by the Australian Institute of Health and Welfare.DiscussionThis is the first randomised trial to integrate case-detection of potential osteoporotic fractures in a hospital and community setting with direct alerts to the patient’s primary care provider. This study will determine whether such an intervention is effective in improving investigation and/or treatment rates of osteoporosis in patients with a potential osteoporotic fracture.Trial registrationThis study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000658617p.